Clinical characteristics of chylothorax: results from the International Collaborative Effusion database.

Background: Chylothorax is an uncommon medical condition for which limited data are available regarding the contemporary aetiology, management and outcomes. The goal of this study was to better define these poorly characterised features. Methods: The medical records of adult patients diagnosed with chylothorax at 12 centres across Europe, America and South Africa from 2009-2021 were retrospectively reviewed. Descriptive and inferential statistics were performed. Results: 77 patients (median age 69 years, male to female ratio 1.5) were included. Subacute dyspnoea was the most typical presenting symptom (66%). The commonest cause of chylothorax was malignancy (68.8%), with lymphoma accounting for 62% of these cases. Other aetiologies were trauma (13%), inflammatory/miscellaneous conditions (11.7%) and idiopathic cases (6.5%). At the initial thoracentesis, the pleural fluid appeared milky in 73%, was exudative in 89% and exhibited triglyceride concentrations >100 mg·dL-1 in 88%. Lymphangiography/lymphoscintigraphy were rarely ordered (3%), and demonstration of chylomicrons in pleural fluid was never ascertained. 67% of patients required interventional pleural procedures. Dietary measures were infrequently followed (36%). No patient underwent thoracic duct ligation or embolisation. Morbidity included infections (18%), and thrombosis in malignant aetiologies (16%). The 1-year mortality was 47%. Pleural fluid protein >3.5 mg·dL-1 (sub-distribution hazard ratio (SHR) 4.346) or lactate dehydrogenase <500 U·L-1 (SHR 10.21) increased the likelihood of effusion resolution. Pleural fluid protein ≤3.5 mg·dL-1 (HR 4.047), bilateral effusions (HR 2.749) and a history of respiratory disease (HR 2.428) negatively influenced survival. Conclusion: Chylothoraces have a poor prognosis and most require pleural interventions. Despite the standard recommendations, lymphatic imaging is seldom used, nor are dietary restrictions followed.

Pleural effusion secondary to endometriosis: A systematic review.

BACKGROUND: Endometriosis-associated pleural effusion is a rare occurrence with poorly defined clinical characteristics. METHODS: A systematic review was performed to examine all articles on endometriosis-associated pleural effusion extracted from 4 databases (PubMed, Embase, Web of Science and Scopus) from inception until November 2022. RESULTS: A total of 142 articles (isolated cases and small retrospective series) involving 176 patients (median age 33 years) with endometriosis-associated pleural effusion were included. The most frequent symptoms were dyspnea (67%), chest pain (55%) and abdominal pain (40%). Pleural effusion was predominantly unilateral (89%), right-sided (88.5%) and massive (56%). Ascites was evident in 42% of the cases. Pleural fluid had a bloody appearance in 99% of cases and always met the exudate criteria. Pleural fluid cytology identified only 9% of the patients, with pleural biopsy being the most common diagnostic procedure (74%). Most patients were treated with hormones (76%), thoracic surgery (60%) and abdominal surgery (27%). Effusion recurrence was observed in 26% of cases after a median follow-up of 1 year. CONCLUSIONS: The presence of right-sided hemorrhagic pleural effusion in a young woman warrants an assessment for the possibility of endometriosis. Despite conventional treatment, effusion recurs in approximately a quarter of patients.

Investigation and outcomes in patients with nonspecific pleuritis: results from the International Collaborative Effusion database.

Introduction: We present findings from the International Collaborative Effusion database, a European Respiratory Society clinical research collaboration. Nonspecific pleuritis (NSP) is a broad term that describes chronic pleural inflammation. Various aetiologies lead to NSP, which poses a diagnostic challenge for clinicians. A significant proportion of patients with this finding eventually develop a malignant diagnosis. Methods: 12 sites across nine countries contributed anonymised data on 187 patients. 175 records were suitable for analysis. Results: The commonest aetiology for NSP was recorded as idiopathic (80 out of 175, 44%). This was followed by pleural infection (15%), benign asbestos disease (12%), malignancy (6%) and cardiac failure (6%). The malignant diagnoses were predominantly mesothelioma (six out of 175, 3.4%) and lung adenocarcinoma (four out of 175, 2.3%). The median time to malignant diagnosis was 12.2 months (range 0.8-32 months). There was a signal towards greater asbestos exposure in the malignant NSP group compared to the benign group (0.63 versus 0.27, p=0.07). Neither recurrence of effusion requiring further therapeutic intervention nor initial biopsy approach were associated with a false-negative biopsy. A computed tomography finding of a mass lesion was the only imaging feature to demonstrate a significant association (0.18 versus 0.01, p=0.02), although sonographic pleural thickening also suggested an association (0.27 versus 0.09, p=0.09). Discussion: This is the first multicentre study of NSP and its associated outcomes. While some of our findings are reflected by the established body of literature, other findings have highlighted important areas for future research, not previously studied in NSP.

