Pennington, Kelly M.

Abstract Introduction: We present a case of constrictive bronchiolitis with paraneoplastic autoimmune multi-organ syndrome (PAMS) treated with lung transplantation. To our knowledge, this is the first reported case of PAMS with constrictive bronchiolitis managed with this approach. Presentation: A 45-year-old woman presented with 3 months of dyspnea. PFTs showed severe airflow obstruction with air trapping and no immediate bronchodilator response. [FEV1 0.94L (z: -3.9), FVC 2.98L (z: -0.515), TLC 4.89L (z: 1.0), RV 1.70L (z: 2.4) and DLCO 22 ml/min/mmhg (z: 0.58)] CT chest with expiratory views showed air trapping in the left upper lobe and ground glass opacities, consistent with constrictive bronchiolitis. 6 months prior, she was diagnosed with abdominal grade 1 follicular lymphoma, treated with Bendamustine and Rituximab. One month into treatment, she developed a lichenoid rash involving the oro-gential mucosa and erythematous papular skin eruptions. Her eruptions and constrictive bronchiolitis were consistent with PAMS with pulmonary involvement. The rash improved with oral steroids and topical therapies, but her pulmonary symptoms did not. The likelihood of progression was low, so lymphoma was not a contraindication for lung transplantation. To ensure complete metabolic remission, she was further treated with R-CHOP and maintained on Rituximab. During transplant evaluation, FEV1 was 30% with NYHA class II, Karnofsky score 60 and she required 4L oxygen. She grew mycobacterium abscessus subspecies abscessus on 3 different sets of induced sputum. Secondary to radiographic findings consistent with NTM-PD (bronchial wall thickening and mucoid impaction) and pending lung transplant, she was treated with omadacycline, tedizolid, amikacin and clofazimine until sputum culture negativity (3-months). She underwent lung transplantation and received pre-operative Mycophenolate and Methylprednisolone without induction immunosuppression. Post-operatively she was started on Tacrolimus, Mycophenolate Mofetil and Prednisone. M. Abscessus therapy continued for 2 months post-transplant. At 6 months post-transplant, she is well, and PFTs are improving without evidence of organ rejection, lymphoma recurrence, or M. abscessus infection. Discussion: Pulmonary involvement in PAMS is associated with high mortality and is not reversed by treatment of the neoplasm, due to non-reversible destruction of small airways. The only disease modifying therapy is lung transplant. Her lymphoma recurrence risk was very low after 2 years of remission following initial treatment, and as her lymphoma was not associated with immunosuppression, post-transplant immunosuppression likely does not increase risk of recurrence. Additionally, while mycobacterium abscessus poses significant risks, intensive treatment in the peri-transplant period can help allow for safe transplantation.

Abstract Lung transplant recipients are at high risk for pleural complications following transplantation. Pleural effusions are nearly universal immediately after transplant, but most resolve spontaneously in the following weeks. For persistent effusions, there is no consensus on the optimal management strategy, and risks of potential procedures must be balanced with long-term complications. A 58-year-old male presented with 3 months of severe fatigue, brain fog, chills without fever, poor appetite, and weight loss. His medical history included bilateral redo lung transplant 7 months prior for chronic lung allograft dysfunction, type II diabetes mellitus, chronic kidney disease stage IIIb, and heart failure with preserved ejection fraction. His immunosuppression regimen included tacrolimus, prednisone, and mycophenolate, with prophylaxis of trimethoprim/sulfamethoxazole and posaconazole. At the follow up visit, spirometry revealed a significant decline in lung function (FVC 2.31 to 1.97; FEV1 1.84 to 1.51). He was admitted for urgent evaluation. A CT scan revealed a large (20 cm) multiseptated left-sided empyema or hematoma causing mass effect on the spleen and distal pancreas. A 12 French locking loop pigtail catheter was placed into the left pleural space, and fluid analysis showed a total nucleated cell count of 23,306/mcL (100% neutrophils), LDH >9000 U/L, total protein of 1.3 g/dL, glucose <2 mg/dL, and pH <6.80, consistent with empyema. Fungal cultures identified Scedosporium species. The patient received six doses of intrapleural lytics, yielding 3.3 liters of serosanguinous drainage. However, repeat CT showed residual thick fibrinous peel surrounding the pleura. Video-assisted thoracoscopic decortication revealed extensive pleural infection with minimal healthy mucosa, allowing only limited decortication due to bleeding risk. He then underwent open-window thoracostomy (Clagett window) for ongoing drainage, followed by three additional debridement procedures and antifungal therapy with liposomal amphotericin B and voriconazole. This case illustrates the insidious onset of empyema in immunocompromised hosts, such as lung transplant patients, and highlights the rare need for open-window thoracostomy in severe pleural infections.

