Citations

Abstract Rationale Legionella species can cause severe community-acquired pneumonia requiring targeted antimicrobial therapy. The impact of time to effective Legionella-directed therapy on mortality is not well defined. Objectives To evaluate the association between time to effective Legionella-directed therapy and mortality in hospitalized patients with community-acquired Legionella pneumonia and to determine whether differences in treatment timing contribute to the excess mortality observed among immunocompromised patients. Methods A retrospective multicenter cohort study of adults hospitalized with laboratory-confirmed community-acquired Legionella pneumonia (2019–2025) was performed. Time from presentation to effective therapy (macrolide, fluoroquinolone, or doxycycline) was recorded. The primary outcome was 90-day mortality. Multivariable logistic regression analysis was performed, adjusting for age, SOFA-2 score (first 6 hours), and immunocompromised status. Secondary analyses included a 24-hour landmark Cox model for 90-day survival and multivariable logistic regression for 30-day mortality. Results Among 310 patients (median age 66.9 years, 44.8% immunocompromised), 90-day mortality was 17.4%. Every 6-hour delay in effective therapy was independently associated with increased 90-day mortality (adjusted OR per 6 hours: 1.11; 95% CI, 1.06–1.17; P < 0.001). Delays >24 hours were associated with worse 90-day survival (adjusted HR, 2.72; 95% CI, 1.65–4.77; P < 0.001). Time to effective therapy was also independently associated with increased odds of 30 day mortality (adjusted OR per 6 hours: 1.06; 95% CI: 1.01-1.11, p = 0.024). Immunocompromised patients experienced longer delays (median, 7.1 versus 3.3 hours; P < 0.001) and higher unadjusted 90-day mortality (22.3% versus 13.5%; P = 0.041), but immunocompromised status was not independently associated with mortality after adjusting for severity and treatment timing. Conclusion Longer time to effective Legionella-directed therapy was independently associated with increased mortality in a graded fashion. Delays were more common among immunocompromised patients, partially accounting for excess mortality in this group, suggesting that timely pathogen-directed therapy may represent a clinically important and potentially modifiable contributor to risk.

Importance Decentralized clinical trials (DCTs) aim to increase trial access for underrepresented populations (URP) and ensure study outcomes, conclusions, and policy-related decisions are applicable to diverse populations. Objective To assess trends in the percentage of accrued participants from more than 120 miles from the research site upon DCT program implementation. Design, Setting, and Participants This descriptive quality improvement study was conducted from January 2024 to March 2025 at Mayo Clinic, a US multiregional, academic medical center (AMC) comprising 3 sites and an affiliated, community-based health care system. All individuals who consented and/or accrued to an institutional review board–approved clinical trial were included. Exposure DCTs are defined as trials with at least 1 decentralized capability beyond remote consent. DCT program development began July 2022. By January 2024, remote consent, video telehealth visits, remote phlebotomy, and device services were implemented across all sites and departments. Remote monitoring and oral medication delivery were available on a limited basis. Prospective automated program and DCT participant data collection and quarterly reporting began in January 2024. Main Outcomes and Measures Percentage of all DCT accrued participants with a residential zip code more than 120 miles from 1 of 3 AMC sites. Results There were 7469 participants (median [IQR] age, 62 [51-70] years; 3594 [48.1%] female; 241 [3.2%] Asian, 391 [5.2%] Black or African American, and 6347 [85.0%] White individuals) accrued to 765 DCTs. During the study period, the percentage of DCT participants residing more than 120 miles from an AMC site ranged from 18.9% in the first quarter (Q1) of 2024 (383 of 2032 participants) to 29.6% in Q1 of 2025 (346 of 1170 participants). Of those accrued, 1147 (15.4%) were of a racial or ethnic URP, ranging from 12.5% in Q1 of 2024 (253 participants) to 17.4% in Q1 of 2025 (204 participants). There were 1554 (20.8%) participants from a rural location, ranging from 16.6% in Q1 of 2024 (338 participants) to 24.9% in Q1 of 2025 (291 participants). Additionally, by geospatial distance from an AMC site, the male-to-female ratio was nearly 50:50, and the age distribution appeared similar. Conclusions and Relevance In this quality improvement study of a DCT program implementation, DCT accruals trended favorably among those residing more than 120 miles from an AMC site and those of rural or URP populations. While these findings cannot be directly attributed to program implementation, they are reassuring that this strategy may address some barriers to clinical trial access. Future studies should assess the sustained effectiveness and scalability of DCT models in improving equitable trial access.

