key: cord-1031564-2cyx9xww authors: Müller, Jan; Oberhoffer, Renate; Brudy, Leon; Ewert, and Peter title: COVID-19 and paediatric patient involvement (cardiovascular aspects) date: 2020-12-23 journal: Eur Heart J Suppl DOI: 10.1093/eurheartj/suaa168 sha: 1bda28f98e8c6681a243c00327a1bc93aadc2e5c doc_id: 1031564 cord_uid: 2cyx9xww The majority of children with COVID-19 infections, fortunately, shows only milder symptoms. Which however has led that they are considered only for their particular transmission potential. Nevertheless, cases with Multisystem Inflammatory Syndrome in Children and Kawasaki Disease with quite specific COVID-19 involvement have been reported and should be taken seriously. In addition, there are many children with a chronic pre-existing condition such as congenital heart disease, cancer, or lung disease who may be at risk for a severe course of COVID-19 when infected. Protecting these children, and children in general, should be a top priority, as these patients will have to live the rest of their long lives with possible sequelae of COVID-19. While in the current coronavirus disease 2019 (COVID- 19) pandemic the focus is on the geriatric population because of the high mortality rate, the paediatric target group receives less attention regarding their long-term health consequences. Since children are less susceptible to the severe development of COVID-19, they are usually considered only for their particular transmission potential. It may be correct that the vast majority of paediatric patients are showing just mild symptoms such as mild fever, cough, rhinorrhoea, sore throat, or occasional gastrointestinal symptoms, vomit, and diarrhoea. 1 However, the clinical picture of COVID-19 is nevertheless manifold and therefore it is imperative to not lose sight of the small minority becoming severely ill specifically those with cardiac involvement in their medical history. This is made clear by the fact that several authors around the world have reported paediatric inflammatory multisystem syndrome (PIMS) or Kawasaki syndrome like disease in connection to COVID-19 infections. In addition, acute inflammatory response similarly as seen during a cytokine storm causing cardiomyocyte injury, 2 cellular damage because of cardiomyocyte viral invasion, 3 and acute lung injury causing ischaemic injury along with severe hypoxia 4 is reported. Last but not least, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses the enzyme ACE2 as a receptor for entry into the cell. 5, 6 Whether this binding of the virus has an impact on ACE2 expression or leads to a dysregulation in pathways is still unclear but in the worst case, long-term cardiovascular damage could be the result of even a only mild COVID-19 infection. 7 The majority of children with COVID-19 infections show milder symptoms. While few in numbers, previous reports highlight two disease conditions in particular connected to severe disease development: multisystem inflammatory syndrome in children (MIS-C), and Kawasaki disease (KD). MIS-C, sometimes also referred to as PIMS is characterized by fever and laboratory inflammation conditions (such as elevated C-reactive protein, erythrocyte sedimentation rate, fibrinogen, procalcitonin, d-dimer, ferritin, lactic acid dehydrogenase, or interleukin 6, elevated neutrophils, reduced lymphocytes and low albumin) with multisystem (>2) organ involvement (including heart, lungs, kidneys, brain, skin, eyes, or gastrointestinal organs). Specific causes are still unclear. KD is an acute febrile illness that primarily affects children younger than 5 years of age, and the leading cause of acquired heart disease in high-income countries 8 with the diagnostic criteria as shown in Textbox 1. 