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Kawasaki disease (KD) is a syndrome of systemic inflammation with the potential to cause life-threatening aneurysms of the coronary arteries. I sought to contribute to our understanding of this important condition, particularly with regard to Australian children.

By determining the hospitalisation rate and IVIG-treatment rate I estimated the incidence of KD to be about 14 per 100,000 children under the age of 5 between 2007 and 2015. I also showed that the hospitalisation rate nationally had increased on average 3.5% annually between 1993 and 2018, with significant changes in the age distribution over that period.

In collaboration with the Paediatric Active Enhanced Disease Surveillance (PAEDS) network, I undertook a large multicentre prospective surveillance study of KD in Australia. My analysis of that cohort confirmed several of the findings from the survey, such as the preference of Australian clinicians for low-dose aspirin from the time of diagnosis, and the considerable variability around how IVIG resistance is diagnosed and managed. Importantly, I observed that a significant subset of children diagnosed with, and treated for, KD do not meet the diagnostic criteria outlined in the 2017 statement by the American Heart Association.

This work has contributed significantly to the understanding of KD’s epidemiology, management, and outcomes in Australia. I have shown that the incidence of the condition is increasing, and the clinical picture is changing. I identified important areas of practice variation and highlighted the need for international collaboration around agreed definitions (such as for IVIG resistance). Finally, I have played a central role in establishing an important resource for future resource: prospective surveillance of KD in Australia continues, with well over 700 cases recruited so far. It is hoped that this work will be of benefit to the researchers, clinicians, patients, and families affected by KD now, and into the future

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The Epidemiology and Management of Kawasaki Disease in AustraliaDr Ryan David LucasBSc MBBS DCH FRACPSupervisor: A/Prof. Davinder Singh-Grewal Associate Supervisor: Prof. David BurgnerAssociate Supervisor: Prof. Allen ChengA thesis submitted in fulfilment ofthe requirements for the degree ofDoctor of PhilosophyChildren’s Hospital Westmead Clinical SchoolFaculty of Medicine and HealthThe University of SydneyAustralia2024Table of Contents Declaration ...................................................................................................................................... v Works Arising from this Thesis .................................................................................................... vii Acknowledgements ........................................................................................................................ ix Abstract ........................................................................................................................................ xiii List of Tables .................................................................................................................................. xv List of Figures ............................................................................................................................... xix Foreword .......................................................................................................................................... 1 References ............................................................................................................................................. 5 Chapter 1: The Epidemiology of Kawasaki Disease ...................................................................... 11 Incidence ............................................................................................................................................. 11 Age and Sex ........................................................................................................................................ 15 Epidemiology and Aetiology ............................................................................................................ 15 Kawasaki Disease in Australia ......................................................................................................... 16 References ........................................................................................................................................... 23 Chapter 2: The Management of Kawasaki Disease ....................................................................... 33 Part 1: Introduction ........................................................................................................................... 33 Clinical Practice Guidelines .................................................................................................. 33 Treatment Failure ................................................................................................................... 35 Part 2: Intravenous Immunoglobulin ............................................................................................. 36 Background ............................................................................................................................. 36 Primary Therapy for Acute Kawasaki Disease ................................................................... 40 Secondary Therapy After Treatment Failure ...................................................................... 45 Adverse Reactions and Interactions .................................................................................... 45 Clinical Practice Guidelines .................................................................................................. 47 Conclusions ............................................................................................................................. 51 Part 3: Aspirin .................................................................................................................................... 52 Background ............................................................................................................................. 52 Aspirin as Primary Therapy for Acute Kawasaki Disease ................................................ 53 Aspirin for Thromboprophylaxis in Kawasaki Disease .................................................... 54 Adverse Effects and Interactions .......................................................................................... 57 iClinical Practice Guidelines ................................................................................................. 58 Conclusions ............................................................................................................................ 62 Part 4: Corticosteroids ...................................................................................................................... 63 Background ............................................................................................................................. 63 Corticosteroids as Primary Adjunctive Therapy for Acute Kawasaki Disease .............. 64 Corticosteroids Alone as Primary Therapy for Acute Kawasaki Disease ...................... 76 Adverse Effects and Interactions ......................................................................................... 78 Clinical Practice Guidelines ................................................................................................. 78 Conclusions ............................................................................................................................ 83 Part 5: Biologic Agents ..................................................................................................................... 84 Background ............................................................................................................................. 84 TNF-α Blockade: Infliximab and Etanercept ..................................................................... 84 IL-1 Blockade: Anakinra and Canakinumab ..................................................................... 88 Other Novel Agents ............................................................................................................... 91 Conclusions ............................................................................................................................ 92 References ........................................................................................................................................... 94 Chapter 3: Clinician Survey on the Management of Kawasaki Disease ..................................... 133 Introduction ..................................................................................................................................... 133 Variation in the Management of Kawasaki disease in Australia and New Zealand (As published Manuscript) ............................................................................................................ 135 Supplementary Results ................................................................................................................... 143 Chapter 4: Epidemiology of Kawasaki Disease in Australia ...................................................... 163 Introduction ..................................................................................................................................... 163 Epidemiology of Kawasaki Disease in Australia using Two Nationally Complete Datasets (As Published Manuscript) ............................................................................................................ 165 Supplementary Methods ................................................................................................................ 175 Supplementary Results ................................................................................................................... 181 Chapter 5: Live Vaccines After IVIG for KD .............................................................................. 193 Introduction ..................................................................................................................................... 193 Live Vaccines Following Intravenous Immunoglobulin for Kawasaki Disease: Are we Vaccinating Appropriately? (As published Manuscript) ............................................... 195 Supplementary Results ................................................................................................................... 201 Chapter 6: Prospective Surveillance of Kawasaki Disease in Australia ..................................... 203 Introduction ..................................................................................................................................... 203 Prospective Surveillance of Kawasaki Disease in Australia: 2019–2021 ................................... 205 Abstract ................................................................................................................................. 205 Introduction ......................................................................................................................... 206 iiMethods ................................................................................................................................. 206 Results .................................................................................................................................... 208 Discussion ............................................................................................................................. 219 Conclusions ........................................................................................................................... 221 Supplementary Results ........................................................................................................ 222 References .............................................................................................................................. 232 Chapter 7: Conclusions ............................................................................................................... 237 Implications for Policy, Practice, and Research .......................................................................... 240 References ......................................................................................................................................... 242 Chapter 8: Postscript—The Kawasaki Disease Paradigm .......................................................... 245 Introduction ..................................................................................................................................... 245 Contested History of “Kawasaki Disease” .................................................................................... 246 Incompleteness ................................................................................................................................ 250 Global (Re)Emergence .................................................................................................................... 251 An Incoherent Paradigm ................................................................................................................ 252 An Alternative Paradigm ................................................................................................................ 265 Conclusions ...................................................................................................................................... 267 References ......................................................................................................................................... 268 Appendix: Paediatric Inflammatory Multi-system Syndrome Temporally Associated with SARS-CoV-2 ....................................................................... 285 Introduction ..................................................................................................................................... 285 Update on the COVID-19-associated inflammatory syndrome in children and adolescents; paediatric inflammatory multisystem syndrome-temporally associated with SARS-CoV-2 (As Published Manuscript) ............................................................................................................ 287 iiiivDeclaration The work presented in this thesis is, to the best of my knowledge, original except as acknowledged in the text. I hereby declare that appropriate ethical review and approval was sought for this work and that I have not submitted this material, either in full or in part, for a degree at this or any other institution. Signature:  ................................................ Date:  ............................... vviWorks Arising from this Thesis Original Articles in Print 1. Lucas R, Dennington P, Wood E, Dionne A, Ferranti SD, NewburgerJW, et al. Variation in the management of Kawasaki disease inAustralia and New Zealand: A survey of paediatricians. J PaediatrChild Health. 2020 Dec 9;jpc.15290.2. Lucas R, Dennington P, Wood E, Murray KJ, Cheng A, Burgner D, etal. Epidemiology of Kawasaki disease in Australia using twonationally complete datasets. J Paediatr Child Health. 2021 Oct30;jpc.15816.3. Cardenas‐Brown C, Lucas RD, Buttery J, Britton PN, Wood N, Singh‐Grewal D, et al. Live vaccines following intravenous immunoglobulinfor Kawasaki disease: Are we vaccinating appropriately? J PaediatricsChild Health. 2023 Sep 4;jpc.16484.Presentations 1. Kawasaki disease in Australia: epidemiology, management, outcomes.Rheumatology East Coast Journal Club (oral presentation). 2021.2. Prospective surveillance of Kawasaki disease in Australia: diagnosis,management, and outcomes. The 13th International Kawasaki DiseaseSymposium (oral presentation). 2021.3. The Epidemiology & Management of Kawasaki disease in Australia.Grand Rounds — Sydney Children's Hospital, Randwick (oralpresentation). 2019.4. Management of Kawasaki disease in Australia and New Zealand: asurvey of clinician practices. Annual Scientific Meeting —Australasian Society for Infectious Diseases (poster presentation).2019.viiviiiAcknowledgements This thesis would not have been possible without the assistance of many people and organizations. I would like to sincerely thank my primary supervisor, Associate Professor Davinder Singh-Grewal, for his guidance, encouragements, and above all — patience. He has been more than generous with his time, of which I am deeply grateful. Davinder was always at hand to dig me out of troublesome rabbit holes. I am very grateful to Professor David Burgner, my associate supervisor, who patiently honed my scientific writing skills from a blunt instrument to something rather sharper. David’s breadth of knowledge inspired my exploration of rabbit holes; I am wiser for the misadventures. I thank Professor Allen Cheng, my associate supervisor. During the COVID-19 pandemic Allen shouldered unimaginable responsibility as Victoria’s deputy chief health officer; in spite of this he was always available to advise me on statistical methodology (often solving a Stata problem in a single text message of code). Over the last five year I have come to admire each of my supervisors greatly; more than that — I am deeply fond of them and value their friendship. The study presented in Chapter 3 represents an analysis of local responses to an international survey on Kawasaki disease (KD) diagnosis and management. I am indebted to the researchers who planned and undertook that survey: Dr Audrey Dionne, Associate Professor Sarah de Ferranti, Professor Jane Newburger, and Professor Nagib Dahdah. Thank you for graciously allowing me to start my research career on your dataset. The study presented in Chapter 4 (estimating the incidence of KD in Australia using two datasets) was only possible thanks to the Australian Red Cross Lifeblood, who permitted me access to their dataset on intravenous immunoglobulin (IVIG). I would particularly like to thank Dr Peta Dennington, who held my hand as I analysed those data. Her depth of knowledge on the history and processes of immunoglobulin product distribution were absolutely critical to accurately interpreting the data. I am also grateful to Professor Erica Wood for her input and assistance. The study presented in Chapter 5 (a retrospective audit of immunisation with live vaccines in children treated for KD with IVIG) represents the actualisation of an idea that had originally been conceived as an honours thesis by Professor Jim Buttery, Dr Peter Gowdie, and Professor David Burgner. transfusion database. That thesis, prepared by Dr Joel Le Couteur of Monash University, prepared the foundations of this work. I am grateful to everyone who contributed to that work for permitting me to take it further. The study required access to the Australian Immunisation Register (AIR); I am grateful to Professor Nick Wood, who not only facilitated access to AIR, but provided ixinvaluable insights that informed the final work. Finally, I am grateful to my co-author Dr Casandra Cardenas-Brown; much of the leg work for this project was hers, and her assistance in preparing the manuscript was greatly appreciated. The study presented in Chapter 6 (prospective surveillance of KD in Australia) is the largest undertaking in this thesis by far. The project was only possible thanks to the commitment of the many research staff who comprise the Paediatric Active Enhanced Disease Surveillance (PAEDS) network. I am thankful to Professor Kristine Macartney, Professor Nick Wood, Dr Phil Britton, and the PAEDS investigators for giving me the opportunity to undertake this research using the PAEDS network. Having previously walked a similar path, Phil’s sage advice helped me avoid innumerable mistakes — I am in his debt. I am also grateful to the PAEDS surveillance nurses, whose commitment to quality, even during a pandemic, is truly inspirational. I would particularly like to thank Laura Rost, Jocelynne McRae, Kathryn Meredith, Gemma Saravanos, and Nicole Dinsmore; your commitment and friendship are greatly valued. Finally, I am grateful to the children and families afflicted by KD. Their fear, pain, and suffering lie behind the statistics and charts presented herein. The postscript to this thesis was a (ill-informed) hobby horse; it represents my first attempts to articulate deep misgivings about the Kawasaki Disease Paradigm as currently conceived. That my supervisors allowed me such indulgence (the outcome of which was an overdue thesis submission) is a testament to their patience and grace. I am grateful to Professor Werner Ceusters, of The State University of New York. His published works on health informatics, and his gracious personal correspondence, helped me develop the cognitive apparatus necessary for this critique. It has taken me far longer to complete this thesis than I intended — over five years. During those years I lost my father, Dr Graeme Lucas. Dad was the reason I went into medicine, and paediatrics. He was a man of integrity, humanity, and grace — to me he was a giant. I dedicate this thesis to him. The loss of my Dad was a difficult time, yet throughout it my mother Christine gave me her unwavering support; I am deeply grateful. In my relative absence my brother Brad took on many responsibilities for the family; he has my deepest respect and thanks. The greatest burden over these years was born not by me, but by my family: my wife Madeleine and son Arthur, both of whom I love beyond words. Many mornings I left the house before 5AM in search of a quiet place to write before starting my clinical work; the externality of that practice was that Maddie xfunctioned as a single parent, and Arthur started the day without seeing his dad. As I move forward from this endeavour, I dedicate myself to them. xixiiAbstract Background Kawasaki disease (KD) is a syndrome of systemic inflammation with the potential to cause life-threatening aneurysms of the coronary arteries. It almost exclusively affects young children. The current epidemiology, management, and outcomes of KD in Australia has had little attention. In this doctoral work I sought to contribute to our understanding of this important condition, particularly with regard to Australian children. Survey on the Management of KD Firstly, I analysed the Australian and New Zealand responses to an international survey on the management of KD. I identified considerable variation in reported practice on a number of issues; notably, the use of aspirin in the acute phase of the disease, and the diagnosis and management of intravenous immunoglobulin (IVIG) resistant KD.  Epidemiology of KD in Australia Secondly, I analysed two independent national datasets to retrospectively estimate the incidence of KD in Australia. By determining the hospitalisation rate and IVIG-treatment rate I estimated the incidence to be about 14 per 100,000 children under the age of 5 between 2007 and 2015. I also showed that the hospitalisation rate nationally had increased on average 3.5% annually between 1993 and 2018, with significant changes in the age distribution over that period. Finally, by analysing records of IVIG treatment I reported the first evidence of (modest) seasonal variation in KD rates in Australia. Live Vaccines After IVIG for KD Thirdly, I undertook a retrospective audit of immunisation practices among children previously treated with IVIG for KD. Due to the potential for IVIG to interfere with the body’s response to live vaccines, Australian immunisation guidelines recommend that live vaccines be postponed for 11 months after IVIG for KD; however, little is known about real-world practice. I identified that most children who received IVIG in the 11 months prior to a scheduled live vaccine did not have that immunisation postponed. This suggests that some children who are appropriately treated for KD may subsequently be ineffectively immunised and highlights the need for iterative improvement of the public health infrastructure that prevents the re-emergence of vaccine-preventable diseases. xiiiProspective Surveillance of KD in Australia Finally, in collaboration with the Paediatric Active Enhanced Disease Surveillance (PAEDS) network, I undertook a large multicentre prospective surveillance study of KD in Australia. My analysis of that cohort confirmed several of the findings from the survey, such as the preference of Australian clinicians for low-dose aspirin from the time of diagnosis, and the considerable variability around how IVIG resistance is diagnosed and managed. Importantly, I observed that a significant subset of children diagnosed with, and treated for, KD do not meet the diagnostic criteria outlined in the 2017 statement by the American Heart Association. Conclusions This work has contributed significantly to the understanding of KD’s epidemiology, management, and outcomes in Australia. I have shown that the incidence of the condition is increasing, and the clinical picture is changing. I identified important areas of practice variation and highlighted the need for international collaboration around agreed definitions (such as for IVIG resistance). I uncovered vulnerabilities in the immunisation programme, which is poorly equipped to accommodate children with KD. Finally, I have played a central role in establishing an important resource for future resource: prospective surveillance of KD in Australia continues, with well over 700 cases recruited so far. It is hoped that this work will be of benefit to the researchers, clinicians, patients, and families affected by KD now, and into the future. xivList of Tables Chapter 1 Table 1.1: Published Estimates of KD Incidence ...................................................................................... 17 Chapter 2 Table 2.1: Clinical Practice Guidelines for the Management of Acute KD ........................................... 34 Table 2.2: Clinical Practice Guidelines for the Use of IVIG as Primary Therapy in Acute KD ........................................................................................................................................ 48 Table 2.3: Clinical Practice Guidelines for the Use of Aspirin in Acute KD ........................................ 60 Table 2.4: Rate of Coronary Artery Aneurysm Formation by Treatment Protocol, Kato et al (1979) ................................................................................................................................. 63 Table 2.5: Randomised, Controlled Trials of Corticosteroids as Primary Therapy in Acute KD ........................................................................................................................................ 72 Table 2.6: Methylprednisolone versus IVIG as Primary Therapy for Acute KD: Coronary Outcomes at Three Time Points (taken from Aslani, et al) ....................................... 76 Table 2.7: Clinical Practice Guidelines for the Use of Corticosteroids in KD ...................................... 80 Chapter 3 Table 3.1: Descriptive statistics of survey respondents in Australia and New Zealand .................... 137 Table 3.2: Summary of recommendations from international KD guidelines ................................... 139 Supplementary Table 3.1: Diagnosis of KD in the Context of Alternate Diagnoses .......................... 144 Supplementary Table 3.2: Availability of Echocardiography in Australia by Specialty ..................... 145 Supplementary Table 3.3: Criteria Used to Define Giant Coronary Aneurysms ................................ 145 Supplementary Table 3.4: IVIG as Primary Treatment .......................................................................... 145 Supplementary Table 3.5: Primary Therapy for KD ............................................................................... 146 Supplementary Table 3.6: Primary Therapy for KD in Children with Normal Coronary Arteries at Diagnosis ............................................................................. 147 Supplementary Table 3.7: Primary Therapy for KD in Children with non-Giant Coronary Aneurysms at Diagnosis ................................................................... 149 Supplementary Table 3.8: Primary Therapy for KD in Children with Giant Coronary Aneurysms at Diagnosis ........................................................................... 151 Supplementary Table 3.9: Aspirin During Acute KD: Normal Coronary Arteries at Diagnosis ...................................................................................... 153 Supplementary Table 3.10: Aspirin During Acute KD: non-Giant Aneurysms at Diagnosis .............................................................................................. 154 Supplementary Table 3.11: Aspirin During Acute KD: Giant Aneurysms at Diagnosis ...................................................................................................... 155 Supplementary Table 3.12: Definition of Resistance by Time to Defervescence ................................ 156 xvSupplementary Table 3.13: Secondary Therapy for KD in Children with Normal Coronary Arteries at Diagnosis ............................................................................. 157 Supplementary Table 3.14: Secondary Therapy for KD in Children with non-Giant Aneurysms at Diagnosis .................................................................................... 159 Supplementary Table 3.15: Secondary Therapy for KD in Children with Giant Aneurysms at Diagnosis ............................................................................................. 161 Chapter 4 Table 4.1: KD cases identified by Saundankar et al. and Supply Tracking Analysis Reporting System during overlapping years, 2007–2009 ............ 166 Table 4.2: KD cases identified in Supply Tracking Analysis Reporting System and the National Hospital Morbidity Database during overlapping years, 2007–2015 ............... 166 Table 4.3: KD hospitalisation rate, by age: 1993–1997 to 2013–2017 .................................................. 168 Supplementary Table 4.1: Total Numbers of KD Hospitalisations and IVIG-Related Episodes, by Age and Sex ............................................................................................................... 181 Supplementary Table 4.2: KD Hospitalisation Rates and IVIG-Treatment Rates, by Age and Sex ................................................................................................................................. 182 Supplementary Table 4.3: Males as a Percentage of Total KD Hospitalisations and IVIG-Treated Episodes ........................................................................................................... 183 Supplementary Table 4.4: Walter-Elwood Test of Annual Periodicity for Australia and Five Sub-Regions ..................................................................................................................... 183 Chapter 5 Table 5.1: Demographic and patient characteristics .............................................................................. 197 Table 5.2: Risk of breaching recommendations regarding measles containing vaccines after IVIG for KD: MMR1 or MMR2 under the current schedule .......................................... 198 Table 5.3: Adherence with recommendations regarding measles containing vaccines after IVIG for KD ............................................................................................................................ 198 Supplementary Table 5.1: Overall Measles-Containing Vaccine Coverage Among Those Given IVIG for KD .............................................................................................................. 201 Supplementary Table 5.2: Risk of Breaching Recommendations Regarding Measles- Containing Vaccines after IVIG for KD ...................................................................................... 201 Chapter 6 Table 6.1: Baseline Demographic and Clinical Characteristics of Children Diagnosed with KD, by Diagnostic Category ............................................................................. 216 Table 6.2: Clinical Outcomes of Children Diagnosed with KD, by Diagnostic Category .................................................................................................................. 218 Supplementary Table 6.1: Top 5 Countries of Birth of Children with KD, and their Parents ............................................................................................................................. 226 Supplementary Table 6.2: IVIG Infusion-Related Adverse Events ...................................................... 226 xviSupplementary Table 6.3: Aspirin Dosing, by Recruitment Site ........................................................... 226 Supplementary Table 6.4: Baseline Demographic and Clinical Characteristics of Children Diagnosed with KD, by Aspirin Dose ........................................................................................... 227 Supplementary Table 6.5: Baseline Demographic and Clinical Characteristics of Children Diagnosed with KD, by Treatment Response .............................................................................. 228 Supplementary Table 6.6: Multivariable Logistic Regression Model of Non-Response to IVIG as Primary Therapy for KD ............................................................................................. 230 Supplementary Table 6.7: Agents Used as Secondary Therapy for Children Diagnosed with KD ......................................................................................................................... 230 Supplementary Table 6.8: Clinical Outcomes of Children Diagnosed with KD, by Response to Therapy .................................................................................................................. 231 Chapter 8 Table 8.1: Kawasaki Disease, Kawasaki Syndrome, or Mucocutaneous Lymph Node Syndrome —Use in the Academic Literature by Decade .............................................................................. 249 Table 8.2: Categorisation of KD and Related Concepts in Published Biomedical Ontologies .................................................................................................................... 254 Chapter 9 (Appendix) Table 9.1: KD, Kawasaki shock syndrome (KSS), toxic shock syndrome (TSS), and paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS): Comparison of key characteristics .................................................. 288 xviixviiiList of Figures Chapter 1 Figure 1.1: Published estimates of KD incidence from Asia ................................................................... 13 Figure 1.2: Published estimates of KD incidence from North America ................................................ 14 Figure 1.3: Published estimates of KD incidence from Oceania ............................................................ 14 Figure 1.4: Published estimates of KD incidence from Europe .............................................................. 14 Chapter 2 Figure 2.1: Structure of IgG and of different IgG subclasses ................................................................... 37 Figure 2.2: Original forest plot from Green et al ...................................................................................... 68 Figure 2.3: Updated forest plot .................................................................................................................... 69 Chapter 3 Figure 3.1: First-Line Therapies Used in KD ........................................................................................... 138 Figure 3.2: Use of Aspirin in Acute KD ................................................................................................... 138 Figure 3.3: Definition of IVIG Resistance in KD: Time from End of IVIG Infusion to Fever Recurrence .............................................................................................. 139 Chapter 4 Figure 4.1: Hospitalisation rate and IVIG-treatment rate of KD in Australia .................................... 167 Figure 4.2: KD hospitalisations, by age .................................................................................................... 168 Figure 4.3: Treatment of KD with IVIG by age ...................................................................................... 169 Figure 4.4: Males as a percentage of total KD numbers, by age ............................................................ 170 Figure 4.5: Monthly variation of KD treatment rates in Australia ....................................................... 170 Supplementary Figure 4.1a: KD Hospitalisations, by Age (Males) ....................................................... 184 Supplementary Figure 4.1b: KD Hospitalisations, by Age (Females) .................................................. 185 Supplementary Figure 4.2a: Monthly Variation of KD Treatment Rates in Australia, by Region, All of Australia ............................................................................................................. 186 Supplementary Figure 4.2b: Monthly Variation of KD Treatment Rates in Australia, by Region, New South Wales ......................................................................................................... 187 Supplementary Figure 4.2c: Monthly Variation of KD Treatment Rates in Australia, by Region, Queensland and the Northern Territory .................................................................. 188 Supplementary Figure 4.2d: Monthly Variation of KD Treatment Rates in Australia, by Region, South Australia ............................................................................................................. 189 Supplementary Figure 4.2e: Monthly Variation of KD Treatment Rates in Australia, by Region, Victoria and Tasmania ................................................................................................ 190 Supplementary Figure 4.2f: Monthly Variation of KD Treatment Rates in Australia, by Region, Western Australia ........................................................................................................ 191 xixChapter 5 Figure 5.1: Study Flowchart ....................................................................................................................... 197 Figure 5.2: Timing of First Measles-Containing Vaccine After IVIG for KD .................................... 199 Figure 5.3: Timing of First Measles-Containing Vaccine After IVIG for KD .................................... 199 Chapter 6 Figure 6.1: Flowchart of study inclusion and exclusion numbers ........................................................ 209 Figure 6.2: Strict versus Permissive Definition of Complete KD ......................................................... 210 Figure 6.3: Laboratory Markers of Children Diagnosed with KD, by Diagnostic Category .................................................................................................................. 211 Figure 6.4: Probability of Non-Response to Treatment of KD with IVIG, by Time to Treatment ..................................................................................................................... 212 Figure 6.5: Probability of Coronary Aneurysms in Children Diagnosed with KD, by Time to Treatment ..................................................................................................................... 213 Figure 6.6: Maximum Coronary Artery Dimensions of Children Diagnosed with KD, by Day of Echocardiogram ............................................................................................................ 214 Figure 6.7: Probability of Coronary Aneurysms in Children Diagnosed with KD, by Laboratory Markers ................................................................................................................... 215 Supplementary Figure 6.1: Aspirin Dosing for Children Diagnosed with KD, by Diagnostic Category .................................................................................................................. 222 Supplementary Figure 6.2: Probability of Non-Response to Treatment of KD with IVIG, by Laboratory Markers ................................................................................................................... 223 Supplementary Figure 6.3: Coronary Artery Dimensions of Children Diagnosed with KD at Two Timepoints, by Diagnostic Category ........................................................................ 224 Supplementary Figure 6.4: Coronary Artery Dimensions of Children Diagnosed with KD at Two Timepoints, by Time to Treatment .......................................................................... 225 xxForeword Kawasaki disease (KD) is one of the leading causes of acquired heart disease worldwide1; it is an acquired inflammatory condition that typically affects children under the age of five years.2 KD is a systemic vasculitis of arteries, but particularly affects the coronary arteries.3–6 Affected coronary arteries can range from mild dilatation to giant aneurysms—with or without subsequent stenosis, thrombosis, or rupture.7,8 Prior to the introduction of effective treatment, around 15–35% of children afflicted with KD developed aneurysms of their coronary arteries9–11; 1–2% died.12,13 The etiology of KD remains unknown despite over fifty years of intense investigation.14–17 In the absence of a known cause, efforts to develop a diagnostic test have been hampered by poor sensitivity and specificity.18–23 The diagnosis of KD therefore remains clinical—relying on the observation of a minimum set of cardinal clinical features in the context of fever.2,24,25 These criteria are derived from the first case series of KD by Dr Tomisaku Kawasaki and comprise fever, non-purulent conjunctivitis, inflammation of the mucosal membranes, cervical lymphadenopathy, polymorphous rash, and acral oedema.26 Initially intended as an epidemiological case definition of KD, these criteria now form the central diagnostic tool for the condition.2,24,25 The observation of cardiac sequelae in children who did not fulfil these strict criteria (for what is now called “Complete KD”) has lead the recognition of “Incomplete KD”, diagnosed according to an expanded set of clinical and laboratory criteria.27–29 Epidemiological and interventional studies vary as to which definition they use for KD. KD was first reported in Australia in in 1976.30 Subsequent studies suggested a rising incidence of KD in Australia: The Australian Paediatric Surveillance Unit surveyed paediatricians between1993 and 1995, producing a more robust national incidence estimate of 3.7 per 100,000.31 Finally, Saundankar et al undertook a 30-year retrospective chart review of KD cases in Western Australia based on discharge diagnosis. They showed that the annual incidence increased each decade during that period: from 2.8 per 100,000 children under 5 between 1979 and 1989 to 9.3 per 100,000 children under 5 between 1999 and 2009.32 This phenomenon has been widely reported globally, although its drivers remain unclear.33–35 The management of KD rests on the use of intravenous immunoglobulin (IVIG)—a blood product derived from donor blood plasma.2,24,36 IVIG is the only intervention proven to reduce the incidence of coronary artery aneurysms,37 and there is a general consensus that children with KD should receive IVIG at a dose of 2 g/kg as soon as possible.2,24,36 There are a number of important considerations that are relevant to the use of IVIG in the management of KD. Adverse clinical events related to IVIG are rare but do 1  occur.38,39 IVIG has been shown to interfere with seroconversion in response to immunisation with live vaccines—an issue of particular relevance to children with KD, who are often at the age when these vaccines are recommended.40,41 Another issue is that of IVIG resistant KD: while IVIG is largely effective in quelling the inflammation of KD, up to a quarter of children may require additional doses for this effect.2,42,43 There is currently a lack of consensus around how the diagnosis of IVIG resistant KD is made, and how it ought to be managed.44 Finally, as a blood product IVIG is a valuable resource with limited supply. In Australia, IVIG for the treatment of KD is provided without cost to patients by the Australian Red Cross Lifeblood through a funding agreement between the Commonwealth Government and the various States and Territories.45 The use of publicly-funded IVIG is governed by strict criteria and overseen by a dedicated statutory authority—the National Blood Authority.46 There is a strong interest in understanding changing IVIG needs for resource management and planning.47 Aspirin is also commonly used in the management of KD, however there is controversy around its function and dosing.48–51 Aspirin has traditionally been thought to fulfil two roles in KD: suppression of inflammation (largely mediated by COX-2 inhibition at high aspirin doses) and prevention of thrombosis (via COX-1 inhibition at low aspirin doses).48 Most clinical practice guidelines recommend that children with KD receive aspirin in a higher dosing range* during the febrile phase of the disease, after which low-dose aspirin is continued as thromboprophylaxis.2,36,52 Australian guidelines are notable for only recommending low-dose aspirin for children with KD.24,53 Other agents sometimes used in the acute phase of KD include corticosteroids,54 biologic agents (such as the anti-TNF-α drug infliximab55), and immunosuppressive drugs56. The role of these agents is a topic of ongoing research.57 This thesis aims to expand upon our understanding of KD in Australia. The work is presented in three parts. Part One includes two narrative reviews that expand on the brief summary given above. Part Two (the main body of the thesis) includes four original papers (two published manuscripts and two submitted manuscripts), each investigating different aspects of the epidemiology and management of KD in Australia. Part Three includes a concluding chapter and a reflective essay. Finally, three published manuscripts that arose from (but were not a part of) this doctoral work are presented in the Appendices. The works contained in the appendices are associated with the description and surveillance of Paediatric Inflammatory Multisystem Syndrome—Temporally Associated with SARS-CoV-2 in Australia which  * Either moderate-dose aspirin (30–50 mg/kg/day) or high-dose aspirin (80–100 mg/kg/day). 2occurred during the period of KD surveillance and provided an exciting opportunity to be part of ground-breaking work in this area in Australia.  The following paragraphs outline the contribution of each chapter to the thesis:  Part One Chapter One presents a short review summarising the current literature regarding the global epidemiology of KD. Chapter Two presents a longer review of the management of KD. Written in five parts, this comprehensive and critical review addresses the roles of IVIG, aspirin, corticosteroids, and biologic agents in the management of acute KD, and discusses the issue of IVIG resistance. Part Two Chapter Three presents the results of a survey of Australian and New Zealand practitioners on a range of issues relevant to the diagnosis and management of KD. The survey found that there was broad consensus around the use of IVIG but revealed considerable disagreement with regards to aspirin dosing and the diagnosis of IVIG resistance. This study has been published in The Journal of Paediatrics and Child Health and was presented as a poster at the 2019 Annual Scientific Meeting of The Australasian Society for Infectious Disease. Both the published manuscript and supplementary results are included in this thesis. Chapter Four presents the results of an Australia-wide epidemiological study that combined two large datasets to estimate the incidence of KD in Australia. This analysis demonstrated a steady rise in the rate of hospitalisation for KD over 25 years while confirming that the demographic picture of the disease in Australia closely resembles that described elsewhere. This study has been published in The Journal of Paediatrics and Child Health. Chapter Five presents the results of a multi-centre retrospective study of the use of live vaccines in children who had received IVIG for the treatment of KD. This study found that Australian clinicians struggled to comply with national guidelines that recommended postponing live vaccines for a period of 11 months after IVIG for KD. This study has been submitted for publication in The Journal of Paediatrics and Child Health and will be presented at the 2023 Annual Scientific Meeting of The Australian Rheumatological Association. Chapter Six presents the results of a large multi-centre prospective surveillance study of KD: the Paediatric Active Enhanced Surveillance—Foreword3  Kawasaki Disease (PAEDS–KD) study. This study revealed some of the highest rates of IVIG retreatment in the world and sought to understand some of the drivers of this phenomenon. Representing the largest study of its kind in the Southern Hemisphere, the PAEDS–KD study—which continues to enrol participants—promises to provide an invaluable insight into the demographics, treatment, and outcomes of KD in Australia into the future. This analysis has been prepared for submission to The Lancet Regional Health—Western Pacific and was presented as an oral presentation at the 2021 International Kawasaki Disease Symposium. Part Three Chapter Seven presents the Conclusion, summarising and synthesising the key original insights into the epidemiology and management of KD that have emerged from this doctoral research. Suggestions for future research priorities will also be presented. Chapter Eight is a reflective essay presented as a Postscript. In this essay I reflect on the Kawasaki Disease paradigm—its evolution and limitations. I conclude with tentative thoughts on an alternative paradigm, and how this might better serve future research. Appendix The appendix presents an early narrative review on the then-emerging entity of Paediatric Inflammatory Multisystem Syndrome—Temporally Associated with SARS-CoV-2 (PIMS-TS). This work, published in The Journal of Paediatrics and Child Health in early 2020, sought to summarise what was known about the condition at that time, comparing and contrasting with KD, KD shock syndrome, and toxic shock syndrome.   4  References  1.  Taubert KA, Rowley AH, Shulman ST. Nationwide survey of Kawasaki disease and acute rheumatic fever. J Pediatr. 1991 Aug;119(2):279–82.  2.  McCrindle BW, Rowley AH, Newburger JW, Burns JC, Bolger AF, Gewitz M, et al. Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association. Circulation. 2017;135(17):e927–99.  3.  Fujiwara H, Hamashima Y. Pathology of the Heart in Kawasaki Disease. Pediatrics. 1978;61(1):100–7.  4.  Kato H, Koike S, Tanaka C, Yokochi K, Yoshioka F, Takeuchi S, et al. Coronary Heart Disease in Children with Kawasaki Disease. Jpn Circ J. 1979;43(5):469–75.  5.  Amano S, Hazama F, Hamashima Y. Pathology of Kawasaki Disease: I. Pathology and Morphogenesis of the Vascular Changes. Jpn Circ J. 1979;43.  6.  Amano S, Hazama F, Hamashima Y. Pathology of Kawasaki Disease: II. Distribution and Incidence of the Vascular Lesions. Jpn Circ J. 1979;43.  7.  Naoe S, Takahashi K, Masuda H, Tanaka N. Kawasaki Disease With Particular Emphasis on Arterial Lesions. Pathol Int. 1991 Nov;41(11):785–97.  8.  Orenstein JM, Shulman ST, Fox LM, Baker SC, Takahashi M, Bhatti TR, et al. Three Linked Vasculopathic Processes Characterize Kawasaki Disease: A Light and Transmission Electron Microscopic Study. Moretti C, editor. PLOS ONE. 2012 Jun 18;7(6):e38998.  9.  Kato H, Ichinose E, Yoshioka F, Takechi T, Matsunaga S, Suzuki K, et al. Fate of Coronary Aneurysms in Kawasaki Disease: Serial Coronary Angiography and Long-Term Follow-up Study. Am J Cardiol. 1982 May;49(7):1758–66.  10.  Suzuki A, Kamiya T, Kuwahara N, Ono Y, Kohata T, Takahashi O, et al. Coronary Arterial Lesions of Kawasaki Disease: Cardiac Catheterization Findings of 1100 Cases. Pediatr Cardiol. 1986 Mar;7(1):3–9.  11.  Kato H, Koike S, Yamamoto M, Ito Y, Yano E. Coronary Aneurysms in Infants and Young Children with Acute Febrile Mucocutaneous Lymph Node Syndrome. J Pediatr. 1975 Jun;86(6):892–8.  12.  Yanagawa H, Shigematsu I, Kusakawa S, Kawasaki T. Epidemiology of Kawasaki Disease in Japan. Pediatr Int. 2005;21(1):1–10.  13.  Bell DM. Kawasaki Syndrome in the United States: 1976 to 1980. Am J Dis Child. 1983 Mar 1;137(3):211.  Foreword5  14.  Kaneko K, Akagawa S, Akagawa Y, Kimata T, Tsuji S. Our Evolving Understanding of Kawasaki Disease Pathogenesis: Role of the Gut Microbiota. Front Immunol. 2020 Jul 24;11:1616.  15.  Kumrah R, Vignesh P, Rawat A, Singh S. Immunogenetics of Kawasaki disease. Clin Rev Allergy Immunol. 2020 Aug;59(1):122–39.  16.  Menikou S, Langford PR, Levin M. Kawasaki Disease: The Role of Immune Complexes Revisited. Front Immunol. 2019 Jun 12;10:1156.  17.  Rowley AH. Is Kawasaki disease an infectious disorder? Int J Rheum Dis. 2018 Jan;21(1):20–5.  18.  Wen J, Bai X, Niu Y, Hu Z. Diagnostic accuracy of N‐terminal pro‐brain natriuretic peptide for Kawasaki disease: An updated systematic review and meta‐analysis. Int J Clin Pract [Internet]. 2021 Nov [cited 2021 Dec 14];75(11). Available from: https://onlinelibrary.wiley.com/doi/10.1111/ijcp.14538 19.  Zhong J, Huang Q, Wang Y, Gao H, Jia H, Fan J, et al. Distinguishing Kawasaki Disease from Febrile Infectious Disease Using Gene Pair Signatures. BioMed Res Int. 2020 Apr 27;2020:1–13.  20.  Jone PN, Korst A, Karimpour-Fard A, Thomas T, Dominguez SR, Heizer H, et al. Circulating microRNAs differentiate Kawasaki Disease from infectious febrile illnesses in childhood. J Mol Cell Cardiol. 2020 Sep;146:12–8.  21.  Maki H, Maki Y, Shimamura Y, Fukaya N, Ozawa Y, Shibamoto Y. Differentiation of Kawasaki Disease From Other Causes of Fever and Cervical Lymphadenopathy: A Diagnostic Scoring System Using Contrast-Enhanced CT. Am J Roentgenol. 2019 Mar;212(3):665–71.  22.  Wright VJ, Herberg JA, Kaforou M, Shimizu C, Eleftherohorinou H, Shailes H, et al. Diagnosis of Kawasaki Disease Using a Minimal Whole-Blood Gene Expression Signature. JAMA Pediatr. 2018 Oct 1;172(10):e182293.  23.  Jia HL, Liu CW, Zhang L, Xu WJ, Gao XJ, Bai J, et al. Sets of serum exosomal microRNAs as candidate diagnostic biomarkers for Kawasaki disease. Sci Rep [Internet]. 2017 Dec [cited 2019 Jan 27];7(1). Available from: http://www.nature.com/articles/srep44706 24.  The Royal Children’s Hospital. Clinical Practice Guideline on Kawasaki Disease [Internet]. Melbourne, Australia; 2021 Jan [cited 2020 Jul 23]. Available from: https://www.rch.org.au/clinicalguide/guideline_index/Kawasaki_disease/ 25.  Kobayashi T, Ayusawa M, Suzuki H, Abe J, Ito S, Kato T, et al. Revision of diagnostic guidelines for Kawasaki disease (6th revised edition). Pediatr Int. 2020 Oct;62(10):1135–8.  6  26.  Kawasaki T. Acute Febrile Muco-Cutaneous Lymph Node Syndrome in Young Children with Unique Digital Desquamation. Arerugi. 1967;16(3).  27.  Cimaz R, Sundel R. Atypical and incomplete Kawasaki disease. Best Pract Res Clin Rheumatol. 2009 Oct;23(5):689–97.  28.  Rowley AH. Incomplete (atypical) Kawasaki disease: Pediatr Infect Dis J. 2002 Jun;21(6):563–5.  29.  Rowley AH, Gonzalez-Crussi F, Gidding SS, Duffy CE, Shulman ST. Incomplete Kawasaki Disease with Coronary Artery Involvement. J Pediatr. 1987 Mar;110(3):409–13.  30.  Carter R, Hayes M, Morton J. Rickettsia-Like Bodies and Splenitis in Kawasaki Disease. The Lancet. 1976 Dec;308(7997):1254–5.  31.  Royle JA, Williams K, Elliott E, Sholler G, Nolan T, Allen R, et al. Kawasaki disease in Australia, 1993-95. Arch Dis Child. 1998 Jan 1;78(1):33–9.  32.  Saundankar J, Yim D, Itotoh B, Payne R, Jape G, Ramsay J, et al. The Epidemiology and Clinical Features of Kawasaki Disease in Australia. Pediatrics. 2014;133(4):8.  33.  Lin MT, Wu MH. The global epidemiology of Kawasaki disease: Review and future perspectives. Glob Cardiol Sci Pract [Internet]. 2018 Jan 7 [cited 2020 Jan 26];2017(3). Available from: https://globalcardiologyscienceandpractice.com/index.php/gcsp/article/view/279 34.  Singh S, Vignesh P, Burgner D. The epidemiology of Kawasaki disease: a global update. Arch Dis Child. 2015 Nov;100(11):1084–8.  35.  Yim D, Curtis N, Cheung M, Burgner D. Update on Kawasaki disease: Epidemiology, aetiology and pathogenesis: An update on Kawasaki disease: Part I. J Paediatr Child Health. 2013 Sep;49(9):704–8.  36.  Research Committee of the Japanese Society of Pediatric Cardiology and Cardiac Surgery, Committee for Development of Guidelines for Medical Treatment of Acute Kawasaki Disease. Guidelines for Medical Treatment of Acute Kawasaki Disease (2020 Revised Version). J Pediatr Cardiol Card Surg. 2021;5(1):33.  37.  Broderick C, Kobayashi S, Suto M, Ito S, Kobayashi T. Intravenous immunoglobulin for the treatment of Kawasaki disease. Cochrane Vascular Group, editor. Cochrane Database Syst Rev [Internet]. 2021 Jun 18 [cited 2023 Jan 2];2021(6). Available from: http://doi.wiley.com/10.1002/14651858.CD014884 38.  Kaba S, Keskindemirci G, Aydogmus C, Siraneci R, Cipe FE. Immediate adverse reactions to intravenous immunoglobulin in children: a single center experience. Eur Ann Allergy Clin Immunol. 2017;49(1):11–4.  Foreword7  39.  Bruggeman CW, Nagelkerke SQ, Lau W, Manlhiot C, de Haas M, van Bruggen R, et al. Treatment-associated hemolysis in Kawasaki disease: association with blood-group antibody titers in IVIG products. 2020;4(14):11.  40.  Morikawa Y, Sakakibara H, Kimiya T, Obonai T, Miura M. Live attenuated vaccine efficacy six months after intravenous immunoglobulin therapy for Kawasaki disease. Vaccine. 2021 Sep;39(39):5680–7.  41.  Morikawa Y, Sakakibara H, Miura M. Efficacy of live attenuated vaccines after two doses of intravenous immunoglobulin for Kawasaki disease. World J Pediatr [Internet]. 2022 Aug 11 [cited 2022 Sep 2]; Available from: https://link.springer.com/10.1007/s12519-022-00594-6 42.  Burns JC, Capparelli EV, Brown JA, Newburger JW, Glode MP. Intravenous Gamma-Globulin Treatment and Retreatment in Kawasaki Disease: Pediatr Infect Dis J. 1998 Dec;17(12):1144–8.  43.  Tremoulet AH, Best BM, Song S, Wang S, Corinaldesi E, Eichenfield JR, et al. Resistance to Intravenous Immunoglobulin in Children with Kawasaki Disease. J Pediatr. 2008 Jul;153(1):117-121.e3.  44.  Phuong LK, Curtis N, Gowdie P, Akikusa J, Burgner D. Treatment Options for Resistant Kawasaki Disease. Pediatr Drugs. 2018 Feb;20(1):59–80.  45.  National Blood Authority. National Blood Agreement [Internet]. 2002 [cited 2022 Dec 28]. Available from: https://www.blood.gov.au/national-blood-agreement 46.  National Blood Authority (Australia). Criteria for the clinical use of intravenous immunoglobulin in Australia. 2012.  47.  National Blood Authority. National Report on the Issue and Use of Immunoglobulin (Ig) Annual Report 2015-16 [Internet]. Canberra; 2016 [cited 2022 Dec 29]. Available from: https://www.blood.gov.au/system/files/Report-on-the-Issues-and-Use-of-IVIg-2015-16-Final-May18.pdf 48.  Amarilyo G, Koren Y, Simon DB, Bar-Meir M, Bahat H, Helou MH, et al. High-dose aspirin for Kawasaki disease: outdated myth or effective aid? Clin Exp Rheumatol. 2017;  49.  Dhanrajani A, Chan M, Pau S, Ellsworth J, Petty R, Guzman J. Aspirin Dose in Kawasaki Disease: The Ongoing Battle. Arthritis Care Res. 2018;70(10):1536–40.  50.  Huang X, Huang P, Zhang L, Xie X, Xia S, Gong F, et al. Is aspirin necessary in the acute phase of Kawasaki disease?: Aspirin and Kawasaki disease. J Paediatr Child Health. 2018 Jun;54(6):661–4.  8  51.  Jia X, Du X, Bie S, Li X, Bao Y, Jiang M. What dose of aspirin should be used in the initial treatment of Kawasaki disease? A meta-analysis. Rheumatology. 2020 Aug 1;59(8):1826–33.  52.  de Graeff N, Groot N, Ozen S, Eleftheriou D, Avcin T, Bader-Meunier B, et al. European consensus-based recommendations for the diagnosis and treatment of Kawasaki disease – the SHARE initiative. Rheumatology. 2019 Apr 1;58(4):672–82.  53.  Perth Children’s Hospital. Kawasaki disease [Internet]. https://pch.health.wa.gov.au. 2021 [cited 2022 Dec 30]. Available from: https://pch.health.wa.gov.au/For-health-professionals/Emergency-Department-Guidelines/Kawasaki-disease 54.  Chang LS, Kuo HC. The role of corticosteroids in the treatment of Kawasaki disease. Expert Rev Anti Infect Ther. 2020 Feb 1;18(2):155–64.  55.  Eun LY. Infliximab, Is It Really a New Horizon for the Treatment of Kawasaki Disease? Korean Circ J. 2019;49(2):192.  56.  Suzuki H, Terai M, Hamada H, Honda T, Suenaga T, Takeuchi T, et al. Cyclosporin A Treatment for Kawasaki Disease Refractory to Initial and Additional Intravenous Immunoglobulin. Pediatr Infect Dis J. 2011 Oct;30(10):871.  57.  Lei WT, Chang LS, Zeng BY, Tu YK, Uehara R, Matsuoka YJ, et al. Pharmacologic interventions for Kawasaki disease in children: A network meta-analysis of 56 randomized controlled trials. eBioMedicine. 2022 Apr 1;78:103946.   Foreword910Chapter 1: The Epidemiology of Kawasaki Disease Kawasaki published the first case series of the condition he termed muco-cutaneous lymph node syndrome in 1967; the series included fifty patients from the Tokyo area.1 Since that publication Kawasaki disease (KD) has been reported in populations throughout the world,2–5 however the incident rate remains highest* in Japan.7 Incidence Methodological Considerations Incidence is defined as the number of new cases of a disease divided by the population at risk over a set interval of time.8 The population at risk depends on the nature of the disease: the incidence of endometrial cancer in a given year would be calculated as: !"#$#	&'	$()&*$+,-".	/"(/$,	-(	#+0)1	1$",2$&3.$	4-+ℎ	"	0+$,0#	-(	+ℎ$	3&30."+-&(	+ℎ"+	1$", Such that males and women who had undergone a hysterectomy are excluded from the analysis. KD largely occurs in children <5 years of age, and so the population at risk is usually defined according to age—most frequently as the number of cases of KD in children <5 years† per 100,000 children <5 years of age,7,10–12 as follows: 67	/"#$# < 5	1$",#	&'	":$	-(	#+0)1	1$",!ℎ-.),$( < 5	1$",#	&'	":$	-(	#+0)1	1$", × 100,000 Incidence in other age brackets is also frequently reported, including <1 year of age, 5–9 years of age, and 10–14 years of age.10‡  Estimates of the incidence of KD have been published from populations around the world (Table 1.1). Various approaches to case ascertainment have been used, including intermittent hospital or practitioner surveys,7,11,14–17 audits of administrative data (such as discharge diagnosis codes or insurance claims data),18–20 and prospective surveillance.21,22 Prospective studies, and * Japan’s high incidence of KD is matched only by that of Hawai’i.6† While the numerator almost always represents has the same age brackets as thedenominator, this is not always clearly specified in the Methods sections ofepidemiological papers. As standard convention8 it can usually be assumed, howevernot always: Du et al (2007) appear to have used the total case number for thenumerator in their calculation of KD incidence in Beijing.9‡ This is often dictated by the availability of population data, determined by thereporting practices of national censuses. Other age brackets have been used:Anderson and Hurwitz reported KD incidence in children ≤8 years of age.1311some retrospective studies with access to clinical information, seek to apply a strict epidemiological case definition—such as those published by the Japan Kawasaki Disease Research Committee (JKDRC),23,24 the Centers for Disease Control and Prevention (CDC),25 and the American Heart Association (AHA).26–28 The main strengths of these studies are specificity and comparability: since each case is reviewed individually there is opportunity to critically appraise the diagnosis according to standardised criteria—criteria that can be applied by other researchers for comparison between populations or in one population over time.29 An issue can arise when there are differences between case definitions (such as between those published in North America and Japan*) or when case definitions change over time. While the former has been a relatively minor issue (the differences between North American and Japanese definitions being subtle), the latter has been significant. The recognition that the epidemiological case definition lacked sensitivity for so-called “incomplete KD” lead to the construction of expanded criteria for enhanced clinical diagnosis.30,31 This not only complicates comparisons over time, but highlights the systematic under-counting of cases using this approach. These kinds of studies are also limited by the labour required to review case notes; for this reason, they have tended to be limited in scope both geographically and temporally. Another approach has been to estimate incidence by leveraging large administrative datasets without access to individual patient clinical information, typically from hospital discharge codes (such as the International Classification of Disease [ICD] codes ICD-9 446.1 or ICD-10 M30.3)32–34 or from insurance claims data.35 In these studies the rate of disease occurrence (i.e. incidence) is assumed to be similar to another variable, such as the hospitalisation rate. These methods benefit from access to comparatively large datasets, the analysis of which is relatively cheap in terms of research time and capital.29 Unfortunately, the core assumption—that one hospitalisation equals one case (and vice versa)—is frequently untrue. At least 10% of KD cases require readmission during the disease episode,20,36,37 however these repeated admissions can be difficult (or impossible) to differentiate from the index admission in large datasets.