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. 2022 Mar 28;7:e5–e23. doi: 10.5114/amsad.2022.115008

Prevalence of comorbidities and symptoms stratified by severity of illness amongst adult patients with COVID-19: a systematic review

Ritambhara Pandey 1, Devesh Rai 1,✉, Muhammad Waqas Tahir 1, Abdul Wahab 2, Dhrubajyoti Bandyopadhyay 3, Emil Lesho 4, Maryrose Laguio-Vila 4, Emilio Fentanes 5, Raseen Tariq 1, Srihari S Naidu 3, Wilbert S Aronow 3
PMCID: PMC9081912  PMID: 35582712

Abstract

Introduction

We performed a systematic review of comorbidities and symptoms of adult patients with coronavirus disease 2019 (COVID-19) to evaluate comorbidities, symptoms, and severity.

Material and methods

We searched databases and extracted comorbidities and symptoms from the included studies. We stratified the similar signs and symptoms in groups and on the basis of severity and compared them with stratified analysis. Individual case reports and case series with < 5 patients were excluded.

Results

A total of 163 studies with 43,187 patients were included. Mean age was 54.6 years. There were significantly fewer women in the study (43.9% vs. 56.1%, p < 0.0001). Prevalent cardiovascular comorbidities were hypertension (31.9%), obesity (27.9%), hyperlipidemia (26.4%), smoking (18.9%), diabetes mellitus (17.2%), atherosclerotic disease (9.2%) and arrhythmia (5.0%). The most frequently reported constitutional symptoms of COVID-19 were fever (73.9%), fatigue (33.4%), malaise (29.9%), myalgia and/or arthralgia (19.2%), generalized weakness (19.0%), and chills (11.3%). For the cardiovascular system, chest pain and/or tightness were most often reported (19.6%), followed by palpitations (5.2%). Hypertension and diabetes were common in severe disease. Obesity and congestive heart failure were not observed in any non-severe cases. Severe cases compared to non-severe cases more frequently had fever (87.8% vs. 58.5%, p < 0.001), shortness of breath (47.4% vs. 20.6%, p < 0.001), cough (66.8% vs. 62.9%, p < 0.001), sputum production (35.4% vs. 26.5%, p < 0.001) and rhinorrhea (32.2% vs. 7.3%, p < 0.001).

Conclusions

Hypertension, diabetes, and atherosclerotic diseases are common comorbidities across the world, with obesity as the second most common in the US and more common in men.

Keywords: symptoms, comorbidities, severity, COVID-19, SARS-CoV-2

Introduction

Coronavirus disease 2019 (COVID-19) is now a global pandemic caused by a novel coronavirus. The first case of COVID-19 was reported in December 2019 in Wuhan, China. Since then, it has affected over 138,010,168 people and caused over 2,970,000 deaths across the world [1]. Similar to other coronaviruses, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily affects the pulmonary system. However, multi-system involvement, including cardiac, vascular, and neurological complications, has been reported [2]. The clinical manifestations range from asymptomatic infection or mild disease with fever, myalgias, and cough to severe disease characterized by shortness of breath, hypoxemia, acute respiratory distress syndrome requiring mechanical ventilation, multi-organ failure, and death [3]. However, due to this disease’s novelty, within the first year of the initial description, the prevalence of various symptoms and comorbidities associated with the disease remains unclear.

Several studies have evaluated the prevalence of various symptoms. A systematic review of 3600 patients reported fever, cough, and fatigue as most common [4]. Similarly, another meta-analysis of 78 studies found the prevalence of gastrointestinal symptoms to be 1 out of every 5 COVID-19 patients [5]. Another systematic review described the prevalence of acute myocardial injury in COVID-19 infection and found a pooled prevalence of nearly 20% [6]. Given the variable presentations and unclear prevalence of comorbidities and the accrual of interim experience, we performed a systematic review to assess the contemporary prevalence of comorbidities and symptoms from all the published studies.

Material and methods

We performed a systematic review following the Cochrane Handbook for Systematic Reviews and Intervention statement in health care interventions [7].

Selection criteria

We included observational studies, case series (retrospective, prospective, descriptive), randomized controlled trials, and survey studies that included adults’ comorbidities or symptoms with confirmed COVID-19 infection. Individual case reports and case series with < 5 patients were excluded.

Data Sources and Search Strategy

A comprehensive literature search was done on Ovid MEDLINE(R) and Epub Ahead of Print, In-Process; Other Non-Indexed Citations and Daily, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus from March 2019 to June 18, 2020. The main keywords used in the search were: (Corona virinae or corona virus or Coronavirinae or coronavirus or COVID or nCoV or 2019; or novel or new) or (Corona virinae or & corona virus; or Coronavirinae or coronavirus or COVID or nCoV) and wuhan) or Corona virinae19; or ;Corona virinae 2019 or &quot;corona virus19 or &;corona virus2019; or Coronavirinae19 or Coronavirinae2019 or coronavirus19 or coronavirus2019 or COVID19 or COVID2019 or nCOV19 or nCOV2019 or;2019-nCOV or 2019nCOV or SARS Corona virus or SARS Coronavirus or SARS-COV-2. Two investigators (D.R. and R.P.) reviewed the titles and abstracts of the identified studies independently and screened them as per the selection criteria mentioned above. Any conflict was resolved with the consensus of a third investigator (R.T.).

