Infections In Lung Transplant Recipients Research Articles

186: CD8+ pp65-Specific T Cell Responses and T-Bet Levels Predict Relapsing Viremia Following Primary CMV Infection in Lung Transplant Recipients

Lung transplant recipients (LTRs) mismatched for CMV (D+R-) are at highest risk for active CMV infection and have increased 1-and 5-year mortality. We have previously shown the acquisition of functional CMV-specific CD8+ T cells during primary infection with persistence into chronic infection. However, we observed relapsing viremia within the first 6 months following primary infection in 30% of our D+R- cohort following discontinuation of antiviral therapy. Therefore, we compared CMV-specific CD8+ T cell responses in those LTRs with relapsing viremia compared to those who demonstrated immune control.

Low incidence of severe respiratory syncytial virus infections in lung transplant recipients despite the absence of specific therapy.

BackgroundRespiratory syncytial virus (RSV) infections in lung transplant recipients (LTRs) have been associated with significant morbidity and mortality. Immunoglobulins, ribavirin, and palivizumab are suggested treatments for both pre-emptive and therapeutic purposes. However, in the absence of randomized, placebo-controlled trials, efficacy is controversial and there is toxicity as well as cost concerns.MethodsWe retrospectively reviewed cases of lower respiratory tract RSV infections in adult LTRs. Diagnosis was based on clinical history, combined with a positive polymerase chain reaction (PCR) and/or viral cultures of bronchoalveolar lavage (BAL) specimens.ResultsTen symptomatic patients were identified (7 men and 3 women, age range 28 to 64 years). All were hospitalized for community-acquired respiratory tract infections. Two patients had a concomitant acute Grade A3 graft rejection, and 1 patient had a concomitant bacterial pneumonia. Eight patients did not receive a specific anti-RSV treatment because of clinical stability and/or improvement at the time of RSV diagnosis. Only 2 patients (1 with Grade A3 allograft rejection and 1 requiring mechanical ventilation) received ribavirin and palivizumab. All patients recovered without complications and with no persistent RSV infection. However, bronchiolitis obliterans (BOS) staging worsened in 6 patients during the mean follow-up of 45 months.ConclusionsOur data suggest that mild RSV infections in LTRs might evolve favorably in the absence of specific anti-viral therapy. However, this observation needs confirmation in a large clinical trial specifically investigating the development of BOS in untreated vs treated patients.

Clinical outcomes of solid organ transplant recipients with ehrlichiosis

Because of our experience with severe Ehrlichia infections in lung transplant recipients, we reviewed all cases of ehrlichiosis in solid organ transplant recipients at Barnes-Jewish Hospital in St. Louis, Missouri. Between 1996 and 2007, 25 cases of ehrlichiosis were identified. We retrospectively collected demographic, clinical, laboratory, and outcomes data, and we compared the 5 cases in lung transplant recipients with 20 cases in other solid organ transplant recipients (heart, 2; kidney, 13; liver, 5). The presenting symptoms in the majority of both groups consisted of fever and headache. Clinical outcomes were worse in the lung transplant group and included a greater need for intensive care unit treatment (80% vs. 20%, P=0.02), longer length of hospital stay (21 vs. 5 days, P=0.02), and propensity to develop acute lung injury or acute respiratory distress syndrome (60% vs. 10%, P=0.04). No mortalities occurred in either group of patients. In an endemic area, ehrlichiosis is not unusual in solid organ transplant recipients, and lung transplant recipients tend to have a more severe illness.

Community-Acquired Respiratory Viral Infections in Lung Transplant Recipients: A Single Season Cohort Study

The impact of community-acquired respiratory virus (CARV) infections on bronchiolitis obliterans syndrome (BOS) and outcome after lung transplantation (LTx) and diagnostic techniques were prospectively evaluated. A single-center prospective cohort study was performed in LTx-outpatients between October 31, 2005 and April 30, 2006. Symptoms of respiratory tract infections were recorded and nasopharyngeal and oropharyngeal swabs were obtained. Lower respiratory sampling was performed when indicated. Immunofluorescence testing, cultures, and polymerase chain reaction for 12 different CARV were applied. Patients were followed up until December 31, 2007. New onset and BOS-stage was recorded 1 year after presentation. Three hundred eighty-eight LTx-recipients were screened. Fifty-one percent reported of symptoms of respiratory tract infection. Seven hundred seventy upper and 180 lower respiratory samples were obtained. Thirty-four CARV were detected in 30 patients (7.7%): 12 parainfluenza, 7 respiratory syncytial virus, 6 metapneumovirus, 5 coronavirus, 3 rhinovirus, and 1 influenza virus. At 1 year, 43 new cases of BOS developed. One-year incidence of BOS was 25.0% in CARV-positive versus 9.0% in CARV-negative patients (log-rank P=0.01). Symptomatic CARV-infection proved to be a significant covariate for 1-year BOS-free survival in multivariate analysis (P=0.002, adjusted hazard ratio 4.13). CARV-infection did not influence BOS progression in 88 patients with prior BOS (P 0.45). After paramyxovirus infection, 8 of 24 patients developed new-onset BOS, whereas no case was recorded after rhinovirus and coronavirus infection. Surveillance detected CARV in LTx outpatients infrequently. Symptomatic CARV-infection increases the risk for new onset of BOS, but not progression. Risk to develop BOS was especially increased after paramyxovirus infection.

