Cryptococcus neoformans infective endocarditis after lung transplantation: a case report and review of the literature.

Cryptococcus neoformans infective endocarditis is rarely reported. In this report, we present a case of infective endocarditis secondary to Cryptococcus neoformans in a lung-transplant recipient and review the relevant literature. A 65-year-old man was hospitalized with hypoxemic respiratory failure and underwent left-sided single lung transplantation. In the setting of worsening hypoxemia, blood cultures were drawn, which grew C. neoformans. Lumbar puncture was performed, and CSF PCR was also positive for Cryptococcus. Further exposure history revealed that he had raised chickens while living in Peru. Transesophageal echocardiography showed an aortic valve vegetation, and he was diagnosed with cryptococcal infective endocarditis. He received liposomal amphotericin B and flucytosine for two weeks and was later transitioned to fluconazole. This case highlights the need for thorough social history prior to lung transplantation, as pulmonary colonization with C. neoformans may result in infective endocarditis after immunosuppression.

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.

Geographic disparities in donor lung supply and lung transplant waitlist outcomes: A cohort study.

Despite the Final Rule mandate for equitable organ allocation in the United States, geographic disparities exist in donor lung allocation, with the majority of donor lungs being allocated locally to lower-priority candidates. We conducted a retrospective cohort study of 19 622 lung transplant candidates waitlisted between 2006 and 2015. We used multivariable adjusted competing risk survival models to examine the relationship between local lung availability and waitlist outcomes. The primary outcome was a composite of death and removal from the waitlist for clinical deterioration. Waitlist candidates in the lowest quartile of local lung availability had an 84% increased risk of death or removal compared with candidates in the highest (subdistribution hazard ratio [SHR]: 1.84, 95% confidence interval [CI]: 1.51-2.24, P < .001). The transplantation rate was 57% lower in the lowest quartile compared with the highest (SHR: 0.43, 95% CI: 0.39-0.47). The adjusted death or removal rate decreased by 11% with a 50% increase in local lung availability (SHR: 0.89, 95% CI: 0.85-0.93, P < .001) and the adjusted transplantation rate increased by 19% (SHR: 1.19, 95% CI: 1.17-1.22, P < .001). There are geographically disparate waitlist outcomes in the current lung allocation system. Candidates listed in areas of low local lung availability have worse waitlist outcomes.

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.

Geographic disparities in lung transplantation in the United States before and after the November 2017 allocation change.

BACKGROUND: The primary lung allocation unit was expanded from the donation service area to a 250-mile radius in 2017. Prior to the change, geographic disparities in donor lung availability impacted waitlist outcomes. We sought to determine if the new allocation system improved these disparities. METHODS: We conducted a retrospective cohort study comparing the 2-year period before and after the change. Donor lung availability was defined as the ratio of donor lungs to waitlist candidates in the primary allocation unit. Transplant centers were divided into quartiles by donor lung availability. Multivariable competing risk models were used to determine the association between lung availability and waitlist outcomes. Multivariable Cox proportional hazards models compared post-transplant survival. RESULTS: Prior to the allocation change, the unadjusted transplant rate at centers in the lowest and highest quartiles was 132 and 607 transplants per 100 waitlist years. Candidates in the lowest quartile of donor lung availability had a 61% adjusted lower transplantation rate compared to candidates in highest quartile (sub-hazard ratio [sHR]: 0.39, 95% confidence interval [CI]: 0.34-0.44). After the allocation change, the disparity decreased resulting in an unadjusted transplant rate of 141 and 309 among centers in the lowest and highest quartiles. Candidates in the lowest quartile had a 38% adjusted lower transplantation rate compared to those in the highest (sHR: 0.62, 95% CI: 0.57-0.68). There was no significant difference in 1-year post-transplant survival. CONCLUSIONS: Although the expansion of the primary allocation unit improved disparities in waitlist outcomes without any change in post-transplant survival, there still remain significant differences due to geography.

The new allocation era and policy.

Since the Department of Health and Human Services (DHHS) issued the Final Rule in 1998 as a guideline for organ transplantation and allocation policies, the lung allocation system has undergone two major changes. The first change came with the implementation of the lung allocation score (LAS) instead of waiting time as the primary determinant for donor lung allocation. The LAS model helped allocate donor lungs based on medical urgency and likelihood of post-transplant success. The LAS has been successful in prioritizing the sickest candidates and reducing waitlist mortality in line with the Final Rule mandates. However, the LAS model did not address geographic variability in donor lung supply and demand, leading to disparities in waiting list survival based on a patient's listing location, which was inconsistent with the Final Rule. In an urgent response to a lawsuit filed by a patient demanding broader geographic access to lungs in November 2017, the second major change in lung allocation occurred when the primary allocation unit for donor lungs expanded from the local donation service area (DSA) to a 250-nautical mile radius around the donor hospital. The Organ Procurement and Transplantation Network has since undergone a review of the current organ allocation systems and has approved a continuous organ distribution framework to guide the creation of a new organ allocation system without rigid geographic borders. In this review, we will describe the history of lung allocation, the changes to the allocation system and their consequences, and the potential future of lung allocation policy in the U.S.