† Misdiagnoses and data entry errors can also * North American case definitions for KD have required the presence of fever for atleast 5 days (as a sine qua non for the diagnosis) plus at least 4 out of 5 cardinalclinical features (polymorphous exanthem, conjunctival injection, oralmucocutaneous inflammation, cervical lymphadenopathy, and acral changes such aspalmar/solar induration or periungual desquamation).26,27 Japanese case definitionshave differed by treating fever as 1 of 6 cardinal clinical features, of which at least 5must be present for the diagnosis to be made.23,24† Large datasets of discharge diagnoses are usually de-identified and often presentedas aggregated (rather than individualised) data. This is true of Australianhospitalisation data contained in the Australian Institute of Health and Welfare(AIHW) National Hospital Morbidity Database,38 the use of which was central to thework presented in Chapter Four of this thesis.Chapter 112undermine the core assumption.29 All of these issues have resulted in incidence estimates that are not easily compared.12,39 Consequently, caution is advised when interpreting individual estimates. Incidence Estimates Estimates of KD incidence from around the world have been highly heterogenous (Table 1.1). The most recent incidence estimate for KD in Japan was 359 per 100,000 children <5 per year40; this compares with a rate of 196.9 per 100,000 children <5 in Korea16 and 60 per 100,000 children <5 in Taiwan (Figure 1.1).19 Outside of east-Asia the incident rate is much lower: in Canada the incidence was 19.6 per 100,000 children <5 (Figure 1.2),39 and in Australia was 9.3 per 100,000 children <5 per year (Figure 1.3).10 European countries report some of the lowest rates of KD: 4.6 per 100,000 children <5 in the United Kingdom,11 11.7* per 100,000 children <5 in Spain,42 and 8.4 per 100,000 children <5 in Switzerland (Figure 1.4).22  There is evidence that the incidence of KD is increasing, however the rate of increase differs markedly by region. Data from the 22 bi-annual Japanese surveillance studies demonstrate that the current annual incidence of KD in Japan has exceeded the highest peak incidence of any of the previous epidemics (Figure 1.1).15 Indeed, Burns et al found that the incidence had increased by 90% over a fourteen-year period that did not include any discrete epidemics.43 Evidence also exists for an increasing incidence in Canada, India, and England.44–46 * For methodological reasons this number may be an overestimate.410100200300400Mean Annual Incidence(per 100,000 children <5 Years)1970 1980 1990 2000 2010 2020Study Period China Hong Kong India Japan Malaysia Mongolia South Korea Taiwan ThailandAsiaFigure 1.1: Published estimates of Kawasaki disease incidence from Asia. What appear as point estimates are, in fact, estimates from year- or multi-year-long studies that have been annualised with the marker situated at the midpoint of the study. All estimates are taken from studies listed in Table 1.1. Epidemiology of KD13Figure 1.2: Published estimates of Kawasaki disease incidence from North America. Hawai'iHolman (2000)01020304050Mean Annual Incidence(per 100,000 children <5 Years)1975 1985 1995 2005 2015Study Period Canada USANorth AmericaFigure 1.3: Published estimates of Kawasaki disease incidence from Oceania. Figure 1.4: Published estimates of Kawasaki disease incidence from Europe. 246810Mean Annual Incidence(per 100,000 children <5 Years)1980 1990 2000 2010 2020Study Period Australia New ZealandOceania05101520Mean Annual Incidence(per 100,000 children <5 Years)1990 2000 2010 2020Study Period Denmark Finland Italy Spain Sweden SwtizerlandUK & IrelandEuropeChapter 114Clustering and Seasonality Epidemics of KD have been observed on the large scale, at least three large epidemics identified in the Japanese surveillance data: one in 1979, one in 1982, and another in 1986.15 Clustering of cases on a small scale is much more difficult to identify and prove; Burns et al compared a retrospective Japanese dataset of KD cases against a simulation of random incident cases using a Monte Carlo experiment; they were able to provide evidence of temporal clustering, however this temporal clustering was not mirrored as geographical clustering.14,15,43 Fujita et al undertook a study of KD recurrence within families and found evidence of clustering, with siblings of an index case having a significantly increased risk of KD within the first 10 days.47 There does appear to be some seasonal variation in KD incidence, however the prominent season differs by location. Data from 22 bi-annual Japanese sentinel surveillance studies demonstrate a regular bimodal pattern of seasonality: there is a major peak in January (with lowest annual temperatures), with a minor peak in June/July (the months with the highest annual precipitation.15 Burns et al undertook a sophisticated analysis of all published epidemiologic data on KD from 25 countries; they concluded that there was significant seasonality in the Northern Hemisphere extra-tropical regions, again having a zenith in the Northern winter (from January to March).48 They were unable to find strong evidence for seasonal variation in the tropical regions or in the Southern Hemisphere, though this could be attributed to a paucity of published longitudinal data from these regions.  Age and Sex The age distribution is characteristic. There is a monomodal peak in young childhood, with 85% of cases occurring in children under the age of five; incidence over this age drops precipitously49; conversely, the disease is uncommon under the age of 3 months.50 Studies have repeatedly demonstrated a male predominance in KD incidence, with the male to female ratio usually reported around 1.5:1.17,34,51,52 Epidemiology and Aetiology While the cause of KD remains unclear, epidemiological observations have provided some intriguing clues. Differences in incidence rates have been cited to propose environmental agents as a cause for KD—implicating atmospheric dispersion of an agent from China as a possible reason for the high rates of disease in Japan and low rates in Europe.53 Others have suggested an infectious cause: the rapidly-increasing incidence in East Asia has been attributed to the introduction of a novel pathogen into a naïve population.6 The significance of the age distribution has also been highlighted. Rowley noted that the peak age Epidemiology of KD15for KD matches that of common childhood infections, and suggested that KD is caused by an infectious agent: ubiquitous in early childhood, with immunity arising in most people, and with newborns protected by passively-acquired maternal antibodies.50,54,55 Others have focussed on the apparent seasonal variation in KD incidence: such variation is commonly observed with respiratory pathogens, again leading to the suggestion that KD is (or is triggered by) an infectious disease.43,56–58 It should be noted that apparent “clues” from epidemiological studies can mislead as well as inform. Findings from a case-control study during an apparent outbreak of KD in Colorado in 1982 seemed to implicate exposure to rug shampoo as a trigger for the disease.59 Similar observations by clinicians in New York seemed to support an association,60 however subsequent studies found no evidence of an effect.61 Rug shampoo is no longer thought to have an association with KD.62,63 Similar “associations” between KD and a range of agents have been proposed and subsequently debunked, including childhood vaccines,64–67 coronavirus NL63,68,69 rotavirus,57 adenovirus,70 and—most recently—SARS-CoV-2.71 Caution is again recommended when interpreting the results of epidemiological studies. Kawasaki Disease in Australia The first known case of KD in Australia was reported in 1976: a 5-month-old boy from Adelaide who died after febrile illness lasting 2 weeks and with all of the cardinal clinical features of KD.72 The first Australian epidemiologic study was reported in 1993; also based in Adelaide, it presented a series of 51 patients and estimated the annual incidence for children under 5 years to be 3.9 per 100,000.73 Subsequent studies suggested a rising incidence of KD in Australia: The Australian Paediatric Surveillance Unit surveyed paediatricians between1993 and 1995, producing a more robust national incidence estimate of 3.7 per 100,000.17 Finally, Saundankar et al undertook a 30-year retrospective chart review of KD cases in Western Australia based on discharge diagnosis. They showed that the annual incidence increased each decade during that period: from 2.82 per 100,000 children under 5 between 1979 and 1989 to 9.34 per 100,000 children under 5 between 1999 and 2009.10 There has been comparatively little research on the epidemiology of KD in Australia, with the only nation-wide survey now 30 years old. Given the apparent increase in incidence described in previous studies, and the implications thereof for health resource planning, there is a clear need to update the incidence estimate at a national level. Chapter 116Table 1.1: Published Estimates of Kawasaki Disease Incidence Study Name Region Country Period Cases Incidence Notes Bell (1983)74 North America USA 1976–80 593 0.59 Methodology is difficult to categorise as “...cases come to the attention of the CDC through a variety of mechanisms.” Case definition was according to Bell et al.75 Yanagawa (1988)14 Asia Japan 1964–86 83,857 Multiple Retrospective surveillance through hospital surveys. This paper summarised previous surveys and listed the estimated yearly incidence from 1964 to 1986. Estimates from 1970 inwards are included in graphs. Windsor (1991)76 North America USA (Wisconsin) 1982–89 160 4.0 Prospective surveillance through case reporting to the Wisconsin Division of Health. Case definition was according to the CDC.77 Smith (1993)73 Oceania Australia (Adelaide) 1979–90 55 3.9 Retrospective case review at four major hospitals in Adelaide. Case definition was according to Shulman et al.26 Salo (1993)78 Europe Finland 1982–92 229 3.1–7.2 Prospective surveillance through case reporting. Case definition according to the JKDRC.23 As only a range of incidence values was given, these data are not included in graphs. Dhillon (1993)51 Europe UK 1990 163 3.4 Prospective surveillance through case reporting to the BPSU. Case definition was according to Shulman et al.26 Yanagawa (1995)79 Asia Japan 1991–92 11,221 90 Retrospective surveillance through hospital surveys. Case definition according to the JKDRC.23 Schiller (1995)80 Europe Sweden 1991–92 99 6.2 Prospective surveillance through case reporting to the Swedish Kawasaki Study. Case definition according to the AHA.81 Davis (1995)82 North America USA (Washington) 1985–89 110 6.5 (1985–86) 15.2 (1987–89) Retrospective audit of hospital admissions data (1985–86) and prospective surveillance through case reporting (1987–89). Case definition according to the CDC.25 Royle (1998)17 Oceania Australia 1994 139 3.7 Prospective surveillance via case reporting to the APSU. Yanagawa (1998)83 Asia Japan 1995–96 12,531 102.6 (1995) 108.0 (1996) Retrospective surveillance through hospital surveys. Case definition according to the JKDRC.23 Epidemiology of KD17Continued... Study Name Region Country Period Cases Incidence Notes Holman (2000)32 North America USA (Hawai’i and Connecticut) 1987–96 (Connecticut) 1994–97 (Hawai’i) 366 (Connecticut) 175 (Hawai’i) 16.0 (Connecticut) 47.7 (Hawai’i) Retrospective audit of hospital admission by discharge diagnosis (ICD-9-CM 446.9). Only children <5 years old included. No chart review; readmissions not excluded. Pierre (2000)84 Central & South America Jamaica 1986–89 57 2.7 Retrospective case review at all referral hospitals and regional specialist hospitals. Case definition according to the CDC.85 Bronstein (2000)86 North America USA (San Diego County) 1994–98 169 8.0–15.4 Retrospective case review at six hospitals in the county. Case definition according to AHA.81 Individual yearly estimates for incidence were estimated from a bar chart for inclusion in graphs. Belay (2000)33 North America USA (West Coast) 1993–96) 234 9.7–18.7 Retrospective audit of hospital admission by discharge diagnosis (ICD-9-CM 446.9). No chart review; readmissions were excluded. Yanagawa (2001)87 Asia Japan 1997–98 12,966 108.8 (1997) 111.7 (1998) Retrospective surveillance through hospital surveys. Case definition according to the JKDRC.23 Chang (2002)34 North America USA (California) 1559–99 2,325 15.3 Retrospective audit of hospital admission by discharge diagnosis (ICD-9-CM 446.9). No chart review; readmissions not excluded. Gardner-Medwin (2002)88 Europe UK (West Midlands) 1996–99 73 2.1 Retrospective case review of cases identified through clinician surveys. Case definition according to the AHA.81 Du (2003)89 Asia China (Beijing) 1995–99 537 5.93 Prospective surveillance through case reporting. Case definition not given. Holman (2003)90 North America USA 1988–97 27,546 11.0–17.9 Weighted estimate of hospitalisation rate using the Nationwide Inpatient Sample, which samples hospital admission at a number of states across the USA.  No chart review. Readmissions not excluded. Belay (2003)91 North America USA 1997–99 7,431 10.2 Weighted estimate of hospitalisation rate using a proprietary health database that samples hospitalisations at participating hospitals across the USA. No chart review. Readmissions not excluded. Lynch (2003)92 Europe Ireland 1996–2000 265 15.2 Retrospective audit of hospital admission by discharge diagnosis (ICD-9-CM 446.9). No chart review; readmissions not excluded. Chapter 118Continued... Table 1.1 continued... Study Name Region Country Period Cases Incidence Notes Chang (2004)52 Asia Taiwan 1996–2002 7,305 66.0 Retrospective audit of hospital admission by discharge diagnosis (ICD-9-CM 446.9). No chart review; readmissions not excluded. Panamonta (2004)93 Asia Thailand (Central Northeast) 1991–2003 72 2.2 Retrospective case review at three major referral hospitals. Ng (2005)94 Asia Hong Kong 1994–2000 696 26 (1994–97) 39 (1997–2000) Retrospective audit of hospital admission records (1994–97) and prospective surveillance through case reporting to the HKKDSG (1997–2000). Case definition according to the AHA.81 Yanagawa (2006)95 Asia Japan 1999–2002 32,266 137.7 Retrospective surveillance through hospital surveys. Case definition according to the JKDRC.23 Yearly estimates are included in graphs. Heaton (2006)96 Oceania New Zealand 2001–02 49 8.0 Prospective surveillance via case reporting to the NZSU. Du (2007)9  Asia China (Beijing) 2000–04 1,107 49.4 Retrospective audit of hospital admission by discharge diagnosis (ICD-9-CM 446.9). Case reviews conducted by physicians, however case definition not given. It was not clear from this paper that the numerator for the incidence calculation was children <5 years with KD. Fischer (2007)97 Europe Denmark 1981–2004 360 3.6 Retrospective audit of hospital admission by discharge diagnosis (ICD-8 446.9 or ICD-10 M30.3). No chart reviews. Readmissions were excluded. Nakamura (2008)98 Asia Japan 2005–06 20,475 184.6 Retrospective surveillance through hospital surveys. Case definition according to the JKDRC.23 Huang (2009)19 Asia Taiwan 2003–06 3,877 69 Retrospective audit of hospital admission by discharge diagnosis (ICD-9-CM 446.9). No chart review; readmissions not excluded. MacNeil (2009)57 North America USA (California and New York) 2000–05 n/a 20.7 (California) 23.0 (New York) Retrospective audit of hospital admission by discharge diagnosis (ICD-9-CM 446.9). No chart review; readmissions not excluded. Harnden (2009)3746 Europe England 1998–2003 1,228 8.4 Retrospective audit of hospital admission by discharge diagnosis (ICD-9-CM 446.9). No chart review; readmissions not excluded. Epidemiology of KD19Continued... Table 1.1 continued... Study Name Region Country Period Cases Incidence Notes Coustasse (2009)99 North America USA (Texas) 2004 247 13.8 Retrospective audit of hospital admission by discharge diagnosis (ICD-9-CM 446.9). No chart review; readmissions not excluded. Nakamura (2010)100  Asia Japan 2007–08 23,337 216.9 Retrospective surveillance through hospital surveys. Case definition according to the JKDRC.23 Holman (2010)20 North America USA 1997–2007 n/a 17.1–20.1 Weighted estimate of hospitalisation rate using the Nationwide Inpatient Sample, which samples hospital admission at a number of states across the USA.  No chart review. Readmissions not excluded. Lin (2010)44 North America Canada (Ontario) 1995–2006 2,378 14.4–26.2 Repeated retrospective audit of hospital admissions by discharge diagnosis (ICD-8 446.9 or ICD-10 M30.3). Chart reviews performed. Readmission >7 days after return to baseline were coded as an additional episode of KD. Park (2011)101  Asia South Korea 2006–08 9,039 113.1 Retrospective surveillance through hospital surveys. Nakamura (2012)102  Asia Japan 2009–10 23,730 222.9 Retrospective surveillance through hospital surveys. Case definition according to the JKDRC.23 Kim (2014)103  Asia South Korea 2009–11 13,013 115.4–134.4 Retrospective surveillance through hospital surveys. Annual estimates presented from 2000 to 2014 were used for graphs. Saundankar (2014)10 Oceania Australia (Western Australia) 1979–89 1990–99 2000–09 249 2.82 (1979–89) 7.96 (1990–99) 9.34 (2000–09) Retrospective audit of hospital admission by discharge diagnosis (ICD-9-CM 446.9). Chart reviews were performed, and readmissions excluded. Case definition according to the AHA.27 Makino (2015)15 Asia Japan 2011–12 26,691 243.1 (2011) 264.8 (2012) Retrospective surveillance through hospital surveys. Case definition according to the JKDRC.23 Lin (2015)12 Asia Taiwan 1997–2010 13,179 49.1 Retrospective audit of hospitalisations by discharge diagnosis (ICD-9-CM 446.9). Cross referenced with IVIG use data. Ha (2016)35 Asia South Korea 2007–14 39,082 159.1–217.2 Retrospective audit of private health insurance claims data. No chart review. Annual estimates were used for graphs. Chapter 120Continued... Table 1.1 continued... Study Name Region Country Period Cases Incidence Notes Zhang (2016)104  Asia Mongolia 2001–13 518 3.6 Retrospective audit of hospitalisations by discharge diagnosis (ICD-9-CM 446.9). Case reviews were performed. Case definition according to JKDRC.105  Singh (2016)106  Asia India (Chandigarh) 2009–14 258 1.11–4.71 Single-centre retrospective case review. Case definition as per AHA. Kim (2017)107  Asia South Korea 2012–14 14,916 170.9–194.9 Retrospective surveillance through hospital surveys. Annual estimates were used for graphs. Cimaz (2017)18 Europe Italy 2008–13 2,901 14.7 Retrospective audit of hospitalisations by discharge diagnosis (ICD-9-CM 446.9). Case reviews not performed. Readmissions excluded. Okubo (2017)108  North America USA 2006 2009 2012 16,057 20.8 (2006) 19.1 (2009) 18.0 (2012) Retrospective audit of hospitalisations by discharge diagnosis (ICD-9-CM 446.9). Case reviews not performed. Sánchez-Manubens (2017)109  Europe Spain (Catalonia) 2004–14 399 8.0 Prospective surveillance by case reporting. Makino (2018)110  Asia Japan 2013–14 13,675 302.5–308.0 Retrospective surveillance through hospital surveys. Case definition according to the JKDRC.23 Manlhiot (2018)39 North America Canada 2004–14 4,855 19.6 Passive surveillance and retrospective audit of hospitalisations by discharge diagnosis (ICD-10 M30.3). Riancho-Zarrabeitia (2018)42 Europe Spain 2004–14 3,737 11.7 Retrospective audit of hospitalisations by discharge diagnosis (ICD-9-CM 446.9). Case reviews not performed. Readmissions not excluded. Tulloh (2019)11 Europe UK & Ireland 2013–15 553 4.6 Prospective surveillance through case reporting to the BPSU. Makino (2019)111  Asia Japan 2015–16 31,595 309.0–330.2 Retrospective surveillance through hospital surveys. Case definition according to the JKDRC.23 Chang (2019)56 North America USA (Western New York) 2000–15 n/a 20.2 Retrospective chart review. Case definition according to the AHA.27 Xie (2020)112  Asia China (Shanghai) 2013–17 2,447 94.7 Retrospective audit of hospital admissions by discharge diagnosis (ICD-9 446.9 or ICD-10 M30.3). Chart reviews not performed. Epidemiology of KD21Continued... Table 1.1 continued... Study Name Region Country Period Cases Incidence Notes Pasma (2020)113  Europe Finland 1996–2016 711 6.7–17.9 Retrospective audit of hospital admissions by discharge diagnosis (ICD-10 M30.3). Chart reviews not performed. Kim (2020)16 Asia South Korea 2015–17 15,378 196.9 Retrospective surveillance through hospital surveys. Annual estimates were used for graphs. Ae (2020)40 Asia Japan 2018 17,364 359 Retrospective surveillance through hospital surveys. Case definition according to the JKDRC.23 Mat Bah (2021)21 Asia Malaysia (Johor) 2006–19 661 14.8 Prospective surveillance registry. Case definition according to the AHA.28 Robinson (2021)114  North America Canada (Ontario) 1995–2017 4,346 22.0 Retrospective audit of hospital admissions by discharge diagnosis (ICD-9 446.9 or ICD-10 M30.3). Chart reviews not performed. Taslakian (2021)115  North America USA (Olmsted County, Minnesota) 1979–2016 124 21.4 Retrospective audit of hospital admissions by discharge diagnosis (ICD-9 446.9 or ICD-10 M30.3). Chart reviews were performed. Gradoux (202222) Europe Switzerland 2013–17 175 8.4 Prospective surveillance through case reporting to the SPSU. Ae (2022)7  Asia Japan 2019 17,347 371.0 Retrospective surveillance through hospital surveys. Case definition according to the JKDRC.23 Incidence is given as cases per 100,000 children under the age of 5 years per year. Traditionally, this means KD cases in children under the age of 5 years per 100,000 children under the age of 5 years per year, however that is not always specified and—in the case of Du (2007)—does not appear to be the case. AHA, American Heart Association; APSU, Australian Paediatric Surveillance Unit; BPSU, British Paediatric Surveillance Unit; HKKDSG, Hong Kong Kawasaki Disease Study Group; JKDRC, Japan Kawasaki Disease Research Committee; NZPSU, New Zealand Paediatric Surveillance Unit, SPSU, Swiss Paediatric Surveillance Unit.  Chapter 122Table 1.1 continued... References 1. Kawasaki T. Acute Febrile Muco-Cutaneous Lymph Node Syndrome inYoung Children with Unique Digital Desquamation. Arerugi. 1967;16(3).  2. Uehara R, Belay ED. Epidemiology of Kawasaki Disease in Asia, Europe,and the United States. J Epidemiol. 2012;22(2):79–85. 3. 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Incidence Survey of Kawasaki Disease in 1997 and 1998 in Japan. Pediatrics. 2001 Mar 1;107(3):e33–e33.  Epidemiology of KD29  Chapter 1: The Epidemiology of KD 88.  Gardner-Medwin JM, Dolezalova P, Cummins C, Southwood TR. Incidence of Henoch-Schonlein purpura, Kawasaki disease, and rare vasculitides in children of different ethnic origins. The Lancet. 2002 Oct;360(9341):1197–202.  89.  Du ZD, Zhang TH, Liang L, Meng XP, Li T, Kawasaki T, et al. Epidemiologic Pictures of Kawasaki Disease in Beijing from 1995 to 1999. Pediatr Res. 2003 Jan;53(1):167–167.  90.  Holman RC, Belay ED, Curns AT, Schonberger LB, Steiner C, Chang, RKR. Kawasaki Syndrome Hospitalizations Among Children in the United States, 1988-1997. Pediatrics. 2003 Feb 1;111(2):448–448.  91.  Belay ED, Holman RC, Maddox RA, Foster DA, Schonberger LB. Kawasaki Syndrome Hospitalizations and Associated Costs in the United States. Public Health Rep. 2003;118:6.  92.  Lynch M, Holman RC, Mulligan A, Belay ED, Schonberger LB. Kawasaki syndrome hospitalizations in Ireland, 1996 through 2000: Pediatr Infect Dis J. 2003 Nov;22(11):959–62.  93.  Panamonta M, Chaikitpinyo A, Durongpisitkul K, Somchit S, Petcharatana S, Wongswadiwat Y, et al. Kawasaki Disease in Central Area of Northeast Thailand. J Med Assoc Thai. 2004;87:4.  94.  Ng Y, Sung R, So L, Ho M, Cheng Y, Lee S, et al. Kawasaki disease in Hong Kong, 1994 to 2000. Hong Kong Med J. 2005;11(5):331–5.  95.  Yanagawa H, Nakamura Y, Yashiro M, Uehara R, Oki I, Kayaba K. Incidence of Kawasaki disease in Japan: the nationwide surveys of 1999–2002. Pediatr Int. 2006 Aug;48(4):356–61.  96.  Heaton P, Wilson N, Nicholson R, Doran J, Parsons A, Aiken G. Kawasaki disease in New Zealand. J Paediatr Child Health. 2006 Apr;42(4):184–90.  97.  Fischer TK, Holman RC, Yorita KL, Belay ED, Melbye M, Koch A. Kawasaki Syndrome in Denmark. Pediatr Infect Dis J. 2007 May;26(5):411–5.  98.  Nakamura Y, Yashiro M, Uehara R, Oki I, Watanabe M, Yanagawa H. Epidemiologic Features of Kawasaki Disease in Japan: Results from the Nationwide Survey in 2005-2006. J Epidemiol. 2008;18(4):167–72.  99.  Coustasse A, Larry JJ, Migala W, Arvidson C, Singh KP. Kawasaki Syndrome in Texas. Hosp Top. 2009 Jul;87(3):3–10.  100.  Nakamura Y, Yashiro M, Uehara R, Sadakane A, Chihara I, Aoyama Y, et al. Epidemiologic Features of Kawasaki Disease in Japan: Results of the 2007–2008 Nationwide Survey. J Epidemiol. 2010;20(4):302–7.  101.  Park YW, Han JW, Hong YM, Ma JS, Cha SH, Kwon TC, et al. Epidemiological features of Kawasaki disease in Korea, 2006-2008: Epidemiology of Kawasaki disease. Pediatr Int. 2011 Feb;53(1):36–9.  Chapter 130  102.  Nakamura Y, Yashiro M, Uehara R, Sadakane A, Tsuboi S, Aoyama Y, et al. Epidemiologic Features of Kawasaki Disease in Japan: Results of the 2009–2010 Nationwide Survey. J Epidemiol. 2012;22(3):216–21.  103.  Kim GB, Han JW, Park YW, Song MS, Hong YM, Cha SH, et al. Epidemiologic Features of Kawasaki Disease in South Korea: Data from Nationwide Survey, 2009–2011. Pediatr Infect Dis J. 2014 Jan;33(1):24–7.  104.  Zhang X, Liang Y, Feng W, Su X, Zhu H. Epidemiologic survey of Kawasaki disease in Inner Mongolia, China, between 2001 and 2013. Exp Ther Med. 2016 Aug;12(2):1220–4.  105.  Ayusawa M, Sonobe T, Uemura S, Ogawa S, Nakamura Y, Kiyosawa N, et al. Revision of diagnostic guidelines for Kawasaki disease (the 5th revised edition). Pediatr Int. 2005 Apr;47(2):232–4.  106.  Singh S, Bhattad S. Kawasaki disease incidence at Chandigarh, North India, during 2009–2014. Rheumatol Int. 2016 Oct;36(10):1391–7.  107.  Kim GB, Park S, Eun LY, Han JW, Lee SY, Yoon KL, et al. Epidemiology and Clinical Features of Kawasaki Disease in South Korea, 2012–2014. Pediatr Infect Dis J. 2017 May;36(5):482–5.  108.  Okubo Y, Nochioka K, Sakakibara H, Testa M, Sundel RP. National survey of pediatric hospitalizations due to Kawasaki disease and coronary artery aneurysms in the USA. Clin Rheumatol. 2017 Feb;36(2):413–9.  109.  Sánchez-Manubens J, Antón J, Bou R, Iglesias E, Calzada-Hernandez J, Rodó X, et al. Kawasaki disease is more prevalent in rural areas of Catalonia (Spain). An Pediatría Engl Ed. 2017 Oct;87(4):226–31.  110.  Makino N, Nakamura Y, Yashiro M, Sano T, Ae R, Kosami K, et al. Epidemiological observations of Kawasaki disease in Japan, 2013-2014. Pediatr Int. 2018 Jun;60(6):581–7.  111.  Makino N, Nakamura Y, Yashiro M, Kosami K, Matsubara Y, Ae R, et al. Nationwide epidemiologic survey of Kawasaki disease in Japan, 2015–2016. Pediatr Int. 2019 Apr;61(4):397–403.  112.  Xie L ping, Yan W li, Huang M, Huang M rong, Chen S, Huang G ying, et al. Epidemiologic Features of Kawasaki Disease in Shanghai From 2013 Through 2017. J Epidemiol. 2020 Oct 5;30(10):429–35.  113.  Pasma H, Honkila M, Pokka T, Renko M, Salo E, Tapiainen T. Epidemiology of Kawasaki disease before and after universal Bacille Calmette‐Guérin vaccination program was discontinued. Acta Paediatr. 2020 Apr;109(4):842–6.  114.  Robinson C, Chanchlani R, Gayowsky A, Brar S, Darling E, Demers C, et al. Incidence and short-term outcomes of Kawasaki disease. Pediatr Res. 2021 Sep;90(3):670–7.  Epidemiology of KD31  Chapter 1: The Epidemiology of KD 115.  Taslakian EN, Wi CI, Seol HY, Boyce TG, Johnson JN, Ryu E, et al. Long-term Incidence of Kawasaki Disease in a North American Community: A Population-Based Study. Pediatr Cardiol. 2021 Jun;42(5):1033–40.   Chapter 132Chapter 2: The Management of Kawasaki Disease Part 1: Introduction Early approaches to management of Kawasaki disease (KD) were guided by two seemingly apparent characteristics: that the condition was likely to have an infectious cause, and that it manifested as systemic inflammation. Thus, of Kawasaki’s original cohort 94% received antibiotics and 40% received corticosteroids.1 With the discovery of coronary arteritis identical to that seen in infantile periarteritis nodosa the role of corticosteroids was strengthened, albeit temporarily.2,3 Additional  clinical observations—namely thrombocytosis and fatal thrombosis, as well as arthritis—led to the use of aspirin, with two theorized roles: thromboprophylaxis and the suppression of inflammation.4–8 Early trials of treatment protocols gave conflicting results, and none demonstrated a significant reduction in the incidence of coronary aneurysms.3,9 Intravenous immunoglobulin (IVIG) was the first treatment shown to significantly reduce the incidence of coronary aneurysms in KD, its early use having been informed by success in the treatment of idiopathic thrombocytopenic purpura.10,10 The mechanism of action remains unclear,10,11 however the effect size is undoubtable: with current protocols the incidence of aneurysms is reduced from over 25% to less than five percent.12–14 Multiple meta-analyses have demonstrated the efficacy of IVIG in acute KD,15–17 and it is now the cornerstone of KD management around the world.18–21  The aim of this review is to describe the current evidence for the management of acute KD and summarise major clinical practice guidelines. Except for the anti-platelet role of aspirin, agents used for thromboprophylaxis will not be reviewed here. Clinical Practice Guidelines Online sources were exhaustively reviewed for clinical practice guidelines on the management of acute KD; where an organisation had published multiple revisions of a guideline the most recent (as of December 2022) was used. The final list of documents is presented in Table 2.1.1. Australia does not have a unified guideline on the management of KD, however that produced by the Royal Children’s Hospital in Melbourne has recently been endorsed by the Paediatric Improvement Collaborative for use in Victoria, New South Wales, and Queensland—Australia’s three most populous states.22 Perth Children’s Hospital also produces a guideline,23 and a third is published by the non-for-profit publisher Therapeutic Guidelines.2433Table 2.1: Clinical Practice Guidelines for the Management of Acute Kawasaki Disease Reference Abbreviation Region Date Webb, et al. Kawasaki Disease. Starship Children’s Hospital25 NZ (2022) New Zealand 2022 The Royal Children’s Hospital. Clinical Practice Guideline on Kawasaki Disease.22  AU-RCH (2021) Australia 2021 Perth Children’s Hospital. Kawasaki disease.23  AU-PCH (2021) Australia 2021 Gorelik, et al. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Kawasaki Disease.18  ACR (2021) North America 2021 Marchesi, et al. Revised recommendations of the Italian Society of Pediatrics about the general management of Kawasaki disease.26  ISP (2021) Italy 2021 Research Committee of the Japanese Society of Pediatric Cardiology and Cardiac Surgery, Committee for Development of Guidelines for Medical Treatment of Acute Kawasaki Disease. Guidelines for Medical Treatment of Acute Kawasaki Disease (2020 Revised Version).27 JSPCCS (2020) Japan 2020 Shenoy, et al. Indian Academy of Pediatrics Position Paper on Kawasaki Disease.28  IAP (2020) India 2020 Neudorf, et al. Guideline Kawasaki Syndrome. German Society for Pediatric Cardiology and Congenital Heart Defects.29 DGPK (2020) Germany 2020 de Graeff, et al. European consensus-based recommendations for the diagnosis and treatment of Kawasaki disease – the SHARE initiative.20  SHARE (2019) Europe 2019 Barrios Tascón, et al. National consensus on diagnosis, treatment and cardiological follow-up of Kawasaki disease.30  AEP (2018) Spain 2018 Nordenhäll, et al. National PM for Kawasaki’s Disease.31  SW (2018) Sweden 2018 Systemic Vasculitides – Kawasaki Disease. Therapeutic Guidelines.24 AU-TG (2017) Australia 2017 McCrindle, et al. Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association.21 AHA (2017) North America 2017 Abate, et al. Enfermedad de Kawasaki: Consenso interdisciplinario e intersociedades.32 ASP/ASC (2016) Argentina 2016 Holm, et al. Kawasaki disease. Danish Paediatric Society.33 DM (2015) Denmark 2015 Brogan, et al. Kawasaki disease: an evidence based approach to diagnosis, treatment, and proposals for future research.34 UK (2002) United Kingdom 2002 Chapter 234Treatment Failure Despite the success of IVIG, challenges remain. Persistence of systemic inflammation after treatment in a subset of patients—termed ‘IVIG Resistance’—has been recognised since the first trials of IVIG for KD.12 Children with IVIG resistance are at higher risk of developing coronary artery aneurysms.35 Rates of resistance vary from less than 10%36,37 to over 30%,38 however the lack of a consensus definition for treatment failure makes comparisons challenging.39 All definitions seek to identify the persistence of inflammation after the IVIG infusion, but with key differences around when and how this is determined. The American Heart Association (AHA) Scientific Statement on the Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease refers to IVIG resistance as “...recrudescent or persistent fever at least 36 hours after the end of the first IVIG infusion”21; by contrast Japanese guidelines refer to “...persistent fever after 48 hours of starting IVIG”.40 Other investigators have used a fall in the CRP as evidence of treatment response, with persistently elevated CRP incorporated into a definition of IVIG resistance41 (of note, the AHA Statement explicitly warns against using the erythrocyte sedimentation rate for this purpose, as it is artificially increased after the administration of IVIG21). Finally, some authors use the term ‘Refractory KD’ to refer to ongoing inflammation after at least two doses of IVIG.42,43 With the recognition of increased risk of coronary aneurysm development in patients after treatment failure35,44 there have been significant efforts to develop predictive tools for IVIG resistance (notably the Kobayashi,45 Egami,46 and Sano47 scores). While these systems are used routinely in Japan,48,49 poor test characteristics in other populations has limited their use.50–53 The management of IVIG resistance is a topic of active research, with several treatment protocols under investigation.41,54–57 Management of KD35Part 2: Intravenous Immunoglobulin Background Intravenous immunoglobulin (IVIG) is a therapeutic product derived from the pooled plasma of human donors.58 It contains polyclonal antibodies (mostly IgG59) and was initially used to treat disorders of humoral immunity such as agammaglobulinaemia.58 Subsequent clinical experience with IVIG led to an appreciation of its immunomodulatory effects60—notably in the management of idiopathic thrombocytopaenic purpura (ITP),61 which provided the rationale for early trials in KD.10,10 IVIG is now approved for use in a wide range of clinical conditions,62 and is considered the standard of care for KD.21 Mechanism of Action Given the enigmatic nature of KD’s aetiopathogenesis the mechanism of action of IVIG in the condition remains unclear.63 Indeed, the anti-inflammatory actions of IVIG—central to its use in a diverse range of conditions—remain unclear.60 As mentioned, IVIG is composed almost entirely of the immunoglobulin class G (IgG). IgG is the predominant immunoglobulin class in humans and exemplifies the humoral component of the adaptive immune response.64 IgG is a complex glycoprotein molecule (about 82–96% protein and 4–18% carbohydrate64) with two identical ‘heavy chains’ (bound to each other at the ‘hinge’ by a variable pattern of disulfide bonds), each bound to one of two identical ‘light chains’ (Figure 2.2.1). The IgG molecule is structurally and functionally divided into the Fab (‘fragment antigen-binding’) region, which acts to bind antigen in a highly-specific manner; and the Fc (‘fragment crystalline’) region, which mediates a range of regulatory and effector functions through interacting with a number of receptor molecules (‘Fc receptors’, FcR).64,65 Four subclasses (IgG1, IgG2, IgG3, and IgG4) are defined by variations in the structure of the Fc region (and especially the hinge); their roles in human immunology is still poorly understood and as such they will not be discussed further in this review.64–66 In seeking to understand the mechanism of IVIG investigators have sought to distinguish effects attributable to the Fab region and Fc region. A number of actions have been attributed to the Fab region, including binding to and neutralising endogenous pro-inflammatory complement products C3b and C4b.60,67–69 The predominant action of IVIG is, however, thought to be mediated by the Fc region.67 In the original paper documenting the successful use of IVIG to treat ITP by Imbach et al,61 the inhibition of platelet sequestration in the spleen by the saturation of Fc receptors on phagocytic cells of the reticuloendothelial system (now increasingly referred to as the Chapter 236mononuclear phagocytic system,70 MPS) was proposed. Three observations made this hypothesis likely: Firstly, while most cases of ITP are thought to be caused by destruction of platelet-directed autoantibodies, IVIG effectively raised the platelet count of patients with ITP and agammaglobulinaemia—arguing against the hypothesis that IVIG neutralised auto-antibodies (however Fc-dependent effects on auto-antibodies, such as by shortening auto-antibody half-life by competitive inhibition of the neonatal FcR, have been proposed60). Secondly, IVIG was ineffective at raising the platelet count of patients with ITP who had undergoing a splenectomy—indicating that the mechanism of action was at the point of sequestration. Finally, IVIG that had been treated with pepsin (which cleaves and inactivates the Fc region of the IgG molecule) was ineffective.61 Debré et al would later demonstrate the efficacy of purified Fc fragments in ITP.71 While current theories of the mechanism of IVIG in ITP have been refined, Fc-receptor saturation is still a central function.70 Other proposed Fc-dependent mechanisms of IVIG relate to the complex nature of IgG-FcR interactions in vivo, with different receptors capable of Figure 2.1: Structure of IgG and of different IgG subclasses. a. IgG structure. b. The different domains of Fab and Fc regions of IgG are indicated. Fab RegionFc RegionL ig ht    ch ai nc ha i nHeavyIgG1 IgG2 IgG3 IgG4Disulphide bondHinge regionImmunoglobulin G (IgG)SubclassesManagement of KD37directing pro-inflammatory and anti-inflammatory signal cascades on binding with the Fc ligand.67,68 In KD proposed actions have included stimulating precursor T-cells to preferentially differentiate into regulatory T-cells (Tregs) in a manner mediated by interleukin 10 (IL-10) and possibly directed by dendritic cells.63,72 While low circulating Treg numbers are seen in the acute phased of KD, a population of Fc-specific population has been observed in the peripheral blood of patients who have responded to IVIG (but not in those with IVIG resistance).11,72 Other findings of interest (yet outside the scope of this review) include the inhibition of tumour necrosis factor (TNF)-α and matrix metalloproteinase 9 (MMP9) production in a mouse model of KD,73 and significant evidence that polymorphisms in FcR genes can influence the disease course of KD.74–78 Manufacture and Supply The manufacture of IVIG is resource-intensive and complex. Raw plasma (taken from both plasma donors and whole-blood donors) is pooled,79 with each pool containing plasma from between 1,000 and 100,000 individual donors.80 Donated blood is screened for infectious hazards (including viruses, bacteria, and prions) and undergoes multiple viral inactivation procedures to minimise the risk of transfusion transmitted infections.80 This is followed by fractionation to separate immunoglobulins from other plasma proteins; most modern processes are based on the cold ethanol fractionation described by Cohn in 1946,81 however some (including Intragam®10, commonly used for the treatment of KD in Australia) use the newer chromatographic fractionation process.80,82 Early attempts at intravenous infusion of human immunoglobulin were complicated by high rates of adverse reactions; these were attributed to direct complement activation, which was thought to be dependent on the Fc region of the IgG molecule.83,84 In response, manufacturers introduced pepsin fragmentation, wherein the Fc region of the IgG molecule was proteolytically removed.84 Subsequent processes included the use of plasmin (which cleaves the IgG molecule at fewer locations than pepsin, resulting in fewer fragments83) and chemical modification of the Fc region (including sulphonation, alkylation, and β-propiolactonation) to reduce complement activation.83,85 All of these methods resulted in reduced half-life and efficacy (especially opsonisation).83,84 Modern manufacture methods seek to preserve the integrity of the IgG molecule and the in vitro function of the Fc region.85  Immunoglobulin composition is carefully controlled: ABO blood group antibody titres are reduced due to the risk of haemolytic reactions85 and IgA is removed due to the risk of anaphylaxis in those with IgA deficiency.86,87 Modern IVIG formulations are almost entirely whole IgG (over 98% in the Chapter 238case of Intragam®) as monomers and dimers, with IgG subclass ratios ideally matching that of normal human plasma.59 IVIG is manufactured in Australia by CSL-Behring at its facility in Melbourne, with IVIG derived from Australian donors offered under the brand Intragam®.59 The Commonwealth Government of Australia funds the provision of IVIG for the treatment of selected conditions under the National Blood Agreement with the various States and Territories.88 Strict criteria govern the use of publicly-funded IVIG,62 with KD an approved indication since the first guidelines were published in 1993.89 Australian Red Cross Lifeblood (formerly the Australian Red Cross Blood Service) is responsible for the distribution of publicly-funded IVIG.90 Five brands are available in Australia (Intragam®, Privigen®, Flebogamma®, Gamunex®, and Octagam®),90 however Intragam®10 (10% IgG by weight) is preferentially approved for the treatment of KD.91 Resource Stewardship and Pharmacoeconomics Human immunoglobulin is an expensive resource.92 Pharmacological products have high initial costs, including those associated with research and development, capital costs of manufacturing facilities, regulatory compliance, and patent acquisition.93–95 The marginal cost of production* falls as economies of scale are realised; this, along with market pressures enabled by patent expiry, lead to price reductions in the long term. The economics of blood products is different: the high ongoing cost of collecting, testing, and processing blood from human donors results in a marginal cost of production that is both fixed and high, such that market price largely reflects marginal costs.96 Furthermore, globalised and logistically complex supply chains are vulnerable to disruption (as was seen during the COVID-19 pandemic97–99) leading to supply-demand imbalances and price fluctuations.100,101 Demand for all immunoglobulin products has been increasing both internationally and locally.102–104 Domestic production, which previously accounted for over 90% of immunoglobulin supplied in Australia, now only accounts of 57%.103 IVIG is used at a relatively high dose in the management of KD (2 g/kg), yet the small absolute quantity required for infants and young children means that KD represents a trivial burden on national supply: of the 4.98 million grams of immunoglobulin supplied in Australia in 2015-16 only 15,046 grams (0.3%) was for KD).103 By contrast in Japan—where the incidence of KD is more than an order of magnitude higher than in Australia105,106—KD ranks third for IVIG consumption, after IgG2 deficiency and chronic inflammatory demyelinating polyneuropathy102). * The marginal cost of production is the additional cost incurred to produce additionalproduct. Economy of scale is largely achieved through diminishing marginal costs.Management of KD39  Few studies have assessed the cost effectiveness of IVIG for acute KD. A 1993 Canadian study modelled the costs incurred in the first seven weeks after diagnosis for 100 children with KD treated with either IVIG or aspirin, concluding that the use of high-dose IVIG (preventing an estimated 14 cases of coronary dilatation) resulted in savings of C$323,400 (in 1992 Canadian dollars, equivalent to AUD$653,142 in 2022).107 Healthcare costs—including the cost of IVIG—vary markedly around the world,108,109 making direct comparisons challenging. Health systems also differ in the cost burden that is borne by patients: in Australia IVIG is provided for approved conditions at no extra cost to the patient103,108; in other countries families may need to purchase IVIG for their child’s treatment at prohibitive cost.110 A number of strategies have emerged in response to the resource constraints of IVIG: patient selection based on predicted disease severity,49 dose selection based on predicted disease severity,48,111 and the use of agents other than IVIG.110,112 Primary Therapy for Acute Kawasaki Disease The use of IVIG for the management of KD was first described by Furusho et al in 1983 in a semi-randomised, non-blinded trial with (predominantly) historical controls.10,113 Fourteen patients with KD received IVIG 400 mg/kg daily for five days (replicating the protocol for ITP described by Imbach et al61), controls received aspirin 10–30 mg/kg/day for at least 3 months. Those given IVIG had a shorter time to defervescence and normalisation of C-reactive protein (CRP), and had no coronary aneurysms seen on coronary angiography (compared with aneurysms in 17% of the control patients). These findings were corroborated in a small multi-centre unblinded randomized controlled trial by the same investigators one year later10 and confirmed in an independent American investigator-blinded randomised controlled trial two years after that.114 The latter study was stopped prematurely due to the significant evidence of benefit from IVIG.63 A Cochrane Review in 2003 identified 11 studies that compared IVIG to placebo for the management of acute KD,114–119 of which seven were included in a meta-analysis.15 There were significantly fewer new coronary abnormalities at thirty days among those treated with IVIG versus placebo (relative risk 0.74, 95% confidence interval 0.61 to 0.90); heterogeneity between studies due to different IVIG doses was addressed in subgroup analyses, with a significant reduction in aneurysms observed for doses of 500 mg/kg, 1,200 mg/kg, and 1,600 mg/kg. Among children with no coronary abnormalities at enrolment, those who received IVIG had significantly fewer coronary artery abnormalities at 30 days but not at 60 or 180 days; among those with coronary abnormalities at enrolment there were no significant differences between treatment and control groups at any timepoint.15 In light of more recent studies, and refinements in the methodological approach to meta-analyses, Broderick et al have published a protocol for an updated Chapter 240  systematic review and meta-analysis of IVIG for KD for the Cochrane Collaboration.120 Evidence permitting, it will be important to quantify the treatment effect at various timepoints—especially beyond six months post-treatment. Immunoglobulin Dose When appropriately powered, trials of IVIG for acute KD have consistently reported a positive correlation between dose and efficacy,12,115,121 with single large dose regimens outperforming multiple small dose regimens.12 This lead to the hypothesis that peak serum IgG concentration was of critical importance in terminating the inflammatory process of KD.122 Recent studies have provided further evidence for this hypothesis, with higher post-infusion serum IgG concentrations associated with lower rates of treatment failure and coronary artery aneurysms.123 The optimal dose of IVIG to prevent coronary aneurysms has been assessed in several studies and systematic reviews and meta-analyses,15,17,124 out of which has emerged a general consensus in favour of a single dose of 2 g/kg—both in clinical practice guidelines21,27,125 (Table 2.2.1) and clinical practice.126 Challenges to this consensus have repeatedly been mounted, especially in Japan where the high incidence of KD has significant implications for national IVIG supply.48,49,127 Shiraishi et al49 described a study protocol in which children were initially treated with IVIG 1 g/kg with those who failed primary therapy going on to receive additional higher doses.49 The study did not recruit a control arm but compared the rate of coronary aneurysms in there cohort with that previously reported from nation-wide surveys, reporting lower rates of aneurysms in their cohort. Matsuura et al48 reported the outcomes from a study in which treatment was stratified based on the patient’s Kobayashi score.45 Those at highest risk received IVIG 2 g/kg plus primary adjunctive corticosteroid, those at moderate risk received IVIG 2 g/kg, and those at low risk received IVIG 1 g/kg. There were no significant differences between groups either in time to defervescence or the risk of coronary artery aneurysms. While poor performance of scoring systems outside of Japan makes direct comparison difficult,128 these studies suggest the possibility of a stepwise approach to IVIG dosing in KD. Finally, Suzuki et al111 retrospectively reviewed treatment records to compare the efficacy of low-dose IVIG (1 g/kg) versus high-dose IVIG (2 g/kg) for children over 25 kg bodyweight. They found no significant differences between low-dose and high-dose IVIG in terms of length of stay, rate of treatment failure, or rates of coronary artery aneurysms, noting that the cost of treatment was significantly higher for those in the high-dose group. Although limited by the retrospective study design, these results suggest that Management of KD41  it may be time to reconsider the current weight-based approach to dosing of IVIG in KD. Infusion Duration Despite evidence favouring single large doses of IVIG there remains a lack of consensus around the duration of the infusion (Table 2.2.1). Shorter infusion times (dose given over 10–12 hours) are typical in North America,21 while longer infusion times (12–24 hours) are preferred in Japan106; European guidelines vary between these, with some ending even shorter infusions.125 The National Blood Authority of Australia recommends that the infusion be given over 10–12 hours.129 When to Treat Trials of IVIG for acute KD defined inclusion and exclusion criteria in an attempt to reduce heterogeneity within the cohorts; children who were unable to be treated within a defined period of time from the onset of fever were often excluded. Furusho et al excluded children who could not be treated within 7 days of fever onset,10 while Newburger et al excluded those with a duration of fever greater than 10 days.12,114These late cut-offs for commencing IVIG started to appear in expert recommendations,130 and for a time there was a perception that treatment after day 10 was not indicated.131 Early guidelines responded by emphasising that IVIG should be given within 10 days wherever possible, but that delayed diagnosis ought not necessarily preclude treatment.132 Statements to this effect are included in published guidelines to this day (Table 2.2.1). The problem of how to manage children presenting late in the course of KD is an important one—indeed up to 20% of patients may fall into this category.133 A small number of studies have investigated the efficacy of IVIG in patients with delayed diagnosis of KD. Sittiwangkul et al retrospectively reviewed the cases of 170 children with KD at one institution in Thailand, of whom 20 were diagnosed after day 10 of fever.134 They observed higher rates of coronary artery aneurysms among those treated after day 10 of fever, however due to small case numbers were not able to assess the significance of this at 1 year follow-up. While those treated after day 10 of fever had higher rates of treatment failure, 70% (12/17) still defervesced after a single dose of IVIG. Muta et al compared response to treatment and coronary outcomes in 150 Japanese patients who received IVIG between day 11 and day 20 with age- and gender-matched historical controls.135 They found no difference in rates of defervescence after IVIG but much higher rates of coronary artery aneurysms among those treated after day 10 of fever. Considering only those patients without coronary aneurysms at the time of treatment rates of aneurysm development were identical during the acute phase (up to one month after treatment), with no statistically significant difference between groups in the convalescent phase (more than one month after treatment).135 Unfortunately, Chapter 242  by treating time-to-treatment as a categorical variable (≥10 days versus >10 days) the possible benefits of IVIG on day 11 (for example) are obscured. Qui et al, in a retrospective analysis of 930 Chinese KD patients, treated time-to-treatment as an ordinal variable in logistic regression analysis with coronary aneurysms (at three timepoints) as the outcome variable.136 They found that time-to-treatment was positively associated with the risk of coronary artery aneurysm at 1 month (odds ratio [OR] 1.17, 95% confidence interval [CI] 1.10 to 1.25, P <0.001) and 6 months (OR 1.17, 95% CI 1.06 to 1.28, P = 0.002), but not at 12 months (OR 1.11, 95% CI 0.94 to 1.31, P = 0.226). Unfortunately, the marginal effect of time-to-treatment at each day was not presented, so the efficacy of IVIG beyond ten days was difficult to appreciate. This issue was finally addressed in a large retrospective analysis of coronary outcomes in a Dutch KD cohort by van Stijn et al.137 They estimated the cumulative distribution of time-to-treatment per day in patients with no coronary involvement, as well as small, medium, and giant aneurysms. Time-to-treatment was correlated with the development of medium (OR 1.1, 95% CI 1.1 to 1.2, P <0.001) and giant aneurysms (OR 1.2, 95% CI 1.1 to 1.2, P <0.001), but not small aneurysms (OR 1.0, 95% CI 1.0 to 1.1, P = 0.6). Importantly, there was no specific cut-off point at which treatment was deemed ineffective. While this study sought to address an important question regarding the efficacy of late IVIG it had two significant limitations. Firstly, the authors acknowledge the risk of selection bias, as most patients were referred to their institution after having received initial therapy at a smaller hospital and were therefore likely to represent the more severe end of the disease spectrum. Indeed, the rates of aneurysm formation in the cohort were extremely high (22.8% of those who received IVIG developed coronary aneurysms). Secondly, while we are told that coronary outcomes were assessed within 8 weeks of fever onset the exact timing is not given. The efficacy of IVIG among those with or without aneurysms at the time of treatment, and whether a difference is seen at long-term follow-up, remains unclear. Several investigators have observed equal or lower rates of retreatment among those treated after day 10 of fever versus those treated earlier.138–140 While this has been interpreted as evidence that the anti-inflammatory effect of IVIG persists after 10 days, it may simply reflect the natural history of the condition—most of Kawasaki’s original cohort defervesced spontaneously between day 9 and day 11 despite the lack of an effective treatment.1 The efficacy of IVIG early in the course of acute KD has also been studied. Tse et al found that treatment on or before day 5 of fever was associated with better coronary outcomes at 1 year,141 however other studies have given conflicting results. Muta et al, comparing treatment on or before day 4 with treatment after day 4, observed similar coronary outcomes between groups.142 In a Management of KD43  systematic review and meta-analysis of early IVIG for acute KD Yan et al reported a lack of evidence for an improvement in coronary outcomes with early IVIG as the upper bound of the 95% confidence interval for the odds ratio was 1.00.143 They noted significant heterogeneity between studies however, and on subgroup analysis the studies from China and America did show a statistically significant benefit for early IVIG whereas studies from Japan did not. As was the case for studies of late IVIG however, treating time-to-treatment is likely to obscure important effects, especially as KD is known to be diagnosed and treated earlier in Japan than elsewhere (and so the relative distributions within each group are likely to be different in Japan as compared with other countries).144 The evidence that early treatment is associated with higher rates of retreatment is stronger.38,145,146 In their meta-analysis Yan et al reported that early treatment was significantly associated with retreatment (OR 2.24, 95% CI 1.76 to 2.84, P <0.001), but again noted significant heterogeneity—due, in part, to different definitions for treatment failure resulting in widely varying rates of retreatment between studies.143 Preparation Variables IVIG preparations vary widely in production methods, IgG concentration, stabilization additives, as well as the concentration of other immunoglobulin classes (such as IgA).80,85,147 Harada observed reduced efficacy with pepsin-treated immunoglobulin than with intact immunoglobulin115; this suggests that the Fc region of the IgG molecule may play a crucial role in the treatment of KD.60,63 Tsai et al compared the efficacy of four brands of IVIG available in Taiwan, observing significantly lower efficacy in one brand (Intraglobulin®F) in terms of treatment failure and coronary aneurysm formation.148 Unlike the other brands studied Intraglobulin®F was manufactured using β-propiolactonation, which was hypothesised to significantly modify the Fc region.85,148 Lin et al observed higher rates of treatment failure, but not coronary artery aneurysm formation, in patients who received Intraglobulin®F.149 As IVIG manufacturing processors have moved away from methods that significantly modify the Fc region other variables have been shown to affect efficacy. Manlhiot et al compared outcomes among children with KD treated with two immunoglobulin brands available in Canada; Gamimune® was associated with lower rates of retreatment but higher rates of coronary artery aneurysms when compared with Iveegam®.147 While neither product was manufactured using a process known to affect the Fc region, Gamimune® had significantly higher titres of IgA. Additionally, each used a different stabilisation process: glucose in the case of Iveegam® and acidification in the case of Gamimune®. Lin et al also reported higher rates of coronary aneurysms Chapter 244  among children who received acid stabilised IVIG products (including Gamimune®).149 The authors of both papers hypothesised that the acidifying action of Gamimune® might contribute to elastin degradation and exacerbate aneurysm formation.  