Data abstraction

Data from included studies were independently abstracted by two investigators (D.R. and M.W.T.). The abstracted data included study design and setting, month and year of publication, duration of the study period, gender, comorbidities, symptoms and severity, mortality, survival, and discharge data. Data extraction excluded studies with pediatric patients. All comorbidities were initially abstracted separately, then grouped based on system involvement for data analysis. Similarly, all symptoms were extracted separately, then subsequently grouped for analysis.

Statistical analysis

The frequency of variable occurrence was calculated using percentages. For comorbidity analysis, studies with fewer than 3 reported comorbidities were excluded. Primary analysis involved the calculation of the presence of comorbidities and symptoms in the pooled data. Comorbidities and symptoms were compared based on the severity of the patients studied. For this stratification, we included studies reporting symptoms or comorbidities exclusively for severe or non-severe cases. Studies with severe and non-severe cases with inseparable comorbidity or severity data were excluded. A χ2 test was performed with α set at 0.05. All analyses were performed using SPSS version 25.

Results

The preliminary database search resulted in 4032 studies; 24 other studies were identified from other sources; after the titles’ preliminary screening, 233 full-text studies were reviewed. Of these, 163 studies were included in the systematic reviews and in the primary analysis of symptoms [8–170]. For comorbidity analysis, 41 of 163 studies were excluded based on fewer than three reported comorbidities criteria, as described above, yielding 122 studies. A flow chart of the study selection is shown in Figure 1. The details of the included studies are provided in Table I.

Figure 1.

Figure 1

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Flow chart low study

Table I.

