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. 2022 Nov 1;17(11):e0276774. doi: 10.1371/journal.pone.0276774

Effect of asthma, COPD, and ACO on COVID-19: A systematic review and meta-analysis

Yuka Uruma 1, Toshie Manabe 2,3,*, Yuji Fujikura 4,5, Motoyasu Iikura 6, Masayuki Hojo 6, Koichiro Kudo 7,8
Editor: Dong Keon Yon9
PMCID: PMC9624422  PMID: 36318528

Abstract

Introduction

The prevalence of asthma, chronic obstructive pulmonary disease (COPD), and asthma-COPD overlap (ACO) in patients with COVID-19 varies, as well as their risks of mortality. The present study aimed to assess the prevalence of asthma, COPD, and ACO as comorbidities, and to determine their risks of mortality in patients with COVID-19 using a systematic review and meta-analysis.

Methods

We systematically reviewed clinical studies that reported the comorbidities of asthma, COPD, and ACO in patients with COVID-19. We searched various databases including PubMed (from inception to 27 September 2021) for eligible studies written in English. A meta-analysis was performed using the random-effect model for measuring the prevalence of asthma, COPD, and ACO as comorbidities, and the mortality risk of asthma, COPD, and ACO in patients with COVID-19 was estimated. A stratified analysis was conducted according to country.

Results

One hundred one studies were eligible, and 1,229,434 patients with COVID-19 were identified. Among them, the estimated prevalence of asthma, COPD, and ACO using a meta-analysis was 10.04% (95% confidence interval [CI], 8.79–11.30), 8.18% (95% CI, 7.01–9.35), and 3.70% (95% CI, 2.40–5.00), respectively. The odds ratio for mortality of pre-existing asthma in COVID-19 patients was 0.89 (95% CI, 0.55–1.4; p = 0.630), while that in pre-existing COPD in COVID-19 patients was 3.79 (95% CI, 2.74–5.24; p<0.001). France showed the highest prevalence of asthma followed by the UK, while that of COPD was highest in the Netherlands followed by India.

Conclusion

Pre-existing asthma and COPD are associated with the incidence of COVID-19. Having COPD significantly increases the risk of mortality in patients with COVID-19. These differences appear to be influenced by the difference of locations of disease pathophysiology and by the daily diagnosis and treatment policy of each country.

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first detected in Wuhan, China [1], and it is the causative agent of the coronavirus disease 2019 (COVID-19) pandemic [2]. As many as 50% of patients have reported having at least one comorbidity with COVID-19 [3]. Among them, the highest prevalent comorbidity was hypertension (21.1%), followed by diabetes (9.7%), cardiovascular disease (8.4%), and respiratory system disease (1.5%) [3]. However, the prevalence of asthma, as a comorbidity of patients with COVID-19, has been reported to vary from 1.10% [4] to 36.3% [5]. Additionally, the prevalence of chronic obstructive pulmonary disease (COPD) in COVID-19 ranges from 0.70% [6] to 70.60% [7] and that of asthma-COPD overlap (ACO) ranges from 0.40% [8] to 29.40% [7]. Previous reports have indicated that the global prevalence of asthma in adults is estimated to be 4.3% [9], that of COPD is estimated to be 12.16% [10], and that of ACO ranges from 0.9% to 11.1% [11]. While some studies have reported that asthma, COPD, and ACO are related to an increase in the mortality rate of COVID-19 [12, 13], some studies have reported that they may not be risk factors or may not increase the mortality of COVID-19 [14–17]. However, studies on detailed examinations of the prevalence and risk of mortality of asthma, COPD, and ACO in patients with COVID-19 are still lacking.

Therefore, this study aimed to systematically review and integrate the data from studies with various results on the prevalence of asthma, COPD, and ACO in patients with COVID-19. We also aimed to determine the mortality risks of asthma, COPD, and ACO in patients with COVID-19.

Methods

This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement and the statement by the Meta-analysis of Observational Studies in Epidemiology (MOOSE) group [18–20].

Search strategy

Two investigators (Y.U. and T.M.) independently searched for eligible studies in PubMed, the Cochrane Library, and MedRxiv from inception to 27 September 2021. We used the following key words: “asthma” OR “asthmatic” OR “COPD” OR “Chronic Obstructive Lung” OR “Chronic Obstructive Pulmonary Disease” OR “chronic bronchitis” OR “pulmonary emphysema” OR “pulmonary disease” OR “Chronic Obstructive” OR “Chronic Obstructive Airway Disease” OR “COAD” OR “Chronic Obstructive Lung Disease” OR “Chronic Airflow Obstruction” OR “Obstructive Lung Disease” OR “Obstructive pulmonary Disease” OR “Lung Disease” OR “ACO” OR “asthma-COPD overlap” OR “Asthma-chronic obstructive pulmonary disease overlap syndrome” OR “Asthma and chronic obstructive pulmonary disease overlap syndrome” OR “asthma-COPD overlap syndrome” OR “asthma-COPD” OR “ACOS” OR “mixed asthma-COPD phenotype” OR “Asthma combined with COPD” OR “coexistence of asthma and COPD” OR “coexistence of asthma and COPD” OR “COPD with asthmatic features” OR “overlap of asthma-COPD” AND “COVID-19” OR “novel coronavirus” OR “new coronavirus” OR “emerging coronavirus” OR “2019-nCoV” OR “SARS-CoV-2” OR “COVID” OR “coronavirus” OR “nCov” OR “coronavirus disease 2019” OR “coronavirus 2019”. We also reviewed the reference lists of eligible studies using Google Scholar and performed a manual search to ensure that all appropriate studies were included.