Some pleural effusions labeled as idiopathic could be produced by the inhalation of silica.

Objectives: Exposure to silica nanoparticles has been associated with pleural effusions (PEs) in animal models and case series. We hypothesized that some PEs labelled as "idiopathic" could, in fact, be secondary to inhalation of silica. Methods: A retrospective case control study was designed utilizing a prospectively maintained pleural database. Cases, represented by idiopathic PEs, were matched by age and gender to control patients who had been diagnosed with malignant, cardiac, or infectious PEs. A survey consisting of questions about occupational life and possibility of silica inhalation was conducted. In a subgroup of patients, pleural fluid concentrations of silica were quantified by plasma atomic emission spectrometry analysis. Also, the pleural biopsy of a silica-exposed case was subjected to an energy dispersive X-ray spectroscopy (EDX) to identify the mineral, the size of which was determined by electron microscopy. Results: A total of 118 patients (59 cases and 59 controls) completed the survey. There were 25 (42%, 95% CI 31-55%) and 13 (22%, 95% CI 13-34%) silica-exposed workers in case and control groups, respectively. The exposure attributable fraction was 0.62 (95% CI 0.14-0.83). Four of eight exposed cases showed detectable levels of silica in the pleural fluid (mean 2.37 mg/L), as compared to none of 16 tested controls. Silica nanoparticles of 6-7 nm were identified in the pleural biopsy of an exposed case patient. Conclusions: It is plausible that some idiopathic PEs could actually be caused by occupational silica inhalation.

Prevalence, clinical characteristics, and outcome of pleural effusions in ovarian cancer.

OBJECTIVES: The prevalence, clinical characteristics and prognosis of pleural effusions (PEs) associated with ovarian cancer (OC) have seldom been addressed systematically, as in the current investigation. METHODS: All records of consecutive women with a newly diagnosed OC in our institution over a 13-year period were retrospectively reviewed. Features of PEs on CT scans, pleural fluid analyses, need for definitive therapy of PEs, and the influence of PEs on the overall survival (OS) and progression-free survival (PFS) were evaluated. RESULTS: PEs were observed in 81 (43%) of 189 women with OC, either at presentation of cancer (55 patients) or during the course of the disease (26 patients). The causes of PEs were malignancy (55.5%), unknown (37%), or surgery-related (7.4%). The sensitivity of the cytologic diagnosis of malignant PEs was 79.1%. Sixty percent of malignant PEs required pleurodesis or indwelling pleural catheters for symptomatic relief. The presence of ascites strongly predicted PE development (odds ratio 43.2). Women with PEs fared much worse compared with those without PEs, in terms of OS (26.7 vs. 90.4 months), PFS (9.8 vs. 55.3 months) and tumor recurrences (86.4 vs. 43%). In multivariate analyses, PE remained as a relevant independent variable associated with poor outcome (hazard ratio 9.73 for OS, and 3.87 for PFS). Notably, PEs small enough to preclude tapping, and thus of unknown origin, had a similar bad prognosis as malignant PEs. CONCLUSIONS: OC patients with PEs experience decreased survival, including those with trace effusions not amenable to tapping.

Two vs. three weeks of treatment with amoxicillin-clavulanate for stabilized community-acquired complicated parapneumonic effusions. A preliminary non-inferiority, double-blind, randomized, controlled trial.

