The Registry of the International Society for Heart and Lung Transplantation: twenty-first official adult lung and heart-lung transplant report—2004

Management of pulmonary hypertension (PH) has remained an unmet need in advanced left heart failure with reduced ejection fraction. In fact, patients are frequently denied heart transplant due to untreated pulmonary hypertension. The availability of mechanically circulatory devices and PH therapies has provided a ray of hope. PH specific therapies are currently not FDA approved for patients with left heart failure with reduced ejection fraction. However, clinicians have used these medications in anecdotal manner. With this review, we want to highlight the expanding use of PH specific therapy and mechanical circulatory devices in the management of PH in the setting of advanced heart failure with reduced ejection fraction.

The overall life expectancy of women with cystic fibrosis (CF) is shorter compared with men with CF without accounting for lung transplant recipients. However, it is unclear how donor and recipient gender impact long-term outcomes in patients with CF who undergo lung transplantation. The purpose of this study was to determine if the gender disadvantage seen in women with CF before transplant continues to exist after lung transplant and if this is impacted by donor gender.

Patients with CF entered in the International Society for Heart and Lung Transplantation registry who were at least 18 years old and received a lung transplant between January 2000 and December 2012 were included and divided into groups based on donor-recipient gender combinations. Kaplan-Meier curves were used to determine post-transplant rates of overall survival and bronchiolitis obliterans syndrome (BOS)-free survival.

The analysis included 4,971 patients undergoing lung transplantation for CF. There was no significant difference in BOS-free survival or overall survival rates between genders or between gender-matched vs gender-mismatched recipients after lung transplantation. However, women with CF underwent transplantation at a younger age and died at an earlier overall age than men with CF.

Survival after lung transplantation and time to the development of BOS did not differ based on gender or donor-recipient gender combination. However, women with CF continue to demonstrate a poorer overall life expectancy, as their pre-transplant disadvantage could not be overcome after lung transplantation.

Cardiac allograft vasculopathy (CAV) is a leading expression of chronic organ rejection at and beyond 1 year post-transplantation. Host bone marrow (BM)–derived cell migration to the allograft has been demonstrated in earlier work. Vascular endothelial growth factor (VEGF) is endogenously overexpressed within allografts. Graft neo-angiogenesis has been proposed as a mechanism by which VEGF may contribute to CAV. Herein we assess the therapeutic effect of inhibition of VEGF expression in CAV.

In 129J mice, female donor hearts were heterotopically transplanted into C57/B16 males and treated with soluble VEGF receptor 1 (sVEGFR1) or vehicle control. The effect of VEGF inhibition on BM-mediated microvascular outgrowth and endothelial cell migration and proliferation were assessed using in vitro assays of aortic ring angiogenesis, wound healing and proliferation, respectively.

At 21 days post-transplantation, treatment with sVEGFR1 significantly reduced both percent luminal narrowing (p < 0.05) and percent of vessels affected (p < 0.005). sVEGFR1 significantly reduced average wet heart weight (p < 0.05), whereas mean ventricular cross-sectional area remained similar. Treatment of aortic rings with both sVEGFR1 and VEGFR2 tyrosine phosphorylation inhibitor (Ki 8751) significantly reduced BM-mediated microvascular outgrowth length (p < 0.05) and area (p < 0.05). Treatment of human coronary artery endothelial cells with sVEGFR1 and Ki 8751 significantly reduced BM-mediated endothelial cell migration (p < 0.005) and proliferation (p < 0.05).

VEGF inhibition reduces the severity and incidence of CAV in mouse models of cardiac transplantation, while attenuating myocardial edema and neo-angiogenesis. Using this model, we provide in vitro evidence of the role of VEGF signaling in BM-mediated microvascular outgrowth and endothelial cell migration and proliferation. VEGF inhibition may represent a novel approach to CAV treatment and prevention.

The outcomes of organ transplantation are determined by graft rejection, the mechanisms of which are some of the most important areas of study in the transplantation field. The main cause of rejection is the immunologic response of the recipient toward the transplanted organ. The immunologic responses are regulated by T-cell subsets, especially helper T-cells, which have been characterized as T_H1 or T_H2 cells according to their profiles of cytokines production. A unique subset of recently identified lymphocytes, the regulatory T cells (T_regs), seem to play a role in tolerance. The recently identified T_H17 cells are a subset of effector-helper lymphocytes that specifically secrete interleukin (IL) 17. Interestingly, T_H17 and T_reg both develop from naïve T cells on stimulation by transforming growth factor β. The difference is only the existence of IL-6, a proinflammatory cytokine. T_H17 clears pathogens that are not adequately handled by T_H1 and T_H2 elements, as well as contributing to autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and inflammatory diseases. Autoimmune diseases are caused by reactions to self-antigens. T_H17 (or IL-17) and IL-6 are also thought to be involved in rejection after organ transplantation. We examined the contributions of T_H17 and IL-6 in bronchiolitis obliterans (BO), the histologic finding in chronic rejection of lung transplantations. Earlier studies have reported that T_H17 and IL-6 contribute not only to chronic rejection of lung transplantations, but also to the rejection of other solid organs, e.g., heart, liver, and kidney. In addition, prospective avenues of research on T_H17 and IL-6 in transplantation have emerged from the perspectives of recent studies.

Skin cancer, in particular squamous cell carcinoma (SCC), is the most common malignancy after solid-organ transplantation. SCC has been reported in immunosuppressed patients receiving voriconazole, but the agent has not been shown to be a risk factor. Universal voriconazole prophylaxis and alemtuzumab induction are standard in our lung transplant program.

We performed a retrospective, case–control study (matched 1:3) among lung transplant recipients at our center from 2003 to 2008.

SCC was diagnosed in 3.1% (17 of 543) of patients at a median follow-up of 36 months. Median time to development of SCC was 19 months post-transplant. Risk factors for SCC by univariate analysis included older age (p = 0.02), residence in locations with high levels of sun exposure (p = 0.0001), single-lung transplant (p = 0.02) and duration (p = 0.03) and cumulative dose (p = 0.03) of voriconazole. Duration of voriconazole (hazard ratio [HR] = 2.1; p = 0.04) and residence in locations with high sun exposure (HR = 3.8; p = 0.0004) were independent risk factors by multivariate analysis. SCC lesions were located on the head and neck in 94% of cases, and 53% had multiple lesions. All patients were treated with surgery. At least one independent lesion developed subsequently in 47% of patients. Local spread and distant metastases each occurred in 7% of cases. There were no deaths among the cases.

Voriconazole exposure is a risk factor for SCC after lung transplantation, particularly among older patients living in areas with high sun exposure. Voriconazole should be used cautiously in these patients.