Faculty Bibliography

New methods and technologies within the field of lung biology are beginning to shed new light into the microbial world of the respiratory tract. Long considered to be a sterile environment, it is now clear that the human lungs are frequently exposed to live microbes and their by-products. The nature of the lung microbiome is quite distinct from other microbial communities inhabiting our bodies such as those in the gut. Notably, the microbiome of the lung exhibits a low biomass and is dominated by dynamic fluxes of microbial immigration and clearance, resulting in a bacterial burden and microbiome composition that is fluid in nature rather than fixed. As our understanding of the microbial ecology of the lung improves, it is becoming increasingly apparent that certain disease states can disrupt the microbial-host interface and ultimately affect disease pathogenesis. In this Review, we provide an overview of lower airway microbial dynamics in health and disease and discuss future work that is required to uncover novel therapeutic targets to improve lung health.

BACKGROUND:Shortened telomeres are associated with several different subtypes of interstitial lung disease (ILD), although studies of telomere length and ILD in rheumatoid arthritis (RA) are lacking. METHODS:Within the Veterans Affairs Rheumatoid Arthritis (VARA) registry, we performed cross-sectional and case-control studies of prevalent and incident ILD, respectively. We randomly selected a subset of RA patients with ILD and individually matched them to RA patients without ILD according to age, sex, and VARA enrollment date. Telomere length was measured on peripheral blood leukocytes collected at registry enrollment using quantitative PCR (T/S ratio). Short telomeres were defined as a T/S ratio in the lowest 10th percentile of the cohort. RESULTS:Our cross-sectional study cohort was comprised of 54 RA-ILD patients and 92 RA-non-ILD patients. T/S ratios significantly differed between patients with and without prevalent ILD (1.56 [IQR 1.30, 1.78] vs. 1.96 [IQR 1.65, 2.27], p < 0.001). Similarly, prevalence of ILD was significantly higher in patients with short vs. normal-length telomeres (73.3% vs. 32.8%, p = 0.002). Short telomeres were independently associated with an increased odds of prevalent ILD compared to normal-length telomeres (adjusted OR 6.60, 95% CI 1.78-24.51, p = 0.005). In our case-control analysis, comprised of 22 incident RA-ILD cases and 36 RA-non-ILD controls, short telomeres were not associated with incident RA-ILD (adjusted OR 0.90, 95% CI 0.06-13.4, p = 0.94). CONCLUSION/CONCLUSIONS:Short telomeres were strongly associated with prevalent but not incident ILD among patients with RA. Additional studies are needed to better understand telomere length dynamics among RA patients with and without ILD.

Little is known about the effects of hepatitis C viremia on immunologic outcomes in the era of direct-acting antivirals. We conducted a prospective, single-arm trial of lung transplantation from hepatitis C-infected donors into hepatitis C-naïve recipients (n = 21). Recipients were initiated on glecaprevir-pibrentasvir immediately post-transplant and were continued on therapy for a total of 8 weeks. A control group of recipients of hepatitis C-negative lungs were matched 1:1 on baseline variables (n = 21). The primary outcome was the frequency of acute cellular rejection over 1-year post-transplant. Treatment with glecaprevir-pibrentasvir was well tolerated and resulted in viremia clearance after a median of 16 days of therapy (IQR 10-24 days). At one year, there was no difference in incidence of acute cellular rejection (71.4% vs. 85.7%, P = .17) or rejection requiring treatment (33.3% vs. 57.1%, P = .12). Mean cumulative acute rejection scores were similar between groups (.46 [SD ± .53] vs. .52 [SD ± .37], P = .67). Receipt of HCV+ organs was not associated with acute rejection on unadjusted Cox regression analysis (HR .55, 95% CI .28-1.11, P = .09), or when adjusted for risk factors known to be associated with acute rejection (HR .57, 95% CI .27-1.21, P = .14). Utilization of hepatitis C infected lungs with immediate treatment leads to equivalent immunologic outcomes at 1 year.

