key: cord-1008692-rf57zvn7
authors: Rahman, M. M.; Bhattacharjee, B.; Farhana, Z.; Hamiduzzaman, M.; Chowdhury, M. A. B.; Hossain, M. S.; Siddiqee, M. H.; Islam, M. Z.; Raheem, E.; Uddin, M. J.
title: Prevalence and correlation of symptoms and comorbidities in COVID-19 patients: A systematic review and meta-analysis
date: 2020-08-22
journal: nan
DOI: 10.1101/2020.08.19.20177980
sha: 634cfaefa25806c4429b1c58f092b361051901bc
doc_id: 1008692
cord_uid: rf57zvn7

Background: The COVID-19 affected millions of people, and the patients present a constellation of symptoms and comorbidities. We aimed to chronicle the prevalence and correlations of symptoms and comorbidities, and associated covariates among the patients. Methods: We performed a systematic review and meta-analysis [PROSPERO registration: CRD42020182677]. Databases [PubMed, SCOPUS, EMBASE, WHO, Semantic Scholar, and COVID-19 Primer] were searched for clinical studies published in English from January 1 to April 20, 2020. The pooled prevalence of symptoms and comorbidities were identified using the random effect model, and sub-groups analysis of patients age and locations were investigated. A multivariable factor analysis was also performed to show the correlation among symptoms, comorbidities and age of the COVID-19 patients. Findings: Twenty-nine articles [China (24); Outside of China (5)], with 4,884 COVID-19 patients were included in this systematic review. The meta-analysis investigated 33 symptoms, where fever [84%], cough/dry cough [61%], and fatigue/weakness [42%] were found frequent. Out of 43 comorbidities investigated, acute respiratory distress syndrome (ARDS) [61%] was a common condition, followed by hypertension [23%] and diabetes [12%]. According to the patients age, the prevalence of symptoms like fatigue/weakness, dyspnea/shortness of breath, and anorexia were highly prevalent in older adults [[≥]50 years] than younger adults [<50 years]. Diabetes, hypertension, coronary heart disease, and COPD/lung disease were more prevalent comorbidities in older adults than younger adults. The patients from outside of China had significantly higher prevalence [p<0.005] of diarrhea, fatigue, nausea, sore throat, and dyspnea, and the prevalent comorbidities in that region were diabetes, hypertension, coronary heart disease, and ARDS. The multivariable factor analysis showed positive association between a group of symptoms and comorbidities, and with the patients age. Interpretation: Epitomizing the correlation of symptoms of COVID-19 with comorbidities and patients age would help clinicians effectively manage the patients.

The COVID-19 pandemic caused by Severe Acute Respiratory Virus 2 (SARS-CoV-2) is a serious public health crisis in the history of humanity. Originated in Wuhan, China, SARS-CoV-2 has spread to every corner of the world within a few months. As of June 19, 2020, over 8.37 million cases and 450,087 deaths have been reported from over 216 countries. 1 As the virus is moving fast, various clinical spectrum and differential clinical outcomes are unfolding across different geographic locations. Several symptoms have been reported which includes fever, cough, myalgia, sputum production, headache, hemoptysis, diarrhea, and dyspnea. 2 The severity of has been reported to be linked with various host factors including diabetes, hypertension, cardiovascular disease, chronic obstructive pulmonary disease (COPD), malignancy, and chronic liver disease. 2 While susceptibility to COVID-19 covers all age groups, people with compromised immune systems and or having comorbidity are at a higher risk. 3, 4 The mortality rate is high in older patients with organ dysfunctions comprising shock, acute respiratory distress syndrome (ARDS), acute cardiac injury, and acute kidney injury. 5 The majority of the relevant systematic reviews focused either on symptoms or comorbid conditions. 3, [6] [7] [8] [9] Only a few studies reviewed both symptoms and comorbidities during a shorter time-frame.

Consequently, a wide range of symptoms and comorbidities were excluded from the analysis. 7, 9 Despite COVID-19 being a global pandemic, these studies' findings mostly reflect the demography of China.

Moreover, none of the systematic reviews analysed age-group variations in describing clinical symptoms and comorbidities. The associations of symptoms and comorbidities with the age of the patients are yet to be explored. Updated information on the COVID-19 clinical spectrum associated with comorbidities and other factors is crucial for clinical management and the decision-making process in public health. We attempted a systematic review and meta-analysis to (i) understand the prevalence of symptoms and comorbidities, with subgroup analysis [patient's age-groups and geographical locations];

(ii) study the correlation between a collection of symptoms and comorbidities, and age in the COVID-19 patients.