Eligibility criteria and outcome measures

Studies fulfilling the following selection criteria were included in the meta-analysis: (1) randomized, clinical trials, observational studies, and case series involving >20 patients written in English; and (2) patients with positive laboratory-confirmed SARS-CoV-2 infection who had asthma, COPD, or ACO as comorbidities. The exclusion criteria were as follows: (1) systematic reviews, (2) reviews, (3) animal experimental reports, (4) ≤20 patients in case series, (5) insufficient or incomplete data, (6) unpublished articles, and (7) pediatrics reports.

Data extraction

Two reviewers (Y.U. and T.M.) extracted the data independently. Articles that were retrieved in the search were stored in a citation manager. After removing redundant articles, titles, and abstracts, full-text articles were then investigated. We extracted the following data: study design, observational period, study site, and inclusion/exclusion criteria of each study. Outcome variables were extracted into predesigned data collection forms. We verified the accuracy of the data by comparing the collection of each investigator, and any discrepancies were resolved through discussion.

Level of evidence

The level of evidence was determined using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework, which classifies the level of evidence for each outcome on the basis of the risk of bias, imprecision, inconsistency, indirectness, and publication bias [21]. The authors classified the evidence level for each eligible study in accordance with the revised grading system for recommendation in the evidence-based guideline [22] (S1 Table).

Data analysis

In the meta-analysis, we estimated the odds ratios (ORs) or the proportions of patients for primary outcome variables with 95% confidence intervals (CIs) using the random-effects model (generic inverse variance method). To assess the proportions of the outcome variables in patients with COVID-19, the standard error was calculated using the Agresti-Coull method [23]. Heterogeneity among the original studies was evaluated using the I2 statistic [24]. Publication bias was examined using a funnel plot. For all analyses, significant levels were two-tailed, and p<0.01 was considered significant. All statistical tests were performed using Review Manager (RevMan) ver. 5.4.1 (Cochrane Collaboration, Copenhagen, Denmark) [25].

Ethics approval and consent to participate

The institutional review board and patient consent were not required because of the review nature of this study.

Results

Study selection and characteristics

Of the 2005 references screened, 101 studies reported the outcome variables (Fig 1).

Fig 1. PRISMA flow diagram.

Fig 1

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N indicates the number of articles.

We analyzed 64 studies on asthma, 71 on COPD, and 7 on ACO. Thirty-three studies were duplicated for asthma and COPD, two for asthma and ACO, and four for asthma, COPD, and ACO. Table 1 shows the characteristics of the included studies.

Table 1. The characteristics of the included studies.

