Meera R. Gupta

Effect of Etiology and Timing of Respiratory Tract Infections on Development of Bronchiolitis Obliterans Syndrome

BACKGROUND Among the many potential risk factors influencing the development of bronchiolitis obliterans syndrome (BOS), acute cellular rejection is the most frequently identified. Despite the unique susceptibility of the lung allograft to pathogens, the association with respiratory tract infections remains unclear. In this study we analyze the role respiratory tract infections have on the development of BOS after lung transplantation. METHODS Data from a single center were analyzed from 161 lung recipients transplanted from November 1990 to November 2005, and who survived >180 days. Univariate and multivariate Cox regression analyses were performed using BOS development and the time-scale was reported with hazard ratios (HRs) and confidence intervals (CIs). RESULTS Significant findings by univariate analysis per 100 patient-days prior to BOS onset included acute rejection, cytomegalovirus (CMV) pneumonitis, Gram-negative respiratory tract infections, Gram-positive respiratory tract infections and fungal pneumonias. Multivariate analysis indicated acute rejection, Gram-negative, Gram-positive and fungal pneumonias with HRs (CI) of 84 (23 to 309), 6.6 (1.2 to 37), 6,371 (84 to 485,000) and 314 (53 to 1,856) to be associated with BOS, respectively. Acute rejection, CMV pneumonitis, Gram-positive pneumonia and fungal pneumonitis in the first 100 days had HRs (CI) of 1.8 (1.1 to 3.2), 3.1 (1.3 to 6.9), 3.8 (1.5 to 9.4) and 2.1 (1.1 to 4.0), respectively, and acute rejection and fungal pneumonitis in the late post-operative period with HRs (CI) of 2.3 (1.2 to 4.4) and 1.5 (1.1 to 1.9), respectively. CONCLUSIONS In addition to acute rejection, pneumonias with GP, GN and fungal pathogens occurring prior to BOS are independent determinants of chronic allograft dysfunction. Early recognition and treatment of these pathogens in lung transplant recipients may improve long-term outcomes after transplantation.

Ganciclovir for cytomegalovirus: a call for indefinite prophylaxis in lung transplantation.

BACKGROUND Universal ganciclovir (GCV) prophylaxis is a strategy aimed at reducing cytomegalovirus (CMV) infection and delaying the development of bronchiolitis obliterans syndrome (BOS). However, the optimal duration of GCV prophylaxis remains unclear. We report our experience with GCV prophylaxis administered indefinitely and its effect on CMV pneumonitis, BOS and survival after lung transplantation (LT). METHODS One hundred fifty-one patients surviving >100 days after LT were analyzed. GCV was given to 130 CMV donor- or recipient-seropositive patients. Data from 90 patients who received indefinite GCV prophylaxis (IND) and 40 patients who discontinued their GCV prophylaxis (STOP) were compared. RESULTS CMV pneumonitis occurred in 16%, 8%, 17% and 19% of patients in the D+R+, D-R+, D+R- and D-R- groups, respectively. In the STOP cohort, 15 of 40 patients developed CMV pneumonitis (median time 79 days) after GCV was stopped. Ten of these 15 patients developed BOS (median time 116 days) after discontinuing GCV. The risk of CMV pneumonitis in the STOP cohort was significantly higher when GCV prophylaxis was discontinued within the first year. Cumulative incidence of CMV pneumonitis in the IND and STOP groups at 5 years was 2% and 57%, respectively (p < 0.001). BOS-free survival and survival were similar across both groups. CONCLUSIONS Indefinite GCV prophylaxis prevents CMV pneumonitis in 98% of LT recipients. Thirty-eight percent of patients discontinuing prophylaxis developed CMV pneumonitis, 50% of whom progressed to BOS within 1 year. Continuing ganciclovir prophylaxis indefinitely after lung transplantation should be considered.

Infections in Lung Allograft Recipients: Ganciclovir Era

BACKGROUND Infections are common after lung transplantation. This report analyzes infections and associated pathogens identified in 202 lung transplant recipients. METHODS Infections were tallied according to sites of infection and associated pathogen(s). Infection events were also categorized by post-operative Days 0 to 100, 101 to 365, and after 365, and normalized to 100 patient-days before and after bronchiolitis obliterans syndrome (BOS). RESULTS From November 1990 to November 2005, 202 patients received 208 lung transplants. The follow-up was 702.4 patient-years. A total of 178 lung transplant patients developed 859 infections, with 944 pathogens identified. Infections were in the lung in 559 (65.1%), mucocutaneous (skin, wound, catheter-related, and oral) in 88 (10.2%), in the blood in 85 (9.8%), and in other sites (urine, bowel, eye, and peritoneum) in 127 (14.8%). Most lung pathogens were bacterial (83.6%), and 57.9% were Pseudomonas aeruginosa. Fungi comprised 10.6%, with Aspergillus spp the most common (67.1%) isolate. Cytomegalovirus pneumonitis was seen in 4.3% of respiratory infections. BOS was diagnosed in 87 patients (43.1% of the total). Of all infections seen in the BOS population, there were 0.42 episodes/100 patient-days and 0.70 episodes/100 patient-days before and after BOS, respectively (p = 0.5). CONCLUSIONS These data provide an updated infection profile in the ganciclovir era after lung transplantation. When compared with pre-ganciclovir times, post-transplant cytomegalovirus infection incidence has notably declined, with filamentous fungi emerging as prevalent pathogens in its place. Such findings are important for refining management of infections in order to offer more stringent treatment against aggressive pathogens.

