Effect of comorbid pulmonary disease on severity of COVID-19: A systematic review and meta-analysis

Abstract

Coronavirus disease 2019 (COVID‐19) caused by infection with severe acute respiratory syndrome coronavirus 2 was first detected in Wuhan, China, in late 2019 and continues to spread worldwide. Persistent questions remain about the relationship between the severity of COVID‐19 and comorbid diseases, as well as other chronic pulmonary conditions. In this systematic review and meta‐analysis, we aimed to examine in detail whether the underlying chronic obstructive pulmonary diseases (COPD), asthma and chronic respiratory diseases (CRDs) were associated with an increased risk of more severe COVID‐19. A comprehensive literature search was performed using five international search engines. In the initial search, 722 articles were identified. After eliminating duplicate records and further consideration of eligibility criteria, 53 studies with 658,073 patients were included in the final analysis. COPD was present in 5.2% (2191/42,373) of patients with severe COVID‐19 and in 1.4% (4203/306,151) of patients with non‐severe COVID‐19 (random‐effects model; OR = 2.58, 95% CI = 1.99–3.34, Z = 7.15, p < 0.001). CRD was present in 8.6% (3780/44,041) of patients with severe COVID‐19 and in 5.7% (16,057/280,447) of patients with non‐severe COVID‐19 (random‐effects model; OR = 2.14, 95% CI = 1.74–2.64, Z = 7.1, p < 0.001). Asthma was present in 2.3% (1873/81,319) of patients with severe COVID‐19 and in 2.2% (11,796/538,737) of patients with non‐severe COVID‐19 (random‐effects model; OR = 1.13, 95% CI = 0.79–1.60, Z = 0.66, p = 0.50). In conclusion, comorbid COPD and CRD were clearly associated with a higher severity of COVID‐19; however, no association between asthma and severe COVID‐19 was identified.

Full text

SYSTEMATIC REVIEW
Effect of comorbid pulmonary disease on the severity
of COVID-19: A systematic review and meta-analysis
Askin Gülsen
1,2
| Inke R. König
3
| Uta Jappe
1,2
| Daniel Drömann
4
1
Division of Clinical and Molecular Allergology,
Research Center Borstel, Leibniz Lung Center,
Airway Research Center North (ARCN), Member
of the German Center for Lung Research (DZL),
Borstel, Germany
2
Interdisciplinary Allergy Outpatient Clinic,
Department of Pneumology, University of
Luebeck, Luebeck, Germany
3
Institute of Medical Biometry and Statistics,
Airway Research Center North (ARCN), Member
of the German Center for Lung Research (DZL),
University of Luebeck, Luebeck, Germany
4
Department of Pneumology, Airway Research
Center North (ARCN), Member of the German
Center for Lung Research (DZL), University of
Luebeck, Luebeck, Germany
Correspondence
Askin Gülsen, Interdisciplinary Allergy Outpatient
Clinic, Department of Pneumology, University of
Luebeck, Ratzeburger Allee 160, 23782
Lübeck, Germany.
Email: askin.guelsen@uksh.de
Funding information
Funding of the Federal Ministry of Education and
Research (BMBF) (German Center for Lung
Research)
Associate Editor: Conroy Wong;
Senior Editor: Philip Bardin
Abstract
Coronavirus disease 2019 (COVID-19) caused by infection with severe acute respira-
tory syndrome coronavirus 2 was first detected in Wuhan, China, in late 2019 and
continues to spread worldwide. Persistent questions remain about the relationship
between the severity of COVID-19 and comorbid diseases, as well as other chronic
pulmonary conditions. In this systematic review and meta-analysis, we aimed to
examine in detail whether the underlying chronic obstructive pulmonary diseases
(COPD), asthma and chronic respiratory diseases (CRDs) were associated with an
increased risk of more severe COVID-19. A comprehensive literature search was per-
formed using five international search engines. In the initial search, 722 articles were
identified. After eliminating duplicate records and further consideration of eligibility
criteria, 53 studies with 658,073 patients were included in the final analysis. COPD
was present in 5.2% (2191/42,373) of patients with severe COVID-19 and in 1.4%
(4203/306,151) of patients with non-severe COVID-19 (random-effects model;
OR = 2.58, 95% CI = 1.99–3.34, Z = 7.15, p < 0.001). CRD was present in 8.6%
(3780/44,041) of patients with severe COVID-19 and in 5.7% (16,057/280,447) of
patients with non-severe COVID-19 (random-effects model; OR = 2.14, 95%
CI = 1.74–2.64, Z = 7.1, p < 0.001). Asthma was present in 2.3% (1873/81,319) of
patients with severe COVID-19 and in 2.2% (11,796/538,737) of patients with non-
severe COVID-19 (random-effects model; OR = 1.13, 95% CI = 0.79–1.60, Z = 0.66,
p = 0.50). In conclusion, comorbid COPD and CRD were clearly associated with a
higher severity of COVID-19; however, no association between asthma and severe
COVID-19 was identified.
KEYWORDS
coronavirus disease, COVID-19, lung diseases, meta-analysis, SARS-CoV-2, systematic review
INTRODUCTION
Coronavirus disease 2019 (COVID-19) caused by infection
with severe acute respiratory syndrome (SARS) coronavirus
2 (SARS-CoV-2) was first detected in Wuhan, China, in late
2019 and continues to spread worldwide. COVID-19 can
progress to debilitating pneumonia and SARS, particularly in
elderly patients.
1
As of 29 November, 61.8 million cases of
COVID-19, including 0.5 million new cases, have been
reported worldwide with 1.4 million deaths.
2
The current
global recovery rate is 69.0%, and case fatality rates range
from 1.3% to 9.8% depending on the country, with an
average of 2.3% worldwide.
3
Unlike past outbreaks of Middle
East respiratory syndrome and SARS-CoV, COVID-19 has
higher rates of human-to-human transmission and infectivity
and a lower mortality rate.
4,5
Although there is not yet a clear
consensus on treatment strategies for COVID-19, various
combinations of drugs, including anti-malaria, anti-viral and
biological agents, have been used based on data obtained
from short-term experience with the disease.
It is of vital importance to identify patients at high risk for
severe COVID-19 as early as possible to interrupt the chain of
infection by isolating them from the community. In a retro-
spective study investigating 85 fatal cases of COVID-19, Du
Received: 30 August 2020 Accepted: 24 February 2021
DOI: 10.1111/resp.14049
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the
original work is properly cited.
© 2021 The Authors. Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.
Respirology. 2021;1–14. wileyonlinelibrary.com/journal/resp 1

