Reply to Lipworth et al.: Inhaled Corticosteroids and COVID-19.

From the Editorialists:

We totally agree with the letter by Lipworth and colleagues in response to our editorial emphasizing that patients with asthma need to continue using their inhaled corticosteroid (ICS)-containing controller therapy during the coronavirus disease (COVID-19) pandemic, as this provides optimal asthma control and also confers some protection against viral triggers, perhaps including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (1). They also highlight several interesting papers, published after the publication of our editorial, which address two key research questions: 1) are subjects with asthma at increased risk of COVID-19 infection and related illness? and 2) does ICS use modulate this risk? Because asthma is a very heterogeneous disease, we hypothesize that asthma phenotypes and the type of underlying airway and systemic inflammation need to be taken into account to answer these questions correctly (see Table 1).

Table 1.

Heterogeneity of Asthma and Potential Risk of Severe COVID-19

Characteristic of Subject with Asthma	No Increased Risk of COVID-19 (or Decreased Risk)	Increased Risk of COVID-19
Age	Children and adolescents	Older subjects
Asthma phenotype	Type 2–high asthma	Type 2–low asthma
Airway gene expression	Type 2 cytokines (e.g., IL-13)	IFN-stimulated genes
Systemic inflammation	Low IL-6	High IL-6
Comorbidities	Allergic sensitization	Obesity, diabetes, or hypertension
Asthma severity	Mild-to-moderate asthma: GINA steps 1–4	Severe asthma: GINA step 5
Lung function	Normal	Impaired
Asthma control	Well controlled	Uncontrolled
Exacerbation frequency	No exacerbations	Frequent exacerbations
Controller treatment	ICS	OCS: repetitive bursts or OCS maintenance treatment

Definition of abbreviations: COVID-19 = coronavirus disease; GINA = Global Initiative for Asthma; ICS = inhaled corticosteroids; OCS = oral corticosteroids.

In children with asthma, allergic sensitization and other type 2 biomarkers (such as fractional exhaled nitric oxide and epithelial expression of IL-13, which increases the expression of inducible nitric oxide synthase) were inversely related to ACE2 (angiotensin-converting enzyme 2), the cellular receptor for SARS-CoV-2 (2). Moreover, in ICS-naive adults with mild allergic asthma, segmental allergen bronchoprovocation significantly reduced ACE2 expression in the bronchial epithelium. In contrast, nonatopic asthma was not associated with reduced ACE2 expression, which is in line with the findings by Peters and colleagues (3), demonstrating no difference in ACE2 gene expression in induced sputum of subjects of the SARP-3 (Severe Asthma Research Program-3) as compared with healthy control subjects, as atopy is less prevalent in adults with severe asthma. In addition, in samples from bronchial brushes and biopsies, there were similar levels of ACE2 mRNA expression in healthy volunteers and adult subjects with mild-to-moderate asthma or severe asthma (4). Again, an inverse correlation between ACE2 and T-helper cell type 2 cytokine–dependent gene expression was observed. Indeed, IL-13 treatment of primary airway epithelial cells significantly reduced ACE2 expression but increased expression of TMPRSS2 (transmembrane protease serine 2) (5). Importantly, ACE2 has been identified as an IFN-stimulated gene in human airway epithelial cells and lung type II pneumocytes (6). Because IFNs are key mediators of our host defense against viral infections and because ACE2 is supposed to provide tissue-specific protection during lung injury, this implies that SARS-CoV-2 could exploit IFN-driven upregulation of ACE2 to propagate infection, leading to severe acute respiratory distress syndrome, respiratory failure, and mortality. Intriguingly, increased expression of IFN-stimulated genes has also been demonstrated in samples from airway brushings and in blood cells of patients with mild or severe type 2–low asthma, respectively (7). Lastly, elevated levels of systemic IL-6, most commonly seen in those with concurrent obesity and asthma, are not only associated with more severe asthma (8) but also predict the need for mechanical ventilation in severe cases of COVID-19 (9).

In conclusion, the risk of severe COVID-19 in subjects with asthma is influenced by multiple factors, including demographics (age and sex), ethnicity, genetics, treatment (e.g., ICS treatment), asthma severity, lung function, level of asthma control, exacerbation frequency, asthma phenotype (type 2–high vs. type 2–low asthma) and comorbidities (see Table 1). Large-scale epidemiologic studies, clinical trials, and mechanistic studies are needed to disentangle the relative importance of these and other risk or protective factors in modulating the susceptibility of those with asthma to SARS-CoV-2 infection and severe COVID-19.