key: cord-0995199-kmg8eiah
authors: Rathore, Sawai Singh; Hussain, Nabeel; Manju, Ade Harrison; Wen, Qingqing; Tousif, Sohaib; Avendaño‐Capriles, Camilo Andrés; Hernandez‐Woodbine, Maria Jose; Rojas, Gianpier Alonzo; Vatsavayi, Priyanka; Tera, Chenna Reddy; Ali, Muhammad Adnan; Singh, Romil; Saleemi, Shayan; Patel, Deep Manojkumar
title: Prevalence and clinical outcomes of pleural effusion in COVID‐19 patients: A systematic review and meta‐analysis
date: 2021-09-01
journal: J Med Virol
DOI: 10.1002/jmv.27301
sha: baaf85dd15828df6fce044268570d4df0172cb62
doc_id: 995199
cord_uid: kmg8eiah

Observational studies indicate that pleural effusion has an association with risk and the clinical prognosis of COVID‐19 disease; however, the available literature on this area is inconsistent. The objective of this systematic review and meta‐analysis is to evaluate the correlation between COVID‐19 disease and pleural effusion. A rigorous literature search was conducted using multiple databases. All eligible observational studies were included from around the globe. The pooled prevalence and associated 95% confidence interval (CI) were calculated using the random effect model. Mantel–Haenszel odds ratios were produced to report overall effect size using random effect models for severity and mortality outcomes. Funnel plots, Egger regression tests, and Begg–Mazumdar's rank correlation test were used to appraise publication bias. Data from 23 studies including 6234 COVID‐19 patients was obtained. The overall prevalence of pleural effusion in COVID‐19 patients was 9.55% (95% CI, I (2 )= 92%). Our findings also indicated that the presence of pleural effusions associated with increased risk of severity of disease(OR = 5.08, 95% CI 3.14–8.22, I (2 )= 77.4%) and mortality due to illness(OR = 4.53, 95% CI 2.16–9.49, I (2 )= 66%) compared with patients without pleural effusion. Sensitivity analyses illustrated a similar effect size while decreasing the heterogeneity. No significant publication bias was evident in the meta‐analysis. The presence of pleural effusion can assist as a prognostic factor to evaluate the risk of worse outcomes in COVID‐19 patients hence, it is recommended that hospitalized COVID‐19 patients with pleural effusion should be managed on an early basis.

In December 2019, a new infectious pathogen known as severe acute respiratory syndrome (SARS-CoV-2) came into sight in China. It was linked with an unexplained cause of pneumonia. The disease was later coined coronavirus disease 2019 . 1 Till now, more than 150 million people have been infected by this virus leading to more than 3.15 million deaths. 2 The clinical presentation of COVID-19 varies significantly, fluctuating from minimum symptoms to critical respiratory failure, septic shock, subsequently to multiorgan failure. 3, 4 The spectrum of clinical symptoms of COVID-19 illness comprises fever, dry cough, fatigue, sore throat, and dyspnea, and headache, vomiting, diarrhea, anosmia, and loss of taste. 5, 6 Chest imaging is critical for diagnosing and evaluating the seriousness and extent of the spread of COVID-19 pneumonia. 7 A large number of COVID-19 patients have distinct chest imaging characteristics, such as ground-glass opacities alone or in combination with consolidation, vascular enlargement, and traction bronchiectasis. 8 Pleural effusion associated with COVID-19 is less common in clinical settings. Yu et al. 9 reported the prevalence of pleural effusion in 12.9% of the total 1663 hospitalized patients. Similarly, another study reported pleural effusion in just 2.6% of hospitalized patients. 10 The precise prevalence of pleural effusion in COVID-19 patients remained unknown.

To date, however, there are still significant literature gaps existing between COVID-19 and pleural effusion. The aim of this systematic review and meta-analysis is to evaluate the correlation between COVID-19 disease and pleural effusion and draw more generalized inferences about the effect of pleural effusion on severity and mortality in COVID-19 patients compared with patients without pleural effusion.

The current systematic review and meta-analysis is conveyed and inscribed in conjunction with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. 11 

All eligible observational studies and case series were included for this meta-analysis. To be qualified for this meta-analysis, the article must satisfy the subsequent inclusion criteria: (a) Observational study or case series; (b) article describing pleural effusion and associated outcomes in COVID-19 patients; (c) studies with a sample size of ≥10 patients. These studies were incorporated irrespective of age, gender, ethnicity of the included patients.

The exclusion criteria were pre-determined as follows: (a) if no data regarding pleural effusion is given; (b) duplicate publications;

(c) letters to the editor, case reports, commentaries, reviews, and posters. Following the implementation of these provisions, a thorough interpretation of the residual studies and data extraction were performed in an excel table. 

