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International Journal of Pediatrics
Volume 2013 (2013), Article ID 645391, 7 pages
Kawasaki Disease: A Clinician’s Update
1School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW 2052, Australia
2The Sydney Children’s Hospitals Network, Randwick and Westmead Campuses, Sydney, NSW, Australia
Received 4 August 2013; Accepted 4 September 2013
Academic Editor: Joel R. Rosh
Copyright © 2013 Nathan Jamieson and Davinder Singh-Grewal. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Aims. Kawasaki disease is an acute systemic vasculitis and is the most common cause of acquired heart disease in children in the developed world. This review aims to synthesise recent insights into the disease and provide an update for clinicians on diagnostic and treatment practices. Methods. We conducted a review of the literature exploring epidemiology, aetiology, diagnosis, and management of Kawasaki disease. We searched MEDLINE, Medline In-Process, Embase, Google Scholar, and reference lists of relevant articles. Conclusions. Kawasaki disease is a febrile vasculitis which progresses to coronary artery abnormalities in 25% of untreated patients. The disease is believed to result from a genetically susceptible individual’s exposure to an environmental trigger. Incidence is rising worldwide, and varies widely across countries and within different ethnic groups. Diagnosis is based on the presence of fever in addition to four out of five other clinical criteria, but it is complicated by the quarter of the Kawasaki disease patients with “incomplete” presentation. Treatment with intravenous immunoglobulin within ten days of fever onset improves clinical outcomes and reduces the incidence of coronary artery dilation to less than 5%. Given its severe morbidity and potential mortality, Kawasaki disease should be considered as a potential diagnosis in cases of prolonged paediatric fever.
Kawasaki disease (KD) is an acute systemic vasculitis which progresses to cause coronary artery abnormalities in 25% of untreated patients . It has surpassed rheumatic heart disease as the leading cause of acquired cardiovascular disease in children in the developed world . Though over 40 years have passed since its initial identification in patients by Kawasaki , its aetiology remains largely unknown and a specific diagnostic test eludes researchers and clinicians. Diagnosis is based primarily on clinical criteria; however, the presentation is incomplete in approximately 25% of patients, and this patient subset appears to be at a comparatively higher risk of serious complications . Coronary artery dilation and aneurysms can be prevented by timely administration of intravenous immunoglobulin, a limited and costly resource, placing an onus on practitioners to diagnose the disease promptly and accurately.
Kawasaki disease was shown to account for 23% of all paediatric vasculitides in a United States rheumatology clinic population study and is the second most common multisystem vasculitis of infancy and childhood behind Henoch-Schönlein purpura [5–7]. Though significant differences in epidemiological distribution have been observed worldwide , a number of factors appear relatively constant. These include a male predominance, with a male-to-female ratio of between 1.5 : 1 and 2 : 1 [9–11]; marked seasonality, with heightened incidence in winter and early spring in temperate climates  and summer peaks in some Asian countries  approximately 75% of cases occurring in children under 5 years of age [10, 14]; and a heightened incidence in people of Asian descent, both inside and outside Asia [15–17]. A rising incidence has been observed worldwide over time, perhaps due to heightened awareness and recognition of the disease [8, 10, 14, 18].
Determining the exact nature of the causative mechanism behind KD remains an area of controversy, unresolved since Kawasaki first described the condition in 1967 . It is hypothesised that KD results from the exposure of a genetically predisposed individual to an as-yet unidentified, possibly infectious environmental trigger . As such, the discussion of potential genetic and environmental aetiologies should be viewed as complementary rather than conflicting theories.
3.1. Genetic Aspect of Aetiology
The epidemiology of the condition suggests that Mendelian inheritance is not at play in determining KD susceptibility. Epidemiological data is strongly suggestive of a genetic component to aetiology, with studies worldwide reporting focal heightened incidence in children of East Asian origin. While the highest incidence of KD is observed in Japan, this incidence is matched in North America by Japanese-American children, with an incidence of 210.5/100,000. This trend is also present in children of Pacific Islander, native Hawaiian, and Korean descent [15, 19, 20]. A genetic predisposition is also supported by the higher relative risk of KD within families, whereby siblings of a KD patient are at a 10-fold higher risk of KD compared to the general population [16, 21].