et al.
6
reported that the average age of patients who died from
COVID-19 was 65.8 years, with a 72.9% male predominance
and a high prevalence of comorbid diabetes, especially hyper-
tension and coronary heart disease. Arrhythmia, acute respira-
tory distress syndrome, shock and respiratory failure were
reported in 60.0%, 74.1%, 81.2% and 94.1% of patients, respec-
tively. Therefore, the importance of identifying patients with
COVID-19 and comorbid disease has clearly been established.
Based on epidemiological data from patients with COVID-
19 in China, the prevalence of comorbid chronic respiratory
disease (CRD) and comorbid chronic obstructive pulmonary
disease (COPD) was 1.4% and 2.4%, respectively.
7
The diseases
specified as CRD were not defined in this study.
7
Data on
comorbid asthma remain unclear and are likely to be highly
under-reported. Various bacteria, including Pseudomonas
aeruginosa and Staphylococcus aureus,andotherrespiratory
viruses affect the mortality and morbidity associated with
chronic pulmonary diseases by inducing disease exacerbations
and causing community-acquired pneumonia.
8,9
Forthisrea-
son, it has long been recommended that COPD patients
undergo routine influenza and pneumococcal vaccinations
according to the Global Initiative for Chronic Obstructive Lung
Disease (GOLD) guidelines and that patients with moderate-
to-severe asthma undergo influenza vaccination according to
the Global Initiative for Asthma (GINA) guidelines.
10,11
In
addition, these patients are known to be more susceptible to
respiratory infections due to the use of inhaled corticosteroids,
bacterial colonization and microbiome changes in the lung,
mucus overproduction, systemic inflammation, smoking his-
tory and nutritional disorders.
12
It is not yet known how
inhaled corticosteroids and biological drugs affect the course of
COVID-19. COVID-19 seems to create different clinical sce-
narios, so the possible beneficial or harmful effects of these
drugs should be clarified as soon as possible.
Although Chen et al.
13
reported that comorbid COPD did
not increase the severity of COVID-19, a preliminary meta-
analysis including seven studies reported that patients with
COPD did experience more severe COVID-19.
14
In addition,
activesmokersorCOPDpatientswerereportedinanother
study to have increased mortality rates.
15
Besides, advising
high-risk patients with comorbid diseases to self-isolate at
home may have resulted in fewer hospitalizations in this group
and, consequently, decreased representation in relevant studies.
Therefore, persistent questions remain about the increased sus-
ceptibility of patients with comorbid COPD and other chronic
pulmonary conditions to COVID-19 infections in general and
severe disease course in particular.
16
Accordingly, in this sys-
tematic review and meta-analysis, we aimed to compare the
prevalence of COPD, asthma and undefined CRDs in severe
and non-severe COVID-19 patients, and to examine their
associated risk of a more severe course of COVID-19.
METHODS
Included articles were evaluated according to the Preferred
Reporting Items for Systematic Reviews and Meta-Analysis
(PRISMA) statement.
17
In addition, our meta-analysis was
recorded in the International Prospective Register of Sys-
tematic Reviews (PROSPERO) (https://www.crd.york.ac.uk/
prospero; registration number: CRD42020179122).
Literature search strategy
A comprehensive literature search was performed using five
international search engines with the Cochrane Library, Goo-
gle Scholar, PubMed, Scopus and Web of Science databases.
The following search terms were used to identify relevant
studies available prior to 20 October 2020: ‘COVID-19’OR
‘2019-nCoV’OR ‘SARS-CoV-2’OR ‘novel coronavirus’
AND ‘COPD’OR ‘asthma’OR ‘respiratory disease’AND
‘clinical characteristics’OR ‘risk factor’. The details of our
search strategy are shown in Table S1 in the Supporting
Information. In the initial search, 327 articles were identified.
On 19 October 2020, we re-scanned the databases, and an
additional 395 articles were identified.
Inclusion and exclusion criteria
Articles identified through this search strategy were then
evaluated with consideration of this study’s eligibility criteria,
namely: (1) comparative studies (non-severe vs. severe dis-
ease); (2) epidemiological studies (cross-sectional, observa-
tional, retrospective or prospective); and (3) diagnosis of
COVID-19 based on clinical, radiological and microbiologi-
cal evaluations according to the World Health Organization
criteria.
Case reports/series, editorial letters, reviews, non-English
language articles and studies that did not compare non-
severe to severe COVID-19 were excluded from this analysis.
‘Non-severe’cases were defined using various terminologies
in different studies, including non-severe, mild, common-
type, good outcome, recovered, no need for invasive mechan-
ical ventilation (IMV), no need for intensive care unit (ICU)
treatment, discharged and survivors. ‘Severe’cases were also
defined in different ways, including critical, poor outcome,
severe, refractory to treatment, need for IMV, need for ICU
and non-survivors. The study flow diagram is shown in
Figure 1.
Data extraction
These articles were scanned in detail according to the
inclusion criteria, and the resultant studies were sub-
jected to quality evaluations and data extraction by two
independent reviewers (AG and DD). The obtained data
(first author, publication year, city and country of publi-
cation, mean age and disease prevalence according to the
severity of COVID-19) were recorded. Any disputes over
the included studies were resolved by a third investiga-
tor (UJ).
2GÜLSEN ET AL.

