Khattar, Georges

Purpose: To assess chest computed tomography (CT) manifestations of Legionella pneumonia (LP) in a large, well-characterized immunocompetent and immunocompromised patient cohort. Materials and Methods: This retrospective study identified LP patients across a multicenter hospital system over 84-months. Chest CTs were reviewed for presence and distibution of ground-glass opacity (GGO), consolidation, and numerous other findings. CT findings were categorized into lobar, bronchopneumonia, atypical, and mixed patterns. Evolution on follow-up CT was assessed. Results: 311/346 patients (median age 66.6 y [IQR: 55.9, 74.8]; 178 [57.2%] male) had CT examinations available. GGO (98.1%, 305/311) and consolidation (92%, 286/311) were the most prevalent findings, commonly coexisting. The segmental pattern occurred most frequently. The GGO and reverse halo signs occurred in 6.1% (19/311) and 3.5% (11/311), respectively. Follow-up CT occurred in 58.5% (182/311) (median=47.5 d), demonstrating improvement in 84.1% (153/182), worsening in 10.4% (19/182), stability in 5.5% (10/182), and new CT patterns in 12.6% (23/182). Respiratory co-infection occurred in 27.0% (84/311), commonly bacterial. Cavitation occurred in 7.1% (22/311), more frequently among co-infected patients (14.3%, 12/84) than isolated LP (4.4%, 10/227, P =0.005), even more common among immunocompromised patients (12.0% [18/150] vs. 2.5% [4/161], P =0.001), the highest prevalence among co-infected immunocompromised patients (21.3%, 10/47). Co-infection (odds ratio [OR]=3.26, 95% CI=1.33-8.00; P =0.01) and immunocompromise (OR=4.93, 95% CI=1.61-15.1; P =0.005) were independently associated with cavitation. Conclusions: LP presents nonspecifically with a multilobar segmental pattern of GGO and consolidation. Respiratory co-infection was common, often heralded by cavitation. CT findings improve after LP diagnosis.

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.

ABSTRACT Legionella species are important causes of community-acquired pneumonia. The diagnostic performance and clinical implications of a fluorescence resonance energy transfer (FRET)-based real-time PCR assay targeting the Legionella 5S rRNA gene were evaluated, with emphasis on melting temperature (Tm) analysis to differentiate detected species and associated clinical outcomes. A retrospective multicenter cohort study of adults with laboratory-confirmed Legionella infection between 2019 and 2025 was conducted. PCR crossing point (Cp) and Tm data were analyzed and compared with species identified in culture from respiratory specimens. Associations between Tm and clinical outcomes were assessed using multivariable logistic regression. Among 51,489 PCR tests performed, 823 (1.6%) were positive. Among 376 Legionella infections, PCR demonstrated the highest diagnostic yield. Among patients undergoing all three diagnostic tests, the addition of PCR increased detection from 49% with urine antigen and culture combined to 100% ( P < 0.001). Of 189 PCR-positive patient specimens with available Tm data, Tm showed a bimodal distribution, being either <66°C or ≥66°C. A Tm cutoff of ≥66°C discriminated L. pneumophila / L. longbeachae from other Legionella species with excellent performance (AUC, 1.00). Overall, 29.6% of infections had a Tm <66°C, consistent with non- pneumophila/ non- longbeachae Legionella species. Infections due to L. pneumophila / L. longbeachae , which correspond to high Tm values in the study assay, were independently associated with ICU admission (adjusted odds ratio, 2.85; 95% CI, 1.33–6.11; P = 0.007), but not 90-day mortality. Real-time PCR targeting the Legionella 5S rRNA gene provides superior detection compared to culture and/or urine antigen testing and enables higher-risk species discrimination through Tm analysis. IMPORTANCE Nearly one-third of Legionella infections in this cohort were attributable to non- pneumophila species, highlighting limitations of diagnostic strategies reliant on Legionella urine antigen testing or L. pneumophila PCR. The findings suggest that species-level inference can be derived from melting-temperature data generated during routine PCR testing. Incorporating validated melting-temperature interpretation into reporting workflows may improve epidemiologic surveillance and clinical understanding of characteristics of Legionella pneumonia.

Abstract Background Sulfhemoglobinemia is a rare but potentially life-threatening dyshemoglobinemia resulting from the irreversible incorporation of sulfur into the heme moiety, producing hemoglobin species incapable of oxygen transport. Its clinical presentation often mimics methemoglobinemia, with cyanosis and oxygen saturation (SpO2) readings discordant from arterial partial pressure of oxygen (PaO2). Phenazopyridine, an over-the-counter urinary analgesic, has been implicated as a rare cause, in 3 previously documented cases. Prompt recognition is essential to avoid inappropriate therapy, particularly methylene blue, which can precipitate hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Case Presentation A 71-year-old man with Parkinson’s disease, Crohn’s disease, and chronic anemia presented with unexplained cyanosis and SpO2 readings in the 70-80% range, despite a normal PaO2 of 180 mmHg and absence of respiratory symptoms. He had self-initiated phenazopyridine for dysuria three days prior. CT angiography of the chest and echocardiography with bubble study were unremarkable. Attempts to quantify methemoglobin and carboxyhemoglobin were unsuccessful due to analyzer errors. Laboratory evaluation revealed acute anemia (hemoglobin 5.7 g/dL), indirect hyperbilirubinemia, and low haptoglobin consistent with hemolysis. He was managed supportively with high-flow oxygen, and transfusion of two packed red blood cell units. Although initial G6PD levels were normal, testing during hemolysis can yield false negatives. Given this and the risk of methylene blue-induced oxidative stress, conservative management with ascorbic acid was chosen. The patient’s SpO2 improved gradually, and he was discharged on hospital day three. Send-out tests later confirmed sulfhemoglobinemia (1.1%), elevated cytochrome b5 reductase activity, and normal methemoglobin. Discussion This case underscores the diagnostic and therapeutic challenge of differentiating sulfhemoglobinemia from methemoglobinemia. Both disorders produce functional hypoxia with SpO2-PaO2 dissociation, but sulfhemoglobin cannot revert to hemoglobin and requires erythrocyte turnover for resolution. While methylene blue is the standard therapy for methemoglobinemia, it is ineffective for sulfhemoglobinemia and contraindicated in G6PD deficiency. In our patient, supportive care and transfusion facilitated recovery. Using the Naranjo Adverse Drug Reaction Probability Scale, the causality score was 7, indicating a highly probable relationship between phenazopyridine exposure and sulfhemoglobinemia. A high index of suspicion for G6PD deficiency as well as dyshemoglobinemia with a multidisciplinary collaboration are essential for diagnosis and management of unexplained cyanosis. This abstract is funded by: None

Abstract Introduction Drug-induced pneumonitis is an important mimic of disseminated infection in immunocompromised hosts. Lenalidomide, an immunomodulatory agent widely used in multiple myeloma, has been associated with organizing and eosinophilic pneumonitis, and occasionally sarcoid-like granulomatous inflammation. The coexistence of acute fibrinous injury and granulomatous inflammation is exceptionally rare. We present a case of lenalidomide-associated acute fibrinous and granulomatous pneumonitis presenting with a miliary pattern following autologous stem cell transplant. Case Presentation A 44-year-old woman with kappa light-chain multiple myeloma, chronic kidney disease stage V, presented with 10 days of fever (to 105 °F), dry cough, hemoptysis, dyspnea and hypoxia requiring high flow oxygen. She had been on maintenance therapy with lenalidomide, daratumumab, and weekly dexamethasone after undergoing an autologous stem cell transplant for multiple myeloma, last administered one week before symptom onset.. CT chest (Figure 1-1) showed innumerable randomly distributed micronodules with ground-glass opacities and septal thickening, suggesting disseminated infection. Laboratory results revealed eosinophilia (950/µL), neutropenia, and profound hypogammaglobulinemia. Empiric piperacillin-tazobactam, doxycycline, and fluconazole were started for possible bacterial and/or fungal infection (history of positive Coccidioides IgM). Two bronchoscopies demonstrated multifocal hypervascular airway lesions. BAL differential showed 15 % eosinophils and &gt; 30 % lymphocytes; cultures, Fungitell, and comprehensive testing for bacterial, fungal, mycobacterial, viral, and parasitic pathogens were negative. Cryobiopsy revealed acute fibrinous and granulomatous pneumonitis with negative GMS and acid-fast stains. Following withdrawal of lenalidomide and daratumumab, the patient’s symptoms and CT findings improved without further antimicrobial therapy within the same hospitalization (Figure 1-2). She received an 8-week prednisone taper with inhaled pentamidine prophylaxis. Follow-up CT showed complete clinical and radiographic resolution (Figure 1-3), confirming a grade 3 drug-induced pneumonitis. A bronchoscopy will be repeated to assess the endobronchial vascular lesions. Discussion Lenalidomide related lung injury typically manifests as organizing or eosinophilic pneumonitis. The presence of both fibrinous and granulomatous inflammation suggests a mixed hypersensitivity and immune-complex reaction possibly potentiated by immune reconstitution after autologous transplant. The miliary pattern and BAL eosinophilia closely mimic disseminated fungal or mycobacterial infection. A Naranjo Adverse Drug Reaction Probability Scale score of 7 supported a highly probable causal relationship. Awareness of this pattern is essential, as prompt drug cessation and corticosteroid therapy are curative and prevent progression to fibrotic lung injury. 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.

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.