Pathophysiology and immunopathology

480 | CovidReference.com

mission to ICU seems not to be more likely in younger children. The likelihood of being hospitalised was higher when children had an underlying condition, and a severe course was rare (https://covid19-surveillancereport.ecdc.europa.eu). In a cross-sectional study including 48 children with COVID-19 (median age 13 years; admitted to 46 North American pediatric ICUs between March 14 and April 3, 2020), forty patients (83%) had significant pre-existing co-morbidities and 18 (38%) required invasive ventilation. Targeted therapies were used in 28 patients (61%, mainly HCQ). Two patients (4%) died and 15 (31%) were still hospitalized, with 3 still requiring ventilatory support and 1 receiving ECMO (Shekerdemian 2020). In an observational retrospective cohort study that included 177 children and young adults with clinical symptoms and laboratory confirmed SARS-CoV-2 infection treated between March 15 and April 30, 2020 at the Children’s National Hospital in Washington, 44 were hospitalized and 9 were critically ill. Of these, 6/9 were adolescents and young adults > 15 years of age. Although asthma was the most prevalent underlying condition overall, it was not more common among patients with severe disease (DeBiasi 2020). Although the natural course of COVID-19 is uneventful in most pediatric patients, a very small percentage can develop a potentially fatal severe hyperinflammatory state 2-4 weeks after acute infection with SARS-CoV-2 (Riphagen 2020). This hyperinflammatory state is termed as pediatric inflammatory multisystem syndrome temporarily associated with SARS-CoV-2 (PIMS-TS) (or synonym Multisystem Inflammatory Syndrome in Children (MIS-C). Of the 570 MIS-C cases reported to the CDC by July 2020, 10 patients had died (1.8% ) and 364 (63.9%) patients required treatment in an intensive care unit. Obesity was the most commonly reported underlying medical condition (GodfredCato 2020).

It is unclear why COVID-19 in children is associated with a less severe disease course. The tissue expression pattern of the receptor for CoV-2 angiotensin converting enzyme (ACE2) and the transmembrane serine protease TMPRSS2 (essential for CoV-2 cell entry) as well as the tissue tropism of CoV-2 in childhood are unknown but age-dependent differences in ACE2 receptor expression may explain why outcomes differ in children versus adults (Bunyavanich 2020). ACE2 is expressed on cells of the airways, the lungs, mucosal cells (lids, eyelids, nasal cavities), intestines and on immune cells (monocytes, lymphocytes,

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neutrophils) (Molloy 2020, reviewed in Brodin 2020). It needs to be clarified whether there is neurotropism (e.g. affecting the developing brain of newborns). The main target of CoV-2 is the respiratory tract. As respiratory infections are extremely common in children it is to be expected that there are other viruses present in the respiratory tract of young children concomitantly with the coronavirus, which may limit its growth and the number of CoV-2 copies in the respiratory tract of children. Systematic viral load measurements in the respiratory tract of different viruses in children are underway. Key to the later immunopathologic stages of COVID-19 pneumonia is the macrophage activation syndrome (MAS)-like hyperinflammatory phase with a cytokine storm and acute respiratory distress syndrome (ARDS), usually within 10-12 days after symptom onset. In general, children are not less prone to develop ARDS during respiratory tract infections than adults. In the H1N1 flu pandemic in 2009, being under the age of 1 year was a significant risk factor for developing a severe form of the infection and ARDS (Bautista 2010). Why ARDS is less common in children compared to adults with COVID-19 is unclear. SARS-CoV-2 infection of cardiac tissue can be a major contributor to fatal myocarditis (Dolhnikoff 2020, Prieto 2020). An explanation for the milder disease course in children could be age-related differences in innate or adaptive immune responses to CoV-2 between adults and children. In the innate immune response to any virus, Type I (IFN α, IFN β) and type III (IFN Ω) interferons are the most important cytokines. In 659 patients (1 month to 99 years old) with life-threatening COVID-19 pneumonia, inborn defects in the type 1 IFN signaling were found in 23 unrelated patients (Zhang 2020). Moreover, neutralizing auto-antibodies to type I/III IFN were found in 101/987 patients with life-threatening COVID-10 pneumonia (Bastard 2020). These findings show that inborn defects in the IFN I/II pathway or auto-antibodies to IFN I/III may predispose to life-threatening COVID19. Based on influenza animal models it has been proposed that BCG vaccination (for tuberculosis prevention, done in the first week of life in some countries) may enhance non-specific innate immunity in children to infections like COVID-19 (so-called trained immunity) (Moorlag 2019). A search of the BCG World Atlas and correlation with data of COVID-19 cases and death per country found that countries without universal policies of BCG vaccination (Italy, the Netherlands, USA) have been more severely affected compared to countries with universal and long-standing BCG policies and that BCG vaccination also reduced the number of reported COVID-19 cases in a country (Miyasaka 2020, Hauer 2020). Recent data from a large population-based study did not show decreased infection rates in Israeli adults aged 35 to 41