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PEDIATRICS Vol. 112 No. 3 September 2003, pp. 672-676

COMMENTARY

Kawasaki Syndrome: Where Are the Answers?

H. Cody Meissner, MD and Donald Y. M. Leung, MD, PhD

Division of Pediatric Infectious Diseases
New England Medical Center
Tufts University School of Medicine
Boston, MA 02111
Department of Pediatrics
National Jewish Medical and Research Center
University of Colorado Health Sciences Center
Denver, CO 80262

Abbreviations: IGIV, intravenous immunoglobulin • TSST, toxic shock syndrome toxin • SPEB, streptococcal pyrogenic exotoxin B • SPEC, streptococcal pyrogenic exotoxin C

Thirty-six years ago, Tomisaku Kawasaki penned the first description of a quixotic illness that he called mucocutaneous lymph node syndrome.1 Today this illness has been described in almost every country of the world. In studies from North America, Japan, and Western Europe, Kawasaki syndrome has replaced rheumatic fever as the most common cause of acquired heart disease.2 Despite the importance of Kawasaki syndrome as a cause of disease in children, a surprising number of aspects of this syndrome remain ill-defined. Because the etiology remains incompletely understood, the diagnosis is based on history and physical examination. Because the symptoms of Kawasaki syndrome are not unique and diagnosis can be difficult, it is likely that many cases of incomplete or atypical Kawasaki syndrome, as well as some presentations of classic Kawasaki syndrome, remain undiagnosed and untreated, and the child remains at risk of undetected coronary artery disease. Therapy with intravenous immunoglobulin (IGIV) and aspirin, while effective, is nonspecific and is associated with the problems of gamma globulin infusions. These problems include the need for intravenous cannulation, risk of adverse reactions, concern for possible adventitious agents, interference with the immune response to live vaccines, expense, shortages, and the fact that 2% to 4%% of treated children still develop coronary artery disease. Furthermore, the long-term cardiac outcome of children who experience Kawasaki syndrome both for those with and those without detectable coronary artery involvement is not clear. After >3 decades of study, what is known about Kawasaki syndrome and why are there still so many unanswered questions?

The study by Holman et al3 in this issue of Pediatrics supports previous estimates regarding certain epidemiologic aspects of Kawasaki syndrome and offers important new detail into others. Using hospital discharge data from the Kids’ Inpatient Database (22 participating states), the authors address a number of features of Kawasaki syndrome in the United States. First, they confirm that the hospitalization rate for children <5 years of age is ~17/100 000. When corrected for rehospitalization and for children who may not meet case criteria, this rate falls to ~12 cases/100 000—~1/10 that described in Japan during nonepidemic years.4,5 According to Holman et al, the incidence of Kawasaki syndrome in the United States is similar for the years 1997 and 2000, a figure that appears to have been steady for at least the past decade. The authors confirm a slightly higher hospitalization rate for Kawasaki syndrome during winter and early spring months. Patients with Kawasaki syndrome were more likely to come from a household with a higher median income than non-Kawasaki syndrome patients, a finding consistent with the suggestion of a higher socioeconomic status among families with Kawasaki syndrome patients. The authors report a median hospital stay of 3 days and a median estimated hospital charge of $7779 for children <5 years of age and a total estimated yearly charge of $51 million for all hospitalized children with Kawasaki syndrome. It is likely that incidence figures as well as costs will be considerably higher when a reliable diagnosis of atypical or incomplete Kawasaki syndrome can be made.

