Searching for the cause of Kawasaki disease — cytoplasmic inclusion bodies provide new insight

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Abstract

Although Kawasaki disease (KD) is the most common cause of acquired heart disease in children in the developed world, its aetiology remains unknown. In this Opinion, Anne Rowley and colleagues discuss evidence, including recently identified cytoplasmic inclusion bodies, which suggests that KD is caused by an infectious agent.

Abstract

Kawasaki disease (KD) has emerged as the most common cause of acquired heart disease in children in the developed world. The cause of KD remains unknown, although an as-yet unidentified infectious agent might be responsible. By determining the causative agent, we can improve diagnosis, therapy and prevention of KD. Recently, identification of an antigen-driven IgA response that was directed at cytoplasmic inclusion bodies in KD tissues has provided new insights that could unlock the mysteries of KD.

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Most cited references 82

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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

Jane W Newburger, Masato Takahashi, Michael Gerber … (2004)

Kawasaki disease is an acute self-limited vasculitis of childhood that is characterized by fever, bilateral nonexudative conjunctivitis, erythema of the lips and oral mucosa, changes in the extremities, rash, and cervical lymphadenopathy. Coronary artery aneurysms or ectasia develop in approximately 15% to 25% of untreated children and may lead to ischemic heart disease or sudden death. A multidisciplinary committee of experts was convened to revise the American Heart Association recommendations for diagnosis, treatment, and long-term management of Kawasaki disease. The writing group proposes a new algorithm to aid clinicians in deciding which children with fever for > or =5 days and < or =4 classic criteria should undergo echocardiography, receive intravenous gamma globulin (IVIG) treatment, or both for Kawasaki disease. The writing group reviews the available data regarding the initial treatment for children with acute Kawasaki disease, as well for those who have persistent or recrudescent fever despite initial therapy with IVIG, including IVIG retreatment and treatment with corticosteroids, tumor necrosis factor-alpha antagonists, and abciximab. Long-term management of patients with Kawasaki disease is tailored to the degree of coronary involvement; recommendations regarding antiplatelet and anticoagulant therapy, physical activity, follow-up assessment, and the appropriate diagnostic procedures to evaluate cardiac disease are classified according to risk strata. Recommendations for the initial evaluation, treatment in the acute phase, and long-term management of patients with Kawasaki disease are intended to assist physicians in understanding the range of acceptable approaches for caring for patients with Kawasaki disease. The ultimate decisions for case management must be made by physicians in light of the particular conditions presented by individual patients.

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A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute Kawasaki syndrome.

J Newburger, M. Takahashi, A S Beiser … (1991)

Treatment of acute Kawasaki syndrome with a four-day course of intravenous gamma globulin, together with aspirin, has been demonstrated to be safe and effective in preventing coronary-artery lesions and reducing systemic inflammation. We hypothesized that therapy with a single, very high dose of gamma globulin would be at least as effective as the standard regimen. We conducted a multicenter, randomized, controlled trial involving 549 children with acute Kawasaki syndrome. The children were assigned to receive gamma globulin either as a single infusion of 2 g per kilogram of body weight over 10 hours or as daily infusions of 400 mg per kilogram for four consecutive days. Both treatment groups received aspirin (100 mg per kilogram per day through the 14th day of illness, then 3 to 5 mg per kilogram per day). The relative prevalence of coronary abnormalities, adjusted for age and sex, among patients treated with the four-day regimen, as compared with those treated with the single-infusion regimen, was 1.94 (95 percent confidence limits, 1.01 and 3.71) two weeks after enrollment and 1.84 (95 percent confidence limits, 0.89 and 3.82) seven weeks after enrollment. Children treated with the single-infusion regimen had lower mean temperatures while hospitalized (day 2, P less than 0.001; day 3, P = 0.004), as well as a shorter mean duration of fever (P = 0.028). Furthermore, in the single-infusion group the laboratory indexes of acute inflammation moved more rapidly toward normal, including the adjusted serum albumin level (P = 0.004), alpha 1-antitrypsin level (P = 0.007), and C-reactive protein level (P = 0.017). Lower IgG levels on day 4 were associated with a higher prevalence of coronary lesions (P = 0.005) and with a greater degree of systemic inflammation. The two groups had a similar incidence of adverse effects (including new or worsening congestive heart failure in nine children), which occurred in 2.7 percent of the children overall. All the adverse effects were transient. In children with acute Kawasaki disease, a single large dose of intravenous gamma globulin is more effective than the conventional regimen of four smaller daily doses and is equally safe.

