Discussion
We evaluated the role of asthma, asthma phenotypes, and GINA class on
COVID-19 infection severity in a diverse population of patients spanning
from pre-hospitalization to eight months post-hospitalization. Asthma
does not independently increase the risk for hospitalization, severe
disease, or long-term symptoms in COVID-19. More importantly, allergic
asthma appears to protect against hospitalization.
Our study extensively evaluated 5,596 patients infected with SARS-CoV-2
virus. Obesity, cardiovascular disease, and diabetes have been
identified as risk factors for more severe COVID-19
infection.18,19 When controlling for these comorbid
conditions in our cohort, we discerned that asthmatic patients did not
have an increased risk for hospitalization. Using the NIH COVID-19
Guidelines, we rigorously characterized all patients hospitalized from
March to September 2020. We believe this more meticulous phenotyping of
clinical severity for patients in our cohort adds validity to our
findings as conflicting findings from other studies may in part be due
to the use of surrogate endpoints such as need for critical care or
intensive care unit admission which may be affected by external factors.
We determined that asthmatic patients hospitalized with COVID-19 were
older than those who were treated as outpatients; however, they did not
have an increased risk for more severe COVID-19 infection compared to
non-asthmatics with similar comorbid conditions.
The finding from our cohort that allergic asthmatics are half as likely
to be hospitalized with COVID-19 infection implies that certain asthma
phenotypes may have a protective effect. The ACE2 receptor is
upregulated in diabetes and hypertension, conditions known to increase
the risk for severe COVID-19 disease.20 However, RNA
experiments on nasal and bronchial epithelial cells from patients with
allergic sensitization and allergic asthma showed downregulation of ACE2
expression, which may explain the potential protective effect of
allergic asthma.13
Furthermore, one phenotype of allergic asthma is characterized by
elevated eosinophil counts. In our cohort, asthmatics did have higher
historical eosinophil counts than their non-asthmatic counterparts,
although we were unable to stratify further based on baseline allergic
phenotype. Eosinophils, which are widely recognized as important markers
for allergic inflammation, are also potent pro-inflammatory leukocytes
with antiviral properties through the release of RNAses and reactive
nitrogen species.21 Interestingly, eosinopenia has
been noted to be a marker of early severe COVID-19 disease, which may
result from eosinophil exhaustion, viral inhibition of eosinophil
production, or induction of eosinophil apoptosis.22 In
our study, patients with more severe COVID-19 disease had lower
eosinophil counts throughout hospitalization, independent of asthma
status. This is intriguing and lends further evidence to the potential
important role eosinophils may play in moderating COVID-19 disease
severity. Further studies are needed to elucidate the potentially
protective role of eosinophils in COVID-19 disease pathogenesis. This
may also have implications for patients on biologics, which selectively
inhibit the allergic inflammatory pathway leading to near complete
eosinophil depletion.
The importance of baseline asthma severity on the risk for SARS-CoV-2
infection and COVID-19 severity also warrants further investigation and
may reflect associations between asthma therapies and COVID-19
susceptibility and severity. Recent studies from South Korea and the UK
used various methods to assess asthma severity based on medication use
and showed a possible risk for worse COVID-19 outcomes but also a
potential protective effect from inhaled corticosteroids in some
subgroups of patients. 23-25 These results, while
seemingly conflicting, highlight the nuanced aspects of asthma
phenotypes. In our trial, we classified asthma severity according to the
Global Initiative for Asthma (GINA) guidelines and did not find an
association between severity as based on the GINA scale and COVID-19
clinical outcomes. As GINA classification implies increased steroid
therapy with more severe asthma, it is possible that asthma medications
mitigate any potential association between GINA category and COVID-19
severity. In vitro studies in airway epithelial cells have shown that
certain inhaled glucocorticoids can reduce the replication of
SARS-CoV-2.26 Inhaled corticosteroids were also shown
to downregulate expression of (ACE2) and transmembrane protease serine 2
(TMPRSS2) genes in sputum cells; these genes are critical for coding
receptors involved in SARS-CoV-2 viral entry.27,28
To our knowledge, we are also the first group to compare the long-term
symptoms after COVID-19 infection between asthmatics and non-asthmatics.
Between 10 and 80% of patients are estimated to experience prolonged
symptoms from COVID-19 up to two months after
diagnosis.29,30 The majority of patients in our study
were followed for an average of 141 days, and most still reported
symptoms at 60 and 90 days. There was no difference in time to
resolution of any symptoms or importantly, in time to resolution of
lower respiratory symptoms, between groups. These results suggest that
patients with asthma are not at greater risk for long-term symptoms of
COVID-19 as compared with their non-asthmatic counterparts.
Our study has a few limitations. The data are generated from a single
academic institution from ICD-10 codes extracted from the medical
record; however, we applied independent and consistent chart review,
performing QA/QC on the data. Our approach and rigorous methodology
enabled us the opportunity to confirm others’ findings from larger
cohorts. Moreover, we analyzed well-characterized, detailed meta-data on
each patient from multiple timepoints to highlight the disease course
from pre-hospitalization to eight months following symptom onset to
assess clinical outcomes at many timepoints.
In conclusion, asthmatic patients do not have increased risk of
hospitalization, more severe COVID-19 disease, or long-term respiratory
symptoms. In fact, allergic asthmatics were protected from
hospitalization with COVID-19. Moreover, patients with more severe
COVID-19 disease had lower eosinophil levels during hospitalization than
those with less severe disease, independent of asthma status.
Additional, multi-center studies are needed to evaluate the mechanisms
by which eosinophils and atopic pathways may mitigate COVID-19 disease
severity.