key: cord-0693104-m9hj9fo7 authors: Minh, Le Huu Nhat; Abozaid, Ali Ahmed‐Fouad; Ha, Nam Xuan; Le Quang, Loc; Gad, Abdelrahman Gamil; Tiwari, Ranjit; Nhat‐Le, Tran; Quyen, Dinh Kim; AL‐Manaseer, Balqees; Kien, Nguyen Dang; Vuong, Nguyen Lam; Zayan, Ahmad Helmy; Nhi, Le Huu Hanh; Surya Dila, Kadek Agus; Varney, Joseph; Tien Huy, Nguyen title: Clinical and laboratory factors associated with coronavirus disease 2019 (Covid‐19): A systematic review and meta‐analysis date: 2021-09-02 journal: Rev Med Virol DOI: 10.1002/rmv.2288 sha: 35000dd9def9dad68a37e27a3825e2c2ed9f9901 doc_id: 693104 cord_uid: m9hj9fo7 SARS Coronavirus‐2 is one of the most widespread viruses globally during the 21(st) century, whose severity and ability to cause severe pneumonia and death vary. We performed a comprehensive systematic review of all studies that met our standardised criteria and then extracted data on the age, symptoms, and different treatments of Covid‐19 patients and the prognosis of this disease during follow‐up. Cases in this study were divided according to severity and death status and meta‐analysed separately using raw mean and single proportion methods. We included 171 complete studies including 62,909 confirmed cases of Covid‐19, of which 148 studies were meta‐analysed. Symptoms clearly emerged in an escalating manner from mild‐moderate symptoms, pneumonia, severe‐critical to the group of non‐survivors. Hypertension (Pooled proportion (PP): 0.48 [95% Confident interval (CI): 0.35–0.61]), diabetes (PP: 0.23 [95% CI: 0.16–0.33]) and smoking (PP: 0.12 [95% CI: 0.03–0.38]) were highest regarding pre‐infection comorbidities in the non‐survivor group. While acute respiratory distress syndrome (PP: 0.49 [95% CI: 0.29–0.78]), (PP: 0.63 [95% CI: 0.34–0.97]) remained one of the most common complications in the severe and death group respectively. Bilateral ground‐glass opacification (PP: 0.68 [95% CI: 0.59–0.75]) was the most visible radiological image. The mortality rates estimated (PP: 0.11 [95% CI: 0.06–0.19]), (PP: 0.03 [95% CI: 0.01–0.05]), and (PP: 0.01 [95% CI: 0–0.3]) in severe‐critical, pneumonia and mild‐moderate groups respectively. This study can serve as a high evidence guideline for different clinical presentations of Covid‐19, graded from mild to severe, and for special forms like pneumonia and death groups. In late December of 2019, the World Health Organization (WHO) China Country Office received a report about several patients having pneumonia of unknown etiology. 1 After, new cases started appearing rapidly with common symptoms such as fever, cough and dyspnea with less common presentation consisting of headache, sore throat and runny nose. The cause was later attributed to coronavirus 2019 . With the majority of cases being located in Wuhan, China, the transmission mechanism was mainly presumed to be from exposure to the unique seafood and meat of the Wuhan market. This severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense single-stranded RNA virus closely related in structure to SARS-CoV and the same family as MERS-CoV. 2 According to WHO, the most common symptoms included low-grade fever, dry cough, and fatigue. More serious Covid-19 illness more frequently caused shortness of breath, persistent chest pain, dizziness, anorexia and high-grade fever. 3 This sharp variation in symptoms may be due to the difference in reception of the virus among humans, which brings us difficulty understanding how it behaves and anticipates its development and then controlling and treating the disease. 4 Thus, the number of confirmed Covid-19 cases has exceeded 125 million, with 2.5 million mortalities worldwide. 5 It is currently recommended that people with severe symptoms be provided with intensive care, ventilators and respiratory support. Corticosteroid analogues like dexamethasone are utilised to reduce mortality due to the low effectiveness of current antivirals and antibiotics prescribed to Covid-19 patients. [6] [7] [8] Remdesvir, 9 bamlanivimab plus etesevimab, 10 inhaled interferon-beta, 11 baricitinib, 12 tocilizumab or sarilumab 13, 14 have shown clinical benefits in treatment of Covid-19 along with their safety in various randomised clinical trials. The mechanisms they based on in their actions mainly depend on reducing the cytokine storm increased by SARS-CoV-2, including IL-6, IL-12, TNF-α, and complement fragments C3a and C5a. 15 The study aims to systematically review the published literature on the Covid-19 to estimate the frequency of clinical symptoms by comparing different clinical presentations based on the severity and living status of the cases. We also reveal the complications that appeared after admission to the hospital, clinical outcome, different methods of treatment, and prognosis tendency. Our systematic review and meta-analysis used the global terms of Covid-19 since January 2020. We selected this specific date because no publication has been published for the SARS-CoV-2 of the Wuhan outbreak before that time. The search strategy was conducted on the following seven network databases on 6 March 2020: PubMed, EMBASE, SCOPUS, Web of Science (WoS), Google Scholar, Cochrane Library and WHO Global Health Library (WHO GHL). No restrictions on the origin of cases or filters of age, gender, ethnicity, language, type of publication and human were applied. The entire strategy is shown in Table S1 . The exported databases' results were incorporated into Endnote version X9.0 program to remove detected duplications. After the full-text screening stage, we have done a manual search on 13 March 2020. The manual search method included searching by references reported in related full-text or reviews, by citations of these articles, or even by conducting a simple search in PubMed or Google Scholar. The study's protocol has been published in PROSPERO with ID CRD42020167929. The