Does asthma affect morbidity or severity of COVID-19?
Authors: Kenji Matsumoto, Hirohisa Saito
Journal: Journal of Allergy and Clinical Immunology (2020)

Coronavirus disease 2019 (COVID-19) has afflicted at least 4.9 million patients worldwide, causing more than 328,000 deaths to date. This pandemic impacts not only social and economic activities but also health care workers globally. Patients with COVID-19 exhibit a wide range of symptoms: from almost no symptoms to critical conditions similar to the so-called cytokine storm or fatal acute respiratory distress syndrome. However, we still do not have effective vaccines or specific remedies for this disease. Asthma is characterized by chronic airflow limitation, with inflammation in the lung. The most frequent trigger of asthma exacerbation is airway infection, especially with weakly virulent viruses such as rhinovirus and respiratory syncytial virus, which usually cause upper respiratory tract infections in healthy subjects.1Zheng X.Y. Xu Y.J. Guan W.J. Lin L.F. Regional, age and respiratory-secretion-specific prevalence of respiratory viruses associated with asthma exacerbation: a literature review.Arch Virol. 2018; 163: 845-853Crossref PubMed Scopus (128) Google Scholar Because airway epithelial cells and leukocytes from patients with asthma can show impaired production of antiviral IFNs (IFN-α/β/λ), either primarily or secondary to allergic inflammation, a patient's innate immune system is unable to prevent the spread of these viruses to the lower respiratory tract.2Edwards M.R. Strong K. Cameron A. Walton R.P. Jackson D.J. Johnston S.L. Viral infections in allergy and immunology: how allergic inflammation influences viral infections and illness.J Allergy Clin Immunol. 2017; 140: 909-920Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar This results in respiratory epithelial cell activation/damage, thereby aggravating type 2 inflammation. Such impairment of antiviral responses suggests that patients with asthma might be at high risk of COVID-19 morbidity and mortality. However, our unbiased literature search of epidemiological studies on COVID-19 yielded interesting results. Eight studies including a total of more than 17,000 patients in multiple geographic regions found that the comorbidity rates of COVID-19 with asthma were significantly lower than the reported prevalence of asthma in the respective regions (Table I). In addition, 2 independent studies (Li et al3Li X, Xu S, Yu M, Wang K, Tao Y, Zhou Y, et al. Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan [published online ahead of print April 12, 2020]. J Allergy Clin Immunol https://doi.org/10.1016/j.jaci.2020.04.006.Google Scholar and Singer et al4Singer AJ, Morley EJ, Meyers K, Fernandes R, Rowe AL, Viccellio P, et al. Cohort of 4404 persons under investigation for COVID-19 in a NY hospital and predictors of ICU care and ventilation [published online ahead of print April 23, 2020]. Ann Emerg Med https://doi.org/10.2139/ssrn.3583678.Google Scholar) similarly demonstrated that patients with COVID-19 comorbid with chronic obstructive pulmonary disease or diabetes tended to be more severe, whereas those comorbid with asthma did not (Table II).Table INumbers and percentages of comorbidity in patients with COVID-19RegionNo. of COVID-19 patientsMean or median age (y)No. of comorbid patients (%)∗The number of patients was calculated only if the total number of patients and percentages were presented.Regional asthma prevalenceReferenceAsthmaCOPDDiabetesWuhan, China140570 (0)2 (1.4)17 (12.1)6.4%†Regional asthma prevalence data are cited from Huang et al.Zhang et al, 2020Wuhan, China548605 (0.9)17 (3.1)83 (15.1)6.4%†Regional asthma prevalence data are cited from Huang et al.Li et al,3Li X, Xu S, Yu M, Wang K, Tao Y, Zhou Y, et al. Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan [published online ahead of print April 12, 2020]. J Allergy Clin Immunol https://doi.org/10.1016/j.jaci.2020.04.006.Google Scholar 2020Whole China1,59048.90 (0)24 (1.5)130 (8.2)6.4%†Regional asthma prevalence data are cited from Huang et al.Guan et al, 2020Georgia, USA3056032 (10.5)16 (5.2)121 (39.7)7.7%‡Regional asthma prevalence data are cited from the Centers for Disease Control and Prevention.Gold et al, 2020California, USA5453.53 (0.6)0 (0)11 (20.4)7.7%‡Regional asthma prevalence data are cited from the Centers for Disease Control and Prevention.Rubin et al, 2020New York, USA5,70063513 (9)308 (5.4)1927 (33.8)7.7%‡Regional asthma prevalence data are cited from the Centers for Disease Control and Prevention.Richardson et al, 2020New York, USA1,6515099 (6)66 (4)248 (15.0)7.7%‡Regional asthma prevalence data are cited from the Centers for Disease Control and Prevention.Singer et al,4Singer AJ, Morley EJ, Meyers K, Fernandes R, Rowe AL, Viccellio P, et al. Cohort of 4404 persons under investigation for COVID-19 in a NY hospital and predictors of ICU care and ventilation [published online ahead of print April 23, 2020]. Ann Emerg Med https://doi.org/10.2139/ssrn.3583678.Google Scholar 2020Whole Mexico7,49746270 (6)202 (2.7)1252 (16.7)8.7%§Regional asthma prevalence data are cited from Solé et al.Solís et al, 2020Total17,485922 (5.3)‖P < .0001 by Mantel-Haenszel test.635 (3.6)3789 (21.6)8.0%COPD, Chronic obstructive pulmonary disease.