Abstract Introduction: Calcineurin inhibitor (CNI) nephrotoxicity is a common complication following lung transplant. This is usually treated with dose reduction of CNI, addition of mammalian target of rapamycin inhibitor (mTORi), or rarely, CNI withdrawal which poses the risk of acute and chronic lung allograft rejection. Complete CNI withdrawal and transition to a mTORi based regimen for renal protection is scarcely described in literature with mixed results. Methods: We performed a single center, retrospective chart review of adult lung transplant recipients from January 2010-December 2022 to identify those who underwent complete CNI withdrawal and transition to a mTORi based immunosuppression regimen. Dual organ transplants and external transplant surgeries were excluded. Demographics, and clinical information on immunosuppressive regimens, renal function, rejection episodes, and outcomes were collected. This study was approved by the Mayo Clinic Institutional Review Board. Descriptive statistics were employed. Data is presented as N (%) or median (IQR). Results: A total of 52 patients who underwent CNI withdrawal were identified, and 38 patients (73.1%) were transitioned to a mTORi based regimen for renal failure. The median age at transplant was 59.1 years (IQR 54.2-63.3) and 57.9% were male. The most common transplant indication was pulmonary fibrosis (N = 21, 55.3%). No patients had pre-transplant chronic kidney disease stage 3 or higher. The median length of time from transplant to CNI withdrawal was 13.0 months (IQR 10.0-28.6). Most patients (N = 35 out of 38, 92%) discontinued mTORi and returned to a CNI based regimen after a median duration of use of 4.5 months (IQR 2.4-12.0) for an upcoming procedure/facilitate wound healing (N = 7, 20%), hypervolemia (N =7, 20%), death (N = 6, 17%), lung toxicity (N = 5, 14%), or worsening allograft function (N=5, 14%). Five patients (13.2%) developed ≥ A2 acute cellular rejection. Ten patients (26.3%) developed chronic lung allograft dysfunction. There was no change in creatinine at baseline (just prior to CNI withdrawal) compared to 12 (+/- 3) months after mTORi initiation (p = 0.36). Thirteen patients required dialysis (34.2%), four patients received renal transplants (10.5%), and 1 patient died on the renal transplant waitlist. Conclusions: Our case series demonstrates complete CNI withdrawal and transition to mTORi regimen is associated with short duration of therapy for most patients due to side effects and no change in creatinine one year after transition.

Abstract RATIONALE: Long-term survival after lung transplantation is challenging, with limited research on risk and protective factors. Clinical factors such as younger age, female sex, fewer acute rejection hospitalizations, and double lung transplants are associated with better outcomes. However, the role of psychosocial health and socioeconomic status (SES) remains underexplored. This study aimed to assess the influence of pre-transplant psychosocial health and SES on long-term survival in adult lung transplant recipients. METHODS: We conducted a single-center, retrospective case-control study using the Mayo Clinic Rochester lung transplant registry. Cases (survivors ≥ 6 years) and controls (survivors <6 years) were matched by transplant date (+/- 5 years) and indication for transplant, resulting in 190 subjects (63 cases, 127 controls). We assessed the impact of pre-transplant psychosocial health and SES on long-term survival using initial PACT scores (<2), the HOUSES index, and the national/state area deprivation index (ADI). Additional factors included proximity to the transplant center, insurance type, marital status, primary caregiver status, and employment status. Statistical analyses used the paired Wilcoxon rank-sum test for continuous variables and McNemar's test for categorical variables, with results reported as median (IQR) or percentages. RESULTS: Donor characteristics (age, sex, smoking history, risk criteria, cause of death) and recipient characteristics (age at transplant, sex, BMI, medical condition, functional status, type of transplant) were similar between cases and controls, with no statistically significant differences (all p>0.05). CMV mismatch, waitlist time, and transplant hospital length of stay were also comparable (all p>0.05). Psychosocial health indicators, including proximity to the transplant center, pre-transplant initial PACT score, insurance type, marital status, primary caregiver, and employment status, did not differ significantly between groups (all p>0.05). The HOUSES index was similar between cases and controls (p=0.179). However, long-term survivors had significantly higher national and state ADI scores than controls (national ADI: p=0.029; state ADI: p=0.019). CONCLUSIONS: Pre-transplant psychosocial health indicators, including proximity to the transplant center, initial PACT score, and caregiver support, did not differ significantly between long-term lung transplant survivors and those with shorter survival. Although SES measured by the HOUSES index was not associated with long-term survival, higher national and state ADI scores were linked to increased long-term survival, suggesting unique protective factors for patients from socioeconomically deprived areas. These findings highlight the complex role of socioeconomic factors in lung transplant outcomes and underscore the need for further research into how specific socioeconomic and environmental factors influence long-term survival.