Finally, the effect of IVIG concentration on efficacy has been considered by several investigators. In the study already mentioned Manlhiot et al observed that Gamimune® (10% concentration) had lower rates of treatment failure than Iveegam® (5% concentration), hypothesising that the additional time required to infuse Iveegam® resulted in greater duration of fever (importantly, treatment failure in that study was defined as persistence of fever 36 hours after the start of the IVIG infusion).147 Other investigators have reported contrasting results: both Han et al and Downie et al observed higher rates of treatment failure with 10% IVIG preparation than with 5% preparations,150,151 although with both using different definitions of treatment failure. While Intragam®10 (which is preferentially administered for KD in Australia) does not undergo any processes known to affect the Fc region, it is acid stabilised and presented at 10% concentration.59 The suggestion that these product variables may affect efficacy in KD is of interest, however a lack of consensus around key definitions prevents useful synthesis of the evidence at this time. Secondary Therapy After Treatment Failure Retreatment using additional doses of IVIG was one of the first-reported therapies for IVIG resistance, proving to be both safe and effective.44,152 Current guidelines recommend additional doses of IVIG after treatment failure, but acknowledge a lack of evidence from large controlled trials.20,21,27  Adverse Reactions and Interactions The reported incidence of adverse reactions varies substantially, with most authors describing rates of between 30% and 40%.87,153 The significant majority of adverse reactions are mild and self-resolving, however life-threatening reactions (including haemolysis and thromboembolism) have been reported.154,155 IVIG can also interfere with seroconversion in response to live vaccines, an issue of particular relevance to children treated for KD.156 Mild Immediate and Delayed Infusion Reactions Immediate infusion reactions related to KD (such as headache, chills-fever, fatigue, dyspnoea, nausea, and hypotension) are common and typically mild.87,153 While the cause of these reactions is not clear complement activation and IgG aggregates have been implicated.84,87 Immediate reactions usually occur within the first 30 minutes of the infusion and often respond to a reduction in the infusion rate—indeed, current infusion protocols often utilise a stepped infusion rate for this reason.87,157,158 Premedication with Management of KD45antihistamines, antipyretics, and anti-inflammatory drugs (both non-steroidal and steroidal) have been advocated,87 however there is conflicting evidence around efficacy.159,160 Liu et al, in a single-centre retrospective audit of premedication practices for patients treated for KD, observed high rates of premedication use but significant variability in agents used.161 Currently evidence is lacking to guide premedication choice in KD. Delayed infusion reactions occur after the infusion has ended, and are very common, with headache, fatigue, and abdominal pain being most frequently reported. Headache can last for over a day and can significant limit function.153 Headaches occasionally display features consistent with migraine (including visual changes), and aseptic meningitis can rarely occur. While most guidelines recommend reducing the infusion rate, this is clearly not relevant in cases of delayed reactions.153 There is a need for further research to guide the prevention and management of delayed infusion reactions. Haemolysis Acute haemolysis due to IVIG—while rare—is well recognised,162 with those receiving IVIG for KD at particularly high risk.163–165 The cause is theorised to be passive transfer of anti-A and anti-B IgG to recipients carrying incompatible ABO antigens,166 although conflicting evidence suggests that other mechanisms may be involved.167 Modern IVIG preparations are designed to meet regulated maximum titres of anti-A and anti-B (commonly no higher than 1:64) but actual titres vary between products.166 Bruggeman et al observed a significant increase in the rate of haemolysis among children receiving IVIG for KD in Canada following the introduction of IVIG preparations with relatively high anti-A and anti-B titres.166 Given the relatively high risk of this phenomenon when using IVIG to treat KD clinicians must remain vigilant to changes both at the level of the individual patient and the population receiving IVIG more generally. Thrombosis The infusion of high-dose IVIG has been associated with intravascular thrombosis.168–170 While most cases have been reported in adults, strokes have occurred in children receiving IVIG for KD.155 The mechanism of IVIG-associated thrombosis remains unclear, with conflicting evidence of an effect on blood viscosity.171–173 Despite the rarity of the phenomenon it is of particular relevance in the case of KD, for two reasons. Firstly, marked thrombocytosis and platelet activation mean that KD is a pro-thrombotic state.171,174,175 Secondly, vascular changes (including both aneurysm and arterial spasm) can result in altered tissue perfusion.176,177 Indeed, cerebral hypoperfusion has been observed in acute KD,178 and cerebral infarctions have occurred independent of IVIG administration.179,180 While there has been little research to quantify the risk of IVIG-associated thrombosis in KD, clinical Chapter 246deterioration consistent with thromboembolic disease should prompt immediate consideration of this phenomenon. IVIG and Live Vaccines Passively acquired polyclonal antibodies (such as from IVIG) can interfere with seroconversion following immunisation with live attenuated vaccines.156 Measles-containing vaccines are live-attenuated vaccines that are typically administered in the first few years of life—the peak age of incidence of KD. National immunisation guidelines recommend postponing the administration of live vaccines after IVIG for the treatment of KD, however there is no international consensus regarding the period of postponement;181 North American, and Australian and New Zealand guidelines recommend postponing live vaccines for 11 months after IVIG21,182–186; European20 and Japanese40 guidelines recommend a 6 month postponement. Further work is needed to understand the duration of this effect to better inform immunisation guidelines. Clinical Practice Guidelines There is unanimous consensus around the use of IVIG at a dose of 2 g/kg in a single infusion for acute KD (Table 2.2.1). Where multiple small-dose protocols were discussed it was always for exceptional circumstances (namely congestive cardiac failure wherein the volume of a single high-dose infusion was problematic).31,34 Recommended infusion times varied, however most guidelines recommend that the full dose be given within 12 hours. No guideline advised against administering IVIG too early in the disease course, and all allowed for the administration of IVIG after day 10 if there was evidence of ongoing inflammation (or made no reference to this). Only one guideline discussed pre-medication.32Management of KD47Table 2.2: Clinical Practice Guidelines for the Use of Intravenous Immunoglobulin as Primary Therapy in Acute Kawasaki Disease Guideline IVIG Dose Infusion Duration When to Treat Comment NZ (2022)25 2 g/kg single dose Over 10–12 hours (but notes that infusion rates differ between the two available products: Privigen® and Intragam® P) “...should be given when the diagnosis is strongly suspected” and within 10 days of fever, but: “IVIG should still be administered later than 10 days if there are signs of continuing inflammation (fever, high ESR) or evolving coronary artery disease.” AU-RCH (2021)22 2 g/kg single dose Not given (provided in other institutional documents). “...on diagnosis” and within 10 days of fever, but: “...should also be given to patients diagnosed after 10 days of illness if there is evidence of ongoing inflammation.” AU-PCH (2021)23 2 g/kg single dose Over 8–12 hours Not given ACR (2021)18 2 g/kg single dose Not given Not given ISP (2021)26  2 g/kg single dose Over 12 hours (16–24 hours if signs of cardiac failure) Within 10 days (ideally 7), but: “Treatment before the 5th day of fever should be reserved to exceptional cases of unequivocal diagnosis of KD” And: “IVIG should also be administered to children presenting after the 10th day of illness in case of persistent fever or ongoing systemic inflammation.” JSPCCS (2020)27 2 g/kg single dose, or 200–400 mg/kg/day for 3–5 days (although this is acknowledged as less effective and said to be for exceptional circumstances) Over 12–24 hours No clear recommendations; preference for treatment within 7–9 days. IAP (2020)28 2 g/kg single dose Over 12–24 hours Within 10 days (ideally 7), but: “IVIG should be considered even in patients with >10 days of illness with persistent fever, systemic inflammation evidenced by elevated ESR or CRP (>3.0 mg/L), or presence of CAAs.”Chapter 248Continued... Guideline IVIG Dose Infusion Duration When to Treat Comment DGPK (2020)29 2 g/kg single dose Over 10–12 hours “If the diagnosis is made early, before the 5th day of illness, the administration of IVIG should not be delayed.” And: “Even if the diagnosis is made later (>10 days), IVIG application still makes sense if there are signs of inflammation, fever, and coronary abnormalities.” SHARE (2019)20 2 g/kg single dose Not given “As soon as a patient is diagnosed with KD, treatment should be initiated.” AEP (2018)30 2 g/kg single dose Over 12 hours “...as soon as possible in the first 10 days of illness or even later if febrile symptoms of unknown origin persist, persistent inflammatory activity confirmed by increased CRP or ESR, or the presence of coronary aneurysms.” This document recommends that 5% IVIG be used for the first administration in an individual, and that all infusions should be commenced at a lower rate for the first 30 minutes. SW (2018)31 2 g/kg single dose (but can be split over 2 days if signs of heart failure) Over 8–12 hours “Treatment is started as soon as the diagnosis is made, preferably within 7 days of the onset of symptoms, but should also be given if the diagnosis is made later.” AU-TG (2017)24 2 g/kg single dose Over 10–12 hours Not given AHA (2017)21 2 g/kg single dose Over 10–12 hours “As early as possible...” and within 10 days of fever, but: “IVIG should also be administered to children presenting after the tenth day of illness if they have ongoing systemic inflammation as manifested by elevation of ESR or CRP (CRP >3.0 mg/dL) together with either persistent fever without other explanation or coronary artery aneurysms (luminal dimension Z score >2.5).” Management of KD49Continued... Table 2.2 continued... Guideline IVIG Dose Infusion Duration When to Treat Comment UK (2002)34 2 g/kg single dose (but can be split over 2–4 days in infants with cardiac failure) Over 12 hours “IVIG treatment should be started early in the disease, preferably within the first 10 days of the illness. Importantly, however, clinicians should not hesitate to give IVIG to patients who present after 10 days if there are signs of persisting inflammation.” Chapter 2ASP/ASC (2016)32 2 g/kg single dose Over 10–12 hours “...between days 5 and 10 of the onset of the disease”, but “If the diagnosis is made after 10 days of illness, treatment with g-GEV in patients with fever and persistently elevated acute phase reactants or in the presence of coronary aneurysms.” This document also recommends the use of diphenhydramine 1 mg/kg as premedication 1 hour before the infusion. DM (2015)33 2 g/kg single dose Over 6–8 hours Not given 50Table 2.2 continued... Conclusions IVIG is well established as a treatment for KD, with high-level evidence that it reduces the rate of coronary artery development. While clinical practice guidelines unanimously endorse a dose of 2 g/kg there is emerging evidence to suggest that a more nuanced approach to dosing (either stratifying by disease severity or bodyweight) may be safe. Issues around the global supply and logistics of IVIG may mean that innovation in this area is needed. There is some evidence that a range of administration and product variables might lead to variable response to treatment, yet the lack of a consensus definition of treatment failure makes this difficult to discern. There is a need for global collaboration around an agreed definition of treatment failure to strengthen research in this important area. Management of KD51Part 3: Aspirin Background Aspirin (acetylsalicylic acid) has been used in the management of KD since at least the 1970s,5–7 with early recognition of theoretical benefits both from aspirin’s antiplatelet effects and anti-inflammatory effects.4,5 The appropriate dose of aspirin during the acute phase of the disease has been a point of controversy almost since the first reports of its use, with current guidelines and practice varying substantially.20–22,27 Most guidelines recommend that children receive moderate-dose aspirin (30–50 mg/kg/day in divided doses) until defervescence, at which point low-dose aspirin (3–5 mg/kg/day in a single dose) is commenced.20,25,27,28,187 American guidelines allow for aspirin to be started in the high-dose (80–100 mg/kg/day in divided doses) or moderate-dose range before reducing to the low-dose range.21 Australian recommendations differ: Therapeutic Guidelines discusses high-dose and moderate-dose aspirin in the acute phase without providing a recommendation, and recommends that low-dose aspirin be commenced after defervescence.24 In contrast, guidelines published by the Royal Children’s Hospital in Melbourne (which have been endorsed by the Paediatric Improvement Collaborative for use in Victoria, New South Wales, and Queensland) and the Perth Children’s Hospital only recommend the use of low-dose aspirin22,23; the Australian Medicines Handbook Children’s Dosing Companion similarly recommends low-dose aspirin.188 This recommendation is unusual at a national level—only Swedish guidelines gave similar advice.31,125 History of Aspirin Dosing in Kawasaki Disease Before the effective treatment of KD with IVIG investigators theorised that aspirin might be a useful agent with two important actions: amelioration of the inflammatory process by inhibiting COX-2-dependent synthesis of prostaglandin E2 (a pro-inflammatory eicosanoid) and prevention of thrombosis by inhibiting COX-1-dependent synthesis of thromboxane A2 (responsible for platelet activation).4,8,189–191 There was even hope that aspirin might prevent the development of coronary artery aneurysms.192 While COX-1 inhibition occurs selectively at very low plasma salicylate concentrations, COX-2 remains active until relatively high concentrations are reached.190 Early investigators struggled to achieve plasma salicylate concentrations needed for COX-2 inhibition (theorised to be 200 mg/L6)—variably attributed to impaired intestinal absorption6 or enhanced renal clearance193 and thought to be unique to KD194—leading to the use of extremely high doses of aspirin (up to 200 mg/kg/day6). Around the same time other investigators were raising concerns of a possible paradoxical pro-thrombotic effect of aspirin at high doses through inhibition of COX-2-dependent synthesis of prostacyclin by vascular endothelial cells.8,195,196 Chapter 252  (Indeed, recent studies have confirmed that platelet activation can occur in the presence of high plasma salicylate concentrations through non-COX-dependent mechanisms.197) This was felt to be particularly concerning due to the erratic and unpredictable patterns of intestinal salicylate absorption in the acute phase of the disease.8 These findings resulted in divergent recommendations for aspirin dose in acute KD by the mid-1980s.4,8,192 Aspirin as Primary Therapy for Acute Kawasaki Disease The first intervention trial for acute KD compared five treatment protocols, of which two included aspirin (30 mg/kg/day) during the acute phase:3  Protocol 1: Prednisolone + Cephalexin (n = 17)  Protocol 2: Prednisolone + Warfarin + Cephalexin (n = 7)  Protocol 3: Prednisolone + Aspirin + Cephalexin (n = 7)  Protocol 4: Aspirin + Cephalexin (n = 36)  Protocol 5: Cephalexin alone (n = 25) In all cases cephalexin was discontinued when the possibility of a bacterial infection had been excluded. The investigators observed vastly differing rates of coronary aneurysms between the groups—highest among those who received protocols 1 and 2 and lowest among those who received protocols 3 and 4; there was no significant difference in the rates of aneurysms between those who received protocols 4 and 5. This study had two very significant impacts on the management of acute KD: corticosteroids were (for a time) contraindicated,9,198 and the importance of aspirin was elevated—even as investigators acknowledged the equivalent outcomes for aspirin versus cephalexin alone.192,199 Only one other study compared coronary outcomes by aspirin dose prior to the introduction of IVIG; Ichida et al described a cohort of 110 children with KD in New York, finding no difference in the rates of aneurysm formation by aspirin dose.200 With the recognition of IVIG as an effective treatment for KD many investigators included aspirin dose as a study variable in IVIG trials. Durongpisitkul et al undertook what would be the first of many meta-analyses of these trials.16 They found no evidence that high-dose versus low-dose aspirin (in combination with high-dose IVIG) resulted in fewer coronary aneurysms at 30 or 60 days post-treatment, however none of the included trials used randomised treatment allocation for aspirin dose. Baumer et al undertook a systematic review for the Cochrane Collaboration in 2006, but concluded that the available evidence was of insufficient quality to inform any recommendations.201  More recent studies of aspirin dose have often used time to defervescence or rate of treatment failure (the latter usually defined by the former) as surrogate end points for assessing efficacy.202 While low-dose aspirin has occasionally Management of KD53been associated with longer duration of fever202 and higher rates of treatment failure203 other studies have observed no significant differences.204–207 None of these studies reported differences in rate of coronary aneurysms. Three further meta-analyses have assessed the impact of aspirin dose on outcomes. Zheng et al reviewed six studies for coronary outcomes, five studies for treatment response, and four studies for duration of fever and hospitalisation—they found no evidence that aspirin dose meaningfully influenced any of these outcomes.208 Jia et al did find a small reduction in the duration of fever with high-dose aspirin, although the effect was entirely dependent on one study.209 Moreover, aspirin dose had no effect on rates of aneurysm formation or response to treatment.209 Finally Chiang et al pooled data for patients who received low-dose aspirin and no aspirin; rates of coronary artery lesions were lower in the low-dose/no aspirin group than in the high-dose aspirin group (odds ratio 0.81, 95% confidence interval 0.69 to 0.95, p = 0.01). There was no statistically significant association between aspirin dose and treatment response.210 Aspirin for Thromboprophylaxis in Kawasaki Disease Thromboprophylaxis is recommended in the acute phase of KD (and significantly longer in those with coronary aneurysms) given the risk of thrombosis and consequent myocardial infarction.21 Children with KD are at risk for arterial thrombosis due to a number of predisposing factors, with the risk of thrombosis influenced by the extent of coronary (and systemic) artery disruption, timepoint in the disease process, pharmacotherapy, and a range of other variables. Risk of Thrombosis in Kawasaki Disease Arterial thrombosis (particularly of the coronary arteries) is the leading cause of death in KD; the risk of death being highest in the acute phase (within two months of presentation).211 Thrombosis typically complicates aneurysms (both of the coronary212–214 and systemic215,216 arteries), but have been observed to occur in KD without demonstrable arterial disruption.217 With widespread use of IVIG the incidence of coronary aneurysms has reduced remarkably, however they still occur in 2–9% of cases.37,106,218–220 The development of aneurysms starts early in the disease, with dilatation visible on transthoracic echocardiogram as early as day 4.221 Dilated vessels can follow different trajectories: spontaneous resolution occurs in approximately 80%.222,223 Small- and medium-sized aneurysms are capable of spontaneous regression,222,224–226 however the mechanisms by which this occurs (including luminal myofibroblastic proliferation, intimal proliferation, and neoangiogenesis227,228) can lead to stenosis and consequent myocardial ischemia,224,229 and even normal-appearing sites of regressed aneurysms continue to exhibit an abnormal response to experimental stimuli.230 Large- Chapter 254  and giant-sized aneurysms (with rare exception231) do no undergo spontaneous regression.232,233 Thrombosis will occur in the majority of large- and giant-sized aneurysms; the highest risk for thrombosis formation is in the acute phase (within 30 days) and remains high in persisting large aneurysms.234 The thrombotic risk associated with regressed aneurysms remains unclear. Mechanisms of Thrombosis in Kawasaki Disease The occurrence of marked thrombocytosis in KD was reported from the earliest case series.1,235 (As an aside, early thrombocytopenia in KD is occasionally seen236,237 and is associated with poorer outcomes238: increased risk of coronary artery aneurysms,239,240 the Kawasaki shock syndrome,241 and the macrophage activation syndrome.242–244) Platelet counts typically remain within the normal range during the acute phase, rising in the second and third week of the disease in response to high circulating thrombopoietin.175,245,246 So-called ‘reactive’ or ‘secondary’ thrombocytosis is a normal part of the acute phase reaction, occurring in the context of infection, trauma, surgery, and chronic inflammatory states.247 While reactive thrombocytosis has been associated with increased (venous) thrombosis risk in adults,248 this has not been shown in children.249 Degree of thrombocytosis has, however, been associated with the risk of IVIG non-response and development of coronary artery aneurysms.171 Perhaps of greater importance than thrombocytosis—especially in the very early phase of KD—is platelet activation and aggregation.250 Platelet activating factor (PAF) and related molecules (pro-inflammatory mediators that act both on platelets and endothelial cells) are elevated in KD.251 Indeed, platelet derived microparticles (PDMPs, endoplasmic reticulum-derived vesicles that are discharged by platelets on activation and considered markers of platelet activation) are elevated in the first few days of KD.252 Platelet aggregation has also been demonstrated in the very early days of KD,253 suggesting that a prothrombotic environment exists well before thrombocytosis is seen.252 Haemodynamic factors within aneurysms also produce favourable conditions for thrombosis. Stagnant blood with low flow velocity is classically associated with venous thrombosis, whereas arterial thrombosis is associated with platelet activation at sites of high wall shear-stress (which is why anti-platelet drugs are preferred for the prevention of arterial thrombosis).254 Coronary aneurysms seen in KD demonstrate both of these factors, with regions of low flow velocity and regions of high wall shear-stress.255–257 Indeed, currently-used approaches for thrombotic risk stratification (namely maximum aneurysm dimension as measured by transthoracic echocardiography) do not consider the haemodynamic variables most predictive of thrombus formation (namely regional peak flow velocity and wall shear stress).256 Management of KD55  Efficacy of Aspirin for Thromboprophylaxis in Kawasaki Disease While the relative risk of coronary artery thrombosis in acute KD (and especially among those with large- and giant- aneurysms) is high, the absolute risk remains low. As appropriately-powered studies would need to be prohibitively large, recommendations regarding thromboprophylaxis have largely come from expert consensus informed by extrapolation from adult data.21 The efficacy of aspirin for the primary prevention of coronary heart disease in adults is well established.258–260 While COX-2 inhibition (responsible for the anti-inflammatory effects of aspirin) requires high dosing and frequent administration, COX-1 inhibition (largely responsible for the antiplatelet effects) is effective at low doses and daily administration.261 There are a number of reasons for this: Firstly, aspirin irreversibly acetylates its target site on COX-1 with 50- to 100-times greater effectiveness than for COX-2. Secondly, while production of COX-2 in tissue cells is inducible—and acetylated COX-2 molecules can therefore be replaced, platelets lack the cellular machinery for protein synthesis—meaning that the effect of aspirin on platelets persists for the life of the platelet.261 Despite the population-level efficacy of aspirin for primary prevention of coronary artery disease, myocardial infarctions have occurred among individuals taking aspirin, leading to the recognition of ‘aspirin resistance’.262 While the most common reason for treatment failure is non-compliance,262 other mechanisms are well described: other non-steroidal anti-inflammatory drugs (NSAIDs, such as ibuprofen) compete with aspirin to bind with COX-1 but do so reversibly; unbound aspirin is then readily metabolised and excreted.262,263 It is also known that platelets can be activated by COX-1 independent routes (through platelet surface receptors for adenosine diphosphate [ADP], thrombin, adrenaline, collagen, and fibrinogen)—indeed these pathways seem to be enhanced in patients treated with aspirin.262 Finally, while pharmacokinetic variability (such as inadequate dose) might be thought to result in treatment failure, this is thought to be unlikely.262 Aspirin’s inhibition of COX-1 is thought to be saturable at extremely low concentrations262; indeed, substantially lower doses of aspirin (50 mg daily) than are currently recommended for secondary prevention of myocardial infarction have been shown to have equivalent efficacy.264 As already mentioned, early attempts to utilise the anti-inflammatory effect of aspirin in KD were frustrated by difficulties in achieving expected serum salicylate concentrations despite enormous doses of aspirin.6,193,195 Those investigators were trying to achieve serum salicylic acid concentrations of 200 mg/L, based on the observation (in an observational study by Jacobs et al involving 22 children with acute KD) that this was the dose at which Chapter 256  defervescence typically occurred.6 The reason for this pharmacokinetic anomaly has never been identified: some investigators recovered most of the aspirin dose from the stool265 (suggesting poor absorption), whereas others recovered significant amounts from the urine193 (implying at least some absorption). Indeed, the validity of the estimated therapeutic threshold for aspirin’s anti-inflammatory action is dubious, owing to significant methodological issues in the study. Firstly, some children in the study received corticosteroids; these are anti-inflammatory drugs in their own right, and may enhance the excretion of salicylic acid.266 Secondly, while the elimination half-life of salicylic acid is only around four hours,267 serum concentration was measured only daily; no detail was given as to the relative timing of aspirin administration and sample collection.6 Moreover, the relevance of these findings to the COX-1-dependent inhibition of platelet activation is entirely unclear: the anti-platelet effects of aspirin are mediated by acetylsalicylic acid (ASA)—not salicylic acid.268 While the issue of aspirin resistance continues to be an area of intense research, assays to quantify the anti-platelet effect continue to give highly variable results.269–273 Some investigators have attempted to measure platelet function in children taking aspirin for KD. Akagi et al found equally low concentrations of thromboxane B2 on day 4 of illness between children given aspirin at 100 mg/kg/day and those given aspirin at 30 mg/kg/day (as the production of thromboxane is dependent on COX-1, lower concentrations are thought to reflect more complete COX-1 inhibition).195 Fulton et al also demonstrated equivalent thromboxane suppression in those given aspirin at 30 mg/kg/day versus 60 mg/kg/day, however the timepoint for that result is not clear.274 At 6–8 weeks, after the aspirin dose has been reduced to 3–5 mg/kg/day, thromboxane levels were noted to have slightly increased, suggesting persisting COX-1 activity at that dose. Both of these studies measured the activity of COX-1, however as mentioned there are other pathways for platelet activation.262 Yahata et al reported a significant reduction in circulating circulating PDMPs (a down-stream rather than up-stream surrogate for platelet activation) following the administration of moderate-dose aspirin in acute KD.252 Tanoshima et al attempted a systematic review and meta-analysis of the effectiveness of anti-platelet therapy in KD275; while 20 studies were identified many were more than 20 years old or only available in Japanese. Moreover, significant methodological heterogeneity between studies precluded any analysis. Adverse Effects and Interactions While high rates of salicylism were observed ongoing children receiving extremely high doses of aspirin,276 modern doses are well tolerated.277 Kuo et al reported lower haemoglobin concentrations among those receiving moderate-dose aspirin than those receiving low-dose aspirin,278 while Management of KD57Kawakami et al reported a case of drug reaction with eosinophilia and systemic symptoms (DRESS) in a boy treated with high-dose aspirin for KD.279 One feared complication of aspirin use in children is Reye syndrome. Described as “encephalopathy and fatty degermation of the viscera” by Australian paediatric pathologist Dr Reye in 1963, the condition presented with encephalopathy and seizures and had a high mortality.280,281 There was often hypoglycaemia and low CSF glucose, as well as high serumconcentrations of toxic metabolites. An association with aspirin—especiallywith co-occurring influenza or varicella infection—was later observed,282leading to the use of aspirin in children being deemed contraindicated (exceptfor use in KD).283 Indeed, case reports exist of children presenting with Reyesyndrome while taking aspirin for KD.284 Despite widespread acceptance thecausal link between aspirin and Reye syndrome was controversial.285 Itsdisappearance in the decades since aspirin use in children was discontinuedhas been seen by some as evidence of a successful public safety intervention.286Others have argued that advances in the field of metabolic disorders has seena diverse set of metabolic disorders (possibly exacerbated by aspirin, butinborne nonetheless) reclassified according to a more precise ontology.287–290Regardless of the true ontological status of Reye syndrome, many guidelinescontinue to advise against the use of aspirin for children with KD and co-occurring influenza, as well as recommending annual influenzaimmunisation.21Clinical Practice Guidelines Prior to 2017 the American Heart Association specifically recommended the use of high-dose aspirin in the acute phase of KD291; this changed with the 2017 Statement, which allowed that: Administration of moderate- (30–50 mg/kg/d) to high-dose (80–100 mg/kg/d) ASA is reasonable until the patient is afebrile, although there is no evidence that it reduces coronary artery aneurysms (Class IIa; Level of Evidence C).21 Indeed, high-dose aspirin appears to have fallen out of favour—only two of the reviewed guidelines recommend its use, and both of those pre-date the 2017 AHA Statement (Table 2.3.1).32,33 Almost all of the reviewed guidelines recommend the use of moderate-dose aspirin in the acute phase of KD. Low-dose aspirin is only recommended by one Swedish guideline and two Australian guidelines.22,23,31 Where authors sought to quantify the level of evidence informing recommendations there appeared to be substantial variation in how the evidence was assessed. The authors of the Italian guidelines (published in 2018) suggested that their recommendation in favour of moderate-dose aspirin were based on class I evidence (meta-analyses or systematic reviews Chapter 258from randomized controlled trials).187 One year later the authors of the European consensus-based recommendations for the SHARE initiative graded the evidence for the same recommendation as 2A (controlled study without randomisation). A subsequent revision of the Italian guidelines did not attempt to quantify the quality of evidence or strength of recommendations.26 Management of KD59Table 2.3: Clinical Practice Guidelines for the Use of Aspirin in Acute Kawasaki Disease Guideline Aspirin Dose When to Reduce Dose Comment NZ (2022)25 “7.5–12.5 mg/kg four times daily” (Moderate-dose) “Once the fever is under control” A previous version of this document recommended the same dose, but as “30-50 mg/kg/day in 4 divided doses”.292  AU-RCH (2021)22 “3-5 mg/kg orally daily as a daily dose” (Low-dose) N/A AU-PCH (2021)23 “3-5 mg/kg daily” (Low-dose) N/A ACR (2021)18 No recommendation N/A The document states that “For patients with acute KD, using aspirin is strongly recommended over no aspirin” (emphasis from original), while grading the level of evidence for the recommendation as Very low. ISP (2021)26 “...daily dosage of 30–50 mg/kg divided into 4 doses” (Moderate-dose) After sustained defervescence for 48 hours. The previous iteration of this guideline inexplicably graded the level of evidence for this recommendation as class I (meta-analyses or systematic reviews from randomized controlled trials) with a strength of recommendation grade A (highly recommended). The revised version does not attempt to quantify the quality of evidence or strength of recommendations. JSPCCS (2020)27 “30–50 mg/kg/day, in divided doses 3 times a day” (Moderate-dose) After sustained defervescence for 48–72 hours. This document gives conflicting explanations for the recommended dose, and it is unclear whether a moderate dose is intended to have an anti-inflammatory effect or ensure an antiplatelet effect in the context of poor absorption. IAP (2020)28 “30–50 mg/kg/day in 3-4 divided doses” (Moderate-dose) After sustained defervescence for 48 hours. DGPK (2020)29 “30–50 mg/kg/day” (Moderate-dose) After sustained defervescence for 48–72 hours. SHARE (2019)20 “30–50 mg/kg/day” (Moderate-dose) “...until fever has settled for 48 h, clinical features are improving, and CRP levels are falling.” This document graded the level of evidence as 2A (controlled study without randomisation) and the strength of recommendation as C (based on level 3 or extrapolated from level 1 or 2). Chapter 260Continued... Guideline Aspirin Dose When to Reduce Dose Comment AEP (2018)30 “30–50 mg/kg/day every 6 h, PO” (Moderate-dose) After sustained defervescence for 48–72 hours. This document advises to discontinue aspirin if symptoms of salicylism appear. Concomitant use of ibuprofen is discouraged due to competitive inhibition of COX-2 binding. Finally, relatively extensive advice is given for the prevention of Reye syndrome in children with concomitant influenza or varicella infection. SW (2018)31 “2–5 mg/kg/day” (Low-dose) N/A AU-TG (2017)24 No recommendation, however the use of moderate- or high-dose aspirin in the acute phase is implied. “Once the fever has resolved” AHA (2017)21 Use of moderate- or high-dose aspirin is “reasonable” “Until the patient is afebrile” This document grades the level of evidence as level C (very limited populations evaluated or only consensus opinion of experts, case studies, or standard of care) and estimates the treatment effect as class IIa (benefit >> risk).The previous iteration of AHA guidelines specifically recommended high-dose aspirin without seeking to quantify the level of evidence or strength of recommendation.291ASP/ASC (2016)32 “80–100 mg/kg/day orally (every 6 hours) ... maximum 2.5g” (High-dose) After sustained defervescence for 72 hours. This document (again, inexplicably) grades the level of evidence for this recommendation as level A (strong evidence, from randomized clinical trials or meta-analyses. Multiple groups of populations at risk evaluated. General consistency in the direction and magnitude of the effect) with a recommendation strength of class I (evidence and/or general agreement that the procedure or treatment is beneficial, useful, and effective). DM (2015)33 “80–100 mg/kg/day divided into 4 doses” (High-dose) After sustained defervescence for 48–72 hours. The 2004 AHA statement is cited for this recommendation.291  UK (2002)34 “30–50 mg/kg/day in four divided doses” (Moderate-dose) “When fever settled” This document goes to some lengths to highlight the scant evidence with which to make a recommendation, noting only that “...it is our practice to administer aspirin at a dose of 30 mg/kg/day during the acute phase of the illness”.  Management of KD61Table 2.3 continued... Conclusions Moderate- and high-dose aspirin continues to be recommended for acute KD in most published guidelines, yet a coherent rationale for this recommendation can be harder to find. Recent Japanese guidelines, with reference to their recommendation in favour of moderate-dose aspirin in the acute phase of KD, equivocate: On the one hand they acknowledge the antiplatelet efficacy of low-dose aspirin but emphasise the need for higher doses to achieve anti-inflammatory effects. Later it is suggested that poor absorption of aspirin means that higher doses are needed for adequate antiplatelet effect.27 Progress in this area will be difficult without the articulation of clear and coherent principles for clinical decisions. Clinicians should state clearly what they think is being achieved by using higher doses of aspirin in KD, so that these hypotheses can be interrogated. Some may advocate moderate- or high-dose aspirin for its anti-inflammatory effect; this is unjustified. No evidence has ever been presented to suggest that children given moderate- or high-dose aspirin have better coronary outcomes than those given low-dose aspirin.202,204,205,207–209,293,294 Moreover, if enhanced suppression of inflammation is desirable in individual cases then corticosteroids have now been shown to be both safe and (somewhat) effective—with much less pharmacokinetic uncertainty.295–300 Others may favour moderate- or high-dose aspirin to guarantee antiplatelet efficacy in the context of uncertain absorption in acute KD. While the science underpinning such concerns is shaky at best, such concerns are valid—perhaps especially so in Australia, where access to early echocardiography in the acute phase of the disease may be poor.301 Yet advances in analytic techniques for quantifying antiplatelet activity are making this question increasing amenable to empirical investigation.269,270,302–305 (The literature on thromboelastography in children with a Fontan circulation is particularly interesting and relevant in this regard.304,305) Indeed, Australia—where low-dose aspirin from the time of KD diagnosis is common—is well placed to contribute to such studies. Chapter 262Part 4: Corticosteroids Background Corticosteroids have been used to suppress the systemic inflammation of acute KD since before the condition had been described. Based on their known efficacy in a range of other vasculitides, corticosteroids were used in by Japanese clinicians to treat the mucocutaneous ocular syndrome in the 1950s306 and by American clinicians to treat infantile periarteritis nodosa in the 1960s (both of which may have been—or at least included children with—KD).307 Indeed, many of Kawasaki’s original cohort were administered corticosteroids in a range of formulations.1 The first trial of treatment protocols for KD was undertaken by Kato et al and published in Pediatrics in 1979.3 As described in Section 2: Aspirin, the study comprised five arms, of which three included corticosteroids. Protocol 1: Prednisolone + Cephalexin (n = 17) Protocol 2: Prednisolone + Warfarin + Cephalexin (n = 7) Protocol 3: Prednisolone + Aspirin + Cephalexin (n = 7) Protocol 4: Aspirin + Cephalexin (n = 36) Protocol 5: Cephalexin alone (n = 25) Children treated according to Protocols 1, 2, and 3 were given oral prednisolone 2–3 mg/kg/day for at least two weeks (but until resolution of clinical signs and normalisation of ESR to below 20mm/Hr), which was then weaned to 1.0–1.5 mg/kg/day for another 2 weeks. The primary outcome was coronary artery aneurysms as seen on angiography at 1–2 months after disease onset. Results of the study are shown in Table 2.4.1. Table 2.4: Rate of Coronary Artery Aneurysm Formation by Treatment Protocol, Kato et al (1979) Treatment Protocol Aneurysms 1. Prednisolone + Cephalexin 11/17 (65%) 2. Prednisolone + Warfarin + Cephalexin 2/7 (29%) 3. Prednisolone + Aspirin + Cephalexin 0/7 (0%) 4. Aspirin + Cephalexin 4/36 (11%) 5. Cephalexin 5/25 (20%) As mentioned, these results gave rise to a paradigm whereby the use of corticosteroids in KD was contraindicated—both as primary therapy299,308 and in the increasingly-recognised phenomenon of IVIG-resistant disease.198,199 The findings were, however, controversial: some of Kato’s contemporaries criticised the dosing of prednisolone as insufficient and the timing of corticosteroid therapy as too late.9 To address these concerns Kijima et al tested a protocol consisting of high-dose (30 mg/kg/day) pulse methylprednisolone for 3 days.9 They stratified patients with acute KD into 3 Management of KD63  groups (E1, E2, and E3) according to the degree of involvement of the coronary arteries as seen on echocardiograms (E1: increased echo density; E2: coronary dilatation; E3: coronary aneurysm). Among children with aneurysms (E3), those in the steroid group were much more likely to have improvement of the lesions than those in the control group (50% versus 0%, P <0.005). Improvements in E2 lesions, and the pooled data for E2+E3 lesions, did not meet the threshold for statistical significance. While the study was methodologically more rigorous than that of Kato the paper gives no details about randomisation or blinding, and little information is given about the baseline characteristics of each group. By the time that IVIG was starting to be used for KD opinions regarding the role of corticosteroids were divided. Some worried that corticosteroids worsened coronary outcomes and felt that they were contraindicated.198,199,299,308 Others perceived a role of corticosteroids but advocated very different protocols: Low-dose, long-course (LDLC) corticosteroids (typically involving a weaning course of oral prednisolone over several weeks) were favoured by some investigators (particularly in Japan)297,300,309; conversely, high-dose, short-course (HDSC) corticosteroids (typically intravenous pulse methylprednisolone, either as a single dose or over several days) were pursued elsewhere (notably—although not exclusively—in America).56,296,299 With the efficacy of IVIG having been firmly established, all subsequent trials of corticosteroids as primary therapy for KD evaluated combined IVIG plus corticosteroid (primary adjunctive therapy) against IVIG alone (with one very recent exception295). Other research has assessed the value of corticosteroids for IVIG-resistant KD. Both of these roles are reviewed below. Corticosteroids as Primary Adjunctive Therapy for Acute Kawasaki Disease Corticosteroids as primary adjunctive therapy has been assessed in both unstratified patients295,297,299,309 and at high risk for severe disease (defined either as risk for IVIG resistance298,300,310,311 or the presence of aneurysms at presentation296,312,313). The issue has been subjected to multiple systematic reviews and meta-analyses, with at least seven published in English as of late 2022.314–320 The most recent of these was a systematic review and meta-analysis for the Cochrane Collaboration by Green et al published in May 2022320; it was an update to an earlier Cochrane review by the same investigators published in 2017.318 The investigators identified eight studies that met inclusion criteria, of which only one had not been included in the previous review (and that study only considered corticosteroids as secondary therapy).321 Details of the seven studies on primary adjunctive corticosteroids are shown in Table 2.4.2. Studies differed in primary outcome; some assessed the incidence of coronary artery abnormalities (which was usually defined according to the Japanese Chapter 264  Ministry of Health criteria*), while others compared coronary artery z-scores between groups. In a single-centre trial of at Boston Children’s Hospital, Sundel et al randomised 39 patients with complete KD and normal coronary arteries to receive standard of care (IVIG 2 g/kg and high-dose aspirin) with or without HDSC corticosteroid (a single dose of intravenous methylprednisolone, given prior to the IVIG).299 Those in the corticosteroid group had faster resolution of fever and shorter length of admission compared with those in the control group; rates of in-hospital adverse effects were similar between groups. There were no significant differences in coronary outcomes† at two and six weeks. HDSC corticosteroids were also assessed by Newburger et al in a multi-centre, randomised, double-blinded, placebo-controlled trial.296 The study did not exclude children with incomplete KD or with coronary abnormalities at enrolment. A total of 199 children were randomised to receive IVIG with or without HDSC corticosteroid (treatments were similar to that of Sundel et al). Those in the corticosteroid group had a slightly shorter length of stay (although this was not clinically significant) and faster normalisation of the erythrocyte sedimentation rate (ESR‡) but not C-reactive protein (CRP). There were no differences between groups in terms of rate of retreatment or coronary artery abnormalities§. Finally, Ogata et al compared IVIG plus HDSC corticosteroid to IVIG alone in a single-centre Japanese trial.56 They enrolled children at high risk for treatment failure** but without coronary involvement at diagnosis, randomising them to receive standard of care (IVIG 2 g/kg plus moderate-dose aspirin) with or without a single dose of intravenous pulse methylprednisolone (30 mg/kg) prior to IVIG (those in the corticosteroid group were also maintained on a heparin infusion for the first 24 hours of therapy††). Coronary artery z-scores were higher for those in the control group  * The Japanese Ministry of Health criteria define a coronary artery abnormality by the observation of any of the following: i) a luminal diameter >3.0 mm (age <5 years) or >4.0 mm (age ≥5 years); ii) an artery segment with a luminal diameter ≥1.5 times that of an adjacent segment; iii) a luminal contour that is clearly irregular.322 † While Sundel et al indicated that they assessed coronary arteries using both the Japanese Ministry of Health criteria and by normalised dimensions (i.e., z-score), only the latter was reported. ‡ It should be noted that ESR is an unreliable marker of inflammation after the administration of IVIG due to the net-positive charge of globulins at physiological pH, which promotes rouleaux formation.323–325 § Newburger et al defined coronary artery abnormality either according to the Japanese Ministry of Health criteria or a luminal z-score of ≥2.5 in either the proximal left anterior descending coronary artery or the proximal right coronary artery.  ** Based on an Egami score46 ≥3. †† No explanation for the use of heparin—or why it is only given to those in the corticosteroid group—is given in this paper. Management of KD65than those in the corticosteroid group: the difference was statistically different at 36 hours for the left and right main coronary arteries, and at 1 month for the left main coronary artery. An included boxplot* is more evocative, indicating very large differences in the relative frequency of moderate and large aneurysms in all vessels at both timepoints. While the investigators do refer to this in the text—noting that aneurysms with a z-score ≥2.5 were observed in 9% of those in the corticosteroid group compared with 39% of those in the control group at 1 month (P = 0.04)—the observation is not discussed at length. Ogata et al also reported greater improvement in markers of inflammation at 36 hours among those in the corticosteroid group than in the control group (including lower neutrophil count and fraction, lower CRP, and higher albumin—all of which were statistically significant), as well as shorter duration of fever and lower rates of retreatment in the corticosteroid group.56 Conversely, those in the corticosteroid group had higher rates of adverse events than those in the control group. Unfortunately, the use of heparin only in the corticosteroid group confounds the interpretation of these findings. Heparin has intrinsic anti-inflammatory activity,326,327 which may explain some of the findings of this study. Additionally, this may have contributed to the higher rates of adverse events in that group. Most studies of primary adjunctive corticosteroids in Japan have assessed LDLC corticosteroid protocols. In a multi-centre trial conducted in the Gunma Prefecture of Japan, Okada et al randomised 32 patients with complete KD to receive standard of care (IVIG 1 g/kg/day for 2 days plus moderate-dose aspirin and dipyridamole) with or without LDLC corticosteroids.309 Those in the corticosteroid group were given intravenous prednisolone 2 mg/kg/day until defervescence, then oral prednisolone at the same dose until the CRP had normalised; the dose of prednisolone was then weaned over a period of 10 days. Inflammatory cytokines (IL-2, IL-6, IL-8, and IL-10) were all significantly higher in the control group then the corticosteroid group immediately post-treatment, however the difference was not seen 1 week (for IL-2 and IL-8) or 2 weeks (for any of the cytokines); CRP was also slower to normalise and the duration of fever was longer in the control group compared with the corticosteroid group. No coronary artery abnormalities† were observed in any child. Inoue et al performed a very similar study—also in Gunma Prefecture, with the same investigators and with an overlapping study period—in which children with aneurysms at enrolment were excluded.297 One hundred and * Figure 2 of Ogata et al.56† Okada et al defined coronary artery abnormality according to the JapaneseMinistry of Health criteria.Chapter 266  seventy-eight children were randomised to receive standard of care with or without LDLC corticosteroids (the only difference being a slightly slower wean in the dose of prednisolone compared with Okada et al).297 Rates of coronary artery abnormalities* were lower in the corticosteroid group than in the control group (2% versus 11%, P = 0.017) before one month, but not at one month (0% versus 3%, P = 0.119). Rates of treatment failure were significantly lower in the corticosteroid group compared with the control group (6% versus 18%, P = 0.01). The most anticipated trial of primary adjunctive corticosteroids for acute KD was the RAISE study, conducted by Kobayashi et al.300 This was a large multi-centre (74 recruitment sites throughout Japan), randomised, open-label trial of primary adjunctive corticosteroids for children deemed to be at high risk for IVIG resistance† but without aneurysms at enrolment.45 242 children were randomly assigned to receive standard of care (IVIG 2 g/kg plus aspirin 30 mg/kg/day) with or without LDLC corticosteroids (the corticosteroid protocol was very similar to that of Inoue et al and Okada et al). Echocardiograms were performed at enrolment (to determine eligibility) and then at weeks 1, 2, and 4. The primary endpoint was incidence of coronary artery abnormalities‡ at any timepoint, secondary outcomes included coronary artery abnormalities at 4 weeks, coronary artery z-scores, rate of retreatment, duration of fever, CRP at weeks 1 and 2, and rates of serious adverse events. The study was terminated early due to significantly lower rates of coronary artery abnormalities in the corticosteroid group compared with the control group. The relative risk for coronary artery abnormalities at any timepoint in the corticosteroid group versus the control group was 0.2 (95% CI 0.12–0.28), with the number needed to treat to prevent one occurrence of coronary artery abnormality estimated to be five. For abnormalities at 4 weeks the relative risk was 0.09 (95% CI 0.02–0.16), with an estimated number needed to treat of ten. Coronary artery z-scores were lower in the corticosteroid group for every vessel at every timepoint. The investigators report that only one patient (in the control group) had a giant aneurysm (defined in absolute terms) of the left anterior descending artery, yet an included boxplot§ indicates that there were 3 individuals with right coronary artery z-scores greater than 10 (one in the corticosteroid group and two in the control group, timepoint of measurement not given). Data on the relative incidence of aneurysms by severity are not provided.  * Inoue et al defined coronary artery abnormality according to the Japanese Ministry of Health criteria.  † Based on a Kobayashi score45 ≥5. ‡ Kobayashi et al defined coronary artery abnormality according to the Japanese Ministry of Health criteria.  § Figure 2 of Kobayashi et al.300 Management of KD67In their pooled analysis of the aforementioned studies (Figure 2.4.1), Green et al reported a pooled odds ratio for coronary artery abnormalities in favour of primary adjunctive corticosteroids (OR 0.25, 95% CI 0.10 to 0.58),320 however methodological issues biased the result in favour of corticosteroids. Green et al included an abstract (Ikeda et al328) by the same research group responsible for the paper by Inoue et al. Both report a study at the same institution, at the same time, using the same research ethics approval, and with the same number of patients in each group (90 in the steroid group and 88 in the control group). Inoue et al describes the use of a severity score in their Methods, but the results are not stratified by that variable. By contrast, Ikeda et al only report results by severity strata. Outcome statistics given for both of these studies in the meta-analysis are identical. It seems highly likely that these publications describe the same cohort and represent duplicate data. Indeed, while Ikeda et al was included in this and the previous Cochrane review,318 it was not included in any other meta-analysis on the topic.314–317,319 There is also significant unrecognised heterogeneity with regard to the outcome measure selected for inclusion in the meta-analysis. Three studies defined coronary artery abnormality according to the unmodified Japanese Ministry of Health criteria (Okada et al309*, Inoue et al297, and Kobayashi et al300), while two used luminal z-score alone (Sundel et al: z-score >3,299 Ogata et al: z-score ≥2.556), and one used a combination of the two (Newburger et al: Japanese Ministry of Health criteria or z-score ≥2.5 in either the LAD or RMCA). While it isn’t clear that this introduced systematic bias, heterogeneity in the outcome timepoint did: most studies reported the rate of coronary * As no coronary abnormalities were observed in Okada et al, the study did notcontribute to the estimated treatment effect size.Overall, DL (τ2 = 0.730)Heterogeneity between groups: p = 0.019Subgroup, DL (τ2 = 0.000)WangSecond-line treatmentSubgroup, DL (τ2 = 0.560)SundelOkadaOgataNewburgerKobayashiIkedaInoueFirst-line treatmentIndication and Author20202003200320122007201220062006Year33/4908/408/4025/4500/180/142/2215/954/1212/902/90n/NTreatment83/4966/396/3977/4571/210/1810/2618/9528/12110/8810/88n/NControl0.32 (0.14, 0.75)1.38 (0.43, 4.41)1.38 (0.43, 4.41)0.25 (0.11, 0.58)0.37 (0.01, 9.64)(Insufficient data)0.16 (0.03, 0.84)0.80 (0.38, 1.70)0.11 (0.04, 0.34)0.18 (0.04, 0.83)0.18 (0.04, 0.83)(95% CI)Odds ratio100.0016.8316.8383.175.2112.6420.7717.6213.4613.46Weight%Favours corticosteroid Favours Control.001 .1 1 10 1000Incidence of Coronary Artery AbnormalitiesIntravenous Immunoglobulin with Corticosteroids versus Intravenous Immunoglobulin AloneFigure 2.2: Original forest plot from Green et al. Chapter 268artery abnormalities at around 4 weeks, however Sundel et al measured the outcome at 2 and 6 weeks299; the former was used in the meta-analysis. More significantly, while Kobayashi et al reported the rate of coronary artery abnormalities at 4 weeks as a secondary outcome (RR 0.09, 95% CI 0.02–0.16), their primary outcome was rate of coronary artery abnormalities at any timepoint (weeks 1, 2, and 4; RR 0.20, 95% CI 0.12–0.28)—a significantly larger effect size. Green et al used the latter in their meta-analysis, further biasing their result in favour of corticosteroids. When these issues are considered the new pooled effect size remains significant (Figure 2.4.2), but is smaller (OR 0.36, 95% CI 0.17 to 0.80). Subgroup analysis did reveal additional nuances: Confidence intervals for the odds ratio in favour of steroids (for the prevention of coronary artery abnormalities) excluded 1 in all Japanese trials but no American trials. The reason for this is unclear but may relate to the use of pulse methylprednisolone favoured in American trials, or the selection of higher-risk patients favoured in Japanese trials. The data available to evaluate primary adjunctive corticosteroids are lacking in several ways. Most studies reported the relative frequency of any coronary abnormalities,56,296,297 some reported group differences in coronary artery z-scores56,296,299,300, while one study reported no coronary abnormalities in either group.309 Only one study gave details on the relative frequency of coronary dilatation stratified by magnitude.299 Data showing a reduction in group coronary artery z-scores are compelling (particularly those from Kobayashi et al300), however the clinical relevance of that outcome is not clear. Dilated (but not aneurysmal) coronary arteries are commonly observed in acute KD,222,233,329 and have also been reported in children with systemic Overall, DL (τ2 = 0.406)Heterogeneity between groups: p = 0.064Subgroup, DL (τ2 = 0.000)WangSecond-line treatmentSubgroup, DL (τ2 = 0.313)SundelOgataNewburgerKobayashiInoueFirst-line treatmentIndication and Author202020032012200720122006Year32/3858/408/4024/3451/182/2215/954/1202/90n/NTreatment60/3896/396/3954/3501/2110/2618/9515/12010/88n/NControl0.47 (0.22, 0.99)1.38 (0.43, 4.41)1.38 (0.43, 4.41)0.36 (0.17, 0.80)1.18 (0.07, 20.26)0.16 (0.03, 0.84)0.80 (0.38, 1.70)0.24 (0.08, 0.75)0.18 (0.04, 0.83)(95% CI)Odds ratio100.0019.5619.5680.445.9013.2726.8120.0414.41Weight%Favours corticosteroid Favours Control.001 .1 1 10 1000Incidence of Coronary Artery AbnormalitiesIntravenous Immunoglobulin with Corticosteroids versus Intravenous Immunoglobulin AloneFigure 2.3: Updated forest plot. Ikeda et al has been removed, and all data refer to a single timepoint between 4 and 6 weeks after illness onset. Management of KD69  inflammation not caused by KD.330–332 The vast majority of these ‘lesions’ resolve222,223,333,334; indeed, coronary dilatation may represent a heterogenous group of phenomena—many of which lack aneurysmal potential.335 Technical challenges in coronary measurement, as well as methodological challenges underpinning their parametric normalisation, can result in high variability in z-scores.336* Occasionally, coronary arteries with ‘normal’ z-scores in the acute phase of KD demonstrate a reduction in calibre at follow-up, suggesting that they had been ‘functionally’ dilated.329 Other vessels may have ‘high’ z-scores in the acute phase with no change in calibre over time; this may be consistent with a dominant coronary artery branch.335† Small and moderate coronary aneurysms can also follow a very different natural history to large and giant aneurysms, with logarithmic regression over time being the norm.223,226,329,335‡ Further, while current recommendations focus on maximum calibre to estimate the risk of coronary abnormalities,21 this is not a strong predictor of subsequent thrombosis (which is much more heavily influenced by haemodynamic consequences of disturbed vessel morphology).255–257 Indeed, an over-reliance on coronary z-scores (particularly those representing only ‘dilatation’, and especially at early follow-up) are likely to significantly overestimate disease risk in KD.333 It follows that statistically significant yet small differences in coronary z-scores between groups is likely to result in over-estimation of the likelihood of treatment effect, while providing little information regarding effect size. Future studies should be designed and reported with clinically important outcomes in mind so that meaningful absolute and relative treatment effect sizes can be determined.341–344§ Some of these issues were addressed by Kobayashi et al.300 That was the only study to estimate the number needed to treat for the prevention of coronary artery abnormalities,300 yet the inclusion criteria limit the utility of the results outside of Japan. The Kobayashi score used to define the ‘at risk’ population for the study demonstrates poor accuracy (especially low sensitivity) for predicting IVIG resistance in a number of populations outside of Japan.50,345–350 Additionally, the exclusion of children with coronary abnormalities at diagnosis meant that the cohort (children with KD at high risk for IVIG resistance but without any coronary abnormalities—more than three quarters  * The dimensions of the left main coronary artery demonstrate particularly high variability26,336; consequently, this vessel is excluded in some analyses.226 † Importantly, patterns of coronary dominance differ between populations,337–339 which may not have been reflected in the populations used for parametric normalisation. ‡ Note that ‘regression’ does not imply ‘normalisation’. Aneurysmal vessels that have undergone regression (and which may appear normal on luminography) continue to show intimal thickening and abnormal response to intraluminal dipyridamole.221,225,230,233,335,340 § This would ideally be presented as, for example: the number needed to treat to prevent one high-risk coronary aneurysm (appropriately defined) at 6 months. Chapter 270of whom were diagnosed on or before day 5 of illness) is not representative of the range of children for whom clinicians might be considering primary adjunctive corticosteroids. The exclusion of children with coronary artery abnormalities at enrolment in many of these trials is of particular importance. Ever since the original trial by Kato et al suggested a possible negative effect of corticosteroids on coronary outcomes,3 several investigators have questioned if corticosteroids might interrupt the normal regression of coronary lesions in the sub-acute and convalescent phase of KD.351,352 Most evidence for this hypothesis has come from retrospective studies at high risk for selection bias351,352, with some theoretical support from animal studies353; other studies have suggested enhanced aneurysm regression in those treated with adjuvant corticosteroids.312,313 While some prospective trials have included children with aneurysms at enrolment their numbers have remained small.296,309 Future studies should seek to address this by enrolling patients regardless of coronary status and evaluating outcomes both as strata of initial coronary status and as change from initial coronary status. Finally, while LDLC corticosteroid protocols outperformed HDSC protocols in this meta-analysis, they can reasonably be expected to entail additional costs. These were unquantified, but might include: 1. Increased medication complexity (the need for incremental weaningof corticosteroid doses).2. Increased patient discomfort (the need for repeated venepuncture tomonitor inflammatory markers).3. Increased patient inconvenience (the presumed need for additionaloutpatient visits to facilitate 1 and 2).4. Increased healthcare costs (all of the resources utilised for 1, 2, and3).Any attempt to evaluate competing therapies must consider their relative costs—both in terms of resource utilisation at the health service level, and discomfort and inconvenience at the individual patient level.354,355Management of KD71Table 2.5: Randomised, Controlled Trials of Corticosteroids as Primary Therapy in Acute Kawasaki Disease Reference Location & Study Design Intervention Control Outcomes Sundel (2003)299   USA, single-centre. Randomised treatment allocation. Inclusion: -Fever ≤10 days, and-≥4/5 AHA criteriaExclusion: -Previous KD -Aneurysms at enrolment-Possible infection -Contraindication to steroidsBlinded outcome assessment. (N = 18) IVMP 30 mg/kg over 3 hours before IVIG; PLUS: IVIG 2 g/kg over 10 hours; PLUS: ASA 80–100 mg/kg/day in 4 divided doses until defervescence. (N = 21) IVIG 2 g/kg over 10 hours; PLUS: ASA 80–100 mg/kg/day in 4 divided doses until defervescence. Coronary artery dimensions on days 0, 14, and 42 of illness. Inflammatory markers on days 0, 14, and 42 of illness. Duration of fever. Okada (2003)309  Japan, multi-centre. Randomised treatment allocation. Inclusion: -≥5/6 Japanese criteriaExclusion: - Fever ≤9 daysUnclear is assessment blinded.(N = 14) IVPSL 2 mg/kg/day in 3 divided doses until defervescence, then: OPSL 2 mg/kg/day in 3 divided doses until CRP normalised, then: OPSL 2 mg/kg/day in 2 divided doses for 5 days, then: OPSL 0.5 mg/kg/day daily for 5 days;  PLUS: IVIG 1 g/kg/day for 2 days; PLUS: ASA 30 mg/kg/day; PLUS: DPA 2 mg/kg/day. (N = 18) IVIG 1 g/kg/day for 2 days; PLUS: ASA 30 mg/kg/day; PLUS: DPA 2 mg/kg/day. Coronary artery dimensions on the day of enrolment and on days 6–8, 12–16, and 25–30 of illness. Blood parameters, with cytokines measured before and after treatment. Duration of fever. Chapter 272Continued... Reference Location & Study Design Intervention Control Outcomes Inoue (2006)297  Japan, multi-centre. Randomised treatment allocation. Inclusion: -≥5/6 Japanese criteriaExclusion: -Previous KD -Aneurysm at enrolment-Fever >9 daysNon-blinded outcome assessment. (N = 90) IVPSL 2 mg/kg/day in 3 divided doses (the first dose preceded IVIG) until defervescence, then: OPSL 2 mg/kg/day in 3 divided doses until CRP <5 mg/L, then: OPSL 2 mg/kg/day for 5 days, then: OPSL 1 mg/kg/day for 5 days, then: OPSL 0.5 mg/kg/day daily for 5 days;  PLUS: IVIG 1 g/kg/day for 2 days; PLUS: ASA 30 mg/kg/day; PLUS: DPA 2 mg/kg/day. (N =88) IVIG 1 g/kg/day for 2 days; PLUS: ASA 30 mg/kg/day; PLUS: DPA 2 mg/kg/day. Coronary artery dimensions on the day of enrolment and on days 6–8, 12–16, 18–22, and 25–30 of illness. Duration of fever. Time to normalisation of CRP. Rate of retreatment. Ikeda (2006)328  (Available in abstract form only) Japan, number of centres unclear. Randomised treatment allocation. Inclusion and exclusion criteria unknown. Blinding unknown. (N = 90) PSL (dose and route unknown); PLUS: IVIG (dose unknown) (N = 88) IVIG (dose unknown) Coronary artery abnormalities (no details given). Rate of retreatment. Management of KD73Continued... Table 2.5 continued... Reference Location & Study Design Intervention Control Outcomes Newburger (2007)296  USA, multi-centre. Randomised and blinded treatment allocation. Inclusion: -Day 4–10 of fever, and:-≥4/5 AHA criteria, OR:-Coronary z-score ≥2.5 in LAD or proximal RCA, and ≥2/5 criteria (<6 months) or ≥3/5 criteria (≥6 months)OR:-Coronary aneurysm, and ≥1/5 AHA criteria.Exclusion: -Contraindication to any treatment.-Previous IVIG or steroid.-Previous KD.Blinded outcome assessment. (N = 101) IVMP 30 mg/kg over 2–3 hours; THEN: Diphenhydramine 1 mg/kg; PLUS: IVIG 2 g/kg over 10 hours PLUS: ASA 80–100 mg/kg/day until 48 hours after defervescence (N = 98) Placebo infusion over 2–3 hours; THEN: Diphenhydramine 1 mg/kg; PLUS: IVIG 2 g/kg over 10 hours PLUS: ASA 80–100 mg/kg/day until 48 hours after defervescence Coronary artery dimensions at enrolment and days 7 and 36. Blood parameters at enrolment and days 7 and 36. Duration of fever. Rate of retreatment. Ogata (2012)56 Japan, single-centre. Randomised treatment allocation. Inclusion: -≥5/6 Japanese criteria, and -Egami score ≥3 Exclusion: -Previous KD -Coronary abnormality at enrolment-Given steroids before KD diagnosis Blinded outcome assessment. (N = 22) Heparin 10 U/kg/hour over 24 hours; AND: IVMP 30 mg/kg/dose over 2 hours; THEN: IVIG 2 g/kg over 24 hours; AND: ASA 30 mg/kg/day to defervescence (N = 26) IVIG 2 g/kg over 24 hours; AND: ASA 30 mg/kg/day to defervescence Coronary artery dimensions before treatment and at 36 hours and 1 months after treatment. Blood parameters before treatment and at 36 hours and 1 months after treatment. Duration of fever. Rate of retreatment. Chapter 274Continued... Table 2.5 continued... Reference Location & Study Design Intervention Control Outcomes Kobayashi (2012)300  Japan, multi-centre. Randomised treatment allocation. Inclusion: -≥5/6 Japanese criteria, and -Kobayashi score ≥5Exclusion: -Fever ≥9 days-Coronary abnormality at enrolment-Afebrile at enrolment-Steroids in last 30 days-IVIG in last 180 days-Suspected infectionBlinded outcome assessment. (N = 121) IVPSL 2 mg/kg/day in 3 divided doses for 5 days or defervescence (whichever was later), THEN: OPSL 2 mg/kg/day in 3 divided doses until CRP ≤5 mg/L, THEN: OPSL 1 mg/kg/day for 5 days, THEN: OPSL 0.5 mg/kg/day for 5 days; AND: IVIG 2 g/kg over 24 hours; AND: ASA 30 mg/kg/day until defervescence; AND: Famotidine 0.5 mg/kg/day until PSL discontinued. (N = 121) IVIG 2 g/kg over 24 hours; AND: ASA 30 mg/kg/day until defervescence. Coronary artery dimensions at enrolment and weeks 1, 2, and 4 after enrolment. Rate of retreatment. Duration of fever. CRP at weeks 1 and 2 after enrolment. Aslani (2022)295  (Not included in Green et al) Iran, single-centre. Randomised treatment allocation. Inclusion: -AHA criteria for complete or incomplete KD -Age 6 months to 5 yearsExclusion: -‘Atypical’ KD -MAS-Previous KD -Pre-existing coronary abnormality-Congestive heart failure-Chronic kidney disease-Recent steroid use-Contraindication to steroids(N = 20) IVMP 30 mg/kg/day for 3 days; THEN: OPSL 1 mg/kg/day for 3 days; AND: Aspirin (dose not given). (N = 21) IVIG 2 g/kg; AND: Aspirin (dose not given) Coronary dimensions on day 1 (day of diagnosis), and at 2 and 8 weeks. Duration of fever. AHA criteria, American Heart Association criteria (oro-mucosal inflammation, bilateral non-exudative conjunctival injection, polymorphous rash, extremity changes, and cervical lymphadenopathy); ASA, aspirin; CRP, C-reactive protein; DPA, dipyridamole; IVIG, intravenous immunoglobulin; IVMP, intravenous methylprednisolone; IVPSL, intravenous prednisolone; Japanese criteria (fever >38.0°C, bilateral non-exudative conjunctival injection; oro-pharyngeal inflammation, extremity changes, rash, and cervical lymphadenopathy); LAD, left anterior descending coronary artery; MAS, macrophage activation syndrome; OPSL, oral prednisolone; RCA, right coronary artery. Management of KD75Table 2.5 continued... Corticosteroids Alone as Primary Therapy for Acute Kawasaki Disease While Kijima et al had demonstrated promising results in their small trial assessing standard of care* with or without HDSC corticosteroids,9 no subsequent trials had evaluated corticosteroids alone in acute KD. That changed in 2022 when, less than one month after the publication of the meta-analysis by Green et al, Aslani et al published the results of a single-centre, single-blinded, randomised control trial of corticosteroids alone for acute KD (study details are included in Table 2.4.2 for comparison).295 The study, though small, is of great interest as it represents the only head-to-head trial comparing IVIG and corticosteroid ever published.† Forty-one children with acute KD were randomly allocated to receive standard of care (IVIG 2 g/kg plus aspirin) or HDSC corticosteroid (intravenous methylprednisolone 30 mg/kg/day for 3 days, then oral prednisolone 1 mg/kg/day for 3 days) as monotherapy. The rationale for the study was to establish an evidence base for the management of KD in resource-poor settings where IVIG may not be available.110 The authors reported lower rates of coronary artery abnormalities in the steroid group compared with the IVIG group at 2 weeks (20% versus 50%‡) but not at 8 weeks (5% in each group). The authors present a breakdown of coronary outcomes by lesion size at each of the timepoints, reproduced in Table 2.4.3. Table 2.6: Methylprednisolone versus Intravenous Immunoglobulin as Primary Therapy for Acute Kawasaki Disease: Coronary Outcomes at Three Time Points (taken from Aslani, et al) Vessel Abnormality IVIG Corticosteroid P N = 20 N = 20 At Diagnosis Ectasia 14 (70%) 9 (45%) 0.053 Small aneurysm 0 (0%) 0 (0%) Moderate aneurysm 0 (0%) 0 (0%) Giant aneurysm 1 (5%) 0 (0%) Total 15 (75%) 9 (45%) 2 Weeks Ectasia 9 (45%) 3 (15%) 0.047 Small aneurysm 0 (0%) 0 (0%) Moderate aneurysm 1 (5%) 1 (5%) Giant aneurysm 0 (0%) 0 (0%) Total 10 (50%) 4 (20%) 8 Weeks Ectasia 0 (0%) 0 (0%) 0.7 Small aneurysm 1 (5%) 1 (5%) Moderate aneurysm 0 (0%) 0 (0%) Giant aneurysm 0 (0%) 0 (0%) Total 1 (5%) 1 (5%) One child in the IVIG group was lost to follow-up. IVIG, intravenous immunoglobulin. * Standard of care at that time being aspirin plus heparin.† At least in the available English-language literature.‡ The significance of this finding was not presented in the paper, but is readilycalculated: χ2 = 3.956, P = 0.047.Chapter 276  The study was underpowered to demonstrate the non-inferiority of HDSC corticosteroids as compared with IVIG,* as such these data cannot be used to guide treatment decisions. They do, however, deserve to be replicated in larger trials. Due to the clear efficacy of IVIG in acute KD, comparative trials of other potential treatments have been deemed unethical.358 When an effective (if not curative) treatment is available, its denial in order to test an unproven alternative is ethically problematic; but to imagine this a categorical imperative is to ignore the potential harms if effective alternatives are not pursued. As discussed in Section 2: Intravenous Immunoglobulin, IVIG is expensive and will remain so.110 In a study assessing cost implications of treating Guillain Barre Syndrome with plasma exchange compared with IVIG in India, Maheshwari et al costed IVIG at ₹1530/gram in 2018.359 The cost of IVIG for KD in a small child is therefore prohibitive: A 12 kg child requires 24 grams of IVIG, at a cost of ₹36 720†—close to the median household family income.‡ In India these are often out-of-pocket costs borne by a child’s family.359  There are other reasons to pursue viable alternatives to IVIG as primary therapy for KD. In a 2002 recommended guideline for KD in the United Kingdom, Brogan et al noted their use of corticosteroids for patients who refuse IVIG on religious grounds (i.e., Jehovah’s Witnesses).34 As medical researchers we should seek to generate an evidence base that supports resilient and equitable access to effective therapies.  * Sample-size calculations for non-inferiority trials with binary outcomes are complex, however the following (taken from sealedenvelope.com356) will suffice: ! = #(%, ') × *!