key: cord-0759266-wv75bzaj
authors: Puri, Anju; He, Lin; Giri, Mohan; Wu, Chengfei; Zhao, Qinghua
title: Comparison of comorbidities among severe and non‐severe COVID‐19 patients in Asian versus non‐Asian populations: A systematic review and meta‐analysis
date: 2021-11-10
journal: Nurs Open
DOI: 10.1002/nop2.1126
sha: 7ed8f87c74ec5676137d5dbd5914f5fd6cfd79f1
doc_id: 759266
cord_uid: wv75bzaj

OBJECTIVES: This study aimed to evaluate the comorbidities among severe and non‐severe COVID‐19 patients in Asian versus non‐Asian populations. DESIGN: Systemic review and Meta‐analysis. METHODS: A systematic literature search was conducted using PubMed, Embase, Scopus and the web of science Database up to 24 March 2021. Odds ratios were calculated using a random‐effects model. RESULTS: We identified 66 studies including 39 Asian and 27 non‐Asian studies. This study demonstrated that the proportion of hypertension was significantly higher in severe group than in non‐severe group for Asian (OR = 2.46) and non‐Asian (OR = 1.60, 95% CI: 1.37–1.86, I (2) = 84%; p < .00001) patients. Similarly, the proportion of diabetes, cardiovascular disease and chronic kidney disease was significantly higher in severe group than in non‐severe group for both Asian and non‐Asian studies. We found no statistically significant difference between the severe versus non‐severe group for cancer (OR = 1.26) and chronic obstructive pulmonary disease (OR = 1.32) among non‐Asian patients.

The outbreak of Coronavirus disease , which was first reported in early December 2019 in Wuhan, China has emerged as one of the most serious global pandemic and global health hazard . The cases of COVID-19 are still rapidly increasing with higher morbidity and mortality. Globally, there have been 146,067,511 confirmed COVID-19 patients by 25 April 2021 and among them 3,092,497 lost their lives (World Health Organization, 2021) . The clinical manifestations highly range from asymptomatic to symptomatic and shows clusters of flu like symptoms such as fever, fatigue, myalgia, dry cough, dyspnoea, anorexia and so on Huang, Lian, et al., 2020) . Patients are classified into four type, that is, mild, moderate, severe and critical based on clinical manifestation and laboratory findings. Some studies have documented that COVID-19-infected patients who already have pre-existing comorbidities such as hypertension, diabetes, congestive heart failure, cardiovascular diseases, cerebrovascular disease, chronic kidney disease (CKD), chronic liver disease, cancer, chronic obstructive pulmonary disease and asthma leads to poor prognosis or even fatal outcomes (Giri et al., 2020; Gregoriano et al., 2020; Yang, Zheng, et al., 2020; Zhou, Yang, et al., 2020) . In addition, the older people who already have above listed underlying chronic conditions are more susceptible to COVID-19. Severe cases admitted in intensive care unit with pre-existing comorbidities yield poorer clinical outcomes than those without (Abohamr et al., 2020; Guan et al., 2020; Tabata et al., 2020) .

Thus, it is critical to thoroughly understand and identify the actual high-risk comorbidities, which are closely associated with COVID-19 in order to do prompt management and prevent the deterioration from mild and moderate conditions to the severe ones.

Thus far, most of published meta-analysis about the comorbidity in severe COVID-19 patients included limited studies and most studies included in these meta-analysis were conducted in China. Therefore, it is necessary to carry out a meta-analysis to give systematic evaluation of common comorbidities in severe and non-severe COVID-19 patients around the globe. To the best of our knowledge, this is the first study to compare comorbidities among severe and non-severe COVID-19 patients in Asian versus non-Asian populations.

