Impact of age and telomere length on circulating T cells and rejection risk after lung transplantation for idiopathic pulmonary fibrosis.

BACKGROUND: Most idiopathic pulmonary fibrosis (IPF) lung transplant recipients (IPF-LTRs) have short telomere (ST) length. Inherited mutations in telomere-related genes are associated with the development of T cell immunodeficiency. Despite this, IPF-LTRs with telomere-related rare variants are not protected from acute cellular rejection (ACR). We set out to determine the impact of both age and telomere length on the circulating T cell compartment and ACR burden of IPF-LTRs. METHODS: We identified 106 IPF-LTRs who had telomere length testing using flowFISH (57 with short telomeres and 49 with long telomeres) as well as a subset from both cohorts who had cryopreserved PBMC at least 1 time point, 6 months posttransplantation. Circulating T cells from before transplantation and at 6 and 12 months posttransplantation were analyzed using multiparameter flow cytometry to study phenotype and functional capacity, and bulk T cell receptor sequencing was performed to study repertoire diversity. Linear regression was used to study the relationship of age and telomere length on early (within 1 year) and late (between 1 and 2 years) ACR. RESULTS: IPF-LTRs with ST were found to have premature "aging" of their circulating T cell compartment, with age-agnostic elevations in posttransplant terminal differentiation of CD8+ T cells, increased granzyme B positivity of both CD8+ and CD4+ T cells, upregulation of the exhaustion marker, CD57, and chemotactic protein CCR5, and enhanced T cell receptor clonal expansion. Additionally, we found a significant decline in early ACR burden with increasing age, but only in the ST cohort. CONCLUSIONS: IPF-LTRs with ST have premature "aging" of their circulating T cell compartment posttransplantation and a clear age-related decline in ACR burden.

Malakoplakia Presenting as a Lung Mass in a Lung Transplant Recipient: Case Report.

Lung nodules or masses due to a variety of malignant or benign conditions such as opportunistic infections are observed after lung transplant. Malakoplakia is a rare complication in immunocompromised patients. Here we describe the clinical course and management of a lung transplant recipient with pulmonary malakoplakia and provide a review of the literature. To our knowledge, this is the first report of a case of pulmonary malakoplakia due to Escherichia coli infection in a lung allograft.

Characteristics and outcomes of lung cancer in solid organ transplant recipients.

OBJECTIVES: Lung cancer is the third most common malignancy that develops in patients following solid organ transplantation and is the leading cause of cancer deaths in the general population. The aims of this study are to examine the characteristics of patients who developed lung cancer following solid organ transplantation at our institution and to compare their outcomes to those of lung cancer patients without a history of transplant. MATERIALS AND METHODS: We performed a single-institution retrospective study of 44 solid organ transplant recipients who developed lung cancer and compared their characteristics to a cohort of 74 lung cancer patients without a history of transplant. We performed propensity score weighted analyses to compare outcomes between the two groups, including a cox proportional hazards model of overall survival. RESULTS: 52 % of post-transplant patients who developed lung cancer were diagnosed with stage III or IV disease. In the propensity score weighted analysis that accounted for age at diagnosis, sex, lung cancer stage at diagnosis, Charlson comorbidity index score, and ECOG performance score, post-transplant patients were more likely to have squamous cell histology (p < 0.01) and had worse overall survival compared to the non-transplant cohort (HR = 1.88, 95 % CI 1.13-3.12, p = 0.02). The difference in survival remained significant after accounting for differences in lung cancer histology and treatment (HR = 2.40, 95 % CI 1.27-3.78, p < 0.01). CONCLUSIONS: When compared to non-transplant patients with lung cancer, post-transplant patients have worse overall survival after accounting for differences in age, sex, lung cancer stage, comorbidities, and performance status. This survival difference is not solely attributable to differences in tumor histology and treatments received. This may suggest that post-transplant malignancies are more aggressive and difficult to treat.

COVID-19 in solid organ transplant recipients: Initial report from the US epicenter.

Solid organ transplant recipients may be at a high risk for SARS-CoV-2 infection and poor associated outcomes. We herein report our initial experience with solid organ transplant recipients with SARS-CoV-2 infection at two centers during the first 3 weeks of the outbreak in New York City. Baseline characteristics, clinical presentation, antiviral and immunosuppressive management were compared between patients with mild/moderate and severe disease (defined as ICU admission, intubation or death). Ninety patients were analyzed with a median age of 57 years. Forty-six were kidney recipients, 17 lung, 13 liver, 9 heart, and 5 dual-organ transplants. The most common presenting symptoms were fever (70%), cough (59%), and dyspnea (43%). Twenty-two (24%) had mild, 41 (46%) moderate, and 27 (30%) severe disease. Among the 68 hospitalized patients, 12% required non-rebreather and 35% required intubation. 91% received hydroxychloroquine, 66% azithromycin, 3% remdesivir, 21% tocilizumab, and 24% bolus steroids. Sixteen patients died (18% overall, 24% of hospitalized, 52% of ICU) and 37 (54%) were discharged. In this initial cohort, transplant recipients with COVID-19 appear to have more severe outcomes, although testing limitations likely led to undercounting of mild/asymptomatic cases. As this outbreak unfolds, COVID-19 has the potential to severely impact solid organ transplant recipients.

Long-term outcomes and management of lung transplant recipients.

Lung transplantation is an established treatment for patients with end-stage lung disease. Improvements in immunosuppression and therapeutic management of infections have resulted in improved long-term survival and a decline in allograft rejection. Allograft rejection continues to be a serious complication following lung transplantation, thereby leading to acute graft failure and, subsequently, chronic lung allograft dysfunction (CLAD). Bronchiolitis obliterans syndrome (BOS), the most common phenotype of CLAD, is the leading cause of late mortality and morbidity in lung recipients, with 50% having developed BOS within 5 years of lung transplantation. Infections in lung transplant recipients are also a significant complication and represent the most common cause of death within the first year. The success of lung transplantation depends on careful management of immunosuppressive regimens to reduce the rate of rejection, while monitoring recipients for infections and complications to help identify problems early. The long-term outcomes and management of lung transplant recipients are critically based on modulating natural immune response of the recipient to prevent acute and chronic rejection. Understanding the immune mechanisms and temporal correlation of acute and chronic rejection is thus critical in the long-term management of lung recipients.