(100 − *!) + *"(100 − *")(*! − *" − Δ)#	Where *! and *" are the estimated rates of events in the standard and experimental treatment group respectively, % is the significance level, ' is the power, Δ is the non-inferiority limit, and #(%, ') = [2$%(%) + 2$%(')]# Where 2$% is the cumulative distribution function of a standardised normal deviate. If we take as our endpoint the proportion of patients with at least one coronary artery z-max ≥5 at 12 weeks follow-up, then we can refer to Ogata et al14 to provide our estimate for the event rate among those given IVIG (roughly 6%). Assuming 90% power, 5% significance, and a non-inferiority limit of 10%, the sample-size required is 97 in each group. Given the extensive evidence on coronary outcomes with IVIG alone, the application of Bayesian methods357 and asymmetric trial design may reduce this number. † A course of intravenous methylprednisolone (1 gram for 3 doses at 30 mg/kg) can be up to three orders of magnitude cheaper. ‡ Median annual household income in India was estimated at ₹13 860 in 2011–12,360 and ₹44 901 in 2018.361 Management of KD77Adverse Effects and Interactions While the short-term use of corticosteroids in children is generally well tolerated,362,363 the protocols frequently used for acute KD are associated with a number of potential adverse outcomes.144,364 Avascular Necrosis Avascular necrosis (AVN)* is a condition whereby abnormal bone vasculature results in infarction of bone and bone marrow with subsequent bony destruction.365 While the association between exogenous corticosteroids and AVN has been recognised for over 60 years366 the mechanism of this effect is incompletely understood.367–369 The epiphyses and metaphyses of growing long bones are at highest risk due to high metabolic activity and vulnerable vascular supply.367 The femoral head is by far the most common site for AVN, however the condition can affect all long and short bones—including the humeral,366 radial,370 and metacarpal heads,371 the talus,372 and the vertebrae.373 Corticosteroids are thought to cause AVN via transient hyperlipidaemia, with circulating fat globules occluding the fine vessels of the epiphysis.367–369 While higher rates of AVN are associated with higher daily doses of corticosteroid,374 little else is known regarding predisposing factors for children with KD. Psychiatric Effects The use of corticosteroids has been associated with a range of adverse psychiatric effects in children, including disordered sleep, inattention, mood swings (with irritability and aggression commonly seen) and (rarely375) psychosis.376,377 While there is a dose-response relationship, adverse effects are well documented at prednisolone doses in the 1–2 mg/kg/day range, and can occur at any time during the treatment course (but are commonly seen in the first few days).375,378 These effects (including psychosis) typically resolve after discontinuation of corticosteroids.375,376 Other Adverse Effects Bradycardia is a well-recognised effect of short courses of corticosteroids and has been observed in children with KD, however it rarely requires intervention.379,380 Adrenal suppression also occurs, and can in rare cases precipitate an adrenal crisis.381 Finally, while long-term treatment with corticosteroids is associated with an increased risk of opportunistic infections, this does not appear to be a significant concern with short courses, as used in KD.362 Clinical Practice Guidelines Recommendations for the use of corticosteroids in KD from Clinical Practice Guidelines (CPGs) are shown in Table 2.4.4. There are significant differences * Other names for this condition include aseptic necrosis and osteochondritisdesiccans.Chapter 278in how CPGs discuss the use of corticosteroids, with their role as primary adjunctive therapy or as secondary therapy considered in most documents. As discussed, two broad principles of corticosteroid use have been studied in KD trials—HDSC and LDLC. Most CPDs discussed protocols that fit into one of those categories, however a number of CPDs recommended protocols that combine high-dose pulsed intravenous corticosteroids followed by a weaning oral course over several weeks.20,26 A number of CPDs addressed the difficulty in generalising from Japanese trials due to their frequent use of severity scores, which have poor performance outside of Japan. Common indicators of severe disease that are highlighted include young age (<12 months), signs of shock, the presence of coronary abnormalities at diagnosis, and rare consequences of systemic inflammation such as macrophage activation syndrome (MAS) / haemophagocytic lymphohistiocytosis (HLH). These would seem to describe a different cohort than is identified by the Japanese risk scores (such as the Kobayashi score). Management of KD79Table 2.7: Clinical Practice Guidelines for the Use of Corticosteroids in Kawasaki Disease Guideline Primary Adjunctive Therapy Treatment of IVIG Resistance Comment NZ (2022)25 No recommendation In cases of continuing treatment failure following a second course of IVIG, either HDSC or LDLC corticosteroids can be used. Recommended only after a second course of IVIG. Also mentioned: IFX 5 mg/kg as a single dose AU-RCH (2021)22 For “high risk” patients: (OPSL 2mg/kg (max 60mg) daily for a minimum of 5 days and until CRP normalises. No recommendation The document states that primary adjunctive corticosteroids are: “More likely to be beneficial at the commencement of treatment for KD in high risk patients, rather than after a failure of initial IVIg treatment.” “High risk” is defined as: -Signs of shock.-Patients < 12 months of age.-Asian ethnicity-ALT > 100 IU/L Albumin < 30 g/L -Any patient with evidence of cardiac involvement on echocardiography at time ofpresentation.AU-PCH (2021)23 No recommendation No recommendation ACR (2021)18 No recommendation Second course of IVIG is preferred, however either HDSC or LDLC corticosteroids are acceptable alternatives. ISP (2021)26 For “high risk” patients: Single dose of IVMP 30 mg/kg IVMP 30 mg/kg/day for 3 days; THEN: OPSL 2 mg/kg/day, gradually tapered. “High risk” is defined as: -Age <12 months-CRP >200 mg/L -Severe anaemia at disease onset -Albumin <2.5 g/dL-Liver disease-Overt coronary artery aneurysms -Macrophage activation syndrome-Septic shockChapter 280Continued... Guideline Primary Adjunctive Therapy Treatment of IVIG Resistance Comment JSPCCS (2020)27 For “high risk” patients: Preferred protocol (covered by insurance in Japan) is: LDLC as per RAISE protocol (see Table 2.4.2) Alternatively (not covered by insurance): HDSC with IVMP. LDLC as per RAISE protocol (see Table 2.4.2). “High risk” is defined as a Kobayashi score of ≥5. IAP (2020)28 OPSL 2 mg/kg/day gradually tapered over 15 days after normalization of CRP levels (specific indication note given). Discussed, but no recommendation. DGPK (2020)29 For “high risk” patients: LDLC corticosteroid. LDLC corticosteroid with second dose IVIG HDSC given as an option in subsequent treatment failure. “High risk” is defined as: -Age <1 year-Coronary abnormality (Z-score >2)-Severed disease (MAS, shock).SHARE (2019)20 For “high risk” patients: Regimen 1: IVMP 0.8 mg/kg BD for 5–7 days or until CRP normalises; then OPSL 2 mg/kg/day and wean off over next 2–3 weeks. Regimen 2: IVMP 10–30 mg/kg (max 1g/day) daily for 3 days, then OPSL 2 mg/kg per day until day 7 or CRP normalises; then wean over next 2–3 weeks. Regimen 1: IVMP 0.8 mg/kg BD for 5–7 days or until CRP normalises; then OPSL 2 mg/kg/day and wean off over next 2–3 weeks. Regimen 2: IVMP 10–30 mg/kg (max 1g/day) daily for 3 days, then OPSL 2 mg/kg per day until day 7 or CRP normalises; then wean over next 2–3 weeks. “High risk” is defined as: -Kobayashi score ≥5-Features of HLH -Features of shock-Age <1 year-Coronary and/or peripheral aneurysms.AEP (2018)30 No recommendation. Discussed, but no recommendation. Second dose of IVIG is preferred. SW (2018)31 In “high risk” patients: LDLC corticosteroids, however this regimen can begin with high-dose IVMP in cases of severe inflammation. Discussed, but no recommendation. AU-TG (2017)24 No recommendation. No recommendation. AHA (2017)21 For “high risk” patients: LDLC corticosteroids may be considered. As an alternative to a second dose of IVIG, or following failure of a second dose of IVIG, high-dose IVMP with or without a weaning course of OPSL can be considered. “High risk” not clearly defined. ASP/ASC (2016)  No recommendation. In cases of continuing treatment failure following a second course of IVIG, HDSC corticosteroids can be considered. Management of KD81Continued... Table 2.7 continued... Guideline Primary Adjunctive Therapy Treatment of IVIG Resistance Comment DM (2015)33 No recommendation. In cases of continuing treatment failure following a second course of IVIG, high-dose IVMP followed by a weaning course of OPSL can be considered. UK (2002)34 No recommendation. As an alternative to a second dose of IVIG, either HDSC or LDLC corticosteroids can be used. CRP, C-reactive protein; HDSC, high-dose, short course (corticosteroids); HLH, haemophagocytic lymphohistiocytosis; IFX, infliximab; IVIG, intravenous immunoglobulin; IVMP, intravenous methylprednisolone; LDLC, low-dose, long course (corticosteroids); MAS, macrophage activation syndrome; OPSL, oral prednisolone.Chapter 282Table 2.7 continued... Conclusions While corticosteroids were once contraindicated in KD, it now seems that their use is generally safe and may indeed be beneficial in selected cases. There is some evidence that corticosteroids alone might be effective as primary therapy for KD, however few studies have been conducted.9,295 Issues with availability and acceptability of IVIG mean that this possibility should be pursued. Most trials, however, have focused on corticosteroids as primary adjunctive therapy. Meta-analyses have demonstrated improved coronary outcomes in favour of primary adjunctive corticosteroids, but also highlight significant heterogeneity in patient selection, treatment protocols, and outcome measures. These issues severely limit the ability to pool the results of studies, making research must less cost-effective. It has been suggested that KD research should seek to emulate paediatric oncology research, in which almost all children are enrolled into research and international collaboration is the norm.144,382 Without broad consensus around key points of KD trial design this will not be possible. Collaborative fora for KD research, established more than three decades ago,130 should focus on harmonising key definitions to enhance future clinical research. Management of KD83  Chapter 2: The Management of KD Part 5: Biologic Agents Background The term ‘biologics’, though imprecisely defined, is typically applied to a large and diverse group of therapeutic molecules that are designed to interact with biological processes in a highly specific manner, and which require advanced biological (rather than purely chemical) processes for their manufacture.383,384 Almost all of the molecules included in this review all act by modulating ligand-receptor binding (by binding to the ligand or receptor), with some able to induce cell lysis in specific circumstances. The aim of this review is to identify biologic agents relevant to KD and briefly summarise the rationale for their use and (where possible) evidence for their efficacy. While much of the literature on the inflammatory milieu of KD is inferred from a mouse model of coronary inflammation,* this review will aim to present what is known from studies of KD in humans. TNF-α Blockade: Infliximab and Etanercept Tumour necrosis factor-α (TNF-α) is a proinflammatory cytokine that plays a central role in the pathogenesis of a number of autoimmune and inflammatory conditions, including KD. TNF-α is produced by a range of cell types, notably macrophages and monocytes, in response to a range of stimuli†. It is expressed as a membrane-bound protein (which is biologically active with juxtacrine signalling activity389) and is cleaved by TNF-α-converting enzyme (TACE) to liberate the soluble form of TNF-α.389 The effects of TNF-α in the target cells (involving the up-regulation of pro-inflammatory cytokines and chemokines via the up-regulation of the NF-κB transcription factor) is mediated by two TNF-α receptors: TNFR1 and TNFR2.389,390 TNFR1 is constitutively expressed in all nucleated cells, while the expression of TNFR2 is inducible in certain cell types. Both TNFR1 and TNFR2 can be cleaved by matrix metalloproteinases to liberate a soluble fragment that can bind TNF-α, acting as a negative control mechanism.389  * Certain strains of inbred mice develop coronary arteritis following the intraperitoneal injection of the purified cell-wall extract of group B Lactobacillus casei (LCWE).385 This has been proposed as a model of KD, and has informed much of our understanding of the immunopathology of coronary arteritis.386 Some findings regarding the proximate mechanisms of aneurysm formation appear to correlate well with findings from human KD research—notably the importance of matrix metalloproteinase 9 (MMP9) in the destruction of vascular collagen.387 Yet LCWE-induced arteritis is not KD (LCWE having no proposed role in the aetiopathogenesis of the latter), and the validity of the model with regards to upstream mechanisms is far from clear. † The canonical pathway—elucidated by researchers at the Sloan-Kettering Institute—involves TNF-α production by macrophages in response to bacterial lipopolysaccharide (endotoxin).388 Chapter 284  It is well established that serum TNF-α is increased in KD,391* and while early work suggested that those with coronary aneurysms had higher levels of the cytokine subsequent research has yielded conflicting results.395,396 A number of biologic agents have been produced that block the action of TNF-α389†; of these only infliximab and etanercept have been used in KD.397 Infliximab Infliximab (Remicade®) is a mouse-human chimeric monoclonal antibody‡ against TNF-α.398 It binds TNF-α in its membrane bound, soluble, and receptor-bound forms, and is thought to act via the sequestration of circulating TNF-α and the removal of TNF-α expressing cells (via a range of cytotoxic pathways).398 It was first approved by the US Food and Drug Administration (FDA) for the treatment of Crohn’s disease in 1998, and for rheumatoid arthritis the following year.399 It is now approved for use in a wide range of inflammatory conditions, including ulcerative colitis, plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis. The first use of infliximab in KD was reported by Weiss et al in 2004.400 They described a 3-year-old boy who, despite multiple infusions of IVIG and repeated treatment with pulse corticosteroids, had ongoing systemic inflammation and developed significant aneurysms of multiple coronary arteries. A single dose of infliximab (using a protocol recently approved for rheumatoid arthritis) resulted in prompt defervescence and normalisation of inflammatory markers. A retrospective review the following year identified 17 patients in whom infliximab had been used for refractory KD401; response to therapy was seen in 14§ patients. Results of the first prospective trial** of infliximab in KD were published in 2008.404 Twenty-four children with IVIG-resistant KD†† and coronary artery dilatation were randomly allocated to receive either a second dose of IVIG or infliximab (5 mg/kg); those who failed  * Although given the centrality of TNF-α to the inflammatory response, this is hardly surprising.388,392–394 † Currently approved agents for TNF-α blockade include etanercept, infliximab, adalimumab, certolizumab pegol, and golimumab. Thalidomide and its derivatives also have anti-TNF-α effects. ‡ Infliximab comprises mouse-derived anti-TNF-α variable regions fused to human IgG1 constant region.398 § Response could not be assessed in one patient who underwent plasmapheresis 12 hours after the infliximab infusion. ** The study was a multi-centre, randomised, open-label trial conducted at 6 centres in the United States. The primary outcomes were safety, tolerability, and pharmacokinetics of infliximab, rather than response to treatment or coronary outcomes. It was fundamental to the establishment of the Kawasaki Disease Comparative Effectiveness (KIDCARE) trial,402,403 included in the meta-analysis discussed in the following paragraphs. †† IVIG resistance was defined as persistent or recrudescent fever between 48 hours and 7 days after the end of the first IVIG infusion. Management of KD85  Chapter 2: The Management of KD to respond were re-allocated to the alternate therapy*. While the study was underpowered to evaluate non-inferiority†, more children in the infliximab group (11/12) responded to therapy than did children in the IVIG group (8/12); coronary outcomes were similar between groups. Subsequent trials have been assessed in a number of systematic reviews and meta-analyses,405–410 of which the most recent was by Kabbaha et al in 2022.405 Prospective trials of infliximab versus a second dose of IVIG for children with IVIG resistance were included, with four studies meeting the inclusion criteria—two from the USA, one from Japan, and one from South Korea.54,403,404,411‡ No study reported a statistically significant difference between groups in terms of coronary outcomes, and the pooled risk ratio (RR 1.20; 95% CI 0.54, 2.63§) also indicated no difference between groups.** Rates of secondary treatment failure were significantly lower among those given infliximab versus IVIG (RR 0.40; 95% CI 0.25, 0.64), and there was a trend in favour of infliximab in terms of adverse events (RR 0.63; 95% CI 0.18, 1.12). A more inclusive meta-analysis that included nine trials generated similar results.406 At least two further prospective trials are currently underway.†† A number of studies have considered infliximab for primary adjunctive therapy in KD.312,403,412 Tremoulet et al randomised 196 children with acute KD to receive infliximab or placebo prior to primary therapy with IVIG, with the primary outcome being rate of IVIG resistance.412 There was no difference between groups in the rates of IVIG resistance, length of hospital admission, or coronary outcomes; those who received infliximab had fewer IVIG-relative infusion reactions shorter duration of fever. Dionne et al randomised 121 children with acute KD and coronary abnormalities‡‡ at diagnosis to receive IVIG with adjunctive corticosteroids, IVIG with infliximab, or IVIG alone.312 Adjunctive therapy with either infliximab or corticosteroids was associated with lower rates of aneurysm progression§§ compared with IVIG alone.  * I.e., those with ongoing inflammation after treatment in the infliximab group were given an additional dose of IVIG; those in the IVIG group were given infliximab. † The sample size was calculated based on the primary outcomes (safety, tolerability, and pharmacokinetics of infliximab). ‡ The South Korean study411 was considered to have a high risk of bias, and in sensitivity analysis was excluded from analysis. § Risk ratio of less than 1 favours infliximab. ** On subgroup analysis there was a trend in favour of IVIG (RR 1.92, 95% CI 0.70 to 5.27), whereas there was a trend in favour of infliximab in the Japanese and Korean studies (RR 0.48, 95% CI 0.11 to 2.06). †† NCT02298062 and ChiCTR1900027954. ‡‡ Defined as a z-score of ≥2.5 to <10 in the right main coronary artery or left anterior descending artery. §§ This was statistically significant, but only for the proportion of children who had an increase in the size of their most dilated vessel by at least 1 z-score. Chapter 286  Etanercept Etanercept (Enbrel®) is a fusion protein that combines the extracellular domain of the soluble receptor TNFR2 with an IgG1 Fc region.398 The main mechanism of etanercept is to bind soluble (rather than membrane- or receptor-bound) TNF-α, and it does not result in meaningful cell lysis. It is used for similar dermatologic and musculoskeletal indications as infliximab, but is ineffective in inflammatory bowel disease.398 Direct comparative trials comparing infliximab with etanercept for most conditions are mission, and comparisons are further compounded as infliximab is almost always combined with methotrexate for the treatment of rheumatoid arthritis, whereas etanercept can be used as monotherapy.413 While infliximab is administered intravenously,414 etanercept is given subcutaneously.415 The safety of etanercept as adjunctive therapy in KD was demonstrated by Choueiter et al in a small, prospective, open-label trial that was designed to assess safety and pharmacokinetics.416 This lead to the establishment of the Etanercept as Adjunctive Treatment for Acute Kawasaki Disease (EATAK) trial, which published its results in 2019.417 Children with acute KD (205 in total) were randomised to receive etanercept (0.8 mg/kg by subcutaneous injection) or placebo immediately after primary therapy with IVIG, then weekly for two further doses. The primary outcome was IVIG resistance, with coronary artery z-scores assessed as secondary outcomes. The study reported lower rates of IVIG resistance in the etanercept group, however lower than expected rates of resistance overall resulted in the study being underpowered to demonstrate a difference.418 There were no meaningful differences in coronary outcomes between groups. Safety of TNF-α Blockade Much of the safety data for infliximab and etanercept comes from studies in patients on long-term therapy for chronic inflammatory conditions.419 Opportunistic infections are a known risk of TNF-α blockade; early trials of infliximab in rheumatoid arthritis observed higher rates of serious infections* in the infliximab groups (at all doses) than a methotrexate alone group.420 Indeed, infliximab appears to carry a higher risk for opportunistic infections than does etanercept.421† The relevance of this risk for children with KD (who would typically receive only a single dose of infliximab) is unclear—while few trials reported time-to-infection outcomes, there is evidence that infection risk is associated with cumulative drug exposure.423 Indeed, in their meta-analysis Kabbaha et al found no evidence of higher rates of infection among  * Pneumonia was the main serious infection, with four patients having reactivation of laten tuberculosis. † Although the risk of infection is unclear: patients treated with infliximab for inflammatory bowel disease did not have significantly higher rates of opportunistic infections.422 Management of KD87  Chapter 2: The Management of KD those treated with infliximab versus a second course of IVIG (however the included trials only involved 199 patients).405 Postmarketing surveillance in Japan identified six cases of infections among 291 children treated for KD with infliximab, of which only three were classified as serious (identified as influenza, bronchitis, and orbital cellulitis).424 There are reports of an increased risk of cancer with TNF-α blockade, however the risk in the paediatric population—and especially to children with KD—is unclear. In a meta-analysis of randomised controlled trials in adults, Askling et al identified 130 cases of cancer among 15,418 patients treated with TNF-α inhibitors (0.84%) compared with 48 cases among 7,486 controls (0.64%)425; they concluded that the risk of cancer associated with TNF-α blockade remained uncertain. Given the background risk of cancer in adults compared with children, and the relative contribution of acquired versus inborne genetic risk factors, it is reasonable to expect that the absolute risk of cancer among children receiving TNF-α inhibitors should be very low.426 The matter is however complicated by the increased risk of cancer conferred by the conditions for which TNF-α inhibitors are most commonly prescribed to children (juvenile idiopathic arthritis and inflammatory bowel disease).426 Taking that into consideration, there is currently little evidence to suggest that children are exposed to additional risk by TNF-α blockade.427,428 IL-1 Blockade: Anakinra and Canakinumab The interleukin 1 (IL-1) family* is an evolutionarily ancient group of cytokines that play key roles in orchestrating the early innate immune response to pathogen-associated molecules and tissue damage.429,430 IL-1 comprises two cytokines—IL-1α and IL-1β; though these cytokines act on the same receptor† and have identical effects they differ in tissue distribution, post-transcriptional control, and means of expression.429,430 IL-1α is expressed by diverse cell types (particularly epithelial cells) and is predominantly membrane-bound with juxtacrine functions. IL-1β is predominantly expressed by monocytes and macrophages, and is secreted as a soluble molecule capable of systemic effects.429 The production of IL-1 is tightly controlled via numerous negative feedback loops; these include the IL-1R antagonist IL-1Ra‡ and the complex control of post-transcriptional processing of pro-IL-1β by caspase-1§.431 IL-1β  * Members of the family include IL-1α, IL-1β, IL-1Ra, IL-18, and IL-33, among many others.429 † A heterodimer comprised of IL-1 receptor 1 (IL-1R1) and IL-1 receptor associated protein (IL-1RAP). ‡ The expression of IL-1Ra is upregulated in response to the same stimuli that stimulate IL-1β.429 IL-1Ra binds tightly to the IL-1R without inducing inflammatory effects. § IL-1β is transcribed as an inactive precursor (pro-IL-1β), which must be activated by the enzyme caspase-1. Caspase-1, in turn, is tightly controlled by a complex system of intracellular proteins called the inflammasome(s).431,432 Inherited perturbations of this control mechanism which are responsible for a group of Chapter 288production by monocytes and macrophages is stimulated by molecular signals* associated with pathogens (notably bacterial lipopolysaccharide), as well as endogenous signals of tissue damage (such as adenosine triphosphate and uric acid crystals).429 IL-1 exerts potent pro-inflammatory effects on diverse cell types. Of relevance to KD, IL-1 directs neutrophilic response to tissue damage, with enhanced release of immature cells from the marrow and local recruitment and tissue invasion via cytokine and chemokine release and upregulated expression of adhesins.432,433 IL-1 also supports T cell response by promoting the proliferation and survival of both effector and helper T cells, while blunting the control of regulatory T cells.429,434–436 Early attempts to apply IL-1 blockade to KD were informed by observations from animal models and clinical research. Peripheral blood mononuclear cells from children with acute KD secrete high levels of IL-1 (particularly so from those with coronary aneurysms).437–439 Further, IL-1β was found to be necessary for the development of coronary arteritis in LCWE-treated mice.440 Clinicians were also encouraged by the safety profile of IL-1 blockers (particularly anakinra).441 Anakinra Anakinra (Kineret®), a recombinant form of IL-1Ra, was introduced in 1993 and originally used for the treatment of rheumatoid arthritis.442 It has since been approved for a wide range of autoimmune and autoinflammatory conditions, including systemic juvenile idiopathic arthritis (SJIA) and adult-onset Still’s disease; cryopyrin associated periodic syndrome (CAPS), familial Mediterranean fever (FMF), Muckle-Wells syndrome (MWS), TNF-receptor-associated periodic syndrome (TRAPS), and other autoinflammatory syndromes—including gout.442 The first reported use of anakinra in KD was published by Shafferman et al in 2014.443 They described the case of an 11-week-old girl with apparent KD complicated by macrophage activation syndrome (MAS)† who responded to the use of anakinra. A subsequent literature review identified 11 case reports of the use of anakinra in KD.446 In all cases the use of anakinra was followed inherited autoinflammatory conditions including Muckle-Wells syndrome, familial cold autoinflammatory syndrome (FCAS), neonatal onset multisystem inflammatory disease (NOMID), and Familial Mediterranean Fever (FMF). * Via highly conserved sensing mechanisms such as Toll-like receptors.429† Macrophage activation syndrome (MAS) refers to secondary haemophagocyticlymphohistiocytosis occurring in the context of rheumatological conditions—mostprominently systemic juvenile idiopathic arthritis (SJIA) and adult-onset Still’sdisease, but also systemic lupus erythematosus and KD, among others.444 It ischaracterised by overactivation of T lymphocytes (particularly CD8+T cells) andmacrophages, with consequent systemic hyperinflammation; the condition carries ahigh mortality.444,445 The role of IL-1β in MAS has been hypothesised, in part, due toits importance in SJIA.444Management of KD89  Chapter 2: The Management of KD by defervescence and striking reductions in CRP, and in most cases by a reduction in coronary artery z-scores. Two phase II clinical trials of anakinra in KD have been published as of early 2023.55,447 The KAWAKINRA trial was a multi-centre, single-arm open-label, phase IIa dose escalation trial of anakinra in children with IVIG-resistant KD.55 Enrolled patients received escalating daily doses of subcutaneous anakinra; if defervescence occurred then that dose was continued to two weeks. The study was small (16 patients included in the intention-to-treat group) and had a high rate of post-enrolment exclusion and protocol deviation, with only 8 patients completing the study per-protocol. Administration of anakinra was followed by resolution of fever in most of the patients in both the intention-to-treat group (12/16, 75%) and the per-protocol group (7/8, 87.5%). Safety and tolerability were excellent, with only one adverse event (swelling and pruritis at the injection site) attributed to the anakinra. The ANAKID trial was a multi-centre*, single-arm open-label, phase I/IIa dose escalation trial of anakinra as primary adjunctive therapy for children with KD and coronary artery abnormalities† at diagnosis.447 All participants received subcutaneous anakinra‡ for 2 weeks, with those found to have persistent coronary dilatation§ at that timepoint continuing on the study drug for an additional 4 weeks. Importantly, most of the participants had also received adjunctive infliximab prior to enrolment.** Anakinra was deemed to be safe and tolerable, with no serious adverse events attributable to the study drug. Neither of these trials were designed to assess efficacy, however both provided further evidence in support of anakinra’s safety in this patient population and contributed important pharmacokinetic data†† for future Phase III trials. Canakinumab Canakinumab (Ilaris®)is a human IgG monoclonal antibody against IL-1β. It has similar indications to anakinra, but has the theoretical benefit of being specific for IL-1β; it also has a much longer half-life requiring dosing only  * There were two recruitment sites (Rady Children’s Hospital San Diego and Boston Children’s Hospital), with 20/22 patients recruited at the former. † Coronary abnormalities were defined as a z-score ≥2.5 in the left anterior descending coronary artery of right main coronary artery. ‡ The first two doses were given IV as park of the pharmacokinetics study. § Z-score ≥2.0 in the left anterior descending coronary artery of right main coronary artery. ** The use of infliximab (5 mg/kg) prior to the IVIG infusion is standard of care at Randy Children’s Hospital San Diego—all 20 patients recruited at that site received infliximab. †† The pharmacokinetic findings of these studies are outside the scope of this review. Chapter 290  every 2–3 months.448 It has been intensively studied for a possible role in the secondary prevention of myocardial infarction, with the CANTOS trial demonstrating a small but significant reduction in adverse coronary outcomes among those with a prior myocardial infarction and evidence residual low-level inflammation.449 While no reports of the use of canakinumab in KD have been published, a phase II trial of its use as both primary adjunctive therapy and secondary therapy is currently underway.450 Other Novel Agents Tocilizumab There has been recent interest in the use of tocilizumab for the treatment of systemic inflammatory conditions associated with severe COVID-19.451,452 Tocilizumab (Actemra®) is a human monoclonal IgG antibody against the receptor for IL-6.453 IL-6 is a pleiotropic proinflammatory cytokine capable of inducing diverse inflammatory changes in multiple organ systems.454* IL-6 is thought to play an important role in a number of autoimmune conditions, however its role in some systemic hyperinflammatory states† has suggested its possible usefulness in KD. Tocilizumab was investigated as a potential agent for use in IVIG-resistant KD in a small pilot study in Japan.455 The study was stopped after recruitment of only four patients due to safety concerns. While all four patients had rapid defervescence and improvements in inflammatory markers shortly after receiving tocilizumab, two patients (neither of whom had coronary abnormalities at the time of receiving tocilizumab) had progressive development of giant coronary aneurysms. No further studies have assessed tocilizumab in KD, and its use in multisystem inflammatory syndrome in children (MIS-C, a COVID-19-associated hyperinflammatory syndrome) is controversial.456 Abciximab Abciximab (ReoPro®) is a monoclonal antibody fragment against the platelet glycoprotein IIb/IIIa receptor used to prevent acute thrombotic complications in acute coronary syndrome (and especially during percutaneous coronary intervention).457 The glycoprotein IIb/IIIa receptor is extremely abundant on the surface of platelets (~80,000 copies per platelet).458 The receptor binds  * These include: Upregulated hepatic synthesis of proinflammatory proteins (mostly α- and β-globulins, including CRP, antitrypsin, serum amyloid protein A, and hepcidin; also fibrinogen and complement C3); increased vascular permeability; promotion of a hypercoagulable state through various mechanisms, including increased expression of tissue factor; and impaired cardiomyocyte contractility. † The most striking of these is cytokine release syndrome (CRS), a severe systemic hyperinflammatory state associated with novel T-cell engaged therapies used for some haematological malignancies. Tocilizumab has shown highly promising results in small case series of CRS.454 Management of KD91  Chapter 2: The Management of KD fibrinogen and von Willebrand factor with low affinity, however platelet activation causes a conformational change resulting in high-affinity binding that results in platelet aggregation and the formation of a stable platelet plug.458 Etheridge et al reported a case of rapid regression of large coronary aneurysms in a 4-month-old girl with KD who received abciximab following percutaneous angiography for thromboprophylaxis.459 They hypothesized that abciximab might promote vascular remodelling in patients with coronary aneurysms. Two small retrospective cohort studies have provided evidence in support of this hypothesis.460,461 In both studies children with significant coronary aneurysms who received abciximab had greater reduction in coronary artery z-scores at follow-up than children who did not receive abciximab. Due to their small numbers and retrospective nature both are at risk for selection bias. There is a need for prospective controlled trials to validate these findings. Conclusions There is significant interest in advancing the therapeutic armamentarium available for the treatment of KD—both in response to the high cost of IVIG and the significant proportion of children for whom it is ineffective. Biologic agents may offer a solution. While the development of these synthetic molecules incurs high up-front costs, scalable manufacturing processes mean that the marginal cost of production diminishes with expanded production.462 Further, the rapid development of biosimilar molecules* can enable market competition to influence price before the reference molecule comes off patent.463 While some novel therapies have demonstrated promising results, the case of tocilizumab is a cautionary one. Despite over fifty years of research, the immunopathophysiology of KD is poorly understood.464–467 The anti-inflammatory agents described in this review act on major cytokines central to the inflammatory process to produce non-specific immunosuppression. Greater understanding of the mechanisms of immune dysfunction and aneurysm formation seen in KD might inform more targeted therapies. An exemplar biopharmaceutical in this regard is vedolizumab. Vedolizumab (Entyvio®) is a humanised monoclonal antibody against the α4β7 integrin used for the treatment of inflammatory bowel disease.468 Integrins are heterodimeric cell surface receptors that mediate cell-to-cell adhesion. Integrins composed of different α and β subunit combinations have varied expression in different cell types with diverse functions. Integrin α4β7 is  * “Biosimilars” replicate the in vivo activity of a reference biologic agent to which they are similar but not identical. By contrast, generic drugs are exact copies of a reference drug that can be marketed once the original patent has expired. Biosimilars that replicate both infliximab and etanercept are currently available.463 Chapter 292  expressed on the surface of leukocytes and binds with high specificity with its ligand mucosal addressin cell adhesion molecule-1 (MAdCAM-1).* MAdCAM-1, in turn, is expressed by intestinal endothelial cells. This receptor-ligand binding event facilitates the rolling adhesion and firm adhesion necessary for tissue-specific leukocyte migration.469 Vedolizumab prevents leukocyte migration into the intestinal mucosa, thereby selectively suppressing inflammation in the gastrointestinal tract.† It has proven to be both safe and effective in the management of inflammatory bowel disease.470–472 Gene expression profiling has been used to identify potential target molecules for future therapeutic agents in KD. Hoang et al compared gene expression patterns between children with acute KD, children with known bacterial and viral infections, and well controls.464 Their findings provided further evidence of the centrality of IL-1β to KD, and acknowledged the roles of other pathways (including integrins and matrix metalloproteinases) in diverse infectious conditions. Such approaches are exciting, however key underlying principles are worthy of note. The categories on which machine learning algorithms process bioinformatics data are provided a priori. As such, the validity of the results is dependent on the ontological and methodological precision with which the categories are defined and implemented. This highlights again the need for a collaborative effort to produce carefully designed criteria and definitions for KD research.    * Integrin α4β7 also binds to vascular cell adhesion molecule-1 (VCAM-1) and fibronectin. † This specificity is of critical importance to vedolizumab’s safety. Natalizumab, a monoclonal antibody against the α4 subunit, lacks this specificity. It is used in the treatment of multiple sclerosis but is associated with the development of progressive multifocal leukoencephalopathy due to reactivation of latent JC virus.468 Vedolizumab’s specificity for intestinal mucosa obviates this risk. Vedolizumab was specifically designed not only with receptor specificity, but also ligand specificity. The binding of integrin α4β7 to VCAM-1 and fibronectin is not inhibited by vedolizumab. One final innovation is critical to vedolizumab’s safety: the Fc region of the antibody was mutated to reduce its ability to facilitate both complement-dependent and cellular-dependent cytotoxicity.468 Management of KD93Chapter2:The ManagementofKDReferences 1. Kawasaki T. Acute Febrile Muco-Cutaneous Lymph Node Syndrome inYoung Children with Unique Digital Desquamation. Arerugi. 1967;16(3).  2. Melish ME. 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Infliximab: A Review of its Use in Crohn’s Disease and Rheumatoid Arthritis. Drugs. 2005;65(15):2179–208.  415.  Dhillon S, Lyseng-Williamson KA, Scott LJ. Etanercept: A Review of its Use in the Management of Rheumatoid Arthritis. Drugs. 2007;67(8):1211–41.  416.  Choueiter NF, Olson AK, Shen DD, Portman MA. Prospective Open-Label Trial of Etanercept as Adjunctive Therapy for Kawasaki Disease. J Pediatr. 2010 Dec;157(6):960-966.e1.  417.  Portman MA, Dahdah NS, Slee A, Olson AK, Choueiter NF, Soriano BD, et al. Etanercept With IVIg for Acute Kawasaki Disease: A Randomized Controlled Trial. Pediatrics. 2019 Jun;143(6):e20183675.  418.  Burgner DP, Newburger JW. Etanercept as Adjunctive Primary Therapy in Kawasaki Disease. Pediatrics. 2019 Jun 1;143(6):e20190912.  419.  Downey C. Serious infection during etanercept, infliximab and adalimumab therapy for rheumatoid arthritis: A literature review. Int J Rheum Dis. 2016 Jun;19(6):536–50.  420.  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Infliximab Is Not Associated With Increased Risk ofMalignancy or Hemophagocytic Lymphohistiocytosis in PediatricPatients With Inflammatory Bowel Disease. Gastroenterology. 2017Jun;152(8):1901-1914.e3.428. Kok VC, Horng JT, Huang JL, Yeh KW, Gau JJ, Chang CW, et al.Population-based cohort study on the risk of malignancy in East Asianchildren with Juvenile idiopathic arthritis. BMC Cancer. 2014Dec;14(1):634.429. Sims JE, Smith DE. The IL-1 family: regulators of immunity. Nat RevImmunol. 2010 Feb;10(2):89–102.430. Gabay C, Lamacchia C, Palmer G. IL-1 pathways in inflammation andhuman diseases. Nat Rev Rheumatol. 2010 Apr;6(4):232–41.431. Dinarello CA. A clinical perspective of IL-1β as the gatekeeper ofinflammation. Eur J Immunol. 2011 May;41(5):1203–17.432. Dinarello CA. Immunological and Inflammatory Functions of theInterleukin-1 Family. Annu Rev Immunol. 2009 Apr 1;27(1):519–50.433. Dinarello C. Biologic basis for interleukin-1 in disease. Blood. 1996Mar 15;87(6):2095–147.434. O’Sullivan BJ, Thomas HE, Pai S, Santamaria P, Iwakura Y, Steptoe RJ,et al. IL-1β Breaks Tolerance through Expansion of CD25+ Effector TCells. J Immunol.435. Ben-Sasson SZ, Hogg A, Hu-Li J, Wingfield P, Chen X, Crank M, et al.IL-1 enhances expansion, effector function, tissue localization, andmemory response of antigen-specific CD8 T cells. J Exp Med. 2013 Mar11;210(3):491–502.436. Burns JC, Koné-Paut I, Kuijpers T, Shimizu C, Tremoulet A, Arditi M.Review: Found in Translation: International Initiatives PursuingInterleukin-1 Blockade for Treatment of Acute Kawasaki Disease: IL-1Management of KD129  Chapter 2: The Management of KD BLOCKADE FOR TREATMENT OF KD. Arthritis Rheumatol. 2017 Feb;69(2):268–76.  437.  Leung DonaldYM, Kurt-Jones E, Newburger JaneW, Cotran RamziS, Burns JaneC, Pober JordanS. Endothelial Cell Activation and High Interleukin-1 Secretion in the Pathogenesis of Acute Kawasaki Disease. The Lancet. 1989 Dec;334(8675):1298–302.  438.  Leung DY, Geha RS, Newburger JW, Burns JC, Fiers W, Lapierre LA, et al. Two Monokines, Interleukin 1 and Tumor Necrosis Factor, Render Cultured Vascular Endothelial Cells Susceptible to Lysis by Antibodies Circulating During Kawasaki Syndrome. J Exp Med. 1986 Dec 1;164(6):1958–72.  439.  Maury C, Salo E, Pelkonen P. Circulating Interleukin-1β in Patients with Kawasaki Disease. N Engl J Med. 1988 Dec 22;319(25):1670–1.  440.  Lee Y, Schulte DJ, Shimada K, Chen S, Crother TR, Chiba N, et al. Interleukin-1β Is Crucial for the Induction of Coronary Artery Inflammation in a Mouse Model of Kawasaki Disease. Circulation. 2012 Mar 27;125(12):1542–50.  441.  Aeschlimann FA, Yeung RSM. TNF and IL-1 Targeted Treatment in Kawasaki Disease. Curr Treat Options Rheumatol. 2016 Dec;2(4):283–95.  442.  Dinarello CA, Simon A, van der Meer JWM. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov. 2012 Aug;11(8):633–52.  443.  Shafferman A, Birmingham JD, Cron RQ. High dose anakinra for treatment of severe neonatal Kawasaki disease: a case report. Pediatr Rheumatol. 2014 Dec;12(1):26.  444.  Schulert GS, Grom AA. Pathogenesis of Macrophage Activation Syndrome and Potential for Cytokine- Directed Therapies. Annu Rev Med. 2015 Jan 14;66(1):145–59.  445.  Ravelli A, Davì S, Minoia F, Martini A, Cron RQ. Macrophage Activation Syndrome. Hematol Oncol Clin North Am. 2015 Oct;29(5):927–41.  446.  Kone-Paut I, Cimaz R, Herberg J, Bates O, Carbasse A, Saulnier JP, et al. The use of interleukin 1 receptor antagonist (anakinra) in Kawasaki disease: A retrospective cases series. Autoimmun Rev. 2018 Aug;17(8):768–74.  447.  Yang J, Jain S, Capparelli EV, Best BM, Son MB, Baker A, et al. Anakinra Treatment in Patients with Acute Kawasaki Disease with Coronary Artery Aneurysms: A Phase I/IIa Trial. J Pediatr. 2022 Apr;243:173-180.e8.  448.  Dhimolea E. Canakinumab. mAbs. 2010 Jan 1;2(1):3–13.  Chapter 2130  449.  Everett BM, MacFadyen JG, Thuren T, Libby P, Glynn RJ, Ridker PM. Inhibition of Interleukin-1β and Reduction in Atherothrombotic Cardiovascular Events in the CANTOS Trial. J Am Coll Cardiol. 2020 Oct;76(14):1660–70.  450.  EU Clinical Trials Register. KAWA2019-1962 [Internet]. clinicaltrialsregister.eu. [cited 2023 Jan 13]. Available from: https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-002783-27/NL 451.  Lan SH, Lai CC, Huang HT, Chang SP, Lu LC, Hsueh PR. Tocilizumab for severe COVID-19: a systematic review and meta-analysis. Int J Antimicrob Agents. 2020 Sep;56(3):106103.  452.  Oswal J, Sarangi B, Shankar G, Sharma V. Successful use of tocilizumab in the treatment of multisystem inflammatory disease of childhood refractory to intravenous immunoglobulin and glucocorticoids. J Pediatr Crit Care. 2021;8(2):102.  453.  Sheppard M, Laskou F, Stapleton PP, Hadavi S, Dasgupta B. Tocilizumab (Actemra). Hum Vaccines Immunother. 2017 Sep 2;13(9):1972–88.  454.  Tanaka T, Narazaki M, Kishimoto T. Immunotherapeutic implications of IL-6 blockade for cytokine storm. Immunotherapy. 2016 Jul;8(8):959–70.  455.  Nozawa T, Imagawa T, Ito S. Coronary-Artery Aneurysm in Tocilizumab-Treated Children with Kawasaki’s Disease. N Engl J Med. 2017 Nov 9;377(19):1894–6.  456.  Banday AZ, Vignesh P. Use of tocilizumab in multisystem inflammatory syndrome in children associated with severe acute respiratory syndrome coronavirus 2. J Pediatr. 2021 Jan;228:315.  457.  Ibbotson T, McGavin JK, Goa KL. Abciximab: An Updated Review of its Therapeutic Use in Patients with Ischaemic Heart Disease Undergoing Percutaneous Coronary Revascularisation. Drugs. 2003;63(11):1121–63.  458.  French DL, Seligsohn U. Platelet Glycoprotein IIb/IIIa Receptors and Glanzmann’s Thrombasthenia. Arterioscler Thromb Vasc Biol. 2000 Mar;20(3):607–10.  459.  Etheridge SP, Tani LY, Minich LL, Revenaugh JR. Platelet glycoprotein IIb/IIIa receptor blockade therapy for large coronary aneurysms and thrombi in Kawasaki disease. Cathet Cardiovasc Diagn. 1998 Nov;45(3):264–8.  460.  McCandless RT, Minich LL, Tani LY, Williams RV. Does Abciximab Promote Coronary Artery Remodeling in Patients With Kawasaki Disease? Am J Cardiol. 2010 Jun;105(11):1625–8.  Management of KD131  Chapter 2: The Management of KD 461.  Williams RV, Wilke VM, Tani LY, Minich LL. Does Abciximab Enhance Regression of Coronary Aneurysms Resulting From Kawasaki Disease? Pediatrics. 2002 Jan 1;109(1):e4–e4.  462.  Buyel JF, Twyman RM, Fischer R. Very-large-scale production of antibodies in plants: The biologization of manufacturing. Biotechnol Adv. 2017 Jul;35(4):458–65.  463.  Kvien TK, Patel K, Strand V. The cost savings of biosimilars can help increase patient access and lift the financial burden of health care systems. Semin Arthritis Rheum. 2022 Feb;52:151939.  464.  Hoang LT, Shimizu C, Ling L, Naim ANM, Khor CC, Tremoulet AH, et al. Global gene expression profiling identifies new therapeutic targets in acute Kawasaki disease. Genome Med. 2014;6(102):13.  465.  Menikou S, Langford PR, Levin M. Kawasaki Disease: The Role of Immune Complexes Revisited. Front Immunol. 2019 Jun 12;10:1156.  466.  Senzaki H. The pathophysiology of coronary artery aneurysms in Kawasaki disease: role of matrix metalloproteinases. Arch Dis Child. 2006 Oct 1;91(10):847–51.  467.  Takahashi K, Oharaseki T, Yokouchi Y. Update on etio and immunopathogenesis of Kawasaki disease. Curr Opin Rheumatol. 2014 Jan;26(1):31–6.  468.  Wyant T, Fedyk E, Abhyankar B. An Overview of the Mechanism of Action of the Monoclonal Antibody Vedolizumab. J Crohns Colitis. 2016 Dec;10(12):1437–44.  469.  Yu Y, Zhu J, Mi LZ, Walz T, Sun H, Chen J, et al. Structural specializations of α4β7, an integrin that mediates rolling adhesion. J Cell Biol. 2012 Jan 9;196(1):131–46.  470.  Bye WA, Jairath V, Travis SPL. Systematic review: the safety of vedolizumab for the treatment of inflammatory bowel disease. Aliment Pharmacol Ther. 2017 Jul;46(1):3–15.  471.  Colombel JF, Sands BE, Rutgeerts P, Sandborn W, Danese S, D’Haens G, et al. The safety of vedolizumab for ulcerative colitis and Crohn’s disease. Gut. 2017 May;66(5):839–51.  472.  Engel T, Ungar B, Yung DE, Ben-Horin S, Eliakim R, Kopylov U. Vedolizumab in IBD–Lessons From Real-world Experience; A Systematic Review and Pooled Analysis. J Crohns Colitis. 2018 Jan 24;12(2):245–57.   Chapter 2132  Chapter 3 The following manuscript, entitled “Variation in the management of Kawasaki disease in Australia and New Zealand: A survey of paediatricians” was published in The Journal of Paediatrics and Child Health in 2020. The study, which analysed responses by Australian and New Zealand clinicians to an international survey, sought to describe local practice regarding the diagnosis and management of KD. The findings indicated that there was consensus around the use of IVIG but revealed significant disagreements with regard to the use of aspirin in the acute phase of KD, as well as around criteria for the diagnosis of IVIG-resistant disease. Practitioner’s descriptions of their own practice (reported below) can be compared with observed practice, which is presented in Chapter 6. I am grateful to Dr Audrey Dionne, and her collaborators in the USA and Canada, for providing access to the Australian and New Zealand responses to their survey. A global analysis of the survey was published in The Archives of Disease in Childhood in 2019*.     * Dionne A, Burgner D, De Ferranti S, Singh-Grewal D, Newburger J, Dahdah N. Variation in the management of Kawasaki disease. Arch Dis Child. 2019 Jun 13;archdischild-2019-317191. 133134ORIGINAL ARTICLEVariation in the management of Kawasaki disease in Australia andNew Zealand: A survey of paediatriciansRyan Lucas ,1,2 Peta Dennington ,3 Erica Wood ,4 Audrey Dionne ,5,6 Sarah D de Ferranti ,5,6Jane W Newburger ,5,6 Nagib Dahdah ,7 Allen Cheng ,8 David Burgner 9 and Davinder Singh-Grewal 1,2,101Department of General Medicine, The Sydney Children’s Hospitals Network Randwick and Westmead, 2Children’s Hospital Westmead Clinical School,Discipline of Child and Adolescent Health, The University of Sydney Faculty of Medicine and Health, 3Australian Red Cross Lifeblood, 10School of Women’sand Children’s Health, University of New South Wales Faculty of Medicine, Sydney, New South Wales, 4Transfusion Research Unit, 8Infectious DiseaseEpidemiology Unit, Monash University School of Public Health and Preventive Medicine, 9Infection and Immunity Theme, Murdoch Children’s ResearchInstitute, Melbourne, Victoria, Australia, 5Department of Cardiology, Boston Children’s Hospital, 6Department of Pediatrics, Harvard Medical School,Boston, Massachusetts, United States and 7Department of Pediatric Cardiology, University of Montreal, Montreal, Quebec, CanadaAim: This study aimed to describe the current management practices for Kawasaki disease (KD) in Australia and New Zealand.Methods: We performed a secondary analysis on the Australian and New Zealand responses to a large international survey of clinicians’ per-spectives on KD diagnosis and management.Results: There was general consensus among Australian and New Zealand clinicians regarding the indications for intravenous immunoglobulinand aspirin in the management of acute KD. There was less consensus on the dose of these agents, the definition and management oftreatment-resistant KD and the approach to long-term thromboprophylaxis.Conclusion: Most clinicians use intravenous immunoglobulin for primary treatment of KD. There is variation regarding other aspects of KD diag-nosis and important management issues. Future studies should confirm whether this reported variation occurs in real-world practice and assesspotential impacts on patient outcome.Key words: aspirin; intravenous immunoglobulin; Kawasaki disease; mucocutaneous lymph node syndrome.What is already known on this topic1 Kawasaki disease (KD) is an inflammatory condition of childhoodthat has become a leading cause of paediatric acquired heartdisease in the developed world.2 Intravenous immunoglobulin (IVIG) improves coronary artery out-comes in KD.3 Guidelines for the management of KD vary around the world.What this paper adds1 Clinicians almost unanimously reported prescribing IVIG for theprimary therapy of acute KD, albeit at varying dose.2 There is disagreement about the dose of aspirin in acute KD.3 There is a lack of consensus around important definitions, suchas for IVIG-resistant disease.Kawasaki disease (KD) is a systemic vasculitis that predominantlyaffects young children. The coronary arteries are particularlyaffected, and KD can result in morbidity ranging from mild andself-resolving coronary dilatation to permanent and life-threatening aneurysms.1 Intravenous immunoglobulin (IVIG)reduces the incidence of coronary artery lesions from 25 to 5%2,3and it is the only intervention supported by evidence fromrandomised controlled trials. Aspirin has historically had tworoles in KD: reducing inflammation and preventing thrombosis;evidence supporting either in KD is weak.4,5 Additional therapies(such as corticosteroids and biologics) are also used, althoughwith less certainty as to their efficacy and role.6–8KD that does not respond to primary therapy with IVIG (‘IVIGresistance’) is an important clinical entity, with non-respondersat higher risk for coronary complications.9 Despite this, there isno consensus definition of IVIG resistance, and little evidence toinform management. Other areas of uncertainty include riskstratification of patients, adjunctive primary therapy and the needfor and duration of thromboprophylaxis.10A recently published international survey of physicians’ approachto KD diagnosis and management identified significant practice vari-ation, particularly around adjunctive primary therapy and the defi-nition and management of IVIG-resistant disease.11 We undertook asecondary analysis of the Australian and New Zealand responses inCorrespondence: Dr Ryan Lucas, Children’s Hospital Westmead ClinicalSchool, Discipline of Child and Adolescent Health, The University of Syd-ney Faculty of Medicine and Health, Hawksbury Road and HainsworthStreet, Westmead, Sydney, NSW 2145, Australia. Fax: +61 (2) 9845 0074;email: ryan.lucas@health.nsw.gov.auConflict of interest: None declared.Accepted for publication 14 November 2020.doi:10.1111/jpc.15290Journal of Paediatrics and Child Health (2020)© 2020 Paediatrics and Child Health Division (The Royal Australasian College of Physicians) 135this study to assess local areas of practice variation and to informfuture local guidelines.MethodsWe analysed responses from paediatricians in Australia andNew Zealand participating in an international survey of clinicians’perspectives on KD diagnosis and management.11 The surveywas hosted on SurveyMonkey and was distributed through pro-fessional and personal networks world-wide. As the survey wasnot sent to a pre-determined number of clinicians, it was not pos-sible to assess the response rate. Responses were recordedbetween January and August 2017. This subgroup analysis wasplanned in advance of results from the international survey hav-ing been analysed.There were 42 questions in total (see Supporting Information);respondents could choose not to answer questions. All responseswere anonymous and providing demographic data was optional.Respondents reported their clinical speciality and were categorisedas either generalists (general paediatricians and those whoreported no speciality) or specialists (paediatric sub-specialities:cardiology, infectious disease, immunology or rheumatology).Statistical analyses (frequencies and proportions) were per-formed using Stata/IC 15.1 for Mac (StataCorp 2017. Stata Statis-tical Software: Release 15; StataCorp, College Station, TX, USA).Data are presented as proportions (percent), with non-responsessubtracted from the denominator.The international survey received ethical approval from theCentre Hospitalier Universitaire Sainte-Justine in Montreal,Canada. This sub-analysis was granted exemption from ethicalapproval by the Sydney Children’s Hospitals Network.ResultsRespondentsThere were 108 respondents from Australia and New Zealand;descriptive statistics of respondents are provided in Table 1. Sixty-nine percent (74 of 108) of respondents were general paediatri-cians and 81% (88 of 108) reported managing fewer than fivecases of KD per year.DiagnosisRespondents were asked how evidence for alternative or concur-rent diagnoses would affect their certainty of the diagnosis of KD(in a child fulfilling the full clinical criteria as defined by theAmerican Heart Association (AHA)10). Clinicians retained thediagnosis of KD in the following clinical scenarios: lobar pneumo-nia on chest radiograph, 85% (92 of 108); influenza on nasalswab polymerase chain reaction, 76% (82 of 108); and toxicshock syndrome by clinical criteria, 51% (55 of 108) (Table S1,Supporting Information).Fifty-one percent (40 of 78) of general paediatricians reportedthat echocardiography was readily available at the time of diag-nosis compared to 93% (28 of 30) of paediatric subspecialists(Table S2, Supporting Information). When asked about the defi-nition of giant coronary aneurysms 37% (40 of 108) of respon-dents reported using absolute measurement of the internaldiameter (≥8 mm) and 44% (48 of 108) reported usingnormalised values (Z-score) (Table S3, Supporting Information).Primary therapyAlmost all respondents stated that they use IVIG as primary ther-apy for children with KD (96–97%, depending on coronaryartery status at diagnosis) (Fig. 1, Tables S4–S8, Supporting Infor-mation). The majority of respondents used a dose of 2 g/kg; how-ever, almost 10% used a dose of 1 g/kg (Fig. 1, Table S5,Supporting Information).Aspirin was widely prescribed at the time of diagnosis; only11% of respondents (11 of 104) indicated that they would notprescribe aspirin for children with normal coronary arteries atdiagnosis. Respondents in New Zealand showed a general con-sensus in favour of moderate-dose aspirin (30–50 mg/kg/day),regardless of the coronary artery status. There was less consensusamong respondents in Australia: 48% (38 of 80) used low-doseaspirin (3–5 mg/kg/day) from diagnosis for children with normalcoronary arteries, while 25% each (20 of 80) used moderate-doseand high-dose (80–100 mg/kg/day) aspirin in these patients.Australian respondents were more likely to use high-dose aspirinas the coronary artery involvement worsened, with 40% (27 of67) prescribing high-dose aspirin for children with giant aneu-rysms (Fig. 2, Tables S9–S11, Supporting Information).Use of corticosteroids as adjunctive primary therapy varied bycoronary artery status at diagnosis. Four percent (4 of 104) ofrespondents selected corticosteroids for children with normal cor-onary arteries at diagnosis, compared with 12% (12 of 98) and21% (19 of 89) for children with non-giant and giant aneurysms,respectively. Specialists were more likely than generalists to usecorticosteroids. Biologic agents were infrequently used as primaryadjunctive therapy (Fig. 1, Tables S4–S8, SupportingInformation).IVIG resistance: Definition and managementRespondents were asked how many hours after the end of IVIGinfusion they would consider persistent or recrudescent fever tosignify IVIG non-response. Fever at 24 h was most commonlyselected by respondents in Australia (59% of Australians selected24 h vs. 27% of New Zealanders), whereas fever at 48 h wasmost commonly selected by respondents in New Zealand (50%of New Zealanders vs. 20% of Australians) (Fig. 3, Table S12,Supporting Information).Retreatment with IVIG was the most commonly selected ther-apy for the management of IVIG-resistant KD (89–92% ofrespondents, depending on coronary artery status at diagnosis).Corticosteroids were the second most commonly selected therapyfor IVIG-resistant KD (51–54% of respondents). Corticosteroidswere commonly co-administered with the second dose of IVIG(about 90% of those who selected corticosteroids also selectedIVIG). Intravenous corticosteroids were favoured over oral corti-costeroids. Infliximab (a tumour necrosis factor-alpha inhibitor)was the most commonly selected biologic agent and was usedmore commonly by specialists than generalists. Thirteen percentof respondents selected infliximab for a child with resistant KDand giant coronary aneurysms (Fig. 1, Tables S13–S15,Supporting Information).Journal of Paediatrics and Child Health (2020)© 2020 Paediatrics and Child Health Division (The Royal Australasian College of Physicians)Survey of paediatricians R Lucas et al.Chapter 3136ThromboprophylaxisLow-dose aspirin was the most commonly selected agent forlong-term thromboprophylaxis. The proportion of respondentswho used aspirin varied with the severity of coronary arteryinvolvement at diagnosis: 18% of respondents (18 of 102) indi-cated that they would use long-term, low-dose aspirin for a childwith normal coronary arteries at diagnosis, while 85% (76 of 89)would do so if there was persistent coronary artery dilatation.With increasing severity of coronary artery involvement, respon-dents were more likely to use alternative thromboprophylacticagents instead of, or in addition to, aspirin. For children withgiant aneurysms, 57% (49 of 86) indicated that they would useanother thromboprophylactic agent in the long term, either aloneor in combination with aspirin. Of these, 61% (30 of 49) chosewarfarin while 27% (13 of 49) and 22% (11 of 49), respectively,chose a dual anti-platelet agent or low-molecular weight heparin.DiscussionWe describe the management of KD across Australia andNew Zealand, performing a subgroup analysis of the survey origi-nally reported by Dionne et al.11 That study described significantvariation in the management of KD internationally; IVIG waswidely accepted as first-line therapy, however, there was varia-tion around dose. Other areas of variation included the definitionand management of IVIG-resistant KD. We found consensusaround the indications for IVIG but some variation around thedose used. The efficacy of IVIG in KD correlates with peak plasmaimmunoglobulin concentration,12 and evidence from randomisedcontrolled trials recommends the higher dose of 2 g/kg.13 Currentguidelines recommend a single dose of IVIG at 2 g/kg per dose,given as a single infusion (Table 2).10,14,15We also found significant variation around aspirin dosage inacute KD. Aspirin has dual proposed roles in KD management:inhibition of platelet activation at lower doses (3–5 mg/kg/day)and anti-inflammatory effects at higher doses (>30 mg/kg/day).16There are no convincing data to suggest efficacy of higher doseaspirin compared with anti-platelet dose aspirin in preventingcoronary aneurysms.5,16 There is currently significant disagree-ment among international guidelines around the approach toaspirin during the acute phase of KD (Table 2). The AHA guide-lines suggest it is reasonable to use aspirin at either 30–50 or80–100 mg/kg/day until defervescence.10 The guidelines fromStarship Hospital (Auckland, New Zealand) recommend aspirin at30–50 mg/kg/day, dropping to the lower anti-platelet dose after1 week.15 Clinical Practice Guidelines from the Royal Children’sHospital (Melbourne), widely used in Australia, recommend aspi-rin at 3–5 mg/kg/day from diagnosis; this is based on the lack ofevidence for the efficacy of higher dose aspirin on coronaryartery outcomes and considerable experience of low-dose aspirinfor thromboprophylaxis.14 This seems to be an area of markeddeviation from international standard practice: the internationalsurvey that produced these data showed that of theTable 1 Descriptive statistics of survey respondents in Australia and New ZealandAustralia New Zealand TotalNo. (%) No. (%) No. (%)GenderFemale 45 (55) 14 (54) 59 (55)Male 36 (44) 12 (46) 48 (44)Unknown 1 (1) 0 (0) 1 (1)Total 82 (100) 26 (100) 108 (100)SpecialityGeneral paediatrics 56 (68) 18 (69) 74 (69)Cardiology 4 (5) 4 (15) 8 (7)Infectious diseases 9 (11) 2 (8) 11 (10)Immunology/rheumatology 9 (11) 2 (8) 11 (10)None 4 (5) 0 (0) 4 (4)Total 82 (100) 26 (100) 108 (100)Years of practice≤5 20 (24) 3 (12) 23 (21)6–1 18 (22) 7 (27) 25 (23)11–15 years 10 (12) 3 (12) 13 (12)16–20 15 (18) 6 (23) 21 (19)>20 19 (23) 7 (27) 26 (24)Total 82 (100) 26 (100) 108 (100)KD patients in the last year<5 64 (78) 24 (92) 88 (81)≥5 18 (22) 2 (8) 20 (19)Total 82 (100) 26 (100) 108 (100)KD, Kawasaki disease.Journal of Paediatrics and Child Health (2020)© 2020 Paediatrics and Child Health Division (The Royal Australasian College of Physicians)R Lucas et al.Survey of Paediatricians1370 20 40 60 80 100 0 20 40 60 80 100OtherBiologicIV SteroidOral SteroidIVIG 2 g/kgIVIG 1 g/kgNo TreatmentOtherBiologicIV SteroidOral SteroidIVIG 2 g/kgIVIG 1 g/kgNo TreatmentGeneralist SpecialistPercent of RespondersSecond-Line TherapiesUsed in Kawasaki Disease0 20 40 60 80 100 0 20 40 60 80 100OtherIV SteroidOral SteroidIVIG 2 g/kgIVIG 1 g/kgAspirinNo TreatmentOtherIV SteroidOral SteroidIVIG 2 g/kgIVIG 1 g/kgAspirinNo TreatmentGeneralist SpecialistFirst-Line TherapiesUsed in Kawasaki Disease(a) (b)(c) (d)Fig. 1 Reported therapies used in the treat-ment of Kawasaki disease (KD) in Australiaand New Zealand, by specialisation. Thera-pies selected by general paediatricians(a) and paediatric sub-specialists (b) for thefirst-line management of acute KD. The cate-gory ‘Other’ includes anti-tumour necrosisfactor-alpha agents. Therapies selected bygeneral paediatricians (c) and paediatric sub-specialist (d) for the treatment of intravenousimmunoglobulin-resistant KD. The category‘Biologic’ includes infliximab, etanercept,anakinra and canakinumab; the category‘Other’ includes cyclosporine. Results areprovided in detail in Supporting Information( , normal coronaries; , non-giant aneu-rysms; , giant aneurysms).0 20 40 60 80 0 20 40 60 80Other Anti-PlateletAspirin 80–100 mg/kgAspirin 30–50 mg/kgAspirin 3–5 mg/kgNo AspirinOther Anti-PlateletAspirin 80–100 mg/kgAspirin 30–50 mg/kgAspirin 3–5 mg/kgNo AspirinAustralia New ZealandPercent of RespondentsUse of Aspirin in Acute Kawasaki Disease(a) (b) Fig. 2 Aspirin dose used in the febrilephase of Kawasaki disease (KD) in Australiaand New Zealand, by country. Dose of aspi-rin selected by respondents in Australia(a) and New Zealand (b) for the treatmentof KD during the febrile phase. Results areprovided in detail in Supporting Information( , normal coronaries; , non-giant aneu-rysms; , giant aneurysms).Journal of Paediatrics and Child Health (2020)© 2020 Paediatrics and Child Health Division (The Royal Australasian College of Physicians)R Lucas et al.Chapter 3138724 respondents only 13% used low-dose aspirin in acute KD.17In this context, it is not surprising to find lack of consensus inclinical practice.5There was also considerable variation in practice with respect tomanagement of IVIG resistance, which is inconsistently defined inthe KD literature and in international guidelines (Table 2). Mostdefinitions are based on the presence of ongoing inflammationafter the first dose of IVIG – usually identified by the persistence orrecrudescence of fever.10,14,15,18,19 Studies on the use of adjunctiveanti-inflammatory agents have shown that earlier defervescencedoes not necessarily reduce the risk of coronary artery dilata-tion.4,6,20 Conversely, concurrent infection is a common finding in0 10 20 30 40 50 60 0 10 20 30 40 50 6072 h48 h36 h24 h12 h72 h48 h36 h24 h12 hAustralia New ZealandPercent of Respondentsfrom Each CountryTime from End of IVIG Infusion to Fever Recurrence(a) (b)Table 2 Summary of recommendations from the international Kawasaki disease management guidelinesRegion IVIG (g/kg) Aspirin (mg/kg/day) Definition of resistance (hours from treatment) Treatment of IVIG resistanceAustralia14,25,26 2 3–5 36 1 IVIG2 CorticosteroidsEurope27 2 30–50 initially, then 3–5 36 or 48 1 IVIG2 Corticosteroids3 BiologicsJapan28 2 30–50 initially, then 3–5 24 1 IVIG2 Corticosteroids3 BiologicsNew Zealand15 2 30–50 initially, then 3–5 48–72 1 IVIG2 Corticosteroids3 BiologicsNorth America10 2 30–50 or 80–100 initially, then 3–5 24 or 36 1 IVIG2 Biologics3 CorticosteroidsUK29 2 30–50 or 80–100 initially, then 3–5 36–48 1 IVIG2 Corticosteroids3 BiologicsDrawn from publicly available clinical practice guidelines. IVIG, intravenous immunoglobulin.Journal of Paediatrics and Child Health (2020)© 2020 Paediatrics and Child Health Division (The Royal Australasian College of Physicians)R Lucas et al.Fig. 3 Time after the first dose of intravenous immunoglobulin (IVIG) at which IVIG-resistant Kawasaki disease (KD) is diagnosed by the presence of fever in Australia and New Zealand, by country. IVIG-resistant KD is defined as persistence or recrudescence of fever after the first dose of IVIG; the time at which this diagnosis is made varies. Hours at which the presence of fever indicates failure to respond to treat-ment, as reported by respondents in Australia (a) and New Zealand (b). Results are provided in detail in Supporting Information.Survey of Paediatricians139AcknowledgementLocal analysis was funded by a National Blood Sector Researchand Development Grant (ID111) from the National BloodAuthority, Australia.References1 Friedman KG, Gauvreau K, Hamaoka-Okamoto A et al. Coronaryartery aneurysms in Kawasaki disease: Risk factors for progressivedisease and adverse cardiac events in the US population. J. Am.Heart Assoc. 