Tuberculous pleuritis: clinical presentations and diagnostic challenges.

PURPOSE OF REVIEW: Tuberculous pleuritis (TBP) is one of the most common types of extrapulmonary tuberculosis. We highlight the latest epidemiology of TBP, the heterogeneity of its presentation and the performance of different diagnostic strategies. RECENT FINDINGS: There are differential trends in the incidences of TBP worldwide. Its incidence increased in China but decreased in the United States in the past decade. The presentation of TBP is heterogeneous regarding clinical symptoms, radiological findings and pleural fluid analysis results. Conventional microbiological tests have low sensitivities to diagnose TBP. Recent research focused on various diagnostic tools with better yield. The sensitivity of nucleic acid amplification tests (NAAT) in pleural fluid, including the latest generation of PCR and sequencing-based techniques for detecting tuberculosis, remains suboptimal. Various pleural fluid biomarkers have been explored, but there is a lack of consensus on their clinical utility and cutoff levels. SUMMARY: The heterogeneity of clinical presentation poses obstacles to diagnosing TBP. Further development of diagnostic tools, including more robust NAAT and biomarkers with additional validation, is needed before incorporation into routine clinical practice.

Management of malignant pleural effusion and trapped lung: a survey of respiratory physicians and thoracic surgeons in Australasia.

BACKGROUND: Malignant pleural effusions (MPEs) are common, and a third of them have underlying trapped lung (TL). Management of MPE and TL is suspected to be heterogeneous. Understanding current practices in Australasia is important in guiding policies and future research. AIMS: Electronic survey of Australia-New Zealand respiratory physicians, thoracic surgeons and their respective trainees to determine practice of MPE and TL management. RESULTS: Of the 132 respondents, 56% were respiratory physicians, 23% were surgeons and 20% were trainees. Many respondents defined TL as >25% or any level of incomplete lung expansion; 75% would use large-volume thoracentesis to determine whether TL was present. For patients with TL, indwelling pleural catheters (IPCs) were the preferred treatment irrespective of prognosis. In those without TL, surgical pleurodesis was the most common choice if prognosis was >6 months, whereas IPC was the preferred option if survival was <3 months. Only 5% of respondents considered decortication having a definite role in TL, but 55% would consider it in select cases. Forty-nine per cent of surgeons would not perform decortication when the lung does not fully expand intra-operatively. Perceived advantages of IPCs were minimisation of hospital time, effusion re-intervention and usefulness irrespective of TL status. Perceived disadvantages of IPCs were lack of suitable drainage care, potentially indefinite duration of catheter-in-situ and catheter complications. CONCLUSION: This survey highlights the lack of definition of TL and heterogeneity of MPE management in Australasia, especially for patients with expandable lungs. This survey also identified the main hurdles of IPC use that should be targeted.

Device assessed activity behaviours in patients with indwelling pleural catheter: A sub-study of the Australasian Malignant PLeural Effusion (AMPLE)-2 randomized trial.

BACKGROUND AND OBJECTIVE: Device-assessed activity behaviours are a novel measure for comparing intervention outcomes in patients with malignant pleural effusion (MPE). Australasian Malignant PLeural Effusion (AMPLE)-2 was a multi-centre clinical trial where participants with MPE treated with an indwelling pleural catheter were randomized to daily (DD) or symptom-guided (SGD) drainage for 60-days. Our aim was to describe activity behaviour patterns in MPE patients, explore the impact of drainage regimen on activity behaviours and examine associations between activity behaviours and quality of life (QoL). METHODS: Following randomization to DD or SGD, participants enrolled at the lead site (Perth) completed accelerometry assessment. This was repeated monthly for 5-months. Activity behaviour outcomes were calculated as percent of daily waking-wear time and compared between groups (Mann-Whitney U test; Median [IQR]). Correlations between activity behaviour outcomes and QoL were examined. RESULTS: Forty-one (91%) participants provided ≥1 valid accelerometry assessment (DDn = 20, SGD n = 21). Participants spent a large proportion of waking hours sedentary (72%-74% across timepoints), and very little time in moderate-to-vigorous physical activity (<1% across timepoints). Compared to SGD group, DD group had a more favourable sedentary-to-light ratio in the week following randomization (2.4 [2.0-3.4] vs. 3.2 [2.4-6.1]; p = 0.047) and at 60-days (2.0 [1.9-2.9] vs. 2.9 [2.8-6.0]; p = 0.016). Sedentary-to-light ratio was correlated with multiple QoL domains at multiple timepoints. CONCLUSION: Patients with MPE are largely sedentary. Preliminary results suggest that even modest differences in activity behaviours favouring the DD group could be meaningful for this clinical population. Accelerometry reflects QoL and is a useful outcome measure in MPE populations.

