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      Multisystem inflammatory syndrome in children and Kawasaki disease: a critical comparison

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          Abstract

          Children and adolescents infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are predominantly asymptomatic or have mild symptoms compared with the more severe coronavirus disease 2019 (COVID-19) described in adults. However, SARS-CoV-2 is also associated with a widely reported but poorly understood paediatric systemic vasculitis. This multisystem inflammatory syndrome in children (MIS-C) has features that overlap with myocarditis, toxic-shock syndrome and Kawasaki disease. Current evidence indicates that MIS-C is the result of an exaggerated innate and adaptive immune response, characterized by a cytokine storm, and that it is triggered by prior SARS-CoV-2 exposure. Epidemiological, clinical and immunological differences classify MIS-C as being distinct from Kawasaki disease. Differences include the age range, and the geographical and ethnic distribution of patients. MIS-C is associated with prominent gastrointestinal and cardiovascular system involvement, admission to intensive care unit, neutrophilia, lymphopenia, high levels of IFNγ and low counts of naive CD4 + T cells, with a high proportion of activated memory T cells. Further investigation of MIS-C will continue to enhance our understanding of similar conditions associated with a cytokine storm.

          Abstract

          In this timely Review, the authors compare and contrast two forms of childhood inflammatory vasculitis: Kawasaki disease and the coronavirus disease 2019 (COVID-19)-associated multisystem inflammatory syndrome in children, highlighting epidemiological, clinical and immunological differences that suggest they should be classified as distinct syndromes.

          Key points

          • Multisystem inflammatory syndrome in children (MIS-C) is characterized by exaggerated innate and adaptive immune responses following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in predisposed children.

          • Clinical presentation of MIS-C involves multiple organ systems, with prominent involvement of the gastrointestinal and cardiovascular systems.

          • The factors that trigger the development of MIS-C in children exposed to or infected with SARS-CoV-2 are not yet known.

          • Results from epidemiological, clinical and immunological investigations have revealed that although MIS-C has phenotypic similarities to Kawasaki disease, they are different syndromes.

          • The approach to treatment of MIS-C aims to mute the augmented inflammatory response.

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          Most cited references268

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          SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

          Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.
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            Is Open Access

