DISCUSSION
In a systematic review of the literature, we only found one report described asthma/recurrent wheezing as a potential risk factor for COVID-19 in children. Importantly, none of the largest epidemiological studies including children with COVID-19 reported clinical findings or underlying characteristics to help assess whether asthma –or other chronic lung diseases– constitutes a risk factor for SARS-CoV-2 infection or COVID-19 severity.
COVID-19 affects primarily the lungs, and accordingly several international guidelines have designated some respiratory conditions as a potential risk factor for severe disease. Chinese guidelines(54) state that “children with a history of contact with severe 2019-nCoV infected cases, or with underlying conditions (such as congenital heart disease, bronchial pulmonary hypoplasia, respiratory tract anomaly, with abnormal hemoglobin level, severe malnutrition), or with immune deficiency or immunocompromised status… may become severe cases”. A recent statement from the EAACI Section on Pediatrics(26) declared that “patients with asthma (particularly severe or uncontrolled asthma) and immunodeficiency have also been classified to be at increased risk of developing severe COVID-19, based more on common sense rather than mounting evidence”. The Global Initiative for Asthma (GINA) recommends avoiding the use of nebulizers due to the increased risk of disseminating COVID-19 to other patients and healthcare staff; they thus recommend the use of pressurized metered dose inhalers (pMDI) as the preferred delivery system during asthma attacks(55). A recent randomized controlled trial (RCT)(56) showed that even in children with severe asthma exacerbations, administration of albuterol/salbutamol and ipratropium by MDI with valved-holding chamber and mask along with oxygen by nasal cannula was more effective than nebulized administration. GINA(55) and the British Thoracic Society(57) do not recommend stopping oral steroids in the patients already taking them for asthma management, and they do not recommend avoiding them for acute asthma attacks even if due to COVID-19. The U.S. CDC, the Canadian Pediatric Society, and other professional associations have issued guidance for patients with asthma and/or allergies(58-60). Other professional organizations, such as the American Academy of Pediatrics and the American Thoracic Society, have published interim guidelines that do not specifically address asthma, likely given a paucity of evidence(61, 62).
Rather than a risk factor, a recent review of data in adults reported that both asthma and COPD appear to be under-represented in the comorbidities reported for patients with COVID-19, compared with global estimates of prevalence for these conditions in the general population(63). This is consistent with individual studies that have shown lower-than-expected prevalence of asthma among cases of COVID-19(21-24, 27), and in contrast to the prevalence of other chronic diseases such as diabetes, which occurred with higher frequency among patients with COVID-19 than the estimated national prevalence(63). If asthma is indeed “protective”, this could be due to several factors, including changes in the immune response or decreased risk secondary to chronic medications such as inhaled corticosteroids (ICS). In-vitro models have shown that ICS may suppress both coronavirus replication and cytokine production(64, 65). Analysis of induced sputum samples in a well-characterized cohort of adults with severe asthma found reduced ACE2 (angiotensin-converting enzyme 2) and TMPRSS2(transmembrane protease serine 2) gene expression among patients taking ICS, and especially among those on higher doses(66)ACE2 and TMPRSS2 mediate SARS-CoV-2 cell infection. Similarly, a recent study (in children and adults) showed that patients with asthma and respiratory allergies had reduced ACE2 gene expression in airway cells, suggesting a potential mechanism of reduced COVID-19 risk(67). This is particularly noteworthy considering that one of the potential explanations for children being generally less affected than adults is the hypothesis that children have lower ACE2 receptor expression in alveolar type 2 cells(68). However, the lower prevalence of asthma among COVID-19 cases could also stem from bias due to underdiagnosis and under-reporting, or because patients with chronic lung diseases may be especially cautious in practicing physical distancing and other measures to avoid infection. Finally, it is also conceivable that some milder cases of COVID-19 might be confused with exacerbations of respiratory disease, and/or that these patients may be reluctant to seek medical care even when sick and are thus never counted.
It is important to note that our understanding of the role of asthma –even in adults– is still incipient. In the largest and most recent analysis to date, UK investigators analyzed data from 17 million adults, including 5,683 deaths due to COVID-19, and reported that both asthma (adjusted hazard ratio, aHR: 1.11 [95% confidence interval: 1.02-1.20]) and severe asthma (aHR: 1.25 [1.08-1.44]) were risk factors for COVID-19 mortality(51). This study compared COVID-19 deaths to the general population (regardless of being SARS-CoV-2 positive or not), so the estimates combine both risk of infection and risk of death once infected. These results highlight how incomplete our understanding still is. As with most other studies, this large analysis did not include a pediatric population.