The combined use of IGIV and aspirin has formed the basis of treatment of Kawasaki syndrome for nearly 20 years.6–8 The efficacy of IGIV in prevention of coronary artery abnormalities is dose-dependent, although the optimal dose of IGIV has not been firmly established.9,10 Administration of IGIV, 2 g/kg, as a single dose has benefit over the earlier regimen of 400 mg/kg dose for 4 days in terms of more rapid elimination of fever and less coronary artery disease at 2 weeks’ follow-up (although there is not a statistically significant difference at 7 weeks’ follow-up).8 Doses >2 g/kg have not been studied. Thus, the current standard is 2 g/kg before day 10 of fever, which will reduce the risk of coronary artery disease from ~20% to <5%.11 One of the interesting facts in the study by Holman et al that supports the efficacy of present therapy is the absence of a single death among >4200 hospitalized children with Kawasaki syndrome. The mechanism of action of IGIV is unknown. Whether all gamma globulin products have equivalent efficacy in prevention of coronary artery disease is unknown.12,13

Aspirin is used in the acute stage of illness to decrease the intensity of vasculitis and to provide inhibition of platelet aggregation. Aspirin will not alter the risk of coronary artery disease although the dose may affect the duration of fever.9,10 High-dose aspirin (80–100 mg/kg/d in 4 divided doses) is recommended to maintain adequate serum salicylate levels because of reduced absorption and increased clearance during the acute stage of illness.11,14 Gastrointestinal hemorrhage is a known complication of aspirin therapy, but this is a rare complication of high-dose salicylate therapy in patients with Kawasaki syndrome.

Approximately 85% of children treated within 10 days after onset of illness will experience prompt defervesence and resolution of signs of inflammation in response to IGIV and aspirin therapy. Optimal management has not been established for the remaining children who demonstrate ongoing or recrudescent fever and other signs of inflammation 24 to 72 hours or longer after treatment. Although criteria for retreatment are not established, a second dose of IGIV, 2 g/kg, is generally recommended because ongoing fever correlates with the presence of proinflammatory cytokines and an ongoing risk of coronary artery ectasia or aneurysm formation.15,16 This approach is supported by early studies, which demonstrated improved outcome in children with elevated postinfusion immunoglobulin G serum levels.8 In some instances, a third dose of IGIV may be appropriate, although complications have been reported following large doses of gamma globulin.17

The use of corticosteroid therapy in patients with Kawasaki syndrome is controversial. An early nonrandomized Japanese study involving numbers of patients that were too small to generate statistically significant results raised the concern that steroids might lead to an increased risk of coronary artery disease.18 The results of a recent retrospective case series of patients who received steroid (methylprednisolone) therapy suggested that patients treated with IGIV and aspirin plus prednisolone experienced a shorter duration of fever and a lower risk of coronary artery abnormalities than patients receiving IGIV and aspirin.19 However, the doses of aspirin and of IGIV used in this study were different from those used in the United States. Other reports involving small numbers of patients suggest that for the limited number of patients who are refractory to 2 or 3 doses of IGIV, oral or intravenous methylprednisolone may reduce signs and symptoms of inflammation.20,21 The effect of steroids on the vasculitis is unclear. Before a recommendation can be made for use of steroids in treatment of Kawasaki syndrome, benefits and risks should be evaluated in randomized, controlled clinical trials.

A diagnosis of classic Kawasaki syndrome is based on the presence of well-established criteria in much the same way that a diagnosis of rheumatic fever is based on the Jones criteria (Table 1). Frequently problems arise in the diagnosis of Kawasaki syndrome because none of the criteria are unique to this disorder, and oftentimes not all criteria will be present, even in a patient with classic Kawasaki syndrome. The concept of atypical or incomplete Kawasaki syndrome was introduced to describe those children who present with fever and fewer than 4 of the remaining criteria and still develop coronary artery abnormalities.22 There is some evidence that an increasing number of patients are being diagnosed who do not satisfy the diagnostic criteria for classic Kawasaki syndrome.23


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  		TABLE 1. Diagnostic Criteria for Kawasaki Syndrome

 
Any infectious disease may present with a spectrum of symptoms and disease severity. Current guidelines favor diagnosis of classic Kawasaki syndrome. However, it is important not to miss an opportunity to provide effective therapy to a child with incomplete Kawasaki syndrome when fewer than 4 criteria are present. A possibility of Kawasaki syndrome should be considered in any child with high spiking fever for 4 or 5 days or more if there is no evidence of a well-defined bacterial infection and even one finding such as rash, oral changes, or conjunctivitis is present. The laboratory features of incomplete Kawasaki syndrome are similar to those seen in classic Kawasaki syndrome. Until a reliable laboratory test becomes available, cases that do not fulfill diagnostic criteria will continue to remain undiagnosed and untreated.