Clostridium difficile colitis in lung transplantation

Purpose. Clostridium difficile colitis (CDC) is the most common nosocomial infection of the gastrointestinal tract in patients with recent antibiotic use or hospitalization. Lung transplant recipients receive aggressive antimicrobial therapy postoperatively for treatment and prophylaxis of respiratory infections. This report describes the epidemiology of CDC in lung recipients from a single center and explores possible associations with bronchiolitis obliterans syndrome (BOS), a surrogate marker of chronic rejection.

Alveolar macrophages contribute to the pathogenesis of human metapneumovirus infection while protecting against respiratory syncytial virus infection.

Human metapneumovirus (hMPV) and respiratory syncytial virus (RSV) are leading causes of upper and lower respiratory tract infections in young children and among elderly and immunocompromised patients. The pathogenesis of hMPV-induced lung disease is poorly understood. The lung macrophage population consists of alveolar macrophages (AMs) residing at the luminal surface of alveoli and interstitial macrophages present within the parenchymal lung interstitium. The involvement of AMs in innate immune responses to virus infections remains elusive. In this study, BALB/c mice depleted of AMs by intranasal instillation of dichloromethylene bisphosphonate (L-CL2MBP) liposomes were examined for disease, lung inflammation, and viral replication after infection with hMPV or RSV. hMPV-infected mice lacking AMs exhibited improved disease in terms of body weight loss, lung inflammation, airway obstruction, and hyperresponsiveness compared with AM-competent mice. AM depletion was associated with significantly reduced hMPV titers in the lungs, suggesting that hMPV required AMs for early entry and replication in the lung. In contrast, AM depletion in the context of RSV infection was characterized by an increase in viral replication, worsened disease, and inflammation, with increased airway neutrophils and inflammatory dendritic cells. Overall, lack of AMs resulted in a broad-spectrum disruption in type I IFN and certain inflammatory cytokine production, including TNF and IL-6, while causing a virus-specific alteration in the profile of several immunomodulatory cytokines, chemokines, and growth factors. Our study demonstrates that AMs have distinct roles in the context of human infections caused by members of the Paramyxoviridae family.

Single-institution study evaluating the utility of surveillance bronchoscopy after lung transplantation.

BACKGROUND Many lung transplant physicians advocate surveillance bronchoscopy with transbronchial lung biopsy and bronchoalveolar lavage (TBB/BAL) to monitor lung recipients despite limited evidence this strategy improves outcomes. This report compares rates of infection (INF), acute rejection (AR), bronchiolitis obliterans syndrome (BOS) and survival in lung allograft recipients managed with surveillance TBB/BAL (SB) versus those with clinically indicated TBB/BAL (CIB). METHODS We reviewed 47 consecutive recipients transplanted between March 2002 and August 2005. Of these recipients, 24 consented to a multi-center trial requiring SB and 23 were managed by our usual practice of CIB. Rates of freedom from INF, AR, BOS and survival were compared. BOS and AR were diagnosed according to published guidelines from the International Society for Heart and Lung Transplantation. RESULTS A total of 240 TBB/BALs were performed. CIB and SB groups underwent 84 (3.7 +/- 3.4/patient) and 156 (6.5 +/- 2.0/patient) TBB/BALs, respectively. In the SB group, 54 (2.2 +/- 1.6/patient) TBB/BALs were true surveillance procedures, whereas 102 (4.2 +/- 2.3/patient) were clinically indicated. No AR episode requiring treatment was detected by true surveillance. Freedom from respiratory INF, AR, BOS and survival in the SB and CIB groups showed no significant differences. Five patients in the CIB group remained stable without requiring TBB/BAL. In the SB group, 4 previously asymptomatic patients developed pneumonia within 2 weeks of surveillance TBB/BAL. CONCLUSIONS With no obvious advantage identified, surveillance bronchoscopy may pose a risk to stable lung transplant recipients. A multi-center, controlled trial is required to validate the utility and safety of surveillance bronchoscopy in lung transplantation.

