clinical Kawasaki disease The importance of prompt recognition and early referral Daniel Golshevsky Michael Cheung David Burgner

individuals.3 Timely treatment reduces coronary Background artery damage by up to 75%.4 Kawasaki disease is an , febrile of childhood that affects medium The aetiology of Kawasaki disease is unknown. sized arteries, particularly the . Consequently, it is the leading It is believed that ubiquitous (s) trigger cause of paediatric-acquired disease in developed countries. It is important an abnormal host inflammatory response, leading to have a high index of suspicion for Kawasaki disease in any child with prolonged to Kawasaki disease in genetically predisposed of unknown origin and to refer to a paediatric facility promptly, as timely treatment reduces coronary artery damage. children. The diagnostic criteria include fever of at least 5 days duration, together with four of Objective five cardinal clinical criteria,5 which are often To provide an evidence based review that will help guide the safe and timely sequential and may appear over a number of recognition, referral and management of typical and incomplete Kawasaki disease. days.6 Although 80% of cases occur between Discussion 6 months and 4 years of age, it is important to Kawasaki disease is most common in children aged 6 months to 4 years. A remember the diagnosis in and older high index of suspicion is needed to consider the diagnosis. There are specific children. Occasionally Kawasaki disease is diagnostic criteria, though incomplete Kawasaki disease may occur where the child reported in neonates, adolescents and adults.3 does not meet all diagnostic criteria. There may be co-existing illnesses, which The diagnosis is often delayed or may be make the diagnosis more difficult. Persistent fever, skin manifestations and extreme missed entirely, as it relies on clinical features, may be some cues to consider the diagnosis. If there is strong clinical suspicion the child should be referred, as early treatment significantly decreases some of which are common in children with fever 2 the risk of long term cardiac artery damage. due to other . In addition to the classic or cardinal diagnostic features, Kawasaki disease Keywords is often accompanied by concurrent infections, as Kawasaki disease; fever/child; heart diseases; well as diarrhoea, and ; common clinical features that may mislead clinicians.7

Kawasaki disease is an acute inflammatory Why is Kawasaki disease vasculitis of medium sized arteries, also important? known as mucocutaneous With the potential for significant long term .1 Kawasaki disease is relatively cardiac sequelae, it is imperative that Kawasaki common, with an annual incidence in disease be considered, diagnosed and treated the United Kingdom and United States of promptly. Several cases of myocardial approximately 9–12 per 100 000 children in young adults have been attributed to ‘missed’ aged less than 5 years, compared to an Kawasaki disease in childhood,8 which resulted in age-matched incidence of meningococcal coronary artery aneurysms. disease of approximately 1 per 100 000.2 Mild, diffuse dilatation of coronary arteries usually begins on day 10 from fever onset. If left Kawasaki disease mainly affects children untreated, 25% of these patients progress to true aged 6 months to 4 years and has surpassed aneurysms, with 1% becoming ‘giant aneurysms’ acute as the most common (>8 mm internal diameter). These giant aneurysms cause of paediatric acquired heart disease have the worst , with risk of acute in the industrialised world, causing cardiac and long term risk of myocardial complications in up to 25% of untreated ischaemia. Aneurysms may occasionally occur in

