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.