We followed the PRISMA-P-2009 guidelines in our review [PROSPERO registration: CRD42020182677]. 10 

We conducted a systematic search in major databases, such as PubMed, SCOPUS, EMBASE, WHO, Semantic Scholar, and COVID-19 Primer, to include peer-reviewed and pre-proof research articles published from January 1 to April 20, 2020 [supplementary Table S1 ]. The search terms used included:

"COVID-19" OR "COVID-2019" OR "severe acute respiratory syndrome coronavirus 2" OR "2019-nCoV" OR "2019nCoV" OR "nCoV" OR "SARS-CoV-2" OR "coronavirus" AND "clinical for epidemiological characterization" OR "Symptom" OR "Symptoms" AND "comorbidity" OR "comorbidities". Some articles were manually retrieved from Google Scholar and other databases. We also searched the reference lists of the selected publications. MMR, BB, and MJU independently screened the titles and abstracts of the articles and checked full-text eligibility.

Research articles were selected if they reported clinical characteristics [both symptoms and comorbidities] of the COVID-19 patients. The inclusion criteria for studies were: clinical investigations or consecutive cases; focused on infected patients; reported at least ten cases; considered all age-groups; and published in English and any countries. Studies were excluded if they were: grey literature, case report and secondary studies; specific to children or pregnant women; and only reported symptoms or comorbidities.

A standardized form was used to extract data from eligible studies. Disagreements were resolved through discussion with co-reviewers. For each study, the following information was recorded: publication details [e.g., first author, publication date, journal name, and publisher]; research setting, design and population [e.g., country, study area and time, study design, and case number]; participants' characteristics and major findings [e.g., gender, age range and median age, number of reported symptoms and comorbidities, the prevalence of symptoms and comorbidities, outcome measures, and key reported findings].

The quality of each study was assessed by ZF using the Joanna Briggs Institute (JBI) guidelines on conducting prevalence and incidence reviews. 11 A set of eight questions was used for the quality assessment. To assess asymmetry and publication bias, we used a funnel plot. Egger test [p<0.001] was also performed to test the presence of small-study effects.

We defined the prevalence of symptoms and comorbidities as the proportion of the population with COVID-19 symptoms and comorbidities in the mentioned time period. Summary statistics of the infected patients were recorded, and a random effect model was used to perform a meta-analysis. Heterogeneity was assessed using the Cochran Q and the I 2 statistic. 12, 13 Subgroup analysis was conducted according to age-groups and geographical locations of the COVID-19 patients. A multivariate analysis [multivariable factor analysis (MFA)] was also performed to examine the correlation among symptoms and comorbidities with the patients' age. 14, 15 All statistical analyses were conducted by Stata version 15 (Stata Corp, College Station, TX) using the metaprop, metabias, metafunnel commands, and R-programming language using the FactoMineR package.

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Patients and public were not involved in the development of the research question or conception and design of the study. Because of nature of the study, there was no patient or public involvement in measuring the outcomes, in providing interpretations of the findings, or writing of the manuscript.

PRISMA Flow Diagram visualizes the screening process [ Figure 1 ]. A total of 799 articles [database: 791, other sources: 8] were retrieved. Of them, 403 articles were removed due to duplication and irrelevance. Furthermore, 303 review articles, editorials, case reports, and irrelevant study populations were excluded. Fifty-three articles were excluded as they failed to meet all inclusion criteria. Finally, eleven articles were excluded due to not peer-reviewed and small sample sizes, resulting in the selection of 29 articles for our review.

Supplementary . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 22, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 22, 2020. We performed subgroup meta-analysis using 15 symptoms and ten comorbidities, according to mean or median age of the COVID-19 patients [ CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 22, 2020. . https://doi.org/10.1101/2020.08.19.20177980 doi: medRxiv preprint disease, chronic liver disease, malignancy, chronic kidney disease and cerebrovascular disease resulted no age variation. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The copyright holder for this preprint this version posted August 22, 2020 studies had a sample size of more than 100, and about 96% of studies reported the subjects and design in detail. Validated methods were used in all studies, where the measurement was reliable, and the response rate was 100%. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The funnel plots for symptoms and comorbidities are presented in a figure [supplementary figure S76 -S105]. Funnel plot found the existence of asymmetry and publication bias for all symptoms and comorbidities. The Egger test of symptoms -fever, dyspnea/shortness of breath, diarrhea, myalgia/muscle ache, nausea, anorexia, pharyngalgia, and hemoptysis were found significant [p<0.05], which suggested the presence of small-study effects. The comorbidities-diabetes, cardiovascular disease, cerebrovascular disease, COPD/lung disease, chronic liver disease, chronic renal disease, chronic kidney disease, and malignancy were found significant [p<0.05] by Egger's test, that recommended the presence of small-study effects. Figure 2 presents the association of symptoms/comorbidities with the patients' age. Nineteen symptoms and 11 comorbidities were categorized into: symptom group and comorbidity group. The correlation circle represented the between/within-group integration with the patients' age. The longer vectors indicated more influential than others, and the vectors that were close to each other with the same direction indicated a highly positive association [ Figure 2 ]. Vectors that were the opposite direction showed a negative association, and the vectors with an almost 90-degree angle demonstrated no association. The first principal component showed 31.59% variation and the second one showed 20.45% variation in the dataset.

