Clinical Research Directory

Pleural Space Saline Irrigation in Addition to Standard Intrapleural Thrombolytic Therapy in Empyema/Complicated Parapneumonic Effusion

The purpose of this study is to see if there is any benefit in adding saline irrigation through a chest tube to the standard course of treatment for people diagnosed or suspected of having a pleural space infection.

Intrapleural Alteplase-Tyloxapol vs Intrapleural Alteplase-DNase in Pleural Infection

Pneumonia, thought to be the chief aetiological process in the development of pleural space infection, is defined as an infection of the lung parenchyma with an estimated annual incidence rate of 5-11 cases per 1000 population, with around 50,000 hospital admissions in the U.K. per year. Parapneumonic effusions caused by an infection of the pleural membranes occur in 40-57% of cases of pneumonia. A variable percentage (10-20%) of parapneumonic effusions progresses to empyema (pus) and/or abscess formation (encapsulation). Pleural infection is associated with significant morbidity and mortality, which may be as high as 20-35% in immunocompromised patients. Standard treatment of these collections in adults involves antibiotic therapy, adequate drainage of infected fluid, and surgical intervention if conservative management fails. Appropriate treatment is adequate drainage via an intercostal catheter (ICC) with antibiotic therapy for parapneumonic effusions requiring clearance. Frequently, simple ICC drainage is ineffective due to the presence of loculations, formed predominantly by fibrinous material deposited in the fibrinopurulent phase of empyema, preventing free drainage of infected pleural fluid. The presence of fibrinous septae in the pleural space, known as loculations, may result in inadequate drainage of effusions and, therefore, nonresolution of infection and systemic sepsis. Surgical intervention (VATS or open) is usually required to clear loculations and resolve infection without adequate intercostal catheter drainage. Although the success rate of surgical intervention remains high, the morbidity and mortality of both VATS and open thoracotomy are of concern, particularly in a cohort of patients who may be older and with significant comorbidity. Less invasive therapies, which promote pleural space drainage and effective resolution of pleural infection, are therefore likely to be of considerable clinical utility. The MIST 2 trial has established intrapleural therapy as the mainstay of CPEE treatment, hence avoiding surgery and decreasing the length of hospitalization; however, little is known about the correct dosage needed for tPA and Dornase Alfa/Deoxyribonuclease (DNase). Dose and duration of intrapleural therapy based on MIST 2 involve multiple dosing and can be time-consuming for health care providers. Nevertheless, treatment of pleural infection with fibrinolytic therapy has been incorporated in the British Thoracic Society guideline 2023. Another study in 2022 by Cheong et al. used a modified regimen of intrapleural alteplase 16 mg t-PA with 5 mg DNase for three doses administered sequentially within 24 h. In this study, a modified regimen of t-PA and DNase offers an alternative therapeutic option for patients who are unfit or refuse surgical intervention but have persistent pleural infection. They have demonstrated similar treatment success comparable to other studies, as evidenced by improved pleural fluid drainage and reduced pleural opacity on day 7 chest x-ray, approximately 50% from the baseline. The mechanism of action of t-PA and DNase in the pleural cavity remains unclear. Studies suggested that IPFT may trigger the monocyte chemoattractant protein 1 (MCP-1) pathway, which promotes pleural fluid formation and subsequently causes a therapeutic lavage effect that increases pleural fluid drainage.

Chest Drain Regular Flushing in Complicated Parapneumonic Effusions and Empyemas

Infections of the pleural space are common, and patients require antibiotics and chest drain placement to evacuate the chest from the infected fluid. Chest drains can get blocked by the drainage fluid and material. For this reason, it is thought that flushing the chest drain with saline solution, can help maintain the patency of the tube. This proposed study will evaluate the impact of regular chest drain flushing on the length of time to chest tube removal and total hospitalization as well as improvement in chest imaging and the need for additional interventions on the infected space.

Trial of Reduced Alteplase Dose for Parapneumonic Effusion (TRAPPE)

Objectives: A pilot study to assess the feasibility of a randomization trial protocol comparing low (2.5mg) and standard (10mg) doses of intrapleural tissue plasminogen activator (tPA) with deoxyribonucleases (DNase) in unresolved pleural infection. Hypothesis: The proposed randomized protocol comparing low dose and standard doses of intrapleural tPA (with DNase) therapy will be feasible and acceptable. Design and subjects: A single-center, two-arm, double-blinded, randomized controlled feasibility study which includes subjects with unresolved pleural infection eligible for intrapleural tPA/DNase injection, with follow-ups till 3 months after hospital discharge. Interventions: Recruited subjects will be randomized in 1:1 ratio to receive a maximum of 6 doses of intrapleural tPA (with DNase) starting at either 2.5mg or 10mg. A clinical decision is allowed at or after the third dose of tPA to continue with the assigned regimen (blinded) or convert to open-label use of 10mg doses of tPA to complete the course based on the clinical response. Main outcome measures: The main outcome is the feasibility of the trial protocol, based on the percentage of eligible patients enrolled, retained to discharge, and completing 3 months of follow-up. Other important outcomes include survival at 3 months follow-up and without the need for surgical intervention, the need for additional pleural interventions, the number of decisions to convert to open-labelled use of 10mg intrapleural tPA, clinical and radiographic response after the treatment course, safety profiles, especially bleeding complications and the number and reason for protocol violation. Data analysis and expected results: Feasibility outcomes will be reported as descriptive data. Comparison of outcomes between the two treatment groups will be analyzed on an intention-to-treat basis. Safety outcomes will be reported descriptively for each group. The reported estimates of recruitment rates, adherence, follow-up completeness, and variability and event rates for key clinical and bleeding outcomes will be used, to inform the design and sample size considerations future studies incorporating the current study design

