Association of asthma and its genetic predisposition with the risk of severe COVID-19

Abstract

In individuals with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the severity of illness ranges from asymptomatic to fatal.1Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention [published online ahead of print February 24, 2020]. JAMA. https://doi.org/10.1001/jama.2020.2648.Google Scholar The Centers for Disease Control and Prevention currently list asthma as a risk factor for severe illness from coronavirus disease 2019 (COVID-19).2Centers for Disease Control and PreventionCoronavirus disease 2019 (COVID-19)—people who are at higher risk for severe illness.https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-at-higher-risk.htmlDate: 2020Date accessed: May 17, 2020Google Scholar This is a logical determination because the non–COVID-19 literature indicates that patients with asthma have increased susceptibility to viral respiratory infections.3Jartti T. Gern J.E. Role of viral infections in the development and exacerbation of asthma in children.J Allergy Clin Immunol. 2017; 140: 895-906Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar In addition, case series of patients with COVID-19 have reported that the asthma prevalence is higher4Garg S. Kim L. Whitaker M. O’Halloran A. Cummings C. Holstein R. et al.Hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019-COVID-NET, 14 states, March 1-30, 2020.MMWR Morb Mortal Wkly Rep. 2020; 69: 458-464Crossref PubMed Scopus (0) Google Scholar or nondifferent5Goyal P. Choi J.J. Pinheiro L.C. Schenck E.J. Chen R. Jabri A. et al.Clinical characteristics of covid-19 in New York City.N Engl J Med. 2020; 382: 2372-2374Crossref PubMed Google Scholar in more severe cases. However, despite the clinical and research importance, no studies have specifically examined the relationship of asthma—let alone of its phenotypes—with incident COVID-19. To address the major knowledge gap, we examined the relationship of asthma and its major phenotypes with the risk of developing severe COVID-19. We also examined the relations of their genetic predisposition with severe COVID-19. The determination of risk factors and potential mechanisms—such as the contribution of genetic predispositions—of severe illness is instrumental for the development of prevention, risk-stratification, and treatment strategies for COVID-19. We analyzed data from the UK Biobank—a population-based prospective cohort study. The details of study design, setting, participants, data measurements, and data analysis are described in this article’s Online Repository at www.jacionline.org. Briefly, the UK Biobank enrolled approximately 500,000 adults (aged 40-69 years at enrollment) in the period 2006 to 2010.6Sudlow C. Gallacher J. Allen N. Beral V. Burton P. Danesh J. et al.Uk biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age.PLoS Med. 2015; 12e1001779Crossref PubMed Scopus (2786) Google Scholar Using standardized protocols, the study has collected comprehensive phenotypic data—for example, demographic characteristics, medical history, physical measures (eg, body mass index), performed genome-wide genotyping, and longitudinally measured health outcomes (eg, hospitalizations) through linkages to national data sets.6Sudlow C. Gallacher J. Allen N. Beral V. Burton P. Danesh J. et al.Uk biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age.PLoS Med. 2015; 12e1001779Crossref PubMed Scopus (2786) Google Scholar Starting from March 16, 2020, data of laboratory-confirmed COVID-19 hospitalizations—that is, individuals with severe COVID-19—are available in the UK Biobank. In the current analysis, we identified all participants with asthma and those without asthma or chronic obstructive pulmonary disease (COPD). To investigate the association of asthma with the risk of severe COVID-19, we constructed unadjusted and adjusted logistic regression models. In the multivariable model, we adjusted for potential confounders (ie, causes of both exposure and outcome of interest), including age, sex, race/ethnicity, and body mass index. On the basis of an a priori hypothesis, we also examined the heterogeneity of effect according to 4 asthma phenotypes, through stratifying the main analysis by coexistence of allergic disease (eczema, food allergy, and/or allergic rhinitis) or of COPD. Next, we used genotyping data to compute a polygenic risk score (PRS) for each asthma group of interest—the sum of all risk alleles weighted by