Baseline characteristics of included studies

Author name, year Study period Type of study Patients N Female patients (N) Hospitalization status Severity
Akalin et al., 2020 Mar 16–Apr 1 Retrospective single-center case series 36 10 3 B
An Ping et al., 2020 Jan 17–Jan 24 Retrospective single-center case series 9 5 1
Bangalore et al., 2020 Retrospective single-center case series 18 3
Beigel JH et al., 2020 Feb 21–Apr 19 RCT double blinded 1063 377 1 B
Bhatraju PK et al., 2020 Feb 24–Mar 9 Retrospective multi-center case series 24 9 1 S
Borba MGS et al., 2020 Mar 23–Apr 5 Parallel, double-masked, randomized, phase IIb clinical trial 81 20 1 S
Cai Qingxian et al., 2020 Jan 30–Feb 14 Open labelled non-randomized control study 80 45 1 B
Cai Qingxian et al., 2020 Jan 11–Feb 6 Retrospective single-center case series 298 153 1 B
Cao Jianlei et al., 2020 Jan 3–Feb 1 Retrospective single-center case series 102 49 1 B
Chan Fuk-Woo J et al., 2020 Retrospective single-center case series 6 3 1
Chang De et al., 2020 Jan 16–Jan 29 Retrospective multi-center case series 13 3 1
Chen J et al., 2020 Jan 20–Feb 7 Retrospective single-center case series 249 123 1 B
Chen L et al., 2020 Dec 8–Mar 20 Retrospective multi-center case series 118 B
Chen Nanshan et al., 2020 Jan 1–Jan 20 Retrospective single-center case series 99 32 1 B
Chen Qing et al., 2020 Retrospective single-center case series 9 4 1 NS
Chen Qingqing et al., 2020 Jan 1–Mar 11 Retrospective multi-center case series 145 66 1 B
Chen Tao et al., 2020 Jan 13–Feb 12 Retrospective single-center case series 274 103 S
Chen TL et al., 2020 Jan 1–Feb 10 Retrospective single-center case series 203 95 B
Cholankeril George et al., 2020 Mar 4–Mar 24 Retrospective single-center case series 116 54 1 B
Chu J et al., 2020 Jan 7–Feb 11 Retrospective single-center case series 54 18 1 B
COVID-19 National Emergency Response Center, Epidemiology and Case Management Team, Korea Centers for Disease Control and Prevention Before 2/14/2020 Retrospective multi-center case series 28 13 3 B
COVID-19 National Incident Room Surveillance Team Retrospective single-center case series 295 3 B
Dai H et al., 2020 Jan 10–Feb 7 Retrospective multi-center case series 234 98
Deng Qing et al., 2020 Jan 6–Feb 20 Retrospective single-center case series 112 55 1 B
Dong X et al., 2020 Retrospective multi-center case series 11 6 1
Du Rong-Hui et al., 2020 Dec 25–Feb 7 Prospective single center cohort 179 82 1 B
Du Y et al., 2020 Jan 9–Feb 15 Retrospective single-center case series 85 23 1 S
Escalera-Antezana JP et al., 2020 Mar 2–Mar 15 Retrospective multi-center case series 12 6 2 NS
Hua Fan et al., 2020 Dec 30–Feb 16 Retrospective single-center case series 101 37 1 S
Fei Xiao et al., 2020 Feb 1–Feb 14 Retrospective single-center case series 73 32 1 B
Feng Pan et al., 2020 Jan 12–Feb 6 Retrospective single-center case series 21 15 1 NS
Feng Yun et al., 2020 Jan 1–Feb 15 Retrospective multi-center case series 476 205 1 B
Fernández-Ruiz Mario et al., 2020 March 5–March 23 Retrospective single-center case series 18 4 1 B
Gautret Philippe et al., 2020 Feb–March Prospective single center cohort 80 37 1 B
Geleris et al., 2020 Mar 7–Apr 8 Cross-sectional Multi-center case series 1376 595 1 B
Giacomelli A et al., 2020 Cross-sectional single-center case series 59 19 1
Goyal et al., 2020 Mar 3–mar 27 Retrospective single-center case series 393 155 1 B
Griiti Giuseppe et al., 2020 Retrospective single-center cohort 21 3 1 B
Guan W et al., 2020 Dec 11–Jan 29 Retrospective multi-center case series 1099 459 3 B
Guo Tao et al., 2020 Jan 23–Feb 25 Retrospective single-center case series 187 96 1 B
Hajifathalian K et al., 2020 Mar 4–Apt 9 Retrospective multi-center case series 1059 448 3 B
Han Chaoqun et al., 2020 Feb 13–Feb 29 Retrospective single-center case series 206 115 1 NS
Hong Kyung Soo et al., 2020 Mar–20 Retrospective single-center case series 98 60 1 B
Horby P et al., 2020 Early 2020–June 8 Randomized controlled open labelled trial 6425 2337 1 B
Huang Chaolin et al., 2020 Dec 16–Jan 2 Prospective single center cohort 41 11 1 B
Huang Yihui et al., 2020 Dec–Jan Retrospective single-center case series 34 14 3 B
Israelsen S B et al., 2020 Mar 10–April 23 Retrospective single-center case series 175 90 1 B
Javanian M, et al. 2020 Feb 25–Mar 12 Retrospective multi-center case series 110 49 1
Jin Xi et al., 2020 Jan 17–Feb 8 Retrospective multi-center case series 651 320 1 B
Kaye et al., 2020 Mar 25–Apr 3 Retrospective multi-center case series 237 129
Kim ES et al., 2020 (Korea National Committee for Clinical Management of COVID-19 (KNCCMC)) Feb Prospective multi-center case series 28 13 1 B
Klopfenstein T et al., 2020 Mar 1–Mar 17 Retrospective single-center case series 114 1 B
Kluytmans-van den Bergh M et al., 2020 Mar 7–Mar 12 Cross-sectional multi-center case series 86 71 3 NS
