Kawasaki disesae review (Ho-Chang Kuo, MD)郭和昌醫師


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An review of genetics, infection and immunity in Kawasaki disease

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Kawasaki disesae review (Ho-Chang Kuo, MD)郭和昌醫師

  1. 1. IMMUNOLOGY FOR THE PEDIATRICIAN Edited by: Harry R. Hill, MD Editor’s Note: Kawasaki disease continues to be a not uncommon, serious disorder affecting children with significant consequences in some instances. Dr. Chih-Lu Wang and Dr. Kuender Yang and colleagues of the Chang-Gung Children’s Hospital in Kaohsiung, Taiwan, have seen a very large number of cases of Kawasaki disease and performed some very interesting investigations related to the pathogenesis of the disorder. The presentation, epidemiology and inflammatory aspects of the disease continue to suggest an infectious etiology. The extensive review of their experience is a timely topic for the pediatrician, immunologist and infectious disease specialist. Kawasaki Disease Infection, Immunity and Genetics Chih-Lu Wang, MD, PhD,* Yu-Tsun Wu, MD,‡ Chieh-An Liu, MD,† Ho-Chang Kuo, MD,* and Kuender D. Yang, MD, PhD* finger tips and nonsuppurative lymphadenopathy.1,2 The most Abstract: Kawasaki disease is an acute multisystem vasculitic syndrome of unknown etiology occurring mostly in infants and disastrous complication in KD is acute coronary syndrome, children younger than 5 years of age. In developed countries, including myocardial infarction and coronary artery aneu- Kawasaki disease is currently the leading cause of acquired heart rysms, which are pathognomonic when identified in the diseases in children. However, it is still a mysterious disease. In this setting of a compatible febrile illness.2,3 To date, there are no article, we reviewed and summarized from the aspects based on specific diagnostic tests for KD. The diagnosis of KD is made infection agents, host immune dysregulation and genetic background by the presence of fever for 5 days and 4 of the 5 clinical intended to establish a feasible infection-immunogenetic pathogen- criteria described in Table 1. Atypical cases of KD are, esis for this mysterious disease and also provided the rational however, common (up to 15% of the total) and the diagnosis strategy to explore optimal treatment of this disease. should be considered without the full complement of diag- nostic criteria.4 In addition to the diagnostic criteria, a broad (Pediatr Infect Dis J 2005;24: 998 –1004) range of nonspecific clinical features can be found including irritability, uveitis, aseptic meningitis, cough, vomiting, diar- rhea, abdominal pain, gallbladder hydrops, urethritis, arthral- gia, arthritis, hypoalbuminemia, liver function impairment K awasaki disease (KD) is an acute multisystem vasculitic syndrome of unknown etiology occurring mostly in infants and children younger than 5 years of age. Tomisaku Kawasaki and heart failure.5 In some countries where newborn babies receive Calmette-Guerin bacillus (BCG) vaccination, KD can ´ published the first English language report of 50 patients with be associated with erythematous induration or even ulceration KD in 1974.1 Since then, there have been almost 3000 articles in of BCG scars in one-third of cases.6 As summarized from our the literature related to this disease. We review the clinical and recent collection of 110 cases of KD, the common features of laboratory features of this important pediatric disease and ex- the disease are shown in Figure 1. In developed countries, KD plore the pathogenic mechanisms involved. is currently the leading cause of acquired heart diseases in KD is characterized by prolonged fever, conjunctivitis, children.2,3,5 diffuse mucosal inflammation, polymorphous skin rashes, indu- The incidence of KD is increasing globally.2,7–10 Such rative edema of the hands and feet associated with peeling of an increase is well-documented in Japan, where Yanagawa et al8,11–13 have conducted a series of nationwide surveys. These have indicated that: (1) there are 5000 – 6000 new cases Accepted for publication May 10, 2005. each year; (2) current estimated incidence is 120 to 150 cases From the Divisions of *Pediatric