Analyzing pleural fluid attributes in SARS-CoV-2 infection: a systematic review

Introduction

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease 2019 (COVID-19) (1). Since the first cases were described in December 2019 (2), the dramatic increase in patients has posed numerous challenges to even the most sophisticated and advanced health systems, which led the World Health Organization to declare the outbreak a global pandemic in March 2020 (3).

Clinical manifestations of the disease range from asymptomatic infection to pneumonia, which may progress to acute respiratory distress syndrome, multi-organ failure and finally death (2,4-6). Although early studies did not demonstrate the existence of pleural effusion (PE) (7), two subsequent reviews showed that 7–10% of hospitalized patients may present with PE (8,9), with the frequency increasing as the severity of cases increases (10). Furthermore, PE has been associated with longer hospital stays and mortality (11,12).

Despite these data, there are no sufficiently large series in the literature describing the characteristics of pleural fluid (PF) in this disease and only a few reviews (8,13) collect data on individual cases. The aim of our study is to document the characteristics of PF, establish whether it is a prognostic biomarker and evaluate which treatment is most effective in the management of PEs through a systematic review. We present this article in accordance with the PRISMA reporting checklist for literature search and synthesis of evidence (available at https://jtd.amegroups.com/article/view/10.21037/jtd2025-804/rc) (14).

Methods

All described papers of SARS-CoV-2 and PE infection of any age published in any format, except editorials, reviews or letters to the editor that did not document new cases, were considered valid for inclusion.

Data sources and search strategy

The search strategy included several free database sources available by year of publication, although the full text of the study had to be in English, Spanish, French, Italian or Portuguese.

The literature search was conducted between January 1, 2020 and March 31, 2024 and included the following electronic (online) databases: Medline (through PubMed interface), Embase, Scopus, Cochrane and Web of Science. The search terms were (‘Pleural effusion’ (MeSH) AND ‘sARS-CoV-2’ (Mesh)) OR (‘Pleural effusion’ (Mesh) AND ‘COVID-19’ (Mesh)), accompanied by a hand search of the reference lists of the selected articles. We included all studies that met the above criteria and then independently reviewed and assessed each article, identifying those potentially eligible. Studies were reviewed in three stages according to title, abstract and full text and consensus was sought at each stage of the review. The cases of individuals under 18 years old, reviews, and the letters to the editor that did not provide any clinical cases were excluded.

Data collection process

Data from the selected studies were extracted electronically (Microsoft Excel 2016, Microsoft Corp, USA). The extracted information included the following data: authors, year and number of cases in the series; age and sex; laterality and size of the PE; appearance and characteristics of the PF: transudate/exudate, differential nucleated cell count, total protein, lactate dehydrogenase (LDH) and any biochemical determination analyzed in the PF; culture, cytology and pleural biopsy results (if any); treatment of the PE and response obtained in each case; and complications. Classification into transudates and exudates was based on Light’s criteria (15).

Methodological quality of individual studies

As the papers reviewed were mostly case descriptions, their quality was not assessed in relation to study type, internal validity, generalizability, precision and heterogeneity.

Outcomes of interest

The outcomes of interest were the demographic characteristics of the patients, the biochemical and microbiological behavior of the PE, the treatment received and its response, and the final outcome (survival or death).

Statistical analysis

Due to the wide heterogeneity and descriptive nature of the studies, a simple description (proportion, median and range) was calculated for each outcome of interest.

Results

A total of 18 studies were reviewed that included 32 patients with 37 PF samples analyzed. Figure 1 presents a flowchart showing a complete breakdown of how appropriate studies were identified (16-33), corresponding to isolated case reports (between 1 and 4 cases per article) and a series of 11 patients.

Figure 1 PRISMA flowchart of evidence synthesis.

Demographic and clinical characteristics

Clinical and demographic characteristics of the 32 patients included in the study are shown in Table 1, and age-group distribution is shown in Figure 2. Median age was 61 years (range, 25–81 years; 62.5% of cases between 51–80 years). PE occurred more commonly in men than in women (27/32: 84.4%; ratio 5.4/1). Among the patients’ medical histories, we highlight those who had diseases that could justify the presence of PE: two cases of kidney transplantation (28,32); four cases of cancer [sarcomatoid carcinoma (25), and gastric, thyroid, and hepatocellular carcinoma (27)]; one case of systemic lupus erythematosus; and another of cirrhosis (27).

Figure 2 Age distribution of patients with COVID-19 and pleural effusion. COVID-19, coronavirus disease 2019.