For research article selection the inclusion criteria were as follows: (1) Study population: Studies with patients diagnosed with  (2) Comparative studies: Studies that compared severe or ICU (elevated troponin T (TnT) level as the second choice if severe or ICU data were not given) and non-sever or non-ICU (normal TnT level as the second choice if non-severe or non-ICU data was not given) cases of and (3) The studies reporting parameters of comorbidities such as hypertension, diabetes, cardiovascular disease, cancer, chronic obstructive pulmonary disease and chronic kidney disease. Non-English studies, letters, case studies, editorials, conference abstract, vaccination trials studies and articles with only abstract were excluded. Studies with fewer than 20 cases were also excluded.

This study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement guidelines (Moher et al., 2009 ). PRISMA checklist was followed step by step (Electronic Supplementary information Appendix S1).

We used PubMed, Embase, Scopus and Web of Science online database to conduct a comprehensive search up to 24 March 2021, with following search terms: "COVID-19," "Novel coronavirus," "SARS-CoV-2," "Coronavirus disease-19," "Epidemiological character," "Clinical features," "Clinical character," "Clinical Presentation," "comorbidities," "Comorbidities" and "Complications." Full electronic search strategy in PubMed database can be found here (Electronic Supplementary information Appendix S2). We applied search filters to include English language studies. We screened reference lists of included studies to ensure literature saturation.

Microsoft Excel database was used to record all available information. Two authors (AP and LH) who performed the literature search also independently extracted following items from each article: first author, publication year, country, study design, age, gender, sample size and number of people in severe and non-severe group. In case of missing data, we also contacted the authors of an article to obtain more precise data about the comorbidities of the patients evaluated. Disagreement occurred during research period were resolved by consensus with third author. The primary outcome measure was to compare the proportion of comorbidities such as hypertension, diabetes, cardiovascular disease, and chronic kidney disease in severe group versus non-severe group for both Asian and non-Asian studies.

Methodological index for non-randomized studies (MINORS) (Slim et al., 2003) was used to assess methodological quality of included studies by two independent researchers. Each item in the MINORS has three scores: 0, unreported; 1, reported but inadequately or partially; and 2, adequately reported. The total score is 24. The detailed risk of bias for all the included studies using MINORS criteria score is presented in Table 1 . According to MINORS criteria score the studies were classified as very low quality (0-6), low quality (7-12), moderate quality (13-18) and high quality (19-24). Two reviewers independently assessed the quality of included studies and disagreements were resolved through discussion with third reviewer. Publication bias among included studies was assessed by funnel plots and a symmetrical plot indicated low-risk publication bias.

Meta-analysis was performed using RevMan software version 5.3. We calculated pooled odds ratio (OR) and 95% CI for comorbidities, in severe versus non-severe Asian and non-Asian studies.

Heterogeneity between studies was assessed using the Cochran Q test and I 2 statistics. Generally, in cases of I 2 being larger than 50%, a random-effect model is used, otherwise a fixed-effect model is used. However, owing to the clinical heterogeneity inherent in the data and the different effect sizes of included studies we used random-effects analysis for all meta-analyses. The I 2 values of <25%, 25%-50%, 50%-75% and 75%-100% were regarded as homogeneous, low, moderate and high heterogeneous levels, respectively. The p-value less than 0.05 was used to indicate statistical significance.

Searches in electronic databases found 11,874 articles. After excluding duplicates (N = 7318), 4,556 citation records remained.

Thereafter, 4,556 articles were screened in terms of title and abstract. 4,442 ineligible studies were excluded. The full text of 114 studies was assessed to determine their eligibility. We excluded 48 full texts, comprising 24 review articles, 15 non-comparative studies, five meta-analysis and four editorials. Ultimately, out of 114 full text article finally 66 articles, which met the inclusion criteria were included in the final analysis. Figure 1 shows a flow chart of studies selection process.