Kuang Y et al., 2020 Jan 1–Feb 10 Retrospective multi-center cohort 944 476 B
Kujawski Stephanie et al., 2020 Jan 20–Feb 5 Retrospective multi-center case series 12 4 3 B
Lechien JR et al., 2020 Retrospective multi-center case series 417 263 1 NS
Lei H et al., 2020 Jan 25–Jan 27 Retrospective multi-center case series 8 2 1
Lei S et al., 2020 Jan 1–Feb 5 Retrospective multi-center case series 34 20 1 B
Lei Wang et al., 2020 Jan 21–Feb 5 Retrospective single-center case series 18 8 1
Lei Z et al., 2020 Jan 22–Feb 12 Retrospective single-center case series 20 10
Li Kunhua et al., 2020 Jan–Feb Retrospective multi-center case series 83 39 1 B
Li X et al., 2020 Jan 14–Feb 13 Retrospective single-center case series 25 15 1 S
Li Xiaochen et al., 2020 Jan 26–Feb 5 Retrospective single-center cohort 548 269 1 B
Lian J et al., 2020 Jan 17–Jan 31 Retrospective single-center case series 465 222 B
Lian J et al., 2020 Jan 17–Feb 12 Retrospective multi-center case series 788 381
Liang WH, et al., 2020 Nov 21–Jan 31 Retrospective multi-center case series 1590 674 B
Lin Lu et al., 2020 Jan 17–Feb 15 Retrospective single-center case series 95 50 1 B
Liu Jui-Yao et al., 2020 Jan 21–Apr 6 Retrospective multi-center case series 321 170 NS
Liu Kai et al., 2020 Jan 15–Feb 18 Retrospective single-center case series 56 25 1 B
Liu Kiu et al., 2020 Dec 30 –Jan 24 Retrospective multi-center case series 137 76 1 B
Liu Yingxia et al., 2020 December 26–January Retrospective single-center case series 12 4 1 B
Liu Zhe et al., 2020 Jan 16–Feb 13 Retrospective multi-center case series 72 33 1 B
Lo LI et al., 2020 Jan 21–Feb 16 Prospective single center case series 10 7 1 B
Luo Shihua et al., 2020 Jan 1–Feb 20 Retrospective single-center case series 183 81 1 B
Lu-Xiaofan et al., 2020 Jan 25–Feb 25 Retrospective single-center case series 244 116 1 S
Ma J et al., 2020 Jan 1–Mar 30 Retrospective single-center case series 37 20 1 B
Mahevas M et al., 2020 Mar 12–Mar 31 Retrospective multi-center case series 173 101 1 B
Mathian A et al., 2020 Mar 29–Apr 6 Cross-sectional single-center case series 17 13 3 B
Meng Yifan et al., 2020 Jan 16–Feb 4 Retrospective single-center case series 168 82 1 S
Mi Bobib et al., 2020 Jan 1–Feb 27 Retrospective multi-center case series 10 8 1 B
Million M et al., 2020 Mar 3–Mar 31 Retrospective multi-center cohort 1061 569 3 B
Mo P et al., 2020 Jan 1 –Feb 5 Retrospective single-center case series 155 69 1 B
Moein S et al., 2020 Mar 21–Apr 5 Prospective single center case series 60 20 1 B
Morena V et al., 2020 Mar 10–Mar 23 Prospective single center open label study 51 11 S
Nobel Yael et al., 2020 Mar 10–Mar 21 Retrospective single-center cohort 278 133 B
Pan Lei et al., 2020 Jan 18–Feb 28 Cross-sectional multicenter case series 103 48 1 B
Pung Rachel et al., 2020 Jan–Feb Retrospective multi-center case series 17 10 2 NS
Qi X et al., 2020 Jan 23–Feb 18 Retrospective multi-center case series 70 1 B
Qian GQ et al., 2020 Jan 20–Feb 11 Retrospective multi-center case series 91 54 1 B
Redd WD et al., 2020 Feb 11–Feb 29 Randomized, parallel, open label trial 150 68 1 B
Richardson Safiya et al., 2020 Before April 2 Retrospective multicenter cohort 318 144 1 B
Rodríguez-Cola M et al., 2020 Mar 1–Apr 4 Retrospective multi-center case series 5700 2263 1 B
Ronald LT et al., 2020 Mar 20 –Apr 4 Prospective single center case series 7 2 1 B
Rosenberg ES et al., 2020 Mar 31–Apr 10 Electronic survey 145 94
Sciascia S et al., 2020 Mar 15–Mar 28 Retrospective multi-center cohort 1438 580 1 B
Shaobo Shi et al., 2020 Double-blind, placebo-controlled, multicenter trial 63 7 1 S
Shi Heshui et al., 2020 Jan 1–Feb 23 Retrospective single-center case series 671 349 1 B
Shi Shaobo et al., 2020 Dec 20–Jan 23 Retrospective single-center case series 81 39 1 NS
Shu Lei et al., 2020 Jan 20–Feb 10 Retrospective single-center case series 416 211 1 B
Song F et al., 2020 Feb 13–Feb 29 Retrospective single-center case series 545 281 1 NS
Spiteri Gianfranco 2020 Jan 20–Jan 27 Retrospective single-center case series 51 26 1 NS
Tabata Sakiko et al., 2020 Jan 24 –Feb 21 Retrospective multi-center case series 38 13 3 NS
Tang Wei et al., 2020 Feb 11–Feb 25 Retrospective single-center case series 104 50 1 B
Tian S et al., 2020 Jan 20–Feb 10 Retrospective multi-center case series 262 135 B
Toniati Paola et al., 2020 Mar 9–Mar 20 Multicenter prospective non-randomized study 100 12 1 S
Tu Wen-Jun et al. 2020 Jan 3–Feb 24 Retrospective single-center case series 174 95 1 B
Wan S et al., 2020 Jan 23–Feb 8 Retrospective single-center case series 135 63 3
Wan Yunle et al., 2020 Jan 19–Mar 6 Retrospective multi-center case series 232 101 1 B
Wang Dawei et al., 2020 Jan 1–Jan 28 Retrospective single-center case series 138 63 1 B