Reprinted from Australian Family Physician Vol. 42, No. 6, june 2013 473 clinical Kawasaki disease – the importance of prompt recognition and early referral other arteries, particularly the axillary artery. In criteria. It is sometimes incorrectly referred to addition to coronary artery involvement, children as ‘atypical’ Kawasaki disease, but this term is may develop other acute cardiac complications, reserved for cases with unusual features, such including , ventricular dysfunction, as or renal failure. Incomplete Kawasaki valvular regurgitation,9 pericardial effusion and disease occurs in approximately 15% of cases, although rare, cardiac tamponade.10 although it may be missed and the true incidence The in-hospital mortality rate with Kawasaki is likely higher.6 Incomplete Kawasaki disease disease is low (~0.17%), with almost all attributed is more prevalent in children aged less than to cardiac sequelae. Peak mortality occurs at 1 year, and these patients have a higher risk 15–45 days from fever onset11 – the time when of developing cardiac sequelae.12 The overall coronary artery vasculitis coincides with marked incidence of coronary complications in incomplete thrombophilia and a hypercoagulable state. Kawasaki disease is at least similar to that of the complete disease,13 highlighting the importance What are the diagnostic of a high index of suspicion, together with prompt criteria? referral when Kawasaki disease is suspected, The diagnosis is made by the presence of fever for even if the full diagnostic criteria are not met. at least 5 days (onset of fever considered day one of illness) and at least four out of the following five When should I suspect diagnostic criteria that often appear sequentially: Kawasaki disease? • conjunctival injection – redness without Fever Figure 1. Polymorphous skin exudate, typically bilateral with perilimbal affecting the trunk in a child with sparing (a ring of normal around the Kawasaki disease should be suspected in any confirmed Kawasaki disease iris). This appears early in the illness and due to child with a persistent fever with no other its transitory nature should be sought on history likely explanation. The pyrexia associated with as well as clinical examination. Photophobia Kawasaki disease is typically high (often greater and eye pain are seldom present than 39°C), remittent and unresponsive to • of oral and/or pharyngeal mucosa therapy, and usually also unresponsive – may include strawberry , red to . This pattern of fever may help to and/or red and cracked lips, but no tonsillar distinguish Kawasaki disease from a common viral exudates or ulcers . • erythema and oedema of and feet – this Skin manifestations is a common feature but may only manifest as failure or refusal to weight-bear. In the sub- Rash and peeling () of the nappy acute phase of Kawasaki disease (from about area rash is common in the acute phase. Periungal day 10 onward), there may be desquamation of (fingers and ) desquamation appears 1–3 the fingers and toes weeks after fever onset (convalescent phase), • polymorphous skin rash – usually begins in the by which time treatment would be delayed. The nappy area (where there may be desquamation clinical features may develop over days and are early in the disease) and spreads to involve not always present concurrently. Frequent review Figure 2. Dry, red lips and polymorphous the trunk, extremities and face. Rash may be and careful and repeated history, specifically rash in a child with confirmed Kawasaki maculopapular, annular or scarlatiniform. Non- asking about suggestive features, are important disease blanching or vesicular are not usually seen in making the diagnosis. Figures 1 to 3 provide • cervical – often unilateral examples of Kawasaki disease presentations. Features that make the diagnosis less and large, with node size >1.5 cm. This is the likely include non-blanching rash, bullous or Irritability least frequently seen criteria, but is more vesicular lesions, oral ulceration, generalised common in older children. Extreme irritability – more so than in other febrile lymphadenopathy, and a prompt response to illnesses – is characteristic of Kawasaki disease. . What is incomplete Kawasaki Other suggestive features include inflammation of General practitioners should not wait for the disease? a recent Bacille Calmette-Guerin (BCG) scar and fever to persist and may make the diagnosis and Incomplete Kawasaki disease refers to infants sterile (leucocytes on urine microscopy but referral before 5 days if other clinical features are satisfying fewer than four classic diagnostic sterile by standard culturing techniques).14 present, prompting a strong index of suspicion.

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rate (ESR) and C-reactive protein (CRP)2 following commencement of IVIG, the ESR is • hypoalbuminaemia usually elevated and cannot be used to monitor • anaemia (normocytic, normochromic) response;18 CRP is a better indicator of acute • mildly raised liver enzymes (predominantly inflammation. alanine aminotransferase)17 (ECHO) may be performed • normal platelet count that increases markedly during the initial admission and is used as a by the second week of illness. baseline for coronary artery dimensions and Thrombocytosis – like periungual desquamation morphology. Occasionally large aneurysms are – is a late feature and is not helpful in the acute identified at presentation, although aneurysms