Right single lung transplantation or double lung transplantation compared with left single lung transplantation in chronic obstructive pulmonary disease.

BACKGROUND: Although single and double lung transplantation outcomes for chronic obstructive pulmonary disease (COPD) have been investigated, right and left single lung transplants have never been rigorously compared to evaluate disease-specific differences. Single lung transplants for COPD often have hyperinflation of the contralateral native lung, which may be more pronounced in left lung transplants. METHODS: Using the United Network for Organ Sharing registry, we conducted a retrospective cohort study of 5,585 adults who underwent lung transplantation for COPD from May 4, 2005 to June 30, 2017. Subjects were followed until March 2019. Post-transplant survival was compared using Cox proportional hazards and Royston and Parmar's flexible parametric survival models. We adjusted for donor and recipient factors with known or plausible associations with survival. RESULTS: Lung transplant recipients who received a left single lung transplant for COPD had an increased risk of post-transplant death when compared with those who received a right single lung transplant for COPD (hazard ratio [HR]: 1.24, 95% CI: 1.08-1.48, p = 0.002). Survival did not differ significantly between double lung transplant and right single lung transplant recipients (HR: 0.88, 95% CI: 0.77-1.02, p = 0.086). Adjusted 5-year survival was 57.8% (95% CI: 55.7-60.1) for double lung recipients, 56.7% (95% CI: 55.4-58.0) for right single lung recipients, and 50.9% (95% CI: 47.2-55.0) for left single lung recipients. CONCLUSIONS: In COPD, right single lung transplantation was associated with improved post-transplant survival compared with left single lung transplantation, and no significant difference in post-transplant survival compared with double lung transplantation was found. In light of the ongoing donor lung shortage, preferential allocation of right single lungs to patients with COPD should be considered.

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.

New frontiers in immunosuppression.

Immunosuppressive therapy is arguably the most important component of medical care after lung transplantation. The goal of immunosuppression is to prevent acute and chronic rejection while maximizing patient survival and long-term allograft function. However, the benefits of immunosuppressive therapy must be balanced against the side effects and major toxicities of these medications. Immunosuppressive agents can be classified as induction agents, maintenance therapies, treatments for acute rejection and chronic rejection and antibody directed therapies. Although induction therapy remains an area of controversy in lung transplantation, it is still used in the majority of transplant centers. On the other hand, maintenance immunosuppression is less contentious; but, unfortunately, since the creation of three-drug combination therapy, including a glucocorticoid, calcineurin inhibitor and anti-metabolite, there have been relatively modest improvements in chronic maintenance immunosuppressive regimens. The presence of HLA antibodies in transplant candidates and development of de novo antibodies after transplantation remain a major therapeutic challenge before and after lung transplantation. In this chapter we review the medications used for induction and maintenance immunosuppression along with their efficacy and side effect profiles. We also review strategies and evidence for HLA desensitization prior to lung transplantation and management of de novo antibody formation after transplant. Finally, we review immune tolerance and the future of lung transplantation to limit the toxicities of conventional immunosuppressive therapy.

The methamphetamine-sensitive circadian oscillator (MASCO) in mice.

The suprachiasmatic nucleus (SCN) orchestrates synchrony among many peripheral oscillators and is required for circadian rhythms of locomotor activity and many physiological processes. However, the unique effects of methamphetamine (MAP) on circadian behavior suggest the presence of an SCN-independent, methamphetamine-sensitive circadian oscillator (MASCO). Substantial data collected using rat models show that chronic methamphetamine dramatically lengthens circadian period of locomotor activity rhythms and induces rhythms in animals lacking an SCN. However, the anatomical substrate and the molecular components of the MASCO are unknown. The response to MAP is less well studied in mice, a model that would provide the genetic tools to probe the molecular components of this extra-SCN oscillator. The authors tested the effects of chronic MAP on 2 strains of intact and SCN-lesioned mice in constant dark and constant light. Furthermore, they applied various MAP availability schedules to SCN-lesioned mice to confirm the circadian nature of the underlying oscillator. The results indicate that this oscillator has circadian properties. In intact mice, the MASCO interacts with the SCN in a manner that is strain, sex, and dose dependent. In SCN-lesioned mice, it induces robust free-running locomotor rhythmicity, which persists for up to 14 cycles after methamphetamine is withdrawn. In the future, localization of the MASCO and characterization of its underlying molecular mechanism, as well as its interactions with other oscillators in the body, will be essential to a complete understanding of the organization of the mammalian circadian system.

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.

Morbidity and mortality of orthostatic hypotension: implications for management of cardiovascular disease.

Orthostatic hypotension (OH) is the failure of cardiovascular reflexes to maintain blood pressure on standing from a supine or sitting position. Although OH may cause symptoms of dizziness or syncope, asymptomatic OH (AOH) is far more common and is an independent risk factor for mortality and cardiovascular disease (CVD). The prevalence of AOH increases with age, the presence of hypertension or diabetes and the use of antihypertensive or other medications. The implications of AOH for the treatment of CVD and hypertension are not well defined. This review provides an overview of the current information on this topic and recommends the more frequent assessment of OH in clinical practice and in future clinical trials.