2016; 5: e003289.2 Mori M, Miyamae T, Imagawa T, Katakura S, Kimura K, Yokota S. Meta-analysis of the results of intravenous gamma globulin treatment of coro-nary artery lesions in Kawasaki disease. Mod. Rheumatol. 2004; 14: 7.3 Oates-Whitehead RM, Baumer JH, Haines L et al. Intravenous immu-noglobulin for the treatment of Kawasaki disease in children.Cochrane Database Syst. Rev. 2003; 2003: CD004000.4 Hsieh K-S, Weng K-P, Lin C-C, Huang T-C, Lee C-L, Huang S-M. Treat-ment of acute Kawasaki disease: Aspirin’s role in the febrile stagerevisited. Pediatrics 2004; 114: e689–93.5 Dallaire F, Fortier-Morissette Z, Blais S et al. Aspirin dose and preven-tion of coronary abnormalities in Kawasaki disease. Pediatrics 2017;139: e20170098.6 Kim GB, Yu JJ, Yoon KL et al. Medium- or higher-dose acetylsalicylicacid for acute Kawasaki disease and patient outcomes. J. Pediatr.2017; 184: 125–129.e1.7 Wardle AJ, Connolly GM, Seager MJ, Tulloh RM. Corticosteroids forthe treatment of Kawasaki disease in children. Cochrane DatabaseSyst. Rev. 2017; 1: CD011188.8 Tremoulet AH, Jain S, Jaggi P et al. Infliximab for intensification of pri-mary therapy for Kawasaki disease: A phase 3 randomised, double-blind, placebo-controlled trial. Lancet 2014; 383: 1731–8.9 Eleftheriou D, Levin M, Shingadia D, Tulloh R, Klein N, Brogan P. Man-agement of Kawasaki disease. Arch. Dis. Child. 2013; 10.1–10.10 McCrindle BW, Rowley AH, Newburger JW et al. Diagnosis, treatment,and long-term management of Kawasaki disease: A scientific state-ment for health professionals from the American Heart Association.Circulation 2017; 135: e927–99.11 Dionne A, Burgner D, De Ferranti S, Singh-Grewal D, Newburger J,Dahdah N. Variation in the management of Kawasaki disease. Arch.Dis. Child. 2020; 105: 1004–6.12 Yamazaki-Nakashimada MA, Gámez-González LB, Murata C,Honda T, Yasukawa K, Hamada H. IgG levels in Kawasaki diseaseand its association with clinical outcomes. Clin. Rheumatol. 2019;38: 749–54.13 Durongpisitkul K, Gururaj VJ, Park JM, Martin CF. The prevention ofcoronary artery aneurysm in Kawasaki disease: A meta-analysis onthe efficacy of aspirin and immunoglobulin treatment. Pediatrics1995; 96(6): 1057–61.14 The Royal Children’s Hospital. Clinical Practice Guideline on Kawa-saki Disease. Melbourne; 2017. Available from: https://www.rch.org.au/clinicalguide/guideline_index/Kawasaki_disease/ [accessed23 July 2020].15 Webb R, Nicholson R, Wilson N. Kawasaki Disease. Starship ChildHealth; 2019. Available from: https://www.starship.org.nz/guidelines/kawasaki-disease/ [accessed 25 July 2020].16 Dhanrajani A, Yeung RSM. Revisiting the role of steroids and aspirinin the management of acute Kawasaki disease. Curr. Opin.Rheumatol. 2017; 29: 547–52.17 Dionne A, de Ferranti S, Vanderpluym C et al. Antithrombosis man-agement of patients with Kawasaki disease; results from an interna-tional survey. Can. J. Cardiol. 2018; 34: S86–7.Journal of Paediatrics and Child Health (2020)© 2020 Paediatrics and Child Health Division (The Royal Australasian College of Physicians)acute KD, complicating the interpretation of ongoing fever.21 A fever-based definition of resistant disease may lack sensitivity and specificity. The treatment of resistant KD is an active area of clinical research, and there is a need to establish consensus on the defini-tion to facilitate comparison across studies.22There is variation in the management of treatment-resistant KD.10 After a second dose of IVIG, corticosteroids were the most common adjunctive therapy. This is in keeping with the AHA guidelines, although evidence is limited for this approach.10,23 Infliximab was the most commonly used bio-logic agent for resistant KD. Infliximab has been studied as therapy for IVIG-resistant KD and reductions in inflammatory cytokines and duration of fever have been shown; however, there is no evidence that this approach alters coronary out-comes.18 Given the relatively low incidence of significant coro-nary artery damage in KD, and the heterogeneity of treatment approaches in this patient group, these studies are likely underpowered to demonstrate a lack of benefit; further collab-orative studies into the utility of infliximab in the treatment of KD are required.24In keeping with the findings of the international survey, we found variation in the approach to ongoing thromboprophylaxis among respondents; however, our findings must be interpreted with caution. Ongoing anticoagulation is complex and highly individualised, based on both current coronary size and worst-ever coronary size.10 These decisions are typically made by cardi-ologists, who were relatively under-represented in this survey.We acknowledge some key limitations of this study. First, only a small number of paediatricians in Australia and New Zealand participated in the survey; the distribution of the survey was not systematic and may over-represent practice in tertiary institu-tions and major cities. Second, the questions were by necessity theoretical and assumed that coronary artery status was known at the time of diagnosis. This information is frequently unavailable when initial management decisions are made; how-ever, assessing all possible scenarios of clinical uncertainty would have lengthened the survey to make the participant burden unacceptable. Third, respondents were asked about scenarios that may fall outside their scope of practice (e.g. general paedia-tricians managing thromboprophylaxis in children with giant coronary artery aneurysms) and were not given the option to indicate uncertainty; responses may not have reflected manage-ment decisions that are often taken after specialist multi-disciplinary discussions. We are currently undertaking prospective studies on KD in Australia to better describe these and other aspects of KD management.ConclusionWe demonstrated consensus in clinical practice around the indi-cations for IVIG and aspirin in the management of KD in Australia and New Zealand. There was a lack of consensus on the dose of each agent and in the definition of and approach to the management of IVIG-resistant KD. These findings should inform the development and dissemination of local practice guidelines. They also reinforce the ongoing need for international collabora-tion in KD research to develop and follow common definitions (such as the definition of IVIG resistance) and to clarify the roles of adjunctive therapies.R Lucas et al.Chapter 314018 Mori M, Hara T, Kikuchi M et al. Infliximab versus intravenous immu-noglobulin for refractory Kawasaki disease: A phase 3, randomized,open-label, active-controlled, parallel-group, multicenter trial. Sci.Rep. 2018; 8: 1–10.19 Wallace CA, French JW, Kahn SJ, Sherry DD. Initial intravenousgammaglobulin treatment failure in Kawasaki disease. Pediatrics2000; 105: e78–8.20 Dionne A, Burns JC, Dahdah N et al. Treatment intensification inpatients with Kawasaki disease and coronary aneurysm at diagnosis.Pediatrics 2019; 143: e20183341.21 Joshi AV, Jones KD, Buckley A-M, Coren ME, Kampmann B. Kawasakidisease coincident with influenza A H1N1/09 infection: Kawasaki dis-ease with H1N1/09 infection. Pediatr. Int. 2011; 53: e1–2.22 Dionne A, Le C-K, Poupart S et al. Profile of resistance to IVIG treat-ment in patients with Kawasaki disease and concomitant infection.PLoS One 2018; 13: e0206001.23 Miura M, Tamame T, Naganuma T, Chinen S, Matsuoka M, Ohki H.Steroid pulse therapy for Kawasaki disease unresponsive to addi-tional immunoglobulin therapy. Paediatr. Child Health 2011; 16:479–84.24 Levin M, Burgner D. Treatment of Kawasaki disease with anti-TNF anti-bodies. Lancet 2014; 383: 1700–3.25 Kawasaki Disease. Systemic Vasculitides. eTG complete [digital]Mel-bourne: Therapeutic Guidelines Limited; 2017: https://www.tg.org.au.26 Kawasaki disease (mucocutaneous lymph node syndrome). Criteriafor the clinical use of intravenous immunoglobulin in Australia. 3 Aus-tralia: The National Blood Authority; 2018: https://www.criteria.blood.gov.au/MedicalCondition/View/2564.27 de Graeff N, Groot N, Ozen S, Eleftheriou D, Avcin T, Bader-Meunier B,Dolezalova P, Feldman BM, Kone-Paut I, Lahdenne P, McCann L,Pilkington C, Ravelli A, van Royen-Kerkhof A, Uziel Y, Vastert B,Wulffraat N, Kamphuis S, Brogan P, Beresford MW. European consen-sus-based recommendations for the diagnosis and treatment ofKawasaki disease – the SHARE initiative. Rheumatology. 2019; 58:672–682. http://dx.doi.org/10.1093/rheumatology/key344.28 Guidelines for medical treatment of acute Kawasaki disease:Report of the Research Committee of the Japanese Society of Pedi-atric Cardiology and Cardiac Surgery (2012 revised version). Pedi-atrics International. 2014; 56: 135–158. http://dx.doi.org/10.1111/ped.12317.29 Brogan PA. Kawasaki disease: an evidence based approach todiagnosis, treatment, and proposals for future research. Archivesof Disease in Childhood. 2002; 86: 286–290. http://dx.doi.org/10.1136/adc.86.4.286.Supporting InformationAdditional Supporting Information may be found in the onlineversion of this article at the publisher’s web-site:Table S1. Diagnosis of Kawasaki disease in the context of alter-nate diagnoses.Table S2. Availability of echocardiography in Australia by specialty.Table S3. Criteria used to define giant coronary aneurysms.Table S4. Intravenous immunoglobulin as the primary treatment.Table S5. Primary therapy for Kawasaki disease.Table S6. Primary therapy for Kawasaki disease in children withnormal coronary arteries at diagnosis.Table S7. Primary therapy for Kawasaki disease in children withnon-giant coronary aneurysms at diagnosis.Table S8. Primary therapy for Kawasaki disease in children withgiant coronary aneurysms at diagnosis.Table S9. Aspirin during acute Kawasaki disease: normal coro-nary arteries at diagnosis.Table S10. Aspirin during acute Kawasaki disease: non-giantaneurysms at diagnosis.Table S11. Aspirin during acute Kawasaki disease: giant aneu-rysms at diagnosis.Table S12. Definition of resistance by time to defervescence.Table S13. Secondary therapy for Kawasaki disease in childrenwith normal coronary arteries at diagnosis.Table S14. Secondary therapy for Kawasaki disease in childrenwith non-giant aneurysms at diagnosis.Table S15. Secondary therapy for Kawasaki disease in childrenwith giant aneurysms at diagnosis.Journal of Paediatrics and Child Health (2020)© 2020 Paediatrics and Child Health Division (The Royal Australasian College of Physicians)R Lucas et al.Survey of Paediatricians141Chapter 3142Variation in the Management of Kawasaki Disease in Australia and New Zealand: A survey of paediatricians.  Supplementary Results 143Table 3.S1: Diagnosis of KD in the Context of Alternate DiagnosesGeneralist or SpecialistGeneralistSpecialistTotalNo.%No.%No.%00000034310668102710943551653595524319303331KD & Pneumonia(KD should NOT be excluded):  Strongly Disagree  Disagree  Neither  Agree  Strongly Agree  Total7810030100108100111322912413131291227111034441447484425329303431KD & Influenza(KD should NOT be excluded):  Strongly Disagree  Disagree  Neither  Agree  Strongly Agree  Total781003010010810023133317227232422212751726242127930302817228272523KD & Toxic Shock Syndrome(KD should NOT be excluded):  Strongly Disagree  Disagree  Neither  Agree  Strongly Agree  Total7810030100108100Question (Pneumonia): If a child with the clinical features of Kawasaki disease also has lobar pneumonia diagnosed radiologically at the same time, this should not exclude the diagnosis of Kawasaki disease.Question (Influenza): If a child with the clinical features of Kawasaki disease also has a influenza infection diagnosed by nasal swab PCR at the same time, this should not exclude the diagnosis of Kawasaki disease.Question (Toxic Shock Syndrome): If a child with the clinical features of Kawasaki disease also fulfils the diagnostic criteria for toxic shock syndrome at the same time, this should not exclude the diagnosis of Kawasaki disease.Chapter 3144Table 3.S2: Availability of Echocardiography in Australia by SpecialtyGeneralist or SpecialistGeneralist Specialist TotalNo. % No. % No. %40 51 28 93 68 6322 28 2 7 24 2216 21 0 0 16 15Availability of echocardiograms:  Readily available  Most of the time not available  No access, transfer needed  Total 78 100 30 100 108 100Question: Is echocardiogram readily available in your practice, or does its availability limit patients’ evaluation and follow-up?Table 3.S3: Criteria Used to Define Giant Coronary AneurysmsDefinition of Giant Coronary Artery Aneurysm≥8mm / Z-score ≥8mm Z-score TotalNo. % No. % No. % No. %18 23 25 32 35 45 78 1002 7 15 50 13 43 30 100Generalist or Specialist:  Generalist  Specialist  Total 20 19 40 37 48 44 108 100Question: In patients with coronary artery complications following Kawasaki disease, how would you define giant aneurysms? Please select one response.Survey respondents could chose the following answers: Coronary artery internal luminal diameter ≥8mm and/or Z-score cut-off, Coronary artery internal luminal diameter ≥8 mm in all patients, and Coronary artery Z-score cut-off in all patients. For brevity these have been replaced with: ≥8mm / Z-score, ≥8mm, and Z-score, respectively.Generalist or SpecialistGeneralist Specialist TotalNo. % No. % No. %5 6 1 3 6 61 1 0 0 1 12 3 0 0 2 223 29 4 13 27 2547 60 25 83 72 67All children with KDshould have IVIG as initial therapy:  Strongly Disagree  Disagree  Neither  Agree  Strongly Agree  Total 78 100 30 100 108 100Question: To what extent do you agree or disagree with the following statement on the treatment of Kawasaki disease: All children with KD should have IVIG as initial therapy.Table 3.S4: IVIG as Primary TreatmentSurvey of Paediatricians145Table 3.S5: Primary Therapy for Kawasaki DiseaseCoronary StatusNormal Coronaries non-Giant Aneurysms Giant Aneurysms% % %Treatment:  No Treatment 4 0 0  Aspirin 89 97 97  IVIG 1 g/kg 9 8 8  IVIG 2 g/kg 88 91 91  Oral Steroid 3 6 9  IV Steroid 3 8 17  Anti-TNF-α 0 1 7  Other 0 2 4Question: In your current practice, which therapies are part of your initial treatment of patients diagnosed with acute Kawasaki disease?Chapter 3146Table 3.S6: Primary Therapy for Kawasaki Disease in Children with Normal Coronary Arteries at DiagnosisResponder’s Specialty GroupNo.%No.%No.%No.%No.%No.%None:  No68967100111001110037510096  Yes3400000012544  Total71100710011100111004100104100Aspirin:  No8110000192501111  Yes638971001110010912509389  Total71100710011100111004100104100649068611100111003759591710114000012599IVIG 1 g/kg:  No  Yes  Total7110071001110011100410010410091311400002501212628768611100111002509288IVIG 2 g/kg:  No  Yes  Total71100710011100111004100104100699768611100111004100101972311400000033Oral Steroid:  No  Yes  Total71100710011100111004100104100IV Steroid:  No7099686109111100410010197  Yes1111419000033  Total7110071001110011100410010410071100710011100111004100104100Anti-TNF-α:  No  Total71100710011100111004100104100Continued. ..General PaediatricsCardiologyInfectious DiseaseImmunology/Rheum.NoneTotalSurvey of Paediatricians147...Table 3.S6 ContinuedResponder’s Specialty GroupNo.%No.%No.%No.%No.%No.%Other:  No71100710011100111004100104100  Total71100710011100111004100104100Question: In your current practice, which therapies are part of your initial treatment of patients diagnosed with acute Kawasaki disease? Please select all treatments that you use some or most of the time for each category [‘category’ refers to coronary artery status at diagnosis]. You can select more than one answer.General PaediatricsCardiologyInfectious DiseaseImmunology/Rheum.NoneTotalChapter 3148Table 3.S7: Primary Therapy for Kawasaki Disease in Children with non-Giant Coronary Aneurysms at DiagnosisResponder’s Specialty GroupNo.%No.%No.%No.%No.%No.%None:  No6610081001010010100410098100  Total6610081001010010100410098100Aspirin:  No2300001100033  Yes649781001010099041009597  Total6610081001010010100410098100598978810100101004100909271111200000088IVIG 1 g/kg:  No  Yes  Total6610081001010010100410098100711112000012599598978810100101003758991IVIG 2 g/kg:  No  Yes  Total66100810010100101004100981006497675101008804100929423225002200066Oral Steroid:  No  Yes  Total6610081001010010100410098100IV Steroid:  No629478899088041009092  Yes461121102200088  Total661008100101001010041009810066100810099010100410097990000110000011Anti-TNF-α:  No  Yes  Total6610081001010010100410098100Continued. ..General PaediatricsCardiologyInfectious DiseaseImmunology/Rheum.NoneTotalSurvey of Paediatricians149...Table 3.S7 ContinuedResponder’s Specialty GroupNo.%No.%No.%No.%No.%No.%Other:  No6598810010100101003759698  Yes1200000012522  Total6610081001010010100410098100Question: In your current practice, which therapies are part of your initial treatment of patients diagnosed with acute Kawasaki disease? Please select all treatments that you use some or most of the time for each category [‘category’ refers to coronary artery status at diagnosis]. You can select more than one answer.General PaediatricsCardiologyInfectious DiseaseImmunology/Rheum.NoneTotalChapter 3150Table 3.S8: Primary Therapy for Kawasaki Disease in Children with Giant Coronary Aneurysms at DiagnosisResponder’s Specialty GroupNo.%No.%No.%No.%No.%No.%None:  No591007100910010100410089100  Total591007100910010100410089100Aspirin:  No2300001100033  Yes57977100910099041008697  Total59100710091001010041008910053906869100101004100829261011400000078IVIG 1 g/kg:  No  Yes Total59100710091001010041008910061011400001258953906869100101003758191IVIG 2 g/kg:  No  Yes  Total591007100910010100410089100569557188988041008191352291112200089Oral Steroid:  No  Yes  Total591007100910010100410089100IV Steroid:  No518657177877041007483  Yes814229222330001517  Total591007100910010100410089100569571008898804100839335001112200067Anti-TNF-α:  No  Yes  Total591007100910010100410089100Continued. ..General PaediatricsCardiologyInfectious DiseaseImmunology/Rheum.NoneTotalSurvey of Paediatricians151...Table 3.S8 ContinuedResponder’s Specialty GroupGeneral PaediatricsCardiologyInfectious DiseaseImmunology/Rheum.NoneTotalNo.%No.%No.%No.%No.%No.%Other:  No  Yes  Total5797686910010100375859623114000012544591007100910010100410089100Question: In your current practice, which therapies are part of your initial treatment of patients diagnosed with acute Kawasaki disease? Please select all treatments that you use some or most of the time for each category [‘category’ refers to coronary artery status at diagnosis]. You can select more than one answer.Chapter 3152Table 3.S9: Aspirin During Acute Kawasaki Disease: Normal Coronary Arteries at DiagnosisResponder’s countryAustralia New Zealand TotalNo. % No. % No. %No Aspirin:  No  Yes  Total74 92 24 96 98 936 8 1 4 7 780 100 25 100 105 10042 52 21 84 63 6038 48 4 16 42 40Low-Dose Aspirin:  No  Yes  Total 80 100 25 100 105 10060 75 8 32 68 6520 25 17 68 37 35Medium Dose Aspirin:  No  Yes  Total 80 100 25 100 105 10060 75 21 84 81 7720 25 4 16 24 23High Dose Aspirin:  No  Yes  Total 80 100 25 100 105 10080 100 25 100 105 100Other Antiplatelet:  No  Total 80 100 25 100 105 100Question: In your current practice, which aspirin dosing do you use in the treatment of patients with Kawasaki disease at time of initial diagnosis?Survey of Paediatricians153Table 3.S10: Aspirin During Acute Kawasaki Disease: non-Giant Aneurysms at DiagnosisResponder’s countryAustralia New Zealand TotalNo. % No. % No. %No Aspirin:  No 76 99 25 100 101 99  Yes 1 1 0 0 1 1  Total 77 100 25 100 102 10045 58 24 96 69 6832 42 1 4 33 32Low-Dose Aspirin:  No  Yes  Total 77 100 25 100 102 10055 71 6 24 61 6022 29 19 76 41 40Medium Dose Aspirin:  No  Yes  Total 77 100 25 100 102 10052 68 20 80 72 7125 32 5 20 30 29High Dose Aspirin:  No  Yes  Total 77 100 25 100 102 10074 96 25 100 99 973 4 0 0 3 3Other Antiplatelet:  No  Yes  Total 77 100 25 100 102 100Question: In your current practice, which aspirin dosing do you use in the treatment of patients with Kawasaki disease at time of initial diagnosis?Chapter 3154Table 3.S11: Aspirin During Acute Kawasaki Disease: Giant Aneurysms at DiagnosisResponder’s countryAustralia New Zealand TotalNo. % No. % No. %No Aspirin:  No 65 97 21 95 86 97  Yes 2 3 1 5 3 3  Total 67 100 22 100 89 10044 66 22 100 66 7423 34 0 0 23 26Low-Dose Aspirin:  No  Yes  Total 67 100 22 100 89 10048 72 5 23 53 6019 28 17 77 36 40Medium Dose Aspirin:  No  Yes  Total 67 100 22 100 89 10040 60 18 82 58 6527 40 4 18 31 35High Dose Aspirin:  No  Yes   Total 67 100 22 100 89 10062 93 21 95 83 935 7 1 5 6 7Other Antiplatelet:  No  Yes  Total 67 100 22 100 89 100Question: In your current practice, which aspirin dosing do you use in the treatment of patients with Kawasaki disease at time of initial diagnosis?Survey of Paediatricians155Table 3.S12: Definition of Resistance by Time to DefervescenceTime for definition of resistant KD (hrs)12 hrs 24 hrs36 hrs48 hrs72 hrsNo.%No.%No.%No.%No.%114859172116200028727312135014Responder’s country:  Australia  New Zealand  Total3355512019292711343345141923311100562225112000076419327000076421821800003751250000Responder’s Specialty Group:  General Paediatrics  Cardiology  Infectious Disease  Immunology/Rheumatology  None  Total3355512019292711Question: A patient is treated for Kawasaki disease with IVIG and has persistent fever. How many hours after the end of IVIG infusion would you consider persistent or recrudescent fever to signify IVIG non-response?Chapter 3156Table 3.S13: Secondary Therapy for Kawasaki Disease in Children with Normal Coronary Arteries at DiagnosisResponder’s Specialty GroupNo.%No.%No.%No.%No.%No.%None:  No69978100111001110037510297  Yes2300000012533  Total71100810011100111004100105100649078811100111003759691710112000012599IVIG 1 g/kg:  No  Yes  Total711008100111001110041001051001521112191925020195679788109110912508581IVIG 2 g/kg:  No  Yes  Total71100810011100111004100105100628767587398241008985913225327218001615Oral Steroid:   No  Yes  Total71100810011100111004100105100IV Steroid:  No476656243654541006562  Yes2434338764655004038  Total71100810011100111004100105100Continued. ..General PaediatricsCardiologyInfectious DiseaseImmunology/Rheum.NoneTotalSurvey of Paediatricians157...Table 3.S13 ContinuedResponder’s Specialty GroupNo.%No.%No.%No.%No.%No.%Infliximab:  No709981009821091410010196  Yes1100218190044  Total71100810011100111004100105100Etanercept:  No711008100109111100410010499  Yes000019000011  Total71100810011100111004100105100Anakinra:  No711008100109111100410010499  Yes000019000011  Total7110081001110011100410010510071100810011100111004100105100Canakinumab:  No  Total7110081001110011100410010510071100810011100111004100105100Cyclosporine:  No  Total71100810011100111004100105100Other:  No67948100111001110037510095  Yes4600000012555  Total71100810011100111004100105100Question: In your current practice, which therapies are part of your treatment of patients with acute Kawasaki disease who have not responded to initial treatment (i.e. have ongoing or recrudescence of their fever despite initial therapy)? Please select all treatment that you use some or most of the time for each category [‘category’ refers to coronary artery status at diagnosis]. You can select more than one answer.General PaediatricsCardiologyInfectious DiseaseImmunology/Rheum.NoneTotalChapter 3158Table 3.S14: Secondary Therapy for Kawasaki Disease in Children with non-Giant Aneurysms at DiagnosisResponder’s Specialty GroupNo.%No.%No.%No.%No.%No.%None:  No6510081001110011100410099100  Total651008100111001110041009910061947881110011100375939446112000012566IVIG 1 g/kg:  No  Yes  Total65100810011100111004100991001015112191912514145585788109110913758586IVIG 2 g/kg:  No  Yes   Total6510081001110011100410099100588967587387341008485711225327327001515Oral Steroid:  No  Yes  Total6510081001110011100410099100IV Steroid:  No396045043643641005556  Yes2640450764764004444  Total6510081001110011100410099100Infliximab:  No6498810098287341009394  Yes12002183270066  Total6510081001110011100410099100Etanercept:  No6510081001091109141009798  Yes000019190022   Total6510081001110011100410099100Continued. ..General PaediatricsCardiologyInfectious DiseaseImmunology/Rheum.NoneTotalSurvey of Paediatricians159...Table 3.S14 ContinuedResponder’s Specialty GroupNo.%No.%No.%No.%No.%No.%Anakinra:  No65100810010911110041009899  Yes000019000011  Total65100810011100111004100991006510081001110011100410099100Canakinumab:  No  Total65100810011100111004100991006510081001110011100410099100Cyclosporine:  No  Total6510081001110011100410099100Other:  No6295810011100111003759596  Yes3500000012544  Total6510081001110011100410099100Question: In your current practice, which therapies are part of your treatment of patients with acute Kawasaki disease who have not responded to initial treatment (i.e. have ongoing or recrudescence of their fever despite initial therapy)? Please select all treatment that you use some or most of the time for each category [‘category’ refers to coronary artery status at diagnosis]. You can select more than one answer.General PaediatricsCardiologyInfectious DiseaseImmunology/Rheum.NoneTotalChapter 3160Table 3.S15: Secondary Therapy for Kawasaki Disease in Children with Giant Aneurysms at DiagnosisResponder’s Specialty GroupNo.%No.%No.%No.%No.%No.%None:  No6410081001010011100410097100   Total641008100101001110041009710060947881010011100375919446112000012566IVIG 1 g/kg:  No  Yes  Total64100810010100111004100971001320112110191251718518078899010913758082IVIG 2 g/kg:  No  Yes  Total641008100101001110041009710059927887708734100858858112330327001212Oral Steroid:  No  Yes  Total6410081001010011100410097100IV Steroid  No365633833032741004951  Yes2844562770873004849   Total6410081001010011100410097100Infliximab:  No5992810066076441008487  Yes5800440436001313   Total6410081001010011100410097100Etanercept:  No63988100990109141009497  Yes1200110190033   Total6410081001010011100410097100Continued. ..General PaediatricsCardiologyInfectious DiseaseImmunology/Rheum.NoneTotalSurvey of Paediatricians161...Table 3.S15 ContinuedResponder’s Specialty GroupNo.%No.%No.%No.%No.%No.%Anakinra:  No629781009901110041009497  Yes2300110000033   Total64100810010100111004100971006410081001010011100410097100Canakinumab:  No  Total641008100101001110041009710062978100101001110041009598230000000022Cyclosporine:  No  Yes  Total6410081001010011100410097100Other:  No6094810010100111003759295  Yes4600000012555   Total6410081001010011100410097100Question: In your current practice, which therapies are part of your treatment of patients with acute Kawasaki disease who have not responded to initial treatment (i.e. have ongoing or recrudescence of their fever despite initial therapy)? Please select all treatment that you use some or most of the time for each category [‘category’ refers to coronary artery status at diagnosis]. You can select more than one answer.General PaediatricsCardiologyInfectious DiseaseImmunology/Rheum.NoneTotalChapter 3162  Chapter 4 The following manuscript, entitled “Epidemiology of Kawasaki disease in Australia using two nationally complete datasets” was published in The Journal of Paediatrics and Child Health in 2021. The study sought to update the KD incidence estimate for Australia by analysing two independent nation-wide datasets: one that recorded hospitalisations (using ICD discharge diagnosis codes), and another that recorded the allocation of IVIG by The Australian Red Cross Blood Service (Now Australian Red Cross Lifeblood). We reported that the incidence of KD had been rising, on average, 3.5% annually over a 25-year period. We also observed some evidence of seasonal variation in the rates of IVIG use for KD, noting that this pattern appeared to vary by latitude. This research was made possible by the provision of data by Australian Red Cross Lifeblood. Australian governments fund Australian Red Cross Lifeblood to provide blood, blood products and services to the Australian community. I acknowledge the support of the data custodians in facilitating access to these data. I am grateful to Dr Saundankar (Great Ormond Street Children’s Hospital, Formerly of Children’s Cardiac Centre, Princess Margaret Hospital for Children, Perth, Western Australia, Australia), who provided access to data from her study into the epidemiology of KD in Western Australia. This study was supported by a National Blood Sector Research and Development Pilot Project grant (ID111) from the National Blood Authority of Australia. 163164ORIGINAL ARTICLEEpidemiology of Kawasaki disease in Australia using twonationally complete datasetsRyan Lucas ,1,2 Peta Dennington ,3 Erica Wood ,4,5 Kevin J Murray,6 Allen Cheng ,7,8 David Burgner 9,10and Davinder Singh-Grewal 1,2,111Faculty of Medicine and Health, Discipline of Child and Adolescent Health, The University of Sydney, 2Department of General Medicine, The SydneyChildren’s Hospitals Network Randwick and Westmead, 3Transfusion Medicine Services Team, Australian Red Cross Lifeblood New South Wales andAustralian Capital Territory, 11School of Women’s and Children’s Health, University of New South Wales Faculty of Medicine, Sydney, New South Wales,4Transfusion Research Unit, 8Infectious Disease Epidemiology Unit, Monash University School of Public Health and Preventive Medicine, 5Department ofClinical Haematology, Monash Health, 7Department of Infectious Diseases, Alfred Health, Infection Prevention and Healthcare Epidemiology Unit, 9Infectionand Immunity Theme, Murdoch Children’s Research Institute, 10Melbourne Medical School, Department of Paediatrics, The University of Melbourne,Melbourne, Victoria and 6Department of Rheumatology, Perth Children’s Hospital, Perth, Western Australia, AustraliaAim: The incidence of Kawasaki disease (KD) is reported to be increasing in some populations. We sought to describe long-term trends in theincidence and epidemiology of KD in Australia over 25 years.Methods: Two nationally complete administrative datasets relevant to KD in Australia were analysed and compared. The Australian Red CrossLifeblood Supply Tracking Analysis Reporting System (STARS) recorded all doses of immunoglobulin (IVIG) approved in Australia between January2007 and June 2016. The Australian Institute of Health and Welfare National Hospital Morbidity Database (NHMD) records all episodes of care inhospitals across Australia. Data relevant to KD were extracted an analysed, with comparisons made for the period of data overlap.Results: During the period of data overlap (2007–2015) the IVIG treatment rate in the 0- to 4-year age group (calculated from STARS) was14.31 per 100 000 person-years (95% confidence interval 13.67–14.97). The hospitalisation rate in the same age group (calculated from theNHMD) was 14.99 per 100 000 person-years (95% confidence interval 14.33–15.66). Hospitalisation rates rose at an average rate of 3.54% annuallyover the 25 years to 2017 in the 0- to 4-year age group, almost exclusively in the 1- to 4-year age group.Conclusions: There is evidence of increasing KD diagnosis in Australia. Similar trends have also been reported in Asia but not in North Americaor Europe. Increasing diagnosis may reflect a true increase in disease incidence, increasing recognition or overdiagnosis. Further research isneeded to determine the cause for these trends.Key words: epidemiology; intravenous immunoglobulin; Kawasaki disease; rheumatology; routinely collected health data; vasculitis.What is already known on this topic1 The most recent estimate of KD incidence in Australia was 9.34per 100,000 children under the age of 5 per year.2 There have been inconsistent reports of increasing incidence ofKD from around the world.3 There has been little research on the epidemiology of KD inAustralia.What this paper adds1 We report the current national KD incidence based on two dis-tinct complete national datasets of admissions and treatment.2 We report a clear increasing trend to KD hospitalisation over thelast 25 years.3 We report evidence of seasonal variation in the rates of IVIGtreatment for KD.Kawasaki disease (KD) is a systemic vasculitis that predominantlyaffects children under 5 years of age1 and is a leading cause ofacquired heart disease among children.2 Intravenous immuno-globulin (IVIG) at a dose of 2 g/kg significantly reduces the inci-dence of coronary artery aneurysms3 and is recommended asfirst-line treatment for KD.1 Reported incidence of KD varies,with Japan reporting rates as high as 330.2 per 100 000 person-years in the 0- to 4-year age group4; rates outside of East Asia areat least an order of magnitude lower.5,6 Many countries in Asiahave reported increasing incidence, although this has beenreported less consistently in Europe and North America.7,8Two studies have investigated the incidence of KD in Australia.Royle et al. conducted a nation-wide survey of paediatriciansbetween 1993 and 1995, reporting an incidence of 3.7 perCorrespondence: Dr Ryan Lucas, Children’s Hospital Westmead ClinicalSchool, The Children’s Hospital at Westmead, Hawksbury Road andHainsworth Street, Westmead, NSW 2145, Australia. Fax: +61 2 98450074; email: ryan.lucas@health.nsw.gov.auDavid Burgner and Davinder Singh-Grewal contributed equally asco-senior authors.Conflict of interest: None declared.Accepted for publication 10 October 2021.doi:10.1111/jpc.15816Journal of Paediatrics and Child Health (2021)© 2021 Paediatrics and Child Health Division (The Royal Australasian College of Physicians). 165and brand; and the request date and prescribing hospital. Wewere able to account for children who received multiple doses ofIVIG to determine the total number of IVIG-treated KD episodes(Supplementary Methods in Appendix S1).National Hospital Morbidity DatabaseThe Australian Institute of Health and Welfare is Australia’snational agency for information and statistics on Australia’shealth and welfare; it publishes data on all episodes of care (‘sep-arations’) at all Australian hospitals since 1993, available to thepublic online as the NHMD.14 We retrieved all separations forwhich the primary diagnosis was KD (using International Classifi-cation of Disease (ICD) discharge codes ICD-9-CM 446.1 for1993–1998 and ICD-10-AM M30.3 thereafter) between July1993 and June 2018. The number of separations was presentedin aggregated form but could be disaggregated by age bracket andsex for Australian financial years (1 July to 30 June). From thesedata, we derived the total number of hospitalisations for KD(Supplementary Methods in Appendix S1).Data linkage between the datasets was not possible due to theaggregated nature of the NHMD. Age-specific IVIG-treatmentrates and hospitalisation rates were calculated from STARS andthe NHMD, respectively, using census data from the AustralianBureau of Statistics.15 Both were annualised by Australian financialyears, and summarised by five 5-year periods: 1993–1997, 1998–2002, 2003–2007, 2008–2012 and 2013–2017.To assess the accuracy of the IVIG-treatment rate, we comparedIVIG-treated episodes of KD with data on the incidence of KD inWestern Australia published by Saundankar et al. during the 3 yearsthat the data overlapped (2007–2009).10 We then compared theIVIG-treatment and the hospitalisation rate for the 9 years that theSTARS dataset and the NHMD overlapped. Finally, we extendedthe analysis of each dataset depending on their scope andspaciotemporal resolution: the NHMD was analysed for its full25 years to examine trends in KD hospitalisation over time and spa-tiotemporal analysis of the STARS dataset assessed for seasonal pat-terns in KD treatment rates.Table 1 Kawasaki disease (KD) cases identified by Saundankar et al.and Supply Tracking Analysis Reporting System (Australian Red CrossLifeblood) (STARS) during overlapping years, 2007–2009Saundankar etal. (n = 41) STARS (n = 45)Cases, n (%)0–4 years 29 (71) 34 (76)5–9 years 7 (17) 8 (18)Rate per 100 000 person-years (95% CI)0–4 years 6.77 (4.54–9.73) 7.94 (5.50–11.10)5–9 years 1.68 (0.68–3.47) 1.92 (0.83–3.79)Cases in Saundankar et al. were derived from a state-wide retro-spective discharge audit and chart review in Western Australia.Cases in STARS represent intravenous immunoglobulin-treated epi-sodes of KD in Western Australia. CI, confidence interval.Table 2 Kawasaki disease (KD) cases identified in Supply TrackingAnalysis Reporting System (Australian Red Cross Lifeblood) (STARS)and the National Hospital Morbidity Database (Australian Institute ofHealth and Welfare) (NHMD) during overlapping years, 2007–2015STARS (n = 2590) NHMD (n = 2682)Cases, n (%)0–4 years 1885 (73.0) 1974 (73.6)5–9 years 579 (22.4) 606 (22.6)Rate per 100 000person-years (95% CI)0–4 years 14.31 (13.67–14.97) 14.99 (14.33–15.66)5–9 years 4.57 (4.21–4.96) 4.78 (4.41–5.18)Cases in STARS represent intravenous immunoglobulin-treated epi-sodes of KD. Cases in the NHMD represent hospitalizations forwhich the primary discharge diagnosis was KD. CI, confidenceinterval.Journal of Paediatrics and Child Health (2021)© 2021 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).100 000 person-years in the 0- to 4-year age group.9 Saundankar et al undertook a retrospective discharge audit and case review in Western Australia between 1979 and 2009, reporting an increase in incidence from 2.82 to 9.34 per 100 000 person-years in the 0-to 4-year age group over that period.10Studies of KD incidence often use the hospitalisation rate as a surro-gate for the incidence rate; however, factors such as multiple admis-sions in the same illness episode is likely to overestimate the true incidence.11 We sought to address these methodological shortcomings by using multiple overlapping sources. We analysed datasets of IVIG-treatment and hospitalisations that overlapped for 9 years, determin-ing the IVIG-treatment rate and the hospitalisation rate for that period. We further described trends in KD hospitalisation over a 25-year period and undertook a spatiotemporal analysis of IVIG treat-ment data to assess for seasonal trends in KD treatment rates.MethodsTwo datasets were used to calculate rates of KD diagnosis, each of which was nationally complete over a given period. The Sup-ply Tracking And Reporting System (STARS) recorded doses of IVIG supplied by the national blood bank, while the National Hospital Morbidity Database (NHMD) recorded hospitalisations at all Australian hospitals. The study was conducted in accordance with the REporting of studies Conducted using Observational Routinely-collected health Data statement.12Supply tracking and reporting systemAustralian Red Cross Lifeblood (previously the Australian Red Cross Blood Service) is the single provider of publicly funded blood products in Australia. Strict criteria govern the access to publicly funded IVIG, with KD an approved indication since 1993.13 STARS was the inventory management system used by Australian Red Cross Lifeblood for immunoglobulin products from 2006 to 2016. We analysed records of all doses of IVIG sup-plied for KD from January 2007 to June 2016; data available included patient name, date of birth, sex and weight; IVIG doseR Lucas et al.Chapter 4166Statistical analysis was performed using Stata/IC 15.1 for Mac(StataCorp 2017; Stata Statistical Software: Release 15, CollegeStation, TX, USA). Confidence intervals for rates assume aPoisson distribution; binomial distribution was used for propor-tions. Seasonality was assessed using the Walter-Elwood test.16Ethical approval was granted by the Human Research EthicsCommittee of Australian Red Cross Lifeblood (HREC 2015#12).ResultsSTARS recorded 3176 doses of IVIG issued for the treatment ofKD between January 2007 and June 2016, representing 2694IVIG-treated episodes of KD in 2645 individuals. Of the 2694IVIG-treated episodes of KD, 485 (18.0%) received two or moredoses of IVIG within 30 days (IVIG retreatment). Of the 2645individuals treated with IVIG, 33 (1.2%) had two or more dis-crete IVIG-treated episodes of KD (i.e. doses of IVIG for the treat-ment of KD separated by more than 30 days – classified asdisease recurrence; see Methods for details). The STARS datasetoverlapped with data published by Saundankar et al. for 3 years,during which there was close agreement (Table 1, WesternAustralia data only). The NHMD recorded 6395 episodes of carefor KD between 1993 and 2017, representing 5949 KDhospitalisations.There was close agreement between the IVIG treatmentrate and the hospitalisation rate during the 9 years in whichthe STARS and NHMD datasets overlapped (Table 2, Fig. 1).In the 0- to 4-year age group, the IVIG-treatment rate was14.31 per 100 000 person-years (95% confidence interval(CI) 13.67–14.97), and the hospitalisation rate was 14.99 perFig 1 Hospitalisation rate and intravenous immunoglobulin (IVIG)-treatment rate of Kawasaki disease (KD) in Australia over 25 years, with comparison topublished historical estimates of incidence. Comparison to previous published estimates of Australian KD incidence: Royle et al.9 and Saundankar et al.10The study by Saundankar et al. was performed in only one Australian state – Western Australia. Hospitalisations data are from the National Hospital Mor-bidity Database – Australian Institute of Health and Welfare (NHMD). IVIG-treatment data are from the Supply Tracking Analysis Reporting System –Australian Red Cross Lifeblood (STARS). ( ), NHMD 0–4 years; ( ), STARS 0–4 years; ( ), Saundankar 0–4 years; ( ), Royle 0–4 years; ( ),NHMD 5–9 years; ( ), STARS 5–9 years; ( ), Saundankar 5–9 years; ( ), Royle 5–9 years.Journal of Paediatrics and Child Health (2021)© 2021 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).R Lucas et al.Epidemiology of KD in Australia167100 000 person-years (95% CI 14.33–15.66). Rates in the5- to 9-year age group showed a similar level of agreement(Table 2).Hospitalisation trendsHospitalisation rates in the 0- to 4-year age group rose an averagerate of 3.5% (95% CI 2.9–4.1) annually between 1993 and 2018,increasing from 9.39 per 100 000 person-years (95% CI 8.66–10.16) in 1993–1997 to 17.47 per 100 000 person-years in 2013–2017 (95% CI 16.59–18.47) (Table 3). Similar rates of growthwere observed in the 5- to 9-year and 10- to 14-year age groups,but not in the 0- to 1-year or 15- to 19-year age group (Table 3).Hospitalisation rates by sex are provided in Table S2 (SupportingInformation).Age distributionDifferential rates of change in hospitalisation rates resulted ina changing age structure of KD hospitalisations over the fiveTable 3 Kawasaki disease hospitalisation rate, by age: 1993–1997 to 2013–2017Age group,yearsHospitalisation rate (per 100 000 person-years) Mean annualincrease1993–1997, rate(95% CI)1998–2002, rate(95% CI)2003–2007, rate(95% CI)2008–2012, rate(95% CI)2013–2017, rate(95% CI)1993–2017, %(95% CI)0–4 9.39 (8.66–10.16) 9.39 (8.65–10.17) 12.14 (11.31–13.02) 14.79 (13.91–15.70) 17.51 (16.59–18.47) 3.5 (2.9–4.1)0–1 13.50 (11.57–15.67) 11.03 (9.27–13.03) 13.83 (11.89–16.00) 15.55 (13.61–17.70) 13.77 (11.98–15.75) 0.7 (!0.3–1.8)1–4 8.37 (7.60–9.20) 8.99 (8.18–9.85) 11.71 (10.80–12.69) 14.59 (13.62–15.61) 18.44 (17.39–19.54) 4.3 (3.7–5.0)5–9 2.85 (2.45–3.29) 2.72 (2.34–3.15) 3.23 (2.81–3.69) 4.31 (3.83–4.83) 5.49 (4.98–6.04) 4.0 (2.5–5.4)10–14 0.28 (0.17–0.44) 0.51 (0.35–0.71) 0.51 (0.35–0.71) 0.76 (0.57–1.00) 0.72 (0.53–0.94) 4.5 (2.9–6.2)15–19 0.05 (0.01–0.14) 0.09 (0.03–0.20) 0.12 (0.05–0.23) 0.07 (0.02–0.16) 0.15 (0.07–0.27) 4.2 (!0.1–8.6)Hospitalizations data are from the National Hospital Morbidity Database of the Australian Institute of Health and Welfare. CI, confidence interval.Fig 2 Kawasaki disease hospitalisations, by age: 1993–1997 to 2013–2017. Hospitalisations data are from the National Hospital Morbidity Database – Australian Institute of Health and Welfare. Intravenous immunoglobulin-treatment data are from the Supply Tracking Analysis Reporting System – Australian Red Cross Lifeblood. Data are from the National Hospital Morbidity Database –Australian Institute of Health and Wel-fare. For disaggregation by sex, see Figure S1a,b (Supporting Information).( ), 0–1 years (n); ( ), 1–4 years(n); ( ), 5–9 years (n); ( ),≥10 years (n); ( ), 0–1 years (rate);( ), 1–4 years (rate); ( ), 5–9 years (rate).Journal of Paediatrics and Child Health (2021)© 2021 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).R Lucas et al.Chapter 4168periods, with a disproportionate increase in the 1- to 4-yearage group (Fig. 2, Fig. S1a,b, Supporting Information).Detailed age structure was available from the STARS dataset(Fig. 3a,b), with the overall IVIG-treatment rate peaking inthe second year of life (15.53 per 100 000 person-years, 95%CI 14.15–17.02).0255075100050100150200250300<0.5 0.5–1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 >14Cumulative percentNumber treated with IVIGAge (years)024681012141618200 1 2 3 4 5 6 7 8 9 10 11 12Treatment rate(per 100 000 per year)Age (years)Fig 3 Treatment of Kawasaki dis-ease with intravenous immuno-globulin (IVIG), by age – agedistribution and age-specific treat-ment rate: January 2007 to July2016. (a) Age distribution of 2694individuals for whom IVIG wasissued as treatment for their firstepisode of KD between January2007 and July 2016. (b) Age-specific treatment rate of KD bysingle year of age. IVIG-treatmentdata are from the Supply TrackingAnalysis Reporting System –Australian Red Cross Lifeblood.(a) ( ), Female; ( ), male.(b) ( ), All; ( ), male; ( ),female.Journal of Paediatrics and Child Health (2021)© 2021 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).R Lucas et al.Epidemiology of KD in Australia169(a)(b)Sex distributionMales outnumbered females in all age groups in both datasets (Fig. 3and Fig. S1, Supporting Information), comprising 60.3% all KDhospitalisations (95% CI 59.0–61.5) and 58.5% of all IVIG-treated epi-sodes (95% CI 56.6–60.4). Male to female ratios varied by age in bothdatasets (Fig. 4, Table S3, Supporting Information), with the male pre-dominance higher in the 0- to 1-year age group than other groups.Seasonal variationThere was some evidence of seasonal variation in KD diagnosis,with higher average monthly treatment rates in the second halfof the year compared with the first (18.9 episodes per monthbetween July and December vs. 14.6 per month betweenJanuary and June; P < 0.001). Seasonal variation was poorlymodelled by a sinusoidal function (Walter Elwood tests505560657075800–1 years 1–4 years 5–9 years 10–14 yearsMales (%)Age group(a) (b)505560657075800–1 years 1–4 years 5–9 years 10–14 yearsMales (%)Age groupFig 4 Males as a percentage of total Kawasaki disease numbers, by age: comparison of two datasets. (a) Hospitalisations data are from the National Hos-pital Morbidity Database – Australian Institute of Health and Welfare (NHMD). (b) Intravenous immunoglobulin-treatment data are from the Supply TrackingAnalysis Reporting System – Australian Red Cross Lifeblood (STARS). Bars represent 95% confidence interval assuming a binomial distribution.010203001020300102030010203001020300102030J F M A M J J A S O N D J F M A M J J A S O N D J F M A M J J A S O N DJ F M A M J J A S O N D J F M A M J J A S O N D J F M A M J J A S O N DAustralia NSW and ACT QLD and NTSA VIC and TAS WAMonthly incidence, 0 – 4 years(per 100 000 person-years)MonthFig 5 Monthly variation of Kawasaki disease treatment rates in Australia, by region: 2007–2015. Intravenous immunoglobulin-treatment data are fromthe Supply Tracking Analysis Reporting System – Australian Red Cross Lifeblood. Bars represent 95% confidence interval (CI) assuming a binomial distribu-tion. For plots of individual years, see Figure S2a–f (Supporting Information). ( ), Rate; ( ), 95% CI.Journal of Paediatrics and Child Health (2021)© 2021 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).R Lucas et al.Chapter 4170P < 0.001, peak mid-September – Southern Hemisphere Spring).This pattern varied across Australia; a unimodal distribution wasobserved in temperate south-eastern states (e.g. Victoria, NewSouth Wales), with peak incidence between August and October.There was some indication of a bimodal distribution in the tropi-cal northern states (e.g. Queensland and New Territory), withsmaller peaks occurring in April and December. (Fig. 5, Table S4and Fig. 2a–f, Supporting Information)DiscussionWe used two independent national datasets to derive themost rigorous estimate of KD incidence in Australia to date.For the period 2007–2015, we were able to accurately deter-mine both the IVIG-treatment rate and the KD hospitalisationrate, which we believe provide lower and upper bounds ofthe true diagnosis rate, respectively. We then extended ouranalyses of both datasets, describing trends in hospitalisationsover 25 years and seasonal variation in the IVIG-treatmentrates by region.During the 9 years in which the datasets overlapped, the treat-ment rate of KD with IVIG was 14.31 per 100 000 person-yearsin the 0- to 4-year age group (95% CI 13.67–14.97), while thehospitalisation rate in the same age group was 14.99 per 100 000person-years (95% CI 14.33–15.66). This is markedly higher thanthe previous estimate of Australian incidence of 9.34 per 100 000person-years,10 suggesting that the incidence of KD in Australiais approaching that reported in the USA (20.8 per 100 000 perannum)17 and Canada (20.5 per 100 000 per annum),18 and isconsiderably higher than that reported most recently in the UK(8.39 per 100 000 per annum).19We observed a mean annual increase in the KD hospitalisationrate of 3.5% in the 0- to 4-year age group over 25 years. Thisincrease occurred primarily in the 1- to 4-year age group, whichreplaced the 0- to 1-year age group as the age group with thehighest incidence of KD – a phenomenon not previously reportedelsewhere. It is unclear whether this change in KDhospitalisations reflects a true increase in disease incidence,increasing recognition and/or diagnosis, or both. Increasing KDincidence has been inconsistently reported around the world.Data from Japan are the most convincing; with increasing inci-dence consistently reported from hospital-based surveys foralmost 40 years, albeit with response rates below 75%.20 Evi-dence of increasing incidence in other regions is less clear.5,6,8 Itis notable that the period of this study also saw significantchanges in Australia’s demographic structure, with the propor-tion of Australian residents born in Asia increasing from 5% in1996 to over 12% in 201921; however, the possible influence ofthis demographic change could not be assessed in this study.We observed an overall male to female ratio of 1.52:1 – similarto previously reported data1 – however, this varied by age, withan exaggerated male predominance in the 0- to 1-year and 10-to 14-year age groups (2.08:1 and 1.65:1, respectively). Advaniet al. reported a male to female ratio of 4:1 among adolescents,22however the phenomenon has not previously been reported inthe 0- to 1-year age group (although it is evident in data publi-shed by Makino et al.20).We observed a peak in the IVIG treatment rate in September(Southern Hemisphere spring) nationally, although the seasonalpatterns differed between the temperate south-eastern states –which had a unimodal distribution, and the tropical northernstates – which had a bimodal distribution. Globally, there is widevariation in the reported seasonality of KD.23 While there arefew data on KD seasonality in the Southern Hemisphere, ourobservation of a peak in September is similar to that reported inNew Zealand.24Studies of disease incidence typically take one of twoapproaches to case definition: the ‘formal’ approach where theunit of measure is cases fulfilling strict diagnostic criteria, or the‘pragmatic’ approach, where the unit of measure is physician-made diagnoses. While the formal approach is rigorous, limita-tions arise when the boundaries of the disease expand beyondthe defined criteria, as is the case for KD. A pragmatic approachhas commonly been taken in KD research – using the diagnosisrate as a surrogate for incidence and estimating the diagnosis ratefrom the hospitalisation rate. This approach leverages the avail-ability of large administrative datasets reporting hospitalisations,but has been shown to overestimate true KD numbers.11,25 Wesought to address this bias by using the rate of IVIG treatment asa second measure of the diagnosis rate. This novel approach waspossible as Australia has a single centralised provider of publiclyfunded immunoglobulin, and the concordant results increase ourconfidence in the estimate of the incidence rate.We acknowledge a number of important limitations to thisapproach. We retrospectively analysed administrative datasetsthat were not originally established for research and thereforethe analysis involved a number of assumptions. We consideredall hospital-based episodes of care for KD requiring at least1-night admission in KD hospitalisation. Children treated as out-patients would have been systematically excluded from thisstudy; however, this would be rare as Australian practicethroughout the study period was for inpatient management. Wewere unable to account for children having multiplehospitalisations within the same episode of KD (as might occur intreatment-resistant disease). We addressed this bias in the STARSdataset by defining a 30-day cut-off within which retreatmentconstituted resistance and after which constituted disease recur-rence. We were unable to comment on issues of diagnostic erroror misclassification. We sought to address this by comparing ourestimates of the IVIG treatment rate with estimates derived fromdata by Saundankar et al. that used a formal case definition forKD; this was applied by reviewing individual patient medicalrecords. Estimates from both datasets were similar in the over-lapping years.This study has several key strengths related to the complete-ness and quality of the data sources. Australia has a publiclyfunded universal health-care system (Medicare) that providesfree treatment in public hospitals to citizens and most residents;data about hospitalisations are therefore unlikely to be biassed byissues of inequitable access to health care. Additionally, coding ofdischarge diagnosis is standardised for the purpose of hospitalfunding, ensuring a high level of data quality. Consequently, ourestimate of the hospitalisation rate is likely to be accurate. Ourestimate of the IVIG treatment rate used data from Australia’ssole provider of publicly funded blood products – Australian RedCross Lifeblood. The STARS database has previously been vali-dated for accuracy and completeness of data; estimates of theIVIG treatment rate are therefore also likely to be accurate.Journal of Paediatrics and Child Health (2021)© 2021 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).R Lucas et al.Epidemiology of KD in Australia171and long-term management of Kawasaki disease: A scientific state-ment for health professionals from the American Heart Association.Circulation 2017; 135: e927–99.2 Taubert KA, Rowley AH, Shulman ST. Nationwide survey of Kawasakidisease and acute rheumatic fever. J. Pediatr. 1991; 119: 279–82.3 Oates-Whitehead RM, Baumer JH, Haines L et al. Intravenous immu-noglobulin for the treatment of Kawasaki disease in children.Cochrane Database Syst. Rev. 2003; 2003: CD004000.4 Makino N, Nakamura Y, Yashiro M et al. Nationwide epidemiologicsurvey of Kawasaki disease in Japan, 2015–2016. Pediatr. Int. 2019;61: 397–403.5 Lin YT, Manlhiot C, Ching JCY et al. Repeated systematic surveillanceof Kawasaki disease in Ontario from 1995 to 2006. Pediatr. Int. 2010;52: 699–706.6 Tulloh RMR, Mayon-White R, Harnden A et al. Kawasaki disease: Aprospective population survey in the UK and Ireland from 2013 to2015. Arch. Dis. Child. 2019; 104: 640–6.7 Uehara R, Belay ED. Epidemiology of Kawasaki disease in Asia,Europe, and the United States. J. Epidemiol. 2012; 22: 79–85.8 Maddox RA, Person MK, Kennedy JL et al. Kawasaki disease andKawasaki disease shock syndrome hospitalization rates in theUnited States, 2006–2018. Pediatr. Infect. Dis. J. 2020; 40: 284–8.9 Royle JA, Williams K, Elliott E et al. Kawasaki disease in Australia,1993–95. Arch. Dis. Child. 1998; 78: 33–9.10 Saundankar J, Yim D, Itotoh B et al. The epidemiology and clinical fea-tures of Kawasaki disease in Australia. Pediatrics 2014; 133: e1009–14.11 Gibbons RV, Parashar UD, Holman RC et al. An evaluation of hospitali-zations for Kawasaki syndrome in Georgia. Arch. Pediatr. Adolesc.Med. 2002; 156: 492–6.12 Benchimol EI, Smeeth L, Guttmann A et al. The reporting of studiesconducted using observational routinely-collected health data(RECORD) statement. PLoS Med. 2015; 12: e1001885.13 Keller T, McGrath K, Newland A, Gatenby P, Cobcroft R, Gibson J. Indi-cations for use of intravenous immunoglobulin: Recommendations ofthe Australasian Society of Blood Transfusion consensus symposium.Med. J. Aust. 1993; 159: 204–6.14 Australian Institute of Health and Welfare. Principal Diagnosis data cubes[Internet]. Canberra: Australian Institute of Health and Welfare; 2019 Avail-able from: https://www.aihw.gov.au/reports/hospitals/principal-diagnosis-data-cubes. [accessed 10 November 2020].15 Australian Bureau of Statistics. Australian Demographic Statistics, Jun2018 “Table 59. Estimated Resident Population By Single Year OfAge, Australia” Time Series Spreadsheet. Canberra; 2018 Jun. ReportNo.: 3101.0. Available from: https://www.abs.gov.au/AUSSTATS/abs@.nsf/Lookup/3101.0Main+Features1Jun%202018?OpenDocument [cited24 February 2020].16 Walter SD, Elwood JM. A test for seasonality of events with a vari-able population at risk. J. Epidemiol. Community Health 1975; 29:18–21.17 Holman RC, Belay ED, Christensen KY, Folkema AM, Steiner CA,Schonberger LB. Hospitalizations for Kawasaki syndrome among chil-dren in the United States, 1997–2007. Pediatr. Infect. Dis. J. 2010; 29:483–8.18 Hearn J, McCrindle BW, Mueller B et al. Spatiotemporal clustering ofcases of Kawasaki disease and associated coronary artery aneurysmsin Canada. Sci. Rep. 2018; 8: 17682.19 Harnden A, Mayon-White R, Perera R, Yeates D, Goldacre M,Burgner D. Kawasaki disease in England: Ethnicity, deprivation, andrespiratory pathogens. Pediatr. Infect. Dis. J. 2009; 28: 21–4.20 Makino N, Nakamura Y, Yashiro M et al. Epidemiological observationsof Kawasaki disease in Japan, 2013–2014. Pediatr. Int. 2018; 60:581–7.21 Australian Bureau of Statistics. Migration, Australia, 2018–19. Can-berra: The Bureau; 2020 Apr. Report No.: 3412.0. Available from:https://www.abs.gov.au/AUSSTATS/abs@.nsf/Lookup/3412.0Main+Features12018-19?OpenDocument [cited 17 June 2020].22 Advani N, Santoso LA, Sastroasmoro S. Profile of Kawasaki disease inadolescents: Is it different? Acta Med. Indones. 2019; 51: 6.23 Burgner D, Harnden A. Kawasaki disease: What is the epidemiol-ogy telling us about the etiology? Int. J. Infect. Dis. 2005; 9:185–94.24 Burns JC, Herzog L, Fabri O et al. Seasonality of Kawasaki disease: Aglobal perspective. PLoS One 2013; 8: e74529.25 Manlhiot C, O’Shea S, Bernknopf B et al. Epidemiology of Kawasakidisease in Canada 2004 to 2014: Comparison of surveillance usingadministrative data vs periodic medical record review. Can. J. Cardiol.2018; 34: 303–9.Supporting InformationAdditional Supporting Information may be found in the onlineversion of this article at the publisher’s web-site:Appendix S1. Supplementary methods.Table S1. Total numbers of Kawasaki disease hospitalisationsand IVIG-treated episodes, by age and sex: 1993–1997 to2013–2017.Journal of Paediatrics and Child Health (2021)© 2021 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).ConclusionsWe describe a novel approach to the investigation of KD epidemi-ology and report an increasing incidence of KD in Australia. High-quality, standardised prospective surveillance is warranted to understand the evolving epidemiology of KD in Australia and elsewhere to inform clinical and scientific priorities.AcknowledgementsThis research was made possible by the provision of data by Australian Red Cross Lifeblood. Australian governments fund Australian Red Cross Lifeblood to provide blood, blood products and services to the Australian community. We acknowledge the support of the data custodians in facilitating access to these data. We are also grateful to Dr Saundankar (Great Ormond Street Children’s Hospital, Formerly of Children’s Cardiac Centre, Prin-cess Margaret Hospital for Children, Perth, Western Australia, Australia), for providing access to data from her study into the epidemiology of KD in Western Australia. This study was supported by a National Blood Sector Research and Development Pilot Project grant (ID111) from the National Blood Authority of Australia. D Burgner and E Wood are supported by National Health and Medical Research Council (NHMRC) Investigator Grants. The funding sources had no role in the design and con-duct of the study; collection, management, analysis and interpre-tation of the data; preparation, review or approval of the manuscript, nor the decision to submit the manuscript for publication.References1 McCrindle BW, Rowley AH, Newburger JW et al. Diagnosis, treatment,R Lucas et al.Chapter 4172Table S2. Kawasaki disease hospitalisation rates and IVIG-treatment rates, by age and sex: 1993–1997 to 2013–2017.Table S3. Males as a percentage of total Kawasaki diseasehospitalisation and IVIG-treated episodes, by age: 1993–1997 to2013–2017.Table S4. Walter-Elwood test of annual periodicity for Australiaand five sub-regions.Fig. S1. Kawasaki disease hospitalisations, by age (a, males; b,females): 1993–1997 to 2013–2017.Fig. S2. Monthly variation of Kawasaki disease treatment rates inAustralia, by region: 2007 to 2015 – (a) All of Australia; (b) NewSouth Wales and the Australian Capital Territory; (c) Queenslandand the Northern Territory; (d) South Australia; (e) Victoria andTasmania; (f) Western Australia.Journal of Paediatrics and Child Health (2021)© 2021 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).R Lucas et al.Epidemiology of KD in Australia173174Epidemiology of Kawasaki disease in Australia using two nationally complete datasets Supplementary Methods We analysed two national administrative datasets relevant to KD in Australia. Hospitalisations were derived from the National Hospital Morbidity Database (NHMD), while immunoglobulin treatment was derived from the Supply Tracking Analysis Reporting System (STARS). These datasets overlapped in time allowing for comparison and cross-validation. The NHMD provided 25 years of aggregated data, whereas STARS provided individual-level data over nine years. NHMD The NHMD is a database of “separations” at Australian hospitals, both public and private, from July 1993. A separation is defined as: An episode of care for an admitted patient, which can be a total hospital stay (from admission to discharge, transfer or death) or a portion of a hospital stay beginning or ending in a change of type of care (for example, from acute care to rehabilitation).  Separation also means the process by which an admitted patient completes an episode of care either by being discharged, dying, transferring to another hospital or changing type of care.1 The NHMD is made publicly available by the Australian Institute of Health and Welfare.2 Separation numbers are provided in aggregated form for each Australian financial year, beginning July 1st 1993 (Australian financial years run from July 1st to the following June 30th, and are labelled for the calendar year in which they begin–the 1993 financial year begins on July 1st 1993). Data can be disaggregated by discharge diagnosis, sex, and age bracket (less than 1 year, 1 to 4 years, and 5-year brackets thereafter). Data cannot be disaggregated by jurisdiction or by month. We retrieved annual KD separation numbers using discharge diagnosis codes (International Classification of Disease 9–Clinical Modification [ICD-9-CM] 446.1 to 1997-98 and ICD-10–Australian Modification [ICD-10-AM] M30.3 thereafter). In order to derive data correlating with discrete clinical episodes of KD we excluded “same-day separations” and analysed only those separations involving at least one overnight stay–we describe these encounters as “hospitalisations”. This was based on Australian practice to admit children Epidemiology of KD in Australia175with acute KD overnight for observation and treatment (such as with an infusion of intravenous immunoglobulin–IVIG). Same-day separations were excluded on the basis that they were unlikely to correlate with a discrete episode of KD. Same-day separations may result if a child is admitted to a day-stay unit for IVIG infusion, however we do not believe that this occurs in practice. Same-day separations may otherwise be generated in the course of an admission that included a short transfer to another institution. For example: a child admitted to a metropolitan hospital with a diagnosis of KD might be transferred to a quaternary paediatric centre for a cardiology review and echocardiogram, before returning to the referring hospital on the same day. In this example the same-day separation recorded at the quaternary centre ought not be considered an episode of KD.  