Wang J et al., 2020 Jan–Feb Prospective multicenter case series 93 36
Wang L et al., 2020 Jan 1–Feb 6 Retrospective single-center case series 339 173 1 B
Wang Lizhen et al., 2020 Jan 31–Feb 12 Retrospective single-center case series 26 15 1
Wang Luwen et al., 2020 Jan 14–Feb 13 Prospective single center cohort 116 49 1 B
Wang Min et al., 2020 Jan 21–Feb 2 Retrospective multi-center case series 66 23 1
Wang Ruirui et al., 2020 Jan 20–Feb 9 Retrospective single-center case series 125 71 1 B
Yang Wenjie et al., 2020 Jan 17–Feb 10 Retrospective multi-center cohort 149 68 1 NS
Wang X et al., 2020 Feb 7–Feb 12 Retrospective single-center case series 1012 488 1 NS
Wang X et al., 2020 Jan 10–Feb 24 Retrospective multi-center case series 80 49 1
Wang Yang et al., 2020 Jan 25–Feb 25 Retrospective single-center case series 344 165 1 S
Wang Yanrong et al., 2020 Jan 11–Fbe 29 Retrospective single-center case series 55 22 1 NS
Wang Yeming et al., 2020 Feb 6–Mar 12 Randomized, double-blind, placebo-controlled, multicenter trial 236 96 1 B
Wang Z et al., 2020 Jan 16–Jan 29 Retrospective single-center case series 69 1
Wei XS et al., 2020 Jan 19–Feb 7 Retrospective single-center case series 84 56 1
Wei Jia-Fu et al., 2020 Jan 16–Mar 10 Prospective multicenter cohort 101 47 1 B
Wentao Ni et al., 2020 Retrospective single-center case series 179 1 B
Wolfel Roman et al., 2020 Jan 23–Jan 26 Retrospective single-center case series 9 1 NS
Wu Chaomin et al., 2020 Dec 25–Jan 26 Retrospective single-center case series 201 73 S
Wu J et al., 2020 Jan 22–Feb 14 Retrospective multi-center case series 80 41 1 B
Wu Jiong et al., 2020 Jan –Feb Retrospective multi-center case series 80 38 1 B
Wu Yongjian et al., 2020 Jan 16–Mar 15 Prospective single center case series 74 35 1 B
Xia Xiao-ying et al., 2020 Jan 23–Feb 18 Retrospective single-center case series 10 4 1 B
Xie Hansheng et al., 2020 Feb 2–Feb 23 Retrospective single-center case series 79 35 1 NS
Xiong Fei et al., 2020 Jan 1–Mar 10 Retrospective multi-center cohort 131 56 1 B
Xiong Ying et al., 2020 Jan 11–Feb 5 Retrospective single-center case series 42 17 1 B
Xu T et al., 2020 Jan 23–Feb 18 Retrospective single-center case series 51 26 1
Xu Xi et al., 2020 Jan 23–Feb 4 Retrospective single-center case series 90 51 1 B
Xu Xiaoling et al., 2020 Feb 5–Feb 14 Prospective single center case series 21 3 1 S
Xu XW et al., 2020 Jan 10–Jan 26 Retrospective single-center case series 62 27 1 NS
Xun Ding 2020 Feb–March Retrospective single-center case series 112 61
Yan CH et al., 2020 Mar 3–mar 29 Cross-sectional single-center case series 59 29 3
Yan Yongli et al., 2020 Jan 10–Feb 24 Retrospective single-center case series 193 79 1 S
Yang Fan et al., 2020 Jan 1 –April15 Retrospective single-center case series 52 24 1 B
Yang X 2020 Dec 24–Jan 26 Retrospective single-center case series 52 17 1 S
Young BE el al., 2020 Jan 23–Feb 3 Retrospective multi-center case series 18 9 1 NS
Yu Yuan et al., 2020 27–Feb Prospective multicenter case series 226 87 1 S
Zha Lei et al., 2020 Jan 24–Feb 24 Retrospective multi-center case series 31 11 1 NS
Zhang Guqin et al., 2020 Jan 2–Feb 10 Retrospective multi-center case series 221 113 1 B
Zhang JingCheng et al., 2020 Jan 27–Feb 10 Retrospective single-center case series 14 7 1 NS
Zhang Jin-Jin et al., 2020 Jan 16–Feb 3 Retrospective single-center case series 140 69 1 B
Zhang Jun et al., 2020 Jan 28–Feb 24 Retrospective single-center case series 13 1 B
Zhang L et al., 2020 Jan 13–Feb 26 Retrospective multi-center case series 28 11 1 B
Zhang Xiaoli et al., 2020 Jan 17–Feb 8 Retrospective multi-center case series 645 317 1 B
Zhao Xin-Ying et al., 2020 Jan 16–Feb 10 Retrospective single-center case series 91 42 1 B
Zhao D et al., 2020 Jan 23–Feb 5 Retrospective multi-center case series 19 8 1
Zhao Wei et al., 2020 Retrospective single-center case series 101 45 1
Zheng F et al., 2020 Jan 17–Feb 7 Retrospective single-center case series 161 81 1 B
Zheng Y et al., 2020 Jan 16–Feb 20 Retrospective single-center case series 99 48 1 B
Zhou Fei et al., 2020 Dec 29–Jan 31 Retrospective multi-center cohort 191 119 1 S
Zhou Shuchang et al., 2020 Jan 16–Feb 12 Retrospective single-center case series 100 46 1 NS
Zhou Shuchang et al., 2020 Jan 16–Jan 30 Retrospective single-center case series 62 23 1 B
Zhou Y et al., 2020 Jan 28–Mar 2 Prospective single center case series 21 8 1 S
Zhou Zili et al., 2020 Dec 20–Feb 9 Retrospective single-center case series 254 139 1
Zou Lirong et al., 2020 Jan 7–Jan 26 Retrospective single-center case series 18 9
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Hospitalization: 1: inpatient, 2: outpatient, 3: combined inpatient, and outpatient. S – severe, NS – non-severe, B – Both, N – number, RCT – randomized controlled trial, COVID-19: coronavirus disease 2019.