Impact of hepatitis B core antibody positive donors in lung and heart-lung transplantation: An analysis of the United network for organ sharing database

Background. The availability of suitable lung and heart-lung allografts for transplantation remains poor. Accepting organs from donors with positive serological studies for hepatitis B could potentially expand the donor pool. The aim of this study was to assess the impact of donor hepatitis B core antibody (HBcAb) status on outcomes of lung and heart-lung transplant recipients. Methods. Using United Network for Organ Sharing/Organ Procurement and Transplantation Network data, we compared outcomes of 13,233 recipients of HBcAb negative organs with 333 recipients of HBcAb positive donor organs. Results. We found that the unadjusted 1-year survival of recipients of HBcAb positive donor was worse, but there was no difference in survival after adjusting for baseline donor and recipient differences. On multivariate analysis, recipient and donor age, procedure type, era of transplant, baseline medical condition, diagnosis, and donor hepatitis C antibody status impacted 1- and 5-year survival. However, donor HBcAb status did not impact 1- or 5-year survival posttransplant. Conclusions. Lung and heart-lung allografts from HBcAb positive donors may be safely used, which would increase the number of transplants performed without compromising recipient outcomes.

Clinical spectrum of gram‐positive infections in lung transplantation

Purpose. Gram‐positive (GP) organisms are among the most common cause of infections in early postsurgical and immunocompromised populations. Patients recovering from lung transplantation (LT) are particularly susceptible owing to the physiologic stress imposed by surgery and induction with intense immunosuppression. Sites, types, and timing of GP infections following LT  are not well documented. This report describes the clinical spectrum of GP infections and their effects on surgical airway complications (SAC) and bronchiolitis obliterans syndrome (BOS) following LT.

Differential response of BDCA-1+ and BDCA-3+ myeloid dendritic cells to respiratory syncytial virus infection

BackgroundRespiratory syncytial virus (RSV) is the leading cause of respiratory infections in children, elderly, and immunocompromised individuals. Severe infection is associated with short- and long-term morbidity including pneumonia, recurrent wheezing, and abnormal pulmonary function, and several lines of evidence indicate that impaired adaptive immune responses during infection are critical in the pathophysiology of RSV-mediated disease. Myeloid Dendritic cells (mDCs) play a pivotal role in shaping antiviral immune responses in the respiratory tract; however, few studies have examined the interactions between RSV and individual mDC subsets. In this study, we examined the effect of RSV on the functional response of primary mDC subsets (BDCA-1+ and BDCA-3+) isolated from peripheral blood.MethodsBDCA-1+ and BDCA-3+ mDCs were isolated from the peripheral blood of healthy adults using FACS sorting. Donor-matched BDCA-1+ and BDCA-3+ mDCs were infected with RSV at a multiplicity of infection (MOI) of 5 for 40 hours. After infection, cells were analyzed for the expression of costimulatory molecules (CD86, CD80, and PD-L1), cytokine production, and the ability to stimulate allogenic CD4+ T cell proliferation.ResultsBoth BDCA-1+ and BDCA-3+ mDCs were susceptible to infection with RSV and demonstrated enhanced expression of CD86, and the inhibitory costimulatory molecules CD80 and PD-L1. Compared to BDCA-3+ mDCs, RSV-infected BDCA-1+ mDC produced a profile of cytokines and chemokines predominantly associated with pro-inflammatory responses (IL-1β, IL-6, IL-12, MIP-1α, and TNF-α), and both BDCA-1+ and BDCA-3+ mDCs were found to produce IL-10. Compared to uninfected mDCs, RSV-infected BDCA-1+ and BDCA-3+ mDCs demonstrated a reduced capacity to stimulate T cell proliferation.ConclusionsRSV infection induces a distinct pattern of costimulatory molecule expression and cytokine production by BDCA-1+ and BDCA-3+ mDCs, and impairs their ability to stimulate T cell proliferation.The differential expression of CD86 and pro-inflammatory cytokines by highly purified mDC subsets in response to RSV provides further evidence that BDCA-1+ and BDCA-3+ mDCs have distinct roles in coordinating the host immune response during RSV infection. Findings of differential expression of PD-L1 and IL-10 by infected mDCs, suggests possible mechanisms by which RSV is able to impair adaptive immune responses.

Clarithromycin for prevention of bronchiolitis obliterans syndrome in lung allograft recipients.

Dhillon GS, Valentine VG, Levitt J, Patel P, Gupta MR, Duncan SR, Seoane L, Weill D. Clarithromycin for prevention of bronchiolitis obliterans syndrome in lung allograft recipients. 
Clin Transplant 2012: 26: 105–110. 
© 2011 John Wiley & Sons A/S.