Immunology and †Neonatology, Chang- per 100,000 children younger than 5 years old (in comparison Gung Children’s Hospital at Kaohsiung and Chang-Gung University, Kaohsiung, Taiwan; and the ‡Department of Pediatrics, St. Joseph’s with the incidence of 4 –15 cases per 100,000 children Hospital, Yunlin County, Taiwan younger than 5 years of age found in the United States); (3) Address for reprints: Kuender D. Yang, MD, PhD, 123 Ta-Pei Road, Chang KD is 1.5 times more common in boys than in girls, and 85% Gung Children’s Hospital, Niau-Sung, Kaohsiung 833, Taiwan. of cases occur in children younger than 5 yeard old; and (4) Fax 886-77312867; E-mail yangkd@adm.cgmh.org.tw. Copyright © 2005 by Lippincott Williams & Wilkins the recurrence rate is 4%. The incidence has been steadily ISSN: 0891-3668/05/2411-0998 increasing in Japan since 1987, with that in 1998 being 1.5 DOI: 10.1097/01.inf.0000183786.70519.fa times higher than that in 1987.13 Similarly the incidence has 998 The Pediatric Infectious Disease Journal • Volume 24, Number 11, November 2005
  2. 2. The Pediatric Infectious Disease Journal • Volume 24, Number 11, November 2005 Mechanism of KD tivae much more than the palpebral or tarsal conjunctivae and is TABLE 1. Diagnostic Criteria for Kawasaki Disease* not associated with an exudate. It is usually painless. Desqua- 1. Fever 5 days mation of the fingers and toes usually begins 1–3 weeks after 2. Nonpurulent conjunctivitis, bilateral onset of fever in the periungual region.1,3– 6 3. Cervical lymphadenopathy, 1.5 cm 4. Polymorphous skin rashes Coronary artery aneurysms occur as a sequela of the 5. Abnormalities of lip or oral mucosa: strawberry tongue, fissured lips, vasculitis in 20 –25% of untreated children.3,5 There are several diffuse erythema of oropharynx risk factors for developing coronary arteritis such as low serum 6. Abnormalities of extremities: edema of palm and soles, desquamation of finger tips albumin, age younger than 1 year and long duration of the fever *The diagnosis of Kawasaki disease is considered confirmed by the presence of fever before treatment. Young patients with low albumin run a very and 4 of the remaining 5 criteria if other known diseases can be excluded.3 high risk for coronary artery lesions.14 Although the introduction of intravenous immunoglobulin (IVIG) therapy has greatly de- creased the rate of coronary aneurysm to 3%, 10% of patients also been increasing in the United States,7 the United King- still develop some type of coronary artery lesions. Durongpisit- dom9 and China.10 KD in Chinese was first described in 1976 kul et al15 showed that 11.6% patients are unresponsive to initial in Taiwan and in 1978 in China. The highest incidence is in IVIG (2 g/kg) treatment. The worst prognosis occurs in children Japan, and the lowest is in the United Kingdom. There is with so-called “giant aneurysms of the coronary arteries” (those seasonal variation in different geographic areas. In most with a maximal diameter of 8 mm) because thrombosis is studies, more than one-half of the patients are younger than 2 promoted both by sluggish blood flow within the massively years of age, and cardiac lesions are more common in the dilated vascular space and by the frequent development of youngest (younger than 6 months) age group.5 The recurrence stenotic lesions.3,5,16 rate is higher in those younger than 3 years of age and in Although an infectious agent is highly suspected, the those with coronary lesions during the first episode.8 etiology of KD is unknown. Significant progress has been In KD patients, fever is generally high, spiking and per- made, however, toward understanding the natural history of sistent in the untreated patients for 1–2 weeks or longer. KD this disease, and therapeutic interventions have been devel- should be considered in the differential diagnosis of a young oped that halt the immune-mediated destruction of the vas- child with unexplained fever. Changes in the extremities are cular system. There are also important clues based on the prominent. Erythema of the palms and soles occur along with pathologic findings from autopsy specimens of patients with firm, sometimes painful induration of the