A total of 66 studies were included among them 39 studies were Asian and 27 were non-Asian. Out of 39 Asian studies, most of them were carried out in China (N = 26) Cao, Zheng, et al., 2020; Du et al., 2020; Guan et al., 2020; Guo et al., 2020; Huang, Zhu, et al., 2020; Li, Jiang, et al., 2020; Li, Xu, et al., 2020; Lv et al., 2020; Shi et al., 2020; Tian et al., 2020; Wan et al., 2020; Wang, Hu, et al., 2020; Wang, Xin, et al., 2020; Wang, Yang, et al., 2020; Wang, Zhen, et al., 2020; Wei et al., 2020; Wu et al., 2020; Xiong, Tang, et al., 2020; Yang, Liu, et al., 2020; Zhang, Dong, et al., 2020; Zhang, Hu, et al., 2020; Zhou, Sun, et al., 2020) , followed by Saudi Arabia (N = 4) (Abohamr et al., 2020; Alqahtani et al., 2020; Khan et al., 2020; Shabrawishi et al., 2020) , South Korea (N = 3) Lee, Hong, et al., 2020; , Turkey (N = 2) (Bastug et al., 2020; Güner et al., 2020) , Oman (N = 1) (Khamis et al., 2020) , (Omrani et al., 2020) , Iran (N = 1) (Shahriarirad et al., 2020) , and Japan (N = 1) (Tab ata et al., 2020). Most of the non-Asian studies Filardo TD  2  2  2  2  2  0  1  0  2  2  2  2  19   Garibaldi BT  2  2  2  2  2  0  0  0  2  2  2  2  18   Giustino G  2  2  2  2  2  1  1  0  2  2  2  2  20   Gregoriano C  2  2  2  2  2  1  0  0  2  2  2  2  19 Israelsen SB 2 2 2 2 2 0 0 0 2 2 2 2 18 Table 2 . We performed assessments of risk of bias for all the included studies using MINORS rating scale and reported in Table 1 .

The mean MINORS score was 19.23 ± 0.91 (range: 18-21) out of a possible 24 for comparative studies ( Table 1 ). All of the included studies were moderate-to-high quality.

Fifty eight studies reported data on hypertension in severe and non-severe COVID-19 patients. The overall pooled incidence of Figure 2 ). There was high heterogeneity among the included studies (I 2 = 82%). Similarly, non-Asian studies also showed statistically significant difference in hypertension incidence in severe and non-severe patients (OR = 1.60, 95% CI:

1.37-1.86, I 2 = 84%; p < .00001) ( Table 3 and Figure 2 ).

Data on the diabetes were reported in the 62studies. The overall pooled estimate showed significantly higher incidence of diabetes in severe patients than non-severe patients (OR = 1.95, 95% CI:

1.71-2.22, I 2 = 83%; p < .001) (Table 3 and Figure 3 ). In Asian studies, the proportion of diabetes was statistically significant higher in severe patients compared with non-severe patients (OR = 2.70, 95% CI: 2.16-3.37, I 2 = 71%; p < .00001). In non-Asian studies, the pooled odds of diabetes was also significantly higher in patients with severe disease than in those without (OR = 1.44, 95% CI: 1.27-1.63, I 2 = 75%; p < .00001) (Table 3 and Figure 3 ).

Pooled findings of 48studies revealed significantly higher incidence of cardiovascular disease in severe patients compared to non-severe patients (OR = 2.47, 95% CI: 2.00-3.06, I 2 = 79%; p < .00001) (Table 3 and Figure 4) . The subgroup analysis of both Asian (OR = 3.72, 95%

CI: 2.87-4.81, I 2 = 62%; p < .00001) and non-Asian (OR = 1.52, 95%

CI: 1.20-1.92, I 2 = 71%; p = .0005) ( Table 3 and Figure 4 ) studies demonstrated statistically significant differences in cardiovascular disease incidence between severe and non-severe patients.