Study characteristics

A total of 163 studies with 43,187 patients were included. Of these, 117 were from China, 19 from the European region, 14 from the US, 2 from other countries, and the remaining 11 were from Australia, Brazil, Iran, Japan, S Korea, Singapore, and Taiwan. The earliest study recruitment started on December 11, 2019 and ended on April 19, 2020. There were 80 retrospective single-center case series; 43 retrospective multicenter case series, 7 retrospective multicenter cohorts, 3 retrospective single-center cohorts, 6 prospective single-center series, 3 prospective single-center series, 4 prospective single-center cohort studies, 1 prospective multicenter cohort study, 7 randomized controlled trials of various design, 1 open-label non-randomized control study, 1 descriptive case series, and 1 prospective single-center open-label study (Table I). A total of 128 studies included only hospitalized patients, 13 included both hospitalized and non-hospitalized patients, 2 included only non-hospitalized patients, and 20 studies did not list hospitalization status.

Patient baseline characteristics and outcomes

For a total of 40,632 patients, the mean age was 54.6 years, with a range of 18–98 years. A total of 8 studies, including adult patients with 2,325 patients, did not provide age data. Data regarding gender were not available in 8 studies. There were significantly fewer women in the study (43.9% vs. 56.1%, p < 0.0001). Hospitalization outcomes were reported in 116 studies for 37,349 patients; 48.5% (28,779) were discharged, 29% (18,810) remained in the hospital, and 12.1% (4284) died at the end of the study period for these studies. The details regarding invasive mechanical ventilation (IMV) were reported in 61 studies with 30,190 patients, of whom 9.89% (3,359) underwent IMV.

Comorbidities and symptoms for all patients

Prevalent cardiovascular comorbidities were hypertension (31.9%), obesity (27.9%), hyperlipidemia (26.4%), smoking (18.9%), diabetes mellitus (17.2%), atherosclerotic disease (9.2%) and arrhythmia (5.0%). Asthma (7.8%), followed by chronic obstructive lung disease (COPD) or chronic lung disease (CLD) (6.2%), were the most common respiratory comorbidities. The gastrointestinal comorbidities of hepatitis, liver disease and fatty liver disease had a prevalence of 2.4%. Chronic kidney disease and/or end-stage renal disease were reported in 6.2% of patients. Cerebrovascular disease or cerebrovascular accidents were reported in 3.5% of patients. Cancer and/or malignancy were reported in 4.4%, and HIV and/or immunodeficiency were observed in 1.6% of patients.

The most often reported constitutional symptoms of COVID-19 were fever (73.9%), fatigue (33.4%), malaise (29.9%), myalgia and/or arthralgia (19.2%), generalized weakness (19.0%), and chills (11.3%). For the cardiovascular system, chest pain and/or tightness were most often reported (19.6%), followed by palpitations (5.2%). Cough (60.3%), sputum production (29.7%), shortness of breath (27.3%), loss of smell and/or taste (25.1%), rhinorrhea (12.9%), and sore throat (12.3%) were the most often reported respiratory symptoms. The most common gastrointestinal symptoms were anorexia or loss of appetite (29.4%), followed by diarrhea (14.8%), nausea and/or vomiting (13.2%), and abdominal pain (7.4%). Commonly reported neurological symptoms were headache (12.8%), confusion (9.4%), and dizziness (8.2%). The details of the prevalence of constitutional, cardiovascular, respiratory, and gastrointestinal symptoms, and their related comorbidities, along with the number of studies, are shown in Tables II and III, respectively.

Table II.

Symptoms based on systems involved overall in patients with coronavirus disease 2019

Symptom %Age Number of patients (N) Total patients Number of studies
Constitutional:
 Fever 73.9.0 16999 22987 134
 Myalgia/arthralgia 19.20 3657 19064 96
 Fatigue 33.40 4266 12785 69
 Chills 11.30 546 4816 19
 Generalized weakness 19.00 434 2286 9
 Malaise 29.90 272 909 8
Respiratory/upper respiratory infection:
 Cough 60.30 13739 22778 134
 Dyspnea 27.30 5440 19926 111
 Sore throat 12.30 1877 15302 78
 Sputum production 29.70 3789 12730 64
 Nasal congestion 6.60 507 7658 19
 Hemoptysis 1.90 134 7191 22
 Rhinorrhea 12.90 529 4089 34
 Loss of smell or taste 25.10 740 2952 13
 Conjunctival congestion 0.90 26 2927 4
Cardiovascular:
 Chest pain/tightness 19.60 1251 6394 47
 Palpitations 5.20 22 422 4
Gastrointestinal:
 Diarrhea 14.80 2903 19544 112
 Nausea/vomiting 13.20 1992 15081 76
 Abdominal pain 7.40 504 6783 34
 Anorexia 29.40 1857 6319 37
Neurologic:
 Headache 12.80 2005 15704 75
 Confusion 9.40 191 2025 6
 Dizziness 8.20 293 3564 22
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Table III.

Prevalence of comorbidities overall in patients with coronavirus disease 2019

Comorbidity % N Total Count
Cardiovascular:
 Hypertension 31.90 9818 30792 105
 Diabetes mellitus 17.20 5122 29796 107
 Atherosclerotic disease 9.20 2642 28806 102
 Smoking 18.90 2980 15728 31
 Obesity 27.90 2758 9870 9
 Heart failure 5.90 554 9403 9
 Arrythmia 5.01 65 1297 5
 Hyperlipidemia 26.40 199 753 9
Respiratory:
 COPD/CLD 6.20 1643 26570 83
 Asthma 7.80 555 7136 11
Gastrointestinal:
 Hepatitis/liver disease/fatty liver 2.40 459 19310 60
Renal:
 CKD/ESRD 6.20 1445 23149 58
Neurologic:
 CVA/cerebrovascular disease 3.50 320 9152 40
Other:
 Cancer/malignancy 4.40 1062 23962 66
 HIV/immunodeficiency 1.60 216 13506 23
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COPD – chronic obstructive pulmonary disease, CLD – chronic lung disease, CKD – chronic kidney disease, ESRD – end-stage renal disease, CVA – cerebrovascular accident, HIV – human immunodeficiency virus.