Quality and risk of bias assessments
The methodological index for nonrandomized studies
(MINORS) tool was used to assess the quality and risk of
bias.
18
This tool includes the evaluation of eight sections, as
follows: (1) a clearly stated aim; (2) inclusion of consecutive
patients; (3) prospective collection of data; (4) endpoints
appropriate to the aim of the study; (5) unbiased assessment
of the study endpoint; (6) follow-up period appropriate to
the aim of the study; (7) loss to follow-up less than 5%; and
(8) 2 points (reported and adequate). According to this eval-
uation, studies were categorized as: (1) very low quality (0–4
points), (2) low quality (5–8 points), (3) medium quality
(9–12 points) and (4) high quality (13–16 points).
Data synthesis and statistical analysis
Statistical analysis and meta-analysis were performed using
OpenMeta Analyst software version 10.10 (https://www.cebm.
FIGURE 1 Study flow diagram of the inclusion criteria of included studies. * These studies provide data for more than one disease
COMORBID PULMONARY DISEASES AND COVID-19 3

TABLE 1 Summary of studies included in the meta-analysis
Study Location Design nComparison Age (years) Asthma, n(%) COPD, n(%) CRD, n(%)
Almazeedi
19
Kuwait R, SC 1096 Non-ICU (n= 1054) versus ICU (n= 42) 41.0 43 (3.9) 5 (0.5) —
Argenziano
20
New York, USA R, MC 1000 Non-ICU (n= 764) versus ICU (n= 236) 63.0 113 (11.3) 66 (6.6) 223 (22.3)
Auld
21
Atlanta, USA P, SC 217 Survivors (n= 147) versus non-survivors (n= 62) 64.0 19 (8.8) 21 (9.7) —
Berenguer
22
Spain R, MC 4035 Survivors (n= 2904) versus non-survivors (n= 1131) 70.0 299 (7.5) —715 (17.9)
Buckner
23
Seattle, USA R, MC 105 Non-severe (n= 54) versus severe (n= 51) 69 10 (10.0) 11 (10.0) —
Cai
24
Shenzhen, China P, SC 383 Non-severe (n= 292) versus severe (n= 91) —— 32 (8.3) —
Cao
25
Wuhan, China R, SC 102 Survivors (n= 85) versus non-survivors (n= 17) 54.0 ——10 (9.8)
Caratozzolo
26
Italy P, SC 848 Survivors (n= 807) versus non-survivors (n= 41) 79.7
a
—73 (8.6) —
CDC COVID-19 Response
Team
27
—R, MC 7162 Non-ICU (n= 6180) versus ICU (n= 457) —— — 656 (9.2)
Chen
13
Zhejiang, China R, SC 145 Non-severe (n= 102) versus severe (n= 43) 47.5 —6 (4.1) —
Deng
28
Wuhan, China R, MC 225 Survivors (116) versus non-survivors (n= 109) 54.0 ——25 (11.1)
European Centre for Disease
Prevention and Control,
Week 43
29
European Union R, MC 263,654 Non-severe (n= 224,506) versus severe (n= 39,148) —3625 (1.4) —11,601 (4.4)
Feng
30
Wuhan, China P, SC 114 Good outcome (n= 94) versus poor (n= 20) 63.9
a
—11 (9.6) —
Feng
31
Wuhan, China R, MC 476 Non-severe (n= 352) versus severe (n= 124) —— 22 (4.6) —
Gao
32
Fuyang, China R, SC 43 Mild (n= 28) versus severe (n= 15) 43.7
a
—3 (6.9) —
Giorgi Rossi
33
Italy P, SC 2653 Hospitalized (n= 1075) versus death (n= 217) 63.2
a
—128 (5.4) —
Goyal
34
New York, USA R, MC 393 Non-IMV (n= 263) versus IMV (n= 130) 62.2 49 (12.5) 20 (5.1) —
Grein
35
International P, MC 53 Non-IMV (n= 19) versus IMV (n= 34) 67.0 6 (11.0) ——
Guan
36
Outside Hubei, China R, MC 1099 Non-severe (n= 926) versus severe (n= 173) 47.0 —12 (1.1) —
Gupta
37
USA P, MC 2215 Survivors (n= 1431) versus non-survivors (n= 784) 60.5 258 (11.6) 178 (7.8) 531 (24.0)
Güner
38
Turkey R, SC 222 Mild (n= 172) versus critical (n= 50) 50.6
a
—12 (5.4) —
Harrison
39
TriNetX Study, USA R, MC 31,461 Survivors (30,165) versus non-survivors (n= 1296) 50.0 ——5513 (17.5)
He
40
Wuhan, China R, SC 336 Survivors (n= 203) versus non-survivors (n= 133) 65.0 —28 (8.3) —
Hu
41
Wuhan, China R, SC 323 Non-severe (n= 151) versus severe (n= 172) 61.0 —6 (1.9) 29 (9.0)
Huang
42
Wuhan, China P, SC 41 Non-ICU (n= 28) versus ICU (n= 13) 49.0 —1 (2.4) —
Israelsen
43
Denmark R, SC 175 Non-ICU (n= 148) versus ICU (n= 27) 71.0 20 (11.4) 11 (6.3) —
Javanian
44
Iran R, SC 100 Survivors (n= 81) versus non-survivors (n= 19) 60.1
a
—12 (12.0) —
Lagi
45
Italy R, SC 84 Non-ICU (n= 68) versus ICU (n= 16) 62.0 —5 (5.9) —
Liu
46
Wuhan, China P, MC 78 Improvement (n= 67) versus progression (n= 11) 38.0 —2 (2.5) —
Li
47
Wuhan, China R, SC 548 Non-severe (n= 279) versus severe (n= 269) 60.0 5 (0.9) 17 (3.1) —
Li
48
Wuhan, China R, SC 25 Non-severe (n= 16) versus severe (n=9) —— 5 (20.0) —
Mo
49
Wuhan, China R, SC 155 General (n= 70) versus refractory (n= 85) 54.0 —5 (3.2) —
(Continues)
4GÜLSEN ET AL.