Data on cancer were reported by forty seven studies and pooled analysis revealed significantly higher incidence of cancer in severe Figure 5 ). Furthermore, Asian studies showed statistically significant difference in cancer incidence between severe and non-severe patients (OR = 2.31, 95% CI: 1.68-3.18, I 2 = 29%; p < .00001), while no statistically significant differences in cancer incidence were noted for non-Asian patients with COVID-19 (OR = 1.26, 95% CI: 0.96-1.64, I 2 = 87%; p =.10) (Table 3 and Figure 5 ) in subgroup analysis.

About the COPD thirty nine studies reported data in severe and nonsevere COVID-19 patients. Pooled summary revealed significantly higher incidence of COPD in severe patients compared to non-severe patients (OR = 2.04, 95% CI: 1.60-2.6, I 2 = 64%; p < .00001) (Table 3 and Figure 6 ). In subgroup analysis Asian studies showed statistically significant difference in COPD incidence between severe and nonsevere patients (OR = 4.04, 95% CI: 3.05-5.34, I 2 = 1%; p <.00001) (Table 3 and Figure 6 ). However, no statistically significant differences in COPD incidence were observed between severe versus non-severe for non-Asian patients (OR = 1.32, 95% CI: 1.02-1.70, I 2 = 66%; p = .03).

In terms of chronic kidney disease, thirty eight studies reported data in severe and non-severe COVID-19 patients. Compared with nonsevere, severe patients revealed significantly higher incidence of chronic kidney disease in pooled analysis (OR = 2.23, 95% CI: 1.77-2.8, I 2 = 86%; p < .00001) (Table 3 and Figure 7) . Additionally, there was statistically significant differences in both Asian (OR = 3.24, 95% CI: 2.01-5.23, I 2 = 61%; p < .00001) and non-Asian (OR = 1.79, 95% CI: 1.39-2.30, I 2 = 90%; p < .00001) ( Table 3 and Figure 7 ) studies in terms of chronic kidney disease severity in subgroup analysis.

Funnel plots for all six comorbidities are included in supplementary information ( Figures S1-S6) . Nearly symmetrical graphical funnel F I G U R E 2 Forest plot for the ORs for comparing hypertension between severe and non-severe cases in SARS-CoV-2 infected Asian versus non-Asian patients F I G U R E 3 Forest plots depict the comparison of diabetes between severe and non-severe cases in SARS-CoV-2 infected Asian versus non-Asian patients F I G U R E 4 Forest plot for the ORs for comparing cardiovascular disease between severe and non-severe cases in SARS-CoV-2 infected Asian versus non-Asian patients F I G U R E 5 Forest plots depict the ORs for comparing cancer between severe and non-severe cases in SARS-CoV-2 infected Asian versus non-Asian patients plots were obtained from all included studies evaluating comorbidities between severe and non-severe cases in SARS-CoV-2 infected Asian versus non-Asian patients. This visual symmetry and funnel shape suggested a low risk of publication bias.

The rapid increase in the number of COVID-19 cases and death toll is having devastating social and economic consequences around F I G U R E 6 Forest plots depict the ORs for comparing COPD between severe and non-severe cases in SARS-CoV-2 infected Asian versus non-Asian patients the world. Early identification and timely treatment of severe cases are vitally important in resource-limited countries to save more lives with limited healthcare facilities. This systematic review and meta-analysis of comparative studies suggested that the severity of patients with COVID-19 was significantly associated with pre-existing comorbidities. To the best of our knowledge, this study is the first meta-analysis to compare the comorbidities between severe versus non-severe COVID-19 patients in Asian and non-Asian populations. We found that the incidence of hypertension, diabetes, cardiovascular disease and chronic kidney disease was significantly higher in severe compared to non-severe patients in both Asian and non-Asian group in terms of subgroup analysis.

Forest plots depict the ORs for comparing chronic kidney disease between severe and non-severe cases in SARS-CoV-2 infected Asian versus non-Asian patients

Our findings are consistent with previous studies that showed a statistically significant association of pre-existing comorbidities with severe COVID-19 cases (Del Sole et al., 2020; Yang, Zheng, et al., 2020; Zhang, Lee, et al., 2020; Zhou, Yang, et al., 2020) .