BACKGROUND: The optimal duration of antibiotic treatment for complicated parapneumonic effusions (CPPEs) has not been properly defined. Our aim was to compare the efficacy of amoxicillin-clavulanate for 2 vs. 3 weeks in patients with CPPE (i.e. those which required chest tube drainage). METHODS: In this non-inferiority, randomized, double-blind, controlled trial, patients with community-acquired CPPE were recruited from two centers in Spain and, after having obtained clinical stability following 2 weeks of amoxicillin-clavulanate, they were randomly assigned to placebo or antibiotic for an additional week. The primary objective was clinical success, tested for a non-inferiority margin of<10%. Secondary outcomes were the proportion of residual pleural thickening of>10 mm at 3 months, and adverse events. The study was registered with EudraCT, number 2014-003137-25. We originally planned to randomly assign 284 patients. RESULTS: After recruiting 55 patients, the study was terminated early owing to slow enrolment. A total of 25 patients were assigned to 2 weeks and 30 patients to 3 weeks of amoxicillin-clavulanate. Clinical success occurred in the 25 (100%) patients treated for 2 weeks and 29 (97%) treated for 3 weeks (difference 3%, 95% CI -3 to 9.7%). Respective between-group differences in the rate of residual pleural thickening (-12%, 95%CI -39 to 14%) and adverse events (-7%, 95%CI -16 to 2%) did not reach statistical significance. CONCLUSIONS: In this small series of selected adult patients with community-acquired CPPE, amoxicillin-clavulanate treatment could be safely discontinued by day 14 if clinical stability was obtained.

Predictors of Indwelling Pleural Catheter Removal and Infection: A Single-center Experience With 336 Procedures.

BACKGROUND: Indwelling pleural catheters (IPCs) offer ambulatory management of symptomatic persistent pleural effusions, but their widespread use is somewhat hampered by the risk of pleural infection and the inconvenience of carrying a catheter for a prolonged period of time. Factors associated with these 2 limitations were analyzed in this study. METHODS: Retrospective review of consecutive patients who had undergone IPC placement over a 5 ½-year period. Time to IPC removal was analyzed with the Fine and Gray competing risks survival model, with competing risk being death. A binary logistic regression method was used to evaluate factors influencing IPC-related pleural infections. RESULTS: A total of 336 IPCs were placed in 308 patients, mostly because of malignant effusions (83%). IPC removal secondary to pleurodesis was achieved in 170 (51%) procedures at a median time of 52 days. Higher rates of IPC removal were associated with an Eastern Cooperative Oncology Group (ECOG) grade of 0 to 2 [subhazard ratio (SHR)=2.22], an expandable lung (SHR=1.93), and development of a multiseptated pleural space (SHR=1.37). IPC-related pleural infections occurred in 8% of the cases, and were more often seen in hepatic hydrothoraces [odds ratio (OR)=4.75] and pleural fluids with a C-reactive protein <15 mg/L before the IPC insertion (OR=4.42). CONCLUSION: IPC removal is more likely to occur in patients with good performance status whose lungs fully expand after drainage. Hepatic hydrothorax is the most significant predictor of IPC-related infections.

Relationship of pleural fluid pH and glucose: a multi-centre study of 2,971 cases.

BACKGROUND: Pleural fluid pH and glucose levels are both recommended in the workup of pleural effusions. Whether their levels correlate and predict each other or contribute independent knowledge is unclear. We aimed to investigate the pH/glucose relationship, assess their concordance and ascertain whether performing both tests provides additional information to performing either test alone. METHODS: The pH and glucose measurements from 2,971 pleural fluid samples, from three centers in Spain, UK and Australia, were categorized into Cancer (n=1,045), Infection (n=544), Tuberculosis (n=249) and Others (n=1,133) groups. The relationship between pH and glucose values and their concordance at clinically relevant cutoffs (pH 7.2 and glucose 3.3 mmol/L) were assessed. RESULTS: The mean pH of the cohort was 7.38 (SD 0.22) and median glucose 5.99 (range, 0.00-29.36) mmol/L. A regression model of the relationship between glucose (log-transformed) and pH with a restricted cubic spline showed linear (P<0.01) and nonlinear effects (P<0.01). The relationship was strong with a narrow confidence interval but the prediction interval was wide. Most (91.9%) samples were concordant using pH and glucose levels at cutoffs of 7.20 and 3.30 mmol/L respectively. Using pH alone, without glucose, captured 95.0% of the infection-related effusions with either pH or glucose below cutoff and glucose alone identified 91.7%. CONCLUSIONS: Pleural fluid pH and glucose have a strong non-linear relationship but, in most situations, the level of one cannot accurately predict the other. Concordance rates were high and either test is sufficient in the majority of cases.

