Recent basic research revealed that 2 host molecules play critical roles in the initiation of COVID-19, which is caused by severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2). SARS-CoV-2 uses the SARS-CoV receptor angiotensin-converting enzyme 2 (ACE2) for cell entry, and uses a serine protease transmembrane serine protease 2 (TMPRSS2) for S protein priming of the virus.5 Interestingly, in vitro treatment of airway epithelial cells with IFNs enhanced their ACE2 expression.6
In sharp contrast, in this issue of the Journal, Kimura et al7 reported that IL-13 exposure reduced ACE2 and increased transmembrane serine protease 2 expression in airway epithelial cells from patients with asthma and atopy. In addition, tissues from type 2 cytokine-high patients with allergy showed significantly lower expression of ACE2, and the ACE2 expression levels correlated inversely with the T2 cytokine levels and T2 signature molecule expression.7 Therefore, expression of ACE2 is likely to be regulated reciprocally by IFNs and T2 cytokines; IFNs upregulate, whereas T2 cytokines downregulate. Indeed, ACE2 expression in asthmatic bronchial epithelium was reported to be significantly lower than in healthy subjects.8 Moreover, patients with COVID-19 with serious disease showed significantly higher IFN-related molecular expression (IFN-γ–induced protein 10).9 These findings suggest a hypothesis that patients with asthma are protected from COVID-19 because of the low expression of ACE2 in their epithelial cells. Children with asthma showed a low prevalence of SARS due to SARS-CoV, which uses ACE2 as an entry receptor.10 Conversely, conventional coronaviruses exacerbate asthma upon infection.1 Reported entry receptors for most conventional coronaviruses do not include ACE2. The reported receptors are HLA class I molecule or sialic acids, and caveolin-1 for HCoV-OC43; aminopeptidase N (CD13) for HCoV-229E; dipeptidyl peptidase 4 (also known as CD26) for HCoV-EMC; unknown for HCoV-HKU1; and only HCoV-NL63 uses ACE2. These earlier observations thus support the above hypothesis.
However, there are several limitations to acknowledge in this hypothesis. All the epidemiological data were obtained retrospectively or cross-sectionally, and no tests were performed for IFN production or ACE2 expression in patients with COVID-19, especially those comorbid with asthma. In addition, no detailed information was reported regarding the phenotype/endotype (theoretically only T2-high, but not T2-low, patients with asthma have low ACE2 expression), lung function, control status, or treatment regimen of the patients with asthma. We also do not know whether or not a diminished ACE2 expression level in patients with asthma actually reduces SARS-CoV-2 infections. Of note, a couple of recent studies using clinical specimens reported that ACE2 mRNA expression did not differ significantly between patients with asthma and control subjects. These findings differ from those of the aforementioned studies.
Finally, we would like to emphasize that this Editorial should not lead physicians to underestimate COVID-19 in their patients with asthma. There are no current data that support or recommend step-down of current treatments of patients. In particular, a recently approved biologic, dupilumab—an antibody to IL-4 receptor α chain that blocks both IL-4 and 13—should not be reduced or discontinued only for the purpose of ACE2 downregulation. Further careful investigations are definitely needed to determine whether asthma affects the morbidity and mortality of COVID-19. Recent news released from the National Institutes of Health said that a study called Human Epidemiology and Response to SARS-CoV-2 (HEROS) has just begun enrolling participants. The purpose of this study is to determine the rate of SARS-CoV-2 infection in children and their family members in the United States, and to examine whether rates of SARS-CoV-2 infection differ between children who have asthma or other allergic conditions and children who do not. Intervention studies that prevent the onset and severity of COVID-19 by reducing ACE2 expression are also of great interest. However, currently available data may provide some peace of mind to all physicians who are simultaneously managing patients with asthma and fighting against COVID-19.
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