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

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. Copyright:

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 "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

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

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

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

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

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.