Review 1

PLOS ONE
RESEARCH ARTICLE
Factors associated with disease severity and

mortality among patients with COVID-19: A
systematic review and meta-analysis
Vignesh Chidambaram ID1, Nyan Lynn Tun1, Waqas Z. Haque1, Marie Gilbert Majella ID2,
Ranjith Kumar Sivakumar3, Amudha Kumar4, Angela Ting-Wei Hsu1, Izza A. Ishak1, Aqsha
A. Nur1, Samuel K. Ayeh5, Emmanuella L. Salia6, Ahsan Zil-E-Ali1, Muhammad A. Saeed7,
Ayu P. B. Sarena8, Bhavna Seth9, Muzzammil Ahmadzada7, Eman F. Haque10,
Pranita Neupane5, Kuang-Heng Wang1, Tzu-Miao Pu1, Syed M. H. Ali11, Muhammad
a1111111111 A. Arshad12, Lin Wang ID1, Sheriza Baksh ID1, Petros C. Karakousis5,
a1111111111 Panagis Galiatsatos9*
a1111111111
1 Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America,
a1111111111 2 Department of Preventive and Social Medicine, Jawaharlal Institute of Postgraduate Medical Education and
a1111111111 Research, Puducherry, India, 3 Department of Anaesthesia and Intensive Care, Prince of Wales Hospital,
The Chinese University of Hong Kong, Shatin, Hong Kong, China, 4 Department of Internal Medicine,
University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America, 5 Division of
Infectious Diseases, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland,
United States of America, 6 Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore,
Maryland, United States of America, 7 Johns Hopkins University, Baltimore, Maryland, United States of
OPEN ACCESS
America, 8 Bhayangkara Setukpa Hospital, Sukabumi, Indonesia, 9 Division of Pulmonary and Critical Care
Citation: Chidambaram V, Tun NL, Haque WZ, Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of
Majella MG, Sivakumar RK, Kumar A, et al. (2020) America, 10 Southern Methodist University, Dallas, Texas, United States of America, 11 Fatima Memorial
Hospital, Lahore, Pakistan, 12 Nishtar Hospital, Multan, Pakistan
Factors associated with disease severity and
mortality among patients with COVID-19: A
* [email protected]
systematic review and meta-analysis. PLoS ONE
15(11): e0241541. https://doi.org/10.1371/journal.
pone.0241541
Editor: Girish Chandra Bhatt, All India Institute of

Abstract
Medical Sciences, Bhopal, INDIA
Received: August 3, 2020

Background
Accepted: October 17, 2020
Understanding the factors associated with disease severity and mortality in Coronavirus dis-
Published: November 18, 2020 ease (COVID-19) is imperative to effectively triage patients. We performed a systematic
Peer Review History: PLOS recognizes the review to determine the demographic, clinical, laboratory and radiological factors associated
benefits of transparency in the peer review with severity and mortality in COVID-19.
process; therefore, we enable the publication of
all of the content of peer review and author
responses alongside final, published articles. The Methods
editorial history of this article is available here:
We searched PubMed, Embase and WHO database for English language articles from
https://doi.org/10.1371/journal.pone.0241541
inception until May 8, 2020. We included Observational studies with direct comparison of
Copyright: © 2020 Chidambaram et al. This is an
clinical characteristics between a) patients who died and those who survived or b) patients
open access article distributed under the terms of
the Creative Commons Attribution License, which with severe disease and those without severe disease. Data extraction and quality assess-
permits unrestricted use, distribution, and ment were performed by two authors independently.
reproduction in any medium, provided the original
author and source are credited.
Results
Data Availability Statement: All relevant data are
within the manuscript and its Supporting Among 15680 articles from the literature search, 109 articles were included in the analysis.
information files. The risk of mortality was higher in patients with increasing age, male gender (RR 1.45, 95%
PLOS ONE | https://doi.org/10.1371/journal.pone.0241541 November 18, 2020 1 / 29

PLOS ONE Factors associated with severity and mortality in COVID-19
Funding: The authors received no specific funding CI 1.23–1.71), dyspnea (RR 2.55, 95%CI 1.88–2.46), diabetes (RR 1.59, 95%CI 1.41–
for this work. 1.78), hypertension (RR 1.90, 95%CI 1.69–2.15). Congestive heart failure (OR 4.76, 95%CI
Competing interests: The authors have declared 1.34–16.97), hilar lymphadenopathy (OR 8.34, 95%CI 2.57–27.08), bilateral lung involve-
that no competing interests exist. ment (OR 4.86, 95%CI 3.19–7.39) and reticular pattern (OR 5.54, 95%CI 1.24–24.67) were
associated with severe disease. Clinically relevant cut-offs for leukocytosis(>10.0 x109/L),
lymphopenia(< 1.1 x109/L), elevated C-reactive protein(>100mg/L), LDH(>250U/L) and D-
dimer(>1mg/L) had higher odds of severe disease and greater risk of mortality.
Conclusion
Knowledge of the factors associated of disease severity and mortality identified in our study
may assist in clinical decision-making and critical-care resource allocation for patients with
COVID-19.
Introduction
Since the first documented reports of the severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) infection, the virus has had a global impact, affecting millions, which led the
World Health Organization (WHO) to declare the outbreak a pandemic [1, 2]. Patients who
develop Coronavirus Disease 2019 (COVID-19) may require hospitalization and intensive
care unit admission [3–5].
With variable access to critical care resources across countries, recent guidelines for the
COVID-19 pandemic have called for allocating life sustaining treatments based on a patient’s
risk of mortality [6, 7]. Health systems preparedness requires a deeper understanding of how
to effectively triage patients with COVID-19, in order to maximize the benefit of scarce inten-
sive care unit resources while minimizing the potential harm of outpatient management of ill
patients. While the guidelines warrant utilizing triage scores that have been previously vali-
dated for assessing organ failure/dysfunction and survival (e.g. sequential organ failure assess-
ment, SOFA), these are non-specific in etiology [7, 8]. Thus, having an understanding of the
predisposing conditions and disease-specific clinical, laboratory and radiological parameters,
may lay the groundwork for developing a COVID-19 specific composite score at a later stage,
which can predict unfavorable clinical outcomes.
With the massive influx of studies on COVID-19 in the recent months and their often con-
flicting or unclear findings, a systematic review of the factors associated with survival or dis-
ease severity in patients with COVID-19 that takes into consideration the inherent variability
in study population, will be of great utility to clinicians, researchers and policy makers. In this
systematic review and meta-analysis, we sought to better understand the clinical, laboratory
and radiological parameters associated with mortality and disease severity among patients
with COVID-19.
Methods
Search strategy and study selection
We followed the PRISMA guidelines for reporting in systematic reviews and meta-analyses
[9]. We searched PubMed, Embase and the WHO COVID-19 database by using the search
strategy included in the supplementary document in S1 Appendix (Section I). For PubMed
and Embase, an initial search on March 26, 2020 was conducted, and updated multiple times

with the final update performed on May 7, 2020. The WHO database was initially downloaded
on March 27, 2020 and the final update was performed on May 8, 2020. Only articles published
in the English language were included. We only included article published in peer-reviewed
academic journals; we did not include articles uploaded in the preprint servers, as they are not
peer reviewed and the findings may not be reliable [10].
We included observational studies that included patients with microbiologically confirmed
SARS-CoV-2 infection, irrespective of the age of the participants. The study designs of the
included studies were assessed and recorded independently by two authors (VC and MM) act-
ing as arbiters. The differentiation between case series and cohort studies was made based on
the criteria outlined by Dekkers et al [11]. Case reports, case series, and randomized control
trials were excluded from this review. We included all studies that reported a direct compari-
son of clinical, laboratory or radiologic characteristics between a) patients who died and those
who survived or b) patients with severe disease and those without severe disease. Only those
studies which defined “severe disease” based on the American Thoracic Society guidelines for
the treatment of Community-acquired Pneumonia [12] or the Chinese National Health Com-
mission guidelines for the Treatment of Novel Coronavirus infection [13], were included in
our analysis. Studies which only described the characteristics of patients who died or patients
with severe disease were excluded if there was no comparison group.
We only included studies reporting primary hospital data on patients, while studies with
centralized data from national health agencies and databases were excluded from our review.
Efforts were made, as feasible, to minimize overlap of patients across studies by collecting
information on the name of the hospital, date of hospital admission of the participants and the
names of the investigators.
Literature screening
The COVIDENCE platform was used for conducting this systematic review [14]. After de-
duplication, the titles and abstracts of the articles retrieved from the search strategy were
screened independently by at least two of the following authors (VC, NT, WH, RS, AK, AH, II,
AN, SA, ES, and MS) and conflicts were resolved by consensus between VC and NT. The full
texts of the articles included after title and abstract screening were independently screened by
at least two of the following authors (VC, NT, WH, RS, AK, AH, II, AN, SA, ES, and MS) and
conflicts were resolved based on consensus between VC and NT. Specific reasons for study
exclusion are listed in Fig 1.
Data extraction and quality assessment