9 Symptoms such as eye redness, swelling of lymph glands in the neck, and mouth, lips or throat irritation and inflammation, lips, and throat are often similar to MIS-C. Coronary artery dilations and aneurysms can result of serious complications. KD is also sometimes seen in patients with fever and coronary artery abnormalities but who do not meet the mentioned KD symptoms and is therefore characterized as atypical or incomplete. Since the beginning of SARS-CoV-2 epidemic, it was reported of previously healthy children with fever, multisystem inflammation and non-specific symptoms like rash, gastrointestinal symptoms, and lip swelling. Symptoms ranged to myocardial shock, development of coronary artery aneurysms and some showing characteristics that were similar to KD. 10 An observational study in the province Bergamo, which was extensively affected by SARS-CoV-2 epidemic, reports of a high number of KD-like diseases. Since the beginning of the epidemic a monthly incidence at least 30 times greater than in the previous 5 years has occurred, with a clear starting point of the increase after first COVID-19 cases. Children affected with KD-like disease after SARS-CoV-2 epidemic were older, had higher rate of cardiac involvement and higher incidence of severer form of KD disease than children affected previously by SARS-CoV-19. 11 Heavily affected regions by SARS-CoV-2 in Europe are also reporting of cases with MIS-C. 10, 12, 13 A case series of 58 children diagnosed with MIS-C in British hospitals reported of persistent fever and inflammation. 29 children developed shock and eight children developed coronary artery dilatation or aneurysm. 10 Cardiac involvement has been reported in a proportion of MIS-C patients. 14 MIS-C showed overlapping clinical features as well as substantial differences with KD disease. MIS-C has some of the clinical features of KD like fever, rash, redness of the oropharynx. 15 MIS-C was shown to affect an older age group and shows higher prevalence of gastrointestinal symptoms than KD. 16 MIS-C appears to be a rare complication of SARS-CoV-2 infections with some estimations that MIS-C occurs in two out of 200 000 individuals under the age of 21 years. 17 Until now it has yet to be determined that SARS-CoV-2 is the cause of MIS-C or KD. 15 As KD and MIS-C have shown us new and quite specific COVID-19 involvement, reported experience is described in more detail in Table 1 . With a prevalence of one in 100 live births congenital heart defects (CHDs) are the most common congenital abnormality. 18 However, reports of children with CHD infected with COVID-19 are sparse, and therefore the specific impact on this specific patient population has yet to be fully determined. 7 As the risk for severe COVID-19 infections is reduced in younger populations and incidents of cardiovascular complication rates have been low, we can be hopeful that children and adolescents with CHD are not facing an increased risk. 19 However, although infections are less common and milder in children, a cardiac medical history seems to be not without risk, as severe cardiac development of COVID-19 can include myocarditis, arrhythmia, and myocardial infarction. 4 In addition, experiences with previous viral diseases such as influenza and respiratory syncytial virus have shown a more rigorous impact on children with complex CHD than on otherwise healthy children. 4 Severe COVID-19 clinical course in children has been linked to a complex previous medical history. Paediatric patients with underlying conditions, including those with a history of CHD surgery 20,21 chronic lung disease, cirrhosis, renal disease, 4 or who showed a developmental delay, a genetic anomaly, or who were dependent on technological support for survival (tracheostomy) have been reported with more severe COVID-19 course. 14 Paediatric oncological patients might also deserve particular protection as Textbox 1 Criteria for the diagnosis of Kawasaki disease according to ref. 9 Fever for more than 5 days (4 days if treatment with intravenous immunoglobulin eradicates fever) plus at least four of the following clinical signs not explained by another disease process: • Bilateral conjunctival injection (80-90%)*. • Changes in the oropharyngeal mucous membranes, including one or more of injected and/or fissured lips, strawberry tongue, injected pharynx (80-90%). • Changes in the peripheral extremities, including erythema and/or oedema of the hands and feet (acute phase) or periungual desquamation (convalescent phase) (80%). • Polymorphous rash, primarily truncal; non-vesicular (>90%). • Cervical lymphadenopathy with at least one node >1.5cm (50%). P20 J. Müller et al. • " NT-proBNP (n • Coronary-artery aneurysm (n ¼ 9) • " C-reactive protein (n ¼ 95) • " proBNP levels (n ¼ 74) • Admitted to an intensive care unit (n ¼ 76) • Vasopressor support (n ¼ 59) • Myocarditis (n ¼ 50) • KD or incomplete KD (n ¼ 36) • One or more of the