In symptom group, fever, dyspnea/shortness of breath, nausea, vomiting, abdominal pain, dizziness, anorexia, and pharyngalgia were found positively associated with the patients' age. In contrast, sore throat, headache, rhinorrhea, myalgia/muscle ache, fatigue, and hemoptysis were negatively associated with age. Similarly, in the comorbidity group, diabetes, hypertension, coronary heart disease, COPD/lung disease, and ARDS were in the same direction and positively associated with the patient's age. The . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 22, 2020. . https://doi.org/10.1101/2020.08.19.20177980 doi: medRxiv preprint symptoms like chest tightness/pain and the comorbidities, including chronic liver and kidney diseases, showed no association with the patients' age.

Considering group integration, the fever, dyspnea/shortness of breath, dizziness, pharyngalgia, and anorexia in the symptom group were positively associated with diabetes, ARDS, and kidney, cardiovascular, and liver diseases in comorbidity group. The symptoms like diarrhea, nausea, vomiting, and abdominal pain were positively associated with hypertension, coronary heart disease, and COPD/lung disease. The symptoms of sore throat, headache, rhinorrhea, myalgia/muscle ache, fatigue, and hemoptysis were positively associated with cerebrovascular disease.

The COVID-19 pandemic requires pertinent and precise knowledge of the disease's epidemiological characteristics to contribute to evidence-based clinical practice. But the inquisitive dynamics of transmission and diversities in a clinical presentation are major challenges for early diagnosis and prompt treatment of COVID-19. Considering these realities, we aimed to perform a systematic review and metaanalysis on the prevalence of reported clinical symptoms and comorbidities with proper subgroup analysis. Later, we examined integration between symptoms, comorbidities, and age in patients with COVID-19.

Out of 29 articles, twenty-four [83%] studies performed in China, and five were outside of China. The ratio of infection was reported higher in males than in females [100:82.5], and this result is consistent with previous studies. 2, 6, 16, 17 It is generally assumed that males are more likely to be infected by bacteria and viruses than females, because of the women's robust innate and adaptive immune responses. 3, 18 Moreover, the patterns of occupation, social communication, and lifestyle expose males to be exposed more to the agent factors of infectious diseases than in females. The mean or median age of the patients . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 22, 2020. . https://doi.org/10.1101/2020.08.19.20177980 doi: medRxiv preprint ranged from 40 to 66 years, and we found older people are more susceptible to COVID-19, and our study strongly supports this finding.

We found 33 symptoms and 43 comorbidities in the studies, and our meta-analysis included most reported 19 symptoms and 11 comorbidities. This meta-analysis suggests a prevalence of twelve symptoms and three comorbidities (showed at least 10% pooled prevalence) for the patients with COVID-19. Fever, cough/dry cough, fatigue, dyspnea, anorexia, chest tightness, myalgia, sore throat, rhinorrhea, headache, and diarrhea were highly prevalent symptoms. All studies reported fever [84%] and cough/dry cough [61%] as symptoms consistent with relevant studies across the countries. [19] [20] [21] [22] The rarely found symptoms in the patients with COVID-19 included haemoptysis, pharyngalgia, dizziness, abdominal pain, chest pain, chill, and nasal obstruction or conjunction ache, palpitation, malaise and anorexia, conjunctival congestion, throat congestion, tonsil swelling, rash, retching, anosmia, ageusia, snotty, and arthralgia. Previous studies reported hypertension as the most common comorbidity, 3, 7, 8 , but our study suggests three major comorbidities-acute respiratory distress syndrome (61%), hypertension (23%), and diabetes (12%). Acute respiratory distress syndrome was also found a higher prevalence rate