TABLE 1 (Continued)
Study Location Design nComparison Age (years) Asthma, n(%) COPD, n(%) CRD, n(%)
Parra-Bracamonte
50
Mexico R, MC 331,298 Survivors (n= 292,988) versus non-survivors (n= 38,310) 44.0 8983 (2.7) 5458 (1.6) —
Paranjpe
51
New York, USA R, MC 2199 Discharged (n= 768) versus mortality (n= 310) 65.0 180 (8.2) 113 (5.1) —
Qi
52
Chongqing, China R, MC 267 Non-severe (n= 217) versus severe (n= 50) 48.0 ——25 (9.4)
Salacup
53
Philadelphia R, SC 242 Survivors (n= 190) versus non-survivors (n= 52) 66.0 18 (7.0) 30 (12.0) —
Shi
54
Wuhan, China R, SC 671 Survivors (n= 609) versus non-survivors (n= 62) 63.0 —23 (3.4) —
Tomlins
55
UK R, SC 95 Survivors (n= 75) versus non-survivors (n= 20) 75.0 21 (22.0) 10 (11.0) —
Wan
56
Chongqing, China R, SC 135 Mild (n= 95) versus severe (n= 40) 47.0 —4 (2.9) 5 (3.7)
Wang
57
Wuhan, China R, SC 138 Non-ICU (n= 102) versus ICU (n= 36) 56.0 —4 (2.9) —
Wang
58
Wuhan, China R, SC 339 Survivors (n= 274) versus non-survivors (n= 65) 71.0 —21 (6.2) —
Wang
59
Wuhan, China R, SC 69 SpO
2
≥90% (n= 55) versus SpO
2
< 90% (n= 14) 42.0 2 (2.9) 4 (5.7) —
Wu
60
Yancheng, Fuyang,
Wuxi, China
R, MC 280 Mild (n= 197) versus severe (n= 83) 43.1
a
—1 (0.3) 6 (2.1)
Yan
61
Wuhan, China R, MC 1004 Survivors (n= 964) versus non-survivors (n= 40) —— 8 (0.8) 147 (14.6)
Yang
62
Chongqing, China R, SC 133 Mild (n= 65) versus severe (n= 68) —— 4 (3.0) —
Yang
63
Wuhan, China R, SC 52 Survivors (n= 20) versus non-survivors (n= 32) 51.9 ——4 (7.7)
Zhang
64
Wuhan, China R, SC 140 Non-severe (n= 82) versus severe (n= 58) 57.0 0 (0) 2 (1.4) —
Zhang
65
Wuhan, China R, SC 221 Non-severe (n= 166) versus severe (n= 55) 55.0 —6 (2.7) —
Zhang
66
Wuhan, China R, SC 111 Discharge (n= 93) versus deterioration (n= 18) 38.0 —3 (2.7) —
Zhang
67
Wuhan, China R, SC 120 Common type (n= 90) versus severe (n= 30) 45.4
a
—4 (3.0) —
Zhao
68
New York, USA R, SC 641 Non-ICU (n= 398) versus ICU (n= 195) 60.0 41 (6.4) 36 (5.6) —
Zheng
69
Changsha, China R, SC 161 Non-severe (n= 131) versus severe (n= 30) 45.0 —6 (3.7) —
Zhou
70
Wuhan, China R, MC 191 Survivors (n= 137) versus non-survivors (n= 54) 56.0 —6 (3.1) —
Overall 658,073 0%–22.0% 0.3%–20.0% 2.1%–24.0%
Note: Age-related data were given in median years.
Abbreviations: COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; CRD, chronic respiratory diseases (undefined lung diseases); ICU, intensive care unit; IMV, invasive mechanical ventilation; MC,
multicentre; n, participants; P, prospective; R, retrospective; SC, single centre; SpO
2
, peripheral capillary oxygen saturation.
a
Mean values.
COMORBID PULMONARY DISEASES AND COVID-19 5