Subgroup analysis by severity

For stratification based on severity for comorbidities and symptoms, only 30 studies met the inclusion criteria, with a total of 5,819 cases. Table IV shows the prevalence of comorbidities and symptoms in both groups.

Table IV.

Comorbidities and symptoms by severity vs. non-severity in patients with coronavirus disease 2019

Parameter Non- severe Severe P-value
Comorbidity:
 Hypertension 8.1% 45.2% < 0.001
 Diabetes mellitus 3.5% 19.5% < 0.001
 Atherosclerotic disease 5.2% 10.9% < 0.001
 Smoking 13.5% 3.8% < 0.001
 Obesity 0.0% 30.5% –
 Heart failure 0.0% 5.2% –
 COPD/CLD 9.2% 12.0% 0.083
 Liver disease 2.8% 3.0% 0.814
 CKD/ESRD 0.8% 8.7% < 0.001
 Malignancy 3.8% 3.7% 0.899
Symptom:
 Fever 58.5% 87.8% < 0.001
 Myalgia/Arthralgia 25.8% 19.0% < 0.001
 Fatigue 40.4% 45.1% 0.091
 Cough 62.9% 66.8% 0.03
 Shortness of breath 20.6% 47.4% < 0.001
 Sore throat 12.6% 14.0% 0.279
 Sputum production 26.5% 35.4% < 0.001
 Nasal congestion 4.8% 4.8% 0.998
 Rhinorrhea 7.3% 32.2% < 0.001
 Loss of smell/taste 71.5% 18.6% < 0.001
 Chest pain/tightness 19.3% 21.1% 0.34
 Diarrhea 19.4% 20.2% 0.515
 Nausea/vomiting 8.4% 8.8% 0.643
 Abdominal pain 10.3% 4.2% < 0.001
 Anorexia 41.0% 27.1% < 0.001
 Headache 20.4% 10.6% < 0.001
 Hemoptysis 3.2% 2.5% 0.725
 Chills 15.9% 6.9% 0.001
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COPD – chronic obstructive pulmonary disease, CLD – chronic lung disease, CKD – chronic kidney disease, ESRD – end-stage renal disease.

Comorbidities

Hypertension was the most commonly observed comorbidity among severe cases (45.2% vs. 8.1%, p < 0.001). Diabetes mellitus was also more common in severe disease (19.5% vs. 3.5%, p < 0.001). Obesity and congestive heart failure (CHF) were not observed in any non-severe cases among the studies included for this analysis but were present in severe cases (30.5% and 5.2%, respectively). Smoking was more commonly observed in non-severe cases than severe cases (13.5% vs. 3.8%, p < 0.001). COPD was similar in non-severe and severe cases (9.2% vs. 12.0%, p = 0.083).

Symptoms

Among all the symptoms compared, non-respiratory symptoms were more commonly observed among non-severe cases (headaches, anorexia, abdominal pain, loss of smell/taste). Severe compared to non-severe cases more frequently had fever (87.8% vs. 58.5%, p < 0.001), shortness of breath (47.4% vs. 20.6%, p < 0.001), cough (66.8% vs. 62.9%, p < 0.001), sputum production (35.4% vs. 26.5%, p < 0.001) and rhinorrhea (32.2% vs. 7.3%, p < 0.001). Both groups had a similar prevalence of chest pain (21.1% severe vs. 19.3% non-severe, p = 0.34), diarrhea (20.2% severe vs. 19.4% non-severe, p = 0.515), and nausea/vomiting (8.8% severe vs. 8.4% non-severe, p = 0.643).

Discussion

Since the emergence of SARS-CoV-2 infection in China and its spread worldwide, the knowledge regarding disease course, clinical characteristics, and treatment options has continued to evolve. We performed a comprehensive systematic review of published studies with COVID-19 patients. This systematic review summarized the prevalence of clinical symptoms and comorbidities in COVID-19 patients, stratified by the severity of symptoms [164–170].

This analysis found that the prevalence of COVID-19 was higher in men compared to women. Hypertension, obesity, hyperlipidemia, smoking, diabetes mellitus, and atherosclerotic diseases are the most common comorbidities overall. Fever, cough, fatigue, malaise, sputum production, shortness of breath, and anosmia are the most common symptoms overall. After stratification of patients on the basis of severity, hypertension, diabetes, obesity, and CHF were the most common comorbidities in severe illness. In contrast, smoking is more common in non-severe illnesses. Fever, shortness of breath, cough, sputum production, and rhinorrhea are more commonly reported in patients with severe illness, whereas headache, anorexia, abdominal pain, and loss of smell/taste are reported more often in patients with non-severe illness.

