key: cord-0059805-7a6yslpz authors: Gupta, Atula; Murrell, Dedee F.; Otton, James; Goldust, Mohamad title: COVID-19 date: 2020-07-07 journal: Skin and the Heart DOI: 10.1007/978-3-030-54779-0_13 sha: 7d9059407cf17140ba7dc9e7efec2b53b3624a5a doc_id: 59805 cord_uid: 7a6yslpz A novel SARS -CoV2 virus (COVID 19) that led to an outbreak of pneumonia in Wuhan, China is now known to involve multiple organ systems presenting with acute respiratory distress syndrome, gastrointestinal disease, cardiac disease, skin lesions, renal involvement, hepatic damage, and multi organ failure. Even though the mortality and morbidity of this disease is higher in the older age group, clusters of children having severe illness requiring critical care have also been identified. Severe disease in children infected with COVID 19 is characterized by a multisystem inflammatory condition and a clinical presentation similar to Kawasaki disease. COVID 19 and its multi organ involvement is due to the underlying hyperinflammatory syndrome leading to a surge in cytokine levels causing injury to several cell types including cardiac myocytes and endothelial cells. The binding of SARS CoV2 to the ACE 2 receptor expressed in the endothelial cells, pneumocytes and myocardial cells is responsible for the clinical manifestations occurring in skin, heart and other organs. The new corona virus or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection which initially appeared to present with predominantly respiratory symptoms has now been found to have a wide range of clinical features, from mild self-limiting disease to complications involving several organ systems including acute respiratory distress syndrome, cardiac failure, gastrointestinal disease, cutaneous, hepatic, renal and nervous system involvement. Preexisting cardiovascular disease and related comorbidities are vital determinants of susceptibility, severity, and mortality in this condition. Various skin manifestations from maculopapular rashes, urticarial lesions, vesicular and vasculitic lesions have been identified in various studies. One of the most critical effects of COVID-19 are those on the cardiovascular system. Myocardial infection can arise from multiple mechanisms, perhaps related to the expression of ACE 2, the receptor for the spike protein of COVID-19, in the heart, although the exact mechanism leading to cardiac failure is unclear. It is evident that COVID-19 may thus affect extrapulmonary systems such as the skin and heart separately or together in the form of a multiorgan disease. COVID-19 infection in children has been found to have a much lower mortality than in adults [1, 2] . Previous data had shown that the pediatric age group had less than 2% of positive cases in population below age 20 years [3] . A study of 731 COVID-19 positive children, identified 90% to have asymptomatic or mild illness [2] . Common pediatric manifestations of COVID-19 include fever, malaise, cough, sore throat, and difficulty in breathing. Severe cases may present with gastrointestinal symptoms, respiratory distress, coagulation disturbances and shock. Contrary to several preliminary studies from different countries which had suggested that critical disease and mortality due to COVID-19 among children is rare [4] whether it be reduced vulnerability to infection among children [5] or similar susceptibility but higher number of cases with asymptomatic disease, [6] recent emerging data has revealed the occurrence of a Kawasaki-like disease in the pediatric age group affected by this illness [7] . The relationship of Kawasaki disease (KD) to COVID-19 may be due to the SARS-C0V-2 infection triggering an inflammatory syndrome in some children. In one study, a 6-month-old infant tested positive for COVID-19, had features of classic KD and improved after treatment with intravenous immunoglobulin (IVIG) [8] . Cases of KD were also identified in Bergamo province in Italy [7] . This preliminary data has hinted towards a plausible association between COVID-19 and KD. Vasculitic lesions initiated by post viral immunological reactions have also been seen in COVID-19 confirmed cases in adults [9, 10] . Kawasaki disease (KD) is a severe vasculitic inflammation of the blood vessel walls occurring in children commonly under 5 years of age [11] . It is a self-limiting, acute inflammation of the medium and small sized vessels which in severe form manifest with symptoms such as persistent fever, lymphadenopathy, conjunctival injection, cutaneous lesions, mucosal lesions and coronary artery aneurysm as the major cardiac complication [12, 13] . KD is a diagnosis made on the basis of a defined laboratory and clinical criteria. In Japan, the incidence of children under 4 years of age affected with KD is 300 per 100,000 children versus 25 per 100,000 children less than 5 years of age in North America [14] . KD also known as "mucocutaneous lymph node syndrome" is named after Dr. Tomisacu Kawasaki who first established a correlation between a childhood disease with multiorgan involvement with an outbreak of coronavirus rhinitis. A study conducted in 2005 by Esper et al. further confirmed that coronavirus positive nasal swabs were identified in 8 out of 11 children diagnosed with KD [15] . KD is a clinical diagnosis based on the following criteria [16] : Diagnostic criteria-Four of the five mentioned in Table 13 .1 plus fever of more than 5 days duration. If only aneurysms of the coronary arteries are found without the other features of a classic KD, this may be termed as incomplete or atypical KD [17] . Several respiratory viruses have previously been associated with KD [18] . While various studies have identified a correlation between seasonal coronavirus and KD [19] , few studies have disputed a link between respiratory viruses and KD [20] . Winter and spring are common months for epidemics of KD [21] . Infections with human coronaviruses HCOV-229E and HCoV-0C43 are known to occur in spring and winter. It is known that an abnormal response to an infectious agent triggers a clonal expansion of CD8 + T cells in the host leading to the vasculitic features