The data extraction for each study was autonomously progressed by five authors and was cross verified to depreciate errors. From each study, several details were retrieved including the First author name, the origin country of study, study design, total sample size, number of patients with pleural effusion, severe patients, the definition of severity, mortality, median age, gender (female sex proportion), respiratory disease proportion, diabetes proportion, and hypertension proportion as comorbidity. medcalc.org; 2021) were used for all statistical analyses. The pooled prevalence and associated 95% confidence interval (CI) were calculated using the random effect model. Results for outcome analysis were presented as odds ratios (0Rs) with 95% confidence intervals (CIs) and pooled using the Mantel-Haenszel random-effects model. The I 2 statistics were used to assess the heterogeneity of effect size estimates across these studies with I 2 (low heterogeneity: I 2 ≤ 25%; moderate: 25%-50%; high >75%). Probability values less than 0.05 were considered statistically significant in all cases. A leave-one-out sensitivity analysis was also carried out to assess the effects of individual studies on the statistical results.

Publication bias was explored using funnel plots and Egger's regression test, and Begg-Mazumdar's rank correlation test.

Quality of evidence for the primary and secondary outcomes was rated as high, moderate, low, and very low using GRADE (Grading of Recommendations Assessment, Development, and Evaluation) working group approach. 13 Table 1 . Of these included studies, many reports were from China (n = 15), followed by Iran with three studies and two studies from Italy. There was one study each from Brazil, the USA, and Egypt. The median age of included patients was 53. 5 This result was pooled from 23 studies that included 6234 patients ( Figure 2 ).

Meta-analysis findings revealed that the existence of pleural effusion in COVID-19 patients was associated with an increased risk of severity of disease compared to patients without pleural effusion.(OR = 5.08, 95% CI 3.14-8.22, p < 0.0001). Heterogeneity was high with I 2 = 77.4%. This result was pooled from 22 studies including F I G U R E 2 Forest plot for pleural effusion prevalence analysis F I G U R E 3 Forest plot for severity outcome analysis imprecision, the certainty of the evidence was assessed as low by the GRADE system (Table S1 ).

Meta-analysis findings revealed that the existence of pleural effusion in COVID-19 patients was associated with increased odds of death from the disease compared to patients without pleural effusion.

(OR = 4.53, 95% CI 2.16-9.49, p < 0.0001). Heterogeneity was moderate with I 2 = 66%. This result was pooled from seven studies including 2777 COVID-19 patients (Figure 4 ). Due to the possibility of bias and imprecision, the certainty of the evidence was assessed as low by the GRADE system (Table S1 ). 

The risk of bias assessment and quality appraisal of included studies was done with help of the NOS. 12 Out of 23 studies, 11 studies were of high quality, and 12 were of moderate quality with an average score of 7.34 (Table 1) . Collectively, the evidence employed in these analyses was ascertained as being of high quality.

Visual inspection of the standard funnel plots for the prevalence of Pleural effusion and both mortality and severity analysis were identified to be having substantial symmetry ( Figure 5 ). Furthermore, evaluation of publication bias was also accompanied with the help of Egger's regression test and Begg-Mazumdar's rank correlation test. For both these tests, p < 0.05 was considered significant and analysis was deemed to be having publication bias. There was no apparent publication bias detected con- There are several strengths of this article. This is the first systematic review and meta-analysis in our knowledge that illustrate the association between pleural effusion and odds of severe illness and mortality due to COVID-19. This systematic analysis of 23 indexed studies included from more than a year of publications from the start of the pandemic was performed to more reliably and accurately associate pleural effusion and COVID-19 illness-related outcomes. Another strength is that it incorporated the GRADE approach to rate the certainty of evidence.

Nevertheless, there are some limitations of this meta-analysis that should be considered. Firstly, all the articles incorporated in the metaanalysis were retrospective studies in nature, and thus bias in data aggregation is an inherent concern. Secondly, We included few studies from preprint databases that did not go through peer review at that time. This was deemed a limitation, as peer reviewers could identify further inconsistencies in reporting methods and other details.

Synopsizing the available evidence in the literature, the overall pooled prevalence of pleural effusion in COVID-19 patients was found to be 9.55%. Our findings, also indicate that the presence of pleural effusion in COVID-19 patients is associated with increased severity of disease and mortality due to illness compared with patients without pleural effusion.

The presence of pleural effusion can assist as a prognostic factor to evaluate the risk of worse outcomes in COVID-19 patients hence, it is recommended that hospitalized COVID-19 patients with Pleural effusion should be managed on an early basis.

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Prevalence and clinical outcomes of pleural effusion in COVID-19 patients: A systematic review and meta-analysis