We report a higher prevalence of COVID-19 in men compared to women. An analysis of 14,712 patients revealed men to have significantly higher mortality than women even after adjusting for comorbidities [171]. Gender differences have been reported in the prior influenza pandemic, suggesting that men are more susceptible to viral respiratory illness; this is attributed to females generating stronger innate and adaptive immune responses [172, 173]. Thus, it could be why SARS-CoV-2, being a respiratory virus, was noted to have a higher prevalence in men in our study. One study evaluating 524 SARS-CoV-2 patients ages 51 to 70 found that males were significantly more likely to be hospitalized and had increased mortality regardless of age [174]. It could be hypothesized that women have a robust immune response to viruses as seen with the influenza virus as well; hence that could be the reason for the protection of females against SARS-CoV 2 infection.

We found the most common comorbidities to be hypertension and diabetes; these results are consistent with prior studies with a similar prevalence of hypertension and diabetes ranging from 13% to 27% and 7% to 12%, respectively [4, 175]. The slightly higher prevalence of hypertension and diabetes in this study could be attributed to the inclusion of studies worldwide. In contrast, prior studies included only studies from China. The prevalence of obesity was 27.9% from 9 studies; interestingly, all these studies were from the US. Obesity has also been postulated to be a risk factor for COVID-19 by the dysregulation of the immune system due to excess adiposity and decreased diaphragm contractility [176]. Smoking was more common in non-severe patients; the “smoker’s paradox” has been proposed as a possible mechanism suggesting smoking to have a protective effect, although this hypothesis continues to remain controversial [177].

Hypertension, hyperlipidemia, smoking, diabetes mellitus, and obesity are well-known cardiovascular risk factors [178]. Heart disease, stroke, and diabetes are known risk factors for influenza and its complications. SARS-CoV-2, being a respiratory virus, could also be hypothesized to have a similar risk factor [179]. Several hypotheses have been proposed for the cardiovascular complications of SARS-CoV-2, including angiotensin-converting enzyme-2 mediated cardiac damage, direct viral injury to myocardium, and hypoxemia mediated damage. However, none of these hypotheses have been proven yet [6, 180, 181]. Our findings suggest a higher prevalence of cardiovascular comorbidities in severe cases, which could be likely because of myocardial injury in these patients. The presence of comorbidities, including hypertension, diabetes mellitus, and atherosclerotic disease, was noted to be significantly higher in the severely ill patient population, which is corroborated by prior studies [19, 24, 35, 182].

Our study is in concordance with a prior meta-analysis of 43 studies with 3600 patients reporting fever, cough, and fatigue to be the most common clinical symptoms, suggesting COVID-19 to have primary respiratory system involvement [4]. In our study, fever was the most common presenting symptom as well [4, 35, 54, 109]. Respiratory symptoms of shortness of breath, cough, sputum production, and rhinorrhea were more common in severe illnesses, whereas non-respiratory symptoms are more common in non-severe disease. This could be because dyspnea and the need for supplemental oxygen are the criteria for severe illness. Initial studies were suggestive of COVID-19 being primarily a respiratory illness; however, recent studies suggest COVID-19 to be a multi-system disorder with the involvement of cardiovascular, gastrointestinal, musculoskeletal, and nervous systems. We report the involvement of respiratory, cardiovascular, gastrointestinal, musculoskeletal, and nervous systems, suggesting that COVID-19 is a multi-system disease with primary respiratory system involvement.

Our study reports a low prevalence (25.1% in 7952 from 13 studies) of loss of smell or taste; this is likely because of the inclusion of outpatient and survey studies in our review. A review focusing on olfactory dysfunction reported that up to 80% of patients with COVID-19 might develop subjective olfactory dysfunction in the disease’s initial stages [183]. The lower prevalence in our study can be attributed to the inclusion of more inpatient studies in our analysis, as loss of smell tends to be an early-onset symptom and not recognized in inpatients. A review focusing on musculoskeletal symptoms of 12,046 patients reported occurrence of fatigue in 25.6% and arthralgia and/or myalgia in 15.5% of patients. Our study also showed a similar prevalence of these symptoms, although they seem to be nonspecific and represent viral prodromal symptoms for most of the respiratory viruses [184].

Our study’s strength lies in its large patient population of more than 40,000 cases, including inpatients and outpatients, severe and non-severe cases, and spread over multiple continents. Our study has certain limitations as the majority of studies included in our study are observational. Even though our study included patients across the world, the majority of studies originate from China. Of concern, many of the studies were incomplete and did not include a comprehensive picture of the patients such as outcomes on discharge. Additionally, most of the studies were in inpatient settings, thus under-representing cases within the community. Lastly, the literature evolving around COVID-19 is very dynamic and rapidly evolving, especially in terms of outcomes.

In conclusion, the prevalence of COVID-19 was found to be higher in men. Hypertension, diabetes, and atherosclerotic diseases are common comorbidities globally, and obesity is the second most common in the US. There is a higher prevalence of comorbid hypertension and diabetes amongst severely ill patients and a higher prevalence of fever, myalgia/arthralgia, shortness of breath, and cough symptoms in severely ill patients. We believe that further high-quality prospective studies are needed to identify the demographics and regional differences and ascertain characteristics of outpatient COVID-19 individuals.

Conflict of interest

The authors declare no conflict of interest.

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