brown.edu/open_meta) and StatsDirect version 3.2.10 (StatsDirect
Ltd, Cambridge, UK). The prevalence of pulmonary diseases
in patients with non-severe and severe COVID-19 was
collected in a meta-analysis pool, and ORs and 95% CIs
were calculated. Heterogeneity among studies in the pool
were evaluated using Cochran’sQtest and Higgins’I
2
test.
Homogeneity was accepted if a p-value of >0.1 and an I
2
of
<50% were obtained, and a fixed-effect model was used.
However, if the I
2
was ≥50%, a random-effects model was
used. Forest plots were then used to show the prevalence of
asthma, COPD and CRD in patients with non-severe and
severe COVID-19 in pooled studies. Egger’s test and funnel
plots were used to assess publication bias. Two-sided p-
values of <0.05 were considered to indicate significance,
except for evaluations using the I
2
heterogeneity test.
RESULTS
Study selection procedures
After the initial search in October 2020, 722 relevant
articles from international databases were identified.
After eliminating duplicate records, 645 articles
remained in the pool, and, after abstract and title review,
165 articles remained in the pool. After consideration of
the eligibility criteria, a further 112 studies were elimi-
nated. Thus, 53 studies
13,19–70
remained, which included
data related to COPD (n= 44), CRD (n= 14) and
asthma (n= 18). The general characteristics, locations,
comparisons and prevalence data of these studies are
presented in Table 1.
FIGURE 2 Prevalence of chronic obstructive pulmonary disease in patients with severe versus non-severe coronavirus disease 2019 (COVID-19)
6GÜLSEN ET AL.

Quality assessment and risk of bias summary
The average score of the included articles according to the
MINORS assessment was 10.9 points (range: 6–14). A total
of eight studies were prospective, and the remaining
45 studies were retrospective. There were seven low-quality,
35 medium-quality and 10 high-quality studies. One study
29
was not evaluated because it represented only a weekly
report. The quality and bias risk assessments are summa-
rized in Table 2.
FIGURE 4 Prevalence of chronic respiratory disease in patients with severe versus non-severe coronavirus disease 2019 (COVID-19)
FIGURE 3 (A) Prevalence of chronic obstructive pulmonary disease (COPD) in surviving and non-surviving patients with coronavirus disease 2019
(COVID-19). (B) Prevalence of COPD in patients with COVID-19 who needed intensive care unit (ICU) and non-ICU treatment
COMORBID PULMONARY DISEASES AND COVID-19 7

TABLE 2 Bias risk assessment
Study ❶❷❸❹❺❻❼❽Score
Almazeedi
19
20122220 11
Argenziano
20
12120220 10
Auld
21
22120220 12
Berenguer
22
22121220 12
Buckner
23
12120220 10
Cai
24
22220220 12
Cao
25
22020220 10
Caratozzolo
26
22221100 10
CDC COVID-19 Response Team
27
21121210 10
Chen
13
22120220 11
Deng
28
20100220 7
European Centre for Disease Prevention
and Control, Week 43
29
———————— —
Feng
30
22222220 14
Feng
31
12120220 10
Gao
32
22120220 11
Giorgi Rossi
33
22120210 10
Goyal
34
22122220 13
Grein
35
02220211 10
Guan
36
21122210 11
Gupta
37
22221220 13
Güner
38
21020120 8
Harrison
39
21121220 11
He
40
22120221 12
Hu
41
21021220 10
Huang
42
22222220 14
Israelsen
43
22120120 10
Javanian
44
12120020 8
Lagi
45
22220220 12
Liu
46
20020220 8
Li
47
22122220 13
Li
48
20120220 9
Mo
49
12100020 6
Parra-Bracamonte
50
22120220 11
Paranjpe
51
22122120 12
Qi
52
22120220 11
Salacup
53
21121200 9
Shi
54
21122220 12
Tomlins
55
12020120 8
Wan
56
22020120 9
Wang
57
22122220 13
Wang
58
22120220 11
Wang
59
22022120 11
Wu
60
20100120 6
Yan
61
21020220 9
Yang
62
20120220 9
Yang
63
22122220 13
(Continues)
8GÜLSEN ET AL.