Study, year Country Observational period Study Design No. of participants Sex-Male, n (%) Age, Median (IQR) or mean±SD, years Severity of COVID-19, n (%) Standard of the evidence level
Zhang JJ, 2020 [26] China Jan.16-Feb.3, 2020 - 140 71 (50.7) 57 (range, 25–87) Nonsevere 82
Severe 58		 2-
Wang L, 2020 [27] China Jan.1-Feb.6, 2020 Retrospective single-center study 339 166 69 (65–76) Moderate100(29.5) severe159(46.9) critical80(23.6) 2-
Bhatraju PK, 2020 [28] USA Feb.24-Mar.9, 2020 - 24 15 (63) 64±18 2-
Turan O, 2021 [29] Turkey Mar-Aug, 2020 Multicenter, retrospective cohort study 1069 634 >18 2-
Barrasa H, 2020 [30] Spain Mar.4-Mar.31, 2020 - 48 27 (56) 63 (12)≥18 2-
Mahdavinia M, 2020 [31] USA Mar.12-Apr.3 2020 - 935 417 ≥18 2-
Li P, 2020 [32] China Jan.31-Feb.20, 2020 - 204 100 68 (64–75) Range, 60–95 Mild 64.7%, severe 33.3%, critical 2% 2-
Lian J, 2020 [33] China Jan.17-Feb.12, 2020 retrospective 136 58 68.28±7.314 Mild 102, severe 22, critical 12 2-
Iaccarino G, 2020 [34] Italy Mar.9-Apr.9, 2020 Cross-sectional, multicenter, observational study 1591 64% 66.5±0.4 range18-101 2-
Toussie D, 2020 [35] USA Mar.10-Mar.26, 2020 Retrospective study 338 210 (62) 39 (31–45) Between 21 and 50 Low chest radiograph severity score
0–1:202
2–6:136		 2-
Argenziano M, 2020 [36] USA Mar.1-Apr.5, 2020 Retrospective case series 1000 596 Emergency department55 (40–69)
In hospital 64 (51–77)
ICU, 62 (52–72)		 2-
Cummings MJ, 2020 [37] USA Mar.2-Apr.1, 2020 Prospective cohort study 257 critical 171 (67) 62 (51–72) 2-
Zhu Z, 2020 [38] USA Mar.16 2020- Population-based prospective cohort study 641 288 (45) 56±8 Aged 40–69 2-
Grandbastien M, 2020 [39] France Mar.4-Apr.6, 2020 Monocentric, retrospective, cohort study 106 66 (62.3) 63. 5(54.2–72.0) 2-
Yao Y, 2020 [40] China -Mar.10, 2020 Retrospective, multicenter, cohort study 171 92 (53.8) 50.5±15.2 Severe 71(41.5), critical 29(17.0) 2-
Lieberman-Cribbin W, 2020 [41] USA Feb.29-Apr.24, 2020 - 6245 49% 57 2-
Wang J, 2020 [42] China Jan.24-Feb.23, 2020 Retrospective study 307 156 (50.8) 57.65±15.754 Mild/moderate 259(84.6)
Severe/critical 48(15.6)		 2-
Aggarwal A, 2020 [43] India Apr.10-Apr.30, 2020 Retrospective, single-center case series 32 19 (59.4) 54. 5 (46.25–60) Severe 24
Non-severe 8		 2-
Caminati M, 2020 [44] Italy Mar.1-Apr.30, 2020 - Brescia20
Verona6		 Brescia8
Verona3		 Brescia41-77 (mean 61.5) Verona55-79 (69.3) 2-
Bello-Chavolla OY, 2020 [4] Mexico -June.3, 2020 Population-based statistics 20804 12257 (58.9) ≥ 60 2-
Bravi F, 2020 [45] Italy -Apr.24, 2020 Case-control, retrospective study 1603 47.3% 58.0 (20.9) All adults Mild957
Severe454
Very severe/lethal192		 2-
Song J, 2021 [46] China Feb.1-Mar.6 2020 Retrospective observational study 961 500 (52.0) 63 (49–70) Nonsevere719(74.8) Severe242(25.2) 2-
Wang L, 2020 [47] USA Mar .3-June.8, 2020 - 1827 595 54 (37–66) Hospitalized 565, Non-hospitalized 1262 2-
Canevelli M, 2020 [48] Italy Feb.21-Apr.29, 2020 - 2687 1807 Natives 78.3±10.8
Migrants 71.1±13.1		 2-
De Vito A, 2020 [49] Italy Mar.8-Apr.8, 2020 Retrospective, monocentric study 87 56 (64.4) 72 (62.5–83.5) 2-
Atkins JL, 2020 [50] UK Mar.16-Apr.26, 2020 - 507 311 74.3 (4.5) Aged 65 and older 2-
Zhao Z, 2020 [51] USA Mar.9-Apr.20, 2020 Retrospective study 641 Died 53 (64.6), ICU admission136 (69.7) General admission222 (55.8) Died 77 (66–85) ICU admission 60 (50–70) General admission 58 (46–71) 2-
Pérez-Sastré MA, 2020 [52] Mexico Feb.28-June.21, 2020 - 159017 (52.2) ≥20 2-
Guner R, 2020 [53] Turkey Mar.10-Apr.10, 2020 - 222 132 (59.5) 50.6±16.5 (18–93) Mild172
Critical50		 2-
Somani SS, 2020 [54] USA Feb.27-Apr.12 Retrospective cohort study 2864 1663 ≥18 2-
Yang JM, 2020 [55] Korea Jan.1-May.15, 2020 Propensity-score-matched nationwide cohort 7430 2970 (40.5) 49.0±19.9 2-
Campioli CC, 2020 [56] USA Feb.1-May.15, 2020 Retrospective study 251 103 (41.0) 53 (27) adult 2-
He Y, 2020 [57] China Jan.20-Apr.1　2020 - 336 201 (59.8) 65 (50–77) severe 2-