Data extraction was performed independently by at least two of the authors (VC, NT, WH,
MM, RS, AK, AH, II, AN, SA, ES, MS, AS, KW, and TP) and conflicts were resolved by a con-
sensus between two authors (MM and VC). The data extraction form for this review was cre-
ated using the Qualtrics platform [15]. The primary outcomes were a) death of the patient and
b) the presence of severe disease in the patient. There were no secondary outcomes. Data on
the study characteristics, source of funding, demographic characteristics, comorbidities, clini-
cal symptoms, in-hospital complications, laboratory, and radiological features of the study par-
ticipants were extracted. Data on sex of the patient, smoking status, presence of comorbidities,
clinical symptoms, in-hospital complications, and radiological features were extracted as
binary variables, while age was extracted as continuous data. For the laboratory parameters,
data were extracted as both continuous and categorical variables. Binary data for the laboratory
variables were collected using all the cut-offs described in the included studies. The time points
for lab measurements, radiological evaluation and the disease severity assessment were

Fig 1. Stages of the analysis process, assessing inclusion and exclusion criteria that amounted to the articles addressed in this review.
https://doi.org/10.1371/journal.pone.0241541.g001

extracted for the included studies. Continuous data for the age and laboratory variables were
documented as mean. The median values reported in studies were transformed into mean
[16].
The risk assessment for bias for all the studies included in this review was performed using
the Newcastle-Ottawa quality assessment scale (NOS) for observational and cohort studies
[17]. The three major domains of quality of a study covered by this tool were selection of par-
ticipants, comparability of cohorts and outcome assessment against a total score of 9. This was
performed independently by at least two of the following authors (RS, MM, ES, SA). When
conflicts related to bias arose, the final decision was taken by a consensus between VC and NT.
Data synthesis and analysis

We performed a meta-analysis with random effects model to obtain pooled effect sizes for the
outcomes of interest. The associations between binary parameters and mortality were reported
using pooled risk ratios (with 95%CI). Due to the lack of consistency in the time point of
assessment of disease severity, odds ratios (with 95%CI) were used to determine the associa-
tion between the various factors and the presence of severe disease. When the laboratory
parameters were reported using different cut-offs, we reported the effect sizes for each cut-off
taken separately in addition to the pooled effect sizes for all the cut-offs taken together. Statisti-
cal heterogeneity across the studies was assessed by forest plots, I2 and Tau2 statistics. When
the I2 was more than 60%, we performed subgroup analyses based on the whether the studies
included all patients with COVID-19 or only the patients who were critically ill. If the hetero-
geneity was still higher than 60%, we performed sensitivity analyses by excluding studies with
a low quality (NOS � 5). Sensitivity analyses for the laboratory and radiological parameters
were also performed by excluding studies which did not report the time points of assessment.
Publication bias was assessed by visual inspection of the funnel plot, and Egger’s test was per-
formed for those exposures reported by at least 10 studies. For continuous variables, meta-
regression was performed to assess the percentage change in mortality or the presence of
severe disease with unit increase in the mean of laboratory parameter reported in the studies.
For the binary exposures, unadjusted effect sizes were calculated from the summary data.
Adjusted effect sizes were not used due to the lack of consistency in the parameters that they
are adjusted for, among the included studies. All analyses were carried out using the meta
package in Stata (StataCorp, version 16) [18].
Role of the funding source

This study was not supported by any funding source.
Results
We identified 15680 studies from three databases after removing duplicates, of which the full
text was retrieved for 502 articles. All the articles included were in the English language. The
reasons for exclusion of studies are outlined in Fig 1. A total of 109 studies were included for
this review, of which 42 studies assessed mortality risks [19–60]; 72 studies determined associa-
tion with severe disease [24, 34, 39, 41, 56, 58, 61–126], out of which 5 studies reported both
the outcomes [24, 34, 39, 56, 58]. Of the total 109 studies in the review, 101 were retrospective
cohorts, seven were prospective cohorts, and one of them was an ambispective cohort study.
There were no cross-sectional or case control studies that satisfied the inclusion criteria. Of the
studies that determined the risk of mortality, an aggregate of 20296 participants were assessed,
with 32 studies from China, six from the United States, two from Spain, one from the United
Kingdom, one from Italy, one from Iran and a multi-country study. Five of these studies only

included patients who were critically ill or invasively ventilated [19, 23, 32, 35, 48]. Among the
studies that assessed the association with severe disease, a total of 17992 participants were
included with seventy-one studies from China and one study from Italy. The characteristics of
the included studies, along with the time points for laboratory, radiological and disease severity
assessment, are outlined in the S1 and S2 Tables (in S1 Appendix Section II).
Quality assessment was performed using the New-Castle Ottawa scale (NOS) as all of the
studies used a cohort study design. This revealed that one of the studies (0.9%) had scored 9,
54 studies (49.5%) had scored 8, 39 studies (35.7%) scored 7, six studies (5.5%) scored 6. A
total of nine studies were identified as low-quality studies (NOS � 5) with six studies (5.5%)
scoring 5, and the remaining three studies (2.7%) scoring 4 (S3 and S4 Tables—in S1 Appendix
section III).
Table 1 and Fig 2 show the list of exposures and their relationship with mortality. Males
(RR 1.45, 95%CI 1.23–1.71) and ever-smokers (RR 1.43, 95%CI: 1.09–1.87) had higher risk
of mortality. Patients with diabetes, hypertension, cardiovascular diseases, chronic renal dis-
ease, chronic liver disease and malignancy were associated with an increased risk of mortality;
while hepatitis B and HIV infections did not result in higher risk of mortality. Section V of
the supplementary document in S1 Appendix illustrates the forest and funnel plots of these
associations.
Patients who had dyspnea (RR 2.55, 95%CI: 1.88–3.46) and hemoptysis (RR 1.62, 95%CI:
1.25–2.11) had a significantly higher risk of mortality while other clinical features like fever,
sore throat, cough, expectoration, vomiting, diarrhea, nausea, myalgia, headache, anorexia,
chest pain, abdominal pain, palpitations, and anosmia did not demonstrate any significant
association with mortality. Acute respiratory distress syndrome (ARDS) was associated with
an RR of 20.19 [95%CI: 10.87–37.52] with an I2 of 79%. Cardiac complications such as acute
cardiac injury and acute cardiac failure had higher risk of mortality with RR of 5.42 [95%CI:
3.79–7.77] and 3.10 [95%CI: 2.55–3.77] respectively. Other complications with higher risk of
mortality were sepsis, bacteremia, shock, disseminated intravascular coagulation (DIC), acute
kidney injury and acute liver dysfunction. Association of laboratory parameters (based on spe-
cific cut-offs) with the risk of mortality are mentioned in the Table 2. Among the laboratory
parameters that were assessed using binary cut-offs, increased total leucocyte count, increased
neutrophil count, decreased lymphocyte count and reduced platelet count were associated
with increased risk of death. Inflammatory parameters such as C-reactive protein and procalci-
tonin were associated with increased risk of death with RRs of 5.49 [95%CI: 1.72–17.51] and
3.09 [95%CI: 2.35–4.07] respectively. Abnormal renal and liver parameters, hypernatremia
and hyperkalemia also were associated with increased risk of mortality.
Presence of bilateral lung infiltrates (RR 1.35, 95%CI 1.07–1.69), consolidation (RR 2.07,
95%CI 1.35–3.16) and air-bronchogram (RR 3.56, 95%CI 1.37–9.29) on CT were associated
with increased RR for mortality. The presence of unifocal involvement on CT had lower risk
of death (RR 0.31, 95%CI 0.11–0.92). The presence of ground glass opacities or pleural effusion
on CT demonstrated no association with mortality.
The odds ratios (OR) of severe disease in patients with various clinical characteristics are
shown in Table 1 and Fig 3. The odds of severe disease were high in patients with diabetes,
hypertension, cardiovascular diseases, chronic kidney disease, chronic liver disease and
chronic obstructive pulmonary disease. HIV and hepatitis B infections were not associated
with severe disease. Odds ratios for severe disease were higher in patients with fever, cough,
expectoration, anorexia, chest pain, dyspnea, and hemoptysis. The OR for severe disease in
patients who had dyspnea was 4.72 [95% CI: 3.18–7.01] among 34 studies. Gastrointestinal
symptoms nausea, vomiting and diarrhea did not show association with disease severity.

