Kawasaki disease: Initial treatment and prognosis
- Robert Sundel, MD
Robert Sundel, MD
- Section Editor — Pediatric Rheumatology
- Associate Professor of Pediatrics
- Harvard Medical School
- Section Editors
- Marisa Klein-Gitelman, MD, MPH
Marisa Klein-Gitelman, MD, MPH
- Section Editor — Pediatric Rheumatology
- Chief, Division of Rheumatology
- Ann & Robert H. Lurie Children's Hospital of Chicago
- Professor of Pediatrics
- Northwestern University Feinberg School of Medicine
- Sheldon L Kaplan, MD
Sheldon L Kaplan, MD
- Editor-in-Chief — Pediatrics
- Section Editor — Pediatric Infectious Diseases
- Professor and Vice Chairman for Clinical Affairs
- Baylor College of Medicine
Kawasaki disease (KD), formerly called mucocutaneous lymph node syndrome, is one of the most common vasculitides of childhood . It is typically a self-limited condition with fever and manifestations of acute inflammation lasting for an average of 12 days without therapy. However, KD may cause cardiovascular complications, particularly coronary artery (CA) aneurysms. These, in turn, can lead to coronary occlusion and cardiac ischemia and result in significant morbidity or even mortality. (See "Cardiovascular sequelae of Kawasaki disease".)
The frequency of CA aneurysm development and associated morbidity and mortality have dramatically decreased as a result of intravenous immune globulin (IVIG) therapy. This therapy is effective for preventing CA abnormalities, but the benefits in children who have already developed CA aneurysms are more equivocal. Thus, expeditious diagnosis and timely treatment are critical to achieve the optimal clinical outcome. The initial treatment of KD is discussed in this topic review. The clinical manifestations, diagnosis, cardiovascular sequelae, and treatment of refractory KD are reviewed elsewhere. (See "Refractory Kawasaki disease" and "Kawasaki disease: Clinical features and diagnosis" and "Cardiovascular sequelae of Kawasaki disease".)
Theoretically, it should be possible to stratify therapy for KD according to disease severity defined by the likelihood of developing coronary artery (CA) aneurysms. Many risk scores have been proposed, but none are validated across different populations [2,3]. Since no criteria have been developed that can reliably distinguish children with no risk of developing severe disease at the time of initial presentation, all children diagnosed with KD or incomplete KD are treated at the time of diagnosis . Studies are ongoing to determine whether risk factors for failing to respond to intravenous immune globulin (IVIG) treatment might identify patients who would benefit from more aggressive initial therapy for KD. At this point, however, additional agents are routinely used only for children who fail to respond to standard therapy. (See "Refractory Kawasaki disease", section on 'Risk factors'.)
Guidelines by the American Heart Association (AHA) and the American Academy of Pediatrics (AAP) are available for the treatment of patients who fulfill the diagnostic criteria for KD (table 1) and for those who do not meet criteria, but are still at increased risk of developing coronary artery (CA) aneurysms (so-called incomplete KD) (algorithm 1) [4,5]. The recommended initial therapy includes intravenous immune globulin (IVIG; 2 g/kg) administered as a single infusion over 8 to 12 hours and aspirin (initial dose of 30 to 50 mg/kg daily divided into four doses). Patients are usually observed for 24 hours (minimum 12 hours) following completion of initial therapy to confirm resolution of fever. (See "Kawasaki disease: Clinical features and diagnosis" and "Incomplete (atypical) Kawasaki disease" and 'Refractory KD' below.)
A retrospective review evaluated 195 patients with KD who developed CA aneurysms at four centers in the United States from 1981 to 2006, 53 (27 percent) of whom were not treated for KD, because they did not fulfill diagnostic criteria. Application of the 2004 AHA/AAP guidelines would have resulted in the administration of IVIG therapy to all but three of these children (98 percent) .
- Burns JC, Glodé MP. Kawasaki syndrome. Lancet 2004; 364:533.
- Kobayashi T, Inoue Y, Takeuchi K, et al. Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease. Circulation 2006; 113:2606.