Primary outcome
From these 53 studies,
13,19–70
data from 658,073 patients
were included in the pool, with average ages ranging from
38.0 to 79.7 years. In these studies, the average prevalence
of COPD was 0.9% (range: 0.3%–20.0%, n= 6435), that of
CRD was 2.9% (range: 2.1%–24.0%, n= 19,490) and that of
asthma was 2.0% (range: 0%–22.0%, n= 13,692). The dis-
tributions of patients with COPD, CRD and asthma
according to the severity of the COVID-19 are presented in
Tables S2, S3 and S4, respectively, in the Supporting
Information.
Chronic obstructive pulmonary disease
and COVID-19
COPD was present in 5.2% (2191/42,373) of patients with
severe COVID-19 and in 1.4% (4203/306,151) of patients with
non-severe COVID-19 (random-effects model; OR = 2.58,
95% CI = 1.99–3.34, Z= 7.15, p< 0.001; Figure 2), with sub-
stantial heterogeneity (I
2
= 66.9%, p< 0.001). Egger’stest
showed publication bias (t=−0.63, p= 0.02), but the funnel
plot did not confirm this bias (Figure S1A in the Supporting
Information). An additional sensitivity analysis was per-
formed, as one study
50
was considered to be the major cause
of heterogeneity due to large number of patients. After remov-
ing this study,
50
similar results (random-effects model;
OR = 2.42, 95% CI = 1.91–3.09, Z= 7.20, p= 0.005) were
obtained, with low heterogeneity (I
2
= 39.7%, p< 0.001). The
funnel plot distribution is presented in Figure S1B in the
Supporting Information.
In a subgroup analysis of pooled data, the prevalence of
COPD was 1.3% (3989/299,749) in survivors and 5.1%
(2046/40,169) in non-survivors (random-effects model;
OR = 2.42, 95% CI = 1.68–3.50, Z=4.73, p< 0.001;
Figure 3A), with considerable heterogeneity (I
2
= 79.9%,
p< 0.001). Egger’s test shows publication bias (t=−1.44,
p= 0.02) and the funnel plot supports this finding
(Figure S1C in the Supporting Information). After removing
Parra-Bracamonte et al.,
50
similar results (random-effects
model; OR = 2.20, 95% CI = 1.60–3.03, Z= 4.786, p< 0.001)
were obtained with moderate heterogeneity (I
2
= 45.5%,
p=0.04).Egger’s test provided no publication bias (t=0.41,
p= 0.57), and the funnel plot showed symmetrical distribu-
tion (Figure S1D in the Supporting Information).
In addition, the prevalence of COPD was 5.9% (31/522)
in patients who needed ICU care and 4.9% (115/2346) in
patients who did not need ICU care (random-effect model;
OR = 1.13, 95% CI = 0.64–2.04, Z= 0.43, p= 0.66;
Figure 3B), with low heterogeneity (I
2
= 25.9%, p= 0.25). As
the number of studies in this analysis was less than 10, we
did not apply publication bias analysis.
Chronic respiratory disease and COVID-19
Fourteen articles
20,22,25,27–29,37,39,41,52,56,60,61,63
included data
related to CRD. Because of considerable heterogeneity
(I
2
= 86.0%, p< 0.001), the random-effects model was used.
CRD was present in 8.6% (3780/44,041) of patients with
severe COVID-19 and in 5.7% (16,057/280,447) of patients
with non-severe COVID-19 (random-effects model;
OR = 2.14, 95% CI = 1.74–2.64, Z= 7.1, p< 0.001; Figure 4).
As a result of sensitivity and leave-one-out analysis, no
change in heterogeneity was obtained. The Egger’s test was
not significant (t= 1.09, p= 0.22) and provided no publica-
tion bias. The funnel plot distribution is presented in
Figure S1E in the Supporting Information.
Asthma and COVID-19
Eighteen articles
19–23,29,34,35,37,43,47,50,51,53,55,59,64,68
presented
data on patients with asthma and COVID-19, and the
random-effects model was used because of considerable het-
erogeneity (I
2
= 94.5%, p< 0.001). Asthma was present in
2.3% (1873/81,319) of patients with severe COVID-19 and
in 2.2% (11,796/538,737) of patients with non-severe
COVID-19 (random-effects model; OR = 1.13, 95%
CI = 0.79–1.60, Z= 0.66, p= 0.50; Figure 5). The funnel plot
was distributed symmetrically (Figure S1F in the Supporting
Information), and Egger’s test did not prove a publication
bias (t=−0.06, p= 0.96). However, sensitivity and leave-out
analysis were performed, and two studies,
29,50
with large
sample size which were found to be the cause of heterogene-
ity, were excluded. The result was similar to the first analysis
(random-effects model; OR = 1.08, 95% CI = 0.80–1.46,
TABLE 2 (Continued)
Study ❶❷❸❹❺❻❼❽Score
Zhang
64
20122200 9
Zhang
65
20122220 11
Zhang
66
22122220 13
Zhang
67
22122220 13
Zhao
68
21022220 11
Zheng
69
22120220 11
Zhou
70
22122220 13
COMORBID PULMONARY DISEASES AND COVID-19 9

Z= 0.66, p= 0.50) with moderate heterogeneity (I
2
= 53.0%,
p= 0.60). The Egger’s test was not significant (t= 0.91,
p= 0.16) and funnel plot (Figure S1G in the Supporting
Information) did not show a publication bias.
DISCUSSION
This comprehensive meta-analysis examined the relation-
ship between common chronic lung diseases, including
COPD and asthma, and the severity of COVID-19. In addi-
tion, our analysis included patients who were identified to
have chronic respiratory or lung diseases, although these
diseases were not fully defined. In summary, we observed
that the severity of COVID-19 was higher in patients with
comorbid COPD and CRD, whereas COVID-19 was not
more severe in patients with comorbid asthma.
Thus far, the published research has not clearly identified
the relationship between COPD and COVID-19 severity.
Although some initial studies reported that patients with
COPD have a higher risk for a more severe COVID-19
course,
24,26,31,32,38,40,41,44,45,48,57,58,62,65,67,70
other studies have
reported conflicting results,
13,30,42,43,46,47,49,53–55,59,61,64,66,68,69
highlighting the need for further analyses. Data from five
studies
19,20,42,57,68
found no relationship between COPD and
the need for ICU care.
A recently published study included 1590 patients with
COVID-19 and examined the prevalence of comorbid dis-
eases in this population.
71
In that study, the prevalence of
COPD was 24 of 1590 (1.5%), with ICU admission required
in seven of 24 (29.2%) patients with COPD, IMV required
in five of 24 (20.8%) and death occurring in five of 24 (25%)
patients. In non-COPD patients, these rates were only 92 of
1566 (5.9%), 45 of 1566 (2.9%) and 44 of 1566 (2.8%),
respectively.
71
In the study of Guan et al.,
71
COPD preva-
lence was reported as 1.5% and increased the hazard ratio
(HR) for ICU, IMV and death (HR = 2.681, 95% CI = 1.42–
5.05, p= 0.002). These findings are similar to our study
(COPD prevalence, 0.9%; OR = 2.58, 95% CI = 1.99–3.34,
p< 0.001).
Considering the chronic inflammatory state and low
respiratory capacity of patients with COPD, it is not surpris-
ing that these patients are more likely to experience a more
severe or even critical COVID-19 course. No published
studies have, however, grouped patients according to their
COPD severity, which remains a topic for future research.
Some included studies used more general terms, such as
CRD or ‘lung diseases’, to describe comorbid respiratory con-
ditions.
20,22,25,27–29,37,39,41,52,56,60,61,63
While five of these stud-
ies
22,28,41,52,61
identified a significant relationship between CRD
andsevereCOVID-19,onestudy
25
did not identify any signifi-
cant relationship (7.1% in mild cases and 23.5% in severe
cases, p= 0.10). Other similar studies have provided epidemio-
logical data without any statistical analysis.
20,27,29,37,39,56,60,63
Based on our meta-analysis, patients with pre-existing CRD
were more likely to experience severe COVID-19; however, the
implications of this finding remain unclear because these dis-
eases were not more specifically defined. It is interesting to
note that the prevalence of CRD in COVID-19 patients seems
to be quite lower than that in the general population,
7
although
this should not be construed to show that CRD has protective
properties.
72
According to our pooled studies, the CRD preva-
lence ranged from 2.1% to 24.0%.
A few studies have indicated that comorbid asthma is
not associated with severe COVID-19.
21,22,43,47,55,59,68
Only
two studies reported a significantly higher prevalence of
comorbid asthma in patients with severe COVID-19.
19,53
Several other studies have reported an increased prevalence
FIGURE 5 Prevalence of asthma in patients with severe versus non-severe coronavirus disease 2019 (COVID-19)
10 GÜLSEN ET AL.

of comorbid asthma in patients with severe COVID-19,
although no statistical data were provided. One study con-
ducted by Grein et al.
35
reported a 14.7% prevalence of
comorbid asthma in patients with severe COVID-19 and a
5.2% prevalence of asthma in patients with non-severe
COVID-19, although no further statistical data were pro-
vided. Our results related to comorbid asthma constitute
one of the most important findings in our meta-analysis,
indicating that this condition is not associated with severe
COVID-19. Naturally, this topic requires further research.
Viral infections affecting the respiratory system can pro-
voke asthma attacks and COPD exacerbations by increasing
the immune response and inflammation.
73
The use of
inhaled glucocorticosteroids (ICS) in patients with COPD
and asthma is known to produce undesirable side effects,
including an increased risk of pneumonia and upper respira-
tory tract infections.
74–76
It is important to note, however,
that these two different groups of patients may demonstrate
different immune responses to these types of infections. A
recent study has reported that ciclesonide, an ICS, can
reduce the cytopathic activity of SARS-CoV-2 and may be
useful in preventing COVID-19 and reducing its severity.
77
In our study, we found that patients with asthma did not
have a higher risk of severe COVID-19. As some of these
patients were likely to have a history of allergy/atopy, ICSs
may have been prescribed more frequently to this patient
population when compared to those with CRD and COPD.
Moving forward, more detailed studies are needed to inves-
tigate the relationship between COVID-19, asthma and
inhaled steroids.
In the coming months, potential vaccinations for
COVID-19 will be an important focus of attention. Although
case fatality rates in different countries vary considerably, it
has been demonstrated that many factors (comorbid dis-
eases, age, etc.) can affect mortality rates and that patients
with COPD have an increased risk of a more severe disease
course and higher mortality. Vaccination studies for SARS-
CoV-2 are ongoing and likely to produce further results in
the coming months. If these are successful, prioritizing
patients at risk of severe COVID-19, like those with COPD,
for vaccination is very important.
Interstitial lung diseases and COVID-19
An increase in the severe course of COVID-19 was not
reported in a retrospective study of 401 interstitial lung dis-
ease (ILD) patients receiving immunosuppressive therapy.
78
Contrary to this finding, patients with ILD in another study
had an increased mortality (HR = 1.60, 95% CI = 1.17–2.18,
p= 0.003) due to COVID-19, especially those with obesity
and poor respiratory function parameters, and the highest
mortality has been reported in rheumatoid ILD and chronic
hypersensitivity pneumonitis.
79
Huang et al.
80
reported that
higher D-dimer and IL-1β, IL-8 and IL-10 levels were
observed in COVID-19 patients with ILD than in COVID-
19 patients without ILD. However, whether the immuno-
suppressive therapies used by ILD patients predispose to
greater susceptibility to COVID-19 and infection by other
opportunistic pathogens is not yet clear. Whether immunosup-
pressive therapies prevent the abnormal inflammatory
response and cytokine storm that may develop during
the course of severe COVID-19 is also subject to future
research.
Cystic fibrosis and COVID-19
Limited information is available on cystic fibrosis (CF) and
COVID-19. The most detailed information on this subject
has come from a project carried out by the European Cystic
Fibrosis Society (COVID-CF project in Europe). According
to this project, 268 cases of CF and COVID-19 have been
reported, of which 12 patients (4.5%) needed ICU care and
five patients (1.9%) died.
81
The lower-than-expected preva-
lence and mortality of COVID-19 in patients with CF can
be explained by the increased attention of patients to per-
sonal protection due to their illness. In addition, the poten-
tially protective role of additional long-term treatments
(such as DNase and azithromycin/tobramycin) that these
patients receive requires further research.
82
Bronchiectasis and COVID-19
Bronchiectasis, similar to other rare lung diseases, is also
under-reported in studies. Some of the patients defined as
having CRD, chronic pulmonary disease or lung disease in
included studies may be patients with bronchiectasis. Newly
defined cases of bronchiectasis after severe COVID-19 infec-
tion are also increasing.
83
In the present meta-analysis, a total of 53 articles were
reviewed with the largest sample size of all previous related stud-
ies (n= 658,073); however, this meta-analysis contained some
unavoidable limitations. Nearly half of the data were generally of
Chinese origin and included only English articles that were pub-
lished between January and October 2020. Even though the vast
majority of included studies classified patients as having severe
versus non-severe disease,
13,23,24,29,32,36,38,41,47,48,52,56,60,62,64,65,67,69
some studies used different terminologies, including survivors/
non-survivors,
21,22,25,26,28,33,37,39,40,44,50,51,53–55,58,61,63,70
need for
ICU or IMV/non-ICU or non-IMV,
19,20,27,34,35,43,45,57,59,68
good/
poor outcomes,
30
general treatment/refractory to treatment
49
and
improvement/progression.
46,66
Although the terminology differed
among studies, the characteristics of more severe cases (need for
ICU/IMV, critical, non-survivors, progression and refractory)
seemed to comply with the general framework of our study.
Furthermore, all studies lack information regarding the
definition of comorbid COPD, asthma and CRD. Only nine
of the studies were prospective,
21,24,26,30,33,35,37,42,46
whereas
the rest of the included studies were planned retrospectively.
Patient follow-up times are also very limited in all studies.
COMORBID PULMONARY DISEASES AND COVID-19 11