Linkage analysis and genome-wide association studies have identified several single nucleotide polymorphisms that show an association with genetic susceptibility to KD. Two prominent discoveries include functional polymorphisms of the FC gamma RIIa locus and the ITPKC gene, which have been shown to predispose individuals in Japan and North America to KD and the subsequent development of coronary artery aneurysms [16, 22, 23]. The ITPKC gene is a T-cell activity modulator, and its identification as a susceptibility gene suggests that T-cell activity regulation may be an underlying mechanism in determining predisposition to and severity of the disease course .
3.2. Environmental Aspect of Aetiology
It is widely postulated that, following exposure to one or multiple environmental triggers in childhood, the immune response in a small, genetically susceptible patient subset manifests as systemic vasculitis . This hypothesis is supported by the abrupt symptomatic onset of KD, the seasonal and temporal clustering of cases, the spontaneous resolution of the disease even without treatment in the majority of cases, and the predomination of IgA plasma cells at mucosal surfaces in the immune response, common characteristics of the infectious diseases of childhood [13, 22, 25, 26]. Additionally, KD occurs principally between the ages of three months and five years, when susceptibility to ubiquitous infectious agents is at its highest. This epidemiological clustering suggests that most adults have immunity to the causative agent following exposure, and transplacental antibodies protect newborn infants [17, 18, 27, 28].
It is possible that bacterial or viral infections, superantigens, humoral factors, or a combined superantigen-conventional peptide antigen response may underlie the onset of the disease [29, 30], though to date, no aetiological agents have been confirmed in studies . Up to 33% of KD patients have at least one concurrent infection at the time of diagnosis, but no correlation between a specific agent and the severity of the disease course has been identified . Though the clinical and biochemical similarities seen in KD and staphylococcal and streptococcal toxin-mediated illnesses are suggestive of the involvement of a bacterial toxin in the disease aetiology, Rowley et al.  have isolated intracytoplasmic inclusion bodies in the ciliated bronchial epithelium of acute-stage KD sufferers, suggesting instead that an intracellular viral pathogen is likely to be at work. An intrinsic autoimmune cause seems unlikely based on current evidence, given patients’ lack of autoantibodies and the spontaneous resolution and absence of recurrence seen in the condition .
4.1. Clinical Course
The clinical course of KD consists of four phases: (1) acute, the period lasting 1-2 weeks if untreated, when the child has a spiking, often remittent 40° Celsius fever and principal symptomatic features and may present with cardiac manifestations including valvitis, pericarditis, and myocarditis; (2) subacute, the approximately 2 week period following the abatement of fever when the child is at the greatest risk of sudden death due to myocardial infarction; (3) convalescent, the clinically invisible period following the cessation of symptoms and continuing until acute-phase reactants return to normal serum levels; and (4) chronic, which describes patients who require follow-up management due to coronary artery involvement [11, 18, 33–35]. Diagnosis should occur in the acute stage so that prompt treatment can be administered to abate inflammation and reduce the risk of coronary artery involvement in the later disease phases .
4.2. Diagnosis of Acute KD
There is no specific diagnostic test available for KD to date . Diagnosis is currently based on clinical criteria, as established by the Japanese Ministry of Health and adopted by the American Heart Association  and is presented in Table 1 alongside the nonspecific laboratory tests used to support the diagnosis. Neither the clinical criteria nor laboratory features have been systematically validated as diagnostic tools , and the clinical criteria rely on the recognition of nonspecific symptoms that may not be present in KD but can be present in a number of other vasculitides, toxin-mediated illnesses, viral exanthema, and inflammatory conditions . Differential diagnoses for KD include Epstein-Barr virus, adenovirus, echovirus, measles, toxic shock syndrome, scarlet fever, idiopathic juvenile arthritis, polyarteritis nodosa, Rocky Mountain spotted fever, leptospirosis, juvenile mercury poisoning, and adverse drug reactions, including Stevens-Johnson syndrome [29, 38, 39].
This dependence on clinical criteria is problematic, given that the features of KD may manifest sequentially rather than simultaneously . The principal clinical findings can be accompanied by the multitude of symptoms that accompany febrile vasculitides, including arthritis, gastrointestinal upset, rhinorrhoea, weakness, extreme irritability, hydrops of the gallbladder, and mild anterior uveitis, all of which may contribute to misdiagnosis and treatment delay [2, 41]. Additional occasionally seen features such as pyuria and pleocytosis of the cerebrospinal fluid can suggest that other infectious processes underlie the presenting complaint and delay diagnosis . This variability in patient presentation places pressure on clinicians to consider KD in any case of prolonged and otherwise unexplained fever.
