ABSTRACT
Background: Neutrophil serine proteases (NSPs) are involved in the pathogenesis of COVID19 and are increased in severe and fatal infection. We investigated whether treatment with Brensocatib, an inhibitor of dipeptidyl peptidase-1, an enzyme responsible for the activation of NSPs, would improve outcomes in hospitalized patients with COVID19. Method(s): In a randomized, double-blind, placebo-controlled trial, 406 hospitalized patients with COVID19 with at least one risk factor for severe disease were randomized 1:1 to once-daily Brensocatib 25mg (n=192) or placebo (n=214) for 28 days. Primary outcome was the 7-point World Health Organisation Clinical Status scale at day 29. Secondary outcomes included time to clinical improvement, national early warning score, new oxygen and ventilation use, neutrophil elastase activity in blood and mortality. Finding(s): Brensocatib treatment was associated with worse clinical status at day 29 (adjusted odds ratio 0 72, 95%CI 0 57-0 92) compared to placebo. The adjusted hazard ratio (aHR) for time to clinical improvement was 0 87 (95%CI 0 76-1 00) and time to hospital discharge was 0 98 (95%CI 0 84-1 13). During the 28-day follow-up period, 23 (11%) and 29 (15%) patients died in the placebo and Brensocatib treated groups respectively). Oxygen and new ventilation use were greater in the Brensocatib treated patients. Neutrophil elastase activity in blood was significantly reduced in the Brensocatib group from baseline to day 29. Prespecified subgroup analyses of the primary outcome supported the primary results.
ABSTRACT
BackgroundCo-infection with Aspergillus previously described to cause significant morbidity and mortality in those with severe Influenza, has more recently been described in COVID-19. ‘Influenza-Associated Pulmonary Aspergillosis’ (IAPA) and ‘COVID-Associated Pulmonary Aspergillosis’ (CAPA) have been reported in up to 23% and 35% of severe disease, respectively. Establishing evidence of invasive Aspergillosis (IA) in these patients is challenging, requiring specific clinical, radiological and microbiological criteria. The burden of IAPA and CAPA in the ICU in our region is unknown.AimsTo identify the incidence of invasive Aspergillosis (IA) and other opportunistic fungal infection in those with severe Influenza and COVID-19 in a district general hospital, Fife, Scotland.MethodsRetrospective cohort review of ICU admissions with severe Influenza or COVID-19 from May 2017 - February 2021. IA was diagnosed using international definitions according to EORTC/MSG, AspICU and modified AspICU criteria.Results89 patients were identified with Influenza (27;median age 53.3 yrs, male 56%) and COVID-19 (62;median age 59.1 yrs, male 61%). No case satisfied criteria for definite IA, however, the majority of patients did not undergo all relevant tests;CT imaging features in 26/89 (29.2%), and fungal biomarkers in 3/89 (3.4%). Two patients demonstrated Aspergillus culture from respiratory samples but did not meet other criteria. Fungal infections were identified in 39/89 (44%), the majority Candida (37), mostly from ET secretions (54%). Candida was significantly higher in COVID-19 than in Influenza, including 2 patients with Candidaemia. Positive fungal culture was associated with increased length of stay (43d vs 20d), ICU bed days (26d vs 19d), but not mortality (33.3% vs 30.0%). Few patients (7.9%) received antifungal treatment, with possible explanations including unclear diagnosis, high costs, uncertain benefit. 54/89 (60.7%) demonstrated bacterial co-infection, including 31/89 (34.8%) with bacteraemia (COVID, 23;Influenza, 8).ConclusionsIAPA and CAPA were not identified in this 4-year cohort, although case finding was limited by inadequate diagnostics. Timely access to fungal biomarkers compromises diagnostic testing. The incidence is likely to be low, despite the significant study limitations. We recommend prospective systematic practice of investigations and improved fungal diagnostics to better understand the burden of Aspergillosis in these patients.