            WHO Declares COVID-19 a Pandemic

            The World Health Organization (WHO) on March 11, 2020, has declared the novel coronavirus (COVID-19) outbreak a global pandemic (1). At a news briefing, WHO Director-General, Dr. Tedros Adhanom Ghebreyesus, noted that over the past 2 weeks, the number of cases outside China increased 13-fold and the number of countries with cases increased threefold. Further increases are expected. He said that the WHO is “deeply concerned both by the alarming levels of spread and severity and by the alarming levels of inaction,” and he called on countries to take action now to contain the virus. “We should double down,” he said. “We should be more aggressive.” Among the WHO’s current recommendations, people with mild respiratory symptoms should be encouraged to isolate themselves, and social distancing is emphasized and these recommendations apply even to countries with no reported cases (2). Separately, in JAMA, researchers report that SARS-CoV-2, the virus that causes COVID-19, was most often detected in respiratory samples from patients in China. However, live virus was also found in feces. They conclude: “Transmission of the virus by respiratory and extrarespiratory routes may help explain the rapid spread of disease.”(3). COVID-19 is a novel disease with an incompletely described clinical course, especially for children. In a recente report W. Liu et al described that the virus causing Covid-19 was detected early in the epidemic in 6 (1.6%) out of 366 children (≤16 years of age) hospitalized because of respiratory infections at Tongji Hospital, around Wuhan. All these six children had previously been completely healthy and their clinical characteristics at admission included high fever (>39°C) cough and vomiting (only in four). Four of the six patients had pneumonia, and only one required intensive care. All patients were treated with antiviral agents, antibiotic agents, and supportive therapies, and recovered after a median 7.5 days of hospitalization. (4). Risk factors for severe illness remain uncertain (although older age and comorbidity have emerged as likely important factors), the safety of supportive care strategies such as oxygen by high-flow nasal cannula and noninvasive ventilation are unclear, and the risk of mortality, even among critically ill patients, is uncertain. There are no proven effective specific treatment strategies, and the risk-benefit ratio for commonly used treatments such as corticosteroids is unclear (3,5). Septic shock and specific organ dysfunction such as acute kidney injury appear to occur in a significant proportion of patients with COVID-19–related critical illness and are associated with increasing mortality, with management recommendations following available evidence-based guidelines (3). Novel COVID-19 “can often present as a common cold-like illness,” wrote Roman Wöelfel et al. (6). They report data from a study concerning nine young- to middle-aged adults in Germany who developed COVID-19 after close contact with a known case. All had generally mild clinical courses; seven had upper respiratory tract disease, and two had limited involvement of the lower respiratory tract. Pharyngeal virus shedding was high during the first week of symptoms, peaking on day 4. Additionally, sputum viral shedding persisted after symptom resolution. The German researchers say the current case definition for COVID-19, which emphasizes lower respiratory tract disease, may need to be adjusted(6). But they considered only young and “normal” subjecta whereas the story is different in frail comorbid older patients, in whom COVID 19 may precipitate an insterstitial pneumonia, with severe respiratory failure and death (3). High level of attention should be paid to comorbidities in the treatment of COVID-19. In the literature, COVID-19 is characterised by the symptoms of viral pneumonia such as fever, fatigue, dry cough, and lymphopenia. Many of the older patients who become severely ill have evidence of underlying illness such as cardiovascular disease, liver disease, kidney disease, or malignant tumours. These patients often die of their original comorbidities. They die “with COVID”, but were extremely frail and we therefore need to accurately evaluate all original comorbidities. In addition to the risk of group transmission of an infectious disease, we should pay full attention to the treatment of the original comorbidities of the individual while treating pneumonia, especially in older patients with serious comorbid conditions and polipharmacy. Not only capable of causing pneumonia, COVID-19 may also cause damage to other organs such as the heart, the liver, and the kidneys, as well as to organ systems such as the blood and the immune system. Patients die of multiple organ failure, shock, acute respiratory distress syndrome, heart failure, arrhythmias, and renal failure (5,6). What we know about COVID 19? In December 2019, a cluster of severe pneumonia cases of unknown cause was reported in Wuhan, Hubei province, China. The initial cluster was epidemiologically linked to a seafood wholesale market in Wuhan, although many of the initial 41 cases were later reported to have no known exposure to the market (7). A novel strain of coronavirus belonging to the same family of viruses that cause severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), as well as the 4 human coronaviruses associated with the common cold, was subsequently isolated from lower respiratory tract samples of 4 cases on 7 January 2020. On 30 January 2020, the WHO declared that the SARS-CoV-2 outbreak constituted a Public Health Emergency of International Concern, and more than 80, 000 confirmed cases had been reported worldwide as of 28 February 2020 (8). On 31 January 2020, the U.S. Centers for Disease Control and Prevention announced that all citizens returning from Hubei province, China, would be subject to mandatory quarantine for up to 14 days. But from China COVID 19 arrived to many other countries. Rothe C et al reported a case of a 33-year-old otherwise healthy German businessman :she became ill with a sore throat, chills, and myalgias on January 24, 2020 (9). The following day, a fever of 39.1°C developed, along with a productive cough. By the evening of the next day, he started feeling better and went back to work on January 27. Before the onset of symptoms, he had attended meetings with a Chinese business partner at his company near Munich on January 20 and 21. The business partner, a Shanghai resident, had visited Germany between January 19 and 22. During her stay, she had been well with no signs or symptoms of infection but had become ill on her flight back to China, where she tested positive for 2019-nCoV on January 26. This case of 2019-nCoV infection was diagnosed in Germany and transmitted outside Asia. However, it is notable that the infection appears to have been transmitted during the incubation period of the index patient, in whom the illness was brief and nonspecific. The fact that asymptomatic persons are potential sources of 2019-nCoV infection may warrant a reassessment of transmission dynamics of the current outbreak (9). Our current understanding of the incubation period for COVID-19 is limited. An early analysis based on 88 confirmed cases in Chinese provinces outside Wuhan, using data on known travel to and from Wuhan to estimate the exposure interval, indicated a mean incubation period of 6.4 days (95% CI, 5.6 to 7.7 days), with a range of 2.1 to 11.1 days. Another analysis based on 158 confirmed cases outside Wuhan estimated a median incubation period of 5.0 days (CI, 4.4 to 5.6 days), with a range of 2 to 14 days. These estimates are generally consistent with estimates from 10 confirmed cases in China (mean incubation period, 5.2 days [CI, 4.1 to 7.0 days] and from clinical reports of a familial cluster of COVID-19 in which symptom onset occurred 3 to 6 days after assumed exposure in Wuhan (10-12). The incubation period can inform several important public health activities for infectious diseases, including active monitoring, surveillance, control, and modeling. Active monitoring requires potentially exposed persons to contact local health authorities to report their health status every day. Understanding the length of active monitoring needed to limit the risk for missing infections is necessary for health departments to effectively use resources. A recent paper provides additional evidence for a median incubation period for COVID-19 of approximately 5 days (13). Lauer et al suggest that 101 out of every 10 000 cases will develop symptoms after 14 days of active monitoring or quarantinen (13). Whether this rate is acceptable depends on the expected risk for infection in the population being monitored and considered judgment about the cost of missing cases. Combining these judgments with the estimates presented here can help public health officials to set rational and evidence-based COVID-19 control policies. Note that the proportion of mild cases detected has increased as surveillance and monitoring systems have been strengthened. The incubation period for these severe cases may differ from that of less severe or subclinical infections and is not typically an applicable measure for those with asymptomatic infections In conclusion, in a very short period health care systems and society have been severely challenged by yet another emerging virus. Preventing transmission and slowing the rate of new infections are the primary goals; however, the concern of COVID-19 causing critical illness and death is at the core of public anxiety. The critical care community has enormous experience in treating severe acute respiratory infections every year, often from uncertain causes. The care of severely ill patients, in particular older persons with COVID-19 must be grounded in this evidence base and, in parallel, ensure that learning from each patient could be of great importance to care all population,
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              Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals

              Summary Understanding adaptive immunity to SARS-CoV-2 is important for vaccine development, interpreting coronavirus disease 2019 (COVID-19) pathogenesis, and calibration of pandemic control measures. Using HLA class I and II predicted peptide ‘megapools’, circulating SARS-CoV-2−specific CD8+ and CD4+ T cells were identified in ∼70% and 100% of COVID-19 convalescent patients, respectively. CD4+ T cell responses to spike, the main target of most vaccine efforts, were robust and correlated with the magnitude of the anti-SARS-CoV-2 IgG and IgA titers. The M, spike and N proteins each accounted for 11-27% of the total CD4+ response, with additional responses commonly targeting nsp3, nsp4, ORF3a and ORF8, among others. For CD8+ T cells, spike and M were recognized, with at least eight SARS-CoV-2 ORFs targeted. Importantly, we detected SARS-CoV-2−reactive CD4+ T cells in ∼40-60% of unexposed individuals, suggesting cross-reactive T cell recognition between circulating ‘common cold’ coronaviruses and SARS-CoV-2.

                Author and article information

                Contributors
                Chetan.Sharma@bcm.edu
                bayry@iitpkd.ac.in
                Journal
                Nat Rev Rheumatol
                Nat Rev Rheumatol
                Nature Reviews. Rheumatology
                Nature Publishing Group UK (London )
                1759-4790
                1759-4804
                29 October 2021
                : 1-18
                Affiliations
                [1 ]GRID grid.170693.a, ISNI 0000 0001 2353 285X, Division of Paediatric Cardiology, , Children’s Hospital of San Antonio/Baylor College of Medicine, ; San Antonio, TX USA
                [2 ]GRID grid.267313.2, ISNI 0000 0000 9482 7121, Division of Paediatric Cardiology, , The University of Texas Southwestern Medical Center, ; Dallas, TX USA
                [3 ]GRID grid.413784.d, ISNI 0000 0001 2181 7253, Service de Rhumatologie Pédiatrique, , Centre de Référence des Maladies Auto-Inflammatoires Rares et des Amyloses, CHU de Bicêtre, ; le Kremlin Bicêtre, France
                [4 ]GRID grid.415338.8, ISNI 0000 0004 7871 8733, Division of Paediatrics, , Cohen Children’s Medical Center, ; New Hyde Park, NY USA
                [5 ]GRID grid.414149.d, ISNI 0000 0004 0383 4967, Division of Paediatric Cardiology, , Driscoll Children’s Hospital, ; Driscoll, TX USA
                [6 ]GRID grid.415338.8, ISNI 0000 0004 7871 8733, Division of Paediatric Cardiology, , Cohen Children’s Medical Center, ; New Hyde Park, NY USA
                [7 ]GRID grid.430417.5, ISNI 0000 0004 0640 6474, Division of Paediatric Rheumatology, , The Sydney Children’s Hospitals Network, ; Sydney, NSW Australia
                [8 ]GRID grid.414997.6, ISNI 0000 0004 0450 2040, Division of Neurology, , John F Kennedy Medical Center/Hackensack Meridian University, ; Edison, NJ USA
                [9 ]GRID grid.416477.7, ISNI 0000 0001 2168 3646, Division of Pathology and Laboratory Medicine, , Northwell Health Laboratories, ; Lake Success, NY USA
                [10 ]GRID grid.417925.c, Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, ; Paris, France
                [11 ]GRID grid.494639.5, ISNI 0000 0004 6022 0646, Department of Biological Sciences & Engineering, , Indian Institute of Technology Palakkad, ; Palakkad, India
                Author information
                http://orcid.org/0000-0003-3085-9521
                http://orcid.org/0000-0001-6083-4355
                http://orcid.org/0000-0003-0498-9808
                Article
                709
                10.1038/s41584-021-00709-9
                8554518
                34716418
                3ae5045f-2817-4640-92b6-ce2a061f31a1
                © Springer Nature Limited 2021

                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.

                History
                : 4 October 2021
                Categories
                Review Article

                inflammatory diseases,paediatric research,rheumatic diseases,innate immunity

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