Table 1. Association of clinical characteristics with mortality and severe disease in patients with COVID–19.
Clinical characteristics Risk of Mortality Odds of Severe disease
No. of Studies No. of Patients Pooled RR [95% CI] Heterogeneity No. of Studies No. of Patients Pooled OR [95% CI] Heterogeneity
I2 T2 I2 T2
Baseline characteristics and co–morbidities
PLOS ONE
�
Male sex 26 16422 1.45 [1.23–1.71] 49% 0.07 59 17063 1.38 [1.24–1.53] 31% 0.04
Ever smoker 7 10419 1.43 [1.09–1.87] 0 0 10 4511 1.51 [1.06–2.14] 62% 0.33
�
Diabetes 27 16263 1.59 [1.41–1.78] 23% 0.02 36 7552 2.09 [1.66–2.64] 40% 0.16
�
Hypertension 26 15947 1.90 [1.69–2.15] 28% 0.02 33 7002 2.63 [2.08–3.33] 64% 0.25
Cardiovascular diseases 25 16576 2.27 [1.88–2.79] 71% 0.13 31 6932 2.83 [2.21–3.63] 23% 0.09
Congestive Heart Failure 5 9910 2.08 [1.54–2.80] 0% 0 3 558 4.76 [1.34–16.97] 0% 0
Cerebrovascular Disease 15 2437 2.63 [1.97–3.51] 75% 0.20 13 4246 2.62 [1.76–3.90] 7% 0.04
COPD 15 9717 2.29 [1.90–2.75] 0% 0 19 4790 3.23 [1.97–5.31] 24% 0.27
Asthma 2 643 0.98 [0.42–2.32] 0% 0 ��
CKD 15 6556 2.24 [1.78–2.81] 39% 0.07 14 4442 2.62 [1.46–4.71] 27% 0.31
Chronic liver disease 6 3672 2.18 [1.40–3.40] 20% 0.07 17 8869 1.56 [1.12–2.17] 0% 0
Hepatitis B infection 2 822 1.14 [0.61–2.12] 0% 0 3 1945 0.54 [0.17–1.71] 0% 0
HIV 1 274 1.21 [0.17–8.64] �� 2 397 4.86 [0.50–47.22] 0% 0
Cancer 18 7008 1.52 [1.21–1.90] 0% 0 20 6026 2.90 [1.99–4.24] 4% 0.04
Immunodeficiency �� 4 1838 2.51 [0.62–10.10] 16% 0.36
Endocrine diseases �� 4 1378 2.45 [1.49–4.04] 0% 0
Clinical features
Fever 21 3551 0.82 [0.67–1.00] 28% 0.05 37 7501 1.75 [1.32–2.31] 56% 0.31
Sore throat 4 1256 0.79 [0.44–1.42] 0% 0 20 4721 0.79 [0.60–1.04] 0% 0
PLOS ONE | https://doi.org/10.1371/journal.pone.0241541 November 18, 2020

Cough 22 4098 1.00 [0.88–1.14] 16% 0.01 39 7746 1.22 [1.08–1.38] 5% 0.01
Expectoration 9 1977 1.19 [0.98–1.45] 55% 0.04 21 4960 1.55 [1.27–1.90] 32% 0.06
Vomiting 5 1644 0.86 [0.51–1.44] 0% 0 7 1919 1.02 [0.65–1.60] 0% 0
Diarrhea 14 3230 1.15 [0.85–1.57] 65% 0.17 33 6831 1.31 [1.00–1.71] 43% 0.19
Nausea 7 1725 1.00 [0.67–1.50] 1% 0 13 3809 1.01 [0.61–1.68] 49% 0.34
Myalgia 18 3270 0.91 [0.76–1.08] 8% 0.01 25 5831 1.22 [0.90–1.65] 62% 0.29
Headache 11 2645 0.95 [0.66–1.37] 21% 0.07 26 6340 1.44 [1.00–2.06] 53% 0.37
Anorexia 5 1119 1.04 [0.86–1.26] 0% 0 10 1157 2.72 [1.84–4.01] 0% 0
Chest pain 7 2026 1.16 [0.77–1.75] 43% 0.11 16 3558 2.70 [1.56–4.68] 75% 0.73
Dyspnea 20 3595 2.55 [1.88–3.46] 77% 0.30 34 7356 4.72 [3.18–7.01] 86% 0.90
Hemoptysis 6 1014 1.62 [1.25–2.11] 0% 0 5 2584 2.93 [1.47–5.83] 0% 0
Abdominal pain 5 1498 1.22[0.47–3.16] 7% 0.09 9 2506 2.86 [1.00–8.13] 69% 1.67
Palpitations 1 225 0.94 [0.59–1.49] �� 2 254 3.14 [0.88–11.19] 0% 0
Rhinorrhea 1 52 1.48 [0.96–2.29] �� 4 1096 0.94 [0.38–2.30] 0% 0
Anosmia 1 95 0.45 [0.03–6.40] ��
Complications
�
ARDS 14 2795 20.19 [10.87–37.52] 79% 0.90 ��
Shock 9 1844 6.12 [3.59–10.45] 93% 0.54 ��
Sepsis 3 573 47.95 [11.81–194.72] 0% 0 ��
Bacteremia 6 1365 5.07 [2.02–12.69] 94% 1.18 ��
Acute cardiac injury 14 2860 5.42 [3.79–7.77] 86% 0.36 ��
Acute heart failure 3 495 3.10 [2.55–3.77] 0% 0 ��
(Continued )
7 / 29
Factors associated with severity and mortality in COVID-19
Table 1. (Continued)
Clinical characteristics Risk of Mortality Odds of Severe disease

I2 T2 I2 T2
PLOS ONE
DIC 4 1394 3.41 [2.00–5.81] 95% 0.28 ��

GI bleeding 4 1028 2.53 [1.42–4.49] 76% 0.26 ��
�
Acute Kidney Injury 15 5331 4.65 [3.25–6.65] 95% 0.42 ��
Acute liver injury 10 4796 2.54 [1.77–3.66] 93% 0.28 ��
Hepatic encephalopathy 1 109 3.99 [2.71–5.87] ��
Ventilator associated pneumonia 1 52 0.51 [0.16–1.62] ��
CT features
Peripheral distribution 1 27 0.32 [0.05–2.08] �� 4 313 1.40 [0.36–5.50] 28% 0.57
Bilateral involvement 11 2067 1.35[1.07–1.69] 0 0 19 3515 4.86 [3.19–7.39] 47% 0.28
Consolidation 3 243 2.07 [1.35–3.16] 0 0 9 1084 3.01 [1.32–6.88] 76% 1.09
GGO 5 706 1.41 [0.87–2.28] 55% 0.15 14 2629 1.63 [1.22–2.17] 11% 0.03
Mixed GGO and consolidation �� 3 263 1.63 [0.69–3.85] 0 0
Air bronchogram 1 27 3.56[1.37–9.29] �� 4 333 4.79[1.11–20.61] 85% 1.85
Nodular infiltrates 1 27 0.41 [0.03–5.41] �� 0 4 356 1.03 [0.39–2.73] 46% 0.45
Hilar Lymphadenopathy �� 5 397 8.34 [2.57–27.08] 0% 0
Tree in bud appearance �� 1 120 4.30 [1.07–17.23] . 0
Unifocal involvement 2 463 0.31 [0.11–0.92] 44% 0.27 3 1237 1.13 [0.46–2.81] 66% 0.38
Pleural effusion 2 78 1.06 [0.27–4.21] �� 8 642 5.30 [2.74–10.26] 0% 0
Pleural thickening �� 1 52 1.86[0.35–9.92] �� 0
Inter–lobular septal thickening �� 2 124 2.86 [1.06–7.72] 0% 0