Epithelial cell adhesion molecule (EpCAM) from pleural fluid cell lysates is a highly accurate diagnostic biomarker of adenocarcinomatous effusions.

BACKGROUND AND OBJECTIVE: The discovery of highly accurate pleural fluid (PF) biomarkers of malignancy remains elusive. We assessed the operating characteristics of the PF epithelial cell adhesion molecule (EpCAM), claudin 4 (CL4) and human epididymis protein 4 (HE4) as potential markers of epithelial malignancies. METHODS: The three markers were quantified by immunoassays in the supernatants (s) and cell lysates (cl) of 175 PF samples. The cut-off values with 100% specificity were selected for malignant-benign discrimination. An immunocytochemical staining index score for each marker was also evaluated on PF cell blocks. The resulting best biomarker was further validated in two independent populations of 73 and 48 patients with pleural effusions (PE). RESULTS: An EpCAM(cl) >98 pg/g total lysate protein yielded 75% sensitivity, 100% specificity, negative likelihood ratio of 0.25 and area under the curve of 0.94 for labelling adenocarcinomatous effusions. Sensitivity reached 88% if EpCAM(cl) was combined with EpCAM immunostaining. One-third or more of the malignant effusions exhibiting a false-negative cytological fluid examination were correctly classified by EpCAM(cl) concentrations. Immunoassays for CL4 and HE4 were diagnostically useless. CONCLUSION: EpCAM(cl) is a new biomarker of adenocarcinomatous PE with meaningful discriminating properties.

Migrated T lymphocytes into malignant pleural effusions: an indicator of good prognosis in lung adenocarcinoma patients.

The presence of leukocyte subpopulations in malignant pleural effusions (MPEs) can have a different impact on tumor cell proliferation and vascular leakiness, their analysis can help to understand the metastatic microenvironment. We analyzed the relationship between the leukocyte subpopulation counts per ml of pleural fluid and the tumor cell count, molecular phenotype of lung adenocarcinoma (LAC), time from cancer diagnosis and previous oncologic therapy. We also evaluated the leukocyte composition of MPEs as a biomarker of prognosis. We determined CD4+ T, CD8+ T and CD20+ B cells, monocytes and neutrophils per ml in pleural effusions of 22 LAC and 10 heart failure (HF) patients by flow cytometry. Tumor cells were identified by morphology and CD326 expression. IFNγ, IL-10 and IL-17, and chemokines were determined by ELISAs and migratory response to pleural fluids by transwell assays. MPEs from LAC patients had more CD8+ T lymphocytes and a tendency to more CD4+ T and CD20+ B lymphocytes than HF-related fluids. However, no correlation was found between lymphocytes and tumor cells. In those MPEs which were detected >1 month from LAC diagnosis, there was a negative correlation between pleural tumor cells and CD8+ T lymphocytes. CXCL10 was responsible for the attraction of CD20+ B, CD4+ T and CD8+ T lymphocytes in malignant fluids. Concentrations of IL-17 were higher in MPEs than in HF-related effusions. Survival after MPE diagnosis correlated positively with CD4+ T and CD8+ T lymphocytes, but negatively with neutrophils and IL-17 levels. In conclusion, lymphocyte enrichment in MPEs from LAC patients is mostly due to local migration and increases patient survival.

Diagnostic Accuracy of Pleural Fluid Adenosine Deaminase for Diagnosing Tuberculosis. Meta-analysis of Spanish Studies. / Eficacia diagnóstica de la adenosina desaminasa en líquido pleural para diagnosticar tuberculosis. Metaanálisis de estudios españoles.