hands or feet in the KD. The pathology of the necrotizing vasculitis of KD early phase of KD. A polymorphous exanthema usually appears suggests a primary role for monocytes-macrophages and T within 5 days of the onset of fever. The rash may present various lymphocytes in the acute vascular injury observed.17–19 forms on the trunk and extremities, including an urticarial exanthema, a maculopapular morbilliform eruption, a scarlatini- form erythroderma, an erythema multiforme-like rash and, IS KAWASAKI DISEASE AN rarely, a fine micropustular eruption. Neck lymph node enlarge- INFECTIOUS DISEASE? ment, usually 1.5 cm in diameter, also occurs in the early During the past 30 years, identifying of a definitive phase. Bilateral conjunctival injection usually begins shortly infectious agent that causes KD has not been possible.2 after the onset of fever. It typically involves the bulbar conjunc- Certain intracellular pathogens and superantigens from bacteria have been implicated in the immunopathogenesis of KD.2,18,20 –22 Several lines of evidence support the fact that Fever KD is an infectious disease, such as acute onset of a self- Strawberry tongue limited illness, increased susceptibility in the younger age Conjunctivitis groups and geographic clustering of outbreaks with a sea- sonal predominance (later winter and early spring).2,3,5,21 Desquamation Various bacteria such as Streptococcus pyogenes,23,24 Staph- Polymorphous skin rashes ylococcus aureus,25 Mycoplasma pneumoniae26 and Chla- Induration mydia pneumoniae27 have been sporadically isolated from Pyuria patients with KD. Suspected viral agents, especially lympho- BCG trophic viruses such as adenovirus,28 Epstein-Barr virus,29 LAP parvovirus B19,30 herpesvirus 6,31 parainfluenza type 3 vi- Diarrhea rus,32 human immunodeficiency virus,33 measles,34 rotavi- CAD rus,35 dengue virus36 and varicella37 have been implicated as Arthritis potential causes of KD, but no proof has emerged to incrim- Percentage of Cases inate 1 agent. Recently Takahashi and his colleagues38 iden- tified a novel lymphotropic virus from peripheral blood FIGURE 1. Clinical symptoms and signs of Kawasaki disease. A summary of the clinical features from 110 cases of mononuclear cells in KD patients using a 3-phase screening Kawasaki disease seen in Kaohsiung, Taiwan. LAP indicates procedure. This novel virus has an extensive but low level lymphadenopathy in head and neck area; BCG, reactivation homology (25–33% identity) to the African swine fever virus, of BCG scarring; CAD, coronary artery dilatation defined by which replicates in monocyte-macrophage lineage cells. In an internal diameter of 3 mm. contrast, there are also some clues that do not suggest an © 2005 Lippincott Williams & Wilkins 999
  3. 3. Wang et al The Pediatric Infectious Disease Journal • Volume 24, Number 11, November 2005 infectious etiology, such as a slowly increasing incidence of IS KAWASAKI DISEASE AN KD in different countries without large scale outbreaks, a IMMUNE-MEDIATED DISEASE? lack of person-to-person spread or a common contagious There is no doubt that immune alterations, especially source and similar susceptibility to KD of Japanese living in massive cytokine release resulting in vascular endothelial in- countries other than Japan. flammation, play a crucial role in the immunopathogenesis Recently superantigens have been implicated in the im- of KD.2,3 In the acute stage of KD, activation of numerous munopathogenesis of KD.21,22,39 Superantigens are a family of immunologic factors including T cell activation,17,18,49,50 microbial proteins or exotoxins that directly bind to a large cytokine production,51 nitric oxide production,52 autoanti- number of lymphocytes and antigen-presenting cells and trigger body production53 and enhanced adhesion molecule expres- a disproportionate and nonspecific immune response.40 It is now sion54 are well-documented. Pathologic examination of the apparent that superantigens have a wider role in the pathology of coronary arteritis in the acute stage of KD indicates that infectious diseases than had previously been appreciated. Staph- activated T lymphocyte-dependent processes characterized ylococcus aureus