Bronchiectasis �� 2 221 5.62 [2.22–14.24] 0% 0
Linear infiltrates �� 3 324 3.21[1.00–10.25] 72% 0.74
Crazy pavement sign �� 5 650 4.52 [2.08–9.81] 64% 0.50
Reticular pattern �� 4 425 5.54 [1.24–24.67] 72% 1.61
Abbreviations: ARDS = Acute Respiratory Distress Syndrome. CKD = Chronic Kidney Disease. COPD = Chronic Obstructive Pulmonary Disease. CT = Computed Tomography.
DIC = Disseminated Intravascular Coagulation. GGO = Ground Glass Opacity. GI Bleeding = Gastrointestinal Bleeding. HIV = Human Immunodeficiency Virus. OR = Odds ratio. RR = Risk ratio.
�
denotes presence of publication bias by Egger’s test (p–value < 0�05).
https://doi.org/10.1371/journal.pone.0241541.t001
8 / 29
Fig 2. Meta-analysis to assess risk of mortality for (A) smoking status. (B) hypertension. (C) diabetes mellitus. (D)
COPD. (E) acute cardiac injury. (F) acute kidney injury. (G) bilateral lung involvement. (H) Lung consolidation.
COPD = chronic obstructive pulmonary disease. !Shenzhen Third People’s Hospital, Shenzhen, China. #Tongji
Hospital, Wuhan, China. $Wuhan Jinyintan Hospital, Wuhan, China. � Zhongnan Hospital of Wuhan University,
Wuhan, China. %Tianyou Hospital, Wuhan, China. &Taizhou Public Health Medical Center, Zhejiang, China.
+Chongqing Three Gorges Central Hospital, Chongqing, China. @Renmin Hospital of Wuhan University, Wuhan,
China. ^General Hospital of Central Theater Command of People’s Liberation Army, Wuhan, China.

Table 2. Association of laboratory parameters with mortality in patients with COVID–19.
Laboratory Parameters Pooled Risk of Mortality Lab Cut-offs Risk of Mortality (based on cut-offs)
I2 T2 I2 T2
9
Decreased TLC 8 1534 0.43[0.31–0.59] 0% 0 TLC < 3.5 x10 /L 1 154 0.58[0.26–1.30] - -
PLOS ONE
TLC < 4.0 x109/L 7 1380 0.43 [0.29–0.58] 0% 0

Increased TLC 9 1708 3.85[2.56–5.78] 80.87% 0.06 TLC > 9.5 x109/L 3 353 3.60 [2.22–5.84] 31.88% 0.06
TLC >10.0 x109/L 6 1355 3.97[2.06–7.64] 90.80% 0.55
Decreased Neutrophil 2 727 0.33[0.03–3.15] 72.18% 1.93 N < 1.8 x109/L 1 179 0.94[0.24–3.72] - -
N < 2 x109/L 1 548 0.09[0.01–0.66] - -
Increased Neutrophil 3 1001 4.45 [3.20–6.18] 38.52% 0.03 N > 6.3 x109/L 2 453 3.83 [2.90–5.07] 0% 0
N > 6.5 x109/L 1 548 5.95[3.93–8.99] - -
Decreased Lymphocyte 8 1554 4.09 [1.69–9.91] 83.63% 1.24 L < 0.8 x109/L 2 299 4.45[2.70–7.32] 0% 0
L < 1.0 x109/L 2 329 2.20[0.35–14.07] 91.96% 1.65
L < 1.1 x109/L 4 378 5.97[0.98–36.29] 79.77% 2.68
Decreased Platelet count 6 1439 2.42 [1.78–3.30] 51.04% 0.07 Plt count < 100 x 109/L 3 354 2.45[1.30–4.62] 51.44% 0.16
Plt count < 125 x 109/L 2 537 2.45[1.26–4.75] 74.92% 0.17
Plt count < 150 x 109/L 1 548 2.08 [1.39–3.13] - -
Decreased Albumin 4 1031 3.30[2.61–4.18] 0% 0 Albumin < 32 g/L 1 274 3.52[2.61–4.74] - -
Albumin < 35 g/L 2 702 3.27[2.19–4.88] 0% 0
Albumin < 40 g/L 1 55 1.24[0.36–4.25] - -
Increased Globulin 2 603 1.65[1.15–2.37] 0% 0 Globulin >35 g/L 2 603 1.65[1.15–2.37] 0% 0
Increased T� Bilirubin 3 810 2.74[1.96–3.82] 0% 0 T. Bilirubin > 20 umol/L 3 810 2.74[1.96–3.82] 0% 0
Increased AST 5 1210 2.33[1.93–2.82] 0% 0 AST > 40 U/L 5 1210 2.33 [1.93–2.82] 0% 0

Increased ALT 6 1330 1.48[1.20–1.82] 8.88% 0.01 ALT > 40 U/L 3 976 1.30[1.04–1.64] 0% 0
ALT > 50 U/L 3 354 2.00 [1.39–2.87] 0% 0
Increased GGT ��
Increased ALP ��
Increased INR ��
Increased PT 2 345 1.97[1.41–2.76] 0% 0 PT > 16s 2 345 1.97 [1.41–2.76] 0% 0
Elevated CK–total 4 508 1.96[1.43–2.70] 9.52% 0.01 CK–total > 171 U/L 2 209 1.87[0.88–3.97] 54.89% 0.18
CK–total > 185 U/L 1 191 1.78[1.09–2.91] ��
CK–total > 190 U/L 1 108 1.56[0.47–5.23] ��
Elevated CK-MB 1 108 5.75[2.12–15.62] - - CK-MB > 25 U/L 1 108 5.75[2.12–15.62] ��
Increased BUN 2 702 4.42[2.99–6.55] 45.89% 0.04 BUN � 7.6 mmol/L 1 548 5.34 [3.63–7.85] ��
BUN � 8.3 mmol/L 1 154 3.58 [2.32–5.51] ��
Increased Creatinine 6 1235 2.92[2.35–3.62] 0% 0 Creatinine > 85 umol/L 1 548 2.99[2.35–3.62] ��
Creatinine > 104 umol/L 1 55 2.61[1.36–4.98] ��
Creatinine > 133 umol/L 3 478 3.19 [1.62–6.31] 42.97% 0.15
Increased Na+ 2 428 2.70 [2.00–3.64] 63% 0.03 Na+ > 145 mmol/L 2 428 2.70 [2.00–3.64] 63% 0.03
Increased K+ 3 536 2.34[1.87–2.94] 9.45% 0.00 K+ > 5 mmol/L 2 428 2.36[1.85–3.01] 24.03% 0.01
K+ > 5.4 mmol/L 1 108 2.20[0.57–8.54] 9.45% 0.00
Decreased K+ 3 536 0.99[0.43–2.29] 60.38% 0.33 K+ < 3.5 mmol/L 2 428 0.70[0.22–2.27] 67.68% 0.52
K+ < 3.8 mmol/L 1 108 2.07 [0.69–6.23] ��
Elevated LDH 5 1222 5.37 [2.10–13.74] 80.61% 0.84 LDH > 245 U/L 3 345 4.19[0.85–20.66] 83.47% 1.59
(Continued)
10 / 29
Laboratory Parameters Pooled Risk of Mortality Lab Cut-offs Risk of Mortality (based on cut-offs)
I2 T2 I2 T2
PLOS ONE
LDH > 250 U/L 1 548 13.10[3.26–52.66] ��

LDH > 350 U/L 1 274 6.33[4.16–9.63] ��
Elevated Myoglobin 1 179 5.30 [2.36–11.92] �� 0 Myoglobin> 100 μg/L 1 179 5.30 [2.36–11.92] �� 0
Increased Uric acid ��
Elevated Cystatin C 1 108 1.75[0.41��7.50] �� Cystatin C >1.2mg/L 1 108 1.75[0.41��7.50] ��
Elevated D–Dimer 9 2026 3.98[2.87–5.52] 65.13% 0.13 D–Dimer > 0.5mg/L 4 562 3.33[1.48–7.49] 63.45% ��
D–Dimer > 1mg/L 3 847 4.82[3.29–7.07] 0% 0
D–Dimer > 2mg/L 1 343 5.54[4.15–7.39] ��
D–Dimer > 21mg/L 1 274 3.06[2.44–3.85] ��
Increased CRP 6 1338 5.49[1.72–17.51] 93.21% 1.59 CRP > 10 mg/L 1 108 6.22[0.83–46.36] ��
CRP > 100 mg/L 5 1175 5.72[1.40–23.41] 95.68% 2.12
Elevated ESR 2 603 0.96[0.64–1.44] 0% 0 ESR>15 mm/h 2 603 0.96[0.64–1.44] 0% 0
Elevated Procalcitonin 8 1555 3.09[2.35–4.07] 53.89% 0.07 Procalcitonin >0.05 μg/L 3 810 4.45[3.19–6.21] 0% 0
Procalcitonin >0.5 μg/L 4 690 2.21[1.13–4.33] 87.85% 0.35
Procalcitonin >1 μg/L 1 55 2.67[1.45–4.90] ��
Increased Serum ferritin 1 191 5.6 [1.47–21.6] �� S. ferritin > 300 μg/L 1 191 5.6 [1.47–21.6] ��
Increased SAA ��
Increased IL–1β 1 274 0.84 [0.38–1.83] �� IL–1β > 5 ng/L 1 274 0.84 [0.38–1.83] ��
Increased IL–2 1 274 4.04 [2.18–7.49] �� IL–2 > 710 U/L 1 274 4.04 [2.18–7.49] ��
Increased IL–6 2 503 22.59[3.19–160.03] 0% 0 IL–6 > 2.9 ng/L 1 229 12.66[0.79–202.89] ��

IL–6 > 7 ng/L 1 274 40.13[2.53–636.24] ��
Increased IL–8 1 274 2.29 [1.51–3.45] �� IL–8 > 62 ng/L 1 274 2.29 [1.51–3.45] ��
Increased IL–10 1 274 4.19 [2.56–6.84] �� IL–10 > 9.2 ng/L 1 274 4.19 [2.56–6.84] ��
Increased TNF–Alpha 1 274 2.57 [1.46–4.52] �� TNF–Alpha >8.1 ng/L 1 274 2.57 [1.46–4.52] ��
Increased NT–ProBNP 2 822 5.48 [3.78–7.34] 0% 0 NT–ProBNP > 285 ng/L 1 275 5.87[3.43–10.03] ��
NT–ProBNP > 500 ng/L 1 548 5.136[3.07–8.60] ��
Elevated troponin 6 1006 4.49[3.74–5.38] 0% 0 hs Tn I > 15.6 ng/L 2 375 4.62[2.80–7.65] 52.63% 0.07
hs Tn I > 26.2 ng/L 1 107 6.01[2.80–7.65] ��
hs Tn I > 28 ng/L 1 191 4.29[3.05–6.05] ��
Tn I > 50 ng/L 1 179 5.47[2.44–12.28] ��
hs Tn I > 100 ng/L 1 154 4.28[2.91–6.29] ��
Abbreviations: ALP = Alkaline Phosphatase. ALT = Alanine Aminotransferase. AST = Aspartate Aminotransferase. BNP = Brain Natriuretic Peptide. BUN = Blood Urea Nitrogen. CK = Creatine
Kinase. CRP = C–Reactive Protein. ESR = Erythrocyte Sedimentation Rate. GGT = Gamma–Glutamyl Transferase. IL = Interleukin. INR = International Normalized Ratio. K+ = Potassium.
LDH = Lactate Dehydrogenase. N = Neutrophil count. Na+ = Sodium. NT–ProBNP = N–Terminal Fragment Brain Natriuretic Peptide. Plt count = Platelet count. OR = Odds ratio.
PT = Prothrombin Time. RR = Risk ratio. T Bilirubin = Total Bilirubin. TLC = Total Leucocyte Count. TNF = Tumor Necrosis Factor.
�
11 / 29
Fig 3. Meta-analysis to assess odds of severe disease for (A) smoking status (B) hypertension (C) diabetes mellitus (D)
COPD E. bilateral lung involvement (F) Lung consolidation. COPD = chronic obstructive pulmonary disease. !Shenzhen
Third People’s Hospital, Shenzhen, China. # Tongji Hospital, Wuhan, China. $Wuhan Jinyintan Hospital, Wuhan, China.
�
Zhongnan Hospital of Wuhan University, Wuhan, China. %Tianyou Hospital, Wuhan, China. &Central hospital of Wuhan,
Wuhan. +Chongqing Three Gorges Central Hospital, Chongqing, China. @Renmin Hospital of Wuhan University, Wuhan,
China. ^General Hospital of Central Theater Command of People’s Liberation Army, Wuhan, China.

Among the laboratory parameters that were assessed for association with severe disease
using binary cut-offs (Table 3), decreased lymphocyte count (OR 2.64, 95%CI 1.12–6.23),
decreased serum albumin (OR 5.63, 95%CI 1.45–21.87), increased aspartate transaminase (OR
4.33, 95%CI 2.17–8.63) demonstrated increased odds of severe disease. Inflammatory parame-
ters namely, elevated CRP (OR 3.32, 95%CI 1.92–5.71), elevated procalcitonin (OR 5.50, 95%
CI 3.38–8.93) and increased ESR (OR 1.68, 95%CI 1.13–2.49) had high ORs for severe disease.
Bilateral lung involvement on CT was associated with an OR of 4.86[95%CI: 3.19–7.39] among
19 studies. Other radiological features on CT with higher odds of severe disease were lung con-
solidation, ground glass opacities, air bronchogram, hilar lymphadenopathy, pleural effusion,
crazy-pavement pattern, reticular pattern, tree-in bud appearance, inter-lobar septal thicken-
ing, and bronchiectasis. However, the OR of severe disease were not increased with peripheral
distribution of infiltrates, nodular infiltrates, linear infiltrates, unifocal involvement or pleural
thickening.
Meta-regression of continuous variables (Table 4) revealed that with every ten-year increase
in the mean age of the patients, there was a 7.6% and 11.2% increase in the mortality (p-
value = 0.02) and disease severity (p-value <0.001) respectively. Increase in the mean total leu-
kocyte count (p-value = 0.04) and a decrease in the mean lymphocyte count (p-value = 0.02)
were significantly associated with higher mortality. Higher levels of mean C-reactive protein
and mean D-dimer during admission were linked to higher proportion of both severe disease
as well as mortality. Increasing mean lactate dehydrogenase and creatine kinase among the
included studies were associated with higher mortality but not severe disease. Higher serum
creatinine levels and lower serum albumin levels correlated with disease severity but was not
significantly associated with mortality, though the direction of the relationship was consistent.
Unit increase in the mean blood urea nitrogen resulted in 5.3% increase in the mortality (p-
value = 0.030). Our analysis did not reveal a significant association between mortality or dis-
ease severity and other laboratory parameters, such as platelet count, hemoglobin, prothrom-
bin time, activated partial thromboplastin time (aPTT), procalcitonin, aspartate transaminase
(AST), alanine transaminase (ALT), erythrocyte sedimentation rate, total bilirubin and inter-
leukin-6 levels. Bubble plots assessing the linear relationship between the variables and the out-
comes (proportion with severe disease and proportion who died) are shown in Figs 4 and 5
and Supplementary Section VI in S1 Appendix.
Subgroup analyses based on the restriction of inclusion to critically ill participants are
shown in S5 Table and in the Supplementary Figures in S1 Appendix Section IV. Subgroup
analysis did not significantly reduce heterogeneity between studies except for the association
of elevated procalcitonin levels and presence of diarrhea with mortality. The magnitude of the
effect size changed significantly in the subgroups however the direction of the effect remained
consistent for multiple parameters, including dyspnea, cardiovascular disease, cerebrovascular
disease, diabetes mellitus, bacteremia, and gastrointestinal bleeding. In studies with critically
ill patients, the direction of the effect was reversed for gender and elevated procalcitonin levels,
but the association was not statistically significant in the subgroups. Sensitivity analysis by
excluding low-quality studies (NOS�5) did not significantly reduce heterogeneity or alter the
pooled effect sizes for the exposures with I2>50% for mortality. Sensitivity analysis by exclud-
ing low-quality studies reporting COVID-19 severity yielded a decrease in the heterogeneity
for various exposures, such as smoking, hypertension, myalgia, and air-bronchogram in CT.
Nevertheless, heterogeneity was substantially high for exposures, such as dyspnea, chest pain,
abdominal pain, unifocal involvement in CT and certain laboratory parameters. Sensitivity
analysis for the laboratory and radiological variables by excluding studies with an unclear
timepoint for the assessment of the parameters did not result in change in the direction or sig-
nificance of the association. In our analysis, bias due to small study effect could not be ruled