Implementation of evidence on management of pleural diseases: insights from a territory-wide survey of clinicians in Hong Kong.

BACKGROUND: Major advances in management of common pleural diseases have taken place in the past decade. However, pleural diseases are often managed by physicians of diverse training background and research on implementation of new knowledge is scanty. We aim to evaluate the practice pattern in pleural medicine among physicians in Hong Kong, for identification of possible gaps for clinical service improvement. METHODS: The Hong Kong Thoracic Society undertook a cross-sectional questionnaire survey in 2019, targeting clinicians of various subspecialties in internal medicine and levels of experience (basic and higher trainees, specialists) from twelve regional hospitals of diverse service scopes throughout Hong Kong. Respondents were selected by non-probability quota sampling. The questionnaire tool consisted of 46 questions covering diagnostic and therapeutic aspects of common pleural diseases. The responses were anonymous, and analysed independently using SPSS statistics software. RESULTS: The survey collected 129 responses, 47(36%) were from clinicians specialized in respiratory medicine. Majority of the respondents (98%) managed pleural diseases, including performing pleural procedures in their practice. Fifty-five percent of all the respondents had not received any formal training in transthoracic ultrasonography. A significant proportion of clinicians were unaware of pleuroscopy for investigation of exudative pleural effusion, indwelling pleural catheter for recurrent malignant pleural effusion, and combined intra-pleural Alteplase plus DNase for treatment of pleural infection (30%, 15% and 70% of non-respiratory clinicians respectively). Significant heterogeneity was found in the management of pleural infection, malignant pleural effusion and pneumothorax among respiratory versus non-respiratory clinicians. Contributing factors to the observed heterogeneity included lack of awareness or training, limited accessibility of drugs, devices, or dedicated service support. CONCLUSION: Significant heterogeneity in management of pleural diseases was observed among medical clinicians in Hong Kong. Continuous medical education and training provision for both specialists and non-specialists has to be strengthened to enhance the implementation of advances, improve quality and equity of healthcare provision in pleural medicine.

Role of early definitive management for newly diagnosed malignant pleural effusion related to lung cancer.

BACKGROUND AND OBJECTIVE: The advent of effective anti-cancer therapy has brought about uncertainty on the benefit of early definitive measures for newly diagnosed MPE from lung cancer. This study aims to investigate the outcomes of MPE in this setting. METHODS: Lung cancer patients with MPE at first presentation to a tertiary care hospital were followed up till death or censored from 2011 to 2018. Early MPE control measures included chemical pleurodesis or IPC before or shortly after oncological treatment. Predictors of time to MPE re-intervention were identified with Cox proportional hazard analyses. RESULTS: Of the 509 records screened, 233 subjects were eligible. One hundred and twenty-seven subjects received oral targeted therapy as first-line treatment and 34 (26.8%) underwent early definitive MPE control measures. Early MPE control measures in addition to targeted therapy, as compared to targeted therapy alone, significantly reduced the subsequent need of MPE re-intervention (23.5% vs 53.8%, P = 0.002). Similar benefits from MPE control measures were found in groups receiving systemic anti-cancer therapy or best supportive care (0% vs 52%, P = 0.003; 18% vs 56.7%, P = 0.024, respectively). In the group with targetable mutations, both early MPE control measures (HR: 0.25, 95% CI: 0.12-0.53, P < 0.001) and the use of targeted therapy (HR: 0.22, 95% CI: 0.10-0.46, P < 0.001) were independently associated with longer time to MPE re-interventions. CONCLUSION: Early MPE control measures in lung cancer has additional benefits on reducing the need and prolonging the time to MPE re-intervention, independent of anti-cancer therapies.