Mushtaq J, 2021 [58] Italy Feb.25-Apr.9, 2020 Retrospective single-center study 697 465 (66.7) 62 (52–75) 2-
Goel N, 2020 [59] India May.8-July.3, 2020 Retrospective observational study 35 20 (57.1) 46±17 Symptomatic 29(82.9%), asymptomatic 6(17.1%) 2-
Brendish NJ, 2020 [60] UK Mar.20-Apr.29, 2020 Prospective, interventional, non-randomised study 352 202 (57.4) 68 (50–80) 2-
Ioannou GN, 2020 [61] USA Feb.28-May.14, 2020 Longitudinal cohort study 10131 9221 (91.0) 63.6 (16.2) ≥18 2-
Xiong Q, 2021 [62] China -Mar.1, 2020 Longitudinal study 538 245 (45.5) 52.0 (41.0–62.0) From 20 to 80 General 331(61.5), severe 180(33.5), critical 27(5) 2-
Seaton RA, 2020 [63] UK Apr.20-30, 2020 - 531 274 (51.6) 72(61–82) Range25-104 2-
Abrams MP, 2020 [64] USA Mar.1-Apr.3, 2020 cohort 133 74 (55.6) 81.0 (70.5–88.0) Arrhythmic death11
Nonarrhythmic death122		 2-
Akpinar G, 2021 [65] Turkey Mar.1-May.31, 2020 Retrospective cross-sectional design 88 46 48.0±17.3 2-
Schiavone M, 2021 [66] Italy Feb.23-Apr.1, 2020 Retrospective study 844 521 (61.7) 63.4±16.1 2-
Calmes D, 2020 [67] Belgium Mar.18-Apr.17 2020 - 596 294 ≥35 2-
Rial MJ, 2021 [68] Spain Mar-June, 2020 Multicenter retrospective cohort 35 14 ≥20 2-
Robinson LB, 2020 [69] USA Mar.8-Apr.27, 202 Matched cohort study 403 191 ≥18 2-
Cates J, 2020 [70] USA Mar.1-Mar.31, 2020 - 3948 3710 (94.0) 70 (61–77) 2-
Şanlı DET, 2020 [71] Turkey Mar.11-Apr.11, 2020 Local institutional reveiw 102 73 (72) 48.62±14.42
Ranging 19–94		 2-
Hussein MH, 2020(USA) [72] USA Mar.15-June.9, 2020 Multi-center retrospective study 502 238 Mean age 60.7 ≥18 qSOFA score, CURB65 score 2-
Liao SY, 2021(USA) [5] USA Mar.11-June.23, 2020 Prospective observational study 113 53 (47) 50±16 2-
Tabarsi P, 2021 [73] Iran ? Randomized controlled trial 84 65 IVIg, 54.29±12.85
Control group, 52.47±14.49
Between 18 and 65		 All severe patients 1-
Lee SC, 2020 [74] Korea Jan.20-May.27 2020 Retrospective cohort study 7272 2927 ≥20 Non-severe, severe 2-
Jiang Y, 2020 [75] China Jan.30-Mar.8, 2020 Retrospective observational study 281 143 ≥60 2-
Xiao J, 2020 [76] China Dec.25, 2019-Feb.16, 2020 Retrospective single-center study 243 105 (43.2) 47.0 (range20-89) Moderate203, severe/critical 40 2-
Signes-Costa J, 2021 [77] Spain Mar.23-May.5, 2020 Retrospective, multicenter, cohort study 5847 3432 65.1±16.6 2-
Bello-Chavolla OY, 2020 [78] Mexico Mar.16-Aug.17, 2020 - 3007 Non-severe1227 (50.5)
Severe403 (70.1)		 Non-severe 44 (33–55) Severe 56 (47–66) Non-severe2432
Severe 575		 2-
Lokken EM, 2020 [79] USA Jan.21-Apr.17, 2020 Retrospective study 46 0
Pregnant women		 29 (26–34) 2-
Gómez Antúnez M, 2021 [80] Spain Mar 2020 Retrospective cohort study 10420 5893 (56.7) 69 (55–79) 2-
Ferastraoaru D, 2021 [8] USA Mar.14-Apr.27, 2020 Retrospective study 4558 (31.8) Asthma 60.5±17.07 2-
Monterrubio-Flores E, 2021 [81] Mexico Feb.28-July.31, 2020 - 406966 216908 (53.2) ≥20 2-
Mortaz E, 2021 [82] Iran Apr.10-May.9, 2020 retrospective observational study 29 17 54.45±2.536 (range, 32–79) 2-
Değerli E, 2021 [83] Turkey Mar.23-Oct.23, 2020 Retrospective study 45 23 (51) 60.3±15.65 2-
Laake JH, 2020 [84] Norway Mar.10-June.19, 2020 National cohort 217 162 63 (54.2–72.2) 2-
Lee SC, 2021 [85] Korea Jan.20-May.27, 2020 Retrospective cohort study 4610 1710 ≥40 2-
Jungo S, 2021 [86] France Apr.1-Apr.29, 2020 - 79 37 (46.8) 44 (36–53)
Range, 21–86		 COVID-19-related phenotypes 68(86.1) 2-
Cao L, 2021 [87] USA Mar-Sep, 2020 Prospectively collected cohort 343 192 >18 2-
Fong WCG, 2021 [88] UK Mar.1-May.31, 2020 retrospective 6638(with, w/o covid) 3079 (46.4) 65 (42–79) 2-
Jongbloed M, 2021 [89] Netherland Feb.28-Apr.1, 2020 Retrospective cohort study 303 195 (64) 72±12 2-
Artero A, 2021 [90] Spain Mar.1-May.28, 2020 Multicenter retrospective cohort study 10238 5924 (57.9) 66.6±16.2 2-
Ho KS, 2021 [91] USA Mar.7-June.7, 2020 Retrospective multicenter cohort study 10523 5707 58.35±18.81 2-
Yoshida Y, 2021 [92] USA Feb.27-July.15, 2020 Retrospective case series 776 365 (47.3) 60.5 (16.1) >18 2-
