Autoimmune diseases are independently associated with COVID-19 severity: Evidence based on adjusted effect estimates
Authors: Haiyan Yang, Jie Xu, Xuan Liang, Li Shi, Yadong Wang
Journal: Journal of Infection (2020)

There have been several published articles reporting the association between autoimmune diseases and the risk of severity among patients with coronavirus disease 2019 (COVID-19). But the conclusions across studies are inconsistent.1D'Silva K.M. Serling-Boyd N. Wallwork R. Hsu T. Fu X. Gravallese E.M. et al.Clinical characteristics and outcomes of patients with coronavirus disease 2019 (COVID-19) and rheumatic disease: a comparative cohort study from a US 'hot spot'.Ann Rheum Dis. 2020; 79 (Sep. PubMed PMID: 32457048. Pubmed Central PMCID: 7456555): 1156-1162Crossref PubMed Scopus (223) Google Scholar, 2Faye A.S. Lee K.E. Laszkowska M. Kim J. Blackett J.W. McKenney A.S. et al.Risk of adverse outcomes in hospitalized patients with autoimmune disease and COVID-19: a matched cohort study from New York City.J Rheumatol. 2020; (Nov 1. PubMed PMID: 33132221)https://doi.org/10.3899/jrheum.200989Crossref Google Scholar, 3Morgenthau A.S. Levin M.A. Freeman R. Reich D.L. Klang E. 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Pubmed Central PMCID: 7499657)https://doi.org/10.1093/ije/dyaa140Crossref PubMed Scopus (202) Google Scholar, 6Siso-Almirall A. Kostov B. Mas-Heredia M. Vilanova-Rotllan S. Sequeira-Aymar E. Sans-Corrales M. et al.Prognostic factors in Spanish COVID-19 patients: a case series from Barcelona.PLoS One. 2020; 15 (PubMed PMID: 32822413. Pubmed Central PMCID: 7444503)e0237960Crossref PubMed Scopus (78) Google Scholar Recently, Liu et al. performed a meta-analysis based on six studies with 2091 cases published in Journal of Infection to investigate the association between autoimmune diseases and severe or dead COVID-19.7Liu M. Gao Y. Zhang Y. Shi S. Chen Y. Tian J. The association between severe or dead COVID-19 and autoimmune diseases: a systematic review and meta-analysis.J Infect. 2020; 81 (Sep. PubMed PMID: 32502509. Pubmed Central PMCID: 7264926): e93-ee5Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar Their results demonstrated that autoimmune diseases were not significantly associated with severe or dead COVID-19 (odds ratio (OR) = 1.21, 95% confidence interval (CI): 0.58–2.50 for severity and OR = 1.31, 95% CI: 0.33–5.20 for mortality).7Liu M. Gao Y. Zhang Y. Shi S. Chen Y. Tian J. The association between severe or dead COVID-19 and autoimmune diseases: a systematic review and meta-analysis.J Infect. 2020; 81 (Sep. PubMed PMID: 32502509. Pubmed Central PMCID: 7264926): e93-ee5Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar This is an extremely interesting paper. However, the number of included studies and sample sizes are limited. Up to now, several papers with large sample sizes on this topic are emerging. Therefore, it is required to clarify the association between autoimmune diseases and COVID-19 severity based on updated data. To our knowledge, several factors such as age, gender and underlying disorders (hypertension, diabetes, chronic obstructive pulmonary disease, cerebrovascular disease, cardiovascular disease, chronic kidney disease and obesity, etc.) significantly affected the clinical outcomes of COVID-19. This suggests that these risk factors might modulate the association of autoimmune diseases with COVID-19 severity. To obtain a precise conclusion, this meta-analysis was carried out based on published studies reporting adjusted effect estimates, rather than those reporting un-adjusted effect estimates. This meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. International databases of PubMed, Web of Science and EMBASE were searched to identify potential studies up to December 12, 2020. The following keywords were used: "coronavirus disease 2019″, "COVID-19″, "SARS-CoV-2″, "autoimmune diseases", "rheumatic diseases", "inflammatory bowel disease", "psoriasis" and "systemic lupus erythematosus". Only peer-reviewed articles published in English reporting adjusted effect estimates on the association between autoimmune diseases and