Abstract RATIONALE: Allogeneic hematopoietic stem cell transplant (alloHSCT) is the only curative therapy for multiple hematological malignancies and bone marrow failure syndromes. Graft versus host disease (GvHD), remains one of the leading causes of morbidity and mortality. Bronchiolitis obliterans syndrome (BOS) is the canonical manifestation of chronic GvHD of the lungs, occurring in 3-10% of alloHSCT recipients and conferring poor prognosis. There has been a recent paradigm shift towards using post-transplant cyclophosphamide (PTCy) for GvHD prophylaxis resulting in dramatic decreases in both acute and chronic GvHD compared to traditional regimens using methotrexate and tacrolimus. The effect of PTCy on the development of BOS is not well-studied. METHODS: We performed a retrospective cohort study comparing the cumulative incidence of BOS between 93 patients receiving PTCy and 154 patients receiving non-PTCy containing regimens for GvHD prophylaxis between 2015 and 2023 at a single center (Mayo Clinic, Rochester, MN). Patients were included if they were ever diagnosed with BOS or if they survived and were followed for at least 1 year. BOS was diagnosed using 2014 National Institutes of Health criteria. Patients who met 3 of 4 diagnostic criteria were included if a clinical diagnosis of BOS was made. We performed a competing risks time-to-event analysis to compare the incidence of BOS (or death) between the two cohorts. Outcomes were not adjusted for HSCT type (related, unrelated, or haploidentical [HID]) due to a high degree of collinearity with GvHD prophylaxis strategy. RESULTS: Combined cohorts were median age 55 (40-63), 56% male, and 43% ever smokers. Transplants involved HID donors (59% of PTCy cohort, zero non-PTCy), matched related (10% of PTCy, 44% of non-PTCy), matched unrelated (20% of PTCy, 51% of non-PTCy), and mismatched unrelated donors (11% of PTCy, 5% of non-PTCy). Three-year cumulative incidences of BOS among PTCy and non-PTCy recipients were 7% and 14%, respectively (subdistribution HR 0.52 [95% CI 0.21-1.29], P=0.159). For those who received PTCy, incidence of GvHD was smaller (subdistribution HR 0.64 [95% CI 0.46-0.99], P=0.006) with fewer organs involved (1 versus 2, P=<0.0001) and fewer immunosuppressive therapies employed for treatment (2.0 versus 2.5, P=0.01). CONCLUSION: PTCy may reduce risk of BOS among patients undergoing HSCT. Findings are limited by important differences between the cohorts, such as HCT type, and by small sample size. As PTCy is now increasingly used for non-HID transplants, future studies are needed to examine the effect of PTCy on the development of BOS.

ABSTRACT Background Multiple outpatient therapies have been developed for COVID‐19 in high‐risk individuals, but solid organ transplant (SOT) recipients were not well represented in controlled clinical trials. To date, few comparative studies have evaluated outcomes between outpatient therapies in this population. Methods We performed a retrospective cohort study using de‐identified administrative claims data from OptumLabs Data Warehouse. Patients were included if they were age ≥ 18 years, diagnosed with COVID‐19 between January 2022 and December 2023, and underwent SOT prior to COVID‐19. The primary outcome was 30‐day hospitalization. Stabilized inverse probability of treatment weighting was used to account for potential confounding variables. Results 4192 SOT recipients with COVID‐19 were identified. 1403 received an outpatient COVID‐19 therapy, including anti‐spike monoclonal antibodies ( N = 748, 53.3%), molnupiravir ( N = 327, 23.3%), ritonavir‐boosted nirmatrelvir ( N = 217, 15.5%), or remdesivir ( N = 141, 10.0%). In weighted analysis compared to no treatment, anti‐spike monoclonal antibodies (hazard ratio [HR] 0.39, 95% confidence interval [CI] 0.28–0.55; p < 0.001), molnupiravir (HR 0.56, 95% CI 0.36–0.89; p = 0.013), and nirmatrelvir (HR 0.47, 95% CI 0.25–0.89; p = 0.020) were associated with reduced hospitalization risk, while remdesivir (HR 1.00, 95% CI 0.50–1.98; p = 0.992) was not. Hospitalization rates were similar between the treatment agents, apart from remdesivir showing a higher risk compared to anti‐spike monoclonal antibodies. Conclusions Outpatient COVID‐19 therapies were largely associated with improved outcomes among SOT recipients. These treatment agents showed similar rates of 30‐day hospitalization, except for remdesivir. The choice of outpatient COVID‐19 therapy in SOT recipients should primarily account for patients’ individual circumstances and drug‐drug interactions rather than differential therapeutic efficacy. image