STARS IVIG at a dose of 2 grams per kilogram bodyweight significantly reduces the incidence of coronary artery aneurysms in patients with KD,3 and is recommended as first-line treatment.4 The Australian Red Cross Lifeblood (previously the Australian Red Cross Blood Service) is the sole provider of publicly funded blood products in Australia. STARS was an inventory management system used by the Australian Red Cross Lifeblood for the approval, tracking and distribution of immunoglobulin products from 2006 to 2016. It had previously been validated for accuracy and completeness of data. Strict criteria govern access to publicly funded immunoglobulin,5 with KD an approved indication since the first guidelines in 1993.6 For these reasons, we can be confident that all KD cases receiving IVIG during the study period would have been captured in the STARS database.  We retrieved all allocations of IVIG for KD recorded in STARS from January 2007 to June 2016. Each dose had the following metadata: patient record number, name, date of birth, sex, and weight; IVIG dose and brand; and the request date and delivery hospital. All records were reviewed by hand to identify errors, such as: - Patients entered more than once but with different record numbers.This occurred occasionally if a name was misspelled, or if asubsequent request came from a different hospital. Patient date ofbirth, weight, and physical location were used to re-assign these dosesand, where possible, hospital records departments were contacted toconfirm the accuracy of patient details.- Multiple doses dispatched but not give. This sometimes occurs if a vialof IVIG that had been allocated to a patient was not able to be given(i.e. it broke or expired). This was usually recorded in the commentsection of STARS by Lifeblood staff.Chapter 4176 - Patients entered without a sex. Where possible this was confirmed with the records department of the relevant hospital; one record was not able to be accurately allocated a sex. - Patients entered with incorrect date of birth. This was suspected when the weight recorded or dose allocated was implausible at the age provided. Where possible this was confirmed by calling the records department of the relevant hospital.  The resulting dataset comprised 3,176 unique doses of IVIG allocated for the treatment of IVIG between January 2007 and June 2016. Two clinical phenomena complicated the interpretation of this dataset: IVIG-resistant KD and recurrent KD. In IVIG-resistant KD there is a state of ongoing inflammation after the first dose of IVIG; provision of a second dose of IVIG is a common approach to managing this condition. Recurrent KD occurs when an individual who has previously had KD is diagnosed with KD again, with the underlying assumption of an intervening state of normalcy without systemic inflammation. In both of these scenarios an individual might receive multiple doses of IVIG; in the former these should be interpreted as representing a single ‘episode’ of KD, whereas in the latter they represent multiple discrete episodes. Unfortunately there is no consensus definition of KD recurrence.7–9 We therefore employed a 30-day cut-off such that IVIG doses issued within 30 days constituted retreatment for one episode of KD, whereas doses after 30 days constituted a new episode of KD. This 30 day period was re-calculated for each dose, such that 3 doses given over 40 days but each only 20 days apart would all be considered one episode of KD, whereas 2 doses given 40 days apart would be considered separate episodes.  For comparison with data published by Saundankar, et al KD numbers in STARS were analysed by calendar years. In contrast when KD numbers were compared with those from the NHMD they were analysed by Australian financial years (July 1st to June 30th). Finally, for seasonal analysis using the Walter-Elwood test KD numbers were analysed by calendar month. Dataset Comparison Data linkage between these datasets was not possible due to the aggregated nature of the NHMD. Age-specific incidence rates were calculated from both datasets. Historical age-specific population estimates were obtained from publicly available census data from the Australian Bureau of Statistics.10 Incidence rates are presented graphically by year, but are summarised as average annualised rates for five 5-year periods: Period 1 (1993–1997), Period 2 (1998–2002), Period 3 (2003–2007), Period 4 (2008–2012), and Period 5 (2013–2017). The NHMD and STARS overlapped fully for Period 4. Epidemiology of KD in Australia177 Statistical Analysis Statistical analysis was performed using Stata/IC 15.1 for Mac (StataCorp 2017. Stata Statistical Software: Release 15. College Station, Texas). Confidence intervals for rates assume a Poisson distribution, binomial distribution was assumed for proportions. Seasonality was assessed using the Walter-Elwood test,11 utilising the user-written command seast (authors Pearce MS and Feltbower R). The Walter-Elwood test plots case numbers over a unit circle representing the year; annual variation results in the displacement of the centre of the plot from the centre of the unit circle. The vector so derived has both magnitude and direction (measured in degrees: θº). The magnitude represents the amplitude of annual variance, whereas θ corresponds to the point in the calendar at which the maximal amplitude occurs. This is assessed using a !2 goodness-of-fit test.    Chapter 4178 References 1.  Australian Institute of Health and Welfare. Hospitals info & downloads: Glossary. Published online 2020. Accessed February 11, 2020. https://www.aihw.gov.au/reports-data/myhospitals/content/glossary 2.  Australian Institute of Health and Welfare. Principal Diagnosis Data Cubes. Australian Institute of Health and Welfare; 2019. https://www.aihw.gov.au/reports/hospitals/principal-diagnosis-data-cubes 3.  Oates-Whitehead RM, Baumer JH, Haines L, et al. Intravenous immunoglobulin for the treatment of Kawasaki disease in children. Cochrane Vascular Group, ed. Cochrane Database of Systematic Reviews. Published online October 20, 2003. doi:10.1002/14651858.CD004000 4.  McCrindle BW, Rowley AH, Newburger JW, et al. Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association. Circulation. 2017;135(17):e927–e999. doi:10.1161/CIR.0000000000000484 5.  National Blood Authority (Australia). Criteria for the Clinical Use of Intravenous Immunoglobulin in Australia.; 2012. 6.  Keller T, McGrath K, Newland A, Gatenby P, Cobcroft R, Gibson J. Indications for use of intravenous immunoglobulin: Recommendations of the Australasian Society of Blood Transfusion consensus symposium. Medical Journal of Australia. 1993;159(3):204-206. doi:10.5694/j.1326-5377.1993.tb137790.x 7.  Gibbons RV, Parashar UD, Holman RC, et al. An Evaluation of Hospitalisations for Kawasaki Syndrome in Georgia. Arch Pediatr Adolesc Med. 2002;156(5):492. doi:10.1001/archpedi.156.5.492 8.  Pierre R, Sue-Ho R, Watson D. Kawasaki syndrome in Jamaica: The Pediatric Infectious Disease Journal. 2000;19(6):539-543. doi:10.1097/00006454-200006000-00010 9.  Sudo D, Nakamura Y. Nationwide surveys show that the incidence of recurrent Kawasaki disease in Japan has hardly changed over the last 30 years. Acta Paediatrica. 2017;106(5):796-800. doi:10.1111/apa.13773 10.  Australian Bureau of Statistics. Australian Demographic Statistics, Jun 2018 “Table 59. Estimated Resident Population By Single Year Of Age, Epidemiology of KD in Australia179Australia” Time Series Spreadsheet.; 2018. Accessed February 24, 2020. https://www.abs.gov.au/AUSSTATS/abs@.nsf/Lookup/3101.0Main+Features1Jun%202018?OpenDocument 11. Walter SD, Elwood JM. A test for seasonality of events with a variablepopulation at risk. Journal of Epidemiology & Community Health.1975;29(1):18-21. doi:10.1136/jech.29.1.18Chapter 4180 Epidemiology of Kawasaki disease in Australia using two nationally complete datasets Supplementary Results TablesTable 4.S1: Total Numbers of Kawasaki Disease Hospitalisations and IVIG-Treated Episodes, by Age and Sex: 1993–1997 to 2013–2017 Datasets overlapped for 9 complete years, from July 2007 to June 2016; STARS data here only shown for the 2008–2012 period. *One record did not have sex allocated. Abbreviations: NHMD, National Hospital Morbidity Database–Australian Institute of Health and Welfare; STARS, Supply Tracking and Reporting System–Australian Red Cross Lifeblood.    1993–1997 1998–2002 2003–2007 2008–2012 2013–2017 Data source NHMD NHMD NHMD NHMD STARS NHMD Both       0–4 years 607 599 783 1,067 1,012 1,360   0–1 years 173 138 181 230 202 213   1–4 years 434 461 602 837 810 1,147 5–9 years 184 182 214 295 288 420 10–14 years 18 34 35 53 57 51 15–19 years 3 6 8 5 7 11 ≥20 years 4 1 2 3 4 4 Total 816 822 1,042 1,423 1,368* 1,846 Males       0–4 years 405 358 484 615 579 809   0–1 years 130 85 133 147 132 136   1–4 years 275 273 351 468 447 673 5–9 years 94 103 140 181 166 246 10–14 years 11 23 20 28 36 37 15–19 years 2 5 6 5 6 5 ≥20 years 1 0 1 2 3 4 Total 513 489 651 831 790 1,101 Females       0–4 years 202 241 299 452 432 551   0–1 years 43 53 48 83 70 77   1–4 years 159 188 251 369 362 474 5–9 years 90 79 74 114 122 174 10–14 years 7 11 15 25 21 14 15–19 years 1 1 2 0 1 6 ≥20 years 3 1 0 1 1 0 Total 303 333 391 592 577 745 Epidemiology of KD in Australia181Table 4.S2: Kawasaki Disease Hospitalisation Rates and IVIG-Treatment Rates, by Age and Sex: 1993–1997 to 2013–2017 1993–1997 1998–2002 2003–2007 2008–2012 2013–2017 Data source NHMD NHMD NHMD NHMD STARS NHMD All 0–4 years 9.39 (8.66–10.16) 9.39 (8.65–10.17) 12.14 (11.31–13.02) 14.79 (13.91–15.70) 14.03 (13.17–14.92) 17.51 (16.59–18.47)   0–1 years 13.50 (11.57–15.67) 11.03 (9.27–13.03) 13.83 (11.89–16.00) 15.55 (13.61–17.70) 13.66 (11.84–15.68) 13.77 (11.98–15.75)   1–4 years 8.37 (7.60–9.20) 8.99 (8.18–9.85) 11.71 (10.80–12.69) 14.59 (13.62–15.61) 14.12 (13.16–15.13) 18.44 (17.39–19.54) 5–9 years 2.85 (2.45–3.29) 2.72 (2.34–3.15) 3.23 (2.81–3.69) 4.31 (3.83–4.83) 4.21 (3.73–4.72) 5.49 (4.98–6.04) 10–14 years 0.28 (0.17–0.44) 0.51 (0.35–0.71) 0.51 (0.35–0.71) 0.76 (0.57–1.00) 0.82 (0.62–1.07) 0.72 (0.53–0.94) 15–19 years 0.05 (0.01–0.14) 0.09 (0.03–0.20) 0.12 (0.05–0.23) 0.07 (0.02–0.16) 0.10 (0.04–0.20) 0.15 (0.07–0.27) Males 0–4 years 12.21 (11.05–13.46) 10.94 (9.83–12.13) 14.63 (13.35–15.99) 16.60 (15.32–17.97) 15.63 (14.38–16.96) 20.29 (18.91–21.73)   0–1 years 19.77 (16.52–23.48) 13.25 (10.58–16.38) 19.78 (16.56–23.44) 19.36 (16.35–22.75) 17.38 (14.54–20.61) 17.12 (14.36–20.25)   1–4 years 10.34 (9.15–11.63) 10.37 (9.18–11.68) 13.31 (11.96–14.78) 15.89 (14.48–17.40) 15.18 (13.80–16.65) 21.08 (19.51–22.73) 5–9 years 2.84 (2.30–3.48) 3.01 (2.45–3.64) 4.12 (3.47–4.86) 5.15 (4.43–5.96) 4.73 (4.03–5.50) 6.27 (5.51–7.10) 10–14 years 0.33 (0.17–0.60) 0.68 (0.43–1.01) 0.56 (0.34–0.87) 0.79 (0.52–1.14) 1.01 (0.71–1.40) 1.01 (0.71–1.40) 15–19 years 0.06 (0.01–0.22) 0.15 (0.05–0.35) 0.17 (0.06–0.37) 0.13 (0.04–0.31) 0.16 (0.06–0.35) 0.13 (0.04–0.31) Females 0–4 years 6.42 (5.56–7.36) 7.75 (6.81–8.80) 9.53 (8.48–10.67) 12.87 (11.71–14.12) 12.30 (11.17–13.52) 14.58 (13.39–15.85)   0–1 years 6.90 (4.99–9.29) 8.69 (6.51–11.37) 7.54 (5.56–10.00) 11.53 (9.19–14.30) 9.73 (7.58–12.29) 10.24 (8.08–12.79)   1–4 years 6.30 (5.36–7.36) 7.53 (6.49–8.68) 10.03 (8.83–11.35) 13.22 (11.90–14.64) 12.97 (11.67–14.37) 15.66 (14.28–17.13) 5–9 years 2.86 (2.30–3.51) 2.43 (1.92–3.03) 2.29 (1.80–2.88) 3.42 (2.82–4.11) 3.66 (3.04–4.37) 4.68 (4.01–5.43) 10–14 years 0.22 (0.09–0.46) 0.34 (0.17–0.61) 0.45 (0.25–0.74) 0.74 (0.48–1.09) 0.62 (0.39–0.95) 0.40 (0.22–0.68) 15–19 years 0.03 (0.00–0.18) 0.03 (0.00–0.17) 0.06 (0.01–0.21) 0.00 (0.00–0.10) 0.03 (0.00–0.16) 0.17 (0.06–0.36) Rates given as cases per 100,000 person-years. Datasets overlapped for 9 complete years, from July 2007 to June 2016; STARS data here only shown for the 2008–2012 period. Abbreviations: NHMD, National Hospital Morbidity Database–Australian Institute of Health and Welfare; STARS, Supply Tracking and Reporting System–Australian Red Cross Lifeblood. Chapter 4182Table 4.S3: Males as a Percentage of Total Kawasaki Disease Hospitalisation and IVIG-Treated Episodes, by Age: 1993–1997 to 2013–2017  1993–1997 1998–2002 2003–2007 2008–2012 2013–2017 Data source NHMD NHMD NHMD NHMD STARS NHMD 0–4 years 66.7 (62.9–70.4) 59.8 (55.8–63.6) 61.8 (58.4–65.2) 57.6 (54.7–60.6) 57.2 (54.1–60.2) 59.5 (56.9–62.1)   0–1 years 75.1 (68.2–81.0) 61.6 (53.3–69.3) 73.5 (66.6–79.4) 63.9 (57.5–69.8) 65.3 (58.5–71.6) 63.8 (57.2–70.0)   1–4 years 63.4 (58.7–67.8) 59.2 (54.7–63.6) 58.3 (54.3–62.2) 55.9 (52.5–59.2) 55.2 (51.7–58.6) 58.7 (55.8–61.5) 5–9 years 51.1 (43.9–58.2) 56.6 (49.3–63.6) 65.4 (58.8–71.5) 61.4 (55.7–66.7) 57.6 (51.9–63.2) 58.6 (53.8–63.2) 10–14 years 61.1 (38.5–79.8) 67.6 (50.7–81.0) 57.1 (40.8–72.0) 52.8 (39.7–65.6) 63.2 (50.2–74.5) 72.5 (59.0–83.0) Datasets overlapped for 9 complete years, from July 2007 to June 2016; STARS data here only shown for the 2008–2012 period. Abbreviations: NHMD, National Hospital Morbidity Database–Australian Institute of Health and Welfare (hospitalisations); STARS, Supply Tracking and Reporting System–Australian Red Cross Lifeblood (IVIG-treated episodes). Table 4.S4: Walter-Elwood Test of Annual Periodicity for Australia and Five Sub-Regions. Region Walter Elwood p Angle Month Amplitude All Australia <0.001 254º September 0.2 NSW & ACT <0.001 249º September 0.2 QLD & NT <0.001 339º December 0.3 SA 0.276 210º August 0.2 VIC & TAS <0.001 234º August 0.2 WA <0.001 274º October 0.5 Data from the Supply Tracking and Reporting System–Australian Red Cross Lifeblood. Epidemiology of KD in Australia183Figures Figure 4.S1a: Kawasaki Disease Hospitalisations, by Age (Males): 1993–1997 to 2013–2017 Data from the National Hospital Morbidity Database–Australian Institute of Health and Welfare. Bars represent 95% confidence intervals. 03006009001200150005101520251993-1997 1998-2002 2003-2007 2008-2012 2013-2017Total HospitalisationsHospitalisation Rate(per 100,000 person-years)A. Males0-1 years (n) 1-4 years (n) 5-9 years (n) ≥10 years (n)0-1 years (rate) 1-4 years(rate) 5-9 years (rate)Chapter 4184Figure 4.S1b: Kawasaki Disease Hospitalisations, by Age (Females): 1993–1997 to 2013–2017 Data from the National Hospital Morbidity Database–Australian Institute of Health and Welfare. Bars represent 95% confidence intervals. 03006009001200150005101520251993-1997 1998-2002 2003-2007 2008-2012 2013-2017Total HospitalisationsHospitalisation Rate(per 100,000 person-years)B. Females0-1 years (n) 1-4 years (n) 5-9 years (n) ≥10 years (n)0-1 years (rate) 1-4 years(rate) 5-9 years (rate)Epidemiology of KD in Australia185Figure 4.S2a: Monthly Variation of Kawasaki Disease Treatment Rates in Australia, by Region: 2007–2015, All of Australia Data from the Supply Tracking and Reporting System–Australian Red Cross Lifeblood. 510152025Monthly Incidence, 0 to 4 years(per 100,000 person-years)JFMAMJJASONDMonthIndividual YearsAverageChapter 4186Figure 4.S2b: Monthly Variation of Kawasaki Disease Treatment Rates in Australia, by Region: 2007–2015, New South Wales and the Australian Capital Territory Data from the Supply Tracking and Reporting System–Australian Red Cross Lifeblood. 010203040Monthly Incidence, 0 to 4 years(per 100,000 person-years)JFMAMJJASONDMonthIndividual YearsAverageEpidemiology of KD in Australia187Figure 4.S2c: Monthly Variation of Kawasaki Disease Treatment Rates in Australia, by Region: 2007–2015, Queensland and the Northern Territory Data from the Supply Tracking and Reporting System–Australian Red Cross Lifeblood. 0102030Monthly Incidence, 0 to 4 years(per 100,000 person-years)JFMAMJJASONDMonthIndividual YearsAverageChapter 4188Figure 4.S2d: Monthly Variation of Kawasaki Disease Treatment Rates in Australia, by Region: 2007–2015, South Australia Data from the Supply Tracking and Reporting System–Australian Red Cross Lifeblood. 01020304050Monthly Incidence, 0 to 4 years(per 100,000 person-years)JFMAMJJASONDMonthIndividual YearsAverageEpidemiology of KD in Australia189Figure 4.S2e: Monthly Variation of Kawasaki Disease Treatment Rates in Australia, by Region: 2007–2015, Victoria and Tasmania Data from the Supply Tracking and Reporting System–Australian Red Cross Lifeblood. 010203040Monthly Incidence, 0 to 4 years(per 100,000 person-years)JFMAMJJASONDMonthIndividual YearsAverageChapter 4190Figure 4.S2f: Monthly Variation of Kawasaki Disease Treatment Rates in Australia, by Region: 2007–2015, Western Australia Data from the Supply Tracking and Reporting System–Australian Red Cross Lifeblood. 01020304050Monthly Incidence, 0 to 4 years(per 100,000 person-years)JFMAMJJASONDMonthIndividual YearsAverageEpidemiology of KD in Australia191192Chapter 5 The following manuscript, entitled “Live vaccines following intravenous immunoglobulin for Kawasaki disease: Are we vaccinating appropriately?” was published in The Journal of Paediatrics and Child Health in 2023. The goal of the study was to determine whether Australian children who had received IVIG for KD are potentially at risk for vaccine preventable illnesses due to IVIG’s interference with live vaccines. Australian guidelines recommend that live vaccines be postponed for at least 11 months after IVIG for KD, yet this study found that most children who received IVIG less than 11 months prior to a scheduled live vaccine did not have that vaccination appropriately postponed. The evidence for the 11-month postponement recommendation was reviewed and found to be of poor quality. In the absence of high-quality evidence to guide immunisation guidelines we proposed that further research was needed and recommended that practitioners remain vigilant as to IVIG’s interference with live vaccines. The authors reported no conflicts of interest. Ethical approval was granted by the Human Research Ethics Council of the Sydney Children’s Hospitals Network. Approval 2021/ETH11191 with site specific approval 2021/STE03255 and 2021/STE03256. 193194ORIGINAL ARTICLELive vaccines following intravenous immunoglobulin for Kawasakidisease: Are we vaccinating appropriately?Cassandra Cardenas-Brown ,1 Ryan D Lucas ,2,3 Jim Buttery,4,5,6 Philip N Britton ,3,7,8 Nicholas Wood,2,3,7Davinder Singh-Grewal 1,3,9 and David Burgner 4,5Departments of 1Rheumatology, 2General Medicine, 8Infectious Diseases, The Sydney Children’s Hospitals Network Randwick and Westmead, 3Discipline ofChild and Adolescent Health, The University of Sydney Faculty of Medicine and Health, 7National Centre for Immunisation Research & Surveillance, 9Schoolof Women’s and Children’s Health, University of New South Wales Faculty of Medicine, Sydney, New South Wales, 4Infection and Immunity Theme,Murdoch Children’s Research Institute, 5Melbourne Medical School, Department of Paediatrics, The University of Melbourne and 6Centre for HealthAnalytics, Melbourne Children’s Campus, Melbourne, Victoria, AustraliaAim: Australian and New Zealand guidelines recommend that live vaccines be postponed for 11 months after treatment of Kawasaki disease(KD) with intravenous immunoglobulin (IVIG). We aimed to describe patterns of live-vaccine administration after KD treatment, focusing on themeasles–mumps–rubella/measles–mumps–rubella–varicella (MMR/MMRV) vaccines, and to compare real-world practice with currentrecommendations.Methods: We combined data from inpatient Electronic Health Records and the Australian Immunisation Register for all children who receivedIVIG for the treatment of KD under the age of 5 years at two Australian tertiary children’s hospitals over a 12-year period. Children who receivedIVIG <11 months before a scheduled MMR/MMRV were deemed ‘at risk’ of breaching the guidelines, and those whose subsequent vaccinationoccurred <11 months after the IVIG were deemed to have ‘breached’ the guidelines.Results: Of those at risk, three-quarters (76%) breached the guidelines for their first MMR/MMRV. Findings were similar (50%–80%) for the secondMMR/MMRV dose.Conclusions: The majority of Australian children treated for KD with IVIG may not be optimally protected by MMRV vaccination. Immunisationsystems should address this avoidable risk.Key words: immunisation; intravenous immunoglobulin; Kawasaki disease.What is already known on this topic1 The incidence of Kawasaki disease (KD) in Australia is increasing.2 Australian guidelines recommend postponing live attenuatedviral vaccines – principally measles–mumps–rubella (MMR) andmeasles–mumps–rubella–varicella (MMRV) – for 11 months fol-lowing intravenous immunoglobulin (IVIG) for KD, due to risk ofinterference with seroconversion.3 One Dutch study reported that clinicians did not routinelyadhere to the guidelines recommending postponement ofMMR/MMRV vaccinations following IVIG for KD.What this paper adds1 Almost 40% of children under 5 years of age who received IVIGfor KD were at risk of breaching Australian guidelines that rec-ommend postponing MMR/MMRV vaccines for at least11 months following IVIG.2 We identify in our ‘at risk’ cohort, between 50% and 80% of chil-dren did not have their MMR/MMRV vaccine postponed andhave been potentially sub-optimally immunised and protected.3 We review the evidence base for current Australianimmunisation guidelines recommending postponement ofMMR/MMRV vaccines following IVIG for KD.Kawasaki disease (KD) is a systemic vasculitis that typically affectschildren under the age of 5 years.1 It causes inflammation ofmedium-sized arteries and can lead to aneurysm formation, particu-larly of the coronary arteries. Intravenous immunoglobulin (IVIG)reduces the incidence of coronary artery aneurysm andAustralian and international clinical practice guidelines recom-mend that children with KD receive 2 g/kg IVIG as primarytherapy.1–3IVIG is a therapeutic product derived from the pooled plasmaof thousands of human donors.4 It contains polyclonal antibodies(mostly IgG) and was initially used to treat disorders of humoralimmunity such as agammaglobulinaemia.4 Subsequent clinicalexperience with IVIG led to an appreciation of its immunomodu-latory effects,5 and IVIG is now approved for use in a wide rangeof clinical conditions.6Correspondence: Dr Cassandra Cardenas-Brown, The Children’s Hospitalat Westmead, Hawksbury Road & Hainsworth Street, Westmead, 2145 NSW,Australia. email: cassandra.brown@health.nsw.gov.auConflict of interest: None declared.Accepted for publication 13 August 2023.doi:10.1111/jpc.16484Journal of Paediatrics and Child Health (2023)© 2023 Paediatrics and Child Health Division (The Royal Australasian College of Physicians). 195booster dose at 12 months post-IVIG was effective. Those authorssubsequently assessed seroconversion to MMRV given 6 and9 months after two doses of IVIG (i.e. 4 g/kg).8 They found uni-versal seroconversion to the measles and rubella componentswhen given 9 months post-IVIG, but again observed strikinglylow rates of seroconversion to the mumps and varicella compo-nents. This contrasts with previous studies in which measles sero-conversion was most affected by IVIG.20 Without a control arm itis unclear whether confounding factors account for the poorresponse to mumps and varicella.There is evidence of variation in real-world practice. In a studyby Tacke et al. from the Netherlands it was observed that 78% ofchildren who received IVIG did not have their scheduled MMRVvaccine appropriately delayed by the local recommendation of6 months.20We aimed to describe patterns of immunisation in childrentreated with IVIG for KD at two tertiary Australian children’shospitals to determine current adherence with Australian guide-lines and identify targets for improvement.Materials and MethodsWe undertook a retrospective audit of MMR/MMRV administra-tion of children who received IVIG for KD before the age of5 years at two tertiary children’s hospitals in Sydney, Australiaover a 12-year period. Inpatient datasets were queried for alladmissions with any discharge diagnosis of KD (ICD-10-AMcodes M30.3, G635 and I245) between 1 November 2007 and1 November 2019, limited to children aged less than 5 years atdischarge. The Electronic Health Record was reviewed to confirmreceipt of IVIG and document the date of administration. TheAustralian Immunisation Register (AIR)22 was accessed to deter-mine the date of MMR/MMRV administration. Inclusion andexclusion criteria are shown in Figure 1.The Australian National Immunisation Program (NIP) Sched-ule previously recommended the first MMR/MMRV (‘MMR1’)be given at 12 months of age and the second (‘MMR2’) at 4 yearsof age (the ‘previous schedule’).23 In response to suboptimalmeasles susceptibility among infants, and to bring Australianpractice in line with other countries (especially in Europe), therecommended timing for the MMR2 was brought forward to18 months of age from July 2013 (‘current schedule’).9,24 Wedefined three groups of children who received IVIG <11 monthsbefore an MMR/MMRV was scheduled to be given, who wedefined as being ‘at risk’ of breaching the guidelines:1 For all children: those who received IVIG between 1 and12 months of age (i.e. <11 months before MMR1 was due).2 For children aged 18 months before 1 July 2013: those whoreceived IVIG between 37 and 48 months of age(i.e. <11 months before MMR2 was due under the previousschedule).3 For children aged 18 months after 1 July 2013: those whoreceived IVIG between 7 and 18 months of age(i.e. <11 months before MMR2 was due under the currentschedule).For each group, we calculated the proportion who then receivedthe MMR less than 11 months after the dose of IVIG (i.e. theJournal of Paediatrics and Child Health (2023)© 2023 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).Passively acquired polyclonal antibodies (such as from IVIG) can interfere with seroconversion following immunisation with live attenuated viral vaccines.7,8 Measles-containing vaccines (measles–mumps–rubella, MMR; measles–mumps–rubella–vari-cella, MMRV; henceforth we use ‘MMR/MMRV’ to refer to both vaccines) are live-attenuated viral vaccines that are typically administered in the first few years of life.It is generally agreed that children who receive IVIG for KD prior to receiving an MMR/MMRV should have vaccination post-poned; however, there is no international consensus regarding the period of postponement. Guidelines in Australia9 and New Zealand10 align with those from North America, rec-ommending that live vaccines be postponed for 11 months after receiving IVIG. Canadian and American guidelines,1,11,12 all cite recommendations from the Advisory Committee on Immuniza-tion Practices,13 which advises American states and agencies on matters relating to immunisation.The 11-month interval was derived by extrapolating from an estimated immunoglobulin half-life of 30 days to a theoretical physiological persistence for 10 months, with a 1-month ‘grace period’.13 The recommendation has remained unchanged since 1994, and cites a limited body of literature.14 That literature con-sists of two studies: the first (described in two conference abstracts15,16) studied the persistence of passively acquired mea-sles antibodies following IVIG in 44 children with KD. Measles antibodies persisted for between 3 and 12 months; all children subsequently immunised had an adequate response; however, the timing of the immunisation was not specified.16 The second was a small (n = 167) randomised controlled trial of intramuscu-lar immunoglobulin for the prevention of invasive bacterial dis-ease (Haemophilus influenza type B and Streptococcus pneumoniae) among Apache children, in which it was observed that serocon-version to measles immunisation was inhibited up to 5 months after a series of intramuscular injections of immunoglobulin at 80 mg/kg.17Japanese guidelines recommend an interval between IVIG and live vaccine administration of 6–7 months,18 based on a cohort study of the persistence of passively acquired measles antibodies following IVIG showing measles antibodies were undetectable in 89% of patients 6 months after IVIG.19 Recent European recom-mendations for the treatment of KD state live vaccines ‘should’ be deferred for 6 months, but equivocate – suggesting that theMMR and MMRV ‘might’ be deferred for ‘at least 11 months’, while also asserting that children at high risk of exposure to mea-sles should be vaccinated earlier.2More rigorous studies have been published since those summarised above. Tacke et al. retrospectively evaluated serocon-version to MMR at different intervals following IVIG.20 They found the rates of seroconversion to the mumps and rubella com-ponents (but not the measles component) did not differ between cases and controls (n = 198) for those immunised 6–9 months after IVIG, and that seroconversion to all components was equiv-alent for those immunised more than 9 months after IVIG.20 Without more data on the interval to immunisation beyond 9 months it cannot be determined at what interval measles sero-conversion was assured. In an uncontrolled study, Morikawa et al. prospectively evaluated seroconversion to MMRV given 6 months after IVIG at 2 g/kg.21 They found poor rates of sero-conversion (especially for mumps and varicella), noting that aChapter 5196• IVIG given <30 days after a previous dose of IVIG was consid-ered retreatment within a single episode of KD.• IVIG given ≥30 days after a previous dose of IVIG was consid-ered treatment of a new (i.e. recurrent) episode of KD.25For episodes of KD requiring multiple doses of IVIG, we used thedate of the last dose of IVIG for the analysis. For children withmultiple episodes of KD, we considered all episodes for analysisas separate IVIG exposures.Descriptive demographic data were summarised based on theage of each child at presentation of their first episode ofKD. Analysis was performed using Stata/BE 17.0 for Mac(StataCorp, College Station, TX, USA).Ethics approval was granted by the Sydney Children’s HospitalNetwork Human Research and Ethics Committee. For childrenidentified to have received a measles-containing vaccine less than11 months after IVIG, we undertook to inform both their familiesand general practitioners so that additional booster doses couldbe offered.ResultsThere were 567 inpatient encounters with a discharge diagnosiscode of KD. Of those, 417 were admissions for the treatment ofan acute episode of KD; the remainder largely constituted diag-nostic day admissions for echocardiography and did not receiveIVIG during that admission; these encounters were excluded.Two children were excluded as the diagnosis of KD had beensubsequently revised. The 417 admissions for acute KD represen-ted 396 discrete episodes of KD occurring in 389 individuals(Fig. 1). Ninety-four (24.2%) children required more than onedose of IVIG within an admission for acute KD (i.e. they requiredre-treatment). Twenty-one children (5.4%) were readmitted tohospital after initial discharge during a single episode of KD, pre-sumably for a recurrence of symptoms, and required retreatmentwith IVIG. Seven children (1.8%) had recurrence of KD duringthe study period.Basic demographic data are shown in Table 1. Over 95% of allchildren included in the analysis received either MMR or MMRVvaccine (Table S1, Supporting Information).Overall, of the children under the current vaccination sched-ule, 39.5% (86/218) were at risk of breaching the recommenda-tions for either vaccine; 64% (55/86) of those at risk breachedthe recommendations for at least one vaccine dose (Table 2).Under the previous schedule, 28.7% (49/171) of children were atrisk of breaching either vaccine and this was proportionatelyfewer than the current schedule (P = 0.026, Table S2, SupportingInformation).Overall, regarding the MMR1, 23.1% (90/389) of childrenreceived IVIG for KD <11 months before that vaccine was due(i.e. were at risk of breaching the recommendations); of those,76% (68/90) went on to receive the MMR1 vaccine <11 monthsafter receiving IVIG (i.e. breached the recommendations, Table 3,Fig. 2). Regarding MMR2, 11.7% (20/171) of children under theprevious schedule were at risk for that vaccine, of whom 80%(16/20) breached. Of those under the current schedule, 27.5%(60/218) were at risk, of whom 50% (30/60) breached(Table 3, Fig. 3).Fig. 1 Study flowchart. IVIG given <30 days after a previous dose ofIVIG was considered retreatment within a single episode of KD. IVIG given≥30 days after a previous dose of IVIG was considered treatment of anew (i.e. recurrent) episode of KD. IVIG, intravenous immunoglobulin; KD,Kawasaki disease.Table 1 Demographic and patient characteristicsTotal (n = 389)Male, n (%) 240 (61.7)Retreatment within episode, n (%) 94 (24.2)Recurrent episode, n (%) 7 (1.8)Age at first IVIG (months), median (IQR) 25 (13–41)Age at first IVIG (months), n (%)<6 months 36 (9.3)6–<12 months 55 (14.1)12–<18 months 45 (11.6)18–<24 months 49 (12.6)24–<36 months 79 (20.3)36–<48 months 61 (15.7)≥48 months 64 (16.5)Descriptive data of patient cohort at the time of the first episode ofKawasaki disease. IVIG given <30 days after a previous dose of IVIGwas considered retreatment within a single episode of KD. IVIGgiven ≥30 days after a previous dose of IVIG was considered treat-ment of a new (i.e. recurrent) episode of KD. IQR, interquartilerange; IVIG, intravenous immunoglobulin.Journal of Paediatrics and Child Health (2023)© 2023 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).proportion of those ‘at risk’ for breaching the guidelines that sub-sequently ‘breached’ the guidelines).If children received more than one dose of IVIG, we cat-egorised the dose as follows:Live Vaccines after KD197DiscussionWe analysed MMR/MMRV administration data over a 12-yearperiod for children who received IVIG for KD before 5 years ofage. A recent study confirmed that the incidence of KD inAustralia is increasing, with the hospitalisation rate among chil-dren under 5 estimated to be 17.51 per 100 000 annually (95%CI 16.59–18.47) between 2013 and 2017.25 This figure representsan average of 272 episodes of KD per year among children under5 years in Australia (see supplementary table 1 of reference 17).We found that since the current measles vaccination schedulewas commenced, 40% of children under 5 years of age whoreceived IVIG for KD were at risk of breaching these recommen-dations, which suggests that over 100 children may be at risk ofbreaching national recommendations for live vaccines after IVIGeach year in Australia. Furthermore, this number is expected torise in line with population growth and increasing incidence ofKD and the use of IVIG.A major strength of our study was a relatively large cohortsize, which included children admitted at two hospitals over12 years. There were also important limitations. As we wereunable to undertake comprehensive case reviews for each childincluded in the analysis, we relied on discharge diagnosis codes,which could not be validated against clinical data to identify chil-dren diagnosed with KD. Notwithstanding, the aim of the studywas to understand the subsequent vaccination patters of childrenwho received IVIG for KD, rather than KD diagnosis per se. A fur-ther limitation was our reliance on the AIR for the vaccinationhistory. Only children with a valid Medicare number (eitherAustralian citizens or those on a permanent residency visa) havevaccination details entered into the AIR; we were thereforeunable to consider vaccination patterns for children in other cir-cumstances, who may be at a higher risk for breachingimmunisation recommendations. Finally, we did not seek tounderstand the drivers of deviations in practice, which is the criti-cal next step in seeking to improve the quality of care beingdelivered.The recent global resurgence of measles – particularly inSouth-East Asia and the Pacific – has highlighted the criticalimportance of effective immunisation in achieving measles eradi-cation.26 One potential means of improving the post-IVIG mea-sles vaccination guideline adherence in patients with KD wouldTable 2 Risk of breaching recommendations regarding measles-containing vaccines after intravenous immunoglobulin therapy forKawasaki disease: MMR1 or MMR2 under the current scheduleAt riskNo Yes TotalBreachedNo, n (%) 128 (97.0) 31 (36.0) 159 (72.9)Yes, n (%) 4 (3.0) 55 (63.9) 59 (27.1)Total 132 86 218Timing of measles-containing vaccines after receiving intravenousimmunoglobulin (IVIG) for Kawasaki disease (KD). The AustralianImmunisation Handbook recommends postponing live vaccines for11 months after IVIG for KD. ‘At risk’ means that a child receivedIVIG for the treatment of KD less than 11 months prior to a sched-uled measles-containing vaccine. ‘Breached’ means that a measles-containing vaccine was given less than 11 months after a childreceived IVIG for the treatment of KD. MMR1 refers to thefirst measles-containing vaccine on the National ImmunisationProgramme Schedule and is recommended to be given at12 months of age. MMR2 refers to the second measles-containingvaccine, which is recommended to be given at 18 months of age.Children who were older than 18 months of age on 1 July 2013were immunised according to the previous schedule (not includedhere). MMR, measles–mumps–rubella.Table 3 Adherence with recommendations regarding measles-containing vaccines after intravenous immunoglobulin therapy forKawasaki diseaseAt riskNo Yes TotalMMR1 (all) BreachedNo, n (%) 293 (98.0) 22 (24.4) 315 (81.0)Yes, n (%) 6 (2.0) 68 (75.6) 74 (19.0)Total, n (%) 299 (100.0) 90 (100.0) 389 (100.0)At riskNo Yes TotalMMR2(previousschedule)BreachedNo, n (%) 146 (96.7) 4 (20.0) 150 (87.7)Yes, n (%) 5 (3.3) 16 (80.0) 21 (12.3)Total, n (%) 151 (100.0) 20 (100.0) 171 (100.0)At riskNo Yes TotalMMR2(currentschedule)BreachedNo, n (%) 154 (97.5) 30 (50.0) 184 (84.4)Yes, n (%) 4 (2.5) 30 (50.0) 34 (15.6)Total, n (%) 158 (100.0) 60 (100.0) 218 (100.0)Timing of measles-containing vaccines after receiving intravenousimmunoglobulin (IVIG) for Kawasaki disease (KD). The AustralianImmunisation Handbook recommends postponing live vaccines for11 months after IVIG for KD. ‘At risk’ means that a child receivedIVIG for the treatment of KD less than 11 months prior to a sched-uled measles-containing vaccine. ‘Breached’ means that a measles-containing vaccine was given less than 11 months after a childreceived IVIG for the treatment of KD. MMR1 refers to the firstmeasles-containing vaccine on the National Immunisation Pro-gramme (NIP) Schedule. MMR2 refers to the second measles-containing vaccine on the NIP Schedule. MMR1 is scheduled to begiven at 12 months of age. The schedule changed on 1 July 2013with regards to MMR2: under the previous schedule MMR2 wasgiven at 4 years of age; under the current schedule MMR2 is givenat 18 months of age. Children who were less than 18 months of ageon 1 July 2013 were immunised according to the current schedule.MMR, measles–mumps–rubella.Journal of Paediatrics and Child Health (2023)© 2023 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).Chapter 5198be through improved health-care professional and family educa-tion. Another would involve linking the electronic clinical data-base which in Australia records vaccination status (AIR) and theadministrative database which records IVIG utilisation for KD(Bloodstar) which would allow systematic flagging of ‘at risk’children, so immediate identification of patients who required adelay in measles vaccination at the point of care rather than ret-rospectively as we have done in this study. At present, this is notpossible as the databases mentioned are maintained by separateGovernment departments; AIR by the Australian Department ofHealth and Aged Care and Bloodstar by the National BloodAuthority.The recommendations for vaccination deferment post-IVIGinfusion for KD we have evaluated in our study haveremained unchanged for many years and are based on smallhistorical studies. There is clearly a need for better contempo-rary data to allow the development of better-informedrecommendations.from IVIG to immunisation: ( ),>11 months; ( ), <11 months; ( ), IVIG+ 11 months. MMR/MMRV, measles–mumps–rubella/measles–mumps–rubella–varicella.Fig. 3 MMR2 following intravenous immunoglobulin (IVIG) for Kawasaki disease. Comparison to the Australian Immunisation Handbook guidelines for livevaccines after IVIG. Children given IVIG <11 months before a scheduled MMR/MMRV were deemed ‘at risk’ of breaching the guidelines, and those whosesubsequent vaccination occurred <11 months after the IVIG were deemed to have ‘breached’ the guidelines. All children who were at risk are depicted,with those who breached coloured red. The Australian National Immunisation Program Schedule previously recommended that the first MMR/MMRV(‘MMR1’) be given at 12 months of age and the second (‘MMR2’) at 4 years of age (the previous schedule).15 A change to the schedule, which took effectfrom July 2013, saw the second dose brought forward to 18 months of age (the current schedule). Time from IVIG to immunisation: ( ), >11 months; ( ),<11 months; ( ), IVIG + 11 months. MMR/MMRV, measles–mumps–rubella/measles–mumps–rubella–varicella.Journal of Paediatrics and Child Health (2023)© 2023 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).Fig. 2 MMR1 following intravenous immunoglobulin (IVIG) for Kawasaki dis-ease. Comparison to the Australian Immunisation Handbook guidelines for live vaccines after IVIG. Children given IVIG <11 months before a scheduled MMR/MMRV were deemed ‘at risk’ of breaching the guidelines, and those whose subsequent vaccination occurred <11 months after the IVIG were deemed to have ‘breached’ the guidelines. All chil-dren who were at risk are depicted, with those who breached coloured red. TimeLive Vaccines after KD199and long-term management of Kawasaki disease: A scientific state-ment for health professionals from the American Heart Association.Circulation 2017; 135: e927–99.2 de Graeff N, Groot N, Ozen S et al. European consensus-based rec-ommendations for the diagnosis and treatment of Kawasakidisease – The SHARE initiative. Rheumatology 2019; 58: 672–82.3 Research Committee of the Japanese Society of Pediatric Cardiologyand Cardiac Surgery, Committee for Development of Guidelines forMedical Treatment of Acute Kawasaki Disease. Guidelines for medicaltreatment of acute Kawasaki disease: Report of the Research Com-mittee of the Japanese Society of Pediatric Cardiology and CardiacSurgery (2012 revised version). Pediatr. Int. 2014; 56: 135–58.4 Looney JR, Huggins J. Use of intravenous immunoglobulin G (IVIG).Best Pract. Res. Clin. Haematol. 2006; 19: 3–25.5 Nimmerjahn F, Ravetch JV. Anti-inflammatory actions of intravenousimmunoglobulin. Annu. Rev. Immunol. 2008; 26: 513–33.6 National Blood Authority (Australia). Criteria for the clinical use ofintravenous immunoglobulin in Australia. 2012.7 Esposito S, Bianchini S, Dellepiane RM, Principi N. Vaccines and Kawa-saki disease. Expert Rev. Vaccines 2016; 15: 417–24.8 Morikawa Y, Sakakibara H, Miura M. Efficacy of live attenuated vac-cines after two doses of intravenous immunoglobulin for Kawasakidisease. World J. Pediatr. 2022; 18: 706–9.9 Australian Technical Advisory Group on Immunisation (ATAGI).Australian Immunisation Handbook. Canberra: Australian Govern-ment Department of Health and Aged Care; 2022 Available from:immunisationhandbook.health.gov.au.10 Immunisation Handbook 2020, 2020th edn. Wellington: Ministry ofHealth Manat!u Hauora; 2020 Available from: https://www.health.govt.nz/system/files/documents/publications/immunisation-handbook-2020-v18.pdf.11 Public Health Agency of Canada. Blood products, humanimmunoglobulin and timing of immunization. Canadian ImmunizationGuide. 2021. Available from: https://www.canada.ca/en/public-health/services/canadian-immunization-guide.html12 Active immunization after receipt of immune globulin or other bloodproducts. In: Red Book 2021, 32nd edn. Itasca, IL: AmericanAcademy of Pediatrics; 2021. (Report of the Committee on InfectiousDiseases).13 Kroger A, Bahta L, Hunter P. Timing and Spacing of Immunobiologics.General Best Practice Guidelines for Immunization: Best PracticesGuidance of the Advisory Committee on ImmunizationPractices (ACIP). 2022. Available from: https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/timing.html14 Committee on Infectious Diseases. Recommended timing of routinemeasles immunization for children who have recently receivedimmune globulin preparations. Pediatrics 1994; 93: 682–5.15 Mason W, Takahashi M, Schneider T. Persisting passively acquiredmeasles antibody following gamma globulin therapy for Kawasaki dis-ease and response to live virus vaccination [Abstract 311]. LosAngeles, California; 1992.16 Mason WH, Schneider TL, Takahashi M. Duration of passively acquiredmeasles antibody and response to live virus vaccination allowing gammaglobulin therapy for Kawasaki syndrome. Wailea, Hawaii; 1991.17 Siber GR, Werner BG, Halsey NA et al. Interference of immune globulinwith measles and rubella immunization. J. Pediatr. 1993; 122: 204–11.18 Miura M, Katada Y, Ishihara J. Time interval of measles vaccination inpatients with Kawasaki disease treated with additional intravenousimmune globulin. Eur. J. Pediatr. 2004; 163: 25–9.19 Sonobe T. Intravenous gamma-globulin therapy and vaccination.Shoni-Naika 1994; 26: 1929–33.20 Tacke CE, Smits GP, van der Klis FRM, Kuipers IM, Zaaijer HL,Kuijpers TW. Reduced serologic response to mumps, measles, andrubella vaccination in patients treated with intravenous immunoglobulinfor Kawasaki disease. J. Allergy Clin. Immunol. 2013; 131: 1701–3.21 Morikawa Y, Sakakibara H, Kimiya T, Obonai T, Miura M. Live attenu-ated vaccine efficacy six months after intravenous immunoglobulintherapy for Kawasaki disease. Vaccine 2021; 39: 5680–7.22 Services Australia. Australian Immunisation Register. ServicesAustralia. Available from: https://www.servicesaustralia.gov.au/what-australian-immunisation-register?context=2243623 National Centre for Immunisation Research and Surveillance (NCIRS).Significant events in measles, mumps and rubella vaccination practicein Australia. ncirs.org.au. 2019. Available from: https://www.ncirs.org.au/sites/default/files/2019-12/Measles-mumps-rubella-history-Dec%202019.pdf24 Wood JG, Gidding HF, Heywood A, Macartney K, McIntyre PB,MacIntyre CR. Potential impacts of schedule changes, waning immu-nity and vaccine uptake on measles elimination in Australia. Vaccine2009 Jan; 27: 313–8.25 Lucas R, Dennington P, Wood E et al. Epidemiology of Kawasaki dis-ease in Australia using two nationally complete datasets. J. Paediatr.Child Health 2021; 58: 674–82.26 Durrheim DN, Baker MG, Capeding MR et al. Accelerating measleselimination in the Western Pacific Region during the calm betweenthe storms. Lancet Reg. Health West. Pac. 2022; 23: 100495.Supporting InformationAdditional Supporting Information may be found in the onlineversion of this article at the publisher’s web-site:Table S1. Overall measles-containing vaccine coverage amongthose given intravenous immunoglobulin for Kawasaki disease.Table S2. Risk of breaching recommendations regardingmeasles-containing vaccines after intravenous immunoglobulintherapy for Kawasaki disease: MMR1 or MMR2 under the oldschedule.Journal of Paediatrics and Child Health (2023)© 2023 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).ConclusionsOur findings suggest there is a cohort of Australian children for whom IVIG treatment of KD may have put them at risk of vaccine-preventable infections following immunisation with live vaccines that occurred outside the recommended post-IVIG schedule. Given the poor quality of the data that has informed those recommendations, we need to better understand the mag-nitude and duration of interference by IVIG with protection from live vaccines. In the interim, managing children with KD should be aware that IVIG may interfere with responses to live vaccines and ensure adherence with national guidelines regarding post-ponement of live vaccines for 11 months post-IVIG. This impor-tant information should be communicated to patient’s families and primary care providers as part of standard management of children with KD.AcknowledgementsThe authors would like to thank the National Centre for Immunisation Research & Surveillance for their support.References1 McCrindle BW, Rowley AH, Newburger JW et al. Diagnosis, treatment,Chapter 5200Live vaccines following intravenous immunoglobulin for Kawasaki disease: Are we vaccinating appropriately?  Supplementary Results Table 5.S1: Overall Measles-Containing Vaccine Coverage Among Those Given Intravenous Immunoglobulin for Kawasaki Disease MMR1 (All Patients) MMR2 (Previous Schedule) MMR2 (Current Schedule) Received vaccine Yes, n (%) 380 (97.7) 165 (96.5) 210 (96.3) No, n (%) 9 (2.3) 6 (3.5) 8 (3.7) Total 389 171 218 MMR, measles-mumps-rubella. MMR1 refers to the first measles-containing vaccine on the National Immunisation Programme (NIP) Schedule. MMR2 refers to the second measles-containing vaccine on the NIP Schedule; under the Current Schedule MMR2 also contains varicella. MMR1 is scheduled to be given at 12 months of age. The schedule changed on 1st July 2013 with regards to MMR2: under the previous schedule MMR2 was given at 4 years of age; under the current schedule MMR2 is given at 18 months of age. Children who were less than 18 months of age on 1st July 2013 were immunised according to the current schedule. Table 5.S2: Risk of Breaching Recommendations Regarding Measles-Containing Vaccines after Intravenous Immunoglobulin Therapy for Kawasaki Disease: MMR1 or MMR2 Under the Old Schedule At Risk No Yes Total Breached No, n (%) 100 (82.0) 14 (28.6) 114 (66.7) Yes, n (%) 22 (18.0) 35 (71.4) 57 (33.3) Total 122 49 171 Timing of measles-containing vaccines after receiving intravenous immunoglobulin (IVIG) for Kawasaki disease (KD). The Australian Immunisation Handbook recommends postponing live vaccines for 11 months after IVIG for KD. “At Risk” means that a child received IVIG for the treatment of KD less than 11 months prior to a scheduled measles-containing vaccine. “Breached” means that a measles-containing vaccine was given less than 11 months after a child received IVIG for the treatment of KD. MMR, measles-mumps-rubella. MMR1 refers to the first measles-containing vaccine on the National Immunisation Programme (NIP) Schedule and is recommended to be given at 12 months of age. MMR2 refers to the second measles-containing vaccine, which was recommended to be given at 4 years of age. Children who were less than 18 months of age on 1st July 2013 were immunised according to the current schedule (not included here). Live Vaccines After KD201202Chapter 6 The following manuscript, entitled “Prospective Surveillance of Kawasaki Disease in Australia: 2019–21” has been prepared for submission to The Lancet Regional Health—Western Pacific for consideration for publication. It presents the findings of a cohort of patients prospectively enrolled in the course of a multicentre surveillance programme at sites across Australia. That programme, coordinated and administered by the Paediatric Active Enhanced Disease Surveillance (PAEDS) network, is the largest of its kind from the Southern Hemisphere. The manuscript that follows includes data for children recruited between January 1st 2019 and December 31st 2021; enrolment continues, with 765 cases at the time of writing.* The study sought to describe the clinical presentation, management, and outcomes of children diagnosed with KD in Australia. All children with clinician-diagnosed KD were enrolled, providing important insights into the diagnostic practices of Australian clinicians. One of the key findings of this study was that a significant proportion of those diagnosed with KD did not fulfil the diagnostic criteria outlined in the 2017 statement by the American Heart Association. The Australian approach to the use of aspirin was also described. The authors reported no conflicts of interest. Ethical approval for the PAEDS network (including the KD study) was granted by the Human Research Ethics Committee of the Sydney Children’s Hospitals Network (HREC/18/SCHN/72). * Late March, 2023.203204Prospective Surveillance of Kawasaki Disease in Australia: 2019–21 Abstract Aim:  Kawasaki disease (KD) is frequently encountered by Australian paediatricians. We sought to describe clinical practice with regards to diagnosis and management, and to examine disease outcomes both during the acute hospital admission and at medium-term follow-up. Methods: This study was conducted at eight tertiary paediatric hospitals across Australia as part of an established surveillance network—Paediatric Active Enhanced Disease Surveillance (PAEDS). Children under the age of 16 years who were treated for KD were enrolled in a prospective cohort study. Comprehensive clinical data, including reports of echocardiograms performed during the admission and at 6–8 weeks follow-up, were collected. Cases were classified as Complete KD, Incomplete KD, or Uncertain KD based on the 2017 American Heart Association (AHA) diagnostic criteria. Results: We identified 483 children with a clinical diagnosis of KD: 54.7% were classified as Complete KD, 8.9% as Incomplete KD, and 36.4% as Uncertain KD. Most children (86.9%) treated with aspirin only received low-dose aspirin (3–5 mg/kg/day), as recommended in Australian guidelines. Over 99% received intravenous immunoglobulin (IVIG); of those, 29.0% received additional doses of IVIG due to perceived treatment non-response. There was marked variability in how treatment non-response was diagnosed.  Conclusions: A significant proportion of children treated for KD did not fulfil the AHA diagnostic criteria. The rate of retreatment with IVIG was high, which may reflect overdiagnosis of treatment failure in the absence of an agreed definition. International collaboration is needed to better define IVIG non-responsiveness in the treatment of KD and to better understand the underlying mechanisms of this phenomenon. 205Introduction Kawasaki disease (KD) is a systemic vasculitis that predominantly affects children under 5 years of age.1 It causes inflammation of medium-sized arteries, and can lead to aneurysm and stenosis of the coronary arteries. In the absence of a gold-standard test the diagnosis remains clinical, requiring the observation of a minimum set of cardinal clinical signs.2 Multiple diagnostic criteria have been proposed and revised, reflecting the evolving understanding of the condition’s clinical presentation.1–3 The American Heart Association (AHA) updated their recommendations for the diagnosis of KD in 2017,1 allowing for experienced clinicians to diagnose complete KD before day 5 of fever and providing an algorithm for diagnosing incomplete KD. The management of KD relies on intravenous immunoglobulin (IVIG) as the only intervention proven to reduce the incidence of aneurysms;4 international guidelines agree that children with KD should receive 2 g/kg of IVIG as a single dose.1–3 Guidelines also recommend the use of aspirin, however there is a lack of consensus around dose: most recommend that children be commenced on moderate-dose (30–50 mg/kg/day) or high-dose (80–100 mg/kg/day) aspirin, before stepping down to low-dose (3–5 mg/kg/day) aspirin for thromboprophylaxis.1–3 Recommendations on other aspects of the management of KD—such as the diagnosis and management of cases that fail to respond to initial IVIG—has far less consensus.5 We undertook a multicentre prospective cohort study of KD in Australia to describe the clinical presentation and disease course of KD in Australia and understand the diagnostic and therapeutic decisions of Australian clinicians. Methods Active sentinel surveillance for KD was conducted through the Paediatric Active Enhanced Disease Surveillance (PAEDS) network (https://www.paeds.org.au).6 The PAEDS network is a hospital-based active surveillance system in Australia that prospectively identifies admitted cases of selected serious childhood conditions for clinical research.7,8 Surveillance commenced from January 1, 2019 at seven major Australian hospitals* (including six of Australia’s eight specialist paediatric hospitals) with an eighth site† (a specialist paediatric hospital) contributing data from January 1, * The Children's Hospital at Westmead (CHW; New South Wales), Royal Children’sHospital (RCH; Victoria), Monash Health (MH; Victoria), Women’s and Children’sHospital (WCH; South Australia), Perth Children’s Hospital (PCH, WesternAustralia), Royal Darwin Hospital (RDH, Northern Territory), and QueenslandChildren’s Hospital (QCH; Queensland)† Sydney Children's Hospital (SCH, New South Wales)Chapter 6206  2020 (see Supplementary Methods). We present data for the cohort to December 31, 2021. All children aged <16 years admitted to a participating hospital with a diagnosis of acute KD during the study period were eligible for inclusion. Children were excluded from the study if the diagnosis of KD was subsequently overturned. Where the diagnosis of KD was unclear the decisions of treating clinicians were used to determine the level of diagnostic certainty: children given IVIG or aspirin for presumed KD were included (at least until the diagnosis was overturned). Emergency department and inpatient databases were screened daily by dedicated surveillance staff to identify potential KD cases. Hospital records were periodically audited for individuals with a discharge diagnosis of KD (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Australian Modification code M30.3). Where cases had not been prospectively identified the inpatient records were retrospectively assessed for inclusion. Of particular note was the emergence of a new systemic inflammatory condition of childhood during this study – namely Paediatric Inflammatory Multisystem Syndrome – Temporally associated with SARS-CoV-2 (PIMS-TS), also known as the Multisystem Inflammatory Syndrome in Children associated with COVID-19 (MIS-C). PIMS-TS was first reported from the United Kingdom in early 2020 in the context of the global COVID-19 pandemic.9 In response the Australian Government funded a prospective surveillance program for PIMS-TS in Australia. PIMS-TS surveillance was undertaken by the same research network that was conducting the KD surveillance described here, using a modified version of the Case Reporting Form used for this study. Children were categorised as ‘Confirmed PIMS-TS’* or ‘Possible PIMS-TS’ and could be concurrently included KD surveillance. Children who were categorised as ‘Confirmed PIMS-TS’ were subsequently excluded from KD surveillance, whereas those categorised as ‘Possible PIMS-TS’ were not excluded.  * The case definition for PIMS-TS used in that study was as follows:10 Children and adolescents (up to 18 years of age) with fever ≥3 days AND two of the following: rash or bilateral non-purulent conjunctivitis or muco-cutaneous inflammation signs (oral, hands or feet); age-specific hypotension or “shock” within first 24 hours of presentation; features of myocardial dysfunction, pericarditis, valvulitis or coronary abnormalities (including ECHO findings or elevated Troponin/NT-proBNP); evidence of coagulopathy (by PT, PTT, elevated d-Dimers); acute gastrointestinal problems (diarrhoea, vomiting or abdominal pain). ALL of the following were also required: elevated markers of inflammation such as ESR, C-reactive protein or procalcitonin; exclusion of other infectious causes of inflammation, including bacterial sepsis, staphylococcal or streptococcal toxic shock syndromes; and, evidence of SARS-CoV-2 infection (positive RT-PCR), or confirmed contact with a person with SARS-CoV-2 infection (public health defined), or confirmed positive SARS-CoV-2 serology). Prospective Surveillance of KD in Australia207Study data were collected and managed using the REDCap electronic data capture tool hosted at The University of Sydney. REDCap (Research Electronic Data Capture) is a secure, web-based software platform designed to support data capture for research studies, providing 1) an intuitive interface for validated data capture; 2) audit trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data downloads to common statistical packages; and 4) procedures for data integration and interoperability with external sources.11,12 Participant data was able to be edited only by research staff at each site, and designated investigators centrally. Demographic, clinical and follow-up data were collected from the medical records. Information on recent vaccine administration was sought from caregivers and confirmed via the Australian Immunisation Registry.13 Reports of inpatient echocardiograms, as well as echocardiograms at 6–8 weeks follow-up, were analysed. Maximum coronary artery dimensions were used to generate Z-scores using the method of Dallaire & Dahdah;14 where this was not possible, but a Z-score had been documented, the documented Z-score was used. The AHA diagnostic criteria were applied retrospectively. Briefly, children were classified as having complete KD or incomplete KD, according to the 2017 AHA Guideline1; those not fulfilling the criteria for either diagnosis were classified as uncertain KD. Non-response to primary therapy was determined by the decision of the treating clinicians to administer a second dose of IVIG or treatment escalation (such as corticosteroids) within a single episode of KD due to persistence or recrudescence of fever, clinical signs, or raised inflammatory markers after an initial dose of IVIG. Statistical analysis was performed using Stata/IC 17.0 for Mac (StataCorp 2017. Stata Statistical Software: Release 17. College Station, Texas. Ethical approval was granted by the Human Research Ethics Committee of the Sydney Children’s Hospitals Network (HREC/18/SCHN/72). The study operated under a waiver of consent to allow the collection of de-identified patient data however families could elect to be removed from the study at their discretion. Results We identified 493 children with an initial diagnosis of KD. Ten patients were excluded: nine had their KD diagnosis subsequently revised while one family asked not to be included in the study (Figure 6.1). Thus, 483 cases were included in the analysis: 54.7% (264/483) were classified as complete KD, 8.9% (43/483) as incomplete KD, and 36.4% (176/483) as uncertain KD (Table 6.1). The AHA criteria allow for the diagnosis of complete KD to be made by an Chapter 6208experienced clinician after as little as 3 days of fever—under those criteria 62 of the uncertain KD cases were reclassified as complete KD, with 114 (23.6%) still uncertain. (Figure 6.2). Demographic and Clinical Characteristics Demographic and clinical characteristics of the cohort are shown in Table 6.1. The median age at admission was 2.8 years (IQR 1.3–4.6); those with incomplete KD were significantly younger on average than those with complete or uncertain KD (median 1.5 years, IQR 0.4–3.5 years; p = 0.002). The male to female ratio was 1.46:1 and did not differ between diagnostic groups. The most frequent country of birth of patients and their parents was Australia, followed by China and India (Supplementary Table 6.1). The most common cardinal clinical criterion overall (not including fever) was rash (88.6%, 428/483), followed by conjunctival injection (85.9%, 415/483); rash was the second most frequent cardinal clinical criterion among those with incomplete KD, after conjunctival injection. Pre-treatment laboratory finding are shown in Table 6.1 and Figure 6.3. Anaemia was common: 55.0% (262/476) of age-normalised haemoglobin results were more than two standard deviations below the mean. Leukocytosis ≥15×109/L was observed in 43.8% (210/480), most frequently with a neutrophil predominance (>50% neutrophils in 83.8%, 397/474). No laboratory findings differed significantly between those with Complete KD and those with Uncertain KD. COVID testing (which started in 2020) occurred in 46.2% of cases (271/483), with only 2 cases returning a positive result. Identified on surveillance(n = 493)Included in analysis (n = 483):– CHW: 110 – RCH: 116– QCH: 60 – PCH: 53– WCH: 31 – SCH: 37– MH: 70 – RDH: 6Excluded (n = 10):– Consent revoked: 1– Alternate diagnosis: 9– sJIA: 2– Lymphadenitis: 2– Scarlet fever: 2– Other vasculitis: 1– HLH: 1– PIMS-TS: 1Figure 6.1: Flowchart of Study Inclusion and Exclusion Numbers HLH, hemophagocytic lymphohistiocytosis; PIMS-TS, paediatric inflammatory multisystem syndrome—temporally associated with SARS-CoV infection; sJIA, systemic onset juvenile idiopathic arthritis. Site abbreviations as previously described. Prospective Surveillance of KD in Australia209Treatment and Response IVIG was given to 99.2% (479/483) of patients, with the majority (93.3%, 429/460*) receiving the recommended dose of 2 g/kg; IVIG dosing did not differ between the diagnostic groups (Table 6.1). IVIG was given on or before day 5 of fever in 33.9% (158/466) of patients, and after day 10 of fever in 16.5% (77/466) of patients. The median infusion duration was 8.0 hours (IQR 6.8–10.2 hours). Adverse events related to IVIG were infrequent (occurring in * This is the number for whom a dose in grams/kg was known.N = 264 N = 43 N = 1765102030Fever Onset to IVIG (days)Complete KD Incomplete KD Uncertain KDa126 40138 3127 5615 371 93012345Total number of Primary Clinical FeaturesComplete KD Incomplete KD Uncertain KDbN = 326 N = 43 N = 1145102030Fever Onset to IVIG (days)Complete KD Incomplete KD Uncertain KDc161 5165 427 5615 371 93012345Total number of Primary Clinical FeaturesComplete KD Incomplete KD Uncertain KDdFigure 6.2: Strict versus Permissive Definition of Complete Kawasaki Disease a. Time from fever onset to first dose of IVIG by diagnostic category, where the diagnosis of ‘Complete KD’ requires 5 or more days of fever. b. Total number of Primary Clinical Features of KD by diagnostic category, where the diagnosis of ‘Complete KD’ requires 5 or more days of fever. c. Time from fever onset to first dose of IVIG by diagnostic category, where the diagnosis of ‘Complete KD’ can be made with as few as 3 days of fever. d. Total number of Primary Clinical Features of KD by diagnostic category, where the diagnosis of ‘Complete KD’ can be made with as few as 3 days of fever. IVIG, intravenous immunoglobulin; KD, Kawasaki disease. Chapter 621020.5%, 98/479) and typically mild (Supplementary Table 6.2). The most frequently reported was fever, described in 11.9% (57/479). Aspirin was prescribed in 97.3% (470/483) of patients, with most (86.9%, 399/459) only ever receiving low-dose aspirin (3–5 mg/kg/day). Aspirin dosing clustered within the low-dose but not the moderate- or high-dose ranges (Supplementary Figure 6.1); we therefore analysed aspirin dosing as below or above 10 mg/kg/day. Aspirin dosing differed markedly between sites: three large hospitals—accounting for 57.8% (279/483) of the cohort—did not use aspirin at doses >10 mg/kg/day (Supplementary Table 6.3). Children given aspirin at >10 mg/kg/day did not differ from those given ≤10 mg/kg/day in terms of sex, age, diagnostic category, number of cardinal clinical features, or rates of admission to intensive care (Supplementary Table 6.4). Those given a Figure 6.3: Laboratory Markers of Children Diagnosed with Kawasaki Disease, by Diagnostic Category Results are from blood samples taken prior to the administration of IVIG. Complete KD: fever for ≥5 days plus ≥4/5 cardinal clinical features. Incomplete KD was diagnosed according to the algorithm in McCrindle et al, 2017.6 Children who met inclusion criteria but who did not meet the criteria for Complete KD or Incomplete KD were classified as Uncertain KD. 6080100120140Haemoglobin (g/L)Complete KD Incomplete KD Uncertain KDN = 478Haemoglobin-10-505Normalised Haemoglobin (Z-score)Complete KD Incomplete KD Uncertain KDN = 476Normalised Haemoglobin01020304050White Cells (x109/L)Complete KD Incomplete KD Uncertain KDN = 480White Cell Count010203040Neutrophils (x109/L)Complete KD Incomplete KD Uncertain KDN = 474Neutrophil Count020406080100Neutrophils (%)Complete KD Incomplete KD Uncertain KDN = 474Percent Neutrophils02004006008001000Platelets (x109/L)Complete KDIncomplete KDUncertain KDN = 474Platelet Count050100150200ESR (mm/Hr)Complete KD Incomplete KD Uncertain KDN = 379Erythrocyte Sedimentation Rate0100200300400CRP (mg/L)Complete KD Incomplete KD Uncertain KDN = 470C-Reactive Protein0100200300400500AST (U/L)Complete KD Incomplete KD Uncertain KDN = 233Aspartate Aminotransferase050010001500ALT (U/L)Complete KDIncomplete KDUncertain KDN = 453Alanine Aminotransferase1020304050Albumin (g/L)Complete KD Incomplete KD Uncertain KDN = 450Albumin050100150Bilirubin (μmol/L)Complete KD Incomplete KD Uncertain KDN = 450BilirubinProspective Surveillance of KD in Australia211higher dose of aspirin were more likely to have been transferred from another hospital (35% versus 19%, p = 0.021) and had higher rates of non-response to primary therapy with IVIG (48% versus 28%, p = 0.015); they were also more likely to have coronary artery aneurysms at presentation (p <0.001, see Supplementary Table 6.4). Corticosteroids were used as adjuvant primary therapy in 10.8% (52/483) of patients; oral prednisolone was preferred (75% received oral prednisolone alone or in combination with intravenous corticosteroid), typically at a dose of 1–2 mg/kg/day (median 1.9, IQR 1.1–2.0) (Table 6.1). Non-response to primary therapy with IVIG occurred in 29.0% of patients (139/479, Table 6.2). The diagnosis was based on persistent or recurrent fever in 89% of non-responders (123/139)—frequently less than 36 hours after the end of the IVIG infusion (59%, 65/110*). Children who received IVIG after day 5 of fever were significantly less likely to require additional therapy than those treated on or before day 5 (24% [73/308] versus 40% [63/158], p <0.001). Time from fever onset to the first dose of IVIG was the only clinical variable that predicted treatment non-response (Figure 6.4, Supplementary Table 6.5). Days from fever onset to IVIG administration was included in a logistic regression model with age, sex, and number of cardinal clinical features; the odds ratio was 0.88 (95% CI 0.82–0.95), indicating that children treated earlier had higher odds of treatment failure (Figure 6.4, Supplementary Table 6.6). Neutrophil fraction and C-reactive protein (CRP) were significantly higher in non-responders as compared with responders, whereas platelet count and albumin were significantly lower (Supplementary Table 6.6). These * This is the number for whom the time from the end of the IVIG infusion to thedecision to retreat was known.Figure 6.4: Probability of Non-Response to Treatment of Kawasaki Disease with Intravenous Immunoglobulin, by Time to Treatment Predicted probability of non-response to treatment with IVIG by time from fever onset to treatment with IVIG (as estimated using non-parametric logistic regression). The histogram shows case numbers at each day between fever onset and the first dose of IVIG. IVIG, intravenous immunoglobulin. 