Caspases are a family of endoproteases that provide critical links in cell regulatory networks controlling inflammation and cell death. The activation of these enzymes is tightly controlled by their production as inactive zymogens that gain catalytic activity following signaling events promoting their aggregation into dimers or macromolecular complexes. Activation of apoptotic caspases results in inactivation or activation of substrates, and the generation of a cascade of signaling events permitting the controlled demolition of cellular components. Activation of inflammatory caspases results in the production of active proinflammatory cytokines and the promotion of innate immune responses to various internal and external insults. Dysregulation of caspases underlies human diseases including cancer and inflammatory disorders, and major efforts to design better therapies for these diseases seek to understand how these enzymes work and how they can be controlled.

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Caspase Functions in Cell Death and Disease

Background—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 15% to 25% of untreated children and may lead to ischemic heart disease or sudden death. Methods and Results—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 5 days and 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- 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. Conclusions—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. (Circulation. 2004;110:2747-2771.)

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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

An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study.

Background. 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 ∼15% to 25% of untreated children and may lead to ischemic heart disease or sudden death.
 Methods and Results. 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 ≥5 days and ≤4 classic criteria should undergo electrocardiography, 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-α 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.
 Conclusions. 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.

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

We compared the efficacy of intravenous gamma globulin plus aspirin with that of aspirin alone in reducing the frequency of coronary-artery abnormalities in children with acute Kawasaki syndrome in a multicenter, randomized trial. Children randomly assigned to the gamma globulin group received intravenous gamma globulin, 400 mg per kilogram of body weight per day, 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. Two-dimensional echocardiograms were interpreted blindly and independently by two or more readers. Two weeks after enrollment, coronary-artery abnormalities were present in 18 of 78 children (23 percent) in the aspirin group, as compared with 6 of 75 (8 percent) in the gamma globulin group (P = 0.01). Seven weeks after enrollment, abnormalities were present in 14 of 79 children (18 percent) in the aspirin group and in 3 of 79 (4 percent) in the gamma globulin group (P = 0.005). No child had serious adverse effects from receiving gamma globulin. We conclude that high-dose intravenous gamma globulin is safe and effective in reducing the prevalence of coronary-artery abnormalities when administered early in the course of Kawasaki syndrome.

https://www.nejm.org/doi/pdf/10.1056/NEJM198608073150601?listPDF=true

The treatment of Kawasaki syndrome with intravenous gamma globulin.

What may be a new disease has been afflicting infants and young children in Japan since 1960. It is an acute, febrile, mucocutaneous condition accompanied by swelling of cervical lymph nodes (tentatively called mucocutaneous lymph node syndrome [MLNS]). It may be misdiagnosed as scarlet fever, the Stevens-Johnson syndrome, or infantile periarteritis nodosa. The disease is now known to be widely occurring all over Japan with an increasing incidence each year. More than 6,000 cases have been reported as of 1973. One to two percent of the patients reported have died suddenly of cardiac failure. All the autopsies showed infantile periarteritis nodosa-like arteritis accompanied by coronary thrombosis and aneurysm. Some of the surviving cases have been shown to have similar changes. These findings lead us to believe that this clinical picture is a new clinical entity. Recently, rickettsia-like bodies were found by electron microscopy in biopsy specimens from the skin and lymph nodes of the patients. The bodies were isolated by yolk sac culture and their pathogenicity is now under investigation.

A New Infantile Acute Febrile Mucocutaneous Lymph Node Syndrome (MLNS) Prevailing in Japan

Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children

Objective To determine whether patients with Kawasaki disease have a higher death rate than an age-matched healthy population after disease occurrence. Study Design From July 1, 1982, to December 31, 1992, 52 collaborating hospitals collected data on all patients with a new definite diagnosis of Kawasaki disease. Patients were followed up until December 31, 1999, or death. The expected number of deaths was calculated from Japanese vital statistics data and compared with the observed number. Results Of 6576 patients enrolled, 27 (19 male, 8 female) died. The standardized mortality ratio (the observed number of deaths divided by the expected number of deaths based on the vital statistics in Japan) was 1.25 (95% confidence interval, 0.84-1.85). Despite the high standardized mortality ratios during the acute disease phase, the mortality rate was not high after the acute phase for the entire group of patients. Although the standardized mortality ratio after the acute phase was 0.76 for those without cardiac sequelae, 6 male patients (no female patients) with cardiac sequelae died during this period, and the standardized mortality ratio for the male group with cardiac sequelae was 2.35 (95% confidence interval, 0.96-5.19). Conclusions Although it was not statistically significant, the mortality rate among male patients with cardiac sequelae due to Kawasaki disease seemed higher than that in the general population. On the other hand, mortality rates for female patients with sequelae and both male and female patients without sequelae were not elevated.

https://jamanetwork.com/journals/jamapediatrics/articlepdf/191521/POA10216.pdf

Mortality Among Persons With a History of Kawasaki Disease in Japan: The Fifth Look

This paper discusses the brief history of Kawasaki disease, its main clinical features, diagnosis, main laboratory findings, cardiovascular complications in brief, treatment, epidemiology mainly in Japan, a summary of the pathology and concludes with five major problems which must be solved.

General Review and Problems in Kawasaki Disease

To clarify whether patients with Kawasaki disease have a higher death rate than the age-matched healthy population after the disease occurrence, 6576 persons with a history of Kawasaki disease have been followed-up by the Research Committee. Between July 1982 and December 1992, 52 collaborating hospitals collected data on all patients having a new definite diagnosis of Kawasaki disease. Patients were followed until December 31, 1999, or death. The expected number of deaths was calculated from Japanese vital statistics data and compared with the observed number. Of 6576 patients enrolled, 27 (19 males and 8 females) died. The standardized mortality ratio (SMR) was 1.25. In spite of the high SMRs during acute phase, the mortality rate was not high after the acute phase for all patients. Although the SMR after the acute phase was 0.76 for those without cardiac sequelae, 6 males (no females) with cardiac sequelae died during this period and the SMR for the male group with cardiac sequelae was 2.35.Conclusion. The mortality rate among males with cardiac sequelae due to Kawasaki disease was 2.4 times as high as in general population, whereas mortality rates for females with the sequelae and both males and females without sequelae were not elevated.

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Tomisaku Kawasaki

Papers

A New Infantile Acute Febrile Mucocutaneous Lymph Node Syndrome (MLNS) Prevailing in Japan

Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children

Mortality Among Persons With a History of Kawasaki Disease in Japan: The Fifth Look

General Review and Problems in Kawasaki Disease

Mortality among Persons with a History of Kawasaki Disease in Japan: The Fifth Look