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.