High rates of respiratory symptoms and airway disease in mental health inpatients in a tertiary centre.

BACKGROUND: People with severe mental illness (SMI) have a lower life expectancy due in part to a higher prevalence of cardiac and metabolic disease. Less is known of the prevalence of respiratory disease in this group. AIMS: This cross-sectional, observational study aimed to assess the prevalence of symptoms associated with respiratory disease in patients admitted to an inpatient mental health unit. METHODS: A convenience sample of 82 inpatients had a structured interview and questionnaire completed. The questionnaire included self-reported diagnoses of common diseases and screening questions designed to detect respiratory disease and sleep disordered breathing. Targeted spirometry was performed on the basis of symptoms and smoking status. RESULTS: Patients reported high rates of respiratory symptoms, including wheezing (38%) and dyspnoea (44%); 52% of patients reported daily tobacco use. Productive cough was significantly associated with tobacco use (P < 0.005). Ten patients (18%) had spirometry consistent with chronic obstructive pulmonary disease (COPD) of whom six did not have a formal diagnosis of COPD previously. CONCLUSIONS: People with SMI have high rates of respiratory symptoms with a high prevalence of COPD on spirometry. Half of the COPD cases were not previously diagnosed, suggesting a hidden burden of respiratory disease in patients with SMI.

OPTIMA: An Open-Label, Noncomparative Pilot Trial of Inhaled Molgramostim in Pulmonary Nontuberculous Mycobacterial Infection.

Rationale: Inhaled granulocyte-macrophage colony-stimulating factor (GM-CSF) has been proposed as a potential immunomodulatory treatment for nontuberculous mycobacterial (NTM) infection.Objectives: This open-label, noncomparative pilot trial investigated the efficacy and safety of inhaled GM-CSF (molgramostim nebulizer solution) in patients with predominantly treatment-refractory pulmonary NTM infection (Mycobacterium avium complex [MAC] and M. abscessus [MABS]), either in combination with ongoing guideline-based therapy (GBT) or as monotherapy in patients who had stopped GBT because of lack of efficacy or intolerability.Methods: Thirty-two adult patients with refractory NTM infection (MAC, n = 24; MABS, n = 8) were recruited into two cohorts: those with (n = 16) and without (n = 16) ongoing GBT. Nebulized molgramostim 300 µg/d was administered over 48 weeks. Sputum cultures and smears and clinical assessments (6-min-walk distance, symptom scores, Quality of Life-Bronchiectasis Questionnaire score, and body weight) were collected every 4 weeks during treatment and 12 weeks after the end of treatment. The primary endpoint was sputum culture conversion, defined as three consecutive monthly negative cultures during the treatment period.Results: Eight patients (25%) achieved culture conversion on treatment (seven [29.2%] patients with MAC infection, one [12.5%] patient with MABS infection); in four patients, this was durable after the end of treatment. Of the 24 patients with MAC infection, an additional 4 patients had a partial response, converting from smear positive at baseline to smear negative at the end of treatment, and time to positivity in liquid culture media increased. Two of these patients sustained negative cultures from the end of treatment. Other clinical endpoints were unchanged. Serious adverse events were mainly pulmonary exacerbations or worsening NTM infection. Three deaths, not treatment related, were reported.Conclusions: In this population of patients with severe NTM disease, molgramostim was safe and well tolerated. Sputum culture conversion rates for patients with MAC infection (29.2%) were greater than reported for similar refractory MAC cohorts managed with GBT alone. Less benefit was seen for MABS infection. No serious safety concerns were identified. Further evaluation in a larger cohort is warranted.Clinical trial registered with www.clinicaltrials.gov (NCT03421743).

Anticoagulation Strategies in Non-Critically Ill Patients with Covid-19.

BACKGROUND: Optimal thromboprophylaxis for hospitalized patients with coronavirus disease 2019 (Covid-19) is uncertain. METHODS: In an open-label, adaptive platform trial, we randomly assigned hospitalized adults with Covid-19 to low-dose low-molecular-weight heparin thromboprophylaxis or intermediate-dose or low-dose plus aspirin. In response to external evidence, the aspirin intervention was discontinued and a therapeutic-dose arm added. The primary end point was death or the requirement for new organ support by day 28, analyzed with a Bayesian logistic model. Enrolment was closed as a result of operational constraints. RESULTS: Between February 2021 and March 2022, 1574 patients were randomly assigned. Among 1526 participants included in the analysis (India, n=1273; Australia and New Zealand, n=138; and Nepal, n=115), the primary outcome occurred in 35 (5.9%) of 596 in low-dose, 25 (4.2%) of 601 in intermediate-dose, 20 (7.2%) of 279 in low-dose plus aspirin, and 7 (14%) of 50 in therapeutic-dose anticoagulation. Compared with low-dose thromboprophylaxis, the median adjusted odds ratio for the primary outcome for intermediate-dose was 0.74 (95% credible interval [CrI], 0.43 to 1.27; posterior probability of effectiveness [adjusted odds ratio<1; Pr], 86%), for low-dose plus aspirin 0.88 (95% CrI, 0.47 to 1.64; Pr, 65%), and for therapeutic-dose anticoagulation 2.22 (95% CrI, 0.77 to 6.20; Pr, 7%). Overall thrombotic and bleeding rates were 0.8% and 0.4%, respectively. There were 10 serious adverse reactions related to anticoagulation strategy, of which nine were grade 1 or 2 across study interventions and one grade 4 episode of retroperitoneal hematoma in a patient receiving intermediate-dose anticoagulation. CONCLUSIONS: In hospitalized non­critically ill adults with Covid-19, compared with low-dose, there was an 86% posterior probability that intermediate-dose, 65% posterior probability that low-dose plus aspirin, and a 7% posterior probability that therapeutic-dose anticoagulation reduced the odds of death or requirement for organ support. No treatment strategy met prespecified stopping criteria before trial closure, precluding definitive conclusions. (Funded by Australian National Health and Medical Research Council or Medical Research Future Fund Investigator and Practitioner Grants and others; ClinicalTrials.gov number, NCT04483960.)