Clinical diagnosis is hindered further by the significant subset of patients who present with incomplete KD, characterised as KD wherein less than four of the principal features are present but laboratory results or echocardiography suggests the diagnosis of KD. Patients less than 12 months old and children older than five are more likely to present with incomplete KD [37, 46]. These patients, who make up approximately 25% of the KD cohort , are at a heightened risk of experiencing coronary artery complications because the associated higher rates of misdiagnosis may delay appropriate treatment, an issue compounded by their placement outside the typical KD age cohort [40, 47, 48].
4.3. Diagnostic Procedure for Cardiovascular Sequelae
Two-dimensional echocardiography is fundamental in the assessment of the coronary arteries following the diagnosis of KD based on the presence of the principal clinical features, or if KD is suspected in a patient that otherwise does not fulfill the diagnostic criteria. Echocardiography is a sensitive and specific means of detecting dilation, ectasia, or aneurysms in children , though the use of mild sedative agents may be required in younger children to ensure that the quality of the echocardiographic imaging is not compromised by excessive movement. Abnormal echocardiographs may show ectasia, defined by a body-adjusted score of the dilation of the left anterior descending or right coronary artery of 2.5 or greater, or by the presence of a segmental aneurysm .
Aneurysms in children are classified by the American Heart Association as small (5 mm internal diameter), medium (5–8 mm internal diameter), or giant (8 mm internal diameter). The Japanese Ministry of Health criteria for assessing the coronary arteries are age dependent and state that coronary arteries should be considered abnormal if the internal lumen diameter measures greater than 3 mm in children under 5 years or greater than 4 mm in children of 5 years, if the internal diameter of a segment is 1.5 times the diameter of an adjacent segment, or if obvious lumen irregularities are present . Giant coronary aneurysms are the least likely to regress and have the highest association with progression to stenosis and myocardial infarction . Regression is facilitated by smaller aneurysm size, fusiform morphology, and location in a distal coronary segment .
5. Acute Phase Management
The aim of acute phase management in KD is to reduce inflammation, particularly coronary arteritis and myocarditis . Though the mechanisms underlying KD are not completely understood and the efficacy of intravenous immunoglobulin (IVIG) as a first-line treatment in acute-phase KD has been validated in a number of prospective multicentre treatment trials [51, 52]. The American Heart Association recommends that patients be treated with a single infusion of IVIG over twelve hours at a dosage of 2 g/kg within ten days of fever onset, along with an anti-inflammatory 100 mg/kg/day dose of aspirin (acetylsalicylic acid) spread out over 4 doses until the child is afebrile . A recent Japanese randomised control trial found that the addition of 2 mg/kg/day prednisolone to the standard IVIG regimen significantly reduced adverse coronary outcomes, though these results have yet to be replicated in non-Japanese populations .
While aspirin is a standard component of the treatment regime worldwide, evidence as to its benefit is sparing. To date, no sufficiently-powered randomised control trials have proven the benefit of aspirin versus placebo, though it is believed to be of benefit given its antiplatelet and anti-inflammatory effects at high doses [8, 54]. However, concerns about the risks of high-dose aspirin administration, including aspirin toxicity, Reye’s syndrome, and sensorineural hearing loss, have led to adjustments to dosing practices in some countries including Japan, where the recommended acute-phase dose has been lowered to 30–50 mg/kg/day .
Timely administration of treatment is critical in preventing adverse coronary artery outcomes. IVIG administered ≥ten days after fever onset facilitates a reduction in inflammation but is ineffective in preventing coronary artery lesions . Studies have also reported a higher rate of IVIG resistance if patients are treated before the fifth day of fever, though it is unclear whether early treatment leads to poorer outcomes or if patients that present with KD before the fifth day have a more severe form of the disease .
5.1. IVIG Resistance
Between 11% and 23% of patients may present with IVIG resistance, diagnosed if a patient exhibits persistent or recurrent fever at least 36 hours after the first IVIG dose has been infused [57, 58]. IVIG resistance is problematic because recalcitrant fever is indicative of ongoing arteritis, which places patients at a higher risk of developing coronary artery aneurysms . It is recommended that refractory disease is first treated with a second dose of IVIG 2 g/kg, though the efficacy of a number of other therapeutic options, including intravenous corticosteroid pulse therapy, anti-TNF-alpha antibodies, and cytotoxic agents, is an ongoing area of research [8, 11, 59].