Investigation into the immune status of children with Kawasaki syndrome has revealed a profound degree of immune abnormalities that are not characteristic of the vast majority of febrile exanthems of childhood.24 It is generally agreed that an infectious agent initiates the immune cascade that characterizes children with Kawasaki syndrome. This consensus is based on several observations including 1) the acute self-limited nature of the illness with clinical features that are similar to certain toxin-mediated infectious diseases such as toxic shock syndrome and scarlet fever, 2) a seasonal peak in activity in the winter and spring months, 3) the presence of both endemic and epidemic disease, and 4) the characteristic predilection for infants and children between 6 months and 10 years of age that suggests a loss of maternal antibody early in the first year of life followed by acquisition of immunity to a common agent by the end of the first decade of life.25

Understanding the etiology of Kawasaki syndrome remains a major unresolved issue of pediatrics. Unfortunately, extensive use of a variety of techniques to detect known microbes has failed to identify a pathogen. One group of investigators has suggested that an exaggerated immunoglobulin A immune response in association with plasma cell infiltration of the vascular wall as well as other tissues such as myocardium, respiratory tract, kidney, and pancreas occurs in patients with Kawasaki syndrome. They suggest a mucosal portal of entry of a conventional antigen. No specific microbe has been proposed as the etiologic agent.26–28

Another hypothesis proposes that the profound degree of immunoregulatory abnormalities found in Kawasaki syndrome patients are attributable to bacterial (and perhaps viral) protein toxins that act as superantigens.24 Superantigens differ from conventional antigens in a number of important ways, including polyclonal B-cell activation, extensive proinflammatory cytokine production, and changes in the number of circulating T lymphocytes that bear a specific surface receptor (specifically V ß-restricted T cells). All of these immune aberrations have been described in patients with Kawasaki syndrome.29–33 Only a limited number of lymphocytes respond to a conventional antigen, typically <1 cell per 10 000 lymphocytes. In contrast, superantigens may activate as many as 20% to 30% of circulating lymphocytes with release of unusually large amounts of cytokines from activated T cells. Cytokines then mediate the disease process. Many of the clinical features of Kawasaki syndrome can be explained by such a marked immune activation: high fever and increased acute-phase reactants resulting from interleukin-1, interleukin-6, and tumor necrosis factor.29,30 Cervical adenopathy may reflect the marked B- and T-cell activation. Vascular injury may result from cytokine-induced excess of proinflammatory and prothrombotic responses and the expression of neoantigens on coronary endothelium.

A blinded, randomized trial conducted in 1993 demonstrated the presence of superantigen-producing bacteria from patients with Kawasaki syndrome but not from febrile control patients.34 In that trial, cultures from several anatomic sites (throat, rectum, groin, axilla) were analyzed in a blinded manner from 16 consecutive patients with Kawasaki syndrome and from 15 age-matched febrile control patients. Superantigen-producing bacteria were found in 13 of 16 acute Kawasaki syndrome patients and in only 1 of 15 febrile control patients (P < .001). Eleven of 13 toxin-positive cultures from Kawasaki syndrome patients were toxic shock syndrome toxin (TSST)-secreting Staphylococcus aureus and 2 were group A streptococci-producing streptococcal pyrogenic exotoxins B and C (SPEB, SPEC), all 3 of which possess superantigenic activity. However, this study was criticized because it involved only 1 pediatric hospital.