and Streptococcus pyogenes produce at least by transmural infiltration of activated T lymphocytes occur 19 distinct superantigens. The range of microorganisms known with accumulation of CD8 T cells in vascular lesions.18 to produce superantigens has expanded to include Gram-nega- Recently macrophage activation and altered T helper and tive bacteria, Mycoplasma, viruses, parasites and yeasts.41 The regulatory cell functions are also implicated in dysregula- possible importance of the superantigen in KD is suggested by tion of the immune response in patients with Kawasaki its ability to induce coronary arteritis in a mouse model in which disease.55–57 Lactobacillus casei cell wall extract induces coronary arteritis In our previous studies,52 we found that KD patients that mirrors KD in children.22 Superantigens may directly bind had higher plasma nitric oxide (NO) concentrations (as mea- to a subset of T cells with a unique T cell receptor (TCR) sured by total NO metabolites called NOx) than did the containing variable V chain. Reichardt et al42 further suggest non-KD, febrile controls. The elevated NOx in KD patients that quantitation of the TCR V 2 T cells might be valuable in was significantly associated with the occurrence of coronary making the diagnosis of KD. Binding of superantigens to lym- artery dilatation ( 3 mm). Elevated NOx in KD patients phocytes could induce autoimmune processes by stimulating significantly decreased after IVIG treatment. Inducible but autoreactive T cells as well as autoantibody production by B not constitutive NO synthase (NOS) mRNA and protein in cells.40 Nomura et al43 have proposed that KD in very young mononuclear cells were prominently expressed in acute KD infants might be related to lack of passive placental transfer of but were significantly decreased after IVIG treatment.52 antitoxic shock syndrome toxin 1 (TSST-1) antibodies because CD40 ligand (CD40L, CD154, gp39), a transmembrane the mean anti-TSST-1 titer in the mothers of the KD infants is protein structurally related to tumor necrosis factor (TNF)- , significantly lower than that in the control subjects. was originally identified on activated CD4 T cells. Both Exogenous superantigens, mainly bacterial toxins and membrane-bound and soluble forms of this ligand can inter- viral antigens, are involved in causing several diseases. There is act with CD40, which is constitutively expressed on B cells, evidence that superantigens participate in diseases such as KD, macrophages and endothelial cells, resulting in various im- toxic shock syndrome and possibly even rheumatoid arthritis. mune and inflammatory responses.58 Interaction of CD40L The superantigens could come from a variety of common patho- and CD40 on B cells plays a central role in the switch of IgM gens in the environment. They might induce immunity in most to IgG production.59 CD40L was also recently found on individuals, but they might also lead to the characteristic clinical activated platelets, which induce endothelial cells to secrete presentation of KD in certain susceptible hosts.44 – 46 chemokines and to release tissue factors.60,61 Kotowicz et al62 Esper et al47 have also identified a novel human coro- showed that ligation of CD40L to CD40 on human endothe- navirus, designated New Haven coronavirus (HCoV-NH), in lial cells can lead to endothelial cell activation and induce respiratory secretions from a 6-month-old infant with classic expression of vascular cell adhesion molecule-1, intracellular KD. They further isolated this virus from specimens of adhesion molecule 1 (ICAM-1) and E-selectin, resulting in respiratory secretions from 8 (72.7%) of 11 children with KD recruitment and activation of T cells and neutrophils at sites and from 1 (4.5%) of 22 control subjects tested positive for of inflammation. Mach et al63 demonstrated that activated HCoV-NH by reverse transcriptase-polymerase chain reac- human T cells mediate contact-dependent expression of ma- tion Mantel-Haenszel matched odds ratio, 16.0 (95% confi- trix metalloproteinases in vascular endothelial cells through dence interval, 3.4 –74.4); P 0.0015 . These data suggest CD40-CD40L signaling. Moreover the interaction between