COVID-19 severity (severe, critical and mortal outcomes) were eligibly included. Repeated articles, case reports, reviews, comments, protocols, errata, and articles without sufficient information were excluded. Data were extracted by two independent authors (Jie Xu and Haiyan Yang) from each included study. Questions or disagreements were resolved by discussion or consultation with a third author (Yadong Wang). Baseline information extracted from the included literature includes author name, location, sample sizes, number of autoimmune diseases, types of autoimmune diseases, age, gender distribution, study design, adjusted effect estimates, adjusted risk factors and disease outcomes. All statistical analyses were conducted using Stata 12.1 software. Heterogeneity was tested using I2 statistic. The pooled effects with 95% CI were estimated. Publication bias was examined by Begg's test and Egger's test. Sensitivity analysis was performed to assess the stability of results. The level of significance was set at P < 0.05. A total of thirteen studies1D'Silva K.M. Serling-Boyd N. Wallwork R. Hsu T. Fu X. Gravallese E.M. et al.Clinical characteristics and outcomes of patients with coronavirus disease 2019 (COVID-19) and rheumatic disease: a comparative cohort study from a US 'hot spot'.Ann Rheum Dis. 2020; 79 (Sep. PubMed PMID: 32457048. Pubmed Central PMCID: 7456555): 1156-1162Crossref PubMed Scopus (223) Google Scholar–6Siso-Almirall A. Kostov B. Mas-Heredia M. Vilanova-Rotllan S. Sequeira-Aymar E. Sans-Corrales M. et al.Prognostic factors in Spanish COVID-19 patients: a case series from Barcelona.PLoS One. 2020; 15 (PubMed PMID: 32822413. Pubmed Central PMCID: 7444503)e0237960Crossref PubMed Scopus (78) Google Scholar,8Lauriola M. Pani A. Ippoliti G. Mortara A. Milighetti S. Mazen M. et al.Effect of combination therapy of hydroxychloroquine and azithromycin on mortality in patients with COVID-19.Clin Transl Sci. 2020; (Sep 14. PubMed PMID: 32926573)https://doi.org/10.1111/cts.12860Crossref PubMed Scopus (29) Google Scholar, 9Balbi M. Caroli A. Corsi A. Milanese G. Surace A. Di Marco F. et al.Chest X-ray for predicting mortality and the need for ventilatory support in COVID-19 patients presenting to the emergency department.Eur Radiol. 2020; (Oct 8. PubMed PMID: 33033861. 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Pubmed Central PMCID: 7574532 at www.icmje.org/coi_disclosure.pdf and declare: JHC has received grants from the National Institute for Health Research Biomedical Research Centre, Oxford, John Fell Oxford University Press Research Fund, Cancer Research UK (grant number C5255/A18085) through the Cancer Research UK Oxford Centre, and the Oxford Wellcome Institutional Strategic Support Fund (204826/Z/16/Z) during the conduct of the study, is an unpaid director of QResearch, a not-for-profit organisation which is a partnership between the University of Oxford and EMIS Health who supply the QResearch database used for this work, and is a founder and shareholder of ClinRisk Ltd and was its medical director until 31 May 2019; ClinRisk produces open and closed source software to implement clinical risk algorithms (outside this work) into clinical computer systems; CC reports receiving personal fees from ClinRisk, outside this work; AH is a member of the New and Emerging Respiratory Virus Threats Advisory Group; PJ was employed by NHS England during the conduct of the study and has received grants from Epizyme and Janssen and personal fees from Takeda, Bristol-Myers-Squibb, Novartis, Celgene, Boehringer Ingelheim, Kite Therapeutics, Genmab, and Incyte, all outside the submitted work; AKC has previously received personal fees from Huma Therapeutics, outside of the scope of the submitted work; RL has received grants from Health Data Research UK outside the submitted work; AS has received grants from the Medical Research Council (MRC) and Health Data Research UK during the conduct of the study; CS has received grants from the DHSC National Institute of Health Research UK, MRC UK, and the Health Protection Unit in Emerging and Zoonotic Infections (University of Liverpool) during the conduct