Use of letermovir for cytomegalovirus primary prophylaxis in lung transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) is a driver of negative outcomes after lung transplant (LTX) and primary prophylaxis (PPX) with valganciclovir (VGC) is standard-of-care. VGC is associated with myelosuppression, prompting interest in letermovir (LTV). METHODS: Adults receiving LTX between April 1, 2015, and July 30, 2022, at our institution were evaluated. Patients were excluded if low CMV risk (D-/R-), survived <90 days post-LTX, or transferred care before PPX withdrawal. Primary outcomes were leukopenia (white blood cell count [WBC] ≤ 3.0 × 109/L), severe leukopenia (WBC ≤ 2.0 × 109/L), and neutropenia (absolute neutrophil count ≤ 1500 cells/µL) requiring granulocyte-colony stimulating factor (GCSF) on PPX. Secondary outcomes included breakthrough CMV infection and post-PPX CMV infection. RESULTS: 204 patients met inclusion criteria: 175 patients on VGC and 29 patients on LTV (after VGC conversion). Most patients received bilateral LTX (62.7%) with non-lymphocyte-depleting induction (96.6%) and moderate-risk serostatus (D+/R+, 48.5%). Patients transitioned from VGC to LTV after a mean of 178 days (SD 80.8 days) post-transplant. Patients on VGC experienced significantly more leukopenia (82.3% vs. 58.6%, p = 0.008), severe leukopenia (57.1% vs. 31.0%, p = 0.016), and neutropenia requiring GCSF (70.9% vs. 51.7%, p = 0.048). Breakthrough (5.7% vs. 3.4%, p = 0.955) and post-PPX (24.6% vs. 37.9%, p = 0.199) infections were similar. A subgroup analysis of patients with high-risk serostatus showed similar trends, though did not reach statistical significance. CONCLUSIONS: In this single-center study, the incidence of leukopenia and neutropenia requiring GCSF were reduced with LTV compared to VGC. Breakthrough and post-PPX infections were not significantly different. This evidence suggests that LTV has comparable efficacy with reduced myelosuppression compared to VGC in LTX recipients, and may be an appropriate alternative for PPX.

A Complement to Traditional Treatments for Antibody-Mediated Rejection? Use of Eculizumab in Lung Transplantation: A Review and Early Center Experience.

OBJECTIVE: To review the efficacy and safety of eculizumab for prevention and treatment of antibody-mediated rejection (AMR) in lung transplant recipients (LTRs). DATA SOURCES: A literature search of PubMed and the Cochrane Controlled Trials Register (2007 to mid-October 2023) was performed using the following search terms: eculizumab, complement inhibitor, solid organ transplant, lung transplant, and AMR. STUDY SELECTION AND DATA EXTRACTION: All relevant English-language studies were reviewed and considered. DATA SYNTHESIS: Eculizumab, a monoclonal antibody that binds complement protein C5 to inhibit its cleavage and subsequent generation of the membrane attack complex, is currently approved to treat paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, generalized myasthenia and neuromyelitis optica spectrum disorder. Given the role of antibodies directed against donor antigens that are produced by allospecific B-cells and plasma cells in AMR, eculizumab is being investigated for use within this indication. Three case reports have described the successful use of eculizumab for the prevention and treatment of AMR in LTRs. Given this lack of robust data, evidence for the use of eculizumab in other solid organ transplant recipients is of increased value. Early experiences from a single center's use of eculizumab in LTRs are also described. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Lung transplant is a recognized treatment for end-stage lung disease, though complications posttransplant can be associated with significant morbidity and mortality. While prevention and management of AMR remains a substantial challenge without comprehensive guidance from societal guidelines, recently published literature may be helpful to guide clinical practice using alternative treatment options. However, this remains an area of great clinical importance, given the impact of AMR on long-term allograft function. CONCLUSIONS: Optimizing use of current therapies, as well as identifying and advancing novel therapeutic modalities such as eculizumab, are vital for the improvement of AMR prevention and treatment in LTRs to extend long-term allograft function and survival.