report of the findings was based on PRISMA guidelines published in 2009. [16] [17] [18] Our steps of the systematic review were reported in PRISMA checklist version 2020 (Table S2 ). We conducted the selection phase in two stages: firstly, we screened the studies included after removing duplicates through their titles and abstracts. Then, we checked for full-text eligibility of the included studies from the first stage. The study's inclusive criteria included all possible case reports, case series, and epidemiological observational studies containing any medical information or clinical investigation of confirmed SARS-CoV-2 cases, regardless of the country and time of examination. We also included non-English articles that were written in Chinese. Criteria of exclusion were other original studies such as books, reviews, theses, conference papers, and articles without available full text. Two independent authors were assigned for each step, and the discussion was held to resolve the conflicts with the help of the third senior author to reach the final consensus. Two independent authors were chosen to extract distinguished items of the prepared data extracted from each included full-text article and qualified them. Then the discussion was undertaken to solve any discrepancies between these two by the third reviewer. All included articles were evaluated for study quality. We divided the articles into two types for various method studies: Case report/ case series/case-control studies and observation cohort/Crosssectional studies. We used Study Quality Assessment Tools of the National Institutes of Health (NIH) for included studies. 20 There are nine items to extract for case reports/case series. For observation cohort/cross-sectional studies, there are 13 items. Each item was rated as one or 0/NA-not applicable/NR-not reported/CD-cannot determine. The final score will be calculated as a percentage with equal points for each item. The scoring thresholds are those over 75% 'good' quality, those between 75% and 43% 'fair', and below 43% 'poor'. Two reviewers independently extracted the assessment. Discrepancies were discussed and resolved by a third reviewer. These assessment data were incorporated into a separate excel sheet. Our strategy data synthesis targeted to conduct a qualitative synthesis using systematic review and quantitative one using R software version 3.6.2 software (https://www.r-project.org/). The meta-analysis was conducted for case series, and observation studies that have equal or more than five included Covid-19 patients in each dataset. Ultimately, the values of the variables in five various sets (mild to moderate, severe to critical, pneumonic only, death and survival/discharged patients) were based on the authors' severity classification in each study with the exclusion of 'children' studies. [21] [22] [23] [24] The meta-analysis of the results of CT-Scan has been combined for all groups and for all (less than five patients) studies to understand the most common presentation the patients`can show in this imaging examination. Each group was analysed independently using the single pooled proportion (PP) or raw mean inverse variance random effect size method of meta-analysis with the recommended restricted maximum likelihood tau method. 25 We performed a subgroup meta-analysis for adult studies (≥16 years old participants) for our outcome of interests which was determined after our primary analysis to prove the consistency of results throughout our analysis severity groups. To validate our results, we conducted a secondary comparative metaanalysis (mild-moderate vs. severe-critical) and (survivor vs. nonsurvivor) using odds ratios (OR) for dichotomous variables and standardised mean difference (SMD) for continuous ones with 95% CI. We also performed a meta-regression analysis to estimate the impact of age and number of males factors on our outcome of interests if they reported in >10 publications in one of the divided groups. MINH ET AL. Our literature searches and review of reference lists initially identified 4,309 records through seven database searches. After removing 1,999 duplicates by Endnote software version X9.0, we continued to exclude 2,082 irrelevant articles by screening titles and abstracts. Out of the 228 articles in the full-text review stage, there were 85 articles excluded, and after including 28 articles from the manual search, there were 171 final eligible full-text records. Reasons for exclusion at the full-text stage were irrelative articles, not original, overlapped, non-extractable data or no full-text available, and animal articles. In summary, 148 included publications for both systematic review and meta-analysis, based on the data of 62,949 confirmed patients ( Figure 1 ). Among the 171 included publications shown in Tables S3 and S4 The history of Covid-19 patients is summarised in Table A meta-analysis of a summary of vital signs in Covid-19 patients according to severity and death status is summarised in Table 2 and Table S7 . For laboratory values of Covid-19 were presented in Table S9 and Figure 4 with a comparison between survivors and non- Regarding Some specific treatments have been applied to COVID-19 infections in the meta-analysis of included studies. The results are summarised in Table S10 . Generally, antiviral was the most com- Our subgroup analysis showed consistency results among all groups through comorbidities, symptoms, laboratory findings, vital signs, and complications by removing 'adult and children' studies which are Jiuling/2020/China, 29 Tang/2020/China, 24 Yu-Huan Xu/2020/ China, 21 Qian/2020/China, 30 Wu/2020/China, 31 Zhang/2020/ China, 32 Hu/2020/China, 33 China. 