- Egami K, Muta H, Ishii M, et al. Prediction of resistance to intravenous immunoglobulin treatment in patients with Kawasaki disease. J Pediatr 2006; 149:237.
- Kawasaki disease. In: Red Book: 2015 Report of the Committee on Infectious Diseases, 30th ed, Kimberlin DW, Brady MT, Jackson MA, Long SS (Eds), American Academy of Pediatrics, Elk Grove Village, IL 2015. p.494.
- Newburger JW, Takahashi M, Gerber MA, 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. Circulation 2004; 110:2747.
- Yellen ES, Gauvreau K, Takahashi M, et al. Performance of 2004 American Heart Association recommendations for treatment of Kawasaki disease. Pediatrics 2010; 125:e234.
- Furusho K, Sate K, Soeta K, et al. High-dose intravenous gamma globulin for Kawaskai disease [in Japanese]. Kiso To Rinsho 1983; 17:659.
- Furusho K, Kamiya T, Nakano H, et al. High-dose intravenous gammaglobulin for Kawasaki disease. Lancet 1984; 2:1055.
- Newburger JW, Takahashi M, Burns JC, et al. The treatment of Kawasaki syndrome with intravenous gamma globulin. N Engl J Med 1986; 315:341.
- Newburger JW, Takahashi M, Beiser AS, et al. A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute Kawasaki syndrome. N Engl J Med 1991; 324:1633.
- Durongpisitkul K, Gururaj VJ, Park JM, Martin CF. The prevention of coronary artery aneurysm in Kawasaki disease: a meta-analysis on the efficacy of aspirin and immunoglobulin treatment. Pediatrics 1995; 96:1057.
- Terai M, Shulman ST. Prevalence of coronary artery abnormalities in Kawasaki disease is highly dependent on gamma globulin dose but independent of salicylate dose. J Pediatr 1997; 131:888.
- Oates-Whitehead RM, Baumer JH, Haines L, et al. Intravenous immunoglobulin for the treatment of Kawasaki disease in children. Cochrane Database Syst Rev 2003; :CD004000.
- Klassen TP, Rowe PC, Gafni A. Economic evaluation of intravenous immune globulin therapy for Kawasaki syndrome. J Pediatr 1993; 122:538.
- Hsieh KS, Weng KP, Lin CC, et al. Treatment of acute Kawasaki disease: aspirin's role in the febrile stage revisited. Pediatrics 2004; 114:e689.
- Newburger JW, Sanders SP, Burns JC, et al. Left ventricular contractility and function in Kawasaki syndrome. Effect of intravenous gamma-globulin. Circulation 1989; 79:1237.
- Tse SM, Silverman ED, McCrindle BW, Yeung RS. Early treatment with intravenous immunoglobulin in patients with Kawasaki disease. J Pediatr 2002; 140:450.
- Zhang T, Yanagawa H, Oki I, Nakamura Y. Factors relating to the cardiac sequelae of Kawasaki disease one month after initial onset. Acta Paediatr 2002; 91:517.
- Muta H, Ishii M, Egami K, et al. Early intravenous gamma-globulin treatment for Kawasaki disease: the nationwide surveys in Japan. J Pediatr 2004; 144:496.
- Marasini M, Pongiglione G, Gazzolo D, et al. Late intravenous gamma globulin treatment in infants and children with Kawasaki disease and coronary artery abnormalities. Am J Cardiol 1991; 68:796.
- Muta H, Ishii M, Yashiro M, et al. Late intravenous immunoglobulin treatment in patients with Kawasaki disease. Pediatrics 2012; 129:e291.
- Tsai MH, Huang YC, Yen MH, et al. Clinical responses of patients with Kawasaki disease to different brands of intravenous immunoglobulin. J Pediatr 2006; 148:38.
- Manlhiot C, Yeung RS, Chahal N, McCrindle BW. Intravenous immunoglobulin preparation type: association with outcomes for patients with acute Kawasaki disease. Pediatr Allergy Immunol 2010; 21:515.