COVID-19 in lung transplant recipients.

Solid organ transplant recipients are considered at high risk for COVID-19 infection due to chronic immune suppression; little data currently exists on the manifestations and outcomes of COVID-19 infection in lung transplant recipients. Here we report 8 cases of COVID-19 identified in patients with a history of lung transplant. We describe the clinical course of disease as well as preexisting characteristics of these patients.

Case series: Failure of imaging & biochemical markers to capture disease progression in COVID-19.

We report four individuals admitted for acute respiratory failure due to COVID-19 who demonstrated significant clinical improvement prior to discharge and subsequently were readmitted with worsening respiratory failure, elevated inflammatory markers and worsening chest imaging. We propose a multi-disciplinary discharge criterion to establish a safer discharge process including trending inflammatory markers, daily imaging and pursuing follow up CT chest, particularly in individuals with significant morbidities and health disparities.

Mortality for sarcoidosis patients on the transplant wait list in the Lung Allocation Score era: Experience from a high volume center.

RATIONALE: Sarcoidosis progresses to end stage fibrotic lung disease in 10% of patients and may necessitate lung transplantation. Organ allocation is currently determined by the Lung Allocation Score (LAS), but its performance in a sarcoidosis population has not been evaluated. OBJECTIVES: To determine sarcoidosis-specific wait list mortality and identify predictive factors of death on the transplantation wait list. METHODS: This was a single-center retrospective study of all sarcoidosis patients listed for lung transplant from March 2012 to February 2019. We compared patients who were transplanted to those who died awaiting organs. We collected baseline listing characteristics, physiologic testing, and outcomes data. Statistical analysis was performed by 2-tailed Student's t-test, Mann-Whitney U test, and Chi-Square analysis (where appropriate). Receiver-operating characteristic curves were constructed for variables reaching statistical significance. RESULTS: Twenty eight sarcoidosis patients were included in analysis. Mortality among wait listed patients was 18%, which exceeded the mortality of COPD and IPF. LAS scores did not differ at initial listing (41 vs. 46, p = 0.35) or at transplant/death (41 vs. 41, p = 0.91); wait list times also did not statistically differ (307 days vs. 177 days, p = 0.19). We identified bilirubin (AUC = 0.92), DLCO (AUC = 0.84), FEV1/FVC at transplant/death (AUC = 0.85), and composite physiologic index (AUC = 0.86) as predictors of death on the transplant list. Pulmonary hypertension was not associated with death. CONCLUSION: Unexpected sudden death was common in our cohort and was associated with markers of advanced fibrotic disease, not pulmonary hypertension.

Mutant versions of the S. cerevisiae transcription elongation factor Spt16 define regions of Spt16 that functionally interact with histone H3.

In eukaryotic cells, the highly conserved FACT (FAcilitates Chromatin Transcription) complex plays important roles in several chromatin-based processes including transcription initiation and elongation. During transcription elongation, the FACT complex interacts directly with nucleosomes to facilitate histone removal upon RNA polymerase II (Pol II) passage and assists in the reconstitution of nucleosomes following Pol II passage. Although the contribution of the FACT complex to the process of transcription elongation has been well established, the mechanisms that govern interactions between FACT and chromatin still remain to be fully elucidated. Using the budding yeast Saccharomyces cerevisiae as a model system, we provide evidence that the middle domain of the FACT subunit Spt16--the Spt16-M domain--is involved in functional interactions with histone H3. Our results show that the Spt16-M domain plays a role in the prevention of cryptic intragenic transcription during transcription elongation and also suggest that the Spt16-M domain has a function in regulating dissociation of Spt16 from chromatin at the end of the transcription process. We also provide evidence for a role for the extreme carboxy terminus of Spt16 in functional interactions with histone H3. Taken together, our studies point to previously undescribed roles for the Spt16 M-domain and extreme carboxy terminus in regulating interactions between Spt16 and chromatin during the process of transcription elongation.