Abstract Background In the United States, a growing number of lung transplants are performed each year, necessitating an increased number of general and transplant pulmonologists skilled in the care of these complex patients. However, pulmonary and critical care medicine (PCCM) fellowships across the country do not universally have dedicated lung transplantation curricula, and there is scarce literature in this area. We describe the generation of a content outline for curriculum development created through modified electronic Delphi methodology. Objective To identify “must know” topics in lung transplantation for a graduating PCCM fellows. Methods We developed expert consensus on “must know” lung transplant topics and subtopics (“items”) for a graduating fellow through three survey rounds from July 2023 to October 2023. Thirty-three panelists were asked to rank author-provided items as “must know,” “nice to know,” or “not necessary to know” and to generate new items in round 1 to be submitted for ranking in subsequent rounds. “Must know consensus” was defined as ≥50% must know responses. Results Survey response and completion rates across rounds were 58–70% and 96–100%, respectively. In round 1, panelists were provided eight topics and 30 subtopics for initial ranking. Panelists generated 82 new items in this round, of which 19 were included in round 2 for ranking after author review, together with one item from round 1 that required reranking. From round 2, only two items required reranking, and these items comprised round 3. Seven topics were identified as “must know”: transplant immunology, evaluation of a lung transplant candidate, surgical and peri/postoperative management, rejection, immunosuppression, infections, and other complications, together with 36 subtopics. Conclusion Self-identified lung transplantation experts obtained consensus on seven “must know” topics and 36 subtopics in lung transplantation for graduating PCCM fellows. The findings serve as a starting point for future curriculum development.

A 40 year old woman who underwent combined heart-lung transplant for familial severe pulmonary hypertension experienced episodes of nonsustained ventricular tachycardia followed by sudden ventricular fibrillation arrest 8 days after transplant. Postarrest investigations revealed left lower lobe herniation into the right lower hemithorax, prompting emergent reoperation, and hernia reduction. Arrhythmias resolved following reduction of the herniated lung and facilitated rapid weaning from vasopressor and ventilatory support. To our knowledge, this is the first reported case of cardiac arrest due to lung herniation after combined heart-lung transplantation. Herein, we describe this rare presentation and offer insights and management strategies for the cardiac intensivist.

ABSTRACTBackgroundEvolving trends in organ procurement and technological innovation prompted an investigation into recent trends, indications, and outcomes following combined heart–lung transplantation (HLTx).MethodsThe United Network for Organ Sharing database was queried for all adult (≥18 years) HLTx performed between July 1, 2013 and June 30, 2023. Patients with previous transplants were excluded. The primary endpoint was the effect of donor, recipient, and transplantation characteristics on 1‐ and 5‐year survival. Secondary analyses included a comparison of HLTx at high‐ and low‐volume centers, an assessment of HLTx following donation after circulatory death (DCD), and an evaluation of HLTx volume over time. Cox proportional‐hazards models were used to assess factors associated with mortality. Temporal trends were evaluated with linear regression.ResultsAfter exclusions, 319 patients were analyzed, of whom 5 (1.6%) were DCD. HLTx volume increased from 2013 to 2023 (p < 0.001). One‐ and 5‐year survival following HLTx was 84.0% and 59.5%, respectively. One‐year survival was higher for patients undergoing HLTx at a high‐volume center (88.3% vs. 77.9%; p = 0.012). After risk adjustment, extracorporeal membrane oxygenation support 72 h posttransplant and predischarge dialysis were associated with increased 1‐year mortality (HR = 3.19, 95% CI = 1.86–5.49 and HR = 3.47, 95% CI = 2.17–5.54, respectively) and 5‐year mortality (HR = 2.901, 95% CI = 1.679–5.011 and HR = 3.327, 95% CI = 2.085–5.311, respectively), but HLTx at a high‐volume center was not associated with either.ConclusionsHLTx volume has resurged, with DCD HLTx emerging as a viable procurement strategy. Factors associated with 1‐ and 5‐year survival may be used to guide postoperative management following HLTx.