that HCoV-NH infection is associated with KD. Taking these CD40L and CD40 is also implicated in the modulation of data together, we believe that KD is not a pure infectious tissue structure cells, including smooth muscle cells, and disease but can occur in hosts with certain genetic back- epithelial cells as well as fibroblasts,58,59,64 The CD40L- ground who contract coronavirus or novel lymphotropic virus CD40 interaction is undoubtedly involved in chronic inflam- infection. It deserves additional exploration and confirmation matory diseases including atherosclerosis,59 systemic lupus of the presence of this unique virus in KD patients in different erythematosus65 and the acute coronary syndrome.66 – 68 populations from different countries. The goal of understand- We recently demonstrated that CD40L expression on ing microbial contributions to this inflammatory disease can CD4 and CD8 T cells, as well as platelets, was signifi- be addressed effectively through the thoughtful integration of cantly higher in patients with KD, decreasing 3 days after modern technologies and clinical insight.48 IVIG administration.69 Soluble forms of CD40L (sCD40L) 1000 © 2005 Lippincott Williams & Wilkins
  4. 4. The Pediatric Infectious Disease Journal • Volume 24, Number 11, November 2005 Mechanism of KD were also higher in blood during acute KD, but in contrast, ical vein endothelial cell compared with sera from patients in soluble CD40L amounts were not affected by IVIG treat- the convalescent phase. In contrast, KD sera did not induce ment. We found that CD40L expression on CD4 T cells and Fas expression. This suggests that ICAM-1 but not Fas- platelets, but not on CD8 T cells, is significantly correlated mediated activity is involved in the vasculitis of KD. with the occurrence of coronary artery dilatation, whereas sCD40L is not. This suggests that CD40L might play an IS KAWASAKI DISEASE A GENETIC DISEASE? important role in the immunopathogenesis of coronary artery The higher incidence of KD in Japan, in conjunction with dilatation in KD. We believe that the increase in CD40L a higher incidence of the disease in Japanese descendants in the expression on T cells and platelets associated with elevated United States than in other ethnic populations in the United shedding of sCD40L in KD patients could not only trigger States and England,5,7–9 suggests that a genetic predisposition immune activation but also contribute to the pathogenic might play an important role in the susceptibility to this disease. process of vascular inflammation in this disease. We are There is also evidence that the incidence of KD in siblings is currently determining whether NO is a mediator of CD40L much higher than in the general population.78 This further expression or whether CD40L mediates NO induction. supports the fact that genetic factors contribute to the suscepti- Expansion of the T cells expressing TCR V 2 and V 6 bility to KD.2,8,78 Matsubara et al79 reported the occurrence of 5 chains was reported to be stimulated by streptococcal and episodes of KD during a 6-year period in 3 siblings. Two of the staphylococcal superantigens, such as TSST-1, contributing to 3 children had recurrent KD and developed coronary artery immunopathogenesis of KD in a number of ways.2,21,70 Jabara et lesions, including giant coronary artery aneurysms in the young- al71 showed that TSST-1 promotes CD40L expression on T est sibling. The noncontemporaneous occurrence of the disease cells. CD40L was preferentially expressed in the V 2 subset of in these 3 children emphasizes the importance of a genetic basis T cells expanded by TSST-1.71 Kum et al72 also demonstrated in the occurrence of KD. that ligation of V 2-TCR by TSST-1 induced rapid surface Many gene polymorphisms are associated with KD in expression of CD40L on CD4 T cells, leading to sequential T different populations. For instance, single nucleotide polymor- cell proliferation and monocyte activation. phisms in the monocyte chemoattractant protein 1 gene regula- As noted above, Lactobacillus casei cell wall extract tory region,80 methylenetetrahydrofolate reductase,81 angioten- can induce coronary arteritis in mice that mimics KD.73,74 