Pennington, K

Abstract Rationale Fungal infections are a significant cause of morbidity in lung transplant recipients. Infections caused by non-Aspergillus species (spp.) fungi, such as Alternaria, Cladosporium, Fusarium, Lomentospora, Mucorales, and Scedosporium, among others, occur infrequently, but recognized cases are increasing. There is a paucity of data assessing post-transplant outcomes following pre-transplant fungal colonization with these non-Aspergillus spp. fungal organisms. Methods We retrospectively reviewed all adult (>18 years) patients who underwent bilateral lung transplantation at either Mayo Clinic Rochester and Mayo Clinic Jacksonville between 01/01/2016 through 12/31/2024, comparing those with pre-transplant fungal colonization to those without fungal colonization. Fungal colonization was defined as positive respiratory culture in either sputum, tracheal aspirate, bronchial brush, bronchoalveolar lavage (BAL) fluid, or swab of explanted lung in asymptomatic patients without radiological or endobronchial evidence of infection. Patients who underwent single lung transplantation, multi-organ transplantation, and those who had previously undergone organ transplantation were excluded from the study. Our primary outcome was severe post-transplant fungal infection, which we defined as proven or probable invasive fungal infection (based on EORTC/MSG criteria), that required hospitalization or additional procedural intervention. Baseline characteristics were summarized using medians with interquartile ranges or counts with percentages, group balance was assessed using standardized mean differences, and associations with post-transplant fungal infection and mortality were evaluated using unadjusted risk ratios (RR) with 95% confidence intervals. Results Of the 449 lung transplant recipients who were included in analysis, a total of 83 patients (18.5%) had pre-transplant fungal colonization, 45 patients (10.0%) with Aspergillus spp. and 38 patients (8.5%) with non-Aspergillus fungi. Compared to those without pre-transplant fungal colonization (n = 366), those with fungal colonization differed significantly in age, gender, body mass index (BMI), Cytomegalovirus (CMV) mismatch status, and transplant indication. The pre-transplant fungal colonization cohort had 4 patients (4.8%) develop any severe fungal infection post-transplant (2 Aspergillus spp. and 2 non-Aspergillus spp.). Pre-transplant fungal colonization was not associated with severe post-transplant fungal infection [RR 1.36 (0.45-4.06)] or with severe post-transplant Aspergillus spp. infection specifically [RR 0.80 (0.18-3.55)]. Unadjusted mortality was also not statistically significant [RR 0.74 (0.47-1.17)]. Conclusions In our cohort of bilateral lung transplant recipients, pre-transplant fungal colonization was not associated with severe post-transplant invasive fungal infection. Although limited by the retrospective nature of the study, the results provide supportive evidence that pre-transplant fungal colonization should not be a precluding factor for undergoing lung transplantation. This abstract is funded by: None

Purpose Mycobacterium avium complex lung disease (MAC-LD) represents the most common form of nontuberculous mycobacterial lung infection, particularly affecting women and older adults. Clinical management remains challenging, including prediction and differentiation between progressive and non-progressive disease. Overexpression of PD-1 pathways have been reported in progressive disease, and we hypothesize that PD-1 inhibition can restore antigen-specific immune responses detectable by FluoroSpot assay. Methods Peripheral blood mononuclear cells from 22 participants, including progressive and non-progressive MAC-LD patients, healthy controls, and individuals with latent tuberculosis infection (LTBI) were stimulated with nontuberculous mycobacteria and Mycobacterium tuberculosis antigens. Cytokine secretion of interferon-gamma (IFN-γ) and interleukin-2 (IL-2) were quantified using dual FluoroSpot assay, with and without PD-1 blockade. Results Progressive MAC-LD cases demonstrated significant increases in glycopeptidolipid (GPL)- and PPD-stimulated IFN-γ responses following PD-1 blockade, which was not seen in healthy controls, LTBI, or non-progressive MAC-LD patients. After GPL stimulation and in the presence of anti-PD-1, the number of IFN-γ responses increased from 25% to 75% in samples from progressive MAC-LD patients. This supports an association between PD-1–mediated T-cell dysfunction and disease progression. Mycobacterial MTB300 peptide pool antigen failed to discriminate MAC-LD from healthy controls, underscoring antigen specificity. Conclusions Our pilot study demonstrates that IFN-γ FluoroSpot assays, particularly when combining GPL or PPD stimulation and PD-1 inhibition, may help identify progressive MAC-LD. These findings also support other studies reporting that immune checkpoint dysregulation can be present in some patients with progressive and severe MAC-LD patients. Additional studies are warranted to determine its pathogenic role.

