Discussion
Based on the available literature, there was no clear evidence that
patients with asthma were at a higher risk of being infected or becoming
severely ill with SARS-CoV-2, although recent reports from the USA and
the UK suggest that asthma is much more common in children and adults
with COVID-19 than it was previously reported in Asia and in the first
surveys in continental Europe.
Nevertheless, the prevalence of several underlying conditions identified
in USA hospitalized patients with COVID-19 were similar to those for
hospitalized influenza patients during influenza seasons 2014–15
through 2018–19, namely regarding chronic respiratory diseases (29% to
31%).41
Of particular note in the UK results of the association of asthma with
higher risk of COVID-19 hospital death, with the HR increasing further
for those that received oral corticosteroid (OCS), probably indicating
greater severity of disease. This contrasts with previous findings, in
several countries, where asthma and other chronic respiratory diseases
were underrepresented in hospitalized patients.36 Also
in the UK it was reported asthma in 14,0% and 17,9% of hospitalized
patients but with no increased risk of death.35,37
Among school-age children, viral infection reportedly accounts for up to
85% of asthma exacerbations, and viruses are more frequently isolated
from symptomatic patients than from asymptomatic
patients.42,43 Even though respiratory viruses are one
of the most common triggers for asthma exacerbations in all age groups,
not all of these viruses affect patients equally. In particular, the
human rhinovirus was identified as the main individual contributor for
asthma exacerbations, being coronavirus one of the less identified
trigger of asthma exacerbations in children as in
adults.44 A recent literature review concerning virus
detection during asthma exacerbations, confirmed that exacerbations were
mainly associated with rhinovirus infection in all
continents.45
In previous SARS outbreaks, patients with asthma, in particular
children, appeared to be less susceptible to the coronavirus, with
reported low rate of asthma exacerbations and good prognosis on
follow-up.10,46 In contrast, during influenza
epidemics, asthma was associated with more severe disease, including the
need of mechanical ventilation, not only in adults but also in
children.47 The exact reasons for this remain unknown,
but it was confirmed during the current coronavirus
pandemic.48
From the recent COVID-19 literature, no definite conclusions can be
drawn regarding asthma control or severity. Similarly, no information
can be extrapolated about asthma phenotypes, namely regarding whether
asthma was allergic or not.
COVID-19 outcomes vary from asymptomatic infection to death and it is
possible that this clinical range may reflect different airway levels of
the SARS-CoV-2 receptor, ACE2, and the spike protein activator
transmembrane protease serine 2 (TMPRSS2), considering that the virus
cell entry also depends on S-protein priming by host cell proteases.
Blood eosinophil levels are a well-known predictor of airway T2
inflammation,49 and the measurement of blood
eosinophil levels can be used as an accessible (not strong), proxy for
investigating the association between airway T2 inflammation and
COVID-19 outcomes.
In early reports from China, a detailed clinical investigation of
hospitalized COVID‐19 cases suggested severe eosinopenia together with
lymphopenia as a potential indicator for diagnosis and to a worse
prognosis, including death.15 It was believed that low
eosinophil counts in peripheral blood would be related with the
SARS-CoV-2 infection itself. However, more recent studies from China and
from Italy did not report eosinopenia in patients with severe
COVID-19.26,31,50
Although the relationship between eosinophil counts and COVID-19 is
uncertain, attention is warranted to monitor eosinophil counts among
patients with asthma who are using biological therapies that lead to
decreased eosinophil counts, and the clinical course of COVID-19 if they
get infected with the SARS-CoV-2.51
Sajuthi et al52 studied in children the role for both
T2 inflammation and viral infection in regulating the gene expression of
ACE2 and TMPRSS2 and found a strong influence of T2 cytokine-driven
inflammation on both ACE2 (downregulation) and TMPRSS2 (upregulation)
expression levels, which can have clinical implications on COVID-19
outcomes. In contrast, the authors found an equally strong positive
influence of respiratory virus infections on ACE2
expression.52 So, at least theoretically, in patients
with asthma and high T2 inflammation, the consequence of an interferon
dependent inflammation requires a close monitoring given the enhanced
risk of complications due to SARS-CoV-2 infection.