270: Preceeding Respiratory Viral Infection Is a Strong Risk Factor for Fungal Infection in Lung Transplant Recipients

270: Preceeding Respiratory Viral Infection Is a Strong Risk Factor for Fungal Infection in Lung Transplant Recipients

539: Striking Expansion and Persistence of T-bet+CD8+ CMV-Specific T Cells with Primary Infection in Lung Transplant Recipients

Lung transplant recipients (LTRs) mismatched for CMV (D+R-) are at highest risk of primary CMV infection and have increased 1- and 5-yr mortality. We have previously shown the acquisition of highly functional CMV-specific CD8+ T cells during primary infection with contraction yet persistence during chronic infection in D+R- LTRs. The transcription factor, T-bet, has been shown in mouse models to be central for Type-1 effector responses. We have explored the role of T-bet in directing a highly functional CD8+ T cell response to CMV during human primary infection and its maintenance during chronic infection.

Challenges in the diagnosis and management of Nocardia infections in lung transplant recipients

Nocardia infection occurs in 2.1-3.5% of lung transplant recipients, and may involve cavitary nodular pulmonary lesions, soft tissue infection, or other sites of dissemination. Nocardiosis can pose challenging clinical problems in the areas of diagnosis and treatment. Diagnostic delays may occur, and adverse reactions to therapy are common. This study reviews clinical and epidemiological aspects of nocardiosis in lung transplant recipients, with special attention to pitfalls in management. Clinicians should be alert for these possibilities in order to institute prompt therapy and to achieve successful outcomes. A retrospective cohort study was conducted of 577 lung transplant recipients from January 1991 to May 2007. Demographics, reason for transplant, recent rejection, time from transplantation, site of infection, hypogammaglobulinemia, and/or neutropenia shortly before onset, Pneumocystis jiroveci prophylaxis, Nocardia species, radiographic findings, extrapulmonary lesions, nature and duration of treatment, adverse reactions, and outcomes were recorded. Nocardia infection occurred in 1.9% (11/577). Mean onset was 14.3 months after transplant (range 1.5-39 months). N. asteroides was isolated in 55% (6/11). Emphysema was the most common reason for transplant (7/11, 64%). Six patients were receiving trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis at the time of diagnosis. Three patients had immune globulin G levels <400 mg/dL and 2 were neutropenic in the 3 months preceding diagnosis. Diagnosis was made by bronchoalveolar lavage (55%), skin abscess culture (18%), open lung biopsy (9%), pleural fluid (9%), and sputum culture (9%). Definitive diagnosis required a median of 9 days and a mean of 13.6 days (range 3-35 days) from the time of diagnostic sampling. Soft tissue lesions occurred in 3 and central nervous system involvement in 1 patient. Adverse reactions to therapy occurred in 9/10 (90%) of patients for whom information was available. Nocardia-related mortality occurred in 2/11 patients (18%). Nocardiosis occurred in 1.9% of lung transplant recipients and was associated with a mean of nearly 2 weeks to diagnosis and frequent adverse effects on therapy. TMP-SMX prophylaxis on a thrice weekly basis did not prevent all episodes of nocardiosis. Despite utilization of protocol bronchoscopies with cultures for Nocardia, this organism remains a source of clinical complexity in the lung transplant population.

Nocardia infection in lung transplant recipients

Nocardia is a well-recognized pathogen in immunocompromised hosts, but the incidence of Nocardia infections in lung transplant recipients is not well defined. A chart review from 1990 to 2007 at Clarian Hospital Lung Transplant Center and Indiana University Medical Center revealed Nocardia infections in four of 410 lung transplant recipients despite prophylaxis. All infections were confined to lung and occurred at a median time of 315 d after transplantation. Nocardia nova was isolated in two patients, Nocardia farcinica in one, and unspecified Nocardia sp. in one. Nocardia isolates were susceptible to trimethoprim sulfa (TMP/SMX). Our data suggest that the dose of TMP/SMX, commonly used for Pneumocystis prophylaxis is not protective for Nocardia. Contrary to historic data reporting 40% mortality, none of the patients in our study died because of Nocardia. Nocardia infection is an under-recognized entity in lung transplant recipients, and the optimal duration of therapy and prophylaxis are unclear.