of the study and is a minority owner in Integrum Scientific LLC (Greensboro, NC, USA) outside of the submitted work; KK has received grants from NIHR, is the national lead for ethnicity and diversity for the National Institute for Health Applied Research Collaborations, is director of the University of Leicester Centre for Black Minority Ethnic Health, was a steering group member of the Risk reduction Framework for NHS staff (chair) and for Adult care Staff, is a member of Independent SAGE, and is supported by the NIHR Applied Research Collaboration East Midlands (ARC EM) and the NIHR Leicester Biomedical Research Centre (BRC); RHK was supported by a UKRI Future Leaders Fellowship (MR/S017968/1); KDO was supported by a grant from the Alan Turing Institute Health Programme (EP/T001569/1); no other relationships or activities that could appear to have influenced the submitted work. The views expressed are those of the author(s) and not necessarily those of the NIHR, the NHS, or the Department of Health and Social Care): m3731Crossref PubMed Scopus (394) Google Scholar, 12Gu T. Mack J.A. Salvatore M. Prabhu Sankar S. Valley T.S. Singh K. et al.Characteristics associated with racial/ethnic disparities in COVID-19 outcomes in an academic health care system.JAMA Netw Open. 2020; 3 (Oct 1. PubMed PMID: 33084902. Pubmed Central PMCID: 7578774)e2025197Crossref PubMed Scopus (164) Google Scholar, 13Izzy S. Tahir Z. Cote D.J. Al Jarrah A. Roberts M.B. Turbett S. et al.Characteristics and outcomes of latinx patients with COVID-19 in comparison with other ethnic and racial groups.Open Forum Infect Dis. 2020; 7 (Oct. PubMed PMID: 33088846. Pubmed Central PMCID: 7499713): ofaa401Crossref PubMed Scopus (28) Google Scholar–14Murtas R. Andreano A. Gervasi F. Guido D. Consolazio D. Tunesi S. et al.Association between autoimmune diseases and COVID-19 as assessed in both a test-negative case-control and population case-control design.Auto Immun Highlights. 2020; 11 (Oct 6. PubMed PMID: 33023649. Pubmed Central PMCID: 7537783): 15Crossref PubMed Scopus (33) Google Scholar reporting 58,183 laboratory-confirmed COVID-19 patients were included. The main characteristics of the selected studies are demonstrated in Table 1. Our meta-analysis based on adjusted effect estimates revealed that COVID-19 patients with autoimmune diseases had a significantly increased risk of severity compared to those without autoimmune diseases (pooled effect = 1.19, 95% CI: 1.05–1.35) (Fig. 1A). Sensitivity analysis exhibited that our results were stable and robust (Fig. 1B). Publication bias was observed in Egger's test (P = 0.017), but not in Begg's test (P = 0.127, Fig. 1C). Subgroup analysis by location revealed that co-existing autoimmune diseases were significantly associated with an elevated risk of COVID-19 severity among USA population (pooled effect = 1.36, 95% CI: 1.02–1.81). This significant association was also observed in studies with mean age < 65 years old (pooled effect = 1.29, 95% CI: 1.04–1.60), studies with proportion of male ≥ 50% (pooled effect = 1.31, 95% CI: 1.06–1.62) and OR-reported studies (pooled effect = 1.21, 95% CI: 1.04–1.41).Table 1Main characteristics of the included studies.AuthorLocationNo. of casesNo. of ADMale (%)Age#The values are presented as mean ± SD (standard deviation);.Study designAdjusted-effect (95% CI)Adjusted factorsD'Silva et al. (PMID: 32,457,048)USA1565230.862.9 ± 14.97Comparative cohort studyOR = 3.26 (1.17–9.09)Age, body mass indexPablos et al. (PMID: 32,796,045)Spain45622839.965±18.90Comparative cohort studyOR = 1.82 (1.00–3.30)Age, sex, obesity, diabetes, heart failure, glucocorticoids, antiviralsSisoAlmirall et al. (PMID: 32,822,413)Spain3222150.056.7 ± 17.8Retrospective studyOR = 2.82 (1.00–7.84)Hypertension, diabetes, obesity, dyslipidemia, cancer, chronic kidney disease, heart disease, chronic obstructive pulmonary disease, depression, cardiac arrhythmia, thyroid alterations, asthma, liver disease, cerebrovascular disease, alzheimer diseaseReilev et al. (PMID: 32,887,982)Denmark11,12234842.247.67±21.64Population-based studyOR = 1.1 (0.8–1.6)Age, sexMorgenthau et al. (PMID: 