Table 3. Association of laboratory parameters with disease severity in patients with COVID–19.
Laboratory Parameters Pooled Odds of Disease Severity Lab Cut-offs Pooled Odds of Disease Severity (based on cut-offs)
I2 T2 I2 T2
9
Decreased TLC 11 3074 0.84[0.52–1.37] 78.58% 0.46 TLC < 3.5 x10 /L 4 548 0.70[0.37–1.33] 29.06% ��
PLOS ONE
TLC < 4.0 x109/L 6 2482 0.89[0.43–1.82] 88.86% 0.67

TLC < 5.0 x109/L 1 44 1.21[0.36–4.08] ��
Increased TLC 11 3353 3.70[2.31–5.93] 49.71% 0.27 TLC > 9.5 x109/L 4 548 2.94[2.31–5.93] 47.12% 0.47
TLC >10.0 x109/L 6 1706 4.65[2.17–9.98] 63.09% 0.49
TLC >11.0 x109/L 1 1099 2.54[1.43–4.52] ��
Decreased Neutrophil 2 689 0.33[0.19–0.58] 0% 0 N < 1.8 x109/L 1 141 0.95[0.10–8.97] ��
N < 2 x109/L 1 548 0.31[0.17–0.55] ��
Increased Neutrophil 3 554 2.00[0.93–4.31] 52.14% 0.25 N > 6.3 x109/L 1 141 4.95[1.67–14.68] ��
N > 6.5 x109/L 1 90 1.19[0.32–4.42] ��
N > 7.5 x109/L 1 323 1.52[0.93–2.47] ��
Decreased Lymphocyte 7 2922 2.64[1.12–6.23] 87.02% 1.04 L < 0.8 x109/L 2 342 3.10[0.49–19.69] 83.84% 1.49
L < 1.0 x109/L 1 476 4.04[2.59–6.31] ��
L < 1.1 x109/L 2 638 1.77[0.09–33.23] 94.51% 4.23
L < 1.5 x109/L 1 1143 8.56[0.44–165.38] ��
L < 2.0 x109/L 1 323 1.84[1.12–6.23] ��
Decreased Platelet count 9 2691 2.39[1.72–3.34] 34.31% 0.13 Plt count < 100 x 109/L 3 592 2.27[1.08–4.78] 0% 0
Plt count < 125 x 109/L 3 408 3.09[1.37–6.99] 45.21% 0.23
Plt count < 150 x 109/L 3 1691 2.22[1.32–3.73] 67.23% 0.13
Decreased Albumin 2 663 5.63[1.45–21.87] 77.32% 0.77 Albumin < 35 g/L 1 548 3.19[2.22–4.57] ��

Albumin < 40 g/L 1 115 13.07[3.68–46.40] ��
Increased Globulin 2 663 1.98[1.44–2.72] 0% 0 Globulin >30 g/L 1 115 1.67[0.77–3.64] 0% 0
Globulin >35 g/L 1 548 2.05[1.44–2.90] 0% 0
Increased T� Bilirubin 5 2031 2.23[1.34–3.71] 23.14% 0.08 T. Bilirubin > 20 umol/L 5 2031 2.23[1.34–3.71] 23.14% 0.08
Increased AST 7 2624 4.85[2.52–9.34] 86.47% 0.62 AST > 40 U/L 7 2624 4.85[2.52–9.34] 86.47% 0.62
Increased ALT 7 2920 2.40[1.09–5.29] 89.03% 0.97 ALT > 40 U/L 4 2607 2.36[0.81–6.89] 97.33% 2.41
ALT > 50 U/L 3 313 2.33[0.85–6.38] 0% 0
Increased GGT 1 115 1.42[0.44–4.55] �� GGT > 57 U/L 1 115 1.42[0.44–4.55] ��
Increased ALP 1 115 6.07[1.05–35.03] �� ALP > 120 U/L 1 115 6.07[1.05–35.03] ��
Increased INR 1 115 1.38[0.60–3.18] �� INR > 1.15 1 115 1.38[0.60–3.18] ��
Increased PT 2 413 2.35[1.26–4.41] 0% 0 PT > 12.8s 1 90 1.65[0.58–4.67] ��
PT > 14s 1 323 2.88[1.31–6.32] ��
Elevated CK–total 6 1733 3.11[1.74–5.55] 41.86% 0.21 CK–total > 190 U/L 3 359 3.73[1.97–7.07] 2.42% 0.01
CK–total > 190 U/L 3 1374 2.87[1.03–8.00] 49.25% 0.42
Elevated CK-MB 4 794 1.41[0.42–4.67] 72.23% 1.02 CK-MB > 5 U/L 2 596 0.73[0.14–3.69] 77.79% 1.08
CK-MB > 25 U/L 2 198 2.83[1.03–7.82] 0% 0
Increased BUN 2 871 4.06[2.71–6.07] 0% 0 BUN � 7.6 mmol/L 1 548 4.77[2.75–8.29] ��
BUN � 8 mmol/L 1 323 3.37[1.87–6.09] ��
Increased Creatinine 8 2508 2.49[1.41–4.41] 21.59% 0.14 Creatinine > 87 umol/L 2 709 1.66[1.14–2.43] 0% 0
Creatinine > 97 umol/L 2 225 5.88[0.63–54.73] 47.51% 1.33
Creatinine > 133 umol/L 3 1251 3.81[1.4–10.11] 0% 0
(Continued )
14 / 29
Laboratory Parameters Pooled Odds of Disease Severity Lab Cut-offs Pooled Odds of Disease Severity (based on cut-offs)
I2 T2 I2 T2
+
PLOS ONE
Increased Na ��
Increased K+ 1 108 0.94[0.18–4.86] �� K+ > 5.1 mmol/L 1 108 0.94[0.18–4.86] ��
Decreased K+ 1 108 7.59 [2.67–21.60] �� K+ < 3.8 mmol/L 1 108 7.59 [2.67–21.60] ��
Elevated LDH 7 2425 3.77[1.95–7.30] 82.69% 0.61 LDH > 225 U/L 1 161 4.70[2.02–10.94] ��
LDH > 243 U/L 1 115 5.90[2.33–14.95] ��
LDH > 250 U/L 4 2105 2.92[0.95–8.93] 92.70% 1.18
LDH > 300 U/L 1 44 6.29[1.60–24.73] ��
Elevated Myoglobin 1 273 4.57[2.05–10.17] �� Myoglobin> 100 μg/L 1 273 4.57[2.05–10.17] ��
Increased Uric acid 1 90 3.28[0.52–20.77] �� Uric acid >417 umol/L 1 90 3.28[0.52–20.77] ��
Increased Cystatin C 1 108 2.14[0.66–6.88] �� Cystatin C >1.2mg/L 1 108 2.14[0.66–6.88] ��
Elevated D–Dimer 5 1985 2.75[1.92–3.93] 32.40% 0.05 D–Dimer > 0.25mg/L 2 230 3.44[1.48–8.02] 0% 0
D–Dimer > 0.5mg/L 1 1099 1.94[1.27–2.97] ��
D–Dimer > 1mg/L 2 656 3.33[2.37–4.69] 0% 0
Increased CRP 12 3375 3.32[1.92–5.71] 73.74% 0.55 CRP > 30 mg/L 3 595 1.82[0.63–5.24] 50.77% 0.45
CRP > 50 mg/L 1 108 9.25[2.05–41.80]] ��
CRP > 80 mg/L 2 301 14.43[3.89–53.50] 0% 0
CRP > 100 mg/L 6 2371 2.92[1.55–5.51] 77.52% 0.43
Elevated ESR 1 548 1.68[1.13–2.49] �� ESR>20 mm/h 1 548 1.68[1.13–2.49] ��
Elevated Procalcitonin 8 2392 5.50[3.38–8.93] 38.70% 0.18 Procalcitonin >0.05 μg/L 2 240 3.45[1.61–7.37] 0% 0