A Randomized Trial of Nafamostat for Covid-19.

BACKGROUND: Nafamostat mesylate is a potent in vitro antiviral agent that inhibits the host transmembrane protease serine 2 enzyme used by severe acute respiratory syndrome coronavirus 2 for cell entry. METHODS: This open-label, pragmatic, randomized clinical trial in Australia, New Zealand, and Nepal included noncritically ill hospitalized patients with coronavirus disease 2019 (Covid-19). Participants were randomly assigned to usual care or usual care plus nafamostat. The primary end point was death (any cause) or receipt of new invasive or noninvasive ventilation or vasopressor support within 28 days after randomization. Analysis was with a Bayesian logistic model in which an adjusted odds ratio <1.0 indicates improved outcomes with nafamostat. Enrollment was closed due to falling numbers of eligible patients. RESULTS: We screened 647 patients in 21 hospitals (15 in Australia, 4 in New Zealand, and 2 in Nepal) and enrolled 160 participants from May 2021 to August 2022. In the intention-to-treat population, the primary end point occurred in 8 (11%) of 73 patients with usual care and 4 (5%) of 82 with nafamostat. The median adjusted odds ratio for the primary end point for nafamostat was 0.40 (95% credible interval, 0.12 to 1.34) with a posterior probability of effectiveness (adjusted odds ratio <1.0) of 93%. For usual care compared with nafamostat, hyperkalemia occurred in 1 (1%) of 67 and 7 (9%) of 78 participants, respectively, and clinically relevant bleeding occurred in 1 (1%) of 73 and 7 (8%) of 82 participants. CONCLUSIONS: Among hospitalized patients with Covid-19, there was a 93% posterior probability that nafamostat reduced the odds of death or organ support. Prespecified stopping criteria were not met, precluding definitive conclusions. Hyperkalemia and bleeding were more common with nafamostat. (Funded by ASCOT and others; ClinicalTrials.gov number, NCT04483960.)

Infective endocarditis and rheumatic heart disease in the north of Australia.

BACKGROUND: To prevent infective endocarditis (IE), Australian guidelines recommend providing prophylactic antibiotics to Indigenous patients with rheumatic heart disease (RHD) prior to procedures which may cause bacteremia. In northern Australia RHD remains prevalent. We aimed to determine whether RHD is associated with an increased risk of IE, which risk factors are associated with IE, and the incidence and aetiology of IE. METHODS: A retrospective review of IE patients who fulfilled modified Duke criteria at two tertiary centres in northern Australia. RESULTS: 89 patients were reviewed. The rate of IE was 6.5/100,000 person-years. IE was more common in people with RHD (relative risk (RR) 58), Indigenous Australians (RR 2.0) and men (RR 1.7). RHD-associated IE was not confined to Indigenous Australians with 42% being non-Indigenous. The commonest risk factors for IE were intracardiac prosthetic material, injecting drug use and previous IE. One in five patients died. CONCLUSIONS: In northern Australia the principle risk factor for IE is not RHD. Whilst RHD increased the risk of IE it was not restricted to Indigenous Australians. Current Australian recommendations of providing prophylactic antibiotics to Indigenous patients with RHD prior to procedures which may cause bacteremia may need to be broadened to include non-Indigenous patients.

Intrapleural tissue plasminogen activator and deoxyribonuclease for pleural infection. An effective and safe alternative to surgery.

RATIONALE: Intrapleural tissue plasminogen activator (tPA)/deoxyribonuclease (DNase) therapy for pleural infection given at the time of diagnosis has been shown to significantly improve radiological outcomes. Published cases are limited to only a single randomized controlled trial and a few case reports. OBJECTIVES: Multinational observation series to evaluate the pragmatic "real-life" application of tPA/DNase treatment for pleural infection in a large cohort of unselected patients. METHODS: All patients from eight centers who received intrapleural tPA/DNase for pleural infection between January 2010 and September 2013 were included. Measured outcomes included treatment success at 30 days, volume of pleural fluid drained, improvement in radiographic pleural opacity and inflammatory markers, need for surgery, and adverse events. MEASUREMENTS AND MAIN RESULTS: Of 107 patients treated, the majority (92.3%) were successfully managed without the need for surgical intervention. No patients died as a result of pleural infection. Most patients (84%) received tPA/DNase more than 24 hours after failing to respond to initial conservative management with antibiotics and thoracostomy. tPA/DNase increased fluid drained from a median of 250 ml (interquartile range [IQR], 100-654) in the 24 hours preceding commencement of intrapleural therapy to 2,475 ml (IQR 1,800-3,585) in the 72 hours following treatment initiation (P < 0.05). We observed a corresponding clearance of pleural opacity on chest radiographs from a median of 35% (IQR 25-31) to 14% (7-28) of the hemithorax (P < 0.001), as well as significant reduction in C-reactive protein (P < 0.05). Pain necessitating escalation of analgesia occurred in 19.6% patients, and nonfatal bleeding occurred in 1.8%. CONCLUSIONS: This large series of patients who received intrapleural tPA/DNase therapy provides important evidence that the treatment is effective and safe, especially as a "rescue therapy" in patients who do not initially respond to antibiotics and thoracostomy drainage.