how risky each variant is—representing an individual’s overall genetic risk for asthma (and its phenotypes). Then, we investigated the association of derived asthma PRSs with the risk of severe COVID-19. The details of statistical analysis may be found in this article’s Methods section in the Online Repository at www.jacionline.org. The institutional review board of Harvard University and Massachusetts General Hospital approved the study. The analytic cohort comprised 492,768 participants in the UK Biobank. Overall, the mean age was 56 ± 8years, 55% were female, and 95% were white. Of these, 65,677 participants (13%) had asthma. Between the participants with asthma and those without asthma, there were no clinically significant differences in most characteristics, except that those with asthma were more likely to be women and have allergic disease and coexistent COPD (Table I). The UK Biobank also identified a total of 641 patients with severe COVID-19 (see this article’s Methods section). Participants with asthma, compared with those without, had a significantly higher risk of severe COVID-19 (odds ratio [OR], 1.44; 95% CI, 1.18-1.76; P < .001; Fig 1). The association remained significant after adjusting for potential confounders (adjusted OR, 1.39; 95% CI, 1.13-1.71; P = .002). These findings were driven by the significant association of nonallergic asthma with severe COVID-19 (adjusted OR, 1.48; 95% CI, 1.15-1.92; P = .003). In contrast, allergic asthma had no statistically significant association with severe COVID-19 (P = .09). In the stratified analysis by coexisting COPD, the significant association persisted in both strata, with a larger magnitude in asthma with COPD (adjusted OR, 1.82; 95% CI, 1.16-2.86; P = .009). In contrast, the PRSs were not significantly associated with the risk of severe COVID-19 across all strata, but the direction of effects was consistently positive (see Table E1 in this article’s Online Repository at www.jacionline.org).Table IBaseline characteristics in 492,768 UK Biobank participantsCharacteristicAsthma (n = 65,677; 13%)No asthma (n = 427,091; 87%)DemographicAge (y), mean ± SD56 ± 8.357 ± 8.1Sex: female38,006 (57.9)231,216 (54.1)Race/ethnicity White61,555 (94.3)401,699 (94.6) Asian or Asian British1,388 (2.1)8,400 (2.0) Black or black British1,114 (1.7)6,904 (1.6) Mixed506 (0.8)2,414 (0.6) Chinese153 (0.2)1,408 (0.3) Other groups593 (0.9)3,922 (0.9)Total annual household income (£) ≤18,00014,253 (22.0)79,252 (18.8) 18,000-30,99913,482 (20.8)92,590 (21.9) 31,000-51,99913,713 (21.2)95,770 (22.7) 52,000-100,00010,866 (16.8)74,809 (17.7) ≥100,0002,874 (4.4)19,938 (4.7) Do not know3,235 (5.0)17,396 (4.1) Prefer not to answer6,343 (9.8)42,471 (10.1)Body mass index (kg/m2), mean ± SD28.3 ± 5.427.3 ± 4.7Smoking status Never35,071 (53.4)236,600 (55.4) Previous23,381 (35.6)145,057 (34.0) Current6,809 (10.4)42,972 (10.1)ComorbiditiesAllergic diseases Allergic rhinitis or eczema28,852 (44.1)85,354 (20.1) Food allergy626 (1.0)1,570 (0.4)Cerebrovascular disease1,190 (1.8)5,703 (1.3)COPD7,836 (11.9)0 (0)Coronary artery disease3,732 (6.0)16,928 (4.1)Hypertension18,937 (30.2)107,835 (26.4)Laboratory test at assessment visit, mean ± SDWhite blood cells (109 cells/L)7.17 ± 2.086.82 ± 2.01Neutrophils (109 cells/L)4.45 ± 1.544.18 ± 1.38Lymphocytes (109 cells/L)1.97 ± 1.041.96 ± 1.12Monocytes (109 cells/L)0.47 ± 0.220.49 ± 0.22Eosinophils (109 cells/L)0.22 ± 0.180.17 ± 0.13Basophils (109 cells/L)0.04 ± 0.050.03 ± 0.0525-HydroxyvitaminD (nmol/L)47.2 ± 20.948.9 ± 21.1SARS-CoV-2 PCR test during hospitalization, positive116 ± 0.2525 ± 0.1Data are n (%) of participants unless otherwise indicated. Open table in a new tab Data are n (%) of participants unless otherwise indicated. Consistent with our findings, a case series of adults hospitalized with COVID-19 in 14 US states reported that asthma was one of the most prevalent comorbid conditions (17% prevalence).4Garg S. Kim L. Whitaker M. O’Halloran A. Cummings C. Holstein R. et al.Hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019-COVID-NET, 14 states, March 1-30, 2020.MMWR Morb Mortal Wkly Rep. 2020; 69: 458-464Crossref PubMed Scopus (0) Google Scholar In contrast, a case series from 2 hospitals in New York (n = 393) reported a similar asthma prevalence between patients with mechanical ventilation use and those without.5Goyal P. Choi J.J. Pinheiro L.C. Schenck E.J. Chen R. Jabri A. et al.Clinical characteristics of covid-19 in New York City.N Engl J Med. 2020; 