Abstract Rationale Chronic thromboembolic disease (CTED) is characterized by persistent pulmonary vascular obstruction due to unresolved thromboemboli despite at least three months of anticoagulation. Although resting hemodynamics often remain normal, affected patients frequently develop functional limitation due to exercise-induced pulmonary hypertension, ventilatory inefficiency, limited stroke volume augmentation, or preload insufficiency. Such exercise-induced pathophysiological dysregulation can significantly impair quality of life and contribute to poor long-term outcomes. Pulmonary endarterectomy (PEA) is an established treatment for Chronic Thromboembolic Pulmonary Hypertension (CTEPH), offering significant improvements in hemodynamics and survival. Its role in CTED, however, remains unclear. While CTED has traditionally been managed with anticoagulation and supportive therapy, emerging evidence suggests PEA may provide symptomatic and functional benefit in selected CTED patients. Given the ongoing uncertainty regarding the role of PEA in CTED, we performed a systematic review and meta-analysis to define its safety profile and clinical efficacy in this patient subset. Methods A systematic search of PubMed, Cochrane, Embase, Scopus, Web of Science, ClinicalTrials.gov, and Google Scholar was conducted from database inception to March 1, 2025. Of 2,244 records screened, 34 full-text articles were assessed, and seven met the inclusion criteria. Results Across the included studies, the pooled baseline mean values were 20.48 ± 3.03 mm Hg for mean pulmonary arterial pressure (mPAP), 2.83 ± 1.11 Wood units for pulmonary vascular resistance (PVR), and 397 ± 100.08 m for the 6-minute walk distance (6MWD). Pulmonary Endarterectomy (PEA) was consistently associated with significant improvements in hemodynamic and functional outcomes; PEA reduced mPAP by 3.58 mmHg (pooled Standardized Mean Change (SMC)=-1.03; 95% CI, -1.23 to -0.83; P < .05), PVR by 0.86 Woods units (pooled SMC=-0.86; 95% CI, -1.05 to -0.67; P < .05), while, conversely, increased 6MWD by 37.49 m (pooled SMC, 0.49; 95% CI, 0.32 to 0.67; P < .05). Study-level effect sizes for 6MWD ranged from 0.21 to 1.47 (Figure 1A). This clinical improvement is further reflected in the enhancement of the NYHA functional class, as illustrated in Figure 1B. Conclusion PEA was associated with significant reductions in mPAP and PVR, as well as a considerable improvement in functional capacity in patients with CTED, with robust results across multiple tests for bias, influence, and sensitivity analyses. These findings support PEA as a viable therapeutic option for selected patients with CTED, although further research is warranted. This abstract is funded by: None

OBJECTIVES: Pneumocystis jirovecii pneumonia (PCP) can cause severe hypoxemic respiratory failure in immunocompromised patients. Contemporary outcomes of venovenous extracorporeal membrane oxygenation (VV ECMO) support for PCP are poorly characterized, and existing reports are limited to small case series. DESIGN: Retrospective cohort study. SETTING: International registry study using the Extracorporeal Life Support Organization (ELSO) registry. PATIENTS/SUBJECTS: Adults with PCP-associated hypoxemic respiratory failure supported with VV ECMO between 2011 and 2024. INTERVENTIONS: VV ECMO. MEASUREMENTS AND MAIN RESULTS: A total of 209 patients with PCP-associated respiratory failure supported with VV ECMO were identified. The overall in-hospital mortality was 60.8%. Survivors were younger than nonsurvivors (median age 41.9 vs. 46.8 yr; p = 0.047). Duration of mechanical ventilation before VV ECMO was longer among nonsurvivors (median 4.7 vs. 1.6 d; p = 0.019). The proportion of patients with HIV infection was similar among survivors and nonsurvivors (19.5% vs. 22.1%; p = 0.73). Pre-ECMO vasopressor use, prone positioning, and renal replacement therapy were common and did not differ between groups. Clinical course was characterized by prolonged VV ECMO support (median 18.6 d) and frequent complications, including pneumothorax (21.1%), renal replacement therapy during VV ECMO (31.6%), intracranial hemorrhage or stroke (7.7%), and major pulmonary or gastrointestinal hemorrhage (16.8%). PCP accounted for a small proportion of VV ECMO runs reported to the ELSO registry throughout the study period at 0.36% of reported cases. No significant temporal trend in mortality was observed. CONCLUSIONS: PCP-associated respiratory failure supported with VV ECMO is associated with substantial mortality and prolonged VV ECMO support. These findings provide contemporary benchmarks that may inform VV ECMO candidacy discussions and expectations in this challenging patient population.

Introduction Sepsis is a global health priority with nearly 50 million cases annually. Cardiovascular dysfunction is common, frequently manifesting as hypotension that persists despite fluid resuscitation. Most affected patients require the use of intravenous (IV) vasoactive agents, typically necessitating intensive care unit (ICU)-level monitoring, invasive interventions and contributing substantially to healthcare costs. Midodrine, an oral alpha-1 agonist approved for orthostatic hypotension, has increasingly been used off-label as a vasopressor-sparing (reducing IV vasopressor use) strategy in sepsis, despite limited and inconsistent evidence. This pragmatic, randomised, open-label trial evaluates the efficacy and safety of midodrine in patients with sepsis-associated hypotension. We hypothesise that, compared with standard care, midodrine administration will reduce the duration of IV vasopressor use. Methods and analysis A total of 308 adult patients with sepsis-associated hypotension will be enrolled (154 per arm). The intervention group will, in addition to standard of care, receive enteral midodrine 10 mg three times daily. Outcomes will be ascertained pragmatically via electronic health record-based data retrieval and adjudicated by research coordinators blinded to treatment assignment. The primary outcome is time alive and off IV vasopressors in the first 28 days (in hours) after randomisation. Secondary outcomes include cumulative vasopressor exposure; use and duration of central venous access; cumulative fluid balance over the first 48 hours and up to 7 days of ICU stay; ICU and hospital length of stay; and ICU-, hospital-, and organ support-free days through day 28. Safety outcomes include adverse events potentially attributable to midodrine during hospitalisation including acute kidney injury. Primary analyses will follow an intention-to-treat framework, including all randomised participants according to their assigned treatment groups. Primary and secondary outcomes will be compared using a van Elteren test stratified by randomisation factors. A predefined secondary Bayesian analysis of the primary outcome will provide complementary estimates of treatment effect. Safety outcomes will be summarised descriptively without formal between-arm hypothesis testing. Ethics and dissemination The Mayo Clinic Institutional Review Board approved this protocol and required written informed consent from all participants (IRB# 24–0 00 121). Findings will be disseminated through peer-reviewed publications and international conference presentations. Trial registration number NCT06319248 .

Objective Diffuse alveolar hemorrhage (DAH) is a life‐threatening presentation of antineutrophil cytoplasmic antibody–associated vasculitis (AAV). Patients with AAV are at an increased risk of venous thromboembolic events (VTEs). These manifestations can co‐occur; however, the prognosis and management of these patients are poorly understood. Methods In this retrospective observational study, we included patients diagnosed with AAV who presented with both DAH and VTE during the same outpatient visit or in the same inpatient treatment episode. Results Among 121 patients with proven DAH secondary to AAV managed at our institution, 14 (11.6%) were also diagnosed with VTE. Patients were predominantly men (71%) with median age at diagnosis of 67 (interquartile range 56–72) years. Five patients were diagnosed with DAH followed by VTE, four patients were diagnosed with VTE before developing DAH (T‐AAV), and five patients were diagnosed with VTE and DAH simultaneously (HT‐AAV). Inferior vena cava filters were placed in 13 patients (93%). Although most patients received systemic anticoagulation within 30 days of DAH diagnosis, anticoagulation management was individualized based on clinical presentation. One patient with preexisting interstitial lung disease died of respiratory failure after initially presenting with pulmonary embolism and later developing DAH during hospitalization. Bleeding complications, including recurrent DAH or retroperitoneal hematoma, were observed in six patients (43%). Three patients (21%) experienced progression or recurrence of VTE within 90 days. Conclusion Management of patients with DAH and VTE is challenging and should be guided by the severity of DAH, additional organ manifestations of AAV, and risk stratification of the presenting VTE.

Abstract Background Legionella pneumonia is an important cause of severe pneumonia, yet contemporary data describing its clinical phenotype, diagnostic patterns, and outcomes in the modern era are limited. Methods We conducted a retrospective multicenter cohort study of adults with laboratory-confirmed Legionella pneumonia across an integrated health system between January 2019 and September 2025. The primary outcome was 30-day mortality. Severe disease was defined as having a requirement for high-flow nasal cannula, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). Univariate and multivariable logistic regression were used to identify predictors of mortality and severe disease. Results There were 344 patients with laboratory-confirmed Legionella pneumonia during the study period. The median age was 66.6 years, and 45.1% were immunocompromised. Most patients required hospital admission (94.2%), with 36.1% admitted to the intensive care unit; 22.7% required mechanical ventilation and 1.5% ECMO. Thirty- and 90-day mortality were 11.9% and 16.6%, respectively. In multivariable analysis, cirrhosis (OR 10.2, 95% CI 2.15–48.3, P = .003), immunocompromised status (odds ratio [OR] 2.24, 95% CI 1.05–4.77, P = .036), age (OR 1.03, 95% CI 1.00–1.06, P = .031), and lymphopenia at presentation (OR 2.09, 95% CI 1.02–4.24, P = .043) were independently associated with increased 30-day mortality. Among patients who were polymerase chain reaction (PCR) or culture positive, urinary antigen testing was positive in only 25.6%. Conclusions Legionella pneumonia was associated with substantial short-term mortality. Cirrhosis, age, immunocompromised status, and lymphopenia at presentation emerged as independent predictors of 30-day mortality, underscoring the importance of host vulnerability in determining outcomes.

ABSTRACT Background Solid organ transplant (SOT) recipients are at risk for Pneumocystis jirovecii pneumonia (PCP), yet how their clinical phenotype and outcomes compare with other immunocompromised patients without HIV remains poorly defined. Methods We conducted a multicenter retrospective cohort study of adults with proven or probable PCP from 2017 to 2025, including 95 SOT recipients and 588 non‐SOT, non‐HIV immunocompromised patients. The primary outcome was 90‐day mortality, secondary outcomes included new renal failure requiring dialysis, and 30‐day mortality. Outcomes were analyzed using inverse probability weighting (IPW) with winsorization to adjust for baseline differences. Results In unadjusted analysis, SOT recipients had lower 90‐day mortality (hazard ratio [HR]: 0.62, 95% CI 0.39–0.97, p = 0.037). After IPW with winsorization of extreme weights, SOT status remained associated with lower 90‐day mortality (HR: 0.32, 95% CI 0.13–0.76, p = 0.009), and 30‐day mortality (HR: 0.35, 95% CI: 0.14–0.92, p = 0.034). SOT recipients had higher odds of renal failure requiring dialysis in unadjusted analysis (OR: 3.49, 95% CI 1.94–6.14, p < 0.001), which persisted after IPW adjustment (OR: 1.62, 95% CI: 1.04–2.51, p = 0.032). Conclusions Despite higher rates of renal failure requiring dialysis, SOT recipients with PCP experienced significantly improved short‐ and intermediate‐term survival compared with other non‐HIV immunocompromised patients, underscoring the need for further investigation into transplant‐associated contributors to PCP outcomes.

Introduction: Life-support limits (i.e., code status), the first step in the continuum of palliation and end-of-life (EoL) care, stem from decisions made by patients and their providers to align care near the EoL with patients’ wishes. The pandemic created health care strain that may have influenced life-support limitation practices among patients with serious COVID-19. In this study, we examine variations in life-support limitations (do-not-resuscitate, DNR; do-not-intubate, DNI) depending on the hospital and period of hospitalization. Methods: We included all adults admitted to a hospital in the United States with COVID-19 from January 2020 to December 2021 using the VIRUS registry. Our outcome was any life-support limitation on admission (DNR, DNI, or both) using regression modeling. Main exposures were hospital and period of hospitalization (early vs. late pandemic). Covariates included age, sex, race/ethnicity, comorbidities, and hospitalization diagnoses. Results: There were 42,383 patients from 75 hospitals in the US. The median age was 63 (interquartile range: 50–75), 46.5% were female, and 37.5% were non-Hispanic White. The life-support limitation rate was 7.9%, and the palliative care consultation rate was 2.3%. The odds of life-support limitation were 1.86 (95% CI: 1.6–2.1) depending on the hospital, but the period of hospitalization was not associated with odds of life-support limitation. Older age was associated with the greatest increased odds (4.1 per standard deviation ∼ 17.9 years, 95% CI: 3.9–4.4), followed by comorbidities including paralysis (2.4, 95% CI: 1.8–3.0) and dementia (2.3, 95% CI: 2.0–2.6). Conclusions: After adjusting for patient-level factors, we report significant inter-hospital but no temporal variation in life-support limitation upon admission with COVID-19. Future studies should investigate specific practices that led to health care resilience to temporal practice variations in life-support limitation during the pandemic.