Nanda S, 2021 [93] USA Jan.1-May.23, 2020 retrospective 1169 575 (49.2) 43.9 (17.6) [range18.0–99.0] 2-
De Vito A, 2021 [94] Italy Apr.9-May.31, 2020 Observational retrospective cohort study 264 99 (37.5) 81.93±10.11 Symptomatic 132
Asymptomatic 132		 2-
Rodriguez C, 2021 [95] France Mar.9-30, 2020 - 104 59 Outpatient 50 (range, 19–87) Hospitalized 61 (31–82) ICU, 68 (33–90) 2-
Garibaldi BT, 2021 [96] USA Mar.4-Aug.29, 2020 Retrospective comparative effectiveness research 2299 1193 adults All remdesivir, 60 (46–69) All control, 60 (44–74) 2-
Giovannetti G, 2021 [97] Italy May.18-July.25, 2020 Prospective observational study 38 27 (71.1) 60.6 (10.4)
Between 18 and 75		 Mild11(28.9)
Moderate11(28.9)
Severe3(7.9)		 2-
Khan MS, 2021 [98] USA Jan.1-June.15, 2020 Retrospective, observational cohort study 470 224 (47.7) ≥18 2-
Tsai S, 2021 [99] USA Feb.24-Nov.25, 2020 Retrospective cohort 8308 0 All women 50.69±12.80 Adult 2-
Lobelo F, 2021 [100] USA Mar.3-Oct.29, 2020 Retrospective cohort 5721 2416 (42.2) 44.8 (15.7) ≥18 2-
Chatterjee A, 2021 [101] Netherland Mar.1-July.1, 2020 Retrospective study 2337 Non-mortality1078 (60.9)
Mortality393 (69.2)		 Non-mortality, 65 (55–75)
Mortality, 77 (70–83)		 Non-mortality1769
Mortality568		 2-
Yordanov Y, 2021 [102] France Mar.9-Aug.11, 2020 Prospective cohort 7320 2301 (31.5) 43.0±13.9 2-
Riou M, 2021 [103] France June-Dec, 2020 descriptive 81 59 (73) 61 (51–68) Mild-to-moderate 21, severe 15, critical 45 2-
Wei W, 2021 [104] USA June.1-Dec.9, 2021 Retrospective study 206741 85228 46.7 (17.8) ≥18 - 2-
Hou X, 2021 [105] China Jan.28-Feb.25, 2020 Single-center retrospective cohort study 113 61 (54) 55.1±14.2 Severe113 2-
Valverde-Monge M, 2021 [106] Spain Jan.31-Apr.17, 2020 Retrospective analysis 2539 1275 NCRD 61.1±19.3, CRD 71.4±14.8 - 2-
Cosio BG, 2021 [107] Spain Mar.15-Apr.30, 2020 Case-control study 52 48 (92.3) 72.96±10.75 - 2-
Adir Y, 2021 [108] Israel Mar.1-Dec.7, 2020 Case-control study 8242 4343 43.3±20.4 Moderate, severe 2-
Sen P, 2021 [7] USA Mar.8-Sap.16, 2020 - 1288 499 (38.8) 63.7 (15.2)≥35 - 2-
Chandel A, 2021 [6] USA Mar.1-June.9, 2020 Multicenter retrospective observational study 272 180 57±13 - 2-
Chaudhary S, 2021 [109] USA Mar.15-May.10, 2020 Single-center retrospective observational study 128 71 68 (61–75.5) All adult - 2-
Williamson EJ, 2020 [110] UK Feb.1-May.6, 2020 Cohort study 10926 6126 (0.07) ≥18 - 2-
Abayomi A, 2021 [111] Nigeria Feb.27-Jul.6, 2020 Retrospective cohort study 2075 1379 40 (32–50) Range18-98 Mild/asymptomatic 1179, moderate 743, severe 107, critical 42 2-
Liu YH, 2021 [112] China Feb.10-Apr.10, 2020 Cross-sectional study 1539 738 (47.95) 69 (66–75) Severe238
Non-severe1301		 2-
Munblit D, 2021 [113] Russia Dec.2-Jan.14, 2020 Longitudinal cohort study 1358 675 57 (47–67) Mild841(61.9)
Moderate479(35.3)
Severe38(2.8)		 2-
Sandoaval M, 2021 [114] USA Mar.1-Dec.7, 2020 Retrospective registry-based chart reveiw 1853 704(38.0) 24 (21–27) From 18 to 29 - 2-
Lokken EM, 2021 [115] USA Mar.1-June.30, 2020 Multicenter retrospective cohort study 240 0 (pregnant woman) 28 (24–34) Mild218(90.8)
Severe18(7.5)
Critical4(1.7)		 2-
Cataño-Correa JC, 2021 [116] Colombia Mar-Aug, 2020 - 399 235(58.9) >18 - 2-
Meza D, 2021 [117] USA Feb.2021 - 387008 COPD 3949, no COPD 126324 COPD 70.5, no COPD 57.9 Aged over 35 - 2-
Sun Y, 2021 [118] China Feb.2-Mar.25, 2020 Retrospective study 268 139(51.9) 57.75 (67–73) Range, 20–88 Severe 96
Non-severe 172		 2-
Fernández-Martínez NF, 2021 [119] Spain Mar.1-Apr.15, 2020 Observational longitudinal study 968 530(55) 67 (55–77) - 2-
Cosma S, 2021 [120] Italy Sep.20-Jan.9, 2020 Case-control study 21 0 ≥18 - 2-
Chudasama YV, 2021 [121] UK Mar.16-July.26, 2020 - 1706 981(57.5) 68 (range48-85) severe 2-
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IQR, Interquartile range; SD, Standard deviation; NCRD, non-chronic respiratory disease; CRD, chronic respiratory disease