Use of indwelling pleural/peritoneal catheter in the management of malignant ascites: a retrospective study of 48 patients.

BACKGROUND: Patients suffering from malignant ascites usually require repeated large volume paracentesis (LVP) for symptomatic relief. This often requires hospital admission and has inherent risks. AIMS: To report the first Australian experience of placing tunnelled indwelling peritoneal catheters (IPeC) for management of recurrent malignant ascites. METHODS: A retrospective study was conducted of tunnelled IPeC use in patients with symptomatic malignant ascites in four hospitals in Western Australia (from 2010 to 2018). Procedure data, success rate and safety profile were collected from a database. RESULTS: Forty-eight patients (median age 65 years; female 56%) underwent 51 peritoneal catheter insertion procedures that were performed mostly by pleural specialists. The majority of patients (96%) had prior LVP (median two drainages, interquartile range (IQR) 1-4) before IPeC insertion. The IPeC was inserted successfully under ultrasound guidance in all patients. The median length of hospital stay for IPeC insertion and initial ascites drainage was 2 days (IQR 2-3 days) and most patients (96%) did not require further paracentesis after IPeC placement. The majority (96%) of patients experienced relief from ascites symptoms after catheter insertion. Most IPeC-related adverse events were self-limiting, including pain (in 25% cases), transient hypotension after initial fluid drainage (10%), peritoneal fluid leakage (10%), bacterial peritonitis (8%), fluid loculation (2%) and catheter dislodgement (2%). Six (12%) patients had IPeC removed. All patients with bacterial peritonitis responded to antibiotics and one required catheter removal. CONCLUSIONS: Use of tunnelled IPeC improves symptoms and can minimise further invasive drainage procedures in patients with symptomatic malignant ascites. Placement of IPeC was associated with a low rate of adverse events, most of which could be managed conservatively.

Spontaneous pneumothorax in diffuse cystic lung diseases.

PURPOSE OF REVIEW: Diffuse cystic lung diseases (DCLDs) are a heterogeneous group of disorders with varying pathophysiologic mechanisms that are characterized by the presence of air-filled lung cysts. These cysts are prone to rupture, leading to the development of recurrent spontaneous pneumothoraces. In this article, we review the epidemiology, clinical features, and management DCLD-associated spontaneous pneumothorax, with a focus on lymphangioleiomyomatosis, Birt-Hogg-Dubé syndrome, and pulmonary Langerhans cell histiocytosis. RECENT FINDINGS: DCLDs are responsible for approximately 10% of apparent primary spontaneous pneumothoraces. Computed tomography screening for DCLDs (Birt-Hogg-Dubé syndrome, lymphangioleiomyomatosis, and pulmonary Langerhans cell histiocytosis) following the first spontaneous pneumothorax has recently been shown to be cost-effective and can help facilitate early diagnosis of the underlying disorders. Patients with DCLD-associated spontaneous pneumothorax have a very high rate of recurrence, and thus pleurodesis should be considered following the first episode of spontaneous pneumothorax in these patients, rather than waiting for a recurrent episode. Prior pleurodesis is not a contraindication to future lung transplant. SUMMARY: Although DCLDs are uncommon, spontaneous pneumothorax is often the sentinel event that provides an opportunity for diagnosis. By understanding the burden and implications of pneumothoraces in DCLDs, clinicians can facilitate early diagnosis and appropriate management of the underlying disorders.

Malignant pleural fluid from mesothelioma has potent biological activities.