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ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms.

Yoichi Kaburagi, Tetsushi Yoshikawa, Takeo Tanaka … (2007)

Kawasaki disease is a pediatric systemic vasculitis of unknown etiology for which a genetic influence is suspected. We identified a functional SNP (itpkc_3) in the inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene on chromosome 19q13.2 that is significantly associated with Kawasaki disease susceptibility and also with an increased risk of coronary artery lesions in both Japanese and US children. Transfection experiments showed that the C allele of itpkc_3 reduces splicing efficiency of the ITPKC mRNA. ITPKC acts as a negative regulator of T-cell activation through the Ca2+/NFAT signaling pathway, and the C allele may contribute to immune hyper-reactivity in Kawasaki disease. This finding provides new insights into the mechanisms of immune activation in Kawasaki disease and emphasizes the importance of activated T cells in the pathogenesis of this vasculitis.

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Author and article information

Contributors

Anne H. Rowley: a-rowley@northwestern.edu

Bio :

Anne Rowley is Professor of Pediatrics and Microbiology/Immunology at Northwestern University Feinberg School of Medicine and an attending physician in the Division of Infectious Diseases at Children's Memorial Hospital, Chicago, Illinois, USA. She received her M.D. from SUNY Upstate Medical School, New York, USA. Her research focuses on the aetiology and pathogenesis of Kawasaki disease.

Susan C. Baker:

Bio :

Susan Baker is a professor in the Department of Microbiology and Immunology at the Stritch School of Medicine, Loyola University of Chicago, Illinois, USA. She received her Ph.D. in microbiology from Vanderbilt University, Tennessee, USA, before carrying out postdoctoral studies at the University of Southern California, USA. Her research focuses on investigating the replication of coronaviruses and pursuing the aetiology of Kawasaki disease.

Jan M. Orenstein:

Bio :

Jan Orenstein is Professor of Pathology at the George Washington University School of Medicine, Washington DC, USA. For the past 25 years, he has focused his research on the pathology of HIV-1 AIDS, and studies both the virus and the opportunistic infections that accompany the disease. During the past several years he has also studied the pathology and pathogenesis of Kawasaki disease.

Stanford T. Shulman:

Bio :

Stanford Shulman is the Virginia H. Rogers Professor of Pediatric Infectious Diseases at Northwestern University Feinberg School of Medicine and Chair of the Division of Infectious Diseases at Children's Memorial Hospital, Chicago, Illinois, USA. He received his M.D. from the University of Chicago Medical School. His research interests focus on the group A streptococcus, endocarditis and Kawasaki disease.

Journal

Journal ID (nlm-ta): Nat Rev Microbiol

Journal ID (iso-abbrev): Nat. Rev. Microbiol

Title: Nature Reviews. Microbiology

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 1740-1526

ISSN (Electronic): 1740-1534

Publication date (Print): 2008

Volume: 6

Issue: 5

Pages: 394-401

Affiliations

[1 ]GRID grid.413808.6, ISNI 0000 0004 0388 2248, Anne H. Rowley and Stanford T. Shulman are at the Departments of Pediatrics and Microbiology/Immunology, , Northwestern University Feinberg School of Medicine, The Center for Kawasaki Disease, The Children's Memorial Hospital, Chicago, 60611 Illinois, USA., ; ,

[2 ]GRID grid.164971.c, ISNI 0000 0001 1089 6558, Susan C. Baker is at the Department of Microbiology/Immunology, , Loyola University Stritch School of Medicine, Maywood, 60153, Illinois, USA., ; ,

[3 ]GRID grid.253615.6, ISNI 0000 0004 1936 9510, Jan M. Orenstein is at the Department of Pathology, , George Washington University School of Medicine, 20037, Washington DC, USA., ; ,

Article

Publisher ID: BFnrmicro1853

DOI: 10.1038/nrmicro1853

PMC ID: 7097362

PubMed ID: 18364728

SO-VID: 57be446b-16bb-45fa-b1ec-a300ff5deb13

License:

This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

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Searching for the cause of Kawasaki disease — cytoplasmic inclusion bodies provide new insight

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Biomarkers for Inflammatory Lung Disease

Most cited references 82

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

A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute Kawasaki syndrome.

ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms.

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Cited by 43

Most referenced authors 1,390