In recent years, our understanding of the microbial world within us has been revolutionized by the use of culture-independent techniques. The use of multi-omic approaches can now not only comprehensively characterize the microbial environment but also evaluate its functional aspects and its relationship with the host immune response. Advances in bioinformatics have enabled high throughput and in-depth analyses of transcripts, proteins and metabolites and enormously expanded our understanding of the role of the human microbiome in different conditions. Such investigations of the lower airways have specific challenges but as the field develops, new approaches will be facilitated. In this review, we focus on how integrative multi-omics can advance our understanding of the microbial environment and its effects on the host immune tone in the lungs.

Introduction: Community-acquired Cytomegalovirus (CMV) infection in a seronegative transplant recipient (R) from a seronegative donor (D) is a rare occurrence that carries significant clinical and prognostic implications. Few case reports exist describing this entity in lung transplant recipients. Case Report: A 58-year-old man with bilateral lung transplant for sarcoidosis presented with three days of diarrhea and dyspnea. He underwent an uneventful bilateral lung transplantation (CMV D-/R-) six weeks prior, receiving basiliximab and methylprednisolone for induction. He was discharged two weeks later on tacrolimus, mycophenolate motefil, and prednisone taper as maintenance immunosuppression. He was receiving acyclovir for herpes viruses prophylaxis. He was seen weekly post-discharge and continued to have clear chest radiographs and unremarkable bloodwork. On presentation, his physical examination was notable for decreased breath sounds at the right base. His laboratory values revealed creatinine of 2.4 mg/dL. His chest radiograph showed new right pleural effusion. He was admitted for hydration and diarrhea work up. Abdominal computed tomography (CT) revealed mild diverticulitis with no colitis and his stool studies were positive for Clostridium difficile. Chest CT showed hazy and linear markings with thin-walled cysts in right lower lobe, adjacent to a moderate pleural effusion. CMV by polymerase chain reaction resulted at 318,200 copies/mL. He was treated with intravenous ganciclovir and underwent a thoracenthesis. Half a liter of clear pleural fluid was removed and was notable for lymphocytic predominance of 72% as well as polytypic plasma cells and a small number of B lymphocytes with no surface immunoglobulins on flow cytometry. Subsequent radiograph showed completely re-expanded lung. Within two days, the effusion re-accumulated and additional half a liter were drained, revealing of 95% lymphocytes, with complete re-expansion of the lung. Concomitant viral load remained elevated at 150,328 copies/mL. He was discharged on valganciclovir, his viral load decreased to an undetectable level, and his radiographs have remained free of effusion. While primary CMV infection is rare in low-risk lung transplant recipients, CMV disease should be considered in the differential diagnosis of early post-operative pleural effusion.
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Primary graft dysfunction (PGD) is a form of acute lung injury after transplantation characterized by hypoxemia and the development of alveolar infiltrates on chest radiograph that occurs within 72 hours of reperfusion. PGD is among the most common early complications following lung transplantation and significantly contributes to increased short-term morbidity and mortality. In addition, severe PGD has been associated with higher 90-day and 1-year mortality rates compared with absent or less severe PGD and is a significant risk factor for the subsequent development of chronic lung allograft dysfunction. The International Society for Heart and Lung Transplantation released updated consensus guidelines in 2017, defining grade 3 PGD, the most severe form, by the presence of alveolar infiltrates and a ratio of PaO₂:FiO₂ less than 200. Multiple donor-related, recipient-related, and perioperative risk factors for PGD have been identified, many of which are potentially modifiable. Consistently identified risk factors include donor tobacco and alcohol use; increased recipient body mass index; recipient history of pulmonary hypertension, sarcoidosis, or pulmonary fibrosis; single lung transplantation; and use of cardiopulmonary bypass, among others. Several cellular pathways have been implicated in the pathogenesis of PGD, thus presenting several possible therapeutic targets for preventing and treating PGD. Notably, use of ex vivo lung perfusion (EVLP) has become more widespread and offers a potential platform to safely investigate novel PGD treatments while expanding the lung donor pool. Even in the presence of significantly prolonged ischemic times, EVLP has not been associated with an increased risk for PGD.