[61%] as reported in three studies in China and one in outside China. [23] [24] [25] [26] Our systematic review investigated all the reported symptoms and comorbidities of infected patients. The symptoms like anorexia [26%], chest tightness [25%] and rhinorrhea [13%], and one comorbidity, i.e., acute respiratory distress syndrome[61%] were examined with significant prevalence (p<0.005), but they were under-investigated in the published systematic reviews 6, 7, 27, 28 We reviewed ten studies for older adults [≥50 years] and 19 for younger adults [<50 years]. The subgroup meta-analysis showed that the older adults were experiencing fatigue/weakness, dyspnea/shortness of . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 22, 2020. . https://doi.org/10.1101/2020.08.19.20177980 doi: medRxiv preprint breath, and anorexia comparatively more than the younger adults. In comparison, the prevalence of headache and pharyngalgia were found higher in younger adults. The majority of older adults were suffering from diabetes, hypertension, coronary heart disease, and COPD/lung disease more than younger adults. Human aging is associated with declines in adaptive and innate immunity, and it loses the body's ability to protect against infections. 29, 30 Virologists and clinicians agree that the older adults are more vulnerable to COVID-19, and they present symptoms and comorbid conditions at a higher rate than any other age groups. [31] [32] [33] [34] [35] The meta-analysis based on geographical location presented that the patients from outside China scored more cases of diarrhea, fatigue, nausea, sore throat, and dyspnea in comparison to Chinese patients. This variation could be due to the diversity of food habits, environmental, and lifestyle among the countries.

The analysis also showed that diabetes, hypertension, cardiovascular disease, coronary heart disease, and ARDS had a higher prevalence outside of China. At the same time, no geographical variation was found for chronic liver disease, malignancy, and COPD/lung disease. As the published reviews and metaanalysis studies found a scarcity of data from outside of China, our study added a discussion on the symptoms and comorbidities from outside of China. This is a significant intellectual contribution to the knowledge of epidemiological and clinical attributes of COVID-19. Additionally, a few systematic reviews were conducted in China, and our study findings are consistent with them. 14, 15 Our multivariable factor analysis found that the prevalence rate of symptoms and comorbidities were significantly higher in older patients. Symptoms like fever, dyspnea/shortness of breath, dizziness, pharyngalgia, and anorexia were positively correlated with diabetes, ARDS, kidney, cardiovascular, and liver diseases. Symptoms like diarrhea, nausea, vomiting, and abdominal pain were positively associated . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted August 22, 2020. . https://doi.org/10.1101/2020.08.19.20177980 doi: medRxiv preprint with hypertension, coronary heart disease, and COPD/lung disease; sore throat, headache, rhinorrhea, myalgia/muscle ache, fatigue, haemoptysis were positively associated with cerebrovascular disease.

As a unique initiative, this systematic review and meta-analysis epitomize the correlation of symptoms of COVID-19 with comorbidities and the age of the patients. Additional findings of the present study will contribute to designing comprehensive health care to COVID-19 patients. The study findings will also contribute to strengthening prevention and control activities for the COVID-19, considering the global realities of no-availability of any effective vaccine or drug.

Three limitations we faced were: (i) the majority of the studies were from China, and only five from other countries. More studies outside of China could add value in subgroup and multifactor analyses; (ii) we found no data for <10 years; thus, more studies are warranted in the child COVID-19 patients; (iii) a few studies had low sample size.

In conclusion, this systematic review and meta-analysis is the pioneering effort of its kind that reports all frequent symptoms and comorbidities, and correlation with baseline characteristics of the COVID-19

patients. The study exposes comprehensive clinical symptoms and comorbidities associated with COVID-19, which will help the clinicians, health care providers, policymakers, and stakeholders to devise diverse preventive, primitive, and curative strategies for effective management of the COVID-19 patients. Sore Throat, S8: Myalgia/Muscle Ache, S9: Rhinorrhea, S10: Sputum Production/Expectoration, S11: Chest tightness, S12: Chest pain, S13: Nausea, S14: Vomiting, S15: Abdominal Pain, S16: Dizziness, S17: Anorexia, S18: Pharyngalgia, S19: S9 S10 S11 S12 S13 S14 S15 S16 S17 S18 S19 

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The copyright holder for this preprint this version posted August 22, 2020. . https://doi.org/10.1101/2020.08.19.20177980 doi: medRxiv preprint

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We are thankful to the Health Assistant (Md. Saiful Islam) who supported and provided computer and necessary software during the data analysis.