In 2002 the results of a second blinded and randomized multi-institutional trial were published comparing the prevalence of superantigen-secreting bacteria in patients with Kawasaki syndrome and febrile controls.35 This study was similar to the first trial except that cultures were obtained from 45 patients with Kawasaki syndrome and from 37 febrile control patients at 6 medical centers in the United States with experience in treating patients with Kawasaki syndrome. Results showed that TSST-producing S aureus or SPEB/SPEC-producing group A streptococci were isolated from 20 (44%) of 45 patients with Kawasaki syndrome in contrast to 7 (19%) of 37 controls (P = .019). This result was consistent with the first report that bacteria producing TSST-1, SPEB, or SPEC are isolated at a statistically significantly greater rate from patients with Kawasaki syndrome than from control patients. The second study also evaluated the presence of S aureus that produced enterotoxins B and C (SEB, SEC). These 2 superantigens were isolated with equal frequency from Kawasaki syndrome patients and from control subjects. However, SEB and SEC do not result in V ß 2+T-lymphocyte stimulation, so although they have certain superantigenic characteristics, these specific exotoxins appear not to be associated with the pathogenesis of Kawasaki syndrome.

Based on these observations, the following hypothesis has been proposed: a superantigen-producing organism (TSST-producing S aureus, SPEB- or SPEC-producing group A streptococci, or other superantigen-producing microbes) colonizes the mucous membranes of the gastrointestinal tract of a genetically susceptible individual. The absence of previous exposure to the infectious agent explains the lack of immunity in the child’s antibody repertoire. Toxin is absorbed through the inflamed mucosal surface and stimulates local or circulating mononuclear cells to produce proinflammatory cytokines which in turn result in fever and the clinical picture of Kawasaki syndrome. In response to cytokine-induced stimulation, neoantigens are expressed on the surface of vascular endothelial cells, making them susceptible to attack by cytotoxic antibody and activated T cells, resulting in the characteristic vasculitis.

Understanding the long-term complications of coronary artery involvement in patients with Kawasaki syndrome is restricted by the fact that follow-up is currently limited to <40 years. Among children who do not develop detectable coronary artery abnormalities, the long-term prognosis is felt to be favorable although the consequence of endothelial cell damage and dysfunction at a molecular level is incompletely understood.36,37 Alterations in lipid metabolism suggest that abnormalities may persist for years after acute disease resolves.38 In those children who develop coronary artery aneurysms, ~50% demonstrate regression within 2 years, as measured by angiography, owing to intimal proliferation within the vessel wall.39 Whether such lesions remain at increased risk of atherosclerosis is unknown, although reduced vessel reactivity has been described.40 Children who develop giant aneurysms (>8 mm in diameter) are at particular risk of stenosis or complete obstruction, and understanding of optimal surgical and medical intervention is evolving.41

It is important that the etiology of Kawasaki syndrome be determined so that a definitive test can be developed to rapidly identify and treat those children with classic or incomplete disease. It is unlikely that a more specific form of therapy than IGIV will be found without understanding the etiology. In the meantime new therapies to minimize complications such as a monoclonal antibody Fab fragment (abciximab) directed against a platelet glycoprotein receptor offer the promise of improved outcomes for those with coronary artery involvement.42 Hopefully, a full understanding of the etiology and pathogenesis of this illness will be available before another 36 years passes. This understanding will surely lead to improved treatment and perhaps even a vaccine for prevention.


   FOOTNOTES
 
Received for publication Apr 14, 2003; Accepted Apr 14, 2003.

Address correspondence to H. Cody Meissner, MD, Pediatric Infectious Diseases Division, Tufts-New England Medical Center, 750 Washington St, Boston, MA 02111. E-mail: cmeissner{at}tufts-nemc.org


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PEDIATRICS (ISSN 1098-4275). ©2003 by the American Academy of Pediatrics

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