Abstract Rationale In the early post-lung transplant period, close surveillance is essential to detect allograft dysfunction, infection, or medication toxicity. This requires frequent in-person clinic visits and laboratory testing, creating substantial travel and time burdens for patients and caregivers. Remote patient monitoring (RPM), which uses devices to collect and transmit physiologic and symptom data to the care team, has the potential to reduce geographic barriers and enable earlier detection of changes in patient status. Understanding the feasibility, adherence, and clinical impact of RPM is essential before broader implementation. Methods The Chronic Lung Allograft Monitoring (CLAM) program was launched in August 2024 at our center. Participants were provided a tablet and devices (spirometer, pulse oximeter, scale, and blood pressure cuff) to submit daily physiologic and symptom data. Abnormal parameters triggered review by RPM nurses and escalation to transplant physicians according to protocol. After 12 months of monitoring, patients were transitioned to self-monitoring when clinically appropriate. Demographics, compliance, and escalation characteristics were summarized descriptively. An escalation was defined as any entry triggering an alert to the transplant team. Escalations were categorized by cause and reviewed to determine clinical impact. Results Among 105 enrolled patients, the median age was 64 (IQR 58-68) years, 66 (63%) were male. 70 (67%) remain enrolled, 22 (21%) graduated, and 13 (12%) discontinued monitoring prematurely. reasons for discontinuation included death (n = 7; 7%), patient preference (n = 3; 3%), and non-adherence (n = 3; 3%), yielding an overall dropout rate of 5.7%. Completion rates were 64% for vital sign and spirometry submissions and 91% for symptom questionnaires.There were 395 escalations, with a median of 3 per patient (IQR 1-6); 82 patients (78%) experienced at least one escalation. Causes of escalations are summarized in Figure 1. Of all escalations, 282 (71%) were managed with continued monitoring, while 113 (29%) resulted in changes in care. Seven escalations (1.8%) led to emergency department evaluation and 2 (0.5%) resulted in direct hospital admission. Among non-emergent escalations, 35 (8.8%) prompted expedited clinic visits; of the remainder, 42 (10.6%) led to diagnostic testing orders and 32 (8.0%) resulted in medication initiation or adjustment. Conclusions RPM after lung transplantation was feasible, well accepted, and frequently informed clinical decision-making. The CLAM program demonstrates high engagement and clinical utility, supporting further prospective evaluation of RPM in lung transplant care. This abstract is funded by: None

Abstract Rationale Fungal infections remain a major cause of morbidity and mortality post lung transplant due to unique exposure of the allograft to the external environment and the intensity of immunosuppression. Single-center studies have described variable rates of fungal infections. Contemporary population-level data with temporal trends, pathogen distribution, and associated outcomes are limited. Leveraging a large multicenter real-world dataset, we aimed to characterize incidence, prevalence and clinical outcomes of fungal infections among adult lung-transplant recipients. Methods Data were obtained from the TriNetX Global Collaborative Network (160 HCOs). Adult lung-transplant recipients (≥18 years) were identified between 2005 and 2024, using ICD and CPT procedure codes. Patients with solid organ transplants other than lung, combined-organ transplant or stem-cell transplant and HIV patients were excluded. Patients with pre transplant fungal infections were also excluded. Pre-transplant characteristics included demographics, comorbidities within a year, laboratory values within seven days, and medication within 90 days before transplantation. Post-transplant fungal infections were identified using ICD-10 codes for Aspergillus, Candida, Cryptococcus, Mucorales, Histoplasma, Blastomyces, Coccidioides, and Pneumocystis. TriNetX platform was utilized for statistical analysis. Incidence and prevalence of infections, all-cause mortality and transplant rejection were analyzed. Results A total of 12,857 adult lung-transplant recipients were identified. The mean age at transplantation was 57.6 ± 13.4 years, with a male predominance of (57%) and majority were white (65%). Average BMI was 26.8 ± 5.7 kg/m². The most common pulmonary conditions were COPD (15%), pulmonary fibrosis (17%), pulmonary hypertension (9%), bronchiectasis (3%), and cystic fibrosis (3%). Pre-transplant fungal and viral screening assays were rarely available (<1%). Medication exposure within 90 days prior to transplant demonstrated prednisone prescription (17%) methylprednisolone (7%), tacrolimus (6%), and mycophenolate mofetil (7%). Azathioprine and basiliximab were used in 2% each. Systemic antifungals (voriconazole, posaconazole, or fluconazole) in approximately 1% each.The overall incidence of post-transplant fungal infection was 3 % across full study period, rising to 7% in the modern era (2015-2024). Most frequently identified pathogens were Candida spp. (4.8%) and Aspergillus spp. (2.9%), followed by Pneumocystis Jirovecii (0.5%). Infection rates increased from 22 per 1,000 (2005-2014) to 75 per 1,000 (2015-2024) suggestive of improved diagnostic sensitivity and data capture, and longer post-transplant survival. All-cause mortality 5-year post transplant was 22.1%, and rejection rate was 22.5%. Conclusion Our study highlights a rising burden of fungal infections among lung-transplant recipients with potential implications for early post-transplant surveillance and antifungal prophylaxis strategies. This abstract is funded by: None