sin I-converting enzyme genotype II82 and SLC11A1 (formerly Duong et al22 have recently shown that L. casei cell wall NRAMP1) gene83 have been associated with KD disease in extract induces all the hallmarks of a superantigen-mediated different populations (Table 2). Gene products of the HLA class response: marked proliferation of naive T cells; nonclassic I and class II loci result in expression of peptide fragments on the major histocompatibility restriction with a hierarchy in the surface of cells that bind antigen and initiate the immune efficiency of different class II molecules to present this response. Studies have shown that KD is also associated with superantigen; a requirement for antigen presentation; but not certain gene polymorphisms and major histocompatibility com- processing, and stimulation of T cells in a nonclonal, TCR plex alleles.80 –92 Kato et al86 analyzed HLA types with a V chain-dependent manner. They demonstrate that super- standard microcytotoxicity test in 205 patients with KD and 500 antigenic activity in L. casei cell wall extract is responsible normal controls and showed that HLA-BW22 was more com- for induction of coronary artery disease.22 mon in patients with KD than in normal controls (25.4% versus An increase in autoreactive cells associated with sequen- 11.8%, P 0.0005). Among subtypes of HLA-BW22 antigen, tial immune overactivation might play an important role in the KD was associated with HLA-BW22J2 in Japanese but not in immunopathogenesis in autoimmune diseases including KD. Yi Caucasians.85 This fact suggests that there is a gene or genes et al75 showed a decease in apoptotic cells and DNA fragmen- controlling the susceptibility to KD in different races. Genetic tation in peripheral blood lymphocytes from KD patients com- polymorphisms in the TNF- gene can influence the magnitude pared with normal healthy children. After IVIG treatment, the of this cytokine production after an inflammatory stimulus.92 decrease in apoptotic cells and DNA fragmentation were re- Kamizono et al87 demonstrated that the peripheral blood mono- stored to that of the normal controls, which was accompanied by nuclear cells from KD patients with coronary artery lesions a rapid clinical remission compared with the aspirin-treated produced increased amounts of TNF- in response to bacterial group. The lymphocyte proliferative response was also de- creased 3–5 days after IVIG therapy. They suggest that a decrease in peripheral blood lymphocyte apoptosis could be involved in the pathogenesis of KD. TABLE 2. Candidate Single Nucleotide Polymorphisms Tsujimoto et al76 indicated that neutrophils isolated Involved in Kawasaki Disease from patients with KD had a significantly lower proportion of spontaneous apoptotic polymorphonuclear neutrophils (an- Monocyte chemoattractant protein 1 gene regulatory region polymorphism80 nexin V-positive cells and cells with fragmented DNA) than Methylenetetrahydrofolate reductase polymorphism81 Angiotensin I-converting enzyme genotype II polymorphism82 neutrophils in patients with a bacterial or viral infection or in SLC11A1 (formerly NRAMP1) gene polymorphism83 normal children. Later these authors also showed that high Transmembrane region of MICA gene polymorphism84 dose IVIG therapy for KD decreased the number of circulat- HLA-Bw51 (England )85 HLA-Bw22 (Japanese , England )86 ing neutrophils by accelerating apoptosis. Inoue et al77 indi- Tumor necrosis factor- polymorphism87,88 cated that sera from patients in the acute phase of KD Cytotoxic T lymphocyte antigen-4 49 A/G polymorphism89 CD40L polymorphism90 significantly increased ICAM-1 expression on human umbil- © 2005 Lippincott Williams & Wilkins 1001