Additionally, among Asian studies, there was a statistically significant difference between cancer and COPD incidence between severe and non-severe COVID-19 patients. However, the incidence of cancer and COPD in severe and non-severe non-Asian patients demonstrated no statistically significant difference.

Meta-analysis by Yin et al. (2021) assessed the role of comorbidity in COVID-19 progression in Chinese patients and indicated that chronic kidney disease, cardiovascular disease, cancer, diabetes and hypertension were the strongest risk factor in disease exacerbation. Besides, Yang, Zheng, et al. (2020) showed that the pooled odds ratio of hypertension, respiratory system disease and cardiovascular disease were 2.36, 2.46 and 3.42, respectively, between severe and non-severe patients. Another meta-analysis by Giri et al. (2020) concluded that incidence of hypertension, cardiovascular disease, diabetes and cancer in the severe group was statistically significant higher than non-severe group. However, in their meta-analysis, all included studies were from China.

Although we could not find any meta-analysis that compared comorbidities between severe and non-severe COVID-19 patients for the non-Asian studies only; however, the result of individual studies published in non-Asian countries showed that hypertension, cardiovascular disease, diabetes and cancer incidences were higher in severe or ICU groups (Argenziano et al., 2020; Buckner et al., 2020; Cattelan et al., 2020; Ferguson et al., 2020; Filardo et al., 2020; Pellaud et al., 2020; Schönfeld et al., 2021) . Our findings are in line with current knowledge that patients with comorbidities are more susceptible to severe infection.

Pre-existing cardiovascular disease and cardiovascular risk factors such as hypertension and diabetes enhance vulnerability to COVID-19 as the SARS-CoV-2 enters lung cells via the ACE2 receptor . Furthermore, COVID-19 may induce direct myocardial injury by upregulation of angiotensin-converting enzyme . Additionally, renin-aldosterone-angiotensin system (RAAS) plays a vital role in the pathogenesis of COVID-19 and (Wang, Luo et al., 2021) .

Another study that examined the clinical courses of critically ill COVID-19 patients with and without pre-existing chronic kidney disease suggested that underlying kidney disease confers higher risk for individuals with COVID-19 with poorer COVID-19 outcomes (Flythe et al., 2021) . Therefore, clinicians should closely monitor CKD patients with suspected COVID-19 to prevent disease progression. People with specific comorbid and underlying conditions are at high risk for COVID-19 severity and mortality. Hence, these population groups should be prioritized for access to COVID-19 vaccination regardless of their geographical location.

There are several limitations to this systematic review and metaanalysis. First, most of the studies included in the meta-analysis were retrospective and conducted in different countries, settings and variation in reporting of medical conditions may be present.

Second, high heterogeneity among included studies might be due to the large variation among studies in the sample size. Third, there was heterogeneity in the definition of moderate and severe cases of COVID-19 patients, which might have contributed to the high heterogeneity of the meta-analysis. Fourth, as our topic was related to current pandemic and we already initiated literature searches hence we failed to register in the PROSPERO. However, during systematic processes involved in our literature review we strictly followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines. Despite these limitations, to the best of our knowledge, our study is the first systematic review and meta-analysis that examined comorbidities among severe and non-severe COVID-19 patients by including a large number of high-quality studies from Asian and non-Asian countries with large sample sizes.

In conclusion, this systemic review and meta-analysis showed that the incidence of hypertension, diabetes, cardiovascular disease and chronic kidney disease was significantly higher in severe compared to non-severe patients in both Asian and non-Asian 

Not applicable.

The authors have no conflicts of interest to declare. 

Ethical review and approval is not required as this is systemic review and meta-analysis.

The data used to support the findings of this study are available from the studies included in this meta-analysis.

https://orcid.org/0000-0001-8588-5482

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