Differential CMV-Specific CD8+ Effector T Cell Responses in the Lung Allograft Predominate over the Blood during Human Primary Infection

Acquisition of T cell responses during primary CMV infection in lung transplant recipients (LTRs) appear critical for host defense and allograft durability, with increased mortality in donor+/recipient- (D+R-) individuals. In 15 D+R- LTRs studied, acute primary CMV infection was characterized by viremia in the presence or absence of pneumonitis, with viral loads higher in the lung airways/allograft compared with the blood. A striking influx of CD8+ T cells into the lung airways/allograft was observed, with inversion of the CD4+:CD8+ T cell ratio. De novo CMV-specific CD8+ effector frequencies in response to pooled peptides of pp65 were strikingly higher in lung mononuclear cells compared with the PBMC and predominated over IE1-specific responses and CD4+ effector responses in both compartments. The frequencies of pp65-specific cytokine responses were significantly higher in lung mononuclear cells compared with PBMC and demonstrated marked contraction with long-term persistence of effector memory CD8+ T cells in the lung airways following primary infection. CMV-tetramer+CD8+ T cells from PBMC were CD45RA- during viremia and transitioned to CD45RA+ following resolution. In contrast, CMV-specific CD8+ effectors in the lung airways/allograft maintained a CD45RA- phenotype during transition from acute into chronic infection. Together, these data reveal differential CMV-specific CD8+ effector frequencies, immunodominance, and polyfunctional cytokine responses predominating in the lung airways/allograft compared with the blood during acute primary infection. Moreover, we show intercompartmental phenotypic differences in CMV-specific memory responses during the transition to chronic infection.

Respiratory Virus Infections in Lung Transplant Recipients: a Brazilian Study

Respiratory Virus Infections in Lung Transplant Recipients: a Brazilian Study

Fungal infections in lung transplant recipients

Despite numerous advances in lung transplantation, survival is still significantly compromised by a higher rate of infections. This review intends to provide an overview of the most common fungal infections afflicting lung transplant recipients, focusing on the most recent developments in diagnosis, therapy and prophylaxis. Although detection of galactomannan in serum has poor sensitivity for the diagnosis of invasive aspergillosis in lung transplant recipients, detection of galactomannan in the bronchoalveolar lavage of a lung transplant recipient, with a compatible clinical illness, is highly suggestive of invasive disease. New antifungal agents, with a broader spectrum of activity and a more tolerable side effect profile, have become available for the treatment and prophylaxis of fungal infections. Evidence suggests that, at least for voriconazole, monitoring of drug concentrations may be advisable to prevent clinical failure due to underdosing and toxicity due to excessive dosing. Fungal infections remain a significant cause of morbidity and mortality in lung transplant recipients; however, advances have been made in the recent years, which will allow earlier diagnosis and more effective and tolerated treatment.

119: Dissecting CMV-Specific Immunity in High-Risk Lung Transplant Recipients: Differences between the Lung Allograft and Blood Effector Memory T Cells

Acquisition of CD8+ T cell responses during primary CMV infection in lung transplant recipients (LTRs) is critical for host defense, and perhaps allograft durability, with increased mortality in donor+/recipient- (D+R-) individuals.

41: Outcomes Following Staphylococcus aureus Respiratory Infections in Lung Transplant Recipients Treated with Oral Linezolid Versus Intravenous Vancomycin

41: Outcomes Following Staphylococcus aureus Respiratory Infections in Lung Transplant Recipients Treated with Oral Linezolid Versus Intravenous Vancomycin

Pulmonary infections after lung transplantation

Lung transplantation has become an accepted therapeutic modality for end-stage diseases of the lungs and the pulmonary circulation. In the past two decades more than 20,000 lung transplantations were performed all over the world. Due to improvements in immunosuppressive regimens the mortality rate of severe acute rejections has decreased up to 2% in the first post-transplant year. By contrast, infections became the most common cause of morbidity and mortality after lung transplantation. It was reported that 21.2 and 40% of annual deaths are due to infections in the first 30 days and one year, respectively. In the first month 35-70% of transplant recipients develop bacterial pneumonia caused often by Gram-negative organisms especially by Pseudomonas species. All patients should receive prophylactic antibiotics after the operation, which are to be modified according to the resistance patterns of pathogens isolated from the donor lungs. In the early post-