Characteristics of PE

The laterality of the PE was determined in 21 cases: was unilateral in 15 patients (71.4%), right-sided in 8 (53.3%) and left-sided in 7 (46.7%). In 6 patients, PE was bilateral (28.6%). In the series by Cantley et al., laterality is not specified (27). The size of the PE was documented in 10 cases (31.3%). In 5 cases (50%), it occupied over two thirds of the hemithorax (16,23,26,29,31); in 3 cases (30%) the PE occupied between one and two thirds of the hemithorax (16,20,30); and in 2 cases (20%) less than a third (18,28). The color of the PF was documented in 32 samples (86.5%). It was serous with different shades in 16 (50%) (16,18,21,28,29), hematic or serohematic in 9 (28.1%) (19-21,23,27,33) and purulent in 7 (21.9%) (17,22,24,26).

Biochemical characteristics and cellular differentiation of PF (medians and ranges) were described in only a few cases (Table 2). Data to establish whether the PE was a transudate or an exudate, according to Light’s criteria, were available in 18 patients (48.6%): in 16 (88.9%) it was an exudate (18,20-23,25,26,30-33) and in 2 (11.1%) (28,29), a transudate. However, 36.7% of the PF protein values (11/30) and 54.5% of its ratio to serum (PF/S protein) (6/11) were less than 3 g/dL and 0.5, respectively. Twenty-eight-point-six percent of pH values (6/21) were ≤7.20 (23,27) and 24.0% of glucose values (6/25) ≤60 mg/dL (22,27,32,33). In 46.2% of patients (12/26) the neutrophil count was ≥50% (16,21,22,27,30,31,33), compared to 26.9% (7/26) where it was lymphocytes/monocytes (18,19,21,23,25,27,29). In no case was there a predominance of eosinophils. The median red blood cell count was 88,000/mm³ (range, 2,000–1,010,000 cells/mm³) and 5 cases (45.5%) exceeded 100,000 cells/mm³ (18,20,23,32,33). Polymerase chain reaction (PCR) was positive for SARS-CoV-2 in PF of 6 patients (17-19,25,28) out of 23 (16,20,22,27,29) in whom it was determined (26.1%). In 8 other cases, bacterial [Pseudomonas aeruginosa in 3 patients (22,27,32); Staphylococcus aureus (27) and Enterococcus faecium (33)] or fungal [Candida albicans (17) and Aspergillus niger (24)] growth was observed.

The treatment received by all patients is summarized in Table 3. Almost all patients underwent PF drainage by different methods (therapeutic thoracentesis, thoracic drainage or thoracoscopy). The medical treatment received by the 6 patients with positive PCR for SARS-CoV-2 in the PF varied widely (antibiotics, antifungals, antivirals, hydroxychloroquine, corticosteroids) (Table 3). The outcome of the patients was provided in 25 cases and 10 died (27,30,32) (40%) (Table 3), without the authors providing the time elapsed from admission to death.

Studies that do not include individual data

Denu et al. (34) and Advani et al. (35) conducted two studies analysing the characteristics of PE in patients with COVID-19, but they did not provide individual patient data, and thus could not be included in this systematic review. In the first study (34), 128 PE samples from 106 patients were analysed. Of these, 45.4% had a pleural fluid/serum (PF/S) protein ratio greater than 0.5, 33.9% had a PF/S LDH ratio greater than 0.6, and 56.2% had PF LDH levels above two-thirds of the upper limit of normal serum values. Overall, 68.5% of the effusions met the criteria for exudate. The differential nucleated cell count was predominantly lymphocytic (mean 42.8%) or neutrophilic (median 28.7%). In the second study (35), 31 PE samples were analysed: 13 met the criteria for transudate and 18 for exudate. Lymphocytes were the predominant cell type in both types of effusion, with higher mean levels of LDH and adenosine deaminase in exudates, and no significant differences in total leukocyte count between the two.

Discussion

Despite the large number of people infected by SARS-CoV-2 and the mortality caused by this virus, knowledge about the characteristics of PE in these cases is very limited. In this systematic review, only 32 patients with data from 37 PF samples could be selected. In summary, we can say that in a patient with COVID-19 the PE may be due to other causes and not only to SARS-CoV-2 infection; the PE does not have a well-defined appearance; it is generally an exudate; it is usually predominantly neutrophilic; and, finally, 40% of those who present with it die.

It is currently estimated that the incidence of PE in severe COVID-19 infections varies between 7–10% (8,9), and this percentage may even increase as severity increases (10). Our results are consistent with published data in that it generally affects more men (84.4%) (9) over 50 years of age (62.5% of cases older than this age) (36).