In the 101 included studies, we identified 1,229,434 patients with COVID-19, and 32,301, 10,827, and 818 had asthma, COPD, and ACO, respectively, as the comorbidities. Among the studies, there were 34 reports from USA, 14 from China, 10 from Italy, 8 from Spain, 6 from the UK, 5 from Turkey, 4 from Mexico, 3 from Korea, 2 from the Netherlands, 2 from Iran, and 1 each from Israel, Nigeria, Russia, Norway, and Columbia. The study designs were 52 retrospective studies, 7 prospective studies, 1 population-based statistics, 2 matched cohort studies, 4 longitudinal cohort studies, 2 local institutional reviews, 1 randomized, controlled trial, 2 nation cohort studies, 1 descriptive study, 3 case–control studies, 2 cross-sectional studies, and 24 with an unknown design. The total number of male patients was 616,380 and that of female patients was 737,188. Among the studies, the severity of patients with COVID varied from asymptomatic to a critical condition.

Frequency of asthma, COPD, and ACO in patients with COVID-19

The overall prevalence of asthma, COPD, and ACO was estimated, and their forest plots are shown in Figs 2–4, respectively.

Fig 2. Forest plots of the prevalence of asthma in patients with COVID-19.

Fig 2

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Fig 4. Forest plots of the prevalence of ACO in patients with COVID-19.

Fig 4

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Among the eligible patients with COVID-19, the prevalence of asthma, COPD, and ACO was 10.04% (95% CI, 8.79–11.30) for asthma (Fig 2), 8.18% (95% CI, 7.01–9.35) for COPD (Fig 3), and 3.70% (95% CI, 2.40–5.00) for ACO (Fig 4). In the stratified analysis, the frequencies of asthma in different countries are shown in Table 2, and their forest plots are shown in S1 Fig.

Fig 3. Forest plots of the prevalence of COPD in patients with COVID-19.

Fig 3

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Table 2. Estimated frequencies of asthma, COPD, and ACO in patients with COVID-19 according to countries.

Asthma COPD ACO
Country No. of studies No. of patients Estimated frequency (95% CI) No. of studies No. of patients Estimated frequency (95% CI) No. of studies No. of patients Estimated frequency (95% CI)
USA 28 26692 11.14 (9.55–12.73) 19 4600 10.48 (7.56–13.40) 6 418 4.24 (2.74–5.73)
Mexico 2 452 1.57 (0.69–2.45) 2 1329 3.60 (-1.50–8.70) - - -
UK 6 1729 13.45 (11.23–15.66) 3 123 8.69 (-0.83–18.22) 1 21 1.20 (0.61–1.79)
Italy 3 28 0.10 (0.09-.011) 6 599 11.09 (5.64–16.54) - - -
Spain 3 544 5.83 (4.44–7.23) 6 2651 8.84 (5.77–11.91) - - -
France 4 860 13.50 (9.08–17.92) 4 99 2.60 (0.33–4.88) - - -
Netherland 2 257 9.72 (8.61–10.83) 2 482 17.00 (12.96–21.04) - - -
Turkey 2 6 3.58 (0.02–7.13) 4 86 8.23 (3.47–12.98) - - -
Iran - - - 2 4 3.84 (-4.25–11.93) - - -
India 2 6 8.57 (0.98–16.16) 2 8 11.34 (3.24–19.44) - - -
China 2 112 9.42 (-4.69–23.53) 13 309 4.93 (2.89–6.96) - - -
Korea 2 1411 9.65 (9.16–10.14) 2 491 3.96 (2.30–5.63) - - -
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With regard to the frequency of asthma, France showed a rate of 13.50% (95% CI, 9.08–17.92), which was the highest, followed by 13.45% in the UK (95% CI, 11.23–15.66). The frequency of COPD in patients with COVID-19 was the highest in the Netherlands at 17.00% (95% CI, 12.96–21.04), followed by India at 11.34% (95% CI, 3.24–19.44). The frequency of ACO on the USA and the UK was 4.24% (95% CI, 2.74–5.73) and 1.20% (95% CI, 0.61–1.79), respectively. The forest plots of these data are shown in supplementary figures (S1 Fig).