0204060Probability of Non-Response (%)0 201 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19Fever Onset to First Dose of IVIG (days)Predicted Probability (95% CI) RespondersNon-RespondersN = 466OR = 0·88 (95% CI 0·82–0·95)020406080Case NumbersChapter 6212correlations were independent of time from fever onset to blood sampling (Supplementary Figure 6.2). The best predictors of treatment non-response were albumin and CRP before day 5 of fever (Supplementary Figure 6.2). There was no difference in IVIG dosing between responders and non-responders (Supplementary Table 6.5). The most frequent approach to secondary therapy was further IVIG (given to 89% of non-responders, 123/139), followed by corticosteroids (32%, 44/139). In contrast to their use as primary adjunctive therapy, corticosteroids used as secondary therapy were more frequently given intravenously: of those given corticosteroids 77% received intravenous methylprednisolone alone or in combination with oral steroid (Supplementary Table 6.7). Coronary Artery Outcomes Inpatient echocardiogram reports were available for 82.2% of patients (397/483), and outpatient echocardiogram reports for 79.3% (383/483; Table 6.5). Mild-to-moderate coronary artery dilatation (coronary artery Z-score of 2 to 5) was seen in 29.2% of inpatient echocardiograms (103/353), while medium-to-large aneurysms (Z-score ≥5) were only seen in 6.5% (23/353). Medium-to-large aneurysms were significantly more frequent among those with incomplete KD than the other groups on both echocardiograms (Table 6.5, Supplementary Figure 6.3). The risk of moderate-to-large aneurysms on the echocardiogram at presentation was correlated with time-to-treatment (Figure 6.5, Supplementary Figure 6.4); Large aneurysms (Z-score ≥10) were not observed before day 10 of fever (Figure 6.6). Coronary artery outcomes did not differ by response to treatment (Supplementary Table 6.8) or with laboratory markers (Figure 6.7).  203040506070Probability of Aneurysm (%)0 201 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19Fever Onset to First Dose of IVIG (days)Predicted Probability (95% CI) No Aneurysms≥1 AneurysmN = 466OR = 1·07 (95% CI 1·01–1·13)020406080Case NumbersFigure 6.5: Probability of Coronary Aneurysms in Children Diagnosed with Kawasaki Disease, by Time to Treatment Predicted probability of developing coronary artery aneurysms (defined here as a coronary artery Z-score ≥5) by time from fever onset to treatment with IVIG (as estimated using non-parametric logistic regression). The histogram shows case numbers at each day between fever onset and the first dose of IVIG. IVIG, intravenous immunoglobulin. Prospective Surveillance of KD in Australia213Figure 6.6: Maximum Coronary Artery Dimensions of Children Diagnosed with Kawasaki Disease, by Day of Echocardiogram Each point represents the maximum dimension (Z-score) of a single vessel, as measured by echocardiogram during the acute admission. Red points indicate vessels that went on to have a Z-score <5 at 6–8 week follow-up, whereas blue dots indicate vessels that had a Z-score ≥5 at follow-up. 0102030Maximum Coronary Artery Dimension (Z-score)0 10 20 30Fever Onset to Echocardiogram (days)Complete KD0102030Maximum Coronary Artery Dimension (Z-score)0 10 20 30Fever Onset to Echocardiogram (days)Incomplete KD0102030Maximum Coronary Artery Dimension (Z-score)0 10 20 30Fever Onset to Echocardiogram (days)Uncertain KDChapter 6214 1020304050Probability of Aneurysm (%)0 100 200 300 400C-Reactive Protein (mg/L)N = 410, p = 0·745010203040Case Numbers0·000·250·500·751·00Sensitivity0·00 0·25 0·50 0·75 1·001-specificity0·704 (0·606 – 0·802) 0·580 (0·501 – 0·659)AUCC-Reactive Protein01020304050Probability of Aneurysm (%)0 20 40 60 80 100Neutrophils (%)N = 416, p = 0·67801020304050Case Numbers0·000·250·500·751·00Sensitivity0·00 0·25 0·50 0·75 1·001-specificity0·580 (0·477 – 0·684) 0·537 (0·462 – 0·611)AUCPercent Neutrophils020406080Probability of Aneurysm (%)0 200 400 600 800 1000Platelet Count (×109/L)N = 415, p = 0·49201020304050Case Numbers0·000·250·500·751·00Sensitivity0·00 0·25 0·50 0·75 1·001-specificity0·598 (0·491 – 0·705) 0·624 (0·547 – 0·702)AUCROC analysis uses 1/[Platelet]Platelet Count020406080Probability of Aneurysm (%)10 20 30 40 50Albumin (g/L)N = 393, p = 0·062010203040Case Numbers0·000·250·500·751·00Sensitivity0·00 0·25 0·50 0·75 1·001-specificity0·728 (0·628 – 0·828) 0.597 (0.518 – 0.676)AUCROC analysis uses 1/[Albumin]AlbuminPredictive Power and Clinical Utilityof Selected Blood Markers for Early Coronary AneurysmFigure 6.7: Probability of Coronary Aneurysms in Children Diagnosed with Kawasaki Disease, by Laboratory Markers Each graph on the left depicts the predicted probability of coronary artery aneurysm (defined here as a coronary artery Z-score ≥5) on the echocardiogram at presentation (as estimated using non-parametric logistic regression), superimposed on a histogram of case numbers at each interval for that laboratory variable. Each graph on the left depicts the receiver-operator characteristic (ROC) curve for each laboratory variable as a predictor of coronary artery aneurysms. Prospective Surveillance of KD in Australia215Table 6.1: Baseline Demographic and Clinical Characteristics of Children Diagnosed with Kawasaki Disease, by Diagnostic Category Diagnostic Category Total Complete KD Incomplete KD Uncertain KD P N = 264 N = 43 N = 176 N = 483 Clinical Characteristics Male 152/264 (57.6%) 27/43 (63%) 108/176 (61%) 287/483 (59.4%) 0.65 Age (years) 3.1 (1.4–4.8) 1.5 (0.4–3.2) 2.8 (1.3–4.6) 2.8 (1.3–4.6) 0.002 0–1 36/264 (13.6%) 19/43 (44%) 35/176 (20%) 90/483 (18.6%) !<0.0011–4 166/264 (62.9%) 18/43 (42%) 103/176 (59%) 287/483 (59.4%) 5–9 51/264 (19.3%) 6/43 (14%) 33/176 (19%) 90/483 (18.6%) 10–14 11/264 (4.2%) 0/43 (0%) 5/176 (3%) 16/483 (3.3%) Indigenous 6/264 (2.3%) 1/43 (2%) 4/176 (2%) 11/483 (2.3%) 1.00 Mother’s Place of Birth Africa 2/264 (0.8%) 0/43 (0%) 3/176 (2%) 5/483 (1.0%) ⎭⎪⎬⎪⎫0.29 Americas 2/264 (0.8%) 0/43 (0%) 1/176 (1%) 3/483 (0.6%) Asia 70/264 (26.5%) 16/43 (37%) 50/176 (30%) 138/483 (28.6%) Europe 7/264 (2.7%) 1/43 (2%) 4/176 (2%) 12/483 (2.5%) Oceania 76/264 (28.8%) 13/43 (30%) 33/176 (19%) 122/483 (25.3%) Unknown 107/264 (40.5%) 13/43 (30%) 83/176 (47%) 203/483 (42.0%) Interhospital transfer 51/264 (19.3%) 14/43 (33%) 31/176 (18%) 96/483 (19.9%) 0.052 GP/ED presentations in week before admission 2 (1–3) 2 (1–2) 2 (1–2) 2 (1–3) 0.096 Days from fever onset to hospital admission 5 (4–7) 6 (4–8) 4 (3–6) 5 (3–7) <0.001 Number of Cardinal Clinical Criteria 4 (4–5) 3 (2–3) 3 (2–4) 4 (3–5) <0.001 5 126/264 (47.7%) 0/43 (0%) 40/176 (23%) 166/483 (34.4%) ⎭⎪⎬⎪⎫<0.001 4 138/264 (52.3%) 0/43 (0%) 31/176 (18%) 169/483 (35.0%) 3 0/264 (0.0%) 27/43 (63%) 56/176 (32%) 83/483 (17.2%) 2 0/264 (0.0%) 15/43 (35%) 37/176 (21%) 52/483 (10.8%) 1 0/264 (0.0%) 1/43 (2%) 9/176 (5%) 10/483 (2.1%) 0 0/264 (0.0%) 0/43 (0%) 3/176 (2%) 3/483 (0.6%) Specific Cardinal Clinical Criteria Rash 254/264 (96.2%) 30/43 (70%) 144/176 (82%) 428/483 (88.6%) <0.001 Oro-mucosal changes 246/264 (93.2%) 25/43 (58%) 115/176 (65%) 386/483 (79.9%) <0.001 Conjunctival injection 253/264 (95.8%) 32/43 (74%) 130/176 (74%) 415/483 (85.9%) <0.001 Cervical lymphadenopathy 213/264 (80.7%) 15/43 (35%) 95/176 (54%) 323/483 (66.9%) <0.001 Peripheral changes 216/264 (81.8%) 10/43 (23%) 91/176 (52%) 317/483 (65.6%) <0.001 Chapter 6216Continued... Neutrophils (%) 70 (58–78) [261/264] 69 (56–79) [42/43] 64 (53–74) [171/176] 68 (56–77) [474/483] 0.021 Platelets (×109 /L) 355 (274–450) [260/264] 514 (324–628) [42/43] 344 (273–431) [172/176] 358 (277–458) [474/483] <0.001 ESR (mm/Hr) 74 (44–102) [207/264] 72 (55–95) [37/43] 64 (43–90) [135/176] 70 (44–95) [379/483] 0.37 CRP (mg/L) 100 (52–176) [259/264] 147 (81–208) [43/43] 100 (57–146) [168/176] 104 (59–167) [470/483] 0.001 AST (U/L) 32 (25–50) [129/264] 34 (24–47) [25/43] 42 (29–57) [79/176] 36 (26–51) [233/483] 0.068 ALT (U/L) 31 (17–78) [249/264] 30 (16–64) [43/43] 30 (16–88) [161/176] 30 (17–70) [453/483] 0.91 Albumin (g/L) 33 (29–36) [247/264] 28 (25–34) [42/43] 33 (29–38) [161/176] 33 (28–36) [450/483] <0.001 Bilirubin (μmol/L) 6 (4–9) [247/264] 6 (4–9) [42/43] 6 (4–10) [161/176] 6 (4–10) [450/483] 0.40 Treatment Modalities IVIG 264/264 (100.0%) 45/43 (100%) 170/176 (98%) 479/483 (99.2%) 0.028 1 g/kg 9/256 (3.5%) 1/39 (3%) 5/165 (3%) 15/460 (3.3%) & 0.90 2 g/kg 237/256 (92.6%) 36/39 (92%) 154/165 (95%) 429/460 (93.3%) Other dose 10/256 (3.9%) 2/39 (5%) 4/165 (2%) 16/460 (3.5%) Unknown 8/264 (3.0%) 4/43 (9%) 7/176 (4%) 19/479 (4.0%) 0.18 Days from fever onset to IVIG 7 (6–8) 8 (7–10) 5 (4–7) 6 (5–8) <0.001 Aspirin 256/264 (97.0%) 42/43 (98%) 172/176 (98%) 470/483 (97.3%) 0.97 3–5 mg/kg/day 219/252 (86.9%) 36/40 (85%) 144/167 (87%) 399/459 (86.9%) !0.9730–50 mg/kg/day 9/252 (3.6%) 1/40 (3%) 5/167 (3%) 15/459 (3.3%) 80–100 mg/kg/day 1/252 (0.4%) 0/40 (0%) 0/167 (0%) 1/459 (0.2%) Other dose 23/252 (9.1%) 5/40 (13%) 16/167 (10%) 44/459 (9.6%) Unknown 4/256 (1.6%) 2/42 (5%) 5/170 (3%) 11/470 (2.3%) 0.39Corticosteroids 25/264 (9.5%) 8/43 (19%) 19/176 (11%) 52/483 (10.8%) 0.25Oral only 15/25 (60.0%) 2/8 (25%) 9/19 (47%) 26/52 (50.0%) & 0.22 Intravenous only 3/25 (12.0%) 4/8 (50%) 6/19 (32%) 13/52 (25.0%) Oral and Intravenous 7/25 (28.0%) 2/8 (25%) 4/19 (21%) 13/52 (25.0%) Anticoagulant 3/264 (1.1%) 3/45 (7%) 0/174 (0%) 6/483 (1.2%) 0.001 Enoxaparin 2/3 (66.7%) 3/3 (100%) –(–)5/6 (83.3%) 0.27 Warfarin 1/3 (33.3%) 0/3 (0%) –(–)1/6 (16.7%) 0.27 Diagnosis of Complete KD required fever for ≥5 days plus ≥4/5 cardinal clinical features. Incomplete KD was diagnosed according to the algorithm in McCrindle et al, 2017.1 Children who met inclusion criteria but who did not meet the criteria for Complete KD or Incomplete KD were classified as Uncertain KD. Laboratory data are from blood samples taken prior to the administration of IVIG. Categorical data are summarised as frequency (%) and compared using Pearson’s χ2 statistic. Continuous data are summarised as median (interquartile range) and compared using the Kruskal–Wallis test—except for the normalised haemoglobin, which is summarised as mean (standard deviation) and compared using ANOVA. ALT, alanine transaminase; AST, aspartate transaminase; CRP, C–reactive protein; ED, emergency department; ESR, erythrocyte sedimentation rate. GP, general practitioner; IVIG, intravenous immunoglobulin; KD, Kawasaki disease.  Prospective Surveillance of KD in Australia217Laboratory Variable, Median (IQR) [n/N] <0.001 <0.001 0.001 Haemoglobin (g/L) Normalised Haemoglobin (Z–score) White Cells (×109/L) Neutrophils (×109 /L) 111 (103–118) [261/264] -2.4 (2.0) [260/264]13.9 (10.6–17.6) [263/264] 9.1 (6.5–12.9) [261/264] 100 (91–105) [43/43] -3.9 (1.9) [43/43]16.9 (13.2–21.4) [43/43] 11.4 (8.3–15.3) [42/43] 112 (103–119) [174/176] -2.2 (2.1) [174/176]13.7 (10.5–16.8) [174/176] 8.5 (6.1–11.0) [171/176] 110 (102–118) [478/483] -2.4 (2.1) [476/483]14.1 (10.8–17.9) [480/483] 9.0 (6.5–12.3) [474/483] <0.001 Table 6.1 continued... Table 6.2: Clinical Outcomes of Children Diagnosed with Kawasaki Disease, by Diagnostic Category Diagnostic Category Total Complete KD Incomplete KD Uncertain KD P Treatment Outcomes Non-Response to Primary Therapy 72/264 (27.3%) 13/43 (30%) 54/172 (31%) 139/479 (29.0%) 0.64 Persistent / recurrent fever 67/72 (93%) 10/13 (77%) 46/54 (85%) 123/139 (89%) 0.15 Hours post-IVIG 32 (22–42) 90 (74–104) 29 (12–34) 32 (18–44) 0.004 Persistent / recurrent clinical features 30/72 (42%) 5/13 (39%) 27/54 (50%) 62/139 (45%) 0.58 Hours post-IVIG 32 (24–40) 70 (29–104) 34 (14–50) 34 (24–46) 0.48 Raised inflammatory markers 17/72 (24%) 6/13 (46%) 17/54 (32%) 40/139 (29%) 0.22 Hours post-IVIG 30 (24–38) 101 (62–144) 32 (24–41) 32 (24–42) 0.10 Admission Outcomes Admitted to ICU/HDU 13/264 (4.9%) 4/43 (9%) 8/176 (5%) 25/483 (5.2%) 0.43 Respiratory Support 5/13 (39%) 1/4 (25%) 3/8 (38%) 9/25 (36%) 0.88 Blood Pressure Support 6/13 (46%) 2/4 (50%) 3/8 (38%) 11/25 (44%) 0.90 ECMO 0/13 (0%) 0/4 (0%) 1/8 (13%) 1/25 (4%) 0.33 Total admitted days 11 (8–15) 14 (12–26) 10 (8–14) 12 (8–15) 0.11 Acute Coronary Artery Outcomes Inpatient Echocardiogram 217/264 (82.2%) 36/43 (84%) 142/176 (81%) 397/483 (82.2%) 0.52 Fever Onset to Echocardiogram (days) 8 (6–10) 8 (7–12) 6 (5–9) 8 (6–10) <0.001 Worst Coronary Artery Z–score <2 125/188 (67%) 12/34 (35%) 90/131 (69%) 227/353 (64.3%) ⎭⎪⎬⎪⎫<0.001 2 to <2.5 13/188 (7%) 3/34 (9%) 18/131 (14%) 34/353 (9.6%) 2.5 to <5 39/188 (21%) 12/34 (35%) 18/131 (14%) 69/353 (19.5%) 5 to <10 8/188 (4%) 3/34 (9%) 5/131 (4%) 16/353 (4.5%) ≥10 3/188 (3%) 4/34 (12%) 0/131 (0%) 7/353 (2.0%) Subacute Coronary Artery Outcomes Follow–Up Echocardiogram 214/264 (81.1%) 35/43 (81%) 134/176 (76%) 383/483 (79.3%) 0.79 Discharge to Echocardiogram (weeks) 6 (5–8) 7 (5–12) 6 (5–8) 6 (5–8) 0.071 Worst Coronary Artery Z–score <2 142/183 (78%) 17/30 (57%) 105/118 (89%) 264/331 (79.8%) ⎭⎪⎬⎪⎫<0.001 2 to <2.5 16/183 (9%) 2/30 (7%) 6/118 (5%) 24/331 (7.3%) 2.5 to <5 16/183 (9%) 4/30 (13%) 7/118 (6%) 27/331 (8.2%) 5 to <10 5/183 (3%) 1/30 (3%) 0/118 (0%) 6/331 (1.8%) ≥10 4/183 (2%) 6/30 (20%) 0/118 (0%) 10/331 (3.0%) Diagnosis of Complete KD required fever for ≥5 days plus ≥4/5 cardinal clinical features. Incomplete KD was diagnosed according to the algorithm in McCrindle et al, 2017.1 Children who met inclusion criteria but who did not meet the criteria for Complete KD or Incomplete KD were classified as Uncertain KD. Wherever possible coronary artery Z-scores were re-calculated using the method of Dallaire & Dahdah (Dallaire F, Dahdah N. New Equations and a Critical Appraisal of Coronary Artery Z Scores in Healthy Children. Journal of the American Society of Echocardiography. 2011 Jan;24(1):60–74); where this was not possible, but a Z-score had been documented, the documented Z-score was used. Categorical data are summarised as frequency (%) and compared using Pearson’s χ2 statistic. Continuous data are summarised as median (interquartile range) and compared using the Kruskal-Wallis test. ECMO, extracorporeal membrane oxygenation; ICU/HDU, intensive care unit / high dependency unit.Chapter 6218Discussion We report findings from a large, prospective, multi-centre surveillance network recruiting children admitted to referral hospitals with clinician-diagnosed KD. This is the largest cohort of children with KD from the Southern Hemisphere, and one of the largest prospectively recruited KD cohorts outside of Asia. Australian guidelines use the AHA criteria1 for the diagnosis of KD, yet over one third of the patients in our cohort did not fulfil those criteria for either Complete or Incomplete KD. Even when the less rigorous definition for Complete KD (allowing for the diagnosis to be made with as few as 3 days of fever in the setting of four or more cardinal clinical features) was applied, almost one quarter did not meet criteria for either diagnosis. There were no significant differences in clinical or laboratory variables between those with Complete versus Uncertain KD, however comparatively few coronary artery lesions were observed in the latter group. It is possible that a significant proportion of the children who did not fulfil the diagnostic criteria for KD had an alternative process underlying their presentation. The rate of treatment failure in this cohort was is higher than has been described in similar studies1,15–17. This may be a result of how the diagnosis of treatment failure was made, as most of the diagnoses of treatment failure on the basis of persistent or recurrent fever were given less than 36 hours after the end of the IVIG infusion. There is currently no consensus definition of treatment failure in KD. The AHA statement uses ‘IVIG Resistance’ to refer to the persistence or recurrence of fever “...at least 36 hours after the end of [the] IVIG infusion” (emphasis added),1 however the term “at least” is sometimes omitted when that definition is cited.15 Those with treatment failure in our cohort were not at increased risk for coronary artery aneurysms. This is in contrast to previous observations that treatment failure was associated with higher rates of coronary artery aneurysms.18,19 One possible explanation for this observation is that treatment failure was over diagnosed in Australia. Over diagnosis of treatment failure risks exposing children to additional medical procedures and blood products and expends scarce resources. There is a need for a clear well communicated consensus definition of treatment failure. The high proportion of children started on aspirin in the ‘anti-platelet’ low-dose range (3–5 mg/kg) rather than the ‘anti-inflammatory’ moderate- or high-dose ranges (30–50 or 80–100 mg/kg) is strikingly different from that described in other studies,20,21 but aligns with Australian guidelines and the survey-reported preferences of Australian clinicians, as previously described.22,23 Moderate- or high-dose aspirin has never been shown to improve outcomes in KD.24–27 Some authors have reported that the use of low-dose aspirin was associated with a higher risk of treatment non-response,28 Prospective Surveillance of KD in Australia219  however this association has not been replicated in large studies nor in a recent meta-analysis.26,27,29 The authors of that meta-analysis noted that although the time to resolution of fever was shorter among those receiving high-dose aspirin compared with low-dose aspirin, this might merely indicate an antipyretic effect rather than a signal of treatment failure.26 Moreover, that meta-analysis found that the current weight of evidence suggests that aspirin dose does not influence the development of coronary artery aneurysms and there is no trial-level evidence to support its widespread use.26 We do not believe that the high rates of treatment failure that we observed were attributable to the use of low-dose aspirin as those who received higher doses of aspirin had higher rates of treatment non-response. Early use of IVIG was common and significantly associated with higher rates of treatment failure. The association between early IVIG treatment failure in KD has been reported in several studies.30–33 The use of IVIG observed in this study was largely in line with both local and international guidelines23,34: over 99% of patients received IVIG, of whom over 90% were given a dose of 2 g/kg. While one third of infusion-related adverse events were generally rare, fever during the infusion was frequently reported. Fever during the infusion may simply reflect the underlying systemic inflammatory process, but may prompt interruption of the infusion in line with national guidelines for the management of suspected transfusion reactions35—potentially resulting in sub-optimal IVIG dosing for children with KD. Given that serious infusion reactions appear to be uncommon, there may be scope to clarify infusion protocols for children receiving IVIG for KD. This study has several limitations. The recruitment sites were major referral centres and included seven out of the eight specialist paediatric hospitals in the country. Since smaller units frequently use clinical practice guidelines from (or seek advice from) their referral paediatric hospital, we are reasonably confident that the treatment practices that we described are broadly generalisable to Australia as a whole. Surveillance was largely independent of treating teams and relied on clinical documentation to infer diagnostic and treatment decisions, which in the face of sparse or ambiguous documentation was challenging. We collaborated with a well-established paediatric acute illness surveillance network with over a decade of experience in case identification and data acquisition, and with established protocols for confirming data quality.8 Without a gold-standard diagnostic test the diagnosis of KD presents complex challenges. Many of the children in our cohort did not fulfil the diagnostic criteria for KD, however our ability to retrospectively classify cases by diagnostic category presented an opportunity to better understand diagnostic and therapeutic practices on the ground. We were also limited by the focus on the acute KD presentation: we did not seek to reassess children in the subacute phase when signs such as periungual Chapter 6220  desquamation (a diagnostic feature if peripheral changes are not present in the acute illness1) may have been present. It is also possible that for some children an alternative diagnosis (such as systemic juvenile idiopathic arthritis) may have become apparent after diagnosis, which may not have been captured. Conclusions We report demographic, clinical, and treatment data from a large, prospective surveillance study of KD in Australia. KD was frequently diagnosed in children who did not fulfil diagnostic criteria, and the rate of treatment failure was higher than has been reported elsewhere. Observed practice with regards to aspirin dosing also differed markedly from both international guidelines and practice but was better aligned with published evidence. International collaboration is needed to better define IVIG non-responsiveness in the treatment of KD and to better understand the underlying mechanisms of this phenomenon.  Prospective Surveillance of KD in Australia221Supplementary Results n=252 n=40 n=167020406080Dose (mg/kg/day)Complete KD Incomplete KD Uncertain KDSupplementary Figure 6.1:  Aspirin Dosing for Children Diagnosed with Kawasaki Disease, by Diagnostic Category First dose of aspirin prescribed during KD episode. Dashed green lines represent the “low dose” range of 3–5 mg/kg/day. Diagnosis of Complete KD required fever for ≥5 days plus ≥4/5 cardinal clinical features. Incomplete KD was diagnosed according to the algorithm in McCrindle et al, 2017. Children who met inclusion criteria but who did not meet the criteria for Complete KD or Incomplete KD were classified as Uncertain KD. Chapter 6222020406080100Probability of Non-Response (%)0 100 200 300 400C-Reactive Protein (mg/L)N = 408, p <0·00101020304050Case Numbers0·001·000·750·500·25Sensitivity0·00 0·25 0·50 0·75 1·001-specificity0·704 (0·606 – 0·802) 0·580 (0·501 – 0·659)AUCC-Reactive Protein0204060Probability of Non-Response (%)0 20 40 60 80 100Neutrophils (%)N = 414, p = 0·09701020304050Case Number0·000·250·500·751·00Sensitivity0·00 0·25 0·50 0·75 1·001-specificity0·580 (0·477 – 0·684) 0·537 (0·462 – 0·611)AUCPercent Neutrophils020406080Probability of Non-Response (%)0 200 400 600 800 1000Platelet Count (×109/L)N = 413, p <0·0010204060Case Numbers0·000·250·500·751·00Sensitivity0·00 0·25 0·50 0·75 1·001-specificity0·598 (0·491 – 0·705) 0·624 (0·547 – 0·702)AUCPlatelet Count020406080100Probability of Non-Response (%)10 20 30 40 50Albumin (g/L)N = 391, p <0·0010204060Case Numbers0·000·250·500·751·00Sensitivity0·00 0·25 0·50 0·75 1·001-specificity0·728 (0·628 – 0·828) 0·597 (0·518 – 0·676)AUCAlbuminPredictive Power and Clinical Utilityof Selected Blood Markers for Treatment FailureSupplementary Figure 6.2: Probability of Non-Response to Treatment of Kawasaki Disease with Intravenous Immunoglobulin, by Laboratory Markers Each graph on the left depicts the predicted probability of non-response to treatment with intravenous immunoglobulin (as estimated using non-parametric logistic regression), superimposed on a histogram of case numbers at each interval for that laboratory variable. Each graph on the left depicts the receiver-operator characteristic (ROC) curve for each laboratory variable as a predictor of non-response to treatment with intravenous immunoglobulin. Prospective Surveillance of KD in Australia223N = 188N = 34N = 1310102030Coronmary Artery Dimension (Z-score)Complete KDIncomplete KDUncertain KDEchocardiogram at PresentationN = 183N = 30N = 1180102030Coronmary Artery Dimension (Z-score)Complete KDIncomplete KDUncertain KDEchocardiogram at Follow-UpSupplementary Figure 6.3: Coronary Artery Dimensions of Children Diagnosed with Kawasaki Disease at Two Timepoints, by Diagnostic Category Each point represents the measurement of the largest coronary artery for each child. Diagnosis of Complete KD required fever for ≥5 days plus ≥4/5 cardinal clinical features. Incomplete KD was diagnosed according to the algorithm in McCrindle et al, 2017.6 Children who met inclusion criteria but who did not meet the criteria for Complete KD or Incomplete KD were classified as Uncertain KD. Chapter 62240102030 0102030 0102030051015202530051015202530051015202530Complete KDIncomplete KDUncertain KDMaximum Coronary Artery Dimension (Z-score)Fever Onset to First Dose of IVIG (days)Echocardiogram at Presentation010203040 010203040 010203040051015202530051015202530051015202530Complete KDIncomplete KDUncertain KDMaximum Coronary Artery Dimension (Z-score)Fever Onset to First Dose of IVIG (days)Echocardiogram at Follow-UpSupplementary Figure 6.4: Coronary Artery Dimensions of Children Diagnosed with Kawasaki Disease at Two Timepoints, by Time to Treatment Each point represents the measurement of a coronary artery, such that multiple measurements for each child may be shown. Diagnosis of Complete KD required fever for ≥5 days plus ≥4/5 cardinal clinical features. Incomplete KD was diagnosed according to the algorithm in McCrindle et al, 2017.6 Children who met inclusion criteria but who did not meet the criteria for Complete KD or Incomplete KD were classified as Uncertain KD. Prospective Surveillance of KD in Australia225Supplementary Table 6.1: Top 5 Countries of Birth of Children with Kawasaki Disease, and their Parents Patient Mother Father 1. Australia 435/471 (92.4%) 1. Australia 116/280 (41.4%) 1. Australia 101/267 (37.8%) 2. China 8/471 (1.7%) 2. China 59/280 (21.1%) 2. China 54/267 (20.2%) 3. India 5/471 (1.1%) 3. India 15/280 (5.4%) 3. India 17/267 (6.4%) 4. Hong Kong 3/471 (0.6%) 4. Japan 8/280 (2.9%) 4. Vietnam 8/267 (3.0%) 4. US 3/471 (0.6%) 5. Afghanistan 7/280 (2.5%) 5. South Korea 7/267 (2.6%) 5. Japan 2/471 (0.4%) 5. Vietnam 7/280 (2.5%) 5. South Korea 2/471 (0.4%) 5. Singapore 2/471 (0.4%) Denominators indicate the number of cases for which the country of birth was known. Supplementary Table 6.2: Intravenous Immunoglobulin Infusion-Related Adverse Events Received IVIG 479 Any Reaction 98 (20.5) Fever 57 (11.9) Headache 7 (1.5) Abdominal Pain 3 (0.6) Hypotension 9 (1.9) Anaphylaxis 1 (0.2) Dizziness 1 (0.2) Chills 7 (1.5) Haemolysis 9 (1.9) Thrombotic Event 1 (0.2) Renal Failure 1 (0.2) Other 75 (15.7) The occurrence of fever during the infusion was not specifically sought in the case reporting form as fever is expected as part of the underlying KD. Fever presented here was documented in a free-text field (see Supplementary Methods: Case Reporting Form). Results are given as frequency (%). IVIG, intravenous immunoglobulin; KD, Kawasaki disease. Supplementary Table 6.3: Aspirin Dosing, by Recruitment Site Aspirin Dose Site ≤10 mg/kg/day >10 mg/kg/day P CHW (N = 08) 108/108 (100%) 0/108 (0%) <0.001 RCH (N = 115) 115/115 (100%) 0/115 (0%) QCH (N = 55) 46/55 (84%) 9/55 (16%) PCH (N = 51) 51/51 (100%) 0/51 (0%) RDH (N = 6) 3/6 (50%) 3/6 (50%) WCH (N = 26) 23/26 (88%) 3/26 (12%) MH (N = 62) 60/62 (97%) 2/62 (3%) SCH (N = 36) 22/36 (61%) 14/36 (39%) CHW, The Children’s Hospital at Westmead (Sydney); MH, Monash Hospital (Melbourne); PCH, Perth Children’s Hospital; QCH, Queensland Children’s Hospital (Brisbane); RCH, Royal Children’s Hospital (Melbourne); RDH, Royal Darwin Hospital; SCH, Sydney Children’s Hospital; WCH, Women’s and Children’s Hospital (Adelaide). Chapter 6226Supplementary Table 6.4: Baseline Demographic and Clinical Characteristics of Children Diagnosed with Kawasaki Disease, by Aspirin Dose Aspirin Dose All ≤10 mg/kg/day >10 mg/kg/day P N = 428 N = 31 N = 459 Male 258/428 (60.3%) 18/31 (58%) 276/459 (60.1%) 0.808 Age (years) 2.8 (1.3–4.5) 2.1 (0.9–4.9) 2.8 (1.3–4.6) 0.193 0–1 77/428 (18.0%) 9/31 (29%) 86/459 (18.7%) 0.506 1–4 259/428 (60.5%) 16/31 (52%) 275/459 (59.9%) 5–9 78/428 (18.2%) 5/31 (16%) 83/459 (18.1%) 10–14 14/428 (3.3%) 1/31 (3%) 15/459 (3.3%) Interhospital Transfer 79/428 (18.5%) 11/31 (35%) 90/459 (19.6%) 0.021 GP/ED presentations in week before admission 2 (1–3) 2 (1–2) 2 (1–3) 0.195 Days from fever onset to hospital admission 5 (3–7) 4 (2–6) 5 (3–7) 0.017 Diagnostic Category Complete KD 235/428 (54.9%) 17/31 (55%) 252/459 (54.9%) 0.662 Incomplete KD 36/428 (8.4%) 3/31 (13%) 40/459 (8.7%) Uncertain KD 157/428 (36.7%) 10/31 (32%) 167/459 (36.4%) Total number of Cardinal Clinical Features 5 148/428 (34.6%) 8/31 (26%) 156/459 (34.0%) 0.123 4 150/428 (35.1%) 13/31 (42%) 163/459 (35.5%) 3 78/428 (18.2%) 2/31 (6%) 80/459 (17.4%) 2 40/428 (9.4%) 7/31 (23%) 47/459 (10.2%) 1 9/428 (2.1%) 1/31 (3%) 10/459 (2.2%) 0 3/428 (0.7%) 0/31 (0%) 3/459 (0.7%) Non-Response to Primary Therapy 118/424 (27.8%) 15/31 (48%) 133/455 (29.2%) 0.015 Admitted to ICU/HDU 18/428 (4.2%) 3/31 (10%) 21/459 (4.6%) 0.159 Worst Coronary Artery Z–score <2 211/319 (66.1%) 6/20 (30%) 217/339 (64.0%) <0.001 2 to <2.5 32/319 (10.0%) 1/20 (5%) 33/339 (9.7%) 2.5 to <5 59/319 (18.5%) 7/20 (35%) 66/339 (19.5%) 5 to <10 11/319 (3.5%) 5/20 (25%) 16/339 (4.7%) ≥10 6/319 (1.9%) 1/20 (5%) 7/339 (2.1%) Diagnosis of Complete KD required fever for ≥5 days plus ≥4/5 cardinal clinical features. Incomplete KD was diagnosed according to the algorithm in McCrindle et al, 2017.1 Children who met inclusion criteria but who did not meet the criteria for Complete KD or Incomplete KD were classified as Uncertain KD. Laboratory data are from blood samples taken prior to the administration of IVIG. Categorical data are summarised as frequency (%) and compared using Pearson’s χ2 statistic. Continuous data are summarised as median (interquartile range) and compared using the Kruskal–Wallis test—except for the normalised haemoglobin, which is summarised as mean (standard deviation) and compared using ANOVA. ALT, alanine transaminase; AST, aspartate transaminase; CRP, C–reactive protein; ED, emergency department; ESR, erythrocyte sedimentation rate. GP, general practitioner; IVIG, intravenous immunoglobulin; KD, Kawasaki disease.Prospective Surveillance of KD in Australia227Supplementary Table 6.5: Baseline Demographic and Clinical Characteristics of Children Diagnosed with Kawasaki Disease, by Treatment Response Treatment Response All Responders Non-Responders P N = 340 N = 139 N = 483 Clinical Characteristics Male 203/340 (59.7%) 82/139 (59.0%) 287/483 (59.4%) 0.89 Age (years) 3 (1–4) 3 (2–5) 3 (1–5) 0.11 0–1 68/340 (20.0%) 21/139 (15.1%) 90/483 (18.6%) !0.57 1–4 202/340 (59.4%) 84/139 (60.4%) 287/483 (59.4%) 5–9 59/340 (17.4%) 29/139 (20.9%) 90/483 (18.6%) 10–14 11/340 (3.2%) 5/139 (3.6%) 16/483 (3.3%) Indigenous 9/340 (2.6%) 2/139 (1.4%) 11/483 (2.3%) 0.41 Interhospital Transfer 62/340 (18.2%) 34/139 (24.5%) 96/483 (19.9%) 0.12 GP/ED presentations in week before admission 2 (1-3) 2 (1-3) 2 (1-3) 0.56 Days from fever onset to hospital admission 5 (4-7) 4 (3-6) 5 (3-7) 0.002 Diagnostic Category Complete KD 192/340 (56.5%) 72/139 (51.8%) 264/483 (54.7%) & 0.64 Incomplete KD 30/340 (8.8%) 13/139 (9.4%) 43/483 (8.9%) Uncertain KD 118/340 (34.7%) 54/139 (38.8%) 176/483 (36.4%) Total number of Cardinal Clinical Features 5 122/340 (35.9%) 44/139 (31.7%) 166/483 (34.4%) ⎭⎪⎬⎪⎫  0.78 4 113/340 (33.2%) 56/139 (40.3%) 169/483 (35.0%) 3 58/340 (17.1%) 22/139 (15.8%) 83/483 (17.2%) 2 37/340 (10.9%) 14/139 (10.1%) 52/483 (10.8%) 1 8/340 (2.4%) 2/139 (1.4%) 10/483 (2.1%) 0 2/340 (0.6%) 1/139 (0.7%) 3/483 (0.6%) Specific Cardinal Clinical Criteria Rash 299/340 (87.9%) 125/139 (89.9%) 428/483 (88.6%) 0.54 Oro-mucosal changes 277/340 (81.5%) 107/139 (77.0%) 386/483 (79.9%) 0.26 Conjunctival injection 299/340 (87.9%) 115/139 (82.7%) 415/483 (85.9%) 0.13 Peripheral changes 216/340 (63.5%) 98/139 (70.5%) 317/483 (65.6%) 0.14 Cervical lymphadenopathy 227/340 (66.8%) 95/139 (68.3%) 323/483 (66. 9%) 0.74 Chapter 6228Continued... Neutrophils (%) 67 (55–76) [333/340] 70 (59–78) [137/139] 68 (56–77) [474/483] 0.042 Platelets (×109 /L) 374 (292–478) [337/340] 319 (239–426) [133/139] 358 (277–458) [474/483] <0.001 ESR (mm/Hr) 74 (45–100) [268/340] 66 (44–90) [108/139] 70 (44–95) [379/483] 0.13 CRP (mg/L) 95 (53–151) [333/340] 133 (75–209) [133/139] 104 (59–167) [470/483] <0.001 AST (U/L) 36 (26–50) [162/340] 34 (25–59) [70/139] 36 (26–51) [233/483] 0.82 ALT (U/L) 29 (16–72) [320/340] 33 (20–69) [129/139] 30 (17–70) [453/483] 0.25 Albumin (g/L) 34 (30–37) [318/340] 30 (26–35) [128/139] 33 (28–36) [450/483] <0.001 Bilirubin (μmol/L) 6 (4–9) [318/340] 6 (4–10) [128/139] 6 (4–10) [450/483] 0.75 Treatment Modalities IVIG 340/340 (100.0%) 139/139 (100%) 479/483 (99%) 1 (g/kg) 10/326 (3.1%) 5/134 (4%) 15/460 (3%) & 0.92 2 (g/kg) 305/326 (93.6%) 124/134 (93%) 429/460 (93%) Other dose 11/326 (3.4%) 5/134 (4%) 16/460 (4%) Unknown 14/340 (4.1%) 5/139 (4%) 19/479 (4%) Days from fever onset to IVIG 7 (5–9) 6 (5–7) 6 (5–8) <0.001 Aspirin 287/322 (89.1%) 109/133 (82%) 399/459 (87%) 0.010 3–5 (mg/kg/day) 5/322 (1.6%) 10/133 (8%) 15/459 (3%) 30–50 (mg/kg/day) 1/322 (0.3%) 0/133 (0%) 1/459 (0%) 80–100 (mg/kg/day) 29/322 (9.0%) 14/133 (11%) 44/459 (10%) Other dose 10/332 (3.0%) 1/134 (1%) 11/470 (2%) Unknown 28/340 (8.2%) 24/139 (17%) 52/483 (11%) Corticosteroids 17/28 (60.7%) 9/24 (38%) 26/52 (50%) 0.23 Oral only 6/28 (21.4%) 7/24 (29%) 13/52 (25%) Intravenous only 5/28 (17.9%) 8/24 (33%) 13/52 (25%) ‘Treatment Response’ was determined by the administration of a second round of treatment due to perceived failure to respond to an initial dose of IVIG. Only children who received at least one dose of IVIG are included in the ‘Treatment Response’ columns, whereas all children are included in the ‘All’ column. A dose may be listed as Unknown if it was not possible to calculate the dose/kg. Laboratory results are from blood samples taken prior to the administration of IVIG. Haemoglobin is presented as raw data and age–normalised data; normalised haemoglobin is based on normative data as published in the Harriet Lane Handbook, 22nd Edition (see Supplementary Methods). Categorical data are summarised as frequency (%) and compared using Pearson’s χ2 statistic. Continuous data are summarised as median (interquartile range) and compared using the Kruskal–Wallis test, except for the age–normalised haemoglobin, which is summarised as mean (standard deviation) and compared using ANOVA. ALT, alanine transaminase; AST, aspartate transaminase; CRP, C–reactive protein; ED, emergency department; ESR, erythrocyte sedimentation rate. GP, general practitioner; IVIG, intravenous immunoglobulin; KD, Kawasaki disease.  Prospective Surveillance of KD in Australia229Laboratory Variable Median (IQR) [n/N] N = 340 N = 139 N = 483 0.24 0.19 0.47 Haemoglobin (g/L) Normalised Haemoglobin (Z–score) White Cells (×109/L) Neutrophils (×109 /L) 111 (103–118) [336/340] -2.4 (2.1) [334/340]14.3 (11.0–17.6) [338/340] 8.9 (6.7–12.4) [333/340] 108 (101–118) [138/139] -2.6 (2.0) [138/139]13.6 (9.4–18.1) [138/139] 9.5 (6.0–12.3) [137/139] 110 (102–118) [478/483] -2.4 (2.1) [476/483]14.1 (10.8–17.9) [480/483] 9.0 (6.5–12.3) [474/483] 0.93 Supplementary Table 6.5 continued...   Chapter 5: Prospective Surveillance of KD in Australia       Supplementary Table 6.6: Multivariable Logistic Regression Model of Non-Response to Intravenous Immunoglobulin as Primary Therapy for Kawasaki Disease Predictor OR 95% CI P Pseudo-R2 Age (years) 1.07 0.99–1.16 0.08 !0.026 Sex 1.03 0.68–1.56 0.88 Number of cardinal clinical features 0.94 0.77–1.14 0.51 Days from fever onset to IVIG 0.88 0.82–0.95 0.002 The pseudo-R2 was 0.026 and was higher for each predictor removed from the model. CI, confidence interval; OR, odds ratio.      Supplementary Table 6.7: Agents Used as Secondary Therapy for Children Diagnosed with Kawasaki Disease  Non-Responders Received Second Dose IVIG 123/139 (88.5%) IVIG Dose (g/kg)  1 4/118 (3.4%) 2 110/118 (93.2%) Other dose 4/118 (3.4%) Received Corticosteroids 44/139 (31.7%) Corticosteroid Route:  Oral only 9/44 (20.5%) Intravenous only 19/44 (43.2%) Oral and Intravenous 16/44 (36.4%) Received Infliximab 6/139 (4.3%) Data are summarized as frequency (%). IVIG, intravenous immunoglobulin.    Chapter 6230Supplementary Table 6.8: Clinical Outcomes of Children Diagnosed with Kawasaki Disease, by Response to Therapy Treatment Response All Responders Non-Responders P N = 340 N = 139 N = 483 Admission Outcomes Admitted to ICU/HDU 9/340 (2.7%) 16/139 (12%) 25/483 (5.2%) <0.001 Respiratory Support 2/9 (22%) 7/16 (44%) 9/25 (36%) 0.282 Blood Pressure Support 4/9 (44%) 7/16 (44%) 11/25 (44%) 0.973 ECMO 0/9 (0%) 1/16 (6%) 1/25 (4%) 0.444 Total admitted days 3.5 (3–5) 6 (4–10) 4 (3–6) 0.001 Acute Coronary Artery Outcomes Inpatient Echocardiogram 265/332 (79.8%) 128/139 (92.1%) 397/475 (83.6%) 0.001 Fever Onset to Echocardiogram (days) 8 (6–10) 7 (5.5–10) 8 (6–10) 0.299 Worst Coronary Artery Z–score <2 154/238 (64.7%) 70/111 (63%) 227/353 (64.3%) ⎭⎪⎬⎪⎫ 0.451 2 to <2.5 23/238 (9.7%) 10/111 (9%) 34/353 (9.6%) 2.5 to <5 45/238 (18.9%) 24/111 (22%) 69/353 (19.6%) 5 to <10 13/238 (5.5%) 3/111 (3%) 16/353 (4.5%) ≥10 3/238 (1.3%) 4/111 (4%) 7/353 (2.0%) Subacute Coronary Artery Outcomes Follow–Up Echocardiogram 258/325 (79.4%) 122/137 (89.1%) 383/466 (82.2%) 0.013 Discharge to Echocardiogram (weeks) 6 (5–8) 6 (59) 6 (5–8) 0.233 Worst Coronary Artery Z–score <2 182/225 (80.9%) 79/103 (77%) 264/331 (79.8%) ⎭⎪⎬⎪⎫ 0.286 2 to <2.5 17/225 (7.6%) 7/103 (7%) 24/331 (7.3%) 2.5 to <5 17/225 (7.6%) 10/103 (10%) 27/331 (8.2%) 5 to <10 5/225 (2.2%) 1/103 (1%) 6/331 (1.8%) ≥10 4/225 (1.8%) 6/103 (6%) 10/331 (3.0%) Wherever possible coronary artery Z-scores were re-calculated using the method of Dallaire & Dahdah (Dallaire F, Dahdah N. 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Intravenous Gamma-Globulin Treatment and Retreatment in Kawasaki Disease: Pediatr Infect Dis J. 1998 Dec;17(12):1144–8.  20.  Tulloh RMR, Mayon-White R, Harnden A, Ramanan AV, Tizard EJ, Shingadia D, et al. Kawasaki disease: a prospective population survey Prospective Surveillance of KD in Australia233Chapter5:ProspectiveSurveillanceofKD in Australiain the UK and Ireland from 2013 to 2015. Arch Dis Child. 2019 Jul;104(7):640–6.  21. Heaton P, Wilson N, Nicholson R, Doran J, Parsons A, Aiken G.Kawasaki disease in New Zealand. J Paediatr Child Health. 2006Apr;42(4):184–90. 22. Lucas R, Dennington P, Wood E, Dionne A, Ferranti SD, NewburgerJW, et al. Variation in the management of Kawasaki disease inAustralia and New Zealand: A survey of paediatricians. J Paediatr Child Health. 2020 Dec 9;jpc.15290.  23. The Royal Children’s Hospital. Clinical Practice Guideline on KawasakiDisease [Internet]. Melbourne, Australia; 2021 Jan [cited 2020 Jul 23].Available from: https://www.rch.org.au/clinicalguide/guideline_index/Kawasaki_disease/ 24. Amarilyo G, Koren Y, Simon DB, Bar-Meir M, Bahat H, Helou MH, etal. High-dose aspirin for Kawasaki disease: outdated myth or effectiveaid? Clin Exp Rheumatol. 2017; 25. Zheng X, Yue P, Liu L, Tang C, Ma F, Zhang Y, et al. Efficacy betweenlow and high dose aspirin for the initial treatment of Kawasaki disease:Current evidence based on a meta-analysis. PLOS ONE. 2019 May 22;14(5):e0217274.  26. Jia X, Du X, Bie S, Li X, Bao Y, Jiang M. What dose of aspirin should beused in the initial treatment of Kawasaki disease? A meta-analysis.Rheumatology. 2020 Aug 1;59(8):1826–33. 27. Lee G, Lee SE, Hong YM, Sohn S. Is High-Dose Aspirin Necessary in theAcute Phase of Kawasaki Disease? Korean Circ J. 2013;43(3):182.28. Dhanrajani A, Chan M, Pau S, Ellsworth J, Petty R, Guzman J. AspirinDose in Kawasaki Disease: The Ongoing Battle. Arthritis Care Res.2018 Oct;70(10):1536–40. 29. Platt B, Belarski E, Manaloor J, Ofner S, Carroll AE, John CC, et al.Comparison of Risk of Recrudescent Fever in Children With KawasakiDisease Treated With Intravenous Immunoglobulin and Low-Dose vs High-Dose Aspirin. JAMA Netw Open. 2020 Jan 3;3(1):e1918565.  30. Kobayashi T, Inoue Y, Takeuchi K, Okada Y, Tamura K, Tomomasa T,et al. Prediction of Intravenous Immunoglobulin Unresponsiveness inPatients With Kawasaki Disease. Circulation. 2006 Jun 6;113(22):2606–12.  31. Fong NC, Hui YW, Li CK, Chiu MC. Evaluation of the Efficacy ofTreatment of Kawasaki Disease before Day 5 of Illness. Pediatr Cardiol.2004 Feb 1;25(1):31–4. Chapter 623432. Tremoulet AH, Best BM, Song S, Wang S, Corinaldesi E, Eichenfield JR,et al. Resistance to Intravenous Immunoglobulin in Children withKawasaki Disease. J Pediatr. 2008 Jul;153(1):117-121.e3. 33. Yan F, Zhang H, Xiong R, Cheng X, Chen Y, Zhang F. Effect of EarlyIntravenous Immunoglobulin Therapy in Kawasaki Disease: ASystematic Review and Meta-Analysis. Front Pediatr. 2020 Nov 20;8:593435.  34. Systemic Vasculitides – Kawasaki Disease [Internet]. TherapeuticGuidelines. 2017 [cited 2020 Jul 23]. Available from:https://www.tg.org.au 35. Blood Book: Australian Blood Administration Handbook. Melbourne:Australian Red Cross Lifeblood - Victoria; 2020.Prospective Surveillance of KD in Australia235236Chapter 7: Conclusions In the introduction to this thesis I outlined two broad areas fields of inquiry that guided the subsequent research. These were: What is the epidemiology of Kawasaki disease (KD) in Australia? How do clinicians approach the management of KD in Australia? In Part One these questions were explored in two reviews, highlighting specific points of uncertainty or contention. With regard to epidemiology, evidence from around the world of increasing incidence and seasonal variation was reviewed, with gaps in local understanding identified. The challenge of case definition — and implications for comparisons between studies — was also discussed at length. Three specific research questions where then articulated: 1. What is the current incidence of KD in Australia?2. Is there evidence of increasing incidence of KD in Australia?3. Is there evidence of seasonal variation of KD in Australia?These questions were addressed in the study presented in Chapter 4. To address the challenges associated with case definition I used two independent national datasets. The first was the National Hospital Morbidity Database (NHMD); the NHMD is maintained by the Australian Institute of Health and Welfare and records hospitalisations,1 from which it was possible to calculate the hospitalisation rates over a 25-year period. As noted in Chapter One, hospitalisation rate overestimates KD incidence as children can have multiple admissions within an episode of KD. I sought to address this issue by comparing the hospitalisation rate to the treatment rate, derived from the second dataset. The second dataset was the Supply Tracking Analysis Reporting System (STARS), maintained by the Australian Red Cross Lifeblood. STARS records the allocation of intravenous immunoglobulin (IVIG); patient details for each dose of IVIG were available, making it possible to account for children who had received multiple doses within an episode of KD. I hypothesised that the treatment rate would more accurately correlate with the true diagnosis rate. This was supported by results from to other studies (presented in Chapter Three and Chapter Six), which showed very high rates of IVIG use for the treatment of KD. The average annualised treatment rate over the period during which the datasets overlapped was 14.31 per 100,000 children under 5 (95% confidence interval 13.67–14.97); I believe that this is likely to represent the most accurate estimate of KD incidence in Australia. Pleasingly, the average annualised hospitalisation rate over the same period was very similar, at 14.99 per 100,000 237children under 5 (95% CI 14.33–15.66). I therefore felt more confident proceeding with an analysis of hospitalisation data, which extended over 25 years. Over a 25-year period the KD hospitalisation rate in Australia increased from 9.39 per 100,000 children under 5 (1993–97, 95% CI 8.66–10.16) to 17.51 per 100,000 children under 5 (2013–17, 95% CI 16.59–18.47), for a mean annual increase of 3.5% (95% CI 2.9–4.1). Interestingly, all of that increase occurred among children between 1 and 4 years of age, with hospitalisations among children under 1 year changing very little over the period. Finally, the resolution (both spatial and temporal) of the STARS dataset permitted an analysis for evidence of seasonal variation in rate of KD. I found evidence of a small seasonal effect on KD treatment rates, with slightly more cases in July to December as compared with January to June. On regional analysis this effect was not seen in more northern states, however case numbers from those jurisdictions were small. In summary, I derived the most reliable estimate of KD incidence in Australia by combining datasets with different inherent biases. I observed increasing incidence over a 25-year period, concurrent with a changing age distribution. Finally, I reported the first evidence of seasonal variation in KD rates from Australia. The review of KD management in Chapter Two identified a number of important areas characterised by a lack of evidence, a lack of consensus, or a divergence of consensus from evidence. Some of these included: 1. The approach to immunisation with live vaccines after treatmentwith IVIG.2. The role of aspirin in the acute phase of KD, with particularattention to dose.3. The role of corticosteroids in the management of KD.4. The definition and treatment of “IVIG resistant” KD.The first of these was addressed in a stand-alone study, presented in Chapter Five. Australian guidelines align with those from North America, recommending that live vaccines be postponed for 11 months after receiving IVIG.11–13 In a retrospective audit of immunisation practices after IVIG for KD at two specialist children’s hospitals in Sydney, I observed that these recommendations are frequently not followed. Indeed, more than half of the children who received IVIG in the 11 months prior to a scheduled live vaccine went on to receive that vaccine in breach of the recommendations. I argued that this was likely due to under recognition of the issue and poorly integrated care between providers. In reviewing the literature that informed the Chapter 7238   recommendations I also highlighted significant deficits in knowledge, noting that the 11-month postponement interval had been derived by extrapolation from low-quality data.14 In lieu of more robust data I sought to re-emphasize attendance to and maintenance of the  public health systems that ensure high rates of effective immunisation. My analysis of Australian responses to an international survey about the management of KD (presented in Chapter Three) highlighted significant variation in practice with regard to the first three points. Australian guidelines are notable for recommending that low-dose aspirin be initiated at diagnosis2,3; this is in contrast to medium- or high-dose aspirin recommended elsewhere.4–6 The reported practice of Australian clinicians (as observed in their responses to the KD survey) was highly variable, with no consensus around a preferred dose. Actual practice, observed in the prospective cohort study presented in Chapter Six) was very different — 86.9% of patients only ever received low-dose aspirin. This may indicate evolving practice as clinicians become more comfortable with a low-dose only approach. As discussed in Chapter Two, neither medium-dose nor or high-dose aspirin have been shown to be superior to low-dose or no aspirin during the acute phase of KD.7–9 I argue that current Australian practice is best aligned with the available evidence, and hope that recognition of the successful use of this approach in Australia might aid progressive reform in this aspect of KD management globally. I observed a clear difference between responses by generalist and specialist clinicians with regard to the reported use of corticosteroids for the management of KD — specialists were more likely than generalists to prescribe corticosteroids for both primary adjunctive therapy and for the treatment of IVIG resistant disease. The rate of corticosteroid use observed in the prospective cohort study was closer to that reported by specialist clinicians, which likely reflects recruitment from specialist referral hospitals. It is increasingly recognised that corticosteroids do have a role in the management of KD,10 however heterogeneity in study design to date makes the interpretation of results challenging.  Most Australian respondents to the KD survey indicated that they would diagnose IVIG resistance if there was persistent or recrudescent fever 24 hours after the end of the IVIG infusion. This is earlier than recommended in most guidelines (typically 36–48 hours4–6) and was earlier, on average, than responses to that survey by New Zealand clinicians. Data from the prospective cohort study supported this finding, with most cases of IVIG resistance diagnosed less than 36 hours after the end of the IVIG infusion. That cohort had a comparatively high overall rate of IVIG resistance (29%), which may reflect overdiagnosis due to premature attribution of fever to treatment Conclusions239failure. Current recommendations are based on consensus opinion4,6; in the absence of a relevant evidence base there is a clear need for global collaboration around an agreed definition of IVIG resistance. This would not only support enhanced patient care, but would aid research that uses treatment failure as a key outcome. Finally, one key finding from the prospective cohort study in Chapter Six related neither to epidemiology nor management, but to diagnosis: 23.6% of children treated for KD did not fulfil even the most permissive diagnostic criteria outlined in the most recent statement by the American Heart Association.4 This important finding — though unexpected — highlights the strength of the study model, which enrolled cases based on ‘clinician diagnosis’ rather than using a case definition. Those with what I called ‘Uncertain KD’ differed little from those with Complete or Incomplete KD at presentation, yet the incidence and severity of coronary abnormalities in that group were much lower. More than fifty years after Dr Kawasaki’s seminal monograph on what he called mucocutaneous lymph node syndrome the entity now named in his honour is still defined by the clinical features that he observed. This has the effect of rendering important questions difficult to articulate: Did any of the children who failed to meet diagnostic criteria for KD have KD? Did all of the children with complete KD have the same disease process? These are questions of ontology: outside the scope of this thesis, yet fundamental to its subject; I return to them in the Postscript. Putting ontological uncertainties to one side; the rarity of adverse coronary outcomes in children who do not meet the diagnostic criteria for KD should embolden clinicians to adhere to those criteria in the face of diagnostic uncertainty. The majority of those with Uncertain KD received IVIG on or before day five of fever; a watchful waiting approach may help reduce rates of overdiagnosis and associated resource overuse. Implications for Policy, Practice, & Research This work was funded by the National Blood Authority, which oversees the provision of publicly funded blood products in Australia. The appropriate use of a scare resource (IVIG) is obviously of great interest. My research has demonstrated that Australian clinicians largely prescribe IVIG for KD in accordance with international best practice. There are two areas of possible overuse: Firstly, the observation that a significant subset of children was diagnosed and treated for KD without fulfilling diagnostic criteria may indicate an element of overdiagnosis and consequent overtreatment. Secondly, the relatively high rate of retreatment (which may represent premature diagnosis of IVIG resistance) might also represent overuse. I do not believe, however, that efforts on these points are likely to result in significant dividends for resource stewardship. Firstly, any overuse in these areas is likely to be only marginal in the context of IVIG used for KD in Australia. I have Chapter 7240suggested that clinicians take a watchful-waiting approach in cases where the diagnosis of KD is suggested before diagnostic criteria are met. It is possible that most children so managed would still be diagnosed with — and treated for — KD, only slightly later. Secondly, children with KD represent a tiny fraction of the demand for immunoglobulin products in Australia (about 0.3%, as discussed in Chapter Two). While these issues may be marginal at a population level, the impact at a patient level can be significant. Each decision to administer IVIG for the management of KD represents a calculus weighing possible benefits against possible risks. Children who receive IVIG in the context of an incorrect KD diagnosis are exposed to the same risks without any clear benefit. Recommendations about the diagnosis of KD, and of IVIG resistance, are based on consensus agreement of relevant experts. The observation that real-world practice frequently differs from these recommendations is indicative of a state of clinical equipoise; large, prospective studies — whether observational or interventional — that can inform future recommendations around treatment thresholds should be pursued. Such efforts would be greatly aided by coordinated international collaborations that capitalise on existing practice variation. Finally, I propose that there is a need for the KD research community to revisit fundamental questions around the nature of KD. In the Postscript that follows I will seek to highlight some of the ways in which the current paradigm is unsuited to addressing priority topics in KD research. I critique the current syndrome-centred paradigm on the grounds of historical accuracy and ontological precision; I then submit an alternative, process-centred paradigm for consideration and comment. Conclusions241References 1. Australian Institute of Health and Welfare. National Hospital MorbidityDatabase [Internet]. Canberra: Australian Institute of Health and Welfare; 2019. Available from: https://www.aihw.gov.au/reports/hospitals/principal-diagnosis-data-cubes 2. The Royal Children’s Hospital. Clinical Practice Guideline on KawasakiDisease [Internet]. Melbourne, Australia; 2021 Jan [cited 2020 Jul 23]. Available from: https://www.rch.org.au/clinicalguide/guideline_index/Kawasaki_disease/ 3. Perth Children’s Hospital. Kawasaki disease [Internet].https://pch.health.wa.gov.au. 2021 [cited 2022 Dec 30]. Available from: https://pch.health.wa.gov.au/For-health-professionals/Emergency-Department-Guidelines/Kawasaki-disease 4. McCrindle BW, Rowley AH, Newburger JW, Burns JC, Bolger AF, GewitzM, et al. Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association. Circulation. 2017;135(17):e927–99.  5. Research Committee of the Japanese Society of Pediatric Cardiology andCardiac Surgery, Committee for Development of Guidelines for Medical Treatment of Acute Kawasaki Disease. Guidelines for Medical Treatment of Acute Kawasaki Disease (2020 Revised Version). J Pediatr Cardiol Card Surg. 2021;5(1):33.  6. de Graeff N, Groot N, Ozen S, Eleftheriou D, Avcin T, Bader-Meunier B,et al. European consensus-based recommendations for the diagnosis and treatment of Kawasaki disease – the SHARE initiative. Rheumatology. 2019 Apr 1;58(4):672–82.  7. Amarilyo G, Koren Y, Simon DB, Bar-Meir M, Bahat H, Helou MH, et al.High-dose aspirin for Kawasaki disease: outdated myth or effective aid? Clin Exp Rheumatol. 2017;  8. Chiang MH, Liu HE, Wang JL. Low-dose or no aspirin administration inacute-phase Kawasaki disease: a meta-analysis and systematic review. Arch Dis Child. 2021 Jul;106(7):662–8.  9. Dallaire F, Fortier-Morissette Z, Blais S, Dhanrajani A, Basodan D,Renaud C, et al. Aspirin Dose and Prevention of Coronary Abnormalities in Kawasaki Disease. Pediatrics. 2017 Jun;139(6):e20170098.  10. Green J, Wardle AJ, Tulloh RM. Corticosteroids for the treatment ofKawasaki disease in children. Cochrane Vascular Group, editor.Cochrane Database Syst Rev [Internet]. 2022 May 27 [cited 2023 Jan Chapter 7242   1];2022(5). Available from: http://doi.wiley.com/10.1002/14651858.CD011188.pub3 11.  Public Health Agency of Canada. Blood products, human immunoglobulin and timing of immunization [Internet]. Canadian Immunization Guide. 2021 [cited 2022 Sep 2]. Available from: https://www.canada.ca/en/public-health/services/canadian-immunization-guide.html 12.  Active Immunization After Receipt of Immune Globulin or Other Blood Products. In: Red Book 2021. 32nd ed. American Academy of Pediatrics; 2021. (Report of the Committee on Infectious Diseases).  13.  Australian Technical Advisory Group on Immunisation (ATAGI). Australian Immunisation Handbook [Internet]. Canberra: Australian Government Department of Health and Aged Care; 2022 [cited 2022 Aug 29]. Available from: immunisationhandbook.health.gov.au 14.  Kroger A, Bahta L, Hunter P. Timing and Spacing of Immunobiologics [Internet]. General Best Practice Guidelines for Immunization: Best Practices Guidance of the Advisory Committee on Immunization Practices (ACIP). 2022 [cited 2022 Aug 29]. Available from: https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/timing.html  Conclusions243244Chapter 8: Postscript— The Kawasaki Disease Paradigm Introduction Kawasaki disease is an acute vasculitis of childhood that leads to coronary artery aneurysms in ≈25% of untreated cases.1 So begins the 2017 Scientific Statement for Health Professionals from the American Heart Association on the Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease. The line makes several ontological* claims about Kawasaki disease (KD), namely: 1. That KD is a disease entity†. This claim is implied by the following:2. That among disease entities, KD is of the kind ‘vasculitis’.3. That the set of all patients with KD contains a subset (25%) in whomcoronary artery aneurysms are a consequence (in untreated cases).These claims are axiomatic to what has been called the Kawasaki Disease Paradigm.5 The preceding thesis, and the epidemiological studies, interventional trials, and clinical practice guidelines discussed therein, exist within that paradigm. In this critical essay I will highlight logical and linguistic deficiencies of that paradigm and present an alternative paradigm for consideration. * Ontology is the philosophical study of being. It seeks to classify—in a definitive andexhaustive fashion—entities in all spheres of being. It asks questions like “Whatkinds of things exist?”, “To what classes do things belong?”, and “How do theseclasses relate?”2† The term disease entity has a special meaning within realist medical ontology. Adisease entity is a dependent continuant that exists is reality.3 Continuants exist at amoment in time and continue to exist through time, like a person. In contrast,occurrents have temporal parts, like the life of a person. Independent continuants canexist independently (e.g., a person), whereas dependent continuants can only exist byvirtue of another entity (e.g., a rash). The concept of continuants and occurrents isdescribed clearly in chapter 14 of Artificial Intelligence: Foundations ofComputational Agents, 2nd edition. Cambridge University Press, 2017 (available at:https://artint.info/2e/html/ArtInt2e.Ch14.S3.SS3.html).In discussing the levels of abstraction relevant to ontology, Smith and Ceustersoutline three levels: 1, the level of reality; 2, the level of cognitive representations ofthis reality; and 3, the level of textual and graphical artifacts.4 Disease entities (in therealist worldview) exists in the real world—i.e., at the level of reality L1.3245Chapter2:TheManagementofKDContested History of “Kawasaki Disease” In January 1961 Dr Tomisaku Kawasaki—then a paediatrician at Japan Red Cross Central Hospital—reviewed a four-year-old boy who presented with persistent fever for two weeks, with inflamed mucous membranes, cervical lymphadenopathy, and erythematous rash. After considering a range of differential diagnoses (including measles, scarlet fever, and Stevens-Johnson syndrome) Kawasaki discharged the boy without assigning a diagnosis (labelling the case ‘diagnosis unknown’).6 Three years later Kawasaki presented a series of 20 similar patients, identifying them as instances of mucocutaneous ocular syndrome (MCOS)—an entity already described in children by paediatricians Dr Itoga and Dr Yamagishi in 1960.7 “Mucocutaneous Lymph Node Syndrome” By 1967 Kawasaki had amassed a cohort of 50 cases, which he described in the Japanese journal Arerugi.8 The monograph was meticulous, with charts of body temperature and clinical signs reproduced for each child by hand, as well as photographs of clinical signs and photomicrographs of pathological specimens of skin and lymph nodes. All cases had fever for at least 6 days and the vast majority had conjunctival congestion, oro-mucosal inflammation, and an erythematous rash that involved the acral surfaces with subsequent desquamation. Just over half of the cases were under the age of two years. Kawasaki discussed possible infectious and non-infectious causes, rejecting each in turn, before turning his attention to MCOS. Tracing the historical use of the term to at least the 1940s, he made the ontological critique that MCOS subsumed multiple discrete clinical entities (Reiter disease, Behçet’s disease, and ‘multiform exudative erythema syndrome’), and thus was not itself a coherent and distinct entity. Turning to the age distribution he noted that few infantile cases had been described, with Itoga and Yamagishi’s the only series in which most cases were under the age of two years. Finally, he contrasted the clinical features of his cohort with those described by Itoga and Yamagashi. The latter had observed generalised desquamation and blisters whereas Kawasaki observed periungual desquamation and no blisters; subtle differences in the ocular, mucosal, and lymphatic signs were also outlined. He concluded that the entity he presented was distinct, and proposed the name Acute Febrile Muco-Cutaneous Lymph Node Syndrome (MCLS*).8 In the description of MCLS in his Arerugi paper, Kawasaki stated that “...patients spontaneously recover without any sequelae”.8 Evidence to the contrary soon began to accumulate. Nation-wide surveys of the condition in Japan reported a case fatality rate of 1.7%, with sudden death occurring in the * This is variably referred to as MCLS, acute MCLS, and AMCLNS. The former willbe used in this essay.Chapter 8246   context of acute cardiac failure.9 Post-mortem examinations demonstrated sequelae of vasculitis, with the formation of aneurysms in the coronary arteries of many fatal cases10,11; angiograms demonstrated clinically inapparent aneurysms in children who survived.12 A large, single-centre cohort study reported that approximately 25% of untreated patients would have coronary aneurysms in the subacute phase of the illness, of which about half persisted after one year.13* The histopathology of coronary lesions associated with MCLS was described by Fujiwara and Hamashima in 1978.10 They presented the autopsy findings of 20 children who had died from MCLS in Japan, with the time from illness onset to death ranging from 9 days to 4½ years. The child who died at day 9 of illness had no coronary aneurysms, however microvessels and small coronary branches had evidence of both endarteritis (inflammation of the vessel wall) and periarteritis (inflammation of the adventitia); no inflammatory changes were seen in the tunica media. As the time from illness onset to death increased inflammation was increasingly observed in larger arteries, involving the tunica media (described as panarteritis). A diverse range of infiltrating cells (including neutrophils and lymphocytes) was noted, sometimes leading to necrosis of the media.