5.2. Aneurysm Management
Aneurysm management in the acute phase of KD is an area of uncertainty, and it is recommended that a paediatric cardiologist be involved in patient care and the development of an individualised action plan if echocardiography shows dilation or aneurysm of the coronary arteries after diagnosis. The presence of coronary artery dilation necessitates the early involvement of a paediatric cardiologist, frequent echocardiography to monitor the coronary arteries, and long-term regular stress and perfusion tests of the heart [27, 60].
Percutaneous coronary intervention procedures are indicated in patients at high risk of ischaemia. These procedures include intracoronary thrombolysis, balloon angioplasty, stent implantation, and rotational ablation and should be performed on patients presenting with either symptomatic ischaemia, laboratory findings that suggest ischaemia, or severely stenotic lesions that appear likely to progress to coronary artery ischaemia [43, 60]. Coronary artery bypass surgery is indicated if angiography detects severely occlusive lesions or jeopardised collateral blood supply [60, 61].
6. Chronic Phase Management
The aim of chronic phase management is to prevent coronary artery occlusion and myocardial infarction through reducing platelet aggregation and inhibiting thrombogenesis [50, 60]. Long-term treatment consists of antiplatelet aspirin doses of 3–5 mg/kg/day until a normal echocardiograph is seen at 6–8 weeks . If coronary artery abnormalities fail to regress by this time, long-term pharmacological therapy and diagnostic followup are implicated (Table 2).
Patients with coronary artery involvement require long-term antiplatelet doses of aspirin. In addition to this, systemic anticoagulation therapy with warfarin or low molecular weight heparin (LMWH) is indicated in patients with giant or multiple large aneurysms. LMHW is more likely to contribute to a statistically signification reduction in the coronary artery score and is less likely to result in severe bleeding, making it a viable option for young patients with severe coronary artery involvement . Children who have experienced Kawasaki disease and acute phase coronary artery involvement should reduce exposure to atherosclerosis risk factors, including obesity, hyperlipidaemia, and smoking .
It is important that immunisations be delayed in children who have received treatment with IVIG, as this treatment blocks the acquisition of active immunity by preventing the replication of live viral vaccines. Official recommendations state that immunisations should be delayed by 11 months . Inactive immunisations are unaffected by serum IVIG [63, 64].
7. Clinical Outcomes
Possible outcomes for KD include (1) resolution without cardiac sequelae; (2) the development of coronary artery abnormalities, of which approximately 60% regress in a year; (3) cardiac involvement, including myocarditis, aneurysm thrombosis, cardiac dysrhythmia, or myocardial infarction; and (4) KD recurrence in 3% of patients [1, 65, 66].
Prior to the discovery of IVIG as a safe and efficacious treatment, 20–30% of cases progressed to coronary artery dilation, with a 2% mortality rate [67, 68]. If treated with IVIG within ten days of fever onset, transient coronary artery dilation only develops in 3–5% of children and giant aneurysms develop in 1% . Factors that predispose KD patients to cardiovascular sequelae include a longer duration of fever prior to treatment, low serum albumin upon hospital admission (<3 g/L) [9, 69], age under 1 year or over 5 years [29, 70, 71], and presentation with IVIG resistance  or incomplete KD .
A conceivable long-term implication for otherwise healthy KD survivors is the potential for accelerated atherosclerosis development. Only a small number of postmortem cadavers have been available for study, though it appears that endothelial dysfunction and coronary artery scarring are present in patients with coronary artery involvement. Despite the presence of histopathological abnormalities upon biopsy of the myocardium, long-term contractility appears normal in patients affected by transient myocarditis during KD . However, increased arterial stiffness secondary to fibrotic changes within the arterial wall is indicative of an increased risk of developing atherosclerosis, which will likely become apparent as the first cohort of identified KD patients approaches middle age [52, 73].
KD is a disease associated with significant morbidity and potential mortality, yet no specific diagnostic test is available. Increased physician awareness of the principal features of KD and appropriate use of echocardiography have together improved patient outcomes through facilitating timely treatment, but incomplete presentations complicate diagnosis and are associated with significantly worse coronary outcomes. Given the severe consequences of late diagnosis, the immediate benefits offered by available therapies including IVIG, and the rising incidence of KD worldwide, it is important that neonatal and paediatric clinicians consider KD as a diagnosis in cases of prolonged paediatric fever.