Prevalence of death in patients with COVID-19 and asthma or COPD

Forest plots of the prevalence of death in patients with COVID-19 and asthma or COPD are shown in Fig 5A and 5B.

Fig 5.

Fig 5

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Forest plots of the prevalence of death a) in patients with asthma and COVID-19 and b) in patients with COPD and COVID-19.

Among 4,980 patients with asthma and COVID-19, the prevalence of death was 10.17% (95% CI, 7.38–12.97) (Fig 5A). Among 10,525 patients with COPD and COVID-19, the prevalence of death was 40.60% (95% CI, 32.02–49.17) (Fig 5B).

Risk of mortality due to COVID-19 in patients with asthma or COPD

The risk to mortality due to COVID-19 in patients with asthma or COPD was estimated and it is shown in forest plots in Fig 6.

Fig 6.

Fig 6

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Forest plots of the risk of mortality in patients with COVID-19 and a) asthma or b) COPD.

The risk of mortality in pre-existing asthma in COVID-19 patients was not significant (OR, 0.89; 95% CI, 0.55–1.43; p = 0.630) (Fig 6A). However, the risk of mortality in pre-existing COPD in COVID-19 patients was significant (OR, 3.79; 95% CI, 2.74–5.24; p<0.001) (Fig 6B).

Discussion

The present systematic review and meta-analysis on 101 studies showed that pre-existing asthma and COPD affected the incidence of COVID-19, and asthma had a greater effect than COPD. However, pre-existing asthma did not have a significant effect on mortality in patients with COVID-19, while patients with COPD had a 3.8-fold increased risk of mortality among COVID-19 cases. Among patients with COVID-19, the highest prevalence of asthma was observed in France followed by the UK, while the highest prevalence of COPD was observed in the Netherlands followed by India. The various prevalence of these disease in each county indicates the importance of daily clinical control of asthma, COPD, and ACO for preventing and reducing the severity of COVID-19.

The COVID-19 pandemic has disproportionately affected people with chronic diseases, such as asthma and COPD, which are the most common respiratory diseases. Generally, viral infection to the respiratory tract is thought to be one of the triggers for the exacerbation of pre-existing diseases [110]. Respiratory viral infection that is initiated in the upper respiratory tract and innate immunity are critical for the initial control of infection at this site [122]. If the innate immune response is inadequate, the infection can spread to the lower respiratory tract, causing pneumonia [123]. Before the COVID-19 pandemic, the reported global prevalence of adult asthma and COPD was 3.5% [9] and 12.16% [10], respectively. However, in patients with COVID-19 in the present study, which assessed studies published after COVID-19 emerged, the prevalence of pre-existing asthma was 10.04% and that of COPD was 8.18%. The prevalence of asthma after COVID-19 emerged was higher than that before the pandemic. These results indicated that asthma affected the incidence of COVID-19. The increased susceptibility of viral infection in the bronchial airway might be caused by pathophysiological impairment in both of these diseases. Especially in asthma, the main involved sites of the bronchial airway are the upper and lower bronchi [124]. In case of COVID-19, more than 80% of patients have mild illness [123], and the locations where mild COVID-19 is involved are similar to those in patients with asthma. Consequently, the number of patients with asthma may have increased as the number and proportion of mild COVID-19 cases increased. This possibility may also explain why the prevalence of pre-existing asthma was higher than that of COPD. In fact, the Omicron variant was associated with a large number of mild COVID-19 cases [125]. Additionally, a previous meta-analysis, which used only data before the Omicron variant emerged, reported that the prevalence of asthma was similar to that before the COVID-19 pandemic [126]. This result is different from that in the present study, which assessed COVID-19 cases that included infected patients with the Omicron variant. However, a study including hospitalized COVID-19 cases with a history of asthma indicated that none of these patients presented with asthma exacerbation [127]. Owing to the nature of the meta-analysis, we could not evaluate asthma exacerbation after admission among the patients in this study.