∗ The number of patients was calculated only if the total number of patients and percentages were presented.† Regional asthma prevalence data are cited from Huang et al.‡ Regional asthma prevalence data are cited from the Centers for Disease Control and Prevention.§ Regional asthma prevalence data are cited from Solé et al.‖ P < .0001 by Mantel-Haenszel test. Open table in a new tab Table IIAssociation of asthma, COPD, and diabetes comorbidity with the severity of COVID-19Region, country/comorbidityComorbidity+/− (%)P value∗P values were calculated by Fischer exact test, χ2 test, or Mantel-Haenszel test.TotalNonsevereSevereWuhan, China†Li et al.3548279269 Asthma5/543 (0.9)2/277 (0.7)3/266 (1.1).483 COPD17/531 (3.1)4/275 (1.4)13/256 (4.8).019 Diabetes83/465 (15.1)31/248 (11.1)52/217 (19.3).010New York, USA‡Singer et al.41651914737 Asthma99/1552 (6.0)47/867 (5.1)52/685 (7.1).128 COPD66/1585 (4.0)14/900 (1.5)52/685 (7.1).000 Diabetes248/1403 (15.0)49/865 (5.4)199/538 (27.0).000Total219911931006 Asthma104/2095 (4.7)49/1144 (4.1)55/951 (5.5).111 COPD83/2116 (3.8)18/1175 (1.5)65/941 (6.5).000 Diabetes331/1868 (15.1)80/1113 (6.7)251/755 (25.0).000COPD, Chronic obstructive pulmonary disease.∗ P values were calculated by Fischer exact test, χ2 test, or Mantel-Haenszel test.† Li et al.3Li X, Xu S, Yu M, Wang K, Tao Y, Zhou Y, et al. Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan [published online ahead of print April 12, 2020]. J Allergy Clin Immunol https://doi.org/10.1016/j.jaci.2020.04.006.Google Scholar‡ Singer et al.4Singer AJ, Morley EJ, Meyers K, Fernandes R, Rowe AL, Viccellio P, et al. Cohort of 4404 persons under investigation for COVID-19 in a NY hospital and predictors of ICU care and ventilation [published online ahead of print April 23, 2020]. Ann Emerg Med https://doi.org/10.2139/ssrn.3583678.Google Scholar Open table in a new tab COPD, Chronic obstructive pulmonary disease. COPD, Chronic obstructive pulmonary disease. 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.5Hoffmann M. Kleine-Weber H. Schroeder S. Kruger N. Herrler T. Erichsen S. et al.SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.Cell. 2020; 181: 271-280Abstract Full Text Full Text PDF PubMed Scopus (13672) Google Scholar Interestingly, in vitro treatment of airway epithelial cells with IFNs enhanced their ACE2 expression.6Ziegler CGK, Allon SJ, Nyquist SK, Mbano IM, Miao VN, Tzouanas CN, et al. SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is enriched in specific cell subsets across tissues [published online ahead of print April 27, 2020]. Cell. https://doi.org/10.1016/j.cell.2020.04.035.Google Scholar In sharp contrast, in this issue of the Journal, Kimura et al7Kimura H, Francisco D, Conway M, Martinez FD, Vercelli D, Billheimer D, et al. Type 2 inflammation modulates ACE2 and TMPRSS2, mediators of SARS-CoV-2 entry and fusion, in airway epithelial cells [published online ahead of print May 15, 2020]. J Allergy Clin Immunol. https://doi.org/10.1016/j.jaci.2020.05.004.Google Scholar 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.7Kimura H, Francisco D, Conway M, Martinez FD, Vercelli D, Billheimer D, et al. Type 2 inflammation modulates ACE2 and TMPRSS2, mediators of SARS-CoV-2 entry and fusion, in airway epithelial cells [published online ahead of print May 15, 2020]. J Allergy Clin Immunol. https://doi.org/10.1016/j.jaci.2020.05.004.Google Scholar 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.8Jackson DJ, Busse WW, Bacharier LB, Kattan M, O'Connor GT, Wood RA, et al. Association of respiratory allergy, asthma and expression of the SARS-CoV-2 receptor, ACE2 [published online ahead of print April 22, 2020]. J Allergy Clin Immunol. https://doi.org/10.1016/j.jaci.2020.04.009.Google Scholar Moreover, patients with COVID-19 with serious disease showed significantly higher IFN-related molecular expression (IFN-γ–induced protein 10).9Yang Y. Shen C. Li J. Yuan J. Wei J. Huang F. et al.Plasma IP-10 and MCP-3 levels are highly associated with disease severity and predict the progression of COVID-19 [published online ahead of print April 29, 2020].J Allergy Clin Immunol. 2020; https://doi.org/10.1016/j.jaci.2020.04.027Abstract Full Text Full Text PDF Scopus (467) Google Scholar 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.10Van Bever H.P. Chng S.Y. Goh D.Y. Childhood severe acute respiratory syndrome, coronavirus infections and asthma.Pediatr Allergy Immunol. 2004; 15: 206-209Crossref PubMed Scopus (47) Google Scholar Conversely, conventional coronaviruses exacerbate asthma upon infection.1Zheng X.Y. Xu Y.J. Guan W.J. Lin L.F. Regional, age and respiratory-secretion-specific prevalence of respiratory viruses associated with asthma exacerbation: a literature review.Arch Virol. 2018; 163: 845-853Crossref PubMed Scopus (128) Google Scholar 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.