Increased Serum ferritin 1 548 3.57 [2.12–6.01] �� S. ferritin > 500 μg/L 1 548 3.57 [2.12–6.01] ��
Increased SAA 5 830 1.54[0.84–2.82] 19.73% 0.10 SAA > 1mg/L 1 121 0.92[0.43–2.01] ��
SAA > 10mg/L 4 709 2.39[0.92–6.22] 27.08% 0.28
Increased IL–1β 1 548 0.62[0.37–1.02] �� IL–1β > 5 ng/L 1 548 0.62[0.37–1.02] ��
Increased IL–2 1 548 2.60[1.63–4.14] �� IL–2 receptor > 710 U/L 1 548 2.60[1.63–4.14] ��
Increased IL–6 3 778 3.30[0.73–14.93] 82.0% 1.38 IL–6 > 7 ng/L 3 778 3.30[0.73–14.93] 82.0% 1.38
Increased IL–8 1 548 1.83[0.79–4.27] �� IL–8 > 62 ng/L 1 548 1.83[0.79–4.27] ��
Increased IL–10 1 548 1.62[0.98–2.67] �� IL–10 > 9.2 ng/L 1 548 1.62[0.98–2.67] ��
Increased TNF–Alpha 1 548 1.90[1.20–3.03] �� TNF–Alpha >8.1 ng/L 1 548 1.90[1.20–3.03] ��
Increased NT–Pro BNP 2 821 4.43[2.80–7.02] 0% 0 NT–Pro BNP > 500 ng/L 1 548 4.23[2.36–7.59] ��
NT–Pro BNP > 900 ng/L 1 283 4.78[2.27–10.08] ��
Elevated troponin 2 596 3.04 [1.03–8.97] 77.67% 0.48 hs Tn I > 40 ng/L 2 596 3.04 [1.03–8.97] 77.67% 0.48
Abbreviations: ALP = Alkaline Phosphatase. ALT = Alanine Aminotransferase. AST = Aspartate Aminotransferase. BNP = Brain Natriuretic Peptide. BUN = Blood Urea Nitrogen. CK = Creatine
Kinase. CRP = C–Reactive Protein. ESR = Erythrocyte Sedimentation Rate. GGT = Gamma–Glutamyl Transferase. IL = Interleukin. INR = International Normalized Ratio. K+ = Potassium.
LDH = Lactate Dehydrogenase. N = Neutrophil count. Na+ = Sodium. NT–ProBNP = N–Terminal Fragment Brain Natriuretic Peptide. Plt count = Platelet count. OR = Odds ratio.
PT = Prothrombin Time. RR = Risk ratio. T Bilirubin = Total Bilirubin. TLC = Total Leucocyte Count. TNF = Tumor Necrosis Factor.
�
15 / 29
Table 4. Association of clinical parameters expressed as continuous variables with mortality and disease severity in patients with COVID–19 by meta-regression.
Variable Mean increase of No� of No� of Percentage change in p–value No� of No� of Percentage change in p–value
the variable studies patients mortality [95% CI] studies patients severe disease [95% CI]
Age 10 years 41 20296 7.6 [1.0, 14.2] 0.02 70 17799 11.3 [6.5, 16.2] <0.001
Hb 1g/L 12 2519 1.1 [–1.4, 3.6] 0.41 13 3013 –1.1 [–1.6, –0.5] 0.002
TLC 1x10^9/L 20 9797 5.4 [0.2, 10.6] 0.04 28 5370 15.2 [6.23, 24.18] <0.001
Lymphocyte 0�1x10^9/L 24 10097 –4.1 [–7.4, –0.8] 0.02 31 5696 –17.3 [– 35.9, 1.3] 0.07
count
Neutrophil 1x10^9/L 14 8930 10.5 [0.5, 20.6] 0.04 22 3586 9.8 [0.5, 19.1] 0.04
count
Platelet count 50 x 10^9/L 14 3120 –18.8 [–41.6, 3.85] 0.10 15 3190 0.1 [–0.4, 0.51] 0.82
Prothrombin 1s 16 3277 3.3 [–4.2, 10.8] 0.39 ��
time
aPTT 1s 12 2651 1.0 [–0.9, 3.0] 0.24 ��
CRP 100 mg/L 19 3974 6.1 [3.3, 8.9] <0.001 27 4517 5.0 [2.9, 7.0] <0.001
D–dimer 1mg/L 15 3621 21.6 [7.0, 36.4] <0.01 21 3387 2.9 [0.1, 5.8] 0.04
Pro–calcitonin 0�1 mg/L 10 2349 4.5 [–19.3, 28.5] 0.71 19 2725 8.5 [–1.5, 18.4] 0.09
Serum LDH 100 U/L 13 2682 9.1 [2.4, 15.8] 0.01 12 1666 –0.02 [–0.1, 0.1] 0.52
Serum 10 μmol/L 19 3817 0.2 [–0.4, 0.7] 0.51 18 3062 9 [0.7, 17.5] 0.03
creatinine
BUN 1 mmol/L 14 2979 5.3 [0.5, 10.2] 0.03 ��
Total Bilirubin 1 μmol/L 12 2191 2.6 [–0.2, 5.5] 0.07 13 8040 –2.0 [–6.8, 2.7] 0.41
Albumin 10 g/L 12 1986 –4.1 [––22.9, 14.6] 0.67 12 7789 –5.0 [–7.2, –2.8] <0.001
AST 10 U/L 15 8927 1.7 [–0.9, 4.4] 0.19 18 8395 –1.9 [–14.6, 10.8] 0.77
ALT 10 U/L 19 9664 2.6 [–1.2, 6.4] 0.18 20 8836 7.4 [– 7.6, 22.5] 0.33
CK–total 10 U/L 10 2051 1.6 [0.02, 3.1] 0.04 12 2331 –0.3 [–0.7, 0.2] 0.31
IL–6 10 ng/L �� 13 2404 1 [–0.2, 3] 0.09
Abbreviations: ALT = Alanine Aminotransferase. aPTT = activated Partial Thromboplastin Time. AST = Aspartate Aminotransferase. BUN = Blood Urea Nitrogen.
CK = Creatinine Kinase. CRP = C–Reactive Protein. Hb = Hemoglobin. IL = Interleukin. LDH = Lactate Dehydrogenase. TLC = Total Leucocyte Count.
out while assessing risk of mortality for the following exposures, such as gender, diabetes melli-
tus, hypertension, ARDS and acute kidney injury and hence the results for these factors should
be interpreted with caution.
Discussion
A total of 109 articles were deemed suitable for data synthesis and identification of variables
associated with severe COVID-19 disease and mortality. Specific determinants were identified
from a array of clinical parameters such as symptoms, co-morbidities, laboratory, and radio-
logical data. Our findings have potential implications for clinical decision-making, as well as
allocation of scarce critical care resources for patients with COVID-19.
The presence of various comorbidities was reported to be associated with severe disease
and/or death in patients with COVID-19 in prior studies [127]. Although the direction of asso-
ciation was consistent with previous reports, the risks of death in patients with diabetes and
hypertension were lower in our study with an RR of 1.59 [95% CI: 1.41–1.78] and 1.90 [95%
CI: 1.69–2.15] respectively for mortality. The levels of control of diabetes and hypertension in
these patients, as well as pharmacotherapy for these conditions were not taken into consider-
ation in our review, which might account for the clinical heterogeneity. There was a significant
association between pre-existing cardiovascular diseases and COVID-19 attributable mortal-
ity, with an RR of 2.27 [95%CI: 1.88–2.79]. This is similar to the association of cardiovascular

Fig 4. Meta-regression plot showing the proportion increase in mortality among COVID-19 patients regressed against (A) mean age. (B) mean leukocyte count.
(C) mean lymphocyte count. (D) mean serum albumin. (E) mean C-reactive protein. (F) mean D-dimer.