The present study showed that pre-existing COPD in patients had a 3.8-fold higher risk of mortality than in those who did not have COPD. The risk of mortality for pre-existing COPD was stronger than that for pre-existing asthma. Unlike asthma, of which the main involved sites are the upper and lower bronchi, the main impaired lesion of COPD extends from the peripheral small airway to alveolar tissues with architectural damage, which can cause the severe illness. These locations of lesions are compatible with those in COVID-19 when the disease severity is moderate to severe. Indeed, patients with COPD have a high risk of mortality in other respiratory infectious diseases, such as influenza [128] and community-acquired pneumonia [129]. A previous study showed that the long-term use of inhaled corticosteroids for controlling asthma is likely to have a beneficial modulatory effect on COVID-19 [130]. This finding suggests that this efficacy is achieved by reducing epithelial damage and improving the T-cell response. Several studies reported a large number of patients who were receiving either inhaled steroids or systemic steroids at the time of COVID-19 diagnosis [55, 127, 131, 132]. However, the effect of inhaled corticosteroids at the early stage of COVID-19 is controversial [133]. The benefit of systemic corticosteroids for patients with asthma may outweigh the risk of severe outcomes in patients with COVID-19 [134]. Systemic corticosteroids are effective for treating bronchial wall inflammation and bronchial spasm. As the result, uncontrolled asthma is associated with increased intensive care unit admission and intensive respiratory support [135], whereas well-controlled asthma does not have an increased risk of COVID-19-related death [136]. The present study showed that the prevalence of pre-existing asthma in COVID-19 cases varied according to the countries. This finding may be partly due to the fact that each country has different treatment policies and guidelines, as well as available medical resources. In addition, owing to the nature of the meta-analysis in which we did not use individual patient data, we were unable to examine the impact on COVID-19 diagnosis according to age, sex, and stage at which therapy was started. These differences may also influence the severity of COVID-19 in different countries. These factors may be also related to the heterogeneity in the results of the meta-analysis in the present study. A large-sample study showed that the contribution of inhaled corticosteroids for patients with COPD to COVID-19-related death was lower than that for patients with asthma [137]. Additionally, the association with mortality was confounded by the presence of other risk factors for severe COVID-19, such as an older age, cardiovascular disease, hypertension, and diabetes mellitus [123], which are common in people with COPD.

ACO has clinical characteristics derived from asthma and COPD. The risk of mortality from ACO in patients with COVID-19 might be significant and as high as that for COPD. However, in the present study, the prevalence of pre-existing ACO was lower than that of asthma and COPD. Our results regarding ACO cannot be properly assessed because of the number of eligible studies, and the countries that reported pre-existing ACO were only from the USA, UK, and China among the eligible studies. These issues might be due to the short history of the concept of ACO and a lack of global recognition. However, even with the small number of eligible studies, the prevalence of ACO was highest in studies from the USA. Additionally, a study in the USA before the COVID-19 pandemic reported that the prevalence of ACO was 1.05% (0.74%–1.37%) [138], while that in the present study was 4.24%. One of the reasons for this discrepancy between studies may be related to the high smoking rate (14%) in the USA [139–141]. This discrepancy suggests the necessity of considering other cofounding factors for assessing the risk of ACO, such as the rate of smokers and obesity.

Our study has some limitations, including mainly those inherent to the nature of systematic reviews and meta-analyses using observational studies and case series. The eligible studies were limited to articles written in English. The treatment guidelines and available medical resources for COVID-19, and the examined comorbidities may be different according to the different countries, and these could have affected the risk of infection and mortality of COVID-19. The eligible studies were selected from published papers during 1 year and 9 months from the beginning of the COVID-19 pandemic. We were not able to evaluate the change in the risk of COVID-19 caused by the change in SARS-CoV-2 variants and the vaccination availability during this observational period.

Despite these limitations, the present systematic review and meta-analysis of 101 studies suggests the importance of daily clinical management for patients with asthma, COPD, or ACO. Additionally, this study suggests that attention should be paid to the prevention of COVID-19 infection and disease progression, as well as to patients with other high-risk diseases of COVID-19.

Conclusion

The present systematic review and meta-analysis using 101 studies shows that pre-existing asthma and COPD are associated with the incidence of COVID-19. Asthma has a stronger influence on the incidence of COVID-19 than COPD. The presence of COPD as a comorbidity in patients with COVID-19 has a 3.8 times higher risk of mortality, while asthma has no significant effect on COVID-19 related death. These differences appear to be affected by the difference in locations of disease pathophysiology, and by the daily diagnosis and treatment policy of each country.

Supporting information

S1 Checklist

(DOCX)

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S1 Table. Classification standard of the evidence level.

(DOCX)

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S1 Fig. Forrest plots for prevalence of asthma among patients with COVID-19.

(PDF)

Click here for additional data file. (1.1MB, pdf)
S2 Fig. Forrest plots for prevalence of COPD among patients with COVID-19.

(PDF)

Click here for additional data file. (1.3MB, pdf)
S3 Fig. Forrest plots for prevalence of ACO among patients with COVID-19.

(PDF)

Click here for additional data file. (231.6KB, pdf)

Acknowledgments

We thank Ellen Knapp, for editing a draft of this manuscript.

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

This work was supported by a Grant-in-Aid for Scientific Research (KAKENHI, Promotion of Joint International Research B, #20KK0218), and a grant from Japan Science and Technology (JST), JST-Mirai Program (#20345310). The funders had no role in the design, methods, participant recruitment, data collection, analysis, or preparation of the paper. There was no additional external funding received for this study.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Checklist

(DOCX)

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S1 Table. Classification standard of the evidence level.

(DOCX)

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S1 Fig. Forrest plots for prevalence of asthma among patients with COVID-19.

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S2 Fig. Forrest plots for prevalence of COPD among patients with COVID-19.

(PDF)

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S3 Fig. Forrest plots for prevalence of ACO among patients with COVID-19.

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Data Availability Statement

All relevant data are within the paper and its Supporting Information files.

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