32,915,271)USA73373755.561.31±20.02Retrospective studyOR = 1.8 (0.9–3.8)Age, sex, cardiovascular disease, diabetes, chronic kidney disease, chronic obstructive pulmonary disease, cancer, obesity, smokingLauriola et al. (PMID: 32,926,573)Italy3772865.871.8 ± 13.4Retrospective studyHR = 0.851 (0.410–1.765)Sex, age, mechanical ventilation + continuous positive airway pressure, hypertension, diabetes, cancer, cardiovascular disease, chronic obstructive pulmonary disease, cerebrovascular disease, obesity, white blood cell above the median, C-reactive protein above the median, hydroxychloroquine, hydroxychloroquine + azithromycinBalbi et al. (PMID: 33,033,861)Italy340187467±14.15Retrospective studyOR = 3.22 (1.05–9.89)Age, oxygen saturation, ratio of partial pressure of oxygen to fraction of inspired oxygen,% of lung involvementRodriguez-Molinero et al. (PMID: 33,057,443)Spain4182156.965.4 ± 16.6Observational studyOR = 2.28 (0.73–7.08)Age, sex, diabetes mellitus, dyslipidemia, obesity, chronic kidney disease, hypertension, heart failure, atrial fibrillation, dementia, obstructive sleep apnea syndromeClift et al. (PMID: 33,082,154)UK10,77630955.369.63±17.90Cohort studyHR = 1.02 (0.75–1.38)1: Men;.Age, body mass index, townsend material deprivation score, ethnic group, domicile (residential care, homeless, neither), and a range of conditions and treatmentsHR = 1.32 (1.06–1.65)2: Women;.Gu et al. (PMID: 33,084,902)USA1139Unknown46.653.0 ± 17.9Retrospective studyOR = 1.45 (0.92–2.29)Age, sex, race, neighborhood socioeconomic disadvantage indexIzzy et al. (PMID: 33,088,846)USA519015845.851.33±22.25UnknownOR = 0.82 (0.38–1.79)3: White;.Age, gender, smoking status, body mass index, diabetes mellitus, hyperlipidemia, hypertension, obstructive lung disease, interstitial lung disease, coronary artery disease, chronic heart failure, cerebrovascular disease, obstructive sleep apnea, chronic kidney disease, transplantation, malignancy, total comorbiditiesOR = 1.37 (0.41–4.63)4: Latinx;.OR = 1.92 (0.32–11.68)5: African American.Faye et al. (PMID: 33,132,221)USA1866238.763.56±14.6Retrospective studyOR = 0.79 (0.37–1.67)Comorbidities, smokingMurtas et al. (PMID: 33,023,649)Italy20,36466547.565.5 ± 19.4Case-control studyOR = 0.95 (0.74–1.22)Gender, age, chronic conditionsNote: AD, autoimmune diseases; USA, the United States of America; UK, the United Kingdom; CI, confidence interval; OR, odds ratio; HR, hazard ratio.# The values are presented as mean ± SD (standard deviation);.1 : Men;.2 : Women;.3 : White;.4 : Latinx;.5 : African American. Open table in a new tab Note: AD, autoimmune diseases; USA, the United States of America; UK, the United Kingdom; CI, confidence interval; OR, odds ratio; HR, hazard ratio. Limitations should be acknowledged in this study. First, the included studies were mainly from Europe and USA, thus the conclusion should be cautiously extrapolated to other regions (such as Asia and Africa). Second, Begg's test showed no publication bias, but Egger's test revealed obvious publication bias. Thus, our findings should be confirmed in the future when more published studies are available. Third, subgroup analysis by the types of autoimmune diseases was not performed since most of the included studies did not report specific type of autoimmune diseases. Fourth, data on medications of autoimmune diseases were only available in four eligible studies, moreover the medications varied greatly across these studies, we did not further investigate the effect of medications on the association between autoimmune diseases and COVID-19 severity currently. In conclusion, our study based on adjusted effect estimates demonstrates that autoimmune diseases are independently associated with an increased risk of COVID-19 severity, which provides new insight on the association between autoimmune diseases and COVID-19 severity. Therefore, special preventive measures should be taken to protect individuals with co-existing autoimmune diseases from exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and more clinical attention should be allocated to COVID-19 patients with autoimmune diseases to prevent disease progression.