  5. 5. Wang et al The Pediatric Infectious Disease Journal • Volume 24, Number 11, November 2005 products (such as TSST-1). Quasney et al88 showed the lym- Pathogenesis Therapeutic strategies photoxin 250 A/A genotype was more often found in Caucasian children with KD than in controls. The TNF- 308 Etiologies Microbes Primary Prevention Identify infectious agent(s) A/G genotype was significantly higher among whites, but not Super-Antigens Vaccination (?) Japanese, with KD who had coronary artery abnormalities than in those with normal echocardiograms. Our preliminary study in Genetic susceptibility Secondary Prevention Taiwanese children showed that an immune braking gene, cy- Susceptible to infection Avoid contagious exposure Susceptible to immune alteration Identify susceptible hosts totoxic T lymphocyte antigen 4, at 49 A/G polymorphism was significantly associated with severity of KD in males and occur- rence of KD in girls.89 Onouchi et al90 also reported that the CD40L polymorphism of intron 4 (IVS4 121 A G) in KD Immune over-activation Therapeutic strategies patients with coronary artery lesions was more frequent in boys CD40L/Cytokines Current strategies: anti- inflammation: IVIG and aspirin (P 0.030). This suggests that different ethnic populations with Potential strategies: Anti-CD40L and Endothelial cell damage inducible nitric oxide synthase (iNOS) different genetic alleles in different genders may have different Vasculitis inhibitor susceptibility to the occurrence and severity of KD. Coronary artery aneurysm The first generation of patients with KD has now reached FIGURE 2. Pathogenesis and therapeutic strategies of reproductive age, and the incidence of 2-generation cases may Kawasaki disease. thus increase in number.93–95 There have been 5 examples of 2-generation KD cases; this could be critical in analyzing the genetic predisposition to KD. Mori et al93 reported that identical HLA antigens, A24,9 B25,5 and DR2, were detected in mother This postulation is based on our study showing a significant and daughter in a 2-generation transmission pattern of KD. down-regulation of iNOS expression in blood monocytes and The prevalence of KD is increasing worldwide as is decreased blood NOx after effective IVIG therapy.52 This is atopic disease in general.96 Atopic disease is associated also supported by another study showing iNOS induction in with immunoregulatory abnormalities similar to those ob- the macrophages of coronary arteritis lesions in KD mice.101 served in acute KD. Matsuoka et al97showed that a family Another possible strategy may be the use of anti-CD40L history of allergy was significantly more common in the including anti-CD40L antibodies or pharmacologic down- children with a history of KD than in the controls (71% regulation of CD40L expression on leukocytes and platelets. versus 56%, P 0.001). The incidence of atopic dermatitis This proposal is based on the fact that patients with coronary and of allergic rhinitis was significantly higher (by 1.7 ischemia-related angina66 and patients with KD69 had over- times) in the KD children versus the control group. Furukawa expression of soluble and membrane-bound CD40L in the et al98 showed that both more CD23 B lymphocytes and an acute stage, which decreased quickly after therapy. Further- increase in serum IgE appeared during the latter part of the more it was found that KD patients have higher concentra- acute stage in KD. Tang et al99 also indicated a significant tions of leukotrienes in blood.102 Thus leukotriene antago- correlation between KD occurrence and anti-Dermatopha- nists might also benefit KD patients or limit coronary goides pteronyssinus-specific IgE. In a recent study, Matsub- vasculitis in KD. ara et al100 indicated that there was a decrease in the number of interferon- -producing, but not interleukin-4-producing, T REFERENCES 1. Kawasaki T, Kosaki F, Osawa S, Shigemitsu I, Yanagawa S. A new cells during the acute stage of KD. Thus genetic predisposi- infantile acute febrile mucocutaneous lymph node syndrome (MLNS) tion to KD can be associated with atopy. prevailing in Japan. Pediatrics. 1974;54:271–276. 2. Burns JC, Kushner HI, Bastian JF, et al. Kawasaki disease: brief history. Pediatrics. 2000;106:e27.Available at http://www.pediatrics. PREVENTION AND POTENTIAL TREATMENT org/cgi/content/full/106/2/ e27. 3. Burns JC, Glode MP. Kawasaki syndrome. Lancet. 2004;364:533–544. MODALITIES OF KAWASAKI DISEASE 4. Hsieh YC, Wu MH, Wang JK, et al. Clinical features of atypical Efforts to prevent and better treat KD are proposed in Kawasaki disease. J Microbiol Immunol Infect. 2002;35:57– 60. Figure 2. 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