A recent study that included asthma patients from three different
cohorts of children and adults, found that ACE2 receptors expression was
lower in those patients with high allergic sensitization, but non-atopic
asthma was not associated with this reduced
expression.53 These data suggest that this reduced
ACE2 expression may be a potential contributor, among several other
factors, of reduced COVID-19 severity in patients with respiratory
allergies, namely allergic asthma.53
Additionally, there is some early evidence coming from the Severe Asthma
Research Program-3 (SARP), that inhaled corticosteroid therapy is also
associated with reduction on ACE2 and TMPRSS2 gene expression from
sputum.54 These data stress the importance of maintain
asthma controlled using the treatment according to the best practices,
including with inhaled steroids.
There is also evidence to support that taking ICS may be beneficial in
dealing with coronavirus infections. In vitro studies showed
inhibitory actions of budesonide on coronavirus HCoV-229E replication
and cytokine production55 and, preliminary not yet
peer-reviewed data, suggest that ciclesonide blocks SARS-CoV-2
ribonucleic acid replication56 and inhibits its
cytopathic activity57 which may have clinical
implications.
Although gene expression for ACE2 and TMPRSS2 did not differ in healthy
and asthmatic patients, it was also found that males, African Americans
and patients with diabetes have increased expression of ACE2 and TMPRSS2
in their sputum cells, which may be associated with the poor prognosis
of these patients when infected with the SARS-CoV-2.54
Dong et al.58 very elegantly described selected cases
of patients with COVID-19, children and adults, demonstrating the
profile complexity and different clinical presentations from mild to
severe cases. Patients with common allergic diseases, such as rhinitis
or atopic dermatitis, did not develop distinct symptoms or had severe
courses, which may suggest a positive balance of type 2 immune
regulation in COVID-19 pathogenesis.
New data are emerging daily, rapidly updating our understanding of this
novel coronavirus, but it’s crucial that patients with asthma and other
allergic diseases such as allergic rhinitis, maintain their controller
medication, from inhaled corticosteroids to
biologics,51,59,60 including allergen
immunotherapy,61 without self-making any dose
adjustments or stopping medication that may lead to higher risk of
asthma exacerbations, increased OCS use and higher probability to
emergency room access and hospitalization that represent themselves risk
factors for coronavirus exposure and spread. Likewise, it is important
to maintain well-controlled rhinitis and rhinosinusitis, together with
other known risk factors for asthma exacerbations.62
The available data about OCS use in asthma exacerbations, although
limited to 3 reported cases in mild asthmatics,26 are
in accordance with data from previous coronavirus outbreaks, showing
that systemic corticosteroids can be associated with a higher viral
load.63,64 The UK data suggesting an increased death
risk in patients with asthma specially in those that recently received
systemic steroids,36 stress that clinicians must be
cautious and recognize the differences between hypoxic respiratory
failure and bronchospasm to carefully balance the need for OCS
prescription,51 and bronchodilators must be delivered
by metered dose inhalers with spacers in order to prevent the viral
spread related with nebulizers use.65
As it was shown by Kaye et al,66 there is evidence on
increased adherence to asthma (and COPD) pharmacologic treatment during
the first months of the COVID-19 which is encouraging, and hopefully
will have a positive effect on improving control of asthma and minimize
the need for acute care for this inflammatory chronic respiratory
disease.
In conclusion, it is unclear whether patients with asthma are at higher
of developing COVID-19 and/or become severely ill. Future studies in all
age groups are needed to provide greater understanding of the impact of
underlying asthma, other allergic diseases and T2 inflammation on
COVID-19 susceptibility and disease outcomes. The best we will
understand these interactions, the best we will protect the most
vulnerable people included in high risk groups.
Table: Asthma prevalence in COVID-19 studies