OBJECTIVE: To evaluate the usefulness of pleural fluid adenosine deaminase (ADA) for diagnosing tuberculous pleural effusions in the Spanish population, according to laboratory technique and cut-off point, and to compare the results with other populations. METHODS: Meta-analysis of diagnostic studies on pleural fluid ADA in the Spanish population, extracted from the PubMed and Embase databases from inception until July 2017, with no language restrictions. The overall diagnostic accuracy of ADA and that of each of the measurement techniques (Giusti, manual and automated kinetic methods) and selected cut-offs were analyzed. The QUADAS-2 tool was used to evaluate the quality of studies. A bivariate random effects model was used. Results were compared with those obtained from previous meta-analyses in non-Spanish populations. RESULTS: Sixteen studies in a total of 4,147 patients, 1,172 of whom had tuberculous pleural effusions, were included. ADA had 93% sensitivity, 92% specificity, positive likelihood ratio of 12, negative likelihood ratio of 0.08, and an area-under-the-curve of 0.968 for identifying tuberculosis. There were no differences in diagnostic accuracy between the techniques used for ADA measurement or the selected cut-offs. In 73 studies from non-Spanish populations a trend toward lower ADA sensitivity (88%, 95% CI:86%-90%) and specificity (88%, 95% CI: 86%-90%) was noted, but differences did not reach statistical significance. CONCLUSIONS: Pleural fluid ADA in the Spanish population shows good diagnostic accuracy (regardless of the measurement technique or cut-off), similar to that reported in non-Spanish populations.

Tuberculous Pleural Effusion: Clinical Characteristics of 320 Patients. / Derrame pleural tuberculoso: características clínicas de 320 pacientes.

OBJECTIVES: To analyze the clinical and radiological characteristics and features of pleural fluid (PF) in patients with tuberculous pleural effusion (TPE). METHODS: Retrospective analysis of TPEs treated in our clinic over the last 23years. RESULTS: We included 320 patients with TPE (70% men; median age 33years). Mycobacterium tuberculosis was identified in the sputum or PF of 36% of the patients by microscopic examination, solid and liquid media cultures, or nucleic acid amplification tests. The greatest percentage of positive microbiological findings were associated with human immunodeficiency virus (HIV) co-infection (OR: 3.27), and with the presence in PF of proteins <4g/dL (OR: 3.53), neutrophils >60% (OR: 3.23), and glucose <40mg/dL (OR: 3.17). Pleural adenosine deaminase <35U/L was associated with TPEs that occupied less than half of the hemithorax (OR: 6.36) and with PF lactate dehydrogenase levels <500U/L (OR: 8.09). Radiological pulmonary opacities (30%) were more common in TPE occupying less than half of the hemithorax (OR: 2.73), in bilateral TPE (OR: 4.48), and in older patients (OR: 1.02). Factors predicting mortality were: HIV co-infection (OR: 24), proteins in PF <5g/dL (OR: 10), and greater age (OR: 1.05). CONCLUSIONS: Patients with TPE and HIV co-infection and those with lower concentrations of proteins in PF had higher rates of positive microbiological results and death. Moreover, older patients had more pulmonary opacities and a higher incidence of death.

Pleural Effusions in Diffuse Large B-Cell Lymphoma: Clinical and Prognostic Significance.

PURPOSE: Pleural effusion (PEs) may complicate diffuse large B-cell lymphomas (DLBCL). However, their real prevalence and prognostic significance have seldom been approached systematically. METHODS: Retrospective single-center evaluation of consecutive patients with DLBCL was conducted. Baseline characteristics, PEs on CT imaging, pleural fluid analyses, and outcome until death or censoring date were collected. RESULTS: Of 185 DLBCL patients, 55 (30%) had PEs, of which 27 (49%) were analyzed. Most tapped PEs were malignant (n = 24) and cytological and/or flow cytometric analyses provided the diagnosis in about 70% of the cases. Malignant PEs were exudates with adenosine deaminase levels > 35 U/L in 35% of the cases. More than one-third of lymphomatous PEs required definitive pleural procedures for symptomatic relief. PEs greater than 200 mL on CT scans were an independent predictor of poor survival in Cox regression modeling (hazard ratio 1.9). CONCLUSIONS: PEs are common in DLBCL and foreshadow a poor prognosis.

Management of pleural infections.