- H. Kato, T. Sugimura, T. Akagi et al., “Long-term consequences of Kawasaki disease: a 10- to 21-year follow-up study of 594 patients,” Circulation, vol. 94, no. 6, pp. 1379–1385, 1996.
- J. W. Newburger, M. Takahashi, M. A. Gerber, et al., “Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the committee on rheumatic fever, endocarditis, and Kawasaki disease, council on cardiovascular disease in the young, american heart association,” Pediatrics, vol. 114, no. 6, pp. 1708–1733, 2004.
- T. Kawasaki, “Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children,” Arerugī, vol. 16, no. 3, pp. 178–222, 1967.
- C. Manlhiot, E. Christie, B. W. McCrindle, H. Rosenberg, N. Chahal, and R. S. M. Yeung, “Complete and incomplete Kawasaki disease: two sides of the same coin,” European Journal of Pediatrics, vol. 171, no. 4, pp. 657–662, 2012.
- K. Tullus and S. D. Marks, “Vasculitis in children and adolescents: clinical presentation, etiopathogenesis, and treatment,” Pediatric Drugs, vol. 11, no. 6, pp. 375–380, 2009.
- C. Galeotti, J. Bayry, I. Kone-Paut, and S. V. Kaveri, “Kawasaki disease: aetiopathogenesis and therapeutic utility of intravenous immunoglobulin,” Autoimmunity Reviews, vol. 9, no. 6, pp. 441–448, 2010.
- S. Bowyer and P. Roettcher, “Pediatric rheumatology clinic populations in the United States a 3 year survey,” Journal of Rheumatology, vol. 23, no. 11, pp. 1968–1974, 1996.
- N. J. Luca and R. S. Yeung, “Epidemiology and management of Kawasaki disease,” Drugs, vol. 72, no. 8, pp. 1029–1038, 2012.
- D. Singh-Grewal, M. Wong, and D. Isaacs, “Diagnosis, treatment and outcome of Kawasaki disease in an Australian tertiary setting: a review of three years experience,” Journal of Paediatrics and Child Health, vol. 41, no. 9-10, pp. 495–499, 2005.
- Y. T. Lin, C. Manlhiot, J. C. Y. Ching et al., “Repeated systematic surveillance of Kawasaki disease in Ontario from 1995 to 2006,” Pediatrics International, vol. 52, no. 5, pp. 699–706, 2010.
- R. Gerding, “Kawasaki disease: a review,” Journal of Pediatric Health Care, vol. 25, no. 6, pp. 379–387, 2011.
- R.-K. R. Chang, “Hospitalizations for Kawasaki disease among children in the United States, 1988–1997,” Pediatrics, vol. 109, no. 6, p. e87, 2002.
- D. Burgner and A. Harnden, “Kawasaki disease: what is the epidemiology telling us about the etiology?” International Journal of Infectious Diseases, vol. 9, no. 4, pp. 185–194, 2005.
- R. Uehara and E. D. Belay, “Epidemiology of Kawasaki disease in Asia, Europe, and the United States,” Journal of Epidemiology, vol. 22, no. 2, pp. 79–85, 2012.
- Y. Nakamura, M. Yashiro, R. Uehara, et al., “Epidemiologic features of Kawasaki disease in Japan: results of the 2009-2010 nationwide survey,” Journal of Epidemiology, vol. 22, no. 3, pp. 216–221, 2012.
- J. C. Burns and J. W. Newburger, “Genetics insights into the pathogenesis of Kawasaki disease,” Circulation. Cardiovascular Genetics, vol. 5, no. 3, pp. 277–278, 2012.
- J. C. Burns and M. P. Glodé, “Kawasaki syndrome,” The Lancet, vol. 364, no. 9433, pp. 533–544, 2004.
- A. Harnden, M. Takahashi, and D. Burgner, “Kawasaki disease,” BMJ, vol. 338, p. b1514, 2009.
- R. P. Sundel and R. E. Petty, “Kawasaki disease,” in Textbook of Pediatric Rheumatology, J. T. Cassidy, R. E. Petty, R. M. Laxer, and C. B. Lindsley, Eds., pp. 505–520, Elsevier Saunders, Philadelphia, Pa, USA, 6th edition, 2011.