Fig 5. Meta-regression plot shows the proportion increase in severity among COVID-19 patients regressed against (A) mean age. (B) mean leukocyte count. (C)
mean lymphocyte count. (D) mean serum albumin. (E) mean C-reactive protein. (F) mean D-dimer.

diseases with mortality seen in patients with other viral infections [128, 129]. Chronic kidney
disease and chronic liver disease were also associated with higher mortality, but because of the
lack of data in the available studies, distinction could not be made with respect to the stage of
the kidney and liver dysfunction. Pre-existing diseases of the lung were also associated with
adverse outcomes in our study.
The identification of COVID-19-related symptoms associated with mortality and severe
disease is especially important since this is among the most readily accessible information dur-
ing the initial evaluation of patients. Our finding that dyspnea was associated with higher RR
of mortality and higher OR for severe disease is consistent with data reported in other retro-
spective studies on ICU admission and the development of ARDS in patients with COVID-19
[23, 130]. Despite the common occurrence of gastrointestinal symptoms (nausea, vomiting
and diarrhea) in patients with COVID-19, no association was found between the presence of
these symptoms and the presence of severe disease or mortality in our study.
We found that ARDS had a RR of 20.19 [95%CI: 10.87–37.52] for mortality, which is con-
sistent with a previous study reporting a 28-day survival of 50% among COVID-19 patients
with severe ARDS [20]. In contrast to the relatively transient cardiac involvement in SARS-
CoV infection [131], we found that cardiac complications such as acute heart failure and acute
cardiac injury were associated with a high RR of death in COVID-19 in our study. While the
presence of underlying cardiovascular disease increases the risk of developing cardiac compli-
cations, Chen et al reported that COVID-19 related cardiac complications were also frequent
among those without pre-existing cardiovascular diseases [20]. A previous report from 2009
suggested direct cardiac muscle damage in patients with SARS-CoV infection [132]. The car-
diac injury seen in patients with COVID-19, might be due to a similar mechanism. Elevated
troponin levels were associated with an OR of 3.04 [95% CI: 1.03–8.97] for severe disease in
our study. Consistent with our findings, patients with underlying cardiovascular diseases and
non-elevated levels of troponin were shown to have lower death rates compared to those with-
out cardiovascular disease but with elevated troponin [133].
Patients with leukocytosis and lymphopenia had higher OR for severe disease and greater
RR for mortality. The occurrence of lymphopenia in severe disease may be due to apoptosis of
lymphocytes as a result of increased levels of cytokines in the blood in patients with severe dis-
ease [134–136]. Hypoalbuminemia was associated with an increased RR of mortality (RR 3.30,
95%CI 2.61–4.18), and is likely related to the systemic inflammatory response in severe
COVID-19 [74]. Increased levels of acute phase reactants, such as CRP and ferritin in patients
with severe disease, also documented in our review, further supports the inflammatory nature
of the disease [85]. Elevated levels of procalcitonin may indicate a secondary bacterial sepsis in
patients with severe COVID-19, which was associated with a high RR of mortality in our
meta-analysis [137]. COVID-19 has been hypothesized to be a prothrombotic state due to
endothelial dysfunction and increased hypoxia-inducible transcription factor in patients with
severe pneumonia, and plasminogen activation inhibition in patients who develop sepsis
[138–140]. DIC, which is common in patients succumbing to COVID-19, is typically accom-
panied by elevated D-dimer levels [21]. The levels of D-dimer were found in our meta-analysis
to be significantly associated with mortality (RR 3.98, 95%CI 2.87–5.52) and severe disease
(OR 2.75, 95%CI 1.92–3.93). Although their association with mortality has not been fully
investigated, thromboembolic complications, such as pulmonary embolism and acute stroke,
have been noted with increasing frequency in patients with COVID-19 [141, 142].
COVID-19 can manifest in a variety of radiographic patterns on chest CT scan, most of
which are consistent with viral pneumonia. We found that bilateral lung involvement and con-
solidation were associated with higher RR of mortality and higher OR of severe disease. Consis-
tent with our findings, the occurrence of bilateral lung involvement was shown to increase with

disease progression, and is more commonly observed in the late phases of COVID-19 [143]. The
ground-glass opacities seen in a large proportion of COVID-19 patients may be due to the thick-
ening of the alveolar septa following inflammation or the incomplete filling of the alveoli, as seen
in Influenza A [144]. As noted for other respiratory viruses, our data revealed that consolidation
was associated with a higher RR of mortality and OR of severe disease compared to ground glass
opacities in patients with COVID-19 [145, 146]. Hilar lymphadenopathy, though rare in
COVID-19 patients, could be due to infiltration of the hilar lymph nodes by lymphocytes and
macrophages, and appears to be associated with severe disease in our meta-analysis [147–149].
Although this systematic review is able to delineate important parameters associated with dis-
ease severity and mortality in COVID-19, our study has a few limitations. First, we included cur-
rent published articles related to the highly dynamic information available on COVID-19. As
this pandemic has not impacted all regions within the same time frame, there is a potential tim-
ing bias, whereby the majority of patients described are from early-hit regions, which may not be
representative of other patient populations, based on sociodemographic characteristics and pre-
existing conditions. Although a pooled analysis of effect sizes adjusted for potential confounders
would have been desirable, most studies did not uniformly report estimates adjusted for the
same parameters. Time points of evaluation of laboratory, radiological and disease severity
assessment were not clearly defined in many of the studies, which precluded the calculation of
risk ratio of severe disease. We did not take into account the critical care interventions and strat-
egies that potentially impact the course of the disease and/or survival, as such interventions (e.g.
mechanical ventilation, extracorporeal membrane oxygenation, convalescent plasma) vary across
different regions. Further investigation is warranted to evaluate which interventions impact the
morbidity and mortality of patients with COVID-19. Future studies may investigate if individual
and contextual-level sociodemographic factors are associated with morbidity and survival.
In summary, this study comprehensively examined the effect of several demographic, clini-
cal, laboratory and radiological risk factors associated with mortality and severe disease among
patients with COVID-19. Knowledge of these risk factors may help health care professionals to
develop improved clinical management plans based on risk stratification. Policy makers can
utilize these findings to develop triage protocols and effectively allocate resources in resource-
limited settings.
Supporting information
S1 Appendix.
(PDF)
S1 PRISMA Checklist.
(DOC)
S1 File.
(DOCX)
Acknowledgments
We thank Lori Rosman (Lead informationist, Welch Medical Library, Johns Hopkins Univer-
sity) for her advice on the literature search strategy.
Author Contributions
Conceptualization: Vignesh Chidambaram, Nyan Lynn Tun, Waqas Z. Haque, Petros C. Kar-
akousis, Panagis Galiatsatos.

Data curation: Vignesh Chidambaram, Nyan Lynn Tun, Waqas Z. Haque, Ranjith Kumar
Sivakumar, Amudha Kumar, Angela Ting-Wei Hsu, Izza A. Ishak, Aqsha A. Nur, Samuel
K. Ayeh, Emmanuella L. Salia, Ahsan Zil-E-Ali, Muhammad A. Saeed, Ayu P. B. Sarena,
Bhavna Seth, Muzzammil Ahmadzada, Eman F. Haque, Pranita Neupane, Kuang-Heng
Wang, Tzu-Miao Pu, Syed M. H. Ali, Muhammad A. Arshad, Lin Wang, Sheriza Baksh.
Formal analysis: Vignesh Chidambaram, Marie Gilbert Majella, Sheriza Baksh.
Investigation: Vignesh Chidambaram, Angela Ting-Wei Hsu.
Methodology: Vignesh Chidambaram, Marie Gilbert Majella, Lin Wang, Sheriza Baksh, Pana-
gis Galiatsatos.
Supervision: Sheriza Baksh, Petros C. Karakousis, Panagis Galiatsatos.
Visualization: Ranjith Kumar Sivakumar, Amudha Kumar.
Writing – original draft: Vignesh Chidambaram, Nyan Lynn Tun, Marie Gilbert Majella,
Ranjith Kumar Sivakumar, Amudha Kumar, Izza A. Ishak, Emmanuella L. Salia, Bhavna
Seth, Petros C. Karakousis, Panagis Galiatsatos.
Writing – review & editing: Vignesh Chidambaram, Marie Gilbert Majella, Amudha Kumar,
Izza A. Ishak, Sheriza Baksh, Petros C. Karakousis, Panagis Galiatsatos.
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PLOS ONE

Factors associated with disease severity and

Editor: Girish Chandra Bhatt, All India Institute of

Received: August 3, 2020

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Data extraction and quality assessment

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Data synthesis and analysis

Role of the funding source

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Clinical characteristics Risk of Mortality Odds of Severe disease

DIC 4 1394 3.41 [2.00–5.81] 95% 0.28 �� �� �� �� ��

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TLC < 4.0 x109/L 7 1380 0.43 [0.29–0.58] 0% 0

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LDH > 250 U/L 1 548 13.10[3.26–52.66] �� ��

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TLC < 4.0 x109/L 6 2482 0.89[0.43–1.82] 88.86% 0.67

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2020 Apr 8 [cited 2020 May 25]; Available from: https://www.atsjournals.org/doi/10.1164/rccm.

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2020 May 25]; Available from: https://linkinghub.elsevier.com/retrieve/pii/S016344532030219X PMID:

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DIC 4 1394 3.41 [2.00–5.81] 95% 0.28 ��

LDH > 250 U/L 1 548 13.10[3.26–52.66] ��