BACKGROUND AND OBJECTIVE: Malignant pleural effusion (MPE) affects >90% of mesothelioma patients. Research on MPE has focused on its physical impact on breathlessness; MPE is rich in growth mediators but its contribution to tumour biology has not been investigated. We aimed to examine the potential effects of MPE in promoting growth, migration and chemo-resistance of mesothelioma. METHODS: Pleural fluid samples from 151 patients (56 mesothelioma, 60 metastatic pleural cancer and 35 benign) were used. Seven validated human mesothelioma cell lines and three primary cultured mesothelioma lines were employed. RESULTS: Pleural fluid from mesothelioma patients (diluted to 30%) consistently stimulated cell proliferation (trypan-blue cell viability assay) in five mesothelioma cell lines tested by (median) 2.23-fold over controls (all P < 0.0001). The fluid also induced cell migration by (median) 2.13-fold in six mesothelioma cell lines using scratch-wound assay. In a murine flank model of mesothelioma, tumour infused with daily instillations of pleural fluid grew significantly faster over saline controls (median 52.5 cm2 vs 28.0 cm2 at day 13, P = 0.028). Addition of MPE (diluted to 30%) to culture media significantly protected mesothelioma from cisplatin/pemetrexed-induced cell death in all three cell lines tested (median fold reduction of 1.29, 1.98 and 3.90, all P < 0.001 vs control). The growth effects of matched pleural fluid and cultured mesothelioma cells from the same patients did not differ significantly from unmatched pairs. CONCLUSION: This 'proof-of-concept' study reveals potent biological capabilities of malignant pleural fluid in mesothelioma pathobiology.

Associations of physical activity and quality of life in parapneumonic effusion patients.

Introduction: Little is known about activity behaviours and quality of life (QoL) of patients with parapneumonic pleural effusions (PPE) after hospital discharge. This study is a secondary analysis of a randomised trial (dexamethasone versus placebo) for hospitalised patients with PPE. We: 1) described the patients' activity behaviour patterns and QoL measured at discharge and at 30 days post-discharge; and 2) examined the association between activity behaviours and QoL scores. Methods: Activity behaviour (7-day accelerometry; Actigraph GT3X+) and QoL (Medical Outcomes Study Short-Form 36) were assessed. Repeated measures analysis of covariance controlling for baseline values and a series of linear regression models were undertaken. Results: 36 out of 53 eligible participants completed accelerometry assessments. Despite modest increases in light physical activity (+7.5%) and some domains of QoL (>2 points) from discharge to 30 days post-discharge, patients had persistently high levels of sedentary behaviour (>65% of waking wear time) and poor QoL (≤50 out of 100 points) irrespective of treatment group (p=0.135-0.903). Increasing moderate-to-vigorous physical activity was associated with higher scores on most QoL domains (p=0.006-0.037). Linear regression indicates that a clinically important difference of 5 points in physical composite QoL score can be achieved by reallocating 16.1 min·day-1 of sedentary time to moderate-to-vigorous physical activity. Conclusion: Patients with PPE had low levels of physical activity and QoL at discharge and 30 days post-discharge irrespective of treatment. Moderate-to-vigorous physical activity participation was associated with higher QoL scores. Increasing moderate-to-vigorous physical activity following discharge from the hospital may be associated with improvements in QoL.

Phenotyping empyema by pleural fluid culture results and macroscopic appearance: an 8-year retrospective study.