- R. C. Holman, K. Y. Christensen, E. D. Belay et al., “Racial/ethnic differences in the incidence of Kawasaki syndrome among children in Hawaii,” Hawaii Medical Journal, vol. 69, no. 8, pp. 194–197, 2010.
- Y. Onouchi, “Genetics of Kawasaki disease: what we know and don't know,” Circulation Journal, vol. 76, no. 7, pp. 1581–1586, 2012.
- A. H. Rowley, “Kawasaki disease: novel insights into etiology and genetic susceptibility,” Annual Review of Medicine, vol. 62, pp. 69–77, 2011.
- Y. Onouchi, T. Gunji, J. C. Burns et al., “ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms,” Nature Genetics, vol. 40, no. 1, pp. 35–42, 2008.
- R. S. Yeung, “Kawasaki disease: update on pathogenesis,” Current Opinion in Rheumatology, vol. 22, no. 5, pp. 551–560, 2010.
- A. H. Rowley and S. T. Shulman, “Pathogenesis and management of Kawasaki disease,” Expert Review of Anti-Infective Therapy, vol. 8, no. 2, pp. 197–203, 2010.
- A. H. Rowley, “Can a systems biology approach unlock the mysteries of Kawasaki disease?” Wiley Interdisciplinary Reviews. Systems Biology and Medicine, vol. 5, no. 2, pp. 221–229, 2013.
- G. S. Pinna, D. A. Kafetzis, O. I. Tselkas, and C. L. Skevaki, “Kawasaki disease: an overview,” Current Opinion in Infectious Diseases, vol. 21, no. 3, pp. 263–270, 2008.
- J. C. Burns, D. R. Cayan, G. Tong et al., “Seasonality and temporal clustering of Kawasaki syndrome,” Epidemiology, vol. 16, no. 2, pp. 220–225, 2005.
- P. F. Weiss, “Pediatric vasculitis,” Pediatric Clinics of North America, vol. 59, no. 2, pp. 407–423, 2012.
- R. S. M. Yeung, “The etiology of Kawasaki disease: a superantigen-mediated process,” Progress in Pediatric Cardiology, vol. 19, no. 2, pp. 115–122, 2004.
- S. M. Benseler, B. W. McCrindle, E. D. Silverman, P. N. Tyrrell, J. Wong, and R. S. M. Yeung, “Infections and Kawasaki disease: implications for coronary artery outcome,” Pediatrics, vol. 116, no. 6, pp. e760–e766, 2005.
- A. H. Rowley, S. C. Baker, S. T. Shulman et al., “RNA-containing cytoplasmic inclusion bodies in ciliated bronchial epithelium months to years after acute Kawasaki disease,” PLoS ONE, vol. 3, no. 2, Article ID e1582, 2008.
- L. Wood and R. Tulloh, “Kawasaki disease: diagnosis, management and cardiac sequelae,” Expert Review of Cardiovascular Therapy, vol. 5, no. 3, pp. 553–561, 2007.
- Endocarditis, Council on Cardiovascular Disease in the Young Committee on Rheumatic Fever, and Endocarditis and Kawasaki Disease American Heart Association, “Diagnostic guidelines for Kawasaki disease,” Circulation, vol. 103, no. 2, pp. 335–336, 2001.
- J. B. Gordon, A. M. Kahn, and J. C. Burns, “When children with Kawasaki disease grow up. Myocardial and vascular complications in adulthood,” Journal of the American College of Cardiology, vol. 54, no. 21, pp. 1911–1920, 2009.
- H.-C. Kuo, K. D. Yang, W.-C. Chang, L.-P. Ger, and K.-S. Hsieh, “Kawasaki disease: an update on diagnosis and treatment,” Pediatrics and Neonatology, vol. 53, no. 1, pp. 4–11, 2012.
- S. R. Johnson, O. N. Goek, D. Singh-Grewal, et al., “Classification criteria in rheumatic diseases: a review of methodologic properties,” Arthritis and Rheumatism, vol. 57, no. 7, pp. 1119–1133, 2007.
- R. Scuccimarri, “Kawasaki disease,” Pediatric Clinics of North America, vol. 59, no. 2, pp. 425–445, 2012.