INTRODUCTION: The management of infected pleural effusion is complex. Therapeutic resolution requires determining the following: appropriate antibiotic regimen, the need for pleural drainage, the optimal drainage tube size, and the need for intrapleural therapy or surgery. Areas covered: An updating of the latest advances in the management of parapneumonic pleural effusion based on the best evidence available is provided. Expert commentary: The correct management of parapneumonic pleural effusion is based on selecting an antibiotic regimen according to the origin of the pleural infection (community-acquired or nosocomial). If pleural drainage is indicated, a small-bore chest tube is appropriate. Although the administration of fibrinolytics is not required in all cases, when necessary, recombinant t-PA in combination with deoxyribonuclease is the preferred therapy. If surgery is indicated, video-assisted thoracoscopic surgery is as effective - if not superior - as open decortication. All these therapies should be complemented with appropriate nutritional support. Further clinical trials are needed to confirm whether new therapeutic strategies such as a pleural cavity saline wash are more effective in the management of this disease.

Detection of Pleural Fluid Biochemistry Changes in Two Consecutive Thoracenteses for Differentiating Malignant from Benign Effusions. / Cambios en los parámetros bioquímicos del líquido pleural entre 2 toracocentesis consecutivas para diferenciar derrames malignos de benignos.

OBJECTIVE: To assess whether changes in pleural fluid (PF) biochemistries between two consecutive thoracenteses enable clinicians to predict malignant or benign pleural effusions (PE). METHODS: Retrospective study of patients with lymphocytic exudates and negative PF cytology, who underwent a second thoracentesis in our center in the last 15 years in whom a final diagnosis was reached (derivation sample). Absolute (Δa) and percentage differences (Δp) in PF biochemistries which predicted a malignant or benign PE in the derivation sample were evaluated in an independent population (validation sample). RESULTS: The derivation sample included 214 PE patients (70 malignant and 144 benign PE). Δp lactate dehydrogenase (LDH) >0%, Δp neutrophils >-10% (any increase or less than 10% decrease) and Δa protein <0.1g/dL (any increase or less than 0.1g/dL decrease) between the second and the first thoracentesis had an odds ratio of 6.4, 3.9 and 2.1, respectively, to discriminate malignant from benign PE. The presence of the three conditions together had a positive likelihood ratio of 5.6, whereas the absence of any of the 3 parameters had a likelihood ratio of 0.04 for predicting malignancy. These results were reproduced in the validation sample. CONCLUSION: An increase in LDH and neutrophils along with a decrease in protein in a second thoracentesis increase the probability of malignant PE, while the opposite reduces it significantly.

Pleural effusions in acute decompensated heart failure: Prevalence and prognostic implications.

BACKGROUND: The incidence of pleural effusions (PEs) in acute decompensated heart failure (ADHF) is not well established. We aimed to determine their prevalence, clinical characteristics and prognostic implications. METHODS: Retrospective review of 3245 consecutive patients with ADHF from the Spanish RICA Registry. The clinical characteristics of those with or without PEs on chest radiographs were compared and a predictive PE model was generated. RESULTS: Patient's median age was 80 years and 60% had a left ventricular ejection fraction (LVEF) >50%. PEs were seen in 46% of the cases, and their distribution was as follows: 58% bilateral, 27% right-sided and 14% left-sided. Male gender (OR 2.18; 95%CI 1.23-3.87), serum amino-terminal fraction of the pro-brain natriuretic peptide (NT-pro-BNP) levels >3500 pg/ml (OR 2.2; 95%CI 1.25-3.77), estimated systolic pulmonary artery pressure (sPAP) >55 mm Hg by echocardiography (OR 2.05; 95%CI 1.12-3.75), and serum prealbumin <15 mg/l (OR 1.96; 95%CI 1.08-3.52) were associated with PE development in a multivariate analysis. Serum NT-proBNP >8000 pg/ml, and systolic arterial pressure <110 mm Hg, but not PEs, independently predicted overall 1-year mortality. CONCLUSIONS: PEs are present on chest radiographs in nearly half of ADHF patients. They are mainly bilateral or right-sided and predominate in males with elevated sPAP on echocardiography and high serum levels of NT-proBNP. PEs do not independently predict 1-year mortality.