382: 2372-2374Crossref PubMed Google Scholar The largest case series from China (n = 72,314) did not specifically examine asthma as a risk factor for severe COVID-19.1Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention [published online ahead of print February 24, 2020]. JAMA. https://doi.org/10.1001/jama.2020.2648.Google Scholar Contrary to these case series, the validity of our inferences is buttressed by the use of large population-based prospective cohort study with consideration of different asthma phenotypes and robust analytical approaches. The mechanisms underlying the asthma-COVID-19 association are beyond the scope of data. Interestingly, however, we found a nonsignificant association between genetic predisposition for asthma and outcome, suggesting a potentially limited discriminatory performance of the PRS used in this study and/or a complex interplay between the pathogen, environment, and host response (eg, differential angiotensin-converting enzyme 2 [ACE2] expression7Bunyavanich S. Do A. Vicencio A. Nasal gene expression of angiotensin-converting enzyme 2 in children and adults.JAMA. 2020; 382: 2372-2374Google Scholar)—beyond the genetics—in the pathobiology of COVID-19. For example, it is possible that asthma, allergic sensitization, and related airway inflammation jointly contribute to the pathobiology of severe COVID-19. Consistent with our findings, a study reported that asthma with high allergic sensitization was associated with low expression of ACE2 (the SARS-CoV-2 receptor) in the nasal epithelia of children, whereas nonallergic asthma was not associated with ACE2 expression.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]. J Allergy Clin Immunol. https://doi.org/10.1016/j.jaci.2020.04.009.Google Scholar In addition, an analysis of nasal epithelial cells in children with asthma showed that expression of ACE2 and TMPRSS2 (protease that allows efficient virus-receptor binding) is regulated by type 2 inflammation.9Sajuthi SP, DeFord P, Jackson ND, Montgomery MT, Everman JL, Rios CL, et al. Type 2 and interferon inflammation strongly regulate SARS-CoV-2 related gene expression in the airway epithelium [published online ahead of print April 10, 2020]. bioRxiv. https://doi.org/10.1101/2020.04.09.034454.Google Scholar The current study corroborates these non–COVID-19 data, and extends them by identifying relationships of asthma (and its phenotypes) with severe COVID-19. The current study has potential limitations. First, misclassification of asthma and its phenotypes is possible, while it is likely unrelated to the outcome. Therefore, this nondifferential misclassification would have biased the inferences toward the null. Second, as with any observational study, causal inference may be confounded by unmeasured factors (eg, access to health care). Yet, the study focused on severe COVID-19 requiring inpatient management, thereby mitigating this problem. Finally, the study consisted mainly of white individuals and focused on severe COVID-19, and we must cautiously generalize the inferences to other populations or individuals with mild to moderate COVID-19. Regardless, our data are highly relevant for hundreds of thousands of patients hospitalized for COVID-19. In conclusion, the large population-based cohort study demonstrated that adults with asthma had a higher risk of severe COVID-19, which was driven by the increased risk in patients with nonallergic asthma. In contrast, the risk of severe COVID-19 was not significantly elevated in patients with allergic asthma. In addition, the study demonstrated the absence of association between the existing genetic polygenic score for asthma and COVID-19. These observations should help clinicians optimize risk-stratification of patients with asthma (and its phenotypes). Furthermore, our inferences should advance the research into delineating the complex interrelations between SARS-CoV-2 infection, airway inflammation, and outcomes in patients with asthma. The current study is an analysis of data from the UK Biobank—a population-based prospective cohort study. The complete description of the design, settings, participants, and methods of data measurements in the UK Biobank was described elsewhere.E1Sudlow C. Gallacher J. Allen N. Beral V. Burton P. Danesh J. et al.UK Biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age.PLoS Med. 2015; 12e1001779Crossref PubMed Scopus (5349) Google Scholar In brief, the UK Biobank study is a prospective cohort study of 