of KD thereby confirming the that certain hosts may be more predisposed than others [21] . (Fig. 13.1 ). COVID-19 associated KD has similar cardiovascular manifestations as those described in classic KD [22] . Coronary artery aneurysm (CAA) is one of the major complications of KD [23] . Kawasaki disease shock syndrome (KDSS) is a rare but critical presentation which may arise due to an associated myocarditis during the illness [24, 25] . KDSS is characterized by KD associated with a reduction in basal systolic blood pressure of at least 20%, or evident signs of decreased peripheral blood flow [24] . The initial phase of KD is characterized by mild myocarditis identified in cardiac biopsies [26] and it improves mostly as inflammation subsides [26] . KDSS has an incidence of 1.5 to 7% of KD patients with reduced percentage in Asia than in western countries [27] .The pathogenesis of KDSS involves a combination of myocardial dysfunction along with reduced peripheral vascular resistance. Treatment involves IV fluids with administration of inotropic and vasoactive agents. Shock seen in KD may result due to a raised level of pro-inflammatory cytokines such as CRP and IL-6 in circulation [28] . Long lasting diastolic dysfunction is the most recognized feature and left ventricular systolic dysfunction is encountered in only a third of the patients [29] .Multisystem inflammatory syndrome in children (MIS-C) is a newly described term for a syndrome linked to possible previous exposure to SARS-CoV-2. MIS-C has myocardial involvement just like atypical KD but cardiac failure in MIS-C is a result of myocardial edema rather than inflammatory myocardial changes. MIS-C also presents with cardiogenic shock in which left ventricular systolic dysfunction and low systolic blood pressure is identified in all patients [28] . MIS-C can also present with fever, skin rash, diarrhea, and lymphadenopathy, similar to KD. It is questionable whether MIS-C is a separate entity or SARS-CoV-2 induced KD. Coronary artery aneurysms may also lead to clot formation in some children with COVID-19 [30] . The pathogenesis of CAA is related to an endothelial dysfunction caused by an increased accumulation of endothelial inflammatory cells and ACE2 after SARS-CoV-2 infection [31] . Up to 25% children with KD may develop CAA. Intravenous immune globulin (IVIG) is an adjunctive therapy in KD. IVIG exerts an anti-inflammatory action on monocytes and macrophages. IVIG administration should be done within 7 days of KD onset until the patient recovers from symptoms and tests negative for COVID-19. Early diagnosis of SARS-CoV-2 associated KD or MIS-CIS is essential in preventing left ventricular dysfunction and acute heart failure in children. A rapid NT Pro B type Natriuretic Peptide (BNP) should be performed for urgent evaluation of children manifesting with symptoms of COVID-19 associated KD. Treating the cytokine storm by targeting the IL-6 receptor is another potential management approach [27] . Cytokine storm Endothelial dysfunction COVID- 19 Kawasaki Disease Intravenous Immunoglobulin (IVIG) + Anti-inflammatory agents (Aspirin, corticosteroids) Vasculitis ? Coronary Artery Aneurysms Pathogen "X" A. Gupta et al. Myocarditis, ranging from mild to life-threatening, has frequently been reported in association with COVID-19. ECG characteristics may simulate ST elevation myocardial infarction, and imaging may show reduced ventricular function, and classic T2 hyper-intensity and late gadolinium enhancement on cardiac MRI. The cause of this phenomenon is unclear. Although myocytes contain ACE2 receptors, it appears likely that myocarditis manifests from secondary immune effects, the so-called 'cytokine storm' and possibly hypoxia related to microvascular damage and thrombosis [32] . The presence of myocarditis and elevated troponin levels is associated with greatly increased COVID-19 mortality [33] . Myocardial infarction has been frequently reported in association with COVID-19. It is thought that direct vascular injury and pro-thrombotic state may increase the susceptibility towards myocardial infarction, particularly in those with substantial risk factors and pre-existing coronary disease [29] Likewise, type-2 myocardial infarction related to cytokine storm, increased cardiac output or afterload changes may occur in COVID-19. Pulmonary embolism or thrombosis and associated right heart strain is significantly associated with late mortality [34] Typical right ventricular strain on ECG, right ventricular dilatation on echocardiography and troponin elevation may occur after pulmonary embolism. Recent data has revealed ischemic changes like blisters, cyanosis, and asymmetric chilblain like lesions in fingers and toes of patients diagnosed with COVID-19 [35] . An inflammatory thrombogenic vasculopathy with disseminated intravascular coagulation [36] , targetoid lesions [36] , livedo like signs with necrotic areas have all been reported. [9] Chloroquine (CQ) and hydroxychloroquine (HCQ) are drugs that were initially trialled for the treatment of COVID-19. A rare but serious cutaneous adverse effect of both CQ and HCQ is toxic epidermal necrolysis (TEN) [37] . Cardiac complications including QT interval prolongation manifesting as ventricular fibrillations have been well described in various studies [38] [39] [40] . Proximal myopathy associated with respiratory failure are other complications of CQ or HCQ [39] [40] [41] [42] [43] . Both CQ and HCQ have also been shown to cause biventricular dilated or restrictive cardiomyopathy. [44] [45] [46] Heart diseases may be a vital determinant of susceptibility, severity, and mortality in COVID-19. Emerging studies from different countries have suggested an association between SARS-COV2 infection and KD. Establishing an exact pathomechanism in the causation of COVID-19 associated KD requires sero epidemiological and histopathological investigations. Understanding the immune mechanisms and genetic susceptibility of this disease will enable prevention of the severe and fatal manifestations of this condition. 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