- Centers for Disease Control and Prevention (CDC). Outbreak of hepatitis C associated with intravenous immunoglobulin administration--United States, October 1993-June 1994. MMWR Morb Mortal Wkly Rep 1994; 43:505.
- Laub R, Strengers P. Parvoviruses and blood products. Pathol Biol (Paris) 2002; 50:339.
- Yunoki M, Urayama T, Tsujikawa M, et al. Inactivation of parvovirus B19 by liquid heating incorporated in the manufacturing process of human intravenous immunoglobulin preparations. Br J Haematol 2005; 128:401.
- Kusakawa S, Tatara K. Efficacies and risks of aspirin in the treatment of the Kawasaki disease. Prog Clin Biol Res 1987; 250:401.
- Brogan PA, Bose A, Burgner D, et al. Kawasaki disease: an evidence based approach to diagnosis, treatment, and proposals for future research. Arch Dis Child 2002; 86:286.
- Giglia TM, Massicotte MP, Tweddell JS, et al. Prevention and treatment of thrombosis in pediatric and congenital heart disease: a scientific statement from the American Heart Association. Circulation 2013; 128:2622.
- Kuo HC, Lo MH, Hsieh KS, et al. High-Dose Aspirin is Associated with Anemia and Does Not Confer Benefit to Disease Outcomes in Kawasaki Disease. PLoS One 2015; 10:e0144603.
- Berard R, Whittemore B, Scuccimarri R. Hemolytic anemia following intravenous immunoglobulin therapy in patients treated for Kawasaki disease: a report of 4 cases. Pediatr Rheumatol Online J 2012; 10:10.
- Koren G, Silverman E, Sundel R, et al. Decreased protein binding of salicylates in Kawasaki disease. J Pediatr 1991; 118:456.
- Lee JH, Hung HY, Huang FY. Kawasaki disease with Reye syndrome: report of one case. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi 1992; 33:67.
- Wei CM, Chen HL, Lee PI, et al. Reye's syndrome developing in an infant on treatment of Kawasaki syndrome. J Paediatr Child Health 2005; 41:303.
- Matsubara T, Mason W, Kashani IA, et al. Gastrointestinal hemorrhage complicating aspirin therapy in acute Kawasaki disease. J Pediatr 1996; 128:701.
- Kobayashi T, Saji T, Otani T, 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. Lancet 2012; 379:1613.
- Petty RE, Cassidy JT. Kawasaki disease. In: Textbook of pediatric rheumatology, 4th ed, Cassidy JT, Petty RE (Eds), WB Saunders, Philadelphia 2001. p.580.
- Zhu BH, Lv HT, Sun L, et al. A meta-analysis on the effect of corticosteroid therapy in Kawasaki disease. Eur J Pediatr 2012; 171:571.
- Newburger JW, Sleeper LA, McCrindle BW, et al. Randomized trial of pulsed corticosteroid therapy for primary treatment of Kawasaki disease. N Engl J Med 2007; 356:663.
- Chen S, Dong Y, Kiuchi MG, et al. Coronary Artery Complication in Kawasaki Disease and the Importance of Early Intervention : A Systematic Review and Meta-analysis. JAMA Pediatr 2016; 170:1156.
- Sleeper LA, Minich LL, McCrindle BM, et al. Evaluation of Kawasaki disease risk-scoring systems for intravenous immunoglobulin resistance. J Pediatr 2011; 158:831.
- Ogata S, Ogihara Y, Honda T, et al. Corticosteroid pulse combination therapy for refractory Kawasaki disease: a randomized trial. Pediatrics 2012; 129:e17.
- Okada K, Hara J, Maki I, et al. Pulse methylprednisolone with gammaglobulin as an initial treatment for acute Kawasaki disease. Eur J Pediatr 2009; 168:181.
- Kobayashi T, Inoue Y, Otani T, et al. Risk stratification in the decision to include prednisolone with intravenous immunoglobulin in primary therapy of Kawasaki disease. Pediatr Infect Dis J 2009; 28:498.