Background: The clinical impact of phenotyping empyema is poorly described. This study was designed to evaluate clinical characteristics and outcomes based on the two readily available parameters, pleural fluid culture status and macroscopic fluid appearance. Methods: A retrospective study was conducted on patients with empyema hospitalised between 2013 and 2020. Empyema was classified into culture-positive empyema (CPE) or culture-negative empyema (CNE) and pus-appearing empyema (PAE) or non-pus-appearing empyema (non-PAE) based on the pleural fluid culture status and macroscopic fluid appearance, respectively. Results: Altogether, 212 patients had confirmed empyema (CPE: n=188, CNE: n=24; PAE: n=118, non-PAE: n=94). The cohort was predominantly male (n=163, 76.9%) with a mean age of 65.0±13.6 years. Most patients (n=180, 84.9%) had at least one comorbidity. Patients with CPE had higher rates of in-hospital mortality (19.1% versus 0.0%, p=0.017) and 90-day mortality (18.6% versus 0.0%, p=0.017) and more extrapulmonary sources of infection (29.8% versus 8.3%, p=0.026) when compared with patients with CNE. No significant difference in mortality rate was found between PAE and non-PAE during the in-hospital stay and at 30 days and 90 days. Patients with PAE had less extrapulmonary sources of infection (20.3% versus 36.2%, p=0.010) and more anaerobic infection (40.9% versus 24.5%, p=0.017) than those with non-PAE. The median RAPID (renal, age, purulence, infection source, and dietary factors) scores were higher in the CPE and non-PAE groups. After adjusting for covariates, culture positivity was not independently associated with mortality on multivariable analysis. Conclusion: Empyema is a heterogeneous disease with different clinical characteristics. Phenotyping empyema into different subclasses based on pleural fluid microbiological results and macroscopic fluid appearance provides insight into the underlying bacteriology, source of infection and subsequent clinical outcomes.

Very low-dose intrapleural tPA for indwelling pleural catheter-associated symptomatic fluid loculation.

Indwelling pleural catheters (IPCs) are effective management options for malignant pleural effusion. Symptomatic fluid loculation is a recognized complication of IPC use and is usually managed with intrapleural instillation of fibrinolytic drugs, such as tissue plasminogen activator (tPA). A previous multicentre observational study showed significant heterogeneity among centres in their dosing regimen for tPA (from 2 to 20 mg) in treating symptomatic loculations. Potential pleural bleeding, especially in high-risk patients, often deters clinicians from initiating intrapleural fibrinolytic therapy. Lower doses of tPA may reduce bleeding risks. This case report describes the successful use of 0.5 mg (the lowest reported dose) of tPA in a patient with significant bleeding risks whose IPC was complicated by symptomatic loculation.

Steroid therapy and outcome of parapneumonic pleural effusions (STOPPE): Study protocol for a multicenter, double-blinded, placebo-controlled randomized clinical trial.

BACKGROUND: Community-acquired pneumonia (CAP) is a major global disease. Parapneumonic effusions often complicate CAP and range from uninfected (simple) to infected (complicated) parapneumonic effusions and empyema (pus). CAP patients who have a pleural effusion at presentation are more likely to require hospitalization, have a longer length of stay and higher mortality than those without an effusion. Conventional management of pleural infection, with antibiotics and chest tube drainage, fails in about 30% of cases. Several randomized controlled trials (RCT) have evaluated the use of corticosteroids in CAP and demonstrated some potential benefits. Importantly, steroid use in pneumonia has an acceptable safety profile with no adverse impact on mortality. A RCT focused on pediatric patients with pneumonia and a parapneumonic effusion demonstrated shorter time to recovery. The effects of corticosteroid use on clinical outcomes in adults with parapneumonic effusions have not been tested. We hypothesize that parapneumonic effusions develop from an exaggerated pleural inflammatory response. Treatment with systemic steroids may dampen the inflammation and lead to improved clinical outcomes. The steroid therapy and outcome of parapneumonic pleural effusions (STOPPE) trial will assess the efficacy and safety of systemic corticosteroid as an adjunct therapy in adult patients with CAP and pleural effusions. METHODS: STOPPE is a pilot multicenter, double-blinded, placebo-controlled RCT that will randomize 80 patients with parapneumonic effusions (2:1) to intravenous dexamethasone or placebo, administered twice daily for 48 hours. This exploratory study will capture a wide range of clinically relevant endpoints which have been used in clinical trials of pneumonia and/or pleural infection; including, but not limited to: time to clinical stability, inflammatory markers, quality of life, length of hospital stay, proportion of patients requiring escalation of care (thoracostomy or thoracoscopy), and mortality. Safety will be assessed by monitoring for the incidence of adverse events during the study. DISCUSSION: STOPPE is the first trial to assess the efficacy and safety profile of systemic corticosteroids in adults with CAP and pleural effusions. This will inform future studies on feasibility and appropriate trial endpoints. TRIAL REGISTRATION: ACTRN12618000947202 PROTOCOL VERSION:: version 3.00/26.07.18.