- J. Newburger, “Kawasaki disease,” in Pediatric Cardiology, chapter 25, pp. 1067–1078, 2010.
- R. Sittiwangkul, Y. Pongprot, S. Silvilairat, and C. Phornphutkul, “Delayed diagnosis of Kawasaki disease: risk factors and outcome of treatment,” Annals of Tropical Paediatrics, vol. 31, no. 2, pp. 109–114, 2011.
- A. L. Baker, M. Lu, L. L. Minich et al., “Associated symptoms in the ten days before diagnosis of Kawasaki disease,” Journal of Pediatrics, vol. 154, no. 4, pp. 592–595, 2009.
- M. Ayusawa, T. Sonobe, S. Uemura et al., “Revision of diagnostic guidelines for Kawasaki disease (the 5th revised edition),” Pediatrics International, vol. 47, no. 2, pp. 232–234, 2005.
- G. M. Satou, J. Giamelli, and M. H. Gewitz, “Kawasaki disease: diagnosis, management, and long-term implications,” Cardiology in Review, vol. 15, no. 4, pp. 163–169, 2007.
- M. H. Wu, H. C. Chen, S. J. Yeh, M. T. Lin, S. C. Huang, and S. K. Huang, “Prevalence and the long-term coronary risks of patients with Kawasaki disease in a general population LTHEXA40 years: a national database study,” Circulation. Cardiovascular Quality and Outcomes, vol. 5, no. 4, pp. 566–570, 2012.
- L. E. Wood and R. M. R. Tulloh, “Kawasaki disease in children,” Heart, vol. 95, no. 10, pp. 787–792, 2009.
- A. Kentsis, A. Shulman, S. Ahmed, et al., “Urine proteomics for discovery of improved diagnostic markers of Kawasaki disease,” EMBO Molecular Medicine, vol. 5, no. 2, pp. 210–220, 2013.
- J. J. Yu, “Diagnosis of incomplete Kawasaki disease,” Korean Journal of Pediatrics, vol. 55, no. 3, pp. 83–87, 2012.
- M. S. Wilder, L. A. Palinkas, A. S. Kao, J. F. Bastian, C. L. Turner, and J. C. Burns, “Delayed diagnosis by physicians contributes to the development of coronary artery aneurysms in children with Kawasaki syndrome,” Pediatric Infectious Disease Journal, vol. 26, no. 3, pp. 256–260, 2007.
- N. E. Manghat, G. J. Morgan-Hughes, I. D. Cox, and C. A. Roobottom, “Giant coronary artery aneurysm secondary to Kawasaki disease: diagnosis in an adult by multi-detector row CT coronary angiography,” The British Journal of Radiology, vol. 79, no. 946, pp. e133–e136, 2006.
- N. Paredes, T. Mondal, L. R. Brandão, and A. K. C. Chan, “Management of myocardial infarction in children with Kawasaki disease,” Blood Coagulation and Fibrinolysis, vol. 21, no. 7, pp. 620–631, 2010.
- H. Muta, M. Ishii, K. Egami et al., “Early intravenous gamma-globulin treatment for Kawasaki disease: the nationwide surveys in Japan,” Journal of Pediatrics, vol. 144, no. 4, pp. 496–499, 2004.
- R. M. Oates-Whitehead, J. H. Baumer, L. Haines, et al., “Intravenous immunoglobulin for the treatment of Kawasaki disease in children,” The Cochrane Database of Systematic Reviews, no. 4, Article ID CD004000, 2003.
- T. Kobayashi, T. Saji, T. Otani et al., “Efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe Kawasaki disease (RAISE study): a randomised, open-label, blinded-endpoints trial,” The Lancet, vol. 379, no. 9826, pp. 1613–1620, 2012.
- J. H. Baumer, S. J. Love, A. Gupta, L. C. Haines, I. Maconochie, and J. S. Dua, “Salicylate for the treatment of Kawasaki disease in children,” Cochrane Database of Systematic Reviews, no. 4, Article ID CD004175, 2006.
- K.-S. Hsieh, K.-P. Weng, C.-C. Lin, T.-C. Huang, C.-L. Lee, and S.-M. Huang, “Treatment of acute Kawasaki disease: aspirin's role in the febrile stage revisited,” Pediatrics, vol. 114, no. 6, pp. e689–e693, 2004.