503,325 participants, with an overall aim of permitting detailed investigations of nongenetic and genetic determinants of the diseases of middle and old age. The participants registered in the National Health Service with ages ranging 40 from 69 years were recruited out of 9.2 million mailed invitations across the United Kingdom in the period 2006 to 2010. Using standardized protocols,E1Sudlow C. Gallacher J. Allen N. Beral V. Burton P. Danesh J. et al.UK Biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age.PLoS Med. 2015; 12e1001779Crossref PubMed Scopus (5349) Google Scholar the UK Biobank study has collected comprehensive phenotypic information—such as demographic characteristics, environmental factors, medical history, physical measures (eg, anthropometrics including body mass index), tested for hematology and biochemical assays (eg, complete blood panel, 25-hydroxyvitamin D), performed genome-wide genotyping, and longitudinally measured health outcomes (eg, hospitalizations, death registrations) through linkages to national data sets. The detailed procedures used in genotyping, quality control, and imputation are described at the UK Biobank Web site (http://biobank.ctsu.ox.ac.uk). All participants provided informed consent to the UK Biobank. First, according to previous research,E2Zhu Z. Guo Y. Shi H. Liu C.L. Panganiban R.A. Chung W. et al.Shared genetic and experimental links between obesity-related traits and asthma subtypes in UK Biobank.J Allergy Clin Immunol. 2020; 145: 537-549Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, E3Zhu Z. Chung W. et genome-wide analysis from UK Biobank the genetic of asthma and allergic PubMed Scopus Google Scholar, Z. Liu C.L. Shi H. S. Y. et al.Shared of asthma and health a genome-wide J. PubMed Scopus Google Scholar we identified all UK Biobank participants with asthma by the data of illness disease of in the and in the The of were used for the of asthma. In addition, we identified 4 phenotypes of allergic asthma as asthma with an allergic food allergy, and/or rhinitis by data nonallergic asthma without any allergic asthma with COPD by data and asthma without COPD. The of and were used for the of allergic and were used for the of COPD, according to the previous Z. Guo Y. Shi H. Liu C.L. Panganiban R.A. Chung W. et al.Shared genetic and experimental links between obesity-related traits and asthma subtypes in UK Biobank.J Allergy Clin Immunol. 2020; 145: 537-549Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, E3Zhu Z. Chung W. et genome-wide analysis from UK Biobank the genetic of asthma and allergic PubMed Scopus Google Scholar, Z. Liu C.L. Shi H. S. Y. et al.Shared of asthma and health a genome-wide J. PubMed Scopus Google Scholar To patients with COVID-19, we analyzed the of the UK Biobank data with COVID-19 which were on April 16, The data the SARS-CoV-2 PCR in hospitalized participants from March 16, 2020, These hospitalized patients with had of the for SARS-CoV-2 are from which are in for PCR to be (ie, participants were tested from the participants for the current analysis, 641 patients were found to be SARS-CoV-2 positive (ie, severe The detailed on COVID-19 data be found at UK Biobank Web site Biobank COVID-19 data accessed: May 17, 2020Google Scholar First, we described the characteristics by asthma status summary as Next, to investigate the association of asthma status with the risk of severe COVID-19, we constructed unadjusted and adjusted logistic regression models. In the multivariable model, we adjusted for potential confounders (ie, causes of both exposure and outcome of interest), including age, sex, race/ethnicity, and body mass on clinical and a priori R. A. factors for is 2015; Full Text Full Text PDF PubMed Scopus Google Scholar, P. Choi J.J. Pinheiro L.C. Schenck E.J. Chen R. Jabri A. et al.Clinical characteristics of COVID-19 in New York City.N Engl J Med. 2020; 382: 2372-2374Crossref PubMed Scopus Google Scholar Furthermore, on the basis of a a priori hypothesis, we examined the heterogeneity of effect on the outcome according to the 4 asthma phenotypes, by the analysis on potential coexistence of allergic disease or of COPD. In the analysis, we used the data of 65,677 participants with asthma, allergic asthma, nonallergic asthma, asthma with COPD, and asthma without COPD, in to participants without asthma or COPD (the Z. Liu C.L. Shi H. S. Y. et al.Shared of asthma and health a genome-wide J. 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