Pleural Fluid Neutrophil Extracellular Traps Exacerbate Disease Severity and Risk of One-year Mortality in Pleural Infection (TORPIDS-3)

Pleural infection is a severe and complicated disease which is associated with significant morbidity and mortality. People with pleural infection show diverse levels of neutrophil degranulation activity. The investigators examined the biological role of pleural fluid neutrophil extracellular traps in patients with pleural infection. TORPIDS-3 is an observational, International multicohort study.

Diagnostic Utility of Pleural Infection-specific Multiplex PCR Panel

Pleural effusion is a common cause of hospitalization. Pleural infection ranked third among the pleural effusions requiring hospitalization in the United States. Pleural infection, including complicated parapneumonic effusion and empyema, is associated with a 30-day mortality of 10%. Approximately 20-57% of patients with pneumonia have an associated pleural effusion at presentation, of which 5-7% progress to pleural infection. Analyses of several nation-wide healthcare databases in the United States, France and the United Kingdom have showed an increasing incidence of pleural infection in the past decade. Adequate antibiotic coverage and fluid drainage are the two pillars of treatment for pleural infection. The empirical use of antibiotics should be based on the local spectrum of causative microorganisms and the source of infection. Subsequent targeted antibiotic regimen can be guided by the culture results and sensitivity pattern of the cultured microorganisms. The use of blood culture bottles as the transfer medium can improve the culture positivity from 30-40% to 60%. An explorative study of culturing pleural tissue can increase the microbiological yield from 20% to 45%. Despite these methods, the culture positivity rates are far from 100% although clinical evidence of pleural infection. Peripheral blood cultures may occasionally be the only positive source of culture (12%). Occasionally, complicated malignant pleural effusion (MPE) can mimic pleural infection, by sharing similar biochemical features of high neutrophil counts and lactate dehydrogenase in the pleural fluid. This would subject the patients with MPE to unnecessary prolonged course of antibiotic and delay of chemotherapy. Prolonged course of broad-spectrum antibiotics (BSA) is commonly required for culture-negative pleural infection or MPE with complicated features, but it could lead to various antibiotic-related adverse events, including kidney and liver injuries, opportunistic infections (e.g. Clostridioides difficile colitis). These are clinical unmet needs of identifying causative microorganisms in pleural infection. The application of multiplex bacterial polymerase chain reaction (PCR) panel has transformed the care of patients with respiratory infection. Incorporating multiplex bacterial PCR test of bronchoalveolar lavage in hospitalized patients with pneumonia at risk of Gram-negative bacterial infection can significantly shorten the duration of inappropriate antibiotic therapy. For patients with suspected lower respiratory tract infection, this platform allows early antibiotic adjustment (faster antibiotic escalations for Gram-negative or Gram-positive bacteria, and faster antibiotic de-escalations directed at Gram-positive bacteria). The use of multiplex PCR panel designed for pneumonia has been applied to patients with parapneumonic effusion with successful identification of non-culturable microorganism. However, the use of pneumonia multiplex PCR panels has not been fully validated in the clinical management of pleural infection. More importantly, these panels only detect common microorganisms included on their panels specifically designed for pneumonia. Therefore, a dedicated pleural infection-specific multiplex (PRISM) PCR panel is required to enhance the identification for microorganisms in patients presenting with pleural infection. A syndromic real-time PCR panel for diagnosing community-acquired pleural infection has been established by a Norway group, with its components constructed based on the next-generation sequencing results using prior pleural infection samples. Their panel showed a higher diagnostic sensitivity than that of conventional culture-based methods. For bacterial species included in the PCR panel, it had a sensitivity of 99.5%. However, it lacks clinical performance data and may not be applicable in the South-East Asian region as the microbiological spectrum of pleural infection differs geographically, with pneumococci and viridans streptococci the most commonly reported isolates from tropical and temperate regions, respectively. Therefore, a PRISM PCR panel dedicated for South-East Asian population is highly warranted. The investigators has developed a PRISM PCR panel dedicated for local population. The investigators hypothesize that this new PRISM PCR panel has higher diagnostic sensitivity than conventional culture-based methods in identifying causative microorganisms in prospectively collected real-world pleural fluid specimens.