- H. Muta, M. Ishii, M. Yashiro, R. Uehara, and Y. Nakamura, “Late intravenous immunoglobulin treatment in patients with Kawasaki disease,” Pediatrics, vol. 129, no. 2, pp. e291–e297, 2012.
- C. A. Wallace, J. W. French, S. J. Kahn, and D. D. Sherry, “Initial intravenous gammaglobulin treatment failure in Kawasaki disease,” Pediatrics, vol. 105, no. 6, p. E78, 2000.
- K. Durongpisitkul, J. Soongswang, D. Laohaprasitiporn, A. Nana, C. Prachuabmoh, and C. Kangkagate, “Immunoglobulin failure and retreatment in Kawasaki disease,” Pediatric Cardiology, vol. 24, no. 2, pp. 145–148, 2003.
- A. Coustasse, J. Larry, and D. Lee, “Can Kawasaki disease be managed?” The Permanente Journal, vol. 16, no. 2, pp. 70–72, 2012.
- J. J. W. G. JCS Joint Working Group, “Guidelines for diagnosis and management of cardiovascular sequelae in Kawasaki disease (JCS 2008)—digest version,” Circulation Journal, vol. 74, no. 9, pp. 1989–2020, 2010.
- R. Fukazawa and S. Ogawa, “Long-term prognosis of patients with Kawasaki disease: at risk for future atherosclerosis?” Journal of Nippon Medical School, vol. 76, no. 3, pp. 124–133, 2009.
- C. Manlhiot, L. R. Brandão, Z. Somji et al., “Long-term anticoagulation in Kawasaki disease: initial use of low molecular weight heparin is a viable option for patients with severe coronary artery abnormalities,” Pediatric Cardiology, vol. 31, no. 6, pp. 834–842, 2010.
- P. A. Brogan, M. J. Dillon, A. Bose et al., “Kawasaki disease: an evidence based approach to diagnosis, treatment, and proposals for future research,” Archives of Disease in Childhood, vol. 86, no. 4, pp. 286–290, 2002.
- K. B. Dummer and J. W. Newburger, “Acute management of Kawasaki disease,” Progress in Pediatric Cardiology, vol. 19, no. 2, pp. 129–135, 2004.
- A. M. Fimbres and S. T. Shulman, “Kawasaki disease,” Pediatrics in Review, vol. 29, no. 9, pp. 308–316, 2008.
- M. Takahashi, W. Mason, and A. B. Lewis, “Regression of coronary aneurysms in patients with Kawasaki syndrome,” Circulation, vol. 75, no. 2, pp. 387–394, 1987.
- A. S. Dajani, K. A. Taubert, M. A. Gerber et al., “Diagnosis and therapy of Kawasaki disease in children,” Circulation, vol. 87, no. 5, pp. 1776–1780, 1993.
- H. Kato, T. Akagi, T. Sugimura et al., “Kawasaki disease,” Coronary Artery Disease, vol. 6, no. 3, pp. 194–206, 1995.
- H.-C. Kuo, C.-D. Liang, C.-L. Wang, H.-R. Yu, K.-P. Hwang, and K. D. Yang, “Serum albumin level predicts initial intravenous immunoglobulin treatment failure in Kawasaki disease,” Acta Paediatrica, vol. 99, no. 10, pp. 1578–1583, 2010.
- V. E. A. Honkanen, B. W. McCrindle, R. M. Laxer, B. M. Feldman, R. Schneider, and E. D. Silverman, “Clinical relevance of the risk factors for coronary artery inflammation in Kawasaki disease,” Pediatric Cardiology, vol. 24, no. 2, pp. 122–126, 2003.
- S. R. Dominguez, M. S. Anderson, M. El-Adawy, and M. P. Glodé, “Preventing coronary artery abnormalities: a need for earlier diagnosis and treatment of Kawasaki disease,” The Pediatric Infectious Disease Journal, vol. 31, no. 12, pp. 1217–1220, 2012.
- E. S. Yellen, K. Gauvreau, M. Takahashi et al., “Performance of 2004 american heart association recommendations for treatment of Kawasaki disease,” Pediatrics, vol. 125, no. 2, pp. e234–e241, 2010.
- H. Tobayama, K. Takahashi, H. Fukunaga, et al., “Analysis of arterial function in adults with a history of Kawasaki disease,” Journal of Cardiology, vol. 61, no. 5, pp. 330–335, 2013.