† “Infantile Periarteritis Nodosa” The coronary pathology of MCLS shared a striking resemblance to that of infantile periarteritis‡ nodosa (IPN), an entity that had been described in post-mortem reports from at least the 1870s.26–28 The apparent association was one  * This study, which at the time of writing has been cited over 1,600 times, seems largely responsible for this frequently-cited statistic.1,14 Suzuki et al identified aneurysms in only 93 out of 1,100 (8.5%) of children with KD, but at significantly later follow-up (median 4 years 7 months).15 The few studies of the incidence of coronary artery aneurysms in KD that have been performed in non-Japanese populations prior to the use of IVIG have been comparatively small. The reported incidence of aneurysms has ranged from 8% in the UK16 to between 14% and 25% in the USA.17–20 † A later study of both autopsy and heart transplant cases would identify three distinct pathological processes in the coronary arteries of children with severe KD.21 Necrotising arteritis (NA) of medium-sized muscular arteries was observed early in the disease process. It proceeds from the lumen outwards, with neutrophilic invasion and the sequential destruction of the intima, internal elastic lamina, tunica media, and external elastic lamina—sometimes extending to the adventitia. This was followed by an overlapping subacute/chronic (SA/C) vasculitis of both muscular and elastic arteries; lymphocytic invasion was predominant with few neutrophils seen. Both necrotising arteritis and subacute/chronic vasculitis demonstrated destruction of the vessel wall and the development of aneurysms. Finally, a delayed stenosing process (luminal myofibroblastic proliferation, LMP) was observed—seemingly related to SA/C vasculitis. ‡ The terms periarteritis and polyarteritis are used interchangeably in the literature.22–25 The former is used henceforth to emphasize its distinction from classical polyarteritis nodosa. Postscript247  Chapter 2: The Management of KD that Kawasaki actively opposed.26 In an article published in Pediatrics in 1974 he noted the similarities but opined that “...description of the clinical features of [infantile periarteritis nodosa] is insufficient in the literature.” That statement was disingenuous; among the articles cited in that paper was a case report by Canadian pathologist Dr Munro-Faure describing a fatal case of infantile periarteritis nodosa in a 3-month-old boy who fulfilled what would later be the diagnostic criteria for complete KD.29 Autopsy revealed multiple aneurysms of the coronary arteries characterised by necrotising arteritis extending from the intima to the adventitia with destruction of the internal elastic lamina and tunica media. Munro-Faure cited case reports of 18 other cases, many of which would today be identified as KD.* Indeed, throughout the 1970s the relation of these entities was actively discussed. In a letter in The Lancet in 1976, Dutch cardiac pathologist Dr Becker argued that there was no reason to conclude that the two entities were discrete.30 This was followed by a post-mortem study by American pathologists Landing and Larson, published in Pediatrics in 1977. They compared clinical and post-mortem pathological findings from 20 children with IPN, two with MCLS, and three with classical polyarteritis nodosa. They concluded that IPN and fatal MCLS were indistinguishable (and distinct from classical polyarteritis nodosa), and recommended that IPN and MCLS be consolidated under a single term†.34 Indeed, this appears to have occurred: Medline lists only 8 manuscripts published in the years after 1977 that refer to IPN but not to MCLS/KD. “Kawasaki Disease” The label MCLS was in wide use in both the Japanese and English literature in the 1970s. The change to “Kawasaki Disease” can be pinpointed to 1976: first with its adoption by the Japanese MCLS research group,35 followed in English in an editorial in The Lancet.36 Although not without controversy,31,32 the new name was quickly adopted around the world. In support of the adoption of the Kawasaki eponym Landing and Larson pointed to the recognition of the “...great contribution of Japanese workers”.34 This suggests a narrative of consensus under the leadership of one individual, yet the reality was far more complex.26 Kawasaki was not the first in Japan to note the clinical picture that he called MCLS, nor was his conception of the underlying process the most  * A strikingly similar case was described by Sinclair and Nitsch in 1949.25 † They suggested either the label MCLS or Kawasaki disease. This treats the terms syndrome and disease as synonyms, which they are not.26,31,32 The Oxford Concise Medical Dictionary lists only one definition for syndrome (“a combination of signs and/or symptoms that forms a distinct clinical picture indicative of a particular disorder”) but two definitions for disease (the general “any bodily abnormality or failure to function properly, except that resulting directly from physical injury”, and the more specific “disorder with a specific cause (which may or may not be known) and recognizable signs and symptoms”).33 Chapter 8248   complete (he actively opposed the recognition of coronary complications advocated by his peers*).26  The adoption of the descriptor disease was both more complex and more controversial. The Japanese term byō (病, a somewhat vague term meaning “ill” or “sick”39) was chosen over the more technical shōkōgun (症候, meaning “syndrome”39) for the condition’s Japanese name Kawasakibyō (川崎病), as it was thought to be more appropriate for communication with families.26 The adoption of disease in English had a different motivation. In English the word disease has a general meaning (“any bodily abnormality or failure to function properly, except that resulting directly from physical injury”33) and a more technical meaning (“disorder with a specific cause [which may or may not be known] and recognizable signs and symptoms”33). Kushner et al (in their exhaustive historical analysis of the Kawasaki disease paradigm) describe the adoption of the term Kawasaki disease by the CDC; they note that the latter, technical definition that was specifically invoked as a rhetoric response to prevalent scepticism regarding the status of MCLS as a discrete entity26†  Table 8.1: Kawasaki Disease, Kawasaki Syndrome, or Mucocutaneous Lymph Node Syndrome—Use in the Academic Literature by Decade  1970s 1980s 1990s 2000s 2010s 2020s Kawasaki Disease 7‡10,42–47 1415,48–60 1813,61–77 1714,78–93 191,21,90,94–109 20110–129  Kawasaki Syndrome 0 617,130–134 2135,136 3137–139 1140 0 Mucocutaneous Lymph Node Syndrome 139,12,34,41,141–149 0 0 0 0 0 Condition labels used in the titles of the 20 most highly-cited papers in the English-language literature by decade. The label Mucocutaneous Lymph Node Syndrome includes acute mucocutaneous lymph node syndrome and acute febrile mucocutaneous lymph node syndrome.  The term Kawasaki disease remained controversial—Kawasaki himself preferred the term syndrome.26 Indeed, Kawasaki syndrome persisted alongside Kawasaki disease for some time, and is still occasionally encountered.31,40 While some authors have sought to defend the distinction,31,32 the common use of the terms gives the impression that they are interchangeable (an important point to which I will return). The overarching trend has been a consolidation of disparate terms under the now-dominant Kawasaki disease. Of the twenty most highly cited academic papers published on the topic in the English-language literature in the 1970s only 35% used the  * Dr Takajiro Yamamoto had been collating a case series similar to Kawasaki’s during the 1950’s and 60’s, but with an emphasis on cardiac associations.26 Dr Noboru Tanaka had documented sudden cardiac death in a child diagnosed with MCLS by Kawasaki in 196527,37,38; he continued to identify MCSL with IPN against Kawasaki’s vocal opposition.26 † The reader is strongly encouraged to refer to Kushner et al26 for the authoritative historical investigation of this event. ‡ Not counted here is one manuscript entitled “Mucocutaneous Lymph Node Syndrome (Kawasaki Disease) in Adults”41. Postscript249Chapter2:TheManagementofKDlabel Kawasaki Disease; the top 20 papers in the current decade to date have used that label exclusively (Table 8.1). Incompleteness By the early 1980s there was an emerging realisation that coronary pathology characteristic of KD could occur in children who did not fulfil the formal epidemiologic case definition.150,151 Rowley et al presented a series of four cases of coronary artery aneurysms in children with so-called ‘incomplete’ KD, and reviewed the case literature of the phenomenon.48 They highlighted the importance of recognising peripheral desquamation as a delayed sign of KD, and suggested that the diagnosis be considered “...in an infant or child with a prolonged unexplained febrile illness”. The issue was formally addressed in diagnostic recommendations two years later in a consensus statement representing the North American attendees of the Third International Kawasaki Disease Symposium.152 The statement distinguished those children with sufficient clinical signs but fewer than five days of fever (in whom “...some believe...” the diagnosis of KD could be made by experienced individuals) from those without sufficient clinical signs (described as ‘atypical’ or ‘incomplete’*). The authors identified that infants (under 12 months) were at particular risk for this presentation and encouraged the reader to remain vigilant in that age group—observing for associated features, such as thrombocytosis, arthritis, anterior uveitis, and sterile pyuria.  The most recent statement from the American Heart Association (AHA) sought to provide clearer advice around the diagnosis of incomplete KD. The authors proposed a diagnostic algorithm for incomplete KD, acknowledging that in the absence of a ‘gold standard’ for diagnosis “...[the] algorithm cannot be evidence based but rather represents the informed opinion of the expert committee”.1 The algorithm outlines an approach to children with two or three cardinal clinical signs of KD and at least five days of fever, or infants with unexplained fever for at least seven days. For children with raised inflammatory markers† treatment with IVIG is recommended if there is * Both terms are still encountered1 with reference to children who do not fulfilsufficient clinical criteria for a diagnosis of complete KD, however ‘incomplete’ ispreferred. The 2004 American Heart Association statement recommended that‘atypical’ be reserved “...for patients who have a problem, such as renal impairment,that generally is not seen in Kawasaki disease”.14† Defined as a C-reactive protein concentration ≥30 mg/L or an erythrocytesedimentation rate ≥40 mm/hr.Chapter 8250   derangement of specified laboratory markers* or echocardiographic evidence† of coronary abnormalities consistent with KD.1 While the clinical presentation of ‘incomplete KD’ can be less dramatic than complete KD, it is clear that the severity of observable clinical signs does not correlate with the likelihood or severity of adverse coronary outcomes153,154—as stated by Sonobe et al, incomplete KD “...should not be equated with mild KD”.153 To the contrary: the incidence of adverse coronary outcomes appears to be higher among children with incomplete KD.153 This additional risk is likely the result of multiple overlapping factors, such as delayed diagnosis and a slightly younger age profile (incomplete KD is more commonly observed in children under 1 year of age, which also appears to confer additional risk of aneurysm formation).154 Manlhiot et al found no significant demographic, clinical, or laboratory differences between children with incomplete versus complete KD, concluding that the entities are “two sides of the same coin”.155 The distinction between complete and incomplete KD therefore appears to be semantic, rather than ontological; an artifact of a paradigm that defines the disease entity by one of its clinical syndromes. Global (Re)Emergence Following the publication of Kawasaki’s initial case series, in 1970 the Japanese government funded the establishment of what would become the Kawasaki Disease Research Committee. The committee produced and distributed diagnostic guidelines and conducted epidemiological surveys approximately every two years.‡ Surveys conducted through the 1970s consistently reported increasing case numbers, however the number of participating hospitals increased from 1,452 to 1,688 over that decade. On a background of apparent rising incidence the surveys also identified three nation-wide epidemics (in 1979, 1982, and 1986). By the early 2000s the incidence of KD among children under the age of 5 years in Japan exceeded 150 per 100,000 per year. Throughout the 1970s MCLS/KD was also starting to be reported outside of Japan: first in Korea (1973156), then Hawaii (1974157), Greece (1975158), Canada (1975159), the continental United States (1975160), The Netherlands (197628), Australia (197642), West Germany (1977161), Italy (1977162), Belgium (1977163), Sweden (197723), England (1977164), Scotland (197722), Turkey (1977165), and  * These include: anaemia (age corrected), thrombocytopaenia (after the 7th day of fever), hypoalbuminaemia, elevated alanine aminotransferase, leucocytosis, and pyuria. † These include: specified coronary abnormalities, decrease left ventricular function, mitral valve incompetence, and pericardial effusion. ‡ Surveys were sent to every hospital with more than 100 beds and a paediatric department; later, specialist paediatric hospitals with fewer than 100 beds were also included.11  Postscript251  Chapter 2: The Management of KD Kuwait (1978166). KD has now been reported from most countries around the world.167 As already discussed, IPN likely represents the pathological diagnosis given to fatal cases of what we now call KD. The extensive case literature of IPN in America and Europe going back to the 1870s* therefore suggests that the entity we now call KD existed outside of Japan prior to 1967.26,168,169 The possible implications of this have been pursued by Kushner and Abramowsky to suggest a fascinating hypothesis as to the provenance and global spread of IPN/MCLS/KD. Noting the long case history of IPN in America, they proposed that the epidemics of KD in Japan in the 1970s represented the consequence of a novel agent having been introduced into a naïve population during the post-war years.169 They cited a large retrospective review of medical records at Tokyo University Hospital from 1940 to 1965, which found no cases suggestive of KD from 1940–49 but ten cases from 1950–65.170 This is in stark contrast to the traditional narrative that describes the global emergence of KD from Japan but which fails to account for Japan’s unique† explosion in incidence.171 An Incoherent Paradigm The Kawasaki Disease Paradigm suggests that there exists a disease entity characterised by a constellation of cardinal clinical signs, of which a subset of afflicted individuals develop coronary artery aneurysms. The centrality of the clinical syndrome is cemented by the eponymous attribution—when we speak of Kawasaki disease we are talking about that entity described by Dr Kawasaki—even as the diagnostic criteria have shifted to capture instances of sequelae that he did not recognise. I will argue that the Kawasaki Disease Paradigm maps poorly onto the history and clinical spectrum of the entity that causes coronary artery aneurysms in infants and children. The Importance of Nomenclature Many of the conceptual forms and ontological assumptions that I seek to critique are enforced by the semantic and syntactic structures of the paradigm, from which they naturally arose. This constrains the field of critique as certain questions are rendered semantically complicated, if not incoherent. I will  * Much has been written about the history of IPN/MCLS/KD in Europe and America, however the Australian experience has been neglected. Dr Terry Schultz, a pathologist from the rural town of Wangaratta in Victoria, described a case in 1989 of a 34-year-old man who died suddenly after a run. Autopsy revealed multiple calcified coronary artery aneurysms without significant atheroma in the unaffected coronary segments or the aorta. The only time that the man had ever been unwell was as an infant, when he was admitted to hospital for what was then labelled as glandular fever. This suggests the possibility that IPN/MCLS/KD existed in Australia at least 30 years previously (around 1967). † The dramatic emergence of KD in Japan has been matched only in Hawaii.169 Chapter 8252therefore propose an alternative paradigm—not least to assemble a linguistic toolkit more conducive to ontological precision. Central to the paradigm is the name: Kawasaki disease. In the preceding pages I outlined the history of the Kawasaki disease label as it came to dominate over competing forms (such as mucocutaneous lymph node syndrome and Kawasaki syndrome). Two processes seem to have been at play in rendering Kawasaki disease the dominant label for the disease entity: substitution and equivalence*. Substitution, whereby the Kawasaki disease label has come to be used in favour of alternatives, has already been highlighted in Table 8.1. Equivalence, whereby competing labels are treated as interchangeable, can be seen in the titles of academic papers such as “Mucocutaneous Lymph Node Syndrome (Kawasaki Disease) in Adults.41 Equivalence can also be seen in published biomedical ontologies† (Table 8.2). These include the familiar International Classification of Disease and SNOMED CT, as well as the highly domain-specific—such as the Cigarette Smoke Exposure Ontology. Table 8.2 also highlights the diverse (and, I contend, confused) approaches to categorising Kawasaki disease and related concepts. * These terms are mine for the purpose of this discussion.† Ontologies (distinct from the philosophical domain of ontology, described earlier)are important in the fields of computer science and informatics. They seek torepresent, in a clearly-defined logical structure, the categories and relations betweenconcepts in one, or multiple, domains of discourse.Postscript253Table 8.2: Categorisation of Kawasaki Disease and Related Concepts in Published Biomedical Ontologies Ontology Tree Notes Artificial Intelligence Rheumatology Consultant System Ontology172 Examiner’s Diagnosis ↳ Kawasaki Disease Cell Cycle Ontology173 and Gene Expression Ontology174 and Regulation of Gene Expression Ontology175 and Regulation of Transcription Ontology176 and Homeostasis imbalance process ontology177  abstract entity ↳ attribute ⇣ ↳ realizable entity ⇣ ↳ capability ⇣ ↳ disposition ⇣ ↳ disease ⇣ ↳ Kawasaki disease Synonyms: -KWD Cigarette Smoke Exposure Ontology178 entity ↳ continuant ⇣ ↳ dependent_continuant ⇣ ↳ specifically_dependent_continuant ⇣ ↳ realizable_entity ⇣ ↳ disposition ⇣ ↳ Disease ⇣ ↳ Vascular Disorder ⇣ ↳ Non-Neoplastic Vascular Disorder ⇣ ↳ Vasculitis ⇣ ↳ Kawasaki Disease Synonyms: -Mucocutaneous Lymph Node SyndromeChapter 8254Continued... Ontology Tree Notes Computer Retrieval of Information on Scientific Projects Thesaurus179  disease/disorder ↳ cardiovascular disorder ⁞ ↳ blood vessel disorder ⁞ ⇣ ↳ vasculitis ⁞ ⇣ ↳ arteritis ⁞ ⇣ ↳ polyarteritis nodosa ⁞ ⇣ ↳ Goodpasture’s syndrome ⁞ ↳ mucocutaneous lymph node syndrome ⁞ ↳ temporal arteritis ⁞ ↳ Wegener’s granulomatosis ↳ skin disorder ⇣ ↳ mucocutaneous lymph node syndrome ↳ syndrome ⇣ ⁞ ↳ chronic fatigue syndrome ⁞ ↳ mucocutaneous lymph node syndrome ⇣ Synonyms: -Kawasaki diseaseDermatology Lexicon180 DermLex ↳ DermLex terms ⇣ ↳ DLP ENTRIES ⇣ ↳ VASCULAR ⇣ ↳ VASCULITIDES ⇣ ↳ MEDIUM VESSEL VASCULITIDES ⇣ ↳ KAWASAKI DISEASE Emergency Care Ontology181 entitée ↳ objet abstrait ⇣ ↳ objet intentionel ⇣ ↳ état interne ⇣ ↳ état pathologique ⇣ ↳ maladie par mécanisme ⇣ ↳ maladie inflammatoire ⇣ ↳ maladie inflammatoire localisee ⇣ ↳ artérite ⇣ ↳ syndrome de Kawasaki Synonyms: -kawasaki-syndrome adéno-cutanéo- muqueux [Kawasaki]Postscript255Continued... Table 8.2 continued... Ontology Tree Notes Experimental Factor Ontology182 experimental factor ↳ material property ⇣ ↳ disposition ⇣ ↳ disease ⇣ ↳ cardiovascular disease ⁞ ↳ vascular disease ⁞ ⇣ ↳ vasculitis ⁞ ⇣ ↳ predominantly medium-vessel vasculitis ⁞ ⇣ ↳ mucocutaneous lymph node syndrome ⁞ ↳ primary central nervous system vasculitis ⁞ ↳ thromboangiitis obliterans ⁞ ↳ vasculitis due to ADA2 deficiency ↳ genetic disorder ⁞ ↳ mucocutaneous lymph node syndrome ↳ inflammatory disease ⇣ ↳ lymphadenitis ⇣ ↳ cat scratch disease ↳ Kimura disease ↳ mucocutaneous lymph node syndrome ↳ sialadenitis Synonyms: -infantile polyarteritis nodosa-Kawasaki disease-acute febrile mucocutaneous lymph node syndrome [MCLS]-acute febrile mucocutaneous lymph node syndrome-Kawasaki's disease-acute febrile MCLS-Kawasaki syndrome-MLNS-mucocutaneous lymph node syndromeGalen Ontology183 TopCategory ↳ DomainCategory ⇣ ↳ Phenomenon ⇣ ↳ GeneralisedProcess ⇣ ↳ SpecificProcess ⇣ ↳ BodyProcess ⇣ ↳ NAMEDNonNormalProcess ⇣ ↳ NAMEDPathologicalProcess ⇣ ↳ NAMEDSystemicDisease  ⇣ ↳ KawasakiDisease Chapter 8256Continued... Table 8.2 continued... Ontology Tree Notes Genomic Epidemiology Ontology184 entity ↳ continuant ⇣ ↳ specifically dependent continuant ⇣ ↳ realizable entity ⇣ ↳ disposition  ⇣ ↳ disease ⁞ ↳ disease of anatomical entity ⁞ ⇣ ↳ cardiovascular system disease ⁞ ⇣ ↳ heart disease ⁞ ⇣ ↳ cardiac tuberculosis ⁞ ↳ cardiomyopathy ⁞ ↳ complete Kawasaki disease* ⁞ ↳ fulminant myocarditis ⁞ ↳ incomplete Kawasaki disease* ⁞ ⇣ ↳ disease or disorder ⇣ ↳ Mendelian disease ⁞ ↳ mucocutaneous lymph node syndrome ↳ cardiovascular disease ⁞ ↳ vascular disease ⁞ ⇣ ↳ vasculitis ⁞ ⇣ ↳ predominantly medium-vessel vasculitis ⁞ ⇣ ↳ mucocutaneous lymph node syndrome ↳ immune system disease ⁞ ↳ lymphoid system disease ⁞ ⇣ ↳ lymphatic system disease ⁞ ⇣ ↳ lymph node disease ⁞ ⇣ ↳ lymphadenitis ⁞ ⇣ ↳ mucocutaneous lymph node syndrome ↳ inflammatory disease ⇣ ↳ lymphadenitis ⁞ ↳ mucocutaneous lymph node syndrome ↳ vasculitis ⇣ ↳ predominantly medium-vessel vasculitis ⇣ ↳ mucocutaneous lymph node syndrome Synonyms (for complete Kawasaki disease): -complete Kawasaki syndrome Synonyms (for incomplete Kawasaki disease): -incomplete Kawasaki syndrome Synonyms (for mucocutaneous lymph node syndrome): -MLNS-acute febrile mucocutaneous lymph node syndrome [MLNS]-acute febrile MLNS-Kawasaki’s disease-infantile polyarteritis nodosa*These entries contain the following Editor’s note:Planned Obsolescence: this term is a placeholder for a term requested in another ontology. Once the appropriate ontology term is available, this term’s identifier will be obsoleted with a “term replaced by” id of the other term.Postscript257Continued... Table 8.2 continued... Ontology Tree Notes Human Dermatological Disease Ontology185 disease ↳ cutaneous disease ⇣ ↳ disorder caused by infections, infestations, stings, or bites ⇣ ↳ viral skin disease or viral disease with skin manifestations ⇣ ↳ kawasaki disease Synonyms: -KD -mucocutaneous lymph node syndromeHuman Disease Ontology186 and BioAssay Ontology187 and Drug Target Ontology188 disease ↳ disease of anatomical entity ⇣ ↳ immune system disease ⇣ ↳ lymphatic system disease ⇣ ↳ lymph node disease ⇣ ↳ lymphadenitis ⇣ ↳ Kawasaki disease Synonyms: -MLNS-acute febrile MLNS-mucocutaneous lymph node syndrome-acute febrile mucocutaneous lymph node syndrome-Kawasaki’s diseaseHuman Health Exposure Analysis Resource189  Study Indicator ⇣ ↳ Health Outcome ⇣ ↳ Disease ⇣ ↳ lymphatic system disease ⇣ ↳ lymph node disease ⇣ ↳ lymphadenitis ⇣ ↳ Kawasaki disease Synonyms: -MLNS-acute febrile MLNS-mucocutaneous lymph node syndrome-acute febrile mucocutaneous lymph node syndrome-Kawasaki’s diseaseInterlinking Ontology for Biological Concepts190 Life science research field ↳ Terms related to life science ⇣ ↳ Disease, and Symptom ⇣ ↳ Kawasaki disease ⇣ ↳ Acute phase Kawasaki disease ↳ gammaglobulin refractory Kawasaki disease ↳ incomplete Kawasaki disease Synonyms: -Mucocutaneous lymph node syndromeInternational Classification of Disease – 9th Edition191 VII. Diseases of the circulatory system (390-459)↳ Diseases of arteries, arterioles, and capillaries (440-449)⇣ ↳ 446: Polyarteritis nodosa and allied conditions⇣ ↳ 446.1: Acute febrile mucocutaneous lymph node syndrome [MCLS] Chapter 8258Continued... Table 8.2 continued... Ontology Tree Notes International Classification of Disease – 10th Edition192  XIII. Diseases of the musculoskeletal system and connective tissue (M00-M99)↳ Systemic connective tissue disorders (M30-M36)⇣ ↳ M30: Polyarteritis nodosa and related conditions⇣ ↳ M30.3: Mucocutaneous lymph node syndrome [Kawasaki] International Classification of Disease – 11th Edition193 04. Diseases of the immune system ↳ Nonorgan specific systemic autoimmune disorders⇣ ↳ 4A44 Vasculitis⇣ ↳ 4A44.5 Mucocutaneous lymph node syndrome Medical Imaging and Diagnostic Ontology194 entity ↳ continuant ⇣ ↳ specifically dependent continuant ⇣ ↳ realizable entity ⇣ ↳ disposition ⇣ ↳ disease ⇣ ↳ disease of anatomical entity ⇣ ↳ immune system disease ⇣ ↳ lymphatic system disease ⇣ ↳ lymph node disease ⇣ ↳ lymphadenitis ⇣ ↳ Kawasaki disease Synonyms: -MLNS-acute febrile MLNS-mucocutaneous lymph node syndrome-acute febrile mucocutaneous lymph node syndrome-Kawasaki’s diseaseMedical Subject Headings195  Cardiovascular Diseases ⁞ ↳ Vascular Diseases ⁞ ⇣ ↳ Vasculitis ⁞ ⇣ ↳ Mucocutaneous Lymph Node Syndrome ↳ Hemic and Lymphatic Diseases ⁞ ↳ Lymphatic Diseases ⁞ ⇣ ↳ Mucocutaneous Lymph Node Syndrome ↳ Skin and Connective Tissue Disorders ⇣ ↳ Skin Diseases ⇣ ↳ Skin Diseases, Vascular ⇣ ↳ Mucocutaneous Lymph Node Syndrome Synonyms: -Kawasaki SyndromePostscript259Continued... Table 8.2 continued... Ontology Tree Notes Mondo Disease Ontology196 disease or disorder ↳ cardiovascular disorder ⇣ ↳ vascular disorder ⇣ ↳ vasculitis ⇣ ↳ predominantly medium-vessel vasculitis ⇣ ↳ mucocutaneous lymph node syndrome ↳ primary central nervous system vasculitis ↳ thromboangiitis obliterans ↳ vasculitis due to ADA2 deficiency Synonyms: -infantile polyarteritis nodosa-Kawasaki disease-acute febrile mucocutaneous lymph node syndrome [MCLS]-acute febrile mucocutaneous lymph node syndrome-Kawasaki's disease-acute febrile MCLS-Kd-Kawasaki syndrome-MLNS-mucocutaneous lymph node syndrome-infantile polyarteritisNational Cancer Institute Thesaurus197  and Biological and Environmental Research Ontology198 Disease, Disorder, or Finding ↳ Disease or Disorder ⇣ ↳ Disorder by Site ⇣ ↳ Cardiovascular Disorder ⇣ ↳ Vascular Disorder ⇣ ↳ Vasculitis ⇣ ↳ Kawasaki Disease Synonyms: -MLNS-acute febrile MLNS-mucocutaneous lymph node syndrome-acute febrile mucocutaneous lymph node syndrome-Kawasaki’s diseaseNeuroscience Information Framework (NIF) Standard Ontology199 continuant ↳ specifically dependent continuant ⇣ ↳ realizable entity ⇣ ↳ disposition ⇣ ↳ disease ⇣ ↳ lymphatic system disease ⇣ ↳ lymph node disease ⇣ ↳ lymphadenitis ⇣ ↳ Kawasaki disease Synonyms: -acute febrile mucocutaneous lymph node syndrome-Kawasaki's disease-acute febrile MCLS-mucocutaneous lymph node syndrome-MLNSChapter 8260Continued... Table 8.2 continued... Ontology Tree Notes Online Mendelian Inheritance in Man200  KAWASAKI DISEASE (i.e. exists as a top-level class) Synonyms: -Infantile polyarteritis Ontology of Consumer Health Vocabulary201 Concept ↳ UMLS_Concept ⇣ ↳ kawasaki disease Orphanet Rare Disease Ontology202 clinical entity ↳ disorder ⇣ ↳ Biological anomaly ↳ Clinical syndrome ↳ Disease ↳ Kawasaki disease ⇣ ↳ Malformation syndrome ⇣ Synonyms: -mucocutaneous lymph node syndromePLOS Thesaurus203  Medical and health science ↳ Immunology ⇣ ↳ Clinical immunology ⇣ ↳ Autoimmune disease  ⇣ ↳ Kawasaki disease Radiology Lexicon204 RadLex ontology entity ↳ RadLex entity ⇣ ↳ clinical finding ⇣ ↳ pathophysiologic finding ⇣ ↳ infectious or inflammatory disease ⇣ ↳ inflammation ⇣ ↳ Kawasaki disease Synonyms: -mucocutaneous lymph node syndromePostscript261Continued... Table 8.2 continued... Ontology Tree Notes Read Clinical Terminology Version 2205 Circulatory system diseases ↳ Arterial, arteriole and capillary disease ⇣ ↳ Polyarteritis nodosa and allied conditions ⇣ ↳ Acute febrile mucocutaneous lymph node syndrome ⇣ ↳ Acute febrile mucocutaneous lymph node syndrome NOS ↳ Kawasaki disease SNOMED CT206 Clinical finding ↳ Disease ⇣ ↳ Inflammatory disorder ⇣ ↳ Inflammation of specific body organs ⇣ ↳ Vasculitis ⇣ ↳ Systemic vasculitis ⇣ ↳ Primary systemic arteritis ⇣ ↳ Acute febrile mucocutaneous lymph node syndrome ↳ Polyarteritis nodosa ↳ Takayasu’s disease Synonyms: -Mucocutaneous lymph node syndromeSystematized Nomenclature of Medicine, International Version207 DISEASES/DIAGNOSES ↳ Disease of cardiovascular system, NOS ⇣ ↳ Vascular disease, NOS ⇣ ↳ Disease of artery, NOS ⇣ ↳ Acute febrile mucocutaneous lymph node syndrome Synonyms: -Kawasaki’s diseaseThe Stroke Ontology208 Stroke ↳ Stroke type ⇣ ↳ Intracranial hemorrhage ⇣ ↳Etiology of hemorrhagic stroke ⇣ ↳ Vasculitis ⇣ ↳ Systemic vasculitis ⇣ ↳ Kawasaki syndrome Synonyms: -Kawasaki diseaseThe National Center for Biomedical Ontologies (NCBO) was searched for all ontologies that referenced Kawasaki disease and related concepts. Many ontologies explicitly treat labels such as Kawasaki disease and mucocutaneous lymph node syndrome as synonyms. The ontological confusion around these condition labels is also clear: most ontologies categorise Kawasaki disease / mucocutaneous lymph node syndrome as a kind of disease (usually of the kind vasculitis or lymphadenitis) rather than a kind of syndrome. The Orphanet Rare Disease Ontology classifies Kawasaki disease (for which mucocutaneous lymph node syndrome is identified as a synonym) under the heading Disease and not under the heading Clinical syndrome. The Computer Retrieval of Information on Scientific Projects Thesaurus categorises mucocutaneous lymph node syndrome (for which Kawasaki disease is identified as a synonym) under both disease and syndrome. Finally, the Artificial Intelligence Rheumatology Consultant System Ontology categorises Kawasaki disease under Examiner’s diagnosis. Chapter 8262Table 8.2 continued... While it is clear that labels like Kawasakibyō, mucocutaneous lymph node syndrome, Kawasaki syndrome, and Kawasaki disease are used interchangeably, I want to emphasise that they are not semantically isomorphic. In using a general term for illness, Kawasakibyō is essentially agnostic as to the ontological status of its referent. MCLS and Kawasaki syndrome are (potentially) more precise as to the ontological status of the referent: it is the constellation of signs and symptoms (i.e., the syndrome), which implies a unified underlying process. Kawasaki disease is ontologically ambiguous: if the technical meaning of disease is intended then the referent of Kawasaki disease ought to be the unified underlying process, of which the syndrome is a manifestation.* If the non-technical meaning of disease is intended then Kawasaki disease takes on the same ontological agnosticism as Kawasakibyō. The language of these related concepts is clearly imprecise; however, the implications of that imprecision might readily be overlooked. In the section that follows I will seek to demonstrate what is lost by foregoing a more rigorous vocabulary. Thought Experiments on the Ontological Status of “Kawasaki Disease” Imagine that researchers uncover the case records and stored biological samples of a forgotten prospective cohort study of KD from before the introduction of intravenous immunoglobulin. Inclusion criteria were strict—all enrolled children fulfilled the diagnostic criteria for KD (i.e. had complete Kawasaki disease). Demographic and clinical details were recorded at diagnosis, and biological samples were stored. Cardiac outcomes (angiograms or echocardiograms) over the short and long term were also recorded. For the purpose of the thought experiment let us say that there were 1,000 children in the cohort, of whom 200† developed coronary artery aneurysms. The contemporary researchers undertake sophisticated analysis of the samples, with several possible findings—each with radically different implications for the ontological status of Kawasaki disease. For each of the scenarios described the following reflection is informative: To what does the label Kawasaki disease refer? * The semantic confusion becomes even more apparent with terms like CompleteKawasaki disease. This typically connotes the fulfilment of the formal diagnosticcriteria (as opposed to the modified criteria that might be fulfilled in a case ofincomplete Kawasaki disease). This seems semantically closer to Kawasaki syndrome,albeit with greater implied precision.† Following on from the earlier discussion on the published rates of coronary arteryaneurysms prior to the use of IVIG, I have here assumed an aneurysm rate of 20%.Postscript263Scenario 1 Using highly sensitive metagenomic high-throughput sequencing209 researchers identify a novel DNA virus in stored blood samples of all study participants. Subsequent analysis of samples from non-KD febrile controls is unable to identify the virus, which goes on to be named Human Kawasaki Virus (HKV). Scenario 2 HKV is identified in all cases with aneurysms, but not in any other cases. A number of common childhood viruses (including adenovirus, enteroviruses, and human herpes viruses) are identified in the remaining cases. Scenario 3 As for Scenario 1, however researchers identify two closely-related novel viruses—HKV-1 and HKV-2. HKV-2 is found only in cases with aneurysms. Scenario 4 As for Scenario 1, however whole-genome sequencing identifies a single nucleotide polymorphism (SNP) in only those children who developed aneurysms. The affected gene is a critical regulator of the innate immune response. Scenario 5 As for Scenario 2, however HKV is identified in 400 cases—including all who developed aneurysms. Let us now consider how our concepts of KD might be influenced under these different scenarios. Scenario 1 most closely approximates the current Kawasaki Disease Paradigm. The clinical syndrome appears to map precisely to the entity HKV infection, and it appears that a subset go on to develop the entity coronary artery aneurysm.  In Scenario 2 we are forced to concede that the clinical syndrome that we now call Kawasaki disease (or, more precisely, complete KD) does not map on to any single disease process. At best the clinical syndrome functions as a non-specific clinical tool for finding cases of the entity HKV infection, which maps precisely to the entity coronary artery aneurysm (the actual entity of medical interest). In Scenarios 3 and 4 all groups are ontologically coherent entities:  the clinical syndrome maps onto the entity HKV infection, while the entity coronary artery aneurysm can be equated with a process—a particular kind of HKV infection (in Scenario 3), or a process of immune dysregulation triggered by HKV infection in genetically predisposed individuals. Chapter 8264   Finally, Scenario 5 is like Scenario 2 except that the clinical syndrome lacks both specificity and sensitivity for the entities HKV infection and coronary artery aneurysm. Paradigm Implications for Clinical Research The importance of the ontological imprecision of the current KD vocabulary is exemplified in a recent study by Wright et al.210 The authors describe a novel approach to developing a diagnostic test for KD by identifying a gene expression signature in circulating leukocytes. Samples were drawn from participants of a case-control cohort study of children with either KD* or another febrile illness (febrile controls). Blood was drawn prior to treatment with IVIG, and the transcriptome (the set of RNA transcripts isolated from peripheral leukocytes, indicative of the genes being actively transcribed) was characterised for each patient. A number of established machine learning algorithms were applied to identify a transcript signature that discriminated KD cases† from control cases. One novel algorithm (parallel regularized regression model search, written by the study team) identified a 13-transcript signature able to differentiate KD cases from febrile control cases with a sensitivity of 81.7% and a specificity of 92.1%. This innovative approach to diagnostic research has the potential to revolutionise the clinical management of KD, however as currently conceived it remains firmly within the current paradigm. Put differently: the 2017 AHA diagnostic algorithm formed the a priori definition of KD, which the machine learning algorithm operationalised. This perpetuates the assumption that the ontological status of KD is best modelled by Scenario 1 described above. An Alternative Paradigm The purpose of diagnosis is to direct treatment to prevent adverse outcomes. An alternative paradigm ought to focus on the process by which adverse outcomes occur. History suggests such a paradigm: There exists an inflammatory disease process of which the development of coronary artery aneurysms is a consequence: infantile periarteritis nodosa (IPN)‡. Evidence of IPN exists in post-mortem reports dating back to the nineteenth century. In the decades after World War II, and in the context of an emerging epidemic, Japanese clinicians identified a set of clinical features by which IPN might be diagnosed in life (the Classical Kawasaki  * KD was defined according to the 2017 AHA diagnostic criteria.1 † Stratified by diagnostic certainty. ‡ The label IPN is used here for historical continuity, however it is far from perfect. Recognition of “adult Kawasaki disease” presents one problem—not unlike that presented by Still’s disease (adult-onset systemic juvenile idiopathic arthritis). The suggested (though almost certainly incorrect) relation to classical polyarteritis nodosa is also problematic. Postscript265  Criteria). Subsequent clinical trials proved that the inflammation of IPN in patients fulfilling the Classical Kawasaki Criteria could be ameliorated by treatment with IVIG. The cause of IPN remains unclear, however epidemiological evidence implicates an environmental or infectious cause. It is hypothesised that the Japanese population—largely isolated from the rest of the world since the start of the Edo period in 1603—was particularly naïve to this agent. Its introduction in the post-war period thereby preceded a dramatic epidemic of the disease, which continues to this day. In the absence of a diagnostic test for IPN the diagnosis remains clinical. In recognition of the suboptimal sensitivity of the Classical Kawasaki Criteria, researchers proposed the Expanded Kawasaki Criteria. The specificity of the Kawasaki Criteria has been difficult to determine. The large majority of children who fulfil the criteria have no evidence of IPN on echocardiogram; however, that diagnostic modality is imperfect*, and IPN is known to cause lesions in other arterial beds. In light of this clinical uncertainty, IVIG is currently offered to all children who fulfil the Kawasaki Criteria. This IPN-centred paradigm recognises the contributions of a generation of twentieth-century Japanese researchers (rather than Dr Kawasaki alone) for establishing clinical features by which cases of IPN might be diagnosed and treated life, rather than by pathologists after death. Complete Kawasaki disease is reframed as the classical Kawasaki criteria, and incomplete Kawasaki disease as the expanded Kawasaki criteria. The important distinction between the clinical syndrome and the disease entity is thereby made explicit: the Kawasaki criteria is a diagnostic tool for finding cases of IPN. Interrogating and refining the diagnostic performance (sensitivity and specificity) of that tool is therefore a valid and appropriate priority for clinical research. The IPN Paradigm might better inform future research—particularly around aetiology and diagnosis. The methodology used in the study by Wright et al could be modified to discriminate IPN cases from non-IPN cases in a cohort of patients fulfilling the Kawasaki criteria. Discriminating IPN on the basis of echocardiograms early in the disease process can be challenging; many children in our prospective cohort study had mild coronary artery dilatation with subsequent normalisation†. Cases of delayed presentation thus present an opportunity in this regard. In our cohort, children with delayed diagnosis had coronary vessels that were either normal or markedly abnormal. A machine learning algorithm might have enhanced success identifying a  * Transthoracic echocardiography is insensitive to aneurysms of the posterior coronary arteries and distal coronary segments.211 † This may simply represent regression to the mean, especially allowing for an element of demand-driven physiological dilatation in the febrile phase. Chapter 8266   transcriptome signature that discriminates those two groups—at least in the discovery phase. Conclusions The Kawasaki Disease Paradigm represents an important phase in the history of our quest to help children afflicted by this life-threatening condition, however its ambiguous language and lack of ontological precision limit its utility into the future. We must shift to a new paradigm that focusses on the pathological processes driving adverse coronary outcomes, rather than on clinical syndrome constructs.  Postscript267  References 1.  McCrindle BW, Rowley AH, Newburger JW, Burns JC, Bolger AF, Gewitz M, et al. 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Diagnosis of Kawasaki Disease Using a MinimalWhole-Blood Gene Expression Signature. JAMA Pediatr. 2018 Oct1;172(10):e182293.211. van Stijn D, Planken RN, Groenink M, Streekstra GJ, Kuijpers TW,Kuipers IM. Coronary artery assessment in Kawasaki disease withdual-source CT angiography to uncover vascular pathology. EurRadiol. 2020 Jan;30(1):432–41.Postscript283284Appendix In late 2019 reports began to emerge from China of a severe respiratory syndrome caused by a novel human coronavirus (named SARS-CoV-2). The disease—designated COVID-19—spread rapidly around the globe, causing significant mortality in some populations. Population-level data indicated very low morbidity and mortality in children, however case reports emerged of a very rare but devastating complication in that age group. Named paediatric inflammatory multi- system syndrome temporally associated with SARS-CoV-2 (PIMS-TS) by the European Centre for Disease Prevention and Control, and multisystem inflammatory syndrome in children (MIS- C) by the US Centers for Disease Control and Prevention, the condition presented as a severe systemic inflammatory state, usually weeks after the acute SARS-CoV-2 infection. The following manuscript, entitled “Update on the COVID-19-associated inflammatory syndrome in children and adolescents; paediatric inflammatory multisystem syndrome-temporally associated with SARS-CoV-2” was published in The Journal of Paediatrics and Child Health in 2020. It sought to summarise for Australian paediatricians the available literature with regard to PIMS-TS. My contribution to this manuscript was Table 1. Representing a significant literature review, it compares and contrasts the case literature around PIMS-TS, Kawasaki disease, Kawasaki shock syndrome, and toxic shock syndrome. The insights that I gained from researching this piece informed my contribution to the work presented in Appendix Two. 285286VIEWPOINTUpdate on the COVID-19-associated inflammatory syndrome inchildren and adolescents; paediatric inflammatory multisystemsyndrome-temporally associated with SARS-CoV-2Davinder Singh-Grewal ,1,2,3,4 Ryan Lucas ,1,2 Kristine McCarthy,1,2 Allen C Cheng,5,6 Nicholas Wood,1,2Genevieve Ostring,7,8 Philip Britton ,1,2 Nigel Crawford9,10,11 and David Burgner 9,12,13,141Department of Rheumatology, The Sydney Children’s Hospitals Network, 2Paediatrics and Child Health, The University of Sydney, 3School of Maternal andChild Health, University of New South Wales, Sydney, 4Department of Paediatrics, John Hunter Children’s Hospital, Newcastle, New South Wales,5Department of Infectious Diseases, Alfred Health, 6School of Public Health and Preventive Medicine, 14Department of Paediatrics, Monash University,9Infection and Immunity, Murdoch Children’s Research Institute, 10Immunisation Service, 12Infectious Diseases University, Royal Children’s Hospital,11University of Melbourne, 13Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia, 7Paediatric Rheumatology, StarshipChildren’s Hospital and 8University of Auckland, Paediatrics Child and Youth Health, Auckland, New ZealandWe provide an update on the state of play with regards a newly described inflammatory condition which has arisen during the current SARS-CoV-2 pandemic. The condition has been named paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 or multi-system inflammatory syndrome in children. This condition has shown significant similarities to Kawasaki disease and toxic shock syndrome.Paediatricians and many families are aware of the recent reportsof a novel multisystem inflammatory syndrome in children (MIS-C), which appears related to the ongoing SARS-CoV-2 pandemic.The condition has been named paediatric inflammatory multi-system syndrome temporally associated with SARS-CoV-2(PIMS-TS) by the European Centre for Disease Prevention andControl1 and MIS-C by the Centres for Disease Control and Pre-vention in the USA2 and World Health Organization.3 Hence-forth, we use the term PIMS-TS to denote both of these describedentities.PIMS-TS was first reported in the UK in late April through theEuropean Union’s Early Warning and Response System and has nowbeen reported from other European centres, the USA and MiddleEast. Anecdotally, up to 1000 cases have been reported formallyand informally. Fewer than 10 deaths have been publiclyreported to date. No confirmed cases have been reported in Aus-tralia or New Zealand to date.Overall, the reported infection rates with SARS-CoV-2 (thenovel coronavirus) are lower in children than adults, and chil-dren are often asymptomatic or have comparatively milder acutemanifestations.4 Few children have required hospitalisation orintensive care admission as part of the acute infection.5Rather than a manifestation of primary infection, PIMS-TSappears to be a severe but delayed immune response to SARS-CoV-2 infection with uncontrolled inflammation resulting in hosttissue damage.6 The finding that many children with PIMS-TShave positive SARS-CoV-2 serology but are PCR negative onnasopharyngeal swabs supports the hypothesis of a post-infec-tious phenomenon.7–9 This is also supported by the observationthat the peak in PIMS-TS cases lags behind the peak in acuteSARS-COV-2 cases by some weeks.7 The mechanisms areunknown, but it seems plausible that genetic variation in affectedchildren may contribute to this rare syndrome. Both innate (non-specific) and adaptive (both humoral and T-cell mediated) armsof the immune system have been suggested to be involved.9,10A striking feature of PIMS-TS is the overlap with Kawasaki dis-ease (KD) and toxic shock syndrome (TSS), both vasculitideslikely triggered by infection.9 While SARS-COV-2 is the suspectedaetiological agent causing PIMS-TS, the cause of KD is unknownand may involve more than one infectious trigger.11 Interestinglyanother novel coronavirus (coronavirus New Haven – HCoV-NH/HCoV-NL63) was previously implicated as the possible cause ofKD in a series of cases in 2005,11 but this finding could not besubstantiated in other populations.12Children with PIMS-TS seem to present with a severe illnesscharacterised by shock and features often seen in KD or Kawa-saki shock syndrome (KSS) (a rare, more severe form of KD thatshares features with TSS).13 These features include prolongedfever, rash, conjunctival injection, mucosal changes and raisedinflammatory markers. While these features are common to bothKSS and TSS, the inflammation seen in PIMS-TS seems to be fargreater than that of KD.7–9,13 Other differentiating features ofPIMS-TS include an older age of onset (average of 10 years com-pared to 2 years for KD) and abdominal pain and diarrhoea asprominent presenting symptoms; myocardial and renal dysfunc-tion have also been reported.7–9,13 Additionally, children withPIMS-TS have shown marked lymphopaenia andthrombocytopaenia, coagulopathy, raised cardiac enzymes (tro-ponin and brain natriuretic peptide, BNP), hyponatraemia,Correspondence: Dr Davinder Singh-Grewal, The Sydney Children’s Hos-pital Network, Locked Bag 4001, Westmead, NSW 2145, Australia. email:davinder.singhgrewal@health.nsw.gov.auConflict of interest: None declared.Accepted for publication 8 June 2020.doi:10.1111/jpc.15049Journal of Paediatrics and Child Health 56 (2020) 1173–1177© 2020 Paediatrics and Child Health Division (The Royal Australasian College of Physicians) 287Table 1 Kawasaki disease (KD), Kawasaki shock syndrome (KSS), toxic shock syndrome (TSS) and paediatric inflammatory multisystem syndrome-temporally associated with SARS-CoV-2 (PIMS-TS): Comparison of key characteristicsCharacteristic KD KSS TSS PIMS-TSBiologyAetiology Unknown. Infectious trigger ingenetically susceptible hostsuspected.18As for KD Staphylococcus aureusproducing TSST-1, SE-B, orSE-C. (A significantproportion of staphylococcalTSS cases are still menstrualassociated.)Streptococcus pyogenesproducing SPE-A or SPE-C19Role of SARS-CoV-2 as triggersuspected, with a latentperiod of 1–4 weeks.Preceding SARS-CoV-2infection may beasymptomaticPathophysiology Systemic vasculitis with earlyactivation of innate immunesystem (especially IL-1, IL-6,and TNF pathways)18Unknown, but likely severepathophysiology with sharedfeatures of both KD and TSSKDSAG-mediated stimulation ofT-cells causing massivecytokine release withcapillary leak19Unknown. Cardiogenic anddistributive shock reported.Myocardial dysfunction maybe related to acute systemicinflammation. Abnormalcoagulation characteristicEpidemiology (in paediatric population)Age, years –medianPeak age ! 2 years9,20 Slightly older than KD9,20 Reported as a similar age(Whittaker et al.)9 or olderthan KSS (mean 9.4 years inLin et al.)9,21Older than KSS (mean9.6 years in Riphagen et al.and 9 years in Whittaker etal.)7,9,22Sex ratio (male:female)1.4:120 Similar to KD20,23 1:924 1.6:113 and 0.76:19Ethnicity East Asian predominance18,25 No data Caucasian predominance24 Afro-Caribbeanprominence9,13Incidence Geographically widelyvariable. Australia: 17/100 000 per annum<5 years5–7% of KD presentations18,26 !0.5/100000 per annum19 No dataClinical presentationBP N18 #27 #28 #7,13Oedema Non-pitting, painful indurationof hands and feet18As for KD. May developgeneralised oedema fromcapillary leakGeneralised non-pittingoedema from capillary leakNo dataSkin Polymorphous rash,petechiae not typical. Lateperiungual desquamationAs for KD Erythroderma, petechiaetypicalLate desquamationRash in around 50%9,13Mucosa Mucosal hyperaemia,ulceration not typical18As for KD Mucosal hyperaemia,ulceration typical28Odynophagia in 3/813 andmucous membrane changes29%9Eyes Non-purulent conjunctivalinjectionAs for KD Non-purulent conjunctivalinjectionConjunctivitis in 45–62.5%9,13Gastrointestinal Abdominal symptoms (pain,diarrhoea, vomiting)common18,20Abdominal symptoms (pain,diarrhoea, vomiting)morecommon than in KD20Vomiting, diarrhoea,abdominal pain28Diarrhoea in 50–87%9,13Abdominal pain in 50–75%9,13Musculoskeletal Arthralgia and arthritiscommon18As for KD Myalgia +++28 Myalgia in 1/813Neurological Irritability common18 As for KD Headache, confusion28 Headache in 25–25%9,13Renal Acute renal failure rare20 Acute renal failure morecommon than in KD20Acute renal failure common29 22% with acute renal injury9and 1/8 required renalreplacement therapy13Echocardiogram findingsCoronarychanges5–25%22 2–3 times more commonthan KD20,27No data 14% have coronary lesions9Giant aneurysms in 12–25%9,13(Continues)Journal of Paediatrics and Child Health 56 (2020) 1173–1177© 2020 Paediatrics and Child Health Division (The Royal Australasian College of Physicians)D Singh-Grewal et al.Appendix288hypoalbuminaemia and raised lactate dehydrogenase and ferritin;these features have only infrequently been reported in KD.7–9Early reports suggest that 20–25% of PIMS-TS patients demon-strate coronary artery changes (similar to the rate in untreatedKD13); however giant coronary artery aneurysms were uncom-mon (<4%),9 and most lesions have resolved relatively promptly(over a few weeks) with treatment.7,8,13As paediatricians are aware, KD has a much higher inci-dence in children of North East Asian ancestry14,15; it is nota-ble that PIMS-TS has not yet been reported from Asia. Cases ofPIMS-TS reported to date have shown a possible over-repre-sentation of children from African, African-American andAfro-Caribbean ancestry.9,12 Hypothesised explanations forthis observation include the effect of relative social disadvan-tage on disease exposure and transmission, as well as the possi-bility of a specific genetic predisposition to PIMS-TS (analogousbut distinct from that contributing to the ethnic differences inKD incidence15).Patients with PIMS-TS have often required supportive treat-ment for hypotension and circulatory collapse.7–9,13 Intravenousimmunoglobulin (also the primary treatment for KD) and corti-costeroids have also been used extensively,7–9,13 with biologicagents and anticoagulants used in selected cases on appropriatesubspecialty advice. There have been a small number of deaths,but generally the outcomes have been good, with few patientsrequiring extracorporeal membrane oxygenation. The long-termcardiovascular outcomes are yet to be determined.Interestingly, in early April clinicians in the USA reported a caseof KD with concurrent COVID-19,16 and paediatricians in Franceand Italy (both of which have had high incidence of SARS-CoV-2infection) reported marked increases in KD diagnoses (withoutshock but with positive SARS-COV-2 testing).7,8 Many of the casesreported had incomplete KD with fever and less than four of thecardinal 5 clinical features of KD.7,8 However, other regions havenot reported any increases in KD overall during the pandemic. InAustralia and New Zealand, where community transmission andincidence of SARS-CoV-2 remains low, there has not been anychange in expected KD incidence in 2020 to date in as yetunpublished national surveillance data (http://www.paeds.org.au/covid-19-kawasaki-disease-kd-and-pims-ts-children).17Table 1 (Continued)Characteristic KD KSS TSS PIMS-TSReduced EF Rare20 Both cardiogenic anddistributive shock reportedfrequently20,23,30Reported, but distributiveshock predominates31,32Ventricular functionabnormality in 31%9 or 7/8.13Between 40 and 62% withshock had impaired EF7,9Laboratory findingsTotal leukocytecountN/"9,18,26 "9,26 N/"9,21 N/#7,9NeutrophilcountN/"9,18,26 "9,26 N/"9,21 N/"7,9LymphocytecountN9,18 N9 """9,28 ##7,9Haemoglobin N/#9,26 N/#9,26 #9,21,28 #7,9Platelet count N, "" in 2nd–3rd week18# in severe cases18", however # more commonthan in KD9,21,27#9,21,28 #7,9Fibrinogen " initially, normalisesrapidly33,34N/"26,34 "27 "7,9D-Dimer "34–37 "9,34 "9,28 ""7,9ESR "21,26,34 "21,26,34 " "7,9CRP "9,21,26,34 ""9,21,26,34 ""9 ""7,9Sodium N N/#38 #28 #7,9Creatinine N21 "21 "28Albumin N/# more in severecases9,18,20# more than in KD9,20 ##9,28 ##7,9Bilirubin N/"18 No data "39 No dataTroponin N9 N/"9,21,38 No data ""7,9BNP N "37 No data ""7Ferritin N/"9,40,41 "9 No data ""7,9SARS-CoV-2PCRNo data No data No data Positive in 12–26%7,9,13SARS-CoV-2serologyNo data No data No data Positive in 80–87%7,9BNP, brain natriuretic peptide; CRP, C-reactive protein; EF, ejection fraction; ESR, erythrocyte sedimentation rate; PCR, polymerase chain reaction; SAG,superantigen; TNF, tissue necrosis factor.Journal of Paediatrics and Child Health 56 (2020) 1173–1177© 2020 Paediatrics and Child Health Division (The Royal Australasian College of Physicians)D Singh-Grewal et al.COVID-19 & Inflammation in Children289Inflammatory Multisystem Syndrome and SARS-CoV-2 Infection inChildren, 18. Stockholm: The Centre; 2020.2 CDC Health Alert Network. Multisystem Inflammatory Syndrome inChildren (MIS-C) Associated with Coronavirus Disease 2019 (COVID-19). Center for Disease Control and Prevention; 2020. Report No.:CDCHAN-00432. Available from: https://emergency.cdc.gov/han/2020/han00432.asp [accessed 26 May 2020].3 WHO Global. Multisystem Inflammatory Syndrome in Children and Adoles-cents with COVID-19. Geneva: World Health Organization; 2020. ReportNo.: WHO/2019-nCoV/Sci_Brief/Multisystem_Syndrome_Children/2020.1.Available from: https://www.who.int/news-room/commentaries/detail/multisystem-inflammatory-syndrome-in-children-and-adolescents-with-covid-19[accessed 26 May 2020].4 Zimmermann P, Curtis N. Coronavirus infections in children includingCOVID-19: An overview of the epidemiology, clinical features, diagno-sis, treatment and prevention options in children. Pediatr. Infect. Dis.J. 2020; 39: 355–68.5 Dong Y, Mo X, Hu Y et al. Epidemiology of COVID-19 among childrenin China. Pediatrics 2020; 145: e20200702.6 Pain CE, Felsenstein S, Cleary G et al. Novel paediatric presentationof COVID-19 with ARDS and cytokine storm syndrome withoutrespiratory symptoms. Lancet Rheumatol 2020. https://doi.org/10.1016/S2665-9913(20)30137-5.7 Verdoni L, Mazza A, Gervasoni A et al. An outbreak of severeKawasaki-like disease at the Italian epicentre of the SARS-CoV-2epidemic: An observational cohort study. Lancet 2020; 395:1771–8.8 Toubiana J, Poirault C, Corsia A et al. Outbreak of kawasaki disease inchildren during COVID-19 pandemic: A prospective observationalstudy in Paris, France. BMJ 2020; 369: m2094. https://doi.org/10.1101/2020.05.10.20097394.9 Whittaker E, Bamford A, Kenny J et al. Clinical characteristics of 58children with a pediatric inflammatory multisystem syndrome tempo-rally associated with SARS-CoV-2. JAMA 2020; e2010369. https://doi.org/10.1001/jama.2020.10369.10 Cheng MH, Zhang S, Porritt RA, Arditi M, Bahar I. An insertion uniqueto SARS-CoV-2 exhibits superantigenic character strengthened byrecent mutations. bioRxiv 2020; 2020.05.21.109272. https://doi.org/10.1101/2020.05.21.109272.11 Burgner D, Harnden A. Kawasaki disease: What is the epidemiologytelling us about the etiology? Int. J. Infect. Dis. 2005; 9: 185–94.12 Lehmann C, Klar R, Lindner J, Lindner P, Wolf H, Gerling S. Kawasakidisease lacks association with human coronavirus NL63 and humanBocavirus. Pediatr. Infect. Dis. J. 2009; 28: 553–4.13 Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N,Theocharis P. Hyperinflammatory shock in children during COVID-19pandemic. Lancet 2020; 395: 1607–8.14 Holman RC, Belay ED, Christensen KY, Folkema AM, Steiner CA,Schonberger LB. Hospitalizations for Kawasaki syndrome among chil-dren in the United States, 1997–2007. Pediatr. Infect. Dis. J. 2010; 29:483–8.15 Uehara R, Belay ED. Epidemiology of Kawasaki disease in Asia,Europe, and the United States. J. Epidemiol. 2012; 22: 79–85.16 Jones VG, Mills M, Suarez D et al. COVID-19 and Kawasaki disease:Novel virus and novel case. Hosp. Pediatr. 2020; 10: 537–40.17 Paediatric Active Enhanced Surveillance. COVID-19, Kawasaki Disease(KD) and PIMS-TS in Children. New South Wales, Australia: PAEDS;2020. Available from: http://www.paeds.org.au/covid-19-kawasaki-disease-kd-and-pims-ts-children [accessed 4 June 2020].18 McCrindle BW, Rowley AH, Newburger JW et al. Diagnosis, treatment,and long-term management of Kawasaki disease: A scientific state-ment for health professionals from the American Heart Association.Circulation 2017; 135: e927–99.19 McCormick JK, Yarwood JM, Schlievert PM. Toxic shock syndromeand bacterial superantigens: An update. Annu. Rev. Microbiol. 2001;55: 77–104.20 Agrawal H, Altman CA, Seery TJ et al. Incidence and outcomes ofKawasaki shock syndrome in United States: 2004–2014. EC Cardiol.2018; 5: 514–22.21 Lin Y-J, Cheng M-C, Lo M-H, Chien S-J. Early differentiation of Kawasakidisease shock syndrome and toxic shock syndrome in a pediatricintensive care unit. Pediatr. Infect. Dis. J. 2015; 34: 1163–7.22 Newburger JW, Takahashi M, Burns JC et al. The treatment of Kawa-saki syndrome with intravenous gamma globulin. N. Engl. J. Med.1986; 315: 341–7.23 Gatterre P, Oualha M, Dupic L et al. Kawasaki disease: An unexpectedetiology of shock and multiple organ dysfunction syndrome. IntensiveCare Med. 2012; 38: 872–8.24 Hajjeh RA, Reingold A, Weil A, Shutt K, Schuchat A, Perkins BA. Toxicshock syndrome in the United States: Surveillance update, 1979–1996. Emerg. Infect. Dis. 1999 Dec; 5: 807–10.25 Onouchi Y. The genetics of Kawasaki disease. Int. J. Rheum. Dis. 2018Jan; 21: 26–30.26 Kanegaye JT, Wilder MS, Molkara D et al. Recognition of a Kawasakidisease shock syndrome. Pediatrics 2009; 123: e783–9.Journal of Paediatrics and Child Health 56 (2020) 1173–1177© 2020 Paediatrics and Child Health Division (The Royal Australasian College of Physicians)At present, little is known about PIMS-TS. It is unclear whether PIMS-TS represents a severe form of KD triggered by SARS-CoV-2, or a separate entity with a spectrum of disease extending from a mild febrile illness through a KD-like illness to a severe KSS/TSS-like disease. As KD, KSS and TSS are all syn-dromic, with no diagnostic test, as shown by Whittaker et al.,9 it is difficult to define the boundaries between these phenotypes (Table 1).We suggest that clinicians should be aware of this new condi-tion and in the current pandemic should consider PIMS-TS when assessing children with fever and a differential diagnosis of KD, TSS, fever and rash, severe abdominal pain or shock without obvious cause. As with any serious paediatric condition, clinicians should follow recommended clinical management pathways for COVID-19, KD or TSS. For any patient with these conditions suspected to have PIMS-TS, it is important to ensure testing for SARS-CoV-2 by PCR on appropriate specimens but to also collect a blood sample for testing of antibodies (serology) to SARS-CoV-2 prior to IVIG therapy along with convalescent serology. Suspected cases should be discussed with local specialist paediat-ric services (infectious diseases, rheumatology, intensive care, cardiology) as appropriate.In Australia and New Zealand, few if any cases of PIMS-TS would be expected if community transmission of SARS-CoV-2 is low – particularly in children. Nevertheless, the Paediatric Active Enhanced Disease Surveillance network, which already conducts national surveillance for KD and other conditions relevant to paediatrics (www.paeds.org.au) and The Influenza Complications Alert Network are working to establish active surveillance for PIMS-TS in Australia. These groups will be collaborating with other networks to ensure cases of PIMS-TS are rapidly detected and comprehensively investigated. For further information about surveillance and standardised data collection, please refer to http://www.paeds.org.au/covid-19-kawasaki-disease-kd-and-pims-ts-childrenReferences1 European Centre for Disease Prevention and Control. PaediatricD Singh-Grewal et al.Appendix29027 Dominguez SR, Friedman K, Seewald R, Anderson MS, Willis L,Glodé MP. Kawasaki disease in a pediatric intensive care unit: A case-control study. Pediatrics 2008; 122: e786–90.28 Chesney PJ, Davis JP, Purdy WJ, Wand PJ, Chesney RW. Clinical mani-festations of toxic shock syndrome. JAMA 1981; 246: 741–8.29 Chesney W, Joan P, Davis P, Segar E. Renal manifestations of thestaphylococcal toxic-shock syndrome. Am. J. Med. 1981; 71: 6.30 Natterer J, Perez M-H, Di Bernardo S. Capillary leak leading to shockin Kawasaki disease without myocardial dysfunction. Cardiol. Young2012; 22: 349–52.31 Burns JR, Menapace FJ. Acute reversible cardiomyopathy complicat-ing toxic shock syndrome. Arch. Intern. Med. 1982; 142: 3.32 Crews JR. Stunned myocardium in the toxic shock syndrome. Ann.Intern. Med. 1992; 117: 912–3.33 Shirahata A, Nakamura T, Asakura A. Studies on blood coagulation andantithrombotic therapy in Kawasaki disease. Pediatr. Int. 1983; 25: 180–91.34 Li Y, Zheng Q, Zou L et al. Kawasaki disease shock syndrome: Clinicalcharacteristics and possible use of IL-6, IL-10 and IFN-γ as biomarkersfor early recognition. Pediatr. Rheumatol. 2019; 17: 1.35 Imamura T, Yoshihara T, Yokoi K, Nakai N, Ishida H, Kasubuchi Y.Impact of increased D-dimer concentrations in Kawasaki disease. Eur.J. Pediatr. 2005; 164: 526–7.36 Masuzawa Y, Mori M, Hara T, Inaba A, Oba MS, Yokota S. Elevated D-dimer level is a risk factor for coronary artery lesions accompanyingintravenous immunoglobulin-unresponsive Kawasaki disease: Risk fac-tors for coronary artery lesions in Kawasaki disease. Ther. Apher. Dial.2015; 19: 171–7.37 Maggio MC, Corsello G, Prinzi E, Cimaz R. Kawasaki disease in Sicily:Clinical description and markers of disease severity. Ital. J. Pediatr.2016; 42: 92.38 Yim D, Ramsay J, Kothari D, Burgner D. Coronary artery dilatation intoxic shock-like syndrome: The Kawasaki disease shock syndrome.Pediatr. Cardiol. 2010; 31: 1232–5.39 Esper F, Shapiro ED, Weibel C, Ferguson D, Landry ML, Kahn JS. Asso-ciation between a novel human coronavirus and Kawasaki disease. J.Infect. Dis. 2005; 191: 499–502.40 Mizuta M, Shimizu M, Inoue N et al. Serum ferritin levels as a use-ful diagnostic marker for the distinction of systemic juvenile idio-pathic arthritis and Kawasaki disease. Mod. Rheumatol. 2016; 26:929–32.41 Yamamoto N, Sato K, Hoshina T, Kojiro M, Kusuhara K. Utility of ferri-tin as a predictor of the patients with Kawasaki disease refractory tointravenous immunoglobulin therapy. Mod. Rheumatol. 2015; 25:898–902.Journal of Paediatrics and Child Health 56 (2020) 1173–1177© 2020 Paediatrics and Child Health Division (The Royal Australasian College of Physicians)D Singh-Grewal et al.COVID-19 & Inflammation in Children291292

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