Figure 3. Extremities demonstrating diagnosis. are usually not evident on ECHO within 10 erythema, oedema and rash in a child Indications for referral to a paediatric days of fever onset. Other features on initial with Kawasaki disease emergency department include: assessment in the acute phase include coronary • high fever in an irritable child with skin artery ectasia, perivascular brightness, and What are the common manifestations lack of normal coronary artery tapering.22 Some pitfalls in the diagnosis of • prolonged fever and at least four of the five patients may also have evidence of myocarditis Kawasaki disease? diagnostic criteria and/or myocardial dysfunction. The frequency of • prolonged fever but less than four clinical echocardiographic assessment is determined by Early clinical features of Kawasaki disease criteria and no alternative explanation or local practice and findings, but they are usually mimic other self-limiting febrile illnesses and diagnosis performed at least at presentation, and after 6–8 the diagnosis may be difficult. Non-cardinal • if desquamation develops 1–2 weeks post- weeks of the illness. Serial ECHOs are performed diagnostic features (eg. diarrhoea, , onset of fever to monitor progression, and long term treatment abdominal pain and arthralgia) are common • any child aged less than 6 months with fever is dictated by the extent of coronary artery and do not exclude the diagnosis.7 Furthermore, lasting more than 7 days, even if other features involvement. microbiologically confirmed concurrent infections are absent Following resolution of fever, is may be present in up to one-third of cases at • high clinical index of suspicion for Kawasaki continued in a low ‘anti-platelet’ dose (3–5 presentation.15 Antibiotics are often given for disease. mg/kg once per day), at least until the ECHO presumed bacterial lymphadenitis, without effect, at 6–8 weeks demonstrates no evidence of and as the rash may take some days to develop, it What is the treatment? cardiac pathology.23 Some children may need is often mistaken as a drug reaction. Sterile pyuria Kawasaki disease should be treated in an long term treatment with aspirin or additional may be mistaken for a . inpatient paediatric facility by those familiar anticoagulation. It should also be noted that Important differential diagnoses for a rash with the condition and its management. there is a theoretical risk of non-steroidal anti- in the aforementioned regions in the setting Intravenous immunoglobulin (IVIG) is the only inflammatory drugs (NSAIDs) antagonising the of fever are and group A proven therapy that improves coronary artery anti-platelet effect of low-dose aspirin; however, streptococcal infections, particularly . outcomes, reducing the incidence of coronary new adult data suggest this may not be the case, Staphylococcal scalded skin syndrome also shares artery aneurysms to 2–5%.4 It is preferably given and it is yet to be studied in the paediatric setting. some features with Kawasaki disease, but usually within 10 days of fever onset, but should be given Furthermore, there is a small risk that salicylates spares the mucous membranes.16 at any time if the child is febrile or there are are associated with an increased risk of Reye laboratory features of persisting inflammation. syndrome in the setting of active viral infection, What should I do when Intravenous immunoglobulin usually causes rapid although only two cases of Kawasaki disease is suspected? defervescence and clinical improvement in the in patients with previous Kawasaki disease majority (~80%) of cases.18 have been reported in the literature. Varicella There is no specific diagnostic test. However, Aspirin is usually given in addition to this and annual immunisation should be certain laboratory findings are characteristic, treatment, although its use has never been considered in children on long term aspirin although none have a high individual positive subjected to a randomised controlled trial and therapy; expert advice should be sought. predictive value. Referral should not be delayed the dosing regimen is somewhat controversial.19 In addition, anti-viral IgG in IVIG may by awaiting results if there is reasonable clinical Kawasaki disease that does not respond to interfere with the efficacy of live suspicion or concern. the initial IVIG is usually treated with a further (, mumps, rubella [MMR], and varicella). Characteristic laboratory findings include: IVIG dose, then (if necessary), with pulsed The current recommendation is to administer • raised white cell count (predominantly a methylprednisolone20 or consideration of varicella and annual influenza vaccines neutrophilia) anti-TNF therapy.21 Expert advice should be immediately and to delay MMR vaccination • markedly elevated erythrocyte sedimentation sought in these cases. It should be noted that for 11 months after the administration of