35 Details were visualised in Table S12 . The meta-regression analysis presented in Appendix 1 revealed a higher incidence of either cardiovascular disease, hypertension or diabetes in mildmoderate, and pneumonia groups in older people with higher mean CRP and lower mean lymphocytic count. Our secondary comparative meta-analysis results were included in Appendix 2. (Tables S3 and S4 ). between January and March 2020, which is considered higher relatively similar to previous SRs Covid-19 articles (Figure 1 , Tables S3 and S4 ). 36, 37 Subsequently, we proved in our study that hypertension and diabetes were the most common comorbidities associated with a more frequent higher mortality rate, which was consistent with other reports of Covid-19. [38] [39] [40] [41] In detail, the patients with severe to critical and death group always had a higher mean pooled comorbidity rate of hypertension were 0.32 and 0.48, respectively, compared to mild to moderate patients 0.17. For diabetes, the measures were 0.19 and 0.23 compared to 0.08, respectively. Furthermore, we estimated ORs for diabetes to be 0.31 for mild-moderate versus severe-critical and 0.06 for survivor versus non-survivor groups and for hypertension 0.51 and 0.02 respectively ( Figure S8 and S13 in Appendix 2). Moreover, smoking was found to be a considerable risk factor for severity 0.15 and death 0. (Tables 1 and S5) . 43, 44 The findings of vital signs presented that most indicators were not a large range of differences among severity groups apart from SpO 2 . Our study cannot support the notion that tachypnea and tachycardia have a solid relation to severe disease and death. However, results from other studies showed that tachyarrhythmia is among severity levels was higher. 45 SBP and DBP were observed as significant indicators for mortality in Covid-19 but not in our study. 46 The best marker for severeness was SpO 2 , with a mean estimated at 92.36 in critically severe compared to 97.02 mild patients. Moreover, the same study was counted as a risk factor for mortality which agreed with our study findings [ raw mean: 85.76 for mortality compared to 89.9 for survival] (Table S6) . 46 The emergence of symptoms was noticed in an escalating manner in the group of mild and moderate symptoms, pneumonia, severe and critical to the group of non-survivors. The major clinical features noted were fever and cough, consistent with other SRs. 47, 48 Besides, we detected that dyspnea, chest pain and anorexia were relatively ominous clinical signs for the seriousness of the disease and mortality. These findings were indeed the same as the recent WHO classification of Covid-19 severity. Alizadehsani et al. 49 has estimated the significant value of the p-value of anorexia as a risk factor for mortality to be 0.04 in a prospective study compared to healthy individuals. Regarding respiratory imaging features, bilateral GGO involvement with multiple mottling is the most common radiological feature in our SR., with a little higher proportion of lesions seen on the right lung. These findings resemble imaging features of other reports (Tables 2, 3 and S7) . 36, 50 Consequently, our analysis has broadly distinguished the laboratory investigation results in terms of severity and mortality. Firstly, we realised that Covid-19 didn't largely affect the hepatic function with a slight or no increase of liver enzymes in most cases. (Tables S8 and S9 , Figures 3 and 4) . 39, 50 Considerably, although we found in our analysis, the most common treatment used was antiviral and antibiotic drugs. The increasing rate of using corticosteroids, ECMO, NIV, CKRT, MIV, immunoglobulin and oxygen therapy was distinctly witnessed in severity and mortality groups as rescue treatments. The efficacy of these treatments was discussed in a network configuration by Siemieniuk et al. 52 who proved that increased corticosteroid use in mechanical ventilation could reduce fatality risk (Table S10 ). For the impact of antihypertensive drugs (ACEIs/ARBs), several authors found that ACEI/ ARB use has no association with increased in-hospital severity or mortality. 53, 54 We only included a single study that reported the incidence among Covid-19 discharged/death patients. But it doesn`t showed any association to the mortality (p-value > 0.99). 55 Even better, Zhang et al. suggested lower all-cause mortality in ACEI/ARB using inpatient compared with non-users. 56 The explanation could be that ACEI or ARB therapy relates to decreased peak viral load, improved CD3 and CD4 count, and lower levels of IL-6 in peripheral blood, hence lower the rate of severe diseases. 57 Many studies have shown that various complications, including multisystem organ failure, including acute respiratory, cardiac, renal failure and even mortality, are in line with current reports. [58] [59] [60] [61] 63 Our results also showed ARDS, heart injury, septic, AKI were common complications in non-survivor and severe to critical and occurred much less often in the mild disease and survivor groups (Table S11 ). Our outcomes of interest are restricted to adults-only studies, which showed symmetry with our previous findings in Table S12 . However, heterogeneity was still high for non-specified reasons. Most of the previous SRs reported the same heterogeneity even with including only adults into their analysis system. 47 It indicated that the Covid-19 behaviour pattern was so hard to be predicted. However, our study can present a new approach for classifying this disease through different datasets of severity, pneumonia, and dying patients. The studies included in our review were heterogeneous. Some Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR Genomic characterization and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding What Are the Symptoms of COVID-19? World Health Organization Variant analysis of SARS-CoV-2 genomes World Health Organization Are There Treatments for COVID-19? 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