Articles studying the characteristics of PF are scarce, as few thoracenteses have been performed in these cases. This may be because it was considered that there was a high risk of contagion, or because small PEs, detected only by computed tomography (CT), were not considered of sufficient clinical relevance to undergo thoracentesis (9). Whatever the cause, little is known about the characteristics of PF in these patients. However, the availability of these data could help us to better understand the pathophysiological mechanisms involved in the development of PE. In two series not included in our article because they did not provide individual results, the percentage of exudates was 68.5% (34) and 58.1% (35), while in ours it was 88.9%. This could be explained by the fact that not all studies provide the full results of Light’s parameters and, as we know, in order to say that a PE is a transudate, the PF must meet 3 criteria, which are not always provided, so that, in this situation, these cases would remain unclassified. On the other hand, if a single parameter is provided and it meets the exudate criterion, we can say that it is an exudate, even if we do not know the other two. Exudates are mostly LDH-discordant, according to the definition of Agrawal et al. (37), fulfilling the criteria of the PF LDH or the PF/S LDH ratio, but not that of PF/S protein. This could be justified by the current theory that the pathophysiology of PE in these cases is due to a marked severe inflammatory response in the lung and pleura as a consequence of the cytokine ’storm’ that occurs in these patients (9,38), which would cause an increased permeability of the pleural capillaries and produce an LDH-discordant exudate. In our review, we have not taken into account the classification as transudate of the PEs in the series by Cantley et al. (27), as this classification was based solely on PF total protein values (<3 g/dL in all cases).

In a review of the different viruses affecting the pleura, Nestor et al. also observed this inflammatory reaction in PEs due to viral infection, with elevated LDH, as well as variable staining and predominance of nucleated cells (neutrophils vs. lymphocytes/monocytes) (39), similar to what we have observed. It is possible that other aspects may also have influenced the variability of these results. It is known that the time elapsed between the development of PE and the time of thoracentesis definitely influences the predominant cellularity in the PF (40) and in this systematic review this is an aspect that we are unaware of. Furthermore, PE in a patient with COVID-19 does not always have to be due to SARS-CoV-2 infection. In our article, PCR for this virus was positive in only 26.1% of the PF samples (6/23). Some authors justified not puncturing the PE because the patient had a SARS-CoV-2 infection and the clinical presentation was compatible, the epidemiological situation was clear, other causes of PE were excluded, the CT findings were characteristic of COVID-19, or improvement was obtained after draining the PF without subsequent recurrence. However, it is possible that the cases included in this systematic review are not entirely due to SARS-CoV-2 infection, but could be explained by other diseases. Thus, the use of corticosteroids and anti-interleukin-6 drugs is known to increase susceptibility to superimposed infections (41), including those due to bacteria and fungi, as documented in some cases in our review (17,22,24,27,30,32,33). However, it is also possible that both infections coexisted, as PCR for SARS-CoV-2 in PF was not done in some cases. Finally, it is possible that patients with this infection may have an PE as a consequence of different accompanying clinical situations such as cardiac (29) or renal dysfunction, or pulmonary embolism, and not due to direct virus-induced damage. This possible different origin of the PE in patients with COVID-19 could be the cause of the biochemical, cellularity or appearance differences observed in these effusions (8).

The study has some limitations. The number of patients included was very small and most of them are individual clinical cases, which may decrease validity, generalizability and accuracy. Only one article included 11 patients with 13 PF samples analyzed. Possibly this series includes patients whose PEs are not due to SARS-CoV-2 infection per se, but to other diseases that may occur as a consequence of this viral infection. Each article highlights different aspects of each case described (clinical, diagnostic or therapeutic). This heterogeneity of information makes it difficult to correctly classify some effusions or to evaluate the response to a particular treatment. All cases correspond to hospitalized patients with severe infection, so we do not know what happens in patients with non-severe infection who do not require hospitalization. Being a rare disease, it may also have a publication bias as successfully treated or atypical cases are more likely to be published.

Conclusions

This systematic review provides limited information to draw firm conclusions about the characteristics of PF in patients with SARS-CoV-2 infection. However, PE is more common among males aged 50–80 years and is usually unilateral and large in size. Its appearance is highly variable, with features of LDH-discordant exudate, usually predominantly neutrophilic, with treatment similar to that of any other PE and significant mortality. This limited knowledge of their characteristics makes it necessary to carry out extensive prospective studies to provide us with information about the pathophysiological mechanisms by which they occur and thus, in the future, to be able to reduce complications and improve their prognosis.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-804/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-804/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-804/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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