Intrapleural tissue plasminogen activator and deoxyribonuclease therapy for pleural infection.

Pleural infection remains a global health burden associated with significant morbidity. Drainage of the infected pleural fluid is important but can often be hindered by septations and loculations. Intrapleural fibrinolytic therapy alone, to break pleural adhesions, has shown no convincing advantages over placebo in improving clinical outcome. Deoxyribonucleoprotein from degradation of leukocytes contributes significantly to high viscosity of infected pleural fluid. Recombinant deoxyribonuclease (DNase) is effective in reducing pleural fluid viscosity in pre-clinical studies. The combination of tissue plasminogen activator (tPA) and DNase was effective in animal model experiments of empyema. The benefits were established in a randomized clinical trial: those (n=48) treated with tPA/DNase had significantly improved radiological outcomes and reduced need of surgery and duration of hospital stay. A longitudinal observational series of 107 patients further confirmed the effectiveness and safety of tPA/DNase therapy, including its use as 'rescue therapy' when patients failed to respond to antibiotics and chest tube drainage. Overall, a short course of intrapleural tPA (10 mg) and DNase (5 mg) therapy provides a cure in over 90% of patients without requiring surgery. The treatment stimulates pleural fluid formation, enhances radiographic clearance and resolution of systemic inflammation. Serious complications are uncommon; pleural bleeding requiring transfusion occurred in ~2% of cases. Pain can occur, especially with the first dose. Treatment is contraindicated in those with significant bleeding diathesis or a bronchopleural fistula. Future research is required to optimize dosing regimens and in refining patient selection.

Outcome of patients with nonspecific pleuritis/fibrosis on thoracoscopic pleural biopsies.

OBJECTIVE: Medical thoracoscopy is recommended in the investigation of patients with exudative pleural effusions, especially when pleural fluid analysis is uninformative. The histological finding of 'nonspecific pleuritis/fibrosis' is common in thoracoscopic biopsies and presents a great uncertainty for clinicians and patients as the long-term outcome of these patients is unclear, and anxieties about undiagnosed malignancy persist. METHOD: A retrospective case-note study of 142 patients who underwent medical thoracoscopy over a 58-month period in a tertiary referral centre with a high incidence of mesothelioma. Patients with 'nonspecific pleuritis/fibrosis' were followed up until death or for a mean (±SD) period of 21.3 (±12.0) months. RESULTS: A definitive histological diagnosis was achieved in 98 (69%) patients. A total of 44 (31%) patients had 'nonspecific pleuritis/fibrosis'. Five (12%) were subsequently diagnosed with malignant pleural disease after a mean interval of 9.8 (±4.6) months. All five patients had histologically confirmed mesothelioma. In 26 patients with 'nonspecific pleuritis/fibrosis', no cause for the pleural effusion was discovered. The false-negative rate of thoracoscopic biopsy for the detection of pleural malignancy was 5%, with a diagnostic sensitivity of 95% and negative predictive value of 90%. Pleural effusion recurrence was more frequently associated with a false-negative pleural biopsy result. However, there was no correlation with other patient characteristics or the thoracoscopist's prediction based on macroscopic appearances. CONCLUSION: Thoracoscopic pleural biopsy is valuable in the diagnosis of pleural malignancies. Patients with 'nonspecific pleuritis/fibrosis' require follow-up as a malignant diagnosis (especially mesothelioma) may eventually be established in approximately 12% of cases.