- Friedman KG, Gauvreau K, Hamaoka-Okamoto A, et al. Coronary Artery Aneurysms in Kawasaki Disease: Risk Factors for Progressive Disease and Adverse Cardiac Events in the US Population. J Am Heart Assoc 2016; 5.
- Choueiter NF, Olson AK, Shen DD, Portman MA. Prospective open-label trial of etanercept as adjunctive therapy for kawasaki disease. J Pediatr 2010; 157:960.
- Tremoulet AH, Jain S, Jaggi P, et al. Infliximab for intensification of primary therapy for Kawasaki disease: a phase 3 randomised, double-blind, placebo-controlled trial. Lancet 2014; 383:1731.
- Iwashima S, Seguchi M, Matubayashi T, Ohzeki T. Ulinastatin therapy in kawasaki disease. Clin Drug Investig 2007; 27:691.
- Kanai T, Ishiwata T, Kobayashi T, et al. Ulinastatin, a urinary trypsin inhibitor, for the initial treatment of patients with Kawasaki disease: a retrospective study. Circulation 2011; 124:2822.
- Kim T, Choi W, Woo CW, et al. Predictive risk factors for coronary artery abnormalities in Kawasaki disease. Eur J Pediatr 2007; 166:421.
- Nakamura Y, Yanagawa H, Kato H, et al. Mortality among patients with a history of Kawasaki disease: the third look. The Kawasaki Disease Follow-up Group. Acta Paediatr Jpn 1998; 40:419.
- Son MB, Gauvreau K, Ma L, et al. Treatment of Kawasaki disease: analysis of 27 US pediatric hospitals from 2001 to 2006. Pediatrics 2009; 124:1.
- Orenstein JM, Shulman ST, Fox LM, et al. Three linked vasculopathic processes characterize Kawasaki disease: a light and transmission electron microscopic study. PLoS One 2012; 7:e38998.
- Kato H, Sugimura T, Akagi T, et al. Long-term consequences of Kawasaki disease. A 10- to 21-year follow-up study of 594 patients. Circulation 1996; 94:1379.
- Fukushige J, Takahashi N, Ueda K, et al. Long-term outcome of coronary abnormalities in patients after Kawasaki disease. Pediatr Cardiol 1996; 17:71.
- Suzuki A, Arakaki Y, Suhiyama H, et al. Observation of coronary arterial lesion due to Kawasaki disease by intravascular ultrasound. In: Kawasaki disease: Proceedings of the 5th International Kawasaki Disease Symposium, Kato H (Ed), Elsevier, New York 1995. p.451.
- McConnell ME, Hannon DW, Steed RD, Gilliland MG. Fatal obliterative coronary vasculitis in Kawasaki disease. J Pediatr 1998; 133:259.
- Kato H, Ichinose E, Kawasaki T. Myocardial infarction in Kawasaki disease: clinical analyses in 195 cases. J Pediatr 1986; 108:923.
- Hirata S, Nakamura Y, Yanagawa H. Incidence rate of recurrent Kawasaki disease and related risk factors: from the results of nationwide surveys of Kawasaki disease in Japan. Acta Paediatr 2001; 90:40.
- Nakamura Y, Oki I, Tanihara S, et al. Cardiac sequelae in recurrent cases of Kawasaki disease: a comparison between the initial episode of the disease and a recurrence in the same patients. Pediatrics 1998; 102:E66.
- Linnemann CC Jr, Shea L, Partin JC, et al. Reye's syndrome: epidemiologic and viral studies, 1963-1974. Am J Epidemiol 1975; 101:517.
- INITIAL THERAPY
- Intravenous immune globulin
- - Efficacy and dosing
- - Administration
- - Timing of therapy
- - Type of intravenous immune globulin
- - Adverse effects
- ADJUVANT THERAPIES
- - Disease stratification
- Tumor necrosis factor inhibition
- Other therapies
- REFRACTORY KD
- Long-term morbidity
- Monitoring for fever
- Cardiac evaluations
- Physical activity
- SOCIETY GUIDELINE LINKS
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS