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RESEARCH ARTICLE
Prevalence and predictors of death and
severe disease in patients hospitalized due to
COVID-19: A comprehensive systematic
review and meta-analysis of 77 studies and
38,000 patients
Kunchok DorjeeID
1
*, Hyunju Kim
2
, Elizabeth BonomoID
1
, Rinchen Dolma
3
1School of Medicine Division of Infectious Diseases, Center for TB Research, Johns Hopkins University,
Baltimore, Maryland, United States of America, 2Department of Epidemiology, Bloomberg School of Public
Health, Johns Hopkins University, Baltimore, Maryland, United States of America, 3Center for Alcohol and
Addiction Studies, Brown University School of Public Health, Brown University, Providence, Rhode Island,
United States of America
*kdorjee1@jhmi.edu
Abstract
Introduction
Progression of COVID-19 to severe disease and death is insufficiently understood.
Objective
Summarize the prevalence of risk factors and adverse outcomes and determine their asso-
ciations in COVID-19 patients who were hospitalized.
Methods
We searched Medline, Embase and Web of Science for case-series and observational
studies of hospitalized COVID-19 patients through August 31, 2020. Data were analyzed
by fixed-effects meta-analysis using Shore’s adjusted confidence intervals to address
heterogeneity.
Results
Seventy-seven studies comprising 38906 hospitalized patients met inclusion criteria; 21468
from the US-Europe and 9740 from China. Overall prevalence of death [% (95% CI)] from
COVID-19 was 20% (18–23%); 23% (19–27%) in the US and Europe and 11% (7–16%) for
China. Of those that died, 85% were aged60 years, 66% were males, and 66%, 44%,
39%, 37%, and 27% had hypertension, smoking history, diabetes, heart disease, and
chronic kidney disease (CKD), respectively. The case fatality risk [%(95% CI)] were 52%
(46–60) for heart disease, 51% (43–59) for COPD, 48% (37–63) for chronic kidney disease
(CKD), 39% for chronic liver disease (CLD), 28% (23–36%) for hypertension, and 24% (17–
33%) for diabetes. Summary relative risk (sRR) of death were higher for age60 years
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PLOS ONE | https://doi.org/10.1371/journal.pone.0243191 December 7, 2020 1 / 27
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OPEN ACCESS
Citation: Dorjee K, Kim H, Bonomo E, Dolma R
(2020) Prevalence and predictors of death and
severe disease in patients hospitalized due to
COVID-19: A comprehensive systematic review
and meta-analysis of 77 studies and 38,000
patients. PLoS ONE 15(12): e0243191. https://doi.
org/10.1371/journal.pone.0243191
Editor: Davide Bolignano, Universita degli Studi
Magna Graecia di Catanzaro, ITALY
Received: July 13, 2020
Accepted: November 17, 2020
Published: December 7, 2020
Peer Review History: PLOS recognizes the
benefits of transparency in the peer review
process; therefore, we enable the publication of
all of the content of peer review and author
responses alongside final, published articles. The
editorial history of this article is available here:
https://doi.org/10.1371/journal.pone.0243191
Copyright: ©2020 Dorjee et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.
Data Availability Statement: All relevant data are
within the manuscript and its Supporting
information files.
[sRR = 3.6; 95% CI: 3.0–4.4], males [1.3; 1.2–1.4], smoking history [1.3; 1.1–1.6], COPD
[1.7; 1.4–2.0], hypertension [1.8; 1.6–2.0], diabetes [1.5; 1.4–1.7], heart disease [2.1; 1.8–
2.4], CKD [2.5; 2.1–3.0]. The prevalence of hypertension (55%), diabetes (33%), smoking
history (23%) and heart disease (17%) among the COVID-19 hospitalized patients in the US
were substantially higher than that of the general US population, suggesting increased sus-
ceptibility to infection or disease progression for the individuals with comorbidities.
Conclusions
Public health screening for COVID-19 can be prioritized based on risk-groups. Appropriately
addressing the modifiable risk factors such as smoking, hypertension, and diabetes could
reduce morbidity and mortality due to COVID-19; public messaging can be accordingly
adapted.
Introduction
Coronavirus disease-19 (COVID-19) caused by severe acute respiratory syndrome- coronavi-
rus-2 (SARS-CoV-2) that first emerged in Wuhan, China in late December 2019 has spread
with such rapidity and efficiency that in less than 10 months, it has caused more than 36 million
cases and million deaths globally [1]. Driven by an urgency to solve the crisis, studies are being
published at an unprecedented pace. However, across the publications, prevalence of death,
severe disease and their association with epidemiological risk factors have greatly varied [2,3],
with studies showing conflicting results for association of key risk factors such as sex [4–8],
smoking [9–12], hypertension [4,7,8,13,14] and diabetes [4,7,8,13,14] with COVID-19 dis-
ease severity and death. Whether or how cardiovascular risk factors, especially prior hyperten-
sion, diabetes and heart disease are associated with acquisition of SARS-CoV-2 and progression
to severe disease or death is not understood well [15–18]. Meta-analyses conducted so far on
prevalence of epidemiological risk factors and association with disease progression were mostly
based on studies from China [9,11,18–20] and many of the analyses on prevalence estimates
included studies focused on critically ill patients [9,19], which can overestimate the prevalence
and affect generalizability of results. To our knowledge, none of the analyses were restricted to
hospitalized COVID-19 patients. Restricting our analysis to hospitalized patients provides an
efficient sampling frame to investigate disease progression in relation to risk factors.
Therefore, we undertook a comprehensive systematic review and meta-analysis to investi-
gate the association between key epidemiological factors–age, gender, smoking, hypertension,
diabetes, heart disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease
(CKD) and chronic liver disease (CLD)–and progression to death and severe disease in
patients hospitalized due to COVID-19. We additionally compared the 1) the prevalence of
risk factors and death in the US-Europe with that of China; 2) the prevalence of co-morbidities
at baseline with the general population prevalence, and 3) prevalence of cardiovascular disease,
COPD and CKD at baseline with corresponding organ injuries (acute cardiac injury, acute
lung injury, and acute kidney injury) during hospital admission.
Methods
Literature search, study selection and data abstraction
We searched Medline, Embase, Web of Science and the WHO COVID-19 database to identify
studies published through August 31, 2020 that investigated the risk of severe disease or death
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Funding: Dr. Dorjee is supported by grants from
the US National Institute of Allergy and Infectious
Diseases of the National Institute of Health (Grant #
K01AI148583); Johns Hopkins Alliance for a
Healthier World (Grant # 80045453); STOP TB
PARTNERSHIP TB REACH (Grant # 134126); the
Pittsfield Anti-TB Association and dedicated private
philanthropists.
Competing interests: The authors have declared
that no competing interests exist.
in hospitalized patients with confirmed COVID-19 disease. We used search terms, ‘coronavi-
rus disease 19’, ‘COVID-19’, ‘severe acute respiratory syndrome coronavirus 2’ and ‘SARS-
CoV-2’ for COVID-19 and the string ((characteristics) OR (risk factors) OR (epidemiology)
OR (prevalence) OR (intensive care) OR (ventilator) OR (mechanical ventilator) OR (mortal-
ity) OR (survivor) OR (smoking) OR (smoker)) AND ((COVID-19) OR (COVID) OR
(coronavirus)) for studies published between December 15, 2019 and August 31, 2020. We
started the search on March 18, 2020 with biweekly search thereafter and final search on
August 31, 2020. We included case series and observational studies that described the preva-
lence of death or severe disease in adult population stratified by risk factors: age, sex, hyperten-
sion, diabetes, heart disease, COPD, CKD and CLD. We excluded studies that included non-
consecutive patients or exclusively focused on pregnant women, children, and elderly patients.
We excluded studies that exclusively studied critically ill patients from calculation of preva-
lence of death but included them for calculating the association of risk factors with death.
Screening of abstracts and full-text reviews were conducted using Covidence (Melbourne,
Australia).
Risk factors and outcomes
Primary outcomes were prevalence of death and association of risk factors with death.
We extracted data on death as recorded in the publications. We measured prevalence
of severe disease and association with risk factors as secondary outcomes. We defined out-
come as severe disease for any of 1) the study classified COVID-19 disease as severe or criti-
cal, 2) intensive care unit (ICU) admission, 3) acute respiratory distress syndrome, or 4)
mechanical ventilation. Severe disease was defined by studies as respiratory rate30 per
minute, oxygen saturation93%, and PaO
2
/FiO
2
<300 and/or lung infiltrates>50% within
24–48 hours [3]. Critical illness was defined as respiratory failure, shock and/or multiple
organ dysfunction or failure [3]. Heart disease as a pre-existing condition was broadly
defined by most studies as ‘cardiovascular disease’ (CVD). Additional outcomes were
acute cardiac and kidney injury in the hospitalized patients that were defined as such by the
studies.
Statistical analysis
We calculated and reported summary estimates from fixed-effects models [21]. We assessed
heterogeneity across studies using Cochran’s Q-test (χ
2
p value <0.10) [22] and I
2
statistics
(I
2
>30%) [23]. In the presence of heterogeneity, we adjusted the confidence intervals for
between-study heterogeneity using the method described by Shore et al. [24]. We presented
the results from random effects meta-analysis as well. The meta-analysis was performed in
Microsoft
1
Excel 2020 (Microsoft Corporation, Redmond, WA). We analyzed publication
bias using funnel plots and Egger’s tests. Quality of each study was assessed using the New-
castle-Ottawa assessment scales using the PRISMA guidelines. We calculated the following
as a part of our analyses: 1) prevalence of severe disease or death, 2) prevalence of risk fac-
tors, and 3) relative risk for the association of age, sex, and comorbidities with outcome.
When not reported or when unadjusted odds ratio was presented, we calculated the relative
risk (95% CI) using the frequencies provided. Adjusted estimates were used where available.
Case fatality risk (and case severity risk) for a specific risk factor was calculated as number
of deaths (or severe disease) in patients with a risk factor out of all patients possessing the
risk factor.
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Results
Study characteristics
Initial search yielded 30133 citations. Articles were then screened (Fig 1). We identified 410
articles for full text review, of which 77 studies met inclusion criteria (Table 1) [4–8,13,14,
25–94]. The studies were conducted in: China (n = 35), USA (n = 18), Europe (n = 10), rest of
Asia (n = 5) and Africa (n = 1). Two studies were prospective, five cross-sectional, and remain-
ing retrospective in nature.
Population and demographics
There were 38,906 total COVID-19 hospitalized patients including 21468 patients from the US
and Europe (87% from the US), and 9740 patients from China. Median age was 59 years [IQR:
57–62 years; I
2
= 58%; n = 62 studies] and 48% [95% CI: 44–53%; I
2
= 98%; n = 41] were
aged60. Fifty-nine percent [95% CI: 57–60%; I
2
= 98%; n = 75] of the patients were males.
Prevalence of death and severe disease
We calculated an overall prevalence of death of 20% [95% CI: 18–23%; I
2
= 96%; n = 60],
ranging from 1% to 38% across the studies, and of severe disease of 28% [95% CI: 24–33%;
I
2
= 98%; n = 60] for all patients hospitalized due to COVID-19 (Tables 2and 3). Data on
Fig 1. PRISMA flow diagram for selection of studies.
https://doi.org/10.1371/journal.pone.0243191.g001
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Table 1. Characteristics of studies to determine prevalence of risk factors and death or severe disease and their associations in patients hospitalized for COVID-19
globally.
Author, year of
publication
(journal)
Country Region Study
Period
Study Design Size Epidemiological Risk Factor Outcome Measures of
Association
Aggarwal S et al.,
2020 (Diagnosis)
USA Des Moines 3-1-2020 to
4-4-2020
Retrospective 16 Age, sex, smoking, substance
use, obesity, HTN, DM,
CVD, COPD, CKD, Cancer
Prevalence of death
and primary end point
(death, shock, or ICU
admission).
Association of risk
factors with outcome
Unadjusted RR
calculated
Argenziano M. G
et al., 2020 (BMJ)
USA New York City 3-11-2020
to 4-6-2020
Retrospective 1,000 Age, sex, ethnicity, obesity,
smoking, HTN, DM, CVD,
COPD, CKD, cancer, HIV,
viral hepatitis, cirrhosis
Association of risk
factors with disease
severity and death.
Adjusted HR
Brill S. E et al., 2020
(BMC Medicine)
UK Barnet 3-10-2020
to 4-8-2020
Retrospective 450 Age, race, sex, smoking,
HTN, DM, CVD,
immunosuppression
Prevalence of death. Unadjusted RR
calculated
Association of
comorbidities with
disease severity.
Cao Z et al., 2020
(PLOS ONE)
China Beijing 1-21-2020
to 2-12-
2020
Retrospective 80 Sex, age, HTN, CVD, DM,
COPD, smoking
Association of risk
factors with disease
severity.
Unadjusted RR
calculated
CDC (MMWR) USA National 2-12-2020
to 3-28-
2020
Retrospective 5285 Age, Current Smoker, DM,
CVD, COPD, CKD, CLD
Prevalence of ICU
admission.
Association of risk
factors with severe
disease (ICU
admission).
Unadjusted RR
calculated
Chen G et al., 2020
(Journal of Clinical
Investigation)
China Wuhan December
2019 to 01-
27-2020
Retrospective 21 Age, sex, Huanan sea food
market exposure, HTN, DM
Prevalence of severe
disease. Compared
moderate and severe
cases based on risk
factors.
Unadjusted RR
calculated
Chen J et al., 2020
(Journal of
Infection)
China Shanghai 1-20-2020
to 2-6-2020
Retrospective 249 Age, sex Prevalence of ICU
admission.
Association of age and
sex with ICU
admission.
Adjusted OR
reported for age
and sex
Chen Q et al., 2020
(Infection)
China Zhejiang
province
1-1-2020 to
3-11-2020
Retrospective 145 Age, sex, smoking, exposure
history, BMI, HTN, DM,
COPD, CKD, Solid tumor,
Heart disease, HIV infection
Prevalence of severe
disease. Association of
risk factors with severe
disease.
Unadjusted RR
calculated
Chen T et al., 2020
(BMJ)
China Wuhan, Hubei 1-13-2020
to 2-28-
2020
Retrospective 274 Age, sex, sea food market
exposure, contact history,
smoking HTN, DM, CVD,
CHF, heart failure, cancer,
HBV, HIV, CKD
Association of risk
factors with death.
Unadjusted RR
calculated
Compared death and
recovered group.
Presently hospitalized
patients excluded
from study.
Chilimuri S et al.,
2020 (West J Emerg
Med)
USA New York City 3-9-2020 to
4-9-2020
Retrospective 375 Age, sex, ethnicity, HTN,
DM, CVD, COPD, CKD,
HIV/AIDS, CLD
Association of risk
factors with disease
severity and death.
Adjusted OR
reported for age,
sex and
comorbidities
Ciceri F et al., 2020
(Clinical
Immunology)
Italy Milan 2-25-2020
to 5-1-2020
Retrospective 410 Age, sex, ethnicity, BMI,
HTN, CVD, DM, COPD,
CKD, cancer
Prevalence of death. Adjusted HR
Association of risk
factors with disease
severity.
(Continued )
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Table 1. (Continued)
Author, year of
publication
(journal)
Country Region Study
Period
Study Design Size Epidemiological Risk Factor Outcome Measures of
Association
Cummings MJ et al.,
2020 (The Lancet)
USA New York City 3-2-2020 to
4-1-2020
Prospective 257 Age, sex, race, BMI, HTN,
DM, chronic cardiac disease
(CHD and CHF), CKD,
smoking history, COPD,
cancer, HIV, cirrhosis
Association of risk
factors with death.
Adjusted HR
Deng Y et al., 2020
(Chin Med J)
China Wuhan 1-1-2020 to
2-21-2020
Retrospective 116
out
of
964
Age, sex, HTN, DM, Heart
Disease, Cancer
Association of risk
factors with death.
Unadjusted RR
calculated
Compared death and
recovered group.
Presently hospitalized
patients excluded
from study.
Du R-H et al., 2020
(ERJ)
China Wuhan, Hubei 1-25-2020
to 2-7-2020
Retrospective 179 Age, sex, HTN, DM, CVD,
TB, cancer, CKD or CLD
Prevalence of death.
Association of risk
factors with death.
Adjusted OR for
age65 and
CVD. Unadjusted
RR calculated for
other variables
Escalera-Antezana
et al., 2020(Infez
Med)
Bolivia Nationwide 3-2-2020 to
3-29-2020
Retrospective 107 Age, HTN, CVD, DM,
obesity, sex
Prevalence of death. Adjusted OR
Association of risk
factors with disease
severity.
reported for age,
sex and risk
factors
Feng Y et al., 2020
(AJRCCM)
China Wuhan,
Shanghai,
Anhui
province
1-1-2020 to
2-15-2020
Retrospective 476 Age, age groups, sex, Wuhan
exposure, smoking, alcohol,
HTN, anti-hypertensives,
CVD, DM, cancer, COPD,
CKD
Prevalence of death.
Association of risk
factors with severe
disease.
Adjusted HR for
HTN, CVD, DM.
Unadjusted RR
calculated for
other variables
Ferguson J et al.,
2020 (EID)
USA Northern
California
03-13-2020
to 04-11-
2020
Retrospective 72 Sex, race, smoking, HTN,
DM, CKD, Heart Disease,
COPD
Prevalence of ICU
admission.
Association of risk
factors with severe
disease (ICU
admission).
Unadjusted RR
calculated
Galloway J.B et al.,
2020 (Journal of
Infection)
UK London 3-1-2020 to
4-17-2020
Retrospective 1,157 Age, sex, ethnicity, cancer,
CKD, DM, HTN, CVD,
COPD
Prevalence of death. Adjusted HR
reported for age
and sex
Association of risk
factors with disease
severity.
Garibaldi B et al.,
2020 (Ann Intern
Med)
USA Maryland 3-4-2020 to
6-27-2020
Retrospective 832 Age, sex, alcohol, smoking,
BMI, cancer, CVD, COPD,
HTN, liver disease, CKD,
HIV/AIDS DM
Association of risk
factors with disease
severity.
Adjusted HR
Washington
DC
reported for age,
ethnicity and
BMI
Giacomelli A et al.,
2020 (Pharmacol
Res)
Italy Milan 2-21-2020
to 4-20-
2020
Prospective 233 Sex, age, smoking, obesity Prevalence of death. Adjusted HR
Association of risk
factors with disease
severity.
reported for sex,
age, and obesity
Gold J et al, 2020
(MMWR)
USA Georgia 3-1-2020 to
3-30-2020
Retrospective 305 Age, sex, race, HTN, DM,
Heart Disease, COPD, CKD,
Cancer
Prevalence of patient
characteristics, death,
and ICU.
Unadjusted RR
calculated
Goyal P et al. 2020
(NEJM)
USA New York City 3-3-2020 to
3-27-2020
Retrospective 393 Age, sex, race, smoking,
HTN, DM, COPD, Heart
Disease, Asthma
Prevalence of severe
disease (mechanical
ventilation).
Association of risk
factors with severe
disease.
Unadjusted RR
calculated
(Continued )
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Table 1. (Continued)
Author, year of
publication
(journal)
Country Region Study
Period
Study Design Size Epidemiological Risk Factor Outcome Measures of
Association
Gregoriano C
et al.,2020 (Swiss
Medical Weekly)
Switzerland Aarau 2-26-2020
to 4-30-
2020
Retrospective 99 Age, sex, smoking, HTN,
cancer, CVD, COPD,
obesity, DM, rheumatic
disease, organ transplant
recipient, obstructive sleep
apnea
Prevalence of disease
endpoints (transfer to
ICU and in-hospital
mortalities).
Unadjusted OR
Association of
comorbidities with
disease endpoints.
Guan et al., 2020
(NEJM)
China Nationwide 12-11-2019
to 01-31-
2020
Retrospective 1099 Age, sex, smoking, exposure
to transmission source,
HTN, DM, CHD, CKD,
COPD, Cancer, HBV,
cerebrovascular disease,
immunodeficiency
Prevalence of death,
composite outcome,
((Death/MV/ICU)
and severe disease.
Association with
severe disease and
composite outcome.
Unadjusted RR
calculated
Guan Wei-Jie, 2020
(ERJ)
China Nationwide 12-11-2019
to 1-31-
2020
Retrospective 1590 Age, sex, smoking, CKD,
COPD, HTN, DM, CVD,
Cancer, HBV
Prevalence of patient
characteristics, death
and composite
outcome (Death, ICU,
MV).
Adjusted HR
Hewitt J et al., 2020
(Lancet)
UK Nationwide
(UK),
2-27-2020
to 4-28-
2020
Prospective 1,564 Age, sex, smoking, DM,
HTN, CVD, CKD
Prevalence of death. Adjusted HR
Italy Modena (Italy) Association of risk
factors with disease
severity.
Hsu H. E et al., 2020
(Morbidity and
Mortality Weekly
Report)
USA Boston 3-1-2020 to
5-18-2020
Retrospective 2,729 Age, sex, ethnicity, COPD,
cancer, CKD, cirrhosis,
CVD, DM, HIV/AIDS,
HTN, obesity, substance use
disorder
Association of risk
factors with disease
severity.
Unadjusted RR
calculated
Hu L et al., 2020
(CID)
China Wuhan 1-8-2020 to
2-20-2020
Retrospective 323 Age, sex, current smoker,
HTN, DM, CVD, COPD,
CKD, CLD, Cancer
Prevalence of severe
(severe and critical)
disease. Association of
risk factors with
disease severity.
Unadjusted RR
calculated
Huang C et al., 2020
(The Lancet)
China Wuhan 12-16-2020
to 1-2-2020
Prospective 41 Age, sex, Huanan seafood
market exposure, smoking,
HTN, DM, CKD, COPD,
CVD, Cancer, CLD
Association of risk
factors with severe
disease (ICU care).
Unadjusted RR
calculated
Hur K et al., 2020
(Otolaryngol Head
Neck Surg)
USA Chicago 3-1-2020 to
4-8-2020
Retrospective 486 Age, sex, BMI, smoking,
HTN, DM, CVD, COPD,
cancer, immunosuppression,
CKD,
Association of risk
factors with disease
severity.
Adjusted HR (for
age, sex, ethnicity
BMI, HTN,
smoking)
Iaccarino G et al.,
2020 (Hypertension)
Italy Nationwide 3-9-2020 to
4-9-2020
Cross-
sectional
1,591 Age, sex, HTN, obesity, DM,
COPD, CKD, CVD, cancer
Prevalence of death. Adjusted OR
Association of risk
factors with disease
severity.
Inciardi R et el.,
2020 (Eur Heart J)
Italy Lombardy 3-4-2020 to
3-25-2020
Retrospective 99 Sex, smoking, HTN, DM,
coronary artery disease,
COPD, CKD, cancer
Prevalence of death.
Association of risk
factors with death.
Unadjusted RR
calculated
Jang J.G et al., 2020
(Journal of Korean
Medical Science)
South Korea Daegu 2-19-2020
to 4-15-
2020
Retrospective 110 Age, sex, CVD,
cerebrovascular disease,
COPD, dementia, DM,
HTN, connective tissue
disease liver disease,
malignancy, Parkinson’s
disease
Association of risk
factors with disease
severity and death.
Adjusted OR
(Continued )
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Table 1. (Continued)
Author, year of
publication
(journal)
Country Region Study
Period
Study Design Size Epidemiological Risk Factor Outcome Measures of
Association
Javanian M et al.,
2020 (Rom J Intern
Med)
Iran Mazandaran
province
2-25-2020
to 3-12-
2020
Retrospective 100 Age, sex, HTN, DM, CVD,
CKD, cancer, CLD
Prevalence of death.
Association of risk
factors with death.
Unadjusted RR
calculated
Kalligeros M et al.,
2020 (Obesity
Journal)
USA Rhode Island 2-17-2020
to 4-5-2020
Retrospective 103 Age, sex, ethnicity, smoking,
BMI (obesity), cancer, CKD,
cirrhosis, DM, heart disease
(CVD), HTN, lung disease
(COPD), transplant
Association of risk
factors with disease
severity.
Adjusted OR
(for age, sex,
ethnicity, BMI,
DM, HTN, heart
disease, lung
disease)
Khalil K et al., 2020
(Journal of
Infection)
UK London 3-7-2020 to
4-7-2020
Prospective 220 Age, sex, ethnicity, smoking,
COPD, CVD, HTN,
hyperlipidemia, DM, CKD,
CVA, dementia, liver
disease, cancer
Prevalence of death. Unadjusted RR
calculated
Association of risk
factors with disease
severity.
Khamis F et al., 2020
(Journal of Infection
and Public Health)
Oman Muscat 2-24- 2020
to 4-24-
2020
Retrospective 63 Age, sex, smoking, substance
use, HTN, DM, CKD, CVD
Prevalence of severe
disease and death.
Unadjusted RR
calculated
Association of risk
factors with disease
severity.
Lendorf M.E et al.,
2020 (Danish
Medical Journal)
Denmark North Zealand 3-1-2020 to
5-18-2020
Retrospective 111 Age, sex, BMI, cancer, HTN,
CVD, COPD,
immunosuppression, CKD,
DM, smoking
Association of risk
factors with disease
severity and death.
Unadjusted RR
calculated
Li X et al., 2020 (J
Allergy Clin
Immunol)
China
(Wuhan,
Hubei)
Wuhan, Hubei 1-26-2020
to 2-5-2020
Retrospective 548 Age, sex, smoking, HTN,
DM, Heart Disease, CKD,
Cancer, COPD
Prevalence of death
and severe disease.
Unadjusted RR
calculated
Association of risk
factors with severe
disease.
Liu S et al., 2020
(BMC Infectious
Diseases)
China Jiangsu
Province
1-10-2020
to 3-15-
2020
Retrospective 625 Sex, age, HTN, DM, CVD Association of risk
factors with disease
severity.
Adjusted OR
(for age and
HTN)
Liu W et al. 2020
(Chin Med J)
China Wuhan 12-30-2019
to 01-15-
2020
Retrospective 78 Age, sex, smoking history,
exposure to Huanan seafood
market, HTN, diabetes,
COPD, cancer
Compared
progression group and
stabilization group.
Progression group
defined by progression
to severe or critical
disease or death.
Unadjusted RR
calculated
Nikpouraghdam M
et al., 2020 (J Clin
Virol)
Iran Tehran 2-19-2020
to 4-15-
2020
Retrospective 2,964 Age, sex, DM, COPD, HTN,
CVD, CKD, cancer
Prevalence of death. Adjusted OR
Association of risk
factors with disease
severity.
Nowak B et al., 2020
(Pol Arch Intern
Med)
Poland Warsaw 3-16-2020
to 4-7-2020
Retrospective 169 Sex, smoking, HTN, DM,
CVD, COPD, CKD, AKI,
cancer
Prevalence of death.
Association of risk
factors with death.
Unadjusted RR
calculated
Okoh A.K et al.,
2020 (Int J Equity
Health)
USA Newark 3-10-2020
to 4-20-
2020
Retrospective 251 Age, sex, ethnicity, BMI,
HTN, DM, CVD, COPD,
HIV, CKD, cancer
Prevalence of death. Adjusted OR
Association of risk
factors with disease
severity and death.
Palaiodimos L et al.,
2020 (Metabolism)
USA New York 3-9-2020 to
3-22-2020
Retrospective 200 Age, sex, race, smoking,
HTN, DM, coronary artery
disease, COPD, CKD, cancer
Prevalence of death.
Association of risk
factors with death.
Adjusted OR
(provided by the
study)
(Continued )
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Table 1. (Continued)
Author, year of
publication
(journal)
Country Region Study
Period
Study Design Size Epidemiological Risk Factor Outcome Measures of
Association
Pellaud C et al., 2020
(Swiss Medical
Weekly)
Switzerland Fribourg 3-1-2020 to
5-10-2020
Retrospective 196 Sex, age, HTN, DM, obesity,
CVD, COPD, cancer,
immunosuppression,
smoking
Prevalence of death. Unadjusted RR
calculated
Association of risk
factors with disease
severity.
Richardson S et al.,
2020 (JAMA)
USA New York 3-1-2020 to
4-4-2020
Retrospective 5700 Age, sex, race, smoking,
HTN, DM, COPD, asthma,
coronary artery disease,
kidney disease, liver disease,
obesity, cancer
Prevalence of ICU
admission and death.
Unadjusted RR
calculated
Association of risk
factors with death.
Rivera-Izquierdo M
et al., 2020 (PLOS
ONE)
Spain Granada 3-16-2020
to 4-10-
2020
Retrospective 238 Sex, age, smoking, HTN,
DM, CVD, COPD, CKD,
active neoplasia, medications
Prevalence of death. Adjusted HR
Association of risk
factors with disease
severity.
Shabrawishi M et al.,
2020 (Plos One)
Saudi
Arabia
Mecca 3-12-2020
to 4-8-2020
Retrospective 150 Age, sex, HTN, DM, CVD,
CKD, hypothyroidism,
cancer, CVA, COPD, CLD
Association of risk
factors with disease
severity and death.
Unadjusted RR
calculated
Shahriarirad R et al.,
2020 (BMC
Infectious Diseases)
Iran Fars Province 2-20-2020
to 3-20-
2020
Multicenter
Retrospective
113 Age, sex, HTN, DM, CVD,
COPD, CKD, malignancy,
other immunosuppressive
diseases
Prevalence of death. Unadjusted RR
calculated
Association of risk
factors with disease
severity.
Shekhar R et al.,
2020 (Infectious
Diseases)
USA New Mexico 1-19-2020
to 4-24-
2020
Cohort 50 Age, sex, HTN, DM, COPD,
alcoholic cirrhosis, alcohol
use, obesity
Association of risk
factors with disease
severity.
Unadjusted RR
calculated
Shi Y et al., 2020
(Crit Care)
China Zhejiang
province
Not
specified to
02-11-2020
Retrospective 487 Age, sex, smoking, HTN,
DM, CKD, CVD, CLD,
cancer
Prevalence of and
association of risk
factors with severe
disease
Unadjusted RR
calculated
Suleyman G et al.,
2020 (JAMA
Network)
USA Metropolitan
Detroit
3-9-2020 to
3-27-2020
Retrospective 463 Age, sex, ethnicity, COPD,
obstructive sleep apnea, DM,
HTN, CVD, CKD, cancer,
rheumatologic disease, organ
transplant, obesity, smoking
Association of risk
factors with disease
severity.
Adjusted OR
Sun L et al., 2020
(Journal of Medical
Virology)
China Beijing 1-20-2020
to 2-15-
2020
Retrospective 55 Age, sex, exposure, HTN,
DM, CVD, Lung Disease,
CKD, CLD
Prevalence of severe
disease. Association of
risk factors with severe
disease.
Unadjusted RR
calculated
Tambe M et al.,
2020 (Indian J
Public Health)
India Pune 3-31-2020
to 4-24-
2020
Cross-
Sectional
197 Age, sex, HTN, DM, COPD,
CVS, ALD, CKD
Association of risk
factors with disease
severity and death.
Unadjusted RR
calculated
Tian S et al., 2020
(Journal of
Infection)
China Beijing 1-20-2020
to 2-10-
2020
Retrospective 262 Age, sex, contact history,
exposure to Wuhan.
Prevalence of death.
Association of severe
disease with risk
factors.
Unadjusted RR
calculated
Tomlins J et al.,
2020 (Journal of
Infection)
UK Bristol 3-10-2020
to 3-30-
2020
Retrospective 95 Age, sex, HTN, DM, COPD,
CVD, cancer, renal disease,
gastrointestinal disease,
neurological disease
Prevalence of death.
Association of risk
factors with death.
Unadjusted RR
calculated
Turcotte J.J et al.,
2020 (PLOS ONE)
USA Maryland 3-1-2020 to
4-12-2020
Retrospective 117 Age, BMI, sex, DM,
obstructive sleep apnea,
COPD, CVD, CKD, HTN,
smoking, alcohol use, liver
disease
Association of risk
factors with disease
severity and death.
Adjusted OR
(Continued )
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Table 1. (Continued)
Author, year of
publication
(journal)
Country Region Study
Period
Study Design Size Epidemiological Risk Factor Outcome Measures of
Association
Wan S et al., 2020
(Journal of Medical
Virology)
China Northeast
Chongqing
1-23-2020
to 2-8-2020
Retrospective 135 Age, sex, smoking, CKD,
COPD, HTN, DM, CVD,
Cancer, CLD, exposure,
travel history
Prevalence of severe
disease. Association of
risk factors with severe
disease.
Unadjusted RR
calculated
Wang D et al., 2020
(JAMA)
China Wuhan 1-1-2020 to
1-28-2020
Retrospective 138 Age, sex, Huanan Seafood
Market Exposure, HTN,
DM, CVD, COPD, Cancer,
CKD, CLD, HIV
Prevalence of death
and ICU admission.
Unadjusted RR
calculated
Association of risk
factors with severe
disease (ICU care)
Wang R et al., 2020
(Internal Journal of
Infectious Diseases)
China Fuyang 1-20-2020
to 02-09-
2020
Retrospective 125 Age, sex, CVD, Cancer Prevalence of critical
disease. Association of
age, sex, and smoking
with critical disease.
Unadjusted RR
calculated
Wang Z et al., 2020
(CID)
China Wuhan 1-16-2020
to 01-29-
2020
Retrospective 69 Age, sex, HTN, DM, CVD,
COPD, Cancer, HBV,
Asthma
Prevalence of death
and severe disease
(SpO2<90%).
Association of risk
factors with severe
disease.
Unadjusted RR
calculated
Wei Y et al., 2020
(BMC Infectious
Diseases)
China Hubei
Province
1-27-2020
to 3-22-
2020
Retrospective 276 Age, sex, smoking, obesity,
HTN, COPD, CVD, DM,
cerebrovascular disease,
cancer
Association of risk
factors with disease
severity.
Unadjusted RR
calculated
Wu C et al., 2020
(JAMA Intern Med)
China Wuhan 12-15-2019
to 01-26-
2020
Retrospective 201 Age, sex, HTN, DM, CVD,
CKD, Chronic Lung Disease,
Cancer, CLD, Sea Food
Market Exposure.
Prevalence of ARDS,
ICU admission and
death. Association of
risk factors with severe
disease (ARDS) and
death.
Unadjusted RR
calculated
Yang X et al, 2020
(Lancet Respir Med)
China Wuhan 12-24-2019
to 1-26-
2020
Retrospective 52 Age, sex, exposure, COPD,
diabetes, chronic cardiac
disease, smoking,
malnutrition
Association of risk
factors with death.
Unadjusted RR
calculated
Yao Q et al., 2020
(Pol Arch Intern)
China Huanggang,
Hubei
1-30-2020
to 2-11-
2020
Retrospective 108 Age, sex, smoking, HTN,
DM, CVD, CLD, cancer
Prevalence of severe
disease and death.
Unadjusted RR
calculated
Association of risk
factors with severe
disease and death.
Young BE et al.,
2020 (JAMA)
Singapore Singapore 1-23-2020
to 2-3-2020
Retrospective 18 Age, sex Prevalence of severe
disease (receiving
supplemental O2).
Association of severe
disease with age and
sex.
Unadjusted RR
calculated
Yu T et al., 2020
(Clinical
Therapeutics)
China Guangdong January to
February
2020
Cross-
sectional
95 Age, sex, current smoker Prevalence of ARDS. Unadjusted RR
calculated
Association of age,
sex, and smoking with
ARDS.
Yu X et al., 2020
(Transboundary and
Emerging Diseases)
China Shanghai Up to 2-19-
2020
Retrospective 333 Age, sex, BMI, smoking,
alcohol, exposure, HTN,
DM, CVD
Prevalence of death
and severe disease
(Severe/critical
pneumonia).
Association of risk
factors with severe
disease.
Adjusted OR for
age group, sex,
CVD, DM, HTN.
(Continued )
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prevalence of death, severe disease, and risk factors (S1 Table), and association of the risk fac-
tors with death (S2 Table) and severe disease (S3 Table) for the individual studies are presented
in the supplemental tables.
Predictors of death and severe disease (Tables 2and 3)
Age and sex. Median age for people who died was 79 years [IQR: 77–80; I
2
= 89%; n = 28]
and who had severe disease was 61 years [IQR: 59–63; I
2
= 48%; n = 26]. Eighty-five percent
[95% CI: 80–89; I2 = 76%; n = 18] of the deaths were in people aged 60 years and 66% [95%
CI: 64–69; n = 34] were in males. The CFR (95% CI) was 35% (28–43%) for age60 years and
26% (21–32%) for males. Patients aged60 years [summary relative risk (sRR): 3.61; 95% CI:
Table 1. (Continued)
Author, year of
publication
(journal)
Country Region Study
Period
Study Design Size Epidemiological Risk Factor Outcome Measures of
Association
Zhan T et al., 2020 (J
Int Med Res)
China Wuhan 1-12-2020
to 3-8-2020
Retrospective 405 Age, sex, smoking, alcohol
history, CVD,
gastrointestinal disease,
COPD, CKD, CLD
Association of risk
factors with disease
severity.
Unadjusted RR
calculated
Zhang G et al., 2020
BMC Respiratory
Research)
China Wuhan 1-16-2020
to 2-25-
2020
Retrospective 95 Age, sex Prevalence of severe
disease, composite end
point, and death.
Association with
severe disease.
Unadjusted RR
calculated
Zhang J et al., 2020
(Clin Microbiol
Infect)
China Wuhan 1-11-2020
to 2-6-2020
Retrospective 663 Age, sex, COPD, CVD,
gastrointestinal disease,
CKD, cancer
Prevalence of death. Adjusted OR
Association of risk
factors with disease
severity.
Zhang JJ et al., 2020
(Allergy)
China Wuhan 1-16-2020
to 2-3-2020
Retrospective 140 Age, sex, current smoker,
past smoker, exposure
history, HTN, DM, CVD,
COPD, CKD, CLD
Prevalence of severe
disease. Association of
risk factors with severe
disease (ICU
admission).
Unadjusted RR
calculated
Zhao X-Y et al.,
2020 (BMC Inf Dis)
China Hubei (Non-
Wuhan)
1-16-2020
to 2-10-
2020
Retrospective 91 Age, sex, DM, COPD,
Cancer, Kidney disease
Prevalence of death.
Association of risk
factors with severe
disease
Unadjusted RR
calculated
Zheng S et al., 2020
(BMJ)
China Zhejiang
province
1-19-2020
to 2-15-
2020
Retrospective 96 Age, sex, HTN, DM, CVD,
lung disease, Liver disease,
renal disease, malignancy,
viral Load,
immunocompromise
Prevalence of death
and severe disease.
Unadjusted RR
calculated
Association of risk
factors with severe
disease.
Zheng Y et al., 2020
(Pharmacological
Research)
China Shiyan, Hubei 1-16-2020
to 2-4-2020
Retrospective 73 Age, sex, exposure, smoking
history, DM, CVD
Prevalence of severe
(severe/ critical)
disease. Association of
smoking and diabetes
with severe disease.
Unadjusted RR
calculated
Zhou F et al., 2020
(The Lancet)
China Wuhan 12-29-2019
to 1-31-
2020
Retrospective 191 Age, sex, current smoking,
exposure history, HTN, DM,
CVD, COPD, cancer, CKD
Prevalence of severe
disease (ICU
admission) and death.
Association of risk
factors with death.
Adjusted OR for
age and CVD.
Unadjusted RR
calculated for
other variables.
CVD, cardiovascular disease; CKD, chronic kidney disease; CLD, chronic liver disease; COPD, chronic obstructive pulmonary disease; HTN, hypertension; DM,
diabetes mellitus; ICU, intensive care unit; BMI, body mass index; HIV, human immunodeficiency virus; AIDS, acquired immunodeficiency syndrome; RR, relative
risk; HR, hazard ratio; OR, odds ratio.
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2.96–4.39; I
2
= 77%; n = 24] and males [sRR: 1.34; 95% CI: 1.22–1.40; I
2
= 18%; n = 36] had
higher risk of death. The risk of severe disease was similarly higher for age>60 [sRR: 1.57; 95%
CI: 1.36–1.80; I
2
= 85%; n = 29] and males [sRR: 1.26; 95% CI: 1.18–1.35; I
2
= 38%; n = 47].
Hypertension. The prevalence of hypertension in the COVID-19 patients was 50% [95%
CI: 46–54% I
2
= 98%; n = 64], with a CFR in hypertensive patients of 28% [95% CI: 23–36%;
I
2
= 97%; n = 29] and a CSR of 44% [95% CI: 37–53%; I
2
= 95%; n = 39]. Of the COVID-19
patients that died, 66% [95% CI: 61–70%; I
2
= 83%; n = 29] had hypertension. Hypertensives
had higher relative risk of death [sRR: 1.76; 95% CI: 1.58–1.96; I
2
= 56%; n = 32] and severe
disease [sRR: 1.46; 95% CI: 1.28–1.65; I
2
= 77%; n = 40] compared to non-hypertensives
(Fig 2A).
Diabetes. The prevalence of diabetes was 28% [95% CI: 25–31%; I
2
= 97%; n = 67] with a
CFR of 24% [95% CI: 17–33%; I
2
= 98%; n = 29] and CSR of 43% [95% CI: 38–49%; I
2
= 99%;
n = 30] in the diabetics. Of the COVID-19 patients that died, 33% [95% CI: 32–44%; I
2
= 83%;
n = 29] were diabetics. Diabetics had higher relative risk of death [sRR: 1.50; 95% CI: 1.35–
1.66; I
2
= 58%; n = 33] and severe disease [sRR: 1.48; 95% CI: 1.35–1.63; I
2
= 59%; n = 44] com-
pared to non-diabetics (Fig 2B).
Cardiovascular disease. The pooled prevalence of CVD was 17% [95% CI: 15–20%; I
2
=
96%; n = 65] with a CFR of 52% [95% CI: 46–60%; I
2
= 81%; n = 29] and CSR of 56% [95% CI:
48–65%; I
2
= 91%; n = 37] among cardiac patients. Of the patients that died, 37% [95% CI: 32–
Table 2. Pooled prevalence of death stratified by epidemiological risk factors in COVID-19 patients hospitalized between December 2019-August 2020.
Risk factor or
Outcome
Overall prevalence of risk
across studies
Pooled Prevalence of Death (Case Fatality Risk) and
Risk Factor
Summary Relative Risk of Death
No. of
studies
Pooled prevalence
of risk factor and
death,
No. of
studies
Case fatality risk
(Prevalence of death
in risk group),
#
Prevalence of risk
factor in persons
who died,
No. of
studies
Fixed Effects Random
Effects
#
Heterogeneity
Summary relative
risk; 95% CI
(Shore adjusted)
sRR; (95%
CI)
I
2
; c
2
; p value
% (95% CI) % (95% CI) % (95% CI)
Death 60 20 (18–23) N/A N/A N/A N/A N/A N/A N/A
Age 60 years 41 48 (44–53) 18 35 (28–43) 85 (80–89) 24 3.61 (2.96–4.39) 1.29 (1.03–
1.62)
77%; 99;
p<0.01
Male 75 59 (57–60) 31 26 (21–32) 66 (64–69) 36 1.31 (1.22–1.40) 1.34 (1.24–
1.45)
18%; 43;
p = 0.17
Smoking history 41 26 (22–31) 11 27 (24–32) 44 (38–50) 13 1.28 (1.06–1.55) 1.41 (1.12–
1.78)
68%; 37;
p<0.01
Current smoker 21 10 (7–13) 7 21 (14–29) 13 (7–24) 8 1.43 (91–2.26) 1.53 (95–
2.45)
78%; 32;
p<0.01
COPD 52 9 (8–11) 20 51 (36–71) 12 (7–19) 22 1.70 (1.42–2.04) 1.74 (1.43–
2.13)
66%; 61;
p<0.01
Hypertension 64 50 (46–54) 29 28 (23–36) 66 (61–70) 32 1.76 (1.58–1.96) 1.88 (1.66–
2.13)
56%; 70;
p<0.01
Diabetes 67 28 (25–31) 29 24 (17–33) 39 (35–44) 33 1.50 (1.35–1.66) 1.60 (1.42–
1.79)
58%; 77;
p<0.01
Cardiovascular
disease
65 17 (15–20) 29 52 (46–60) 37 (32–43) 34 2.08 (1.81–2.39) 2.25 (1.92–
2.64)
69%; 106;
p<0.01
Chronic kidney
disease
47 13 (11–16) 18 48 (37–63) 27 (21–34) 23 2.52 (2.11–3.00) 2.39 (1.91–
2.99)
72%; 79;
p<0.01
Chronic Liver
Disease
31 2(2–3) 8 39(31–50) 6 (4–8) 9 2.65(1.88–3.75) 1.99 (1.26–
3.16)
77%; 35;
p<0.01
Case fatality risk of represent total number of people that died in the specific risk group divided by total population in the risk group.
#
Prevalence of risk group in dead represent total number of people having the risk group divided by total population that died.
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43%; I
2
= 83%; n = 29] had CVD. Patients with CVD had higher relative risk of death [sRR:
2.08; 95% CI: 1.81–2.39; I
2
= 69%; n = 34] and severe disease [sRR: 1.54; 95% CI: 1.39–1.72; I
2
= 77%; n = 38] compared to patients without CVD (Fig 2C).
Smoking and COPD. The prevalence of any history of smoking in the patients was 26%
[95% CI: 22–31%; I
2
= 98%; n = 41]. For patients with smoking history, the CFR was 27%
[95% CI: 24–32%; I
2
= 61%; n = 11] and CSR was 39% [95% CI: 34–46; I
2
= 78%; n = 27]. Com-
pared to never smokers, patients with smoking history had higher relative risk of death [sRR:
1.28; 95% CI: 1.06–1.55; I
2
= 68%; n = 13] and severe COVID-19 disease [sRR: 1.29; 95% CI:
1.18–1.42; I
2
= 33%; n = 27] (Fig 3A). The prevalence of COPD was 9% [95% CI: 8–11%; I
2
=
94%; n = 52]. Patients with COPD had a CFR of 51% [95% CI: 43–59%; I
2
= 0%; n = 21]; CSR
of 43% [95% CI: 35–52%; I
2
= 84%; n = 24]; a sRR of death of 1.70 [95% CI: 1.42–2.04; I
2
=
66%; n = 22] and of severe disease of 1.71 [95% CI: 1.49–1.97; I
2
= 84%; n = 29] (Fig 3B).
Chronic kidney disease. The prevalence of CKD was 13% [95% CI: 11–16%; I
2
= 96%;
n = 47] with a CFR of 48% [95% CI: 37–63%; I
2
= 89%; n = 18] and CSR of 36% [95% CI: 33–
40%; I
2
= 56%; n = 22] in CKD patients. CKD was present in 27% [95% CI: 21–34%; I
2
= 79%;
n = 18] of all COVID-19 patients that died. CKD patients had higher relative risk of death
[sRR: 2.52; 95% CI: 2.11–3.00; I
2
= 72%; n = 23] and severe disease [sRR: 1.56; 95% CI: 1.31–
1.86; I
2
= 85%; n = 27] compared to non-CKD patients (Fig 3C).
Chronic liver disease. The prevalence of CLD was 2% [95% CI: 2–3%; I
2
= 72%; n = 31]
with a CFR of 39% [95% CI: 31–50%; I
2
= 0%; n = 8] and CSR of 43% [95% CI: 32–57%; I
2
=
5%; n = 12] in CLD patients. CLD was present in 6% [95% CI: 4–8%; I
2
= 0%; n = 8] of the
Table 3. Pooled prevalence of severe disease stratified by epidemiological risk factors in COVID-19 patients.
Risk group or
outcome
Prevalence of Severe Disease (Case Severity Risk) and Risk Factors Summary Relative Risk of Severe Disease
No. of
studies
Prevalence of severe disease
and case severity risk, % (95%
CI)
Prevalence of risk factor in
people with severe disease, %
(95% CI)
No. of
studies
Fixed Effects Random
Effects
#
Heterogeneity
sRR; 95% CI
(Shore adjusted)
sRR; (95%
CI)
I
2
; c
2
; p value
Severe disease 25 20 (16–25) N/A N/A N/A N/A N/A
Age 60 years 26 48 (39–59) 56 (52–61) 29 1.57 (1.36–1.80) 1.76 (1.50–
2.07)
85%; 184;
p<0.01
Male 45 40 (34–47) 63 (61–66) 47 1.26 (1.18–1.35) 1.33 (1.22–
1.44)
38%; 75;
p<0.01
Smoking history 27 39 (34–46) 26 (21–32) 27 1.29 (1.18–1.42) 1.32 (1.18–
1.47)
33%; 39;
p = 0.05
Current smoker 13 38 (28–53) 13 (9–20) 15 1.52 (1.21–1.91) 1.25 (94–
1.66)
75%;56; p<0.01
COPD 24 43 (35–52) 14 (12–17) 29 1.71 (1.49–1.97) 1.83 (1.54–
2.18)
84%;179;
p<0.01
Hypertension 39 44 (37–53) 55 (50–61) 40 1.46 (1.28,1.65) 1.54
(1.33,1.78)
77%;168;
p<0.01
Diabetes 43 43 (38–49) 33 (30–38) 44 1.48 (1.35–1.63) 1.64 (1.47–
1.82)
59%;104;
p<0.01
Cardiovascular
disease
37 56 (48–65) 28 (24–33) 38 1.54 (1.39–1.72) 1.74 (1.52–
1.98)
77%;164;
p<0.01
Chronic kidney
disease
22 36 (33–40) 26 (19–37) 27 1.56 (1.31–1.86) 1.42 (1.15–
1.76)
85%; 176;
p<0.01
Chronic Liver
Disease
12 43(32–57) 5 (3–7) 15 1.63 (1.23–2.15) 1.66 (1.16–
2.36)
82%; 76;
p<0.01
Case severity risk represent total number of people developing severe disease in the specific risk group divided by total population in that risk group.
#
Prevalence of risk factor in severe disease represent total number of people with the risk factor divided by total population with severe disease.
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COVID-19 patients who died. Patients with CLD had higher relative risk of death [sRR: 2.65;
95% CI: 1.88–3.75; I
2
= 77%; n = 9] and severe disease [sRR: 1.63; 95% CI: 1.23–2.15; I
2
= 82%;
n = 15] compared to non-CKD patients (Fig 3D).
COVID-19 related organ system injury
To understand how pre-existing health conditions may be correlated with the risk of specific
organ injury, we calculated the prevalence of acute injury to lung, heart and kidney for studies
that reported prevalence of both the pre-existing condition(s) and corresponding organ injury
(Fig 4A). Pooled across 12 studies [14,25,32,45,48,49,52,54,60,62,79], the prevalence of
COPD at baseline was 6% [95% CI: 4–11%] and the proportion of patients developing ARDS
during hospitalization was 48% [32–73%]. The pooled prevalence of baseline CVD (n = 13
studies) was 11% [95% CI: 9–15%] and that of acute cardiac injury (ACI) during hospitaliza-
tion was 21% [95% CI: 15–28%] [6,14,25,32,35,43,48,49,54,79,84]. The prevalence of
CKD (n = 12 studies) was 14% [95% CI: 8–26%] and that of acute kidney injury during hospi-
talization (AKI) was 27% [95% CI: 21–34%] [6,14,25,32,45,48,65,79].
Regional difference in prevalence of death and risk factors
Upon sub-group analysis, we noted significantly higher prevalence of death and risk factors
among COVID-19 patients in the US and Europe than in China (Fig 4B). The prevalence of
death was 23% [95% CI: 19–27%; I
2
= 97%; n = 29] in the US and Europe, and 11% [95% CI:
7–16%; I
2
= 94%; n = 24] in China. Prevalence of severe disease was 20% [95% CI: 16–25%;
Fig 2. Association of hypertension, diabetes and heart disease with death in COVID-19 patients.
https://doi.org/10.1371/journal.pone.0243191.g002
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I
2
= 98%; n = 25] for US and Europe, and 39% [95% CI: 32–47%; I
2
= 97%; n = 30] for China.
Median age of patients was 65 years [IQR: 63–67 years; I
2
= 0%; n = 24] for the US and Europe
and 55 years [IQR: 52–58 years; I
2
= 57%; n = 27] for China. Fifty-two percent [95% CI: 46–
59%; I
2
= 98%; n = 16] of the patients hospitalized were aged 60 years in the US and Europe
as compared to 36% [95% CI: 30–43%; I
2
= 96%; n = 22] for China. The prevalence of co-mor-
bidities between US-Europe and China differed as follows: 1) US-Europe: HTN = 55% [95%
CI: 52–57%]; diabetes = 31% [95% CI: 29–34]; CVD = 18% [95% CI: 15–21%]; smoking his-
tory = 15% [95% CI: 11–21%]; COPD = 9% [95% CI: 6–13%] and 2) China: HTN = 23% [95%
CI: 20–26%]; diabetes = 12% [95% CI: 10–14%]; CVD = 16% [95% CI: 12–22%]; smoking his-
tory = 11% [95% CI: 9–13%]; CKD = 2.3% [95 CI: 1.6–3.4%] and COPD = 4% [95 CI: 3–5%].
Comorbidities in COVID-19 patients and the general populations in the
US and China
In order to gain some understanding of whether patients with comorbidities are at higher risk
of COVID-19 infection or hospitalization, we compared the prevalence of comorbidities
between COVID-19 patients hospitalized in the US and the prevalence of comorbidities in the
general US population. We observed that the prevalence of hypertension (55%), diabetes
(33%), CVD (17%), and smoking history (23%) were substantially higher in the COVID-19
patients than in the general US population (Fig 4C). For the Chinese population, the overall
prevalence of hypertension (23%) and diabetes (12%) in the COVID-19 patients were similar
Fig 3. Association of smoking, chronic obstructive pulmonary disease, chronic kidney disease and chronic liver disease with death in COVID-19
patients.
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to that of the general Chinese population. However, the prevalence of smoking history (11%),
COPD (4%), CKD (2%), and heart disease (16%) in the COVID-19 patients hospitalized in
China were unexpectedly lower as compared to their corresponding prevalence in the general
Chinese population (Fig 4D).
Sensitivity analyses
The positive associations of age65 years, male sex, smoking history, COPD, hypertension
and diabetes with the risk of death in the COVID-19 patients were relatively homogenous
(I
2
<70%). However, we carried out sensitivity analyses to assess the effects of outliers. For the
risk of death for hypertension and smoking history, we removed the study by Yao et al. [86]
which showed significantly higher risk compared to other studies; the results for both hyper-
tension [sRR = 1.74; 95% CI: 1.58–1.94] and smoking [sRR:1.24; 95% CI: 1.08–1.42] remained
significant. Guan et al. [13] had published a second study with additional patients and reported
adjusted estimates for COPD, diabetes and hypertension. We used the adjusted risk estimates
for the analyses. For the risk of death with other risk factors (CVD, CKD, and CLD) for Guan
et al. [45], we conducted sensitivity analyses by using the counts only from the original study.
Fig 4. Prevalence of acute organ injuries during hospital stay and regional difference in prevalence of death and comorbidities in patients
hospitalized for COVID-19. ARDS, acute respiratory distress syndrome; COPD, chronic obstructive pulmonary disease; ACI, acute cardiac injury; CVD,
cardiovascular disease; AKI, acute kidney injury; CKD, chronic kidney disease; HTN, hypertension.
https://doi.org/10.1371/journal.pone.0243191.g004
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The results [sRR (95% CI)] were similar as: CVD = 2.06 [95 CI: 1.80–2.36], CKD = 2.48 [95%
CI: 2.09–2.94] and CLD = 2.67 [95% CI: 1.85–3.85].
Small study effects and quality assessment
We observed asymmetry in the funnel plot for studies that reported prevalence of death in
COVID-19 patients (Egger’s test p = 0.001) (S1 Fig). On further analysis, the plot remained
asymmetrical when restricted to studies from China (Egger’s p = 0.003) but was symmetrical
for studies from US-Europe (Egger’s p = 0.160). We observed symmetrical funnel plots with
no bias for pooled prevalence severe disease (Egger’s p = 0.128). On average, prospective or
retrospective studies scored a score of 6 out of 9 and cross-sectional studies scored 6 out of 10.
Many studies did not get a full score because they did not adjust for confounders (age, sex, or
other risk factors) or patients remained hospitalized even after the follow-up ended, suggesting
inadequate follow-up period (S4 Table).
Discussion
We carried out a comprehensive systematic review and meta-analysis of 77 studies that
included 38906 hospitalized patients to investigate the prevalence and risk factors for death
and severe disease in COVID-19 patients. We calculated an overall prevalence of death of 20%
and severe disease of 28%. Nearly 50% of the patients admitted to hospitals due to COVID-19
were 60 years of age and 59% were males. We observed high prevalence of hypertension and
diabetes of 50% and 28%, respectively, for the patients. The risk factors were more prevalent
in patients who died and were distributed as: age 60 years: 85%; males: 66%; hypertension:
66%; diabetes: 39%; heart disease: 37%; CKD: 27%; smoking history: 44%; COPD: 12%, and
CLD: 9%. In comparison with the overall prevalence of death of 20% for all COVID-19 hospi-
talized patients, the CFR was higher for male patients (26%) and for patients having the follow-
ing risk factors: age60 years (35%), heart disease (52%), COPD (51%), CKD (48%), CLD
(39%), hypertension (28%), diabetes (24%), and smoking history (27%). The elevation in the
risk of death was statistically significant for age 60 (sRR = 3.6; 95% CI: 3.0–4.4), male sex 1.3
(95% CI: 1.2–1.4), smoking history (sRR = 1.3; 95% CI: 1.1–1.6), COPD (sRR = 1.7; 95% CI:
1.4–2.0), heart disease (sRR = 2.1; 95% CI: 1.8–2.4), CKD (sRR = 2.5; 95% CI: 2.1–3.0), hyper-
tension (sRR = 1.8; 95% CI: 1.7–2.1), and diabetes (sRR = 1.5; 95% CI: 1.4–1.7). All of the risk
factors we analyzed were positively associated with progression to severe disease as well. The
results suggest that older age, male sex and the co-morbidities increase the risk of progression
to severe disease and death in COVID-19 patients.
We observed significant difference in the prevalence of death between US-Europe (23%)
and China (11%). This lower risk of death from COVID-19 for the hospitalized patients in
China may be explained by the lower median age as well as lower prevalence of co-morbidities
for COVID-19 patients in China. However, this >200% lower prevalence of death in China
is incommensurate with our finding of a higher prevalence of severe disease observed for
patients in China (39%) as compared to patients in the US-Europe (20%). Notably, we
observed asymmetry in the funnel plot and a statistically significant tests for publication bias
or small study effects for the prevalence of death for studies from China that could suggest
selective outcome reporting. As such, while the lower median age and prevalence of co-mor-
bidities for COVID-19 patients in China may explain the lower prevalence of death, it is also
possible that a selective under-reporting of death had occurred for studies from China. The
death toll in China was initially under-reported and later updated on April 17, 2020 [95].
Whether or not cigarette smoking has been associated with SARS-CoV-2 acquisition or
progression to severe disease has been strongly debated with studies showing both positive,
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null, and inverse association between smoking and COVID-19 [10,11,96–98]. We found that
patients with any history of smoking have both a higher risk of death (RR: 1.28; 95% CI: 1.06–
1.55) and severe disease (1.29; 95% CI: 1.18–1.42). The case fatality risk for those with smoking
history (27%) was also higher than the overall CFR of 20%. Whereas a higher COVID-19 mor-
tality and morbidity among smokers may be due its causal association with COPD and CVD,
Cai et al. [99] has also observed upregulation of pulmonary Angiotensin Converting Enzyme 2
(ACE2) gene expression and hence, pulmonary ACE2 receptors in smokers suggesting a direct
effect of smoking on COVID-19 susceptibility and disease progression. ACE2 receptors are
used by SARS-CoV-2 to translocate intracellularly [15,100–104].
Our results of higher risk of death and severe disease associated with hypertension, diabetes
and CVD in COVID-19 patients concurred with most studies conducted to date including
studies that specifically investigated these associations [14,65,105,106]. However, it is unclear
if cardiovascular risk factors including smoking, hypertension, diabetes, heart disease and
CKD increases the susceptibility toward SARS-CoV-2 infection in the population [15,100,
101,107]. On one hand, angiotensin-converting enzyme 2 (ACE2)–by blocking the renin
angiotensin aldosterone system (RAAS) and decreasing or countering the vasoconstrictive,
proinflammatory and profibrotic properties of angiotensin-II through catalysis of angiotensin-
II to angiotensin-(1–7)–have been shown to exert cardiovascular protective effect and prevent
acute lung injury from SARS-CoV-2 [15,100,101]. However, on the other hand, a possible
greater expression of ACE2, the functional receptor mediating cellular entry of SARS-CoV-2
in humans, in patients with cardiovascular disease and other comorbidities can lead to
increased susceptibility towards infection with SARS-CoV-2 [108,109]. In this context, it
would be reasonable to posit that a substantially higher prevalence of cardiovascular comor-
bidities in the hospitalized patients compared to the prevalence in the general population may
suggest elevated risk of acquisition of SARS-CoV-2 for patients with cardiovascular risk fac-
tors. To this end, we found that the prevalence of smoking history (23%), hypertension (55%),
diabetes (33%) and heart disease (17%) in the hospitalized COVID-19 patients in the US were
substantially higher than the corresponding prevalence of smoking (14%) [110], hypertension
(29%) [111], diabetes (13%) [112] and heart disease (9%) [113] in the general US population
that could suggest an association between these comorbidities and risk of SARS-CoV-2 infec-
tion or disease progression. However, we note that if the prevalence of these comorbidities in
the asymptomatic individuals with COVID-19 in the general population is similar to that of
their prevalence in the non-COVID-19 general population, then this difference–the higher
prevalence of comorbidities in the hospitalized patients compared to the general population–
could simply imply a higher risk of symptomatic infection or hospitalization for individuals
having SARS-CoV-2 infection. The prevalence of other risk factors i.e. COPD (9%) and CKD
(15%) in the COVID-19 patients in the US was similar to the overall prevalence of COPD (7%)
[114] and CKD (15%) [115] in the country. Generally, we noted a lower prevalence of comor-
bidities for patients in China. The prevalence of hypertension (23%) and diabetes (12%) in the
hospitalized patients in China, which were lower than that of the US, approximate the respec-
tive prevalence of hypertension (23%) [116] and diabetes (15%) [117] in the general population
of China. A previous meta-analysis also noted this observation [19]. Surprisingly, the preva-
lence of smoking (11%) in the COVID-19 patients hospitalized in China are inexplicably lower
than the corresponding prevalence of smoking (23%) among COVID-19 patients in the US
despite a higher prevalence of smoking (47% in Chinese males) [118] in the general Chinese
population is significantly higher than that of the US. The prevalence of CVD (16%), COPD
(4%) and CKD (2%) among COVID-19 patients in China are substantially lower than the cor-
responding prevalence of CVD (21%) [119], COPD (14%) [120], and CKD (11%) [121] in the
general Chinese population. Given these discrepancies, we are unsure whether the lower
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prevalence of comorbidities noted for the COVID-19 patients in China are representative of
the true prevalence. There was a great sense of urgency and a race to publish data in the early
phase of the outbreak. As such, there exists the possibility of substantial under-recording of
data on covariables. Had there been under-reporting, the implication would be a higher true
prevalence estimate. We do not see reason for any systematic difference in reporting of risk
factors based on outcome, or vice-versa, and hence, our summary relative risk estimates for
association of risk factors with death or severe disease should not have been affected.
We assessed if patients with specific co-morbidities at baseline had higher risk of specific
organ injury from SARS-CoV-2 during hospitalization. While the available data did not allow
direct assessment of this relation, we compared the prevalence of comorbidities with the preva-
lence of corresponding organ system injury for studies that reported both baseline comorbid-
ity and corresponding organ injury. We observed that the risk of acute lung injury/ARDS
(48%), ACI (21%), and AKI (27%) were substantially higher than the baseline prevalence of
COPD (6%), heart disease (11%) and CKD (14%), respectively. The higher prevalence of acute
organ injury than the prevalence of baseline comorbidity simply indicates that ARDS, ACI
and AKI were also occurring in patients who did not have a corresponding comorbidity at
baseline in addition to people having the comorbidities.
Most studies reported only frequencies of risk factors and did not present adjusted mea-
sures for disease severity or death. Given this limitation, the risk ratio we calculated from the
frequencies are largely unadjusted estimates. Future studies could additionally present, at the
least, age- and sex-adjusted measures for association of risk of comorbidities with death or
severe disease. Many studies reported odds ratio for the measure of association between pre-
existing conditions and risk of severe disease or death. Odds ratio poorly approximates risk
ratio when the disease prevalence is high at baseline. For example, Zhou et al. [14] calculated
an odds ratio of 5.4 (95% CI: 0.96–30.4) for risk of death from COPD in COVID-19 patients
whereas the risk ratio we calculated from the frequencies presented is RR = 2.47 (95% CI:
1.34–4.55). Prevalence of severe disease or death in COVID-19 patients was high in several
studies. Similarly, several meta-analyses calculated odds ratios instead of risk ratios to summa-
rize the risk of disease severity or death in association with risk factors such as smoking, diabe-
tes, hypertension and cardiovascular disease [10,11,18], often to be interpreted by media and
even by researchers as a measure of relative risk. Lack of rigor in research design, analysis and
interpretation could generate inconsistent and ungeneralizable results across studies leading to
controversy and confusion around serious public health issues such as that existing for associa-
tion (or not) of smoking with COVID-19 disease acquisition, severity or death. As publications
evolve at a pace that could be overwhelming for researchers and practitioners, we attempted to
present a meaningful summary and inference for association of risk factors with death or
severe disease from literatures published globally. Additionally, we provide an epidemiological
framework for the risk of infection by SARS-CoV-2 based on presence of cardiovascular risk
factors. This analysis can inform public health measures for COVID-19 screening and preven-
tion, risk stratification and management of patients in clinical practice, analysis and presenta-
tion strategies for research data and inspire etiological investigations.
Conclusion
Epidemiological risk factors for progression of COVID-19 to severe disease and death and for
acquisition of SARS-CoV-2, the causal agent for COVID-19, based on presence of pre-existing
conditions have been insufficiently understood. Meta-analysis of 77 studies including 39023
COVID-19 patients hospitalized globally revealed case fatality risk of 52% for those having heart
disease, 51% for COPD, 48% for CKD, 39% for CLD, 28% for hypertension, 27% for smoking
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history, 24% for diabetes, 35% for age60 years, and 26% for males. Of all the patients who
died, an overwhelming majority (85%) were in people aged60 years. Also, of the people who
died, 66% were males, 66% had hypertension, 44% had history of smoking, 39% had diabetes,
37% had CVD, 27% had CKD, and 6% had CLD. All of the above risk factors were significantly
associated with death and severe disease in the patients hospitalized for COVID-19. The preva-
lence of ARDS was 48%, ACI 21%, and AKI 28% in the hospitalized patients. A higher preva-
lence of hypertension, diabetes, smoking and heart disease in the COVID-19 inpatients as
compared to that of the general population could imply a higher risk of SARS-CoV-2 infection
or disease progression for patients having these risk factors. These findings could inform public
health strategies for targeted screening and appropriate control of modifiable risk factors such
as smoking, hypertension, and diabetes to reduce morbidity and mortality. Finally, based on the
published literature, there were vast differences in the prevalence of death and risk factors for
the populations in China and in US-Europe that should be further investigated.
Supporting information
S1 Table. Prevalence of death, severe disease and risk factors in COVID-19 patients
(December 2019-August 2020).
(DOCX)
S2 Table. Prevalence of death stratified by risk factors in COVID-19 patients (December
2019-August 2020).
(DOCX)
S3 Table. Prevalence of severe disease stratified by risk factors in COVID-19 patients (Dec
2019-August 2020).
(DOCX)
S4 Table. Newcastle-Ottawa quality assessment (modified) for studies
#
.
#
Award of Points:
Selection: points were awarded based on representativeness of the exposed group and unex-
posed group (2 points), ascertainment of exposures (1 point), and demonstration that outcome
of interest was not present at the start of the study (1 point). Comparability (2 points): points
were awarded based on whether the analyses were adjusted for age, sex, and other risk factors
(2 points for adjustment to age and sex). Outcome (3points): points were awarded based on
ascertainment of outcome through record linkage or independent blind assessment (1 points);
duration of follow-up (1 point) (hospitalization till discharge); and adequacy of follow up for
study population (complete follow up for the patients (vs whether patients were currently
under treatment at the time of study report) (1 point), or if the patients currently under admis-
sion are excluded from outcome assessment (1 point).
(DOCX)
S1 Fig. Publication bias or small study effects for prevalence of death and severe disease.
(TIF)
S1 Checklist. PRISMA 2009 checklist.
(DOC)
Author Contributions
Conceptualization: Kunchok Dorjee.
Data curation: Kunchok Dorjee, Hyunju Kim, Elizabeth Bonomo, Rinchen Dolma.
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Predictors of COVID-19 adverse outcomes: A meta-analysis
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Formal analysis: Kunchok Dorjee, Hyunju Kim, Elizabeth Bonomo.
Investigation: Kunchok Dorjee, Hyunju Kim, Elizabeth Bonomo, Rinchen Dolma.
Methodology: Kunchok Dorjee, Hyunju Kim, Elizabeth Bonomo, Rinchen Dolma.
Project administration: Elizabeth Bonomo.
Software: Kunchok Dorjee, Elizabeth Bonomo, Rinchen Dolma.
Validation: Hyunju Kim, Elizabeth Bonomo, Rinchen Dolma.
Visualization: Elizabeth Bonomo.
Writing – original draft: Kunchok Dorjee.
Writing – review & editing: Kunchok Dorjee, Hyunju Kim, Elizabeth Bonomo, Rinchen
Dolma.
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