following: hypotension or shock, severe cardiac illness, or other severe endorgan illness (n ¼ 29) COVID-19 and cardiac involvement P21 • Gastrointestinal symptoms (n ¼ 14) • Rash (n ¼ 12) • Conjunctivitis (n ¼ 11) • Lip redness/swelling (n ¼ 9) • Hypoxic (3) • Abnormal chest radiograph findings (14) • Mildly decreased left ventricular function (n ¼ 11) • Moderate or more ventricular dysfunction (n ¼ 6) • Coronary arteries prominent or echogenic (n ¼ 7) • Medium-sized aneurysm (z score, 5.2) of the left anterior descending coronary artery (n ¼ 1) • " levels of inflammatory markers (n ¼ 17) • Non-specific ST/T-wave abnormalities (n ¼ 10) 100% SARS-CoV-2 positive 50% complete KD, 50% incomplete KD: • Non-exudative conjunctivitis (n ¼ 7) • Hand and feet anomalies (n ¼ 5) • Polymorphic rash (n ¼ 6) • Associated changes of the lips or oral cavity, or both (n • Left coronary aneurysm (>4 mm), reduced ejection fraction and mitral valve regurgitation (n ¼ 2) • Mitral valve regurgita- • " proBNP (n ¼ 10) • Intravenous immunoglobulin-resistance (n ¼ 7) • Macrophage activation syndrome (n ¼ 5) • " troponin I (n ¼ 5) • " creatine phosphokinase (n ¼ 1) • KD shock (n COVID-19 and cardiac involvement P23 they also possibly develop cardiac complications through treatment. 22 Aside from these, early reports experienced further predisposing factors for increased disease severity such as bronchopulmonary hypoplasia, respiratory tract abnormalities, haemoglobinopathies, severe malnutrition, and immune system deficiency. 23 Most infections in children with COVID-19 appear to be mild. However, children with chronic diseases and complex medical histories require specific attention. Their clinical course during COVID-19 infection can be severe and we do not have any idea about the long-term (cardiovascular) consequences yet. Children always deserve special protection because they are our future and will have to live the longest with possible medical consequences. This paper was published as part of a supplement supported by an educational grant from Abbott. Conflict of interest: none declared. Association between vaccine exemption policy change in california and adverse event reporting Novel Coronavirus Outbreak Research Team. Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore Pathological findings of COVID-19 associated with acute respiratory distress syndrome Coronavirus disease 2019 (COVID-19) pandemic implications in pediatric and adult congenital heart disease Receptor recognition by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus ACE2 receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia The cardiovascular burden of coronavirus disease 2019 (COVID-19) with a focus on congenital heart disease On behalf of the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; Council on Cardiovascular Surgery and Anesthesia; and Council on Epidemiology and Prevention. Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for Health Professionals From the American Heart Association Textbook of Pediatric Rheumatology Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study Multisystem inflammatory syndrome in children in association with COVID-19 Multisystem inflammatory syndrome related to COVID-19 in previously healthy children and adolescents American College of Rheumatology Clinical Guidance for Pediatric Patients with Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with SARS-CoV-2 and Hyperinflammation in COVID-19. Version 1 Understanding SARS-CoV-2-related multisystem inflammatory syndrome in children SARS-CoV-2-related inflammatory multisystem syndrome in children: different or shared etiology and pathophysiology as Kawasaki disease? Multisystem inflammatory syndrome in children in New York state Garne E; a European Surveillance of Congenital Anomalies (EUROCAT) Working Group. Congenital heart defects in Europe: prevalence and perinatal mortality COVID-19 and congenital heart disease: results from a nationwide survey Coronavirus disease (COVID-19) and neonate: what neonatologist need to know Clinical and CT features in pediatric patients with COVID-19 infection: different points from adults Early advice on managing children with cancer during the COVID-19 pandemic and a call for sharing experiences Children's heart and COVID-19: up-to-date evidence in the form of a systematic review