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IVIG, at which point varicella should • Treatment with IVIG reduces coronary sequelae al. Kawasaki disease in adults: report of 10 cases. Medicine 2010;89:149–58. be readministered to ensure adequate significantly and should be initiated promptly. 9. Sumitomo N, Karasawa K, Taniguchi K, et al. immunogenicity. Parents should be advised to Association of sinus node dysfunction, atrioven- Resource tricular node conduction abnormality and ventricular visit their local immunisation centre for further Parent information sheets and support groups in patients with Kawasaki disease and advice and to re-present if an unimmunised child are available via The Royal Children’s Hospital coronary involvement. Circ J 2008;72:274–80. is exposed to varicella. website at www.rch.org.au/kidsinfo/fact_sheets/ 10. Ozdogu H, Boga C. Fatal cardiac tamponade in a patient with Kawasaki disease. Heart Lung Kawasaki_Disease/. 2005;34:257–9. What is the long term 11. Chang RK. Hospitalizations for Kawasaki disease management? Authors among children in the United States, 1988–1997. Daniel Golshevsky MBBS, BMSc(Hons), is 2002;109:e87. Parents should be reassured that Kawasaki Fellow, Royal Children’s Hospital, 12. Genizi J, Miron D, Spiegel R, Fink D, Horowitz Y. disease is not contagious and that most Melbourne, Victoria. [email protected]. Kawasaki disease in very young infants: high preva- lence of atypical presentation and coronary . children recover fully, without any long term au Clin Pediatr 2003;42:263–7. cardiac or other sequelae. Some patients may Michael Cheung BSc, MBChB, MD, MRCP, 13. Sudo D, Monobe Y, Yashiro M, et al. Coronary artery require long term treatment under specialist FRACP, is Associate Professor and Director of lesions of incomplete Kawasaki disease: a nation- Cardiology, Royal Children’s Hospital, Melbourne, wide survey in Japan. Eur J Pediatr 2012;171:651–6. supervision. Approximately half of the coronary 14. Uehara R, Igarashi H, Yashiro M, Nakamura Y, Heart Research Group Leader, Murdoch artery aneurysms resolve within 1–2 years,24 Yanagawa H. Kawasaki disease patients with Children’s Research Institute and Principal but of the affected vessel (at entrance redness or crust formation at the Bacille Calmette- Fellow, Department of Paediatrics, University of Guerin inoculation site. Pediatr Infect Dis J and exit to aneurysmal area) may occur with Melbourne, Victoria 2010;29:430–3. 25 15. Benseler SM, McCrindle BW, Silverman ED, Tyrrell healing. Occasionally this necessitates more David Burgner MBChB, BSc(Hons), MRCP, intensive medical or surgical therapy. The long PN, Wong J, Yeung RS. Infections and Kawasaki MRCPCH, DTM&H, FRACP, PhD, is Paediatric disease: implications for coronary artery outcome. term effects of Kawasaki disease on adult Infectious Diseases Consultant, Monash Pediatrics 2005;116:e760–6. are unclear, as data Children’s, Principal Research Fellow, Murdoch 16. Davies HD, Kirk V, Jadavji T, Kotzin BL. Simultaneous presentation of Kawasaki disease and toxic shock from cohort studies are not yet available. The Children’s Research Institute and Professorial Fellow, Department of Paediatrics, University of syndrome in an adolescent male. Pediatr Infect Dis J opportunity should be taken to advise families of 1996;15:1136–8. Melbourne, Victoria. the potentially increased long term cardiovascular 17. Eladawy M, Dominguez SR, Anderson MS, Glode Competing interests: None. MP. Abnormal liver panel in acute Kawasaki disease. risk and the need for minimisation of risk factors. Pediatr Infect Dis J 2011;30:141–4. It is prudent to advise families to reduce known, Provenance and peer review: Not commissioned; 18. Burns JC. Kawasaki disease. Adv Pediatr modifiable factors for cardiovascular disease, externally peer reviewed. 2001;48:157–77. 19. Baumer JH, Love SJ, Gupta A, Haines LC, such as , smoking and lack of exercise, References Maconochie I, Dua JS. 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Pediatrics 2004;114:1708–33. • The diagnosis should be considered in 7. Zulian F, Falcini F, Zancan L, et al. Acute surgical abdomen as presenting manifestation of Kawasaki any highly irritable, febrile child with skin disease. J Pediatr 2003;142:731–5. manifestations. 8. Gomard-Mennesson E, Landron C, Dauphin C, et

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