BACKGROUND:Previous studies have reported similarities in long-term outcomes following lung transplantation for connective tissue disease-associated interstitial lung disease (CTD-ILD) and idiopathic pulmonary fibrosis (IPF). However, it is unknown whether CTD-ILD patients are at increased risk of primary graft dysfunction (PGD), delays in extubation, or longer index hospitalizations following transplant compared to IPF patients. METHODS:We performed a multicenter retrospective cohort study of CTD-ILD and IPF patients enrolled in the Lung Transplant Outcomes Group registry who underwent lung transplantation between 2012 and 2018. We utilized mixed effects logistic regression and stratified Cox proportional hazards regression to determine whether CTD-ILD was independently associated with increased risk for grade 3 PGD or delays in post-transplant extubation and hospital discharge compared to IPF. RESULTS:A total of 32.7% (33/101) of patients with CTD-ILD and 28.9% (145/501) of patients with IPF developed grade 3 PGD 48-72 hours after transplant. There were no significant differences in odds of grade 3 PGD among patients with CTD-ILD compared to those with IPF (adjusted OR 1.12, 95% CI 0.64-1.97, p = 0.69), nor was CTD-ILD independently associated with a longer post-transplant time to extubation (adjusted HR for first extubation 0.87, 95% CI 0.66-1.13, p = 0.30). However, CTD-ILD was independently associated with a longer post-transplant hospital length of stay (median 23 days [IQR 14-35 days] vs17 days [IQR 12-28 days], adjusted HR for hospital discharge 0.68, 95% CI 0.51-0.90, p = 0.008). CONCLUSION/CONCLUSIONS:Patients with CTD-ILD experienced significantly longer postoperative hospitalizations compared to IPF patients without an increased risk of grade 3 PGD.

OBJECTIVES/OBJECTIVE:Telomere shortening is a well-established marker of biological aging. Whether telomere erosion coincides with age-related increases in antinuclear antibody (ANA) seropositivity remains unknown. Our study aimed to determine the association between ANA seropositivity and shortened telomeres among 1999-2002 National Health and Nutrition Examination Survey (NHANES) subjects. METHODS:We performed a cross-sectional analysis of 2,188 NHANES study participants with available ANA and telomere length data. ANA testing was performed using indirect immunofluorescence. Telomere lengths were measured via quantitative polymerase chain reaction methods. Applying appropriate sample weighting techniques, we used univariate and multivariate logistic regression methods to assess the association between shortened telomeres (i.e. lowest decile of the cohort) and ANA seropositivity. RESULTS:ANAs were positive in 322 out of 2,188 (14.7%, 95% CI 13.3-16.3%) individuals. Subjects with shortened telomeres were more likely to be older (p<0.001), male (p=0.005), and have a cancer history (p<0.001). A higher proportion of non-Hispanic white participants (61.6% vs. 49.3%) and a lower proportion of non-Hispanic black participants (7.8% vs. 17.9%) had shortened telomeres (p<0.001). Shortened telomeres were not independently associated with ANA seropositivity (OR 1.48, 95% CI 0.87-2.52, p=0.14). However, female sex (OR 1.91, 95% CI 1.23-2.96, p=0.006), age ≥80 years (OR 2.06, 95% CI 1.08-3.92, p=0.03), and African American race (OR 1.58, 95% CI 1.00-2.51, p=0.05) were independent risk factors for ANA seropositivity. Neither sex nor race modified the relationship between ANA seropositivity and telomere length. CONCLUSIONS:Telomere erosion does not appear to be responsible for age-related increases in the prevalence of ANA seropositivity.