We analysed patients with recent disease and short-term
follow-up; however, differences may become more evident
during long-term follow-up. In addition, many studies are
published every day. The increase in pre-print publication
(without evaluation by a reviewing process) style makes it
more difficult to stay up to date than before. Our meta-
analysis has not yet adequately addressed the question of the
potential impact of greater age of patients with COPD com-
pared to the average patients with asthma, and this should
be an important component for future analysis. Finally, we
limited our meta-analysis to studies including patients with
COPD, asthma and CRD because current research has not
yet explored the relationship of COVID-19 with other
chronic lung diseases, including bronchiectasis, CF, ILDs
and sarcoidosis. Further studies should investigate these
relationships in more detail.
In conclusion, comorbid COPD and CRD were clearly
associated with higher severity of COVID-19; however, no
association between asthma and severe COVID-19 was
identified. Questions remain regarding the relationships
between COVID-19 and the severity of COPD and asthma,
as well as the relationship of COVID-19 with other pulmo-
nary conditions, including ILDs, bronchiectasis and CF.
ACKNOWLEDGEMENTS
Research funding: Funding of the Federal Ministry of Edu-
cation and Research (BMBF) and German Center for Lung
Research is gratefully acknowledged. Open Access funding
enabled and organized by Projekt DEAL.
AUTHOR CONTRIBUTIONS
Inke R. König: Methodology; supervision; validation;
writing-review & editing. Uta Jappe: Funding acquisition;
investigation; supervision; writing-review & editing. Daniel
Drömann: Data curation; resources; writing-review & editing.
Askin Gulsen: Conceptualization; data curation; formal anal-
ysis; methodology; project administration; resources; software;
visualization; writing-original draft; writing-review & editing.
CONFLICT OF INTEREST
Uta Jappe reports grants and personal fees from the Federal
Ministry of Education and Research, German Center for
Lung Research (DZL), during the conduct of the study. Inke
R. König reports grants from German Research Foundation
and Federal Ministry of Education and Research, outside the
submitted work. The other authors declare that they have
no conflicts of interest.
DATA AVAILABILITY STATEMENT
The data sets analysed during the current study are available
from the corresponding author on reasonable request. Trial
Registration: CRD42020179122 at PROSPERO https://www.
crd.york.ac.uk/prospero
ORCID
Askin Gülsen https://orcid.org/0000-0002-6209-0131
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SUPPORTING INFORMATION
Additional supporting information may be found online in
the Supporting Information section at the end of this article.
How to cite this article: Gülsen A, König IR,
Jappe U, Drömann D. Effect of comorbid pulmonary
disease on the severity of COVID-19: A systematic
review and meta-analysis. Respirology. 2021;1–14.
https://doi.org/10.1111/resp.14049
14 GÜLSEN ET AL.