Abstract Rationale Fungal infections are common after lung transplantation and may adversely affect graft function and survival, but long-term outcomes remain incompletely defined. Using a large multicenter real-world dataset, we aimed to study the impact of post-transplant fungal infections on clinical outcomes of lung transplant recipients. Methods We conducted a retrospective, cohort study using the TriNetX Global Collaborative Network, which aggregates de-identified electronic health records from >160 healthcare organizations across North America, Europe, and Asia. Adult lung transplant recipients (≥18 years) between 2005 and 2024 were identified using ICD-10 and CPT codes. Patients with post-transplant fungal infection (aspergillosis, candidiasis, mucormycosis, histoplasmosis, coccidioidomycosis, blastomycosis) and matched controls without fungal infection within one year before or any time after transplant were identified. The index date was the date of transplantation. Propensity-score matching was performed on demographics, comorbidities, laboratory values, procedures and immunosuppressive medications. Outcomes included all-cause mortality (primary), allograft rejection, and chronic lung allograft dysfunction (CLAD) at 6 months, 1 year, 3 years, and 5 years. Kaplan-Meier and Cox proportional hazards models were used to estimate risk ratios (RRs), hazard ratios (HRs), and 95% confidence intervals (CIs). Analyses were conducted in TriNetX Analytics (v25.0, Cambridge, MA). Results A total of 3,083 patients with post-transplant fungal infection and 11,625 patients without infection were identified. Mean age was 58 ± 13 years, and 56% were male. The most common pulmonary comorbidities were chronic obstructive pulmonary disease, unspecified pulmonary fibrosis, idiopathic pulmonary fibrosis and bronchiectasis. Immunosuppression exposure was similar across groups. After propensity score matching across 56 clinical variables, both groups (1,790 per group) were well balanced. Mortality was higher in the fungal infection cohort at all follow-up points: 13.% vs 9% at 6 months (RR 1.45, 95% CI 1.2-1.75, p = 0.001), 17.8% vs 13% at 1 year (RR 1.36, p = 0.0001), 27.7% vs 21% at 3 years (RR 1.28, p < 0.0001), and 33 % vs 25% at 5 years (RR 1.32, p < 0.0001). Allograft rejection remained consistently higher (46-61% vs 22-34%), while CLAD occurred two- to three-fold more frequently (1.8-5.7% vs 0.7-2%). Conclusion Post-transplant fungal infection is independently associated with significantly increased mortality, acute rejection, and CLAD following lung transplantation. These findings underscore the need for early fungal surveillance, optimized antifungal prophylaxis, and individualized immunosuppression strategies to improve long-term patient outcomes. This abstract is funded by: None

Abstract Introduction E-cigarette use has risen dramatically in the past decade, accompanied by recognition of e-cigarette or vaping-use associated lung injury (EVALI). Although increasingly reported, the pathophysiology of EVALI remains poorly defined, and its clinical presentation and diagnostic evaluation are often nonspecific. Clinicians should maintain a high index of suspicion given its varied manifestations. We describe a young patient with EVALI complicated by histopathologic evidence of secondary pulmonary alveolar proteinosis (PAP), progressing to severe hypoxemic respiratory failure that ultimately required bilateral lung transplantation. Case Presentation A 28-year-old man with a nine-year history of vaping nicotine and THC-containing hash oil presented with chronic hypoxemic respiratory failure requiring BiPAP. One year earlier, he developed digital clubbing, followed by progressive cough and exertional dyspnea. Initial chest CT showed diffuse centrilobular ground-glass opacities without septal thickening, thought to represent hypersensitivity pneumonitis. Despite vaping cessation several months prior to presentation, his symptoms progressed rapidly, and he required high-flow supplemental oxygen (Fi02 80% at 50 L/min) within weeks of admission. Bronchoscopy with bronchoalveolar lavage and biopsy demonstrated focal organizing pneumonia, pigmented foamy macrophages, and eosinophilic acellular debris within alveoli, consistent with pulmonary alveolar proteinosis (PAP). Cultures and cytology were negative for infection or malignancy. Autoimmune serologies were unrevealing, and no alternative exposures were identified. Due to worsening hypoxemic respiratory failure and lack of response to vaping cessation, steroids, and nebulized sargramostim (recombinant human granulocyte-macrophage colony-stimulating factor), he underwent bilateral lung transplantation. Whole lung lavage was considered but not pursued due to concern for further deterioration. Explant pathology showed interstitial fibrosis with a nonspecific interstitial pneumonia pattern and extensive PAP-like reaction with cholesterol clefts and small airway injury. Discussion EVALI encompasses a broad spectrum of radiographic and histopathologic findings, but secondary pulmonary alveolar proteinosis (PAP) is rarely reported. Diagnostic criteria include e-cigarette use within 90 days and pulmonary infiltrates or ground-glass opacities, with exclusion of malignant, autoimmune, and infectious causes. Although most often associated with ground-glass opacities and organizing pneumonia with diffuse alveolar damage, the pathology of EVALI is variable and poorly understood, further complicated by heterogeneity in vaping exposures. This case highlights PAP as a potential manifestation of EVALI, raising the possibility that impaired alveolar macrophage function and surfactant clearance contribute to hypoxemia in severe disease. Clinicians should maintain a high index of suspicion for EVALI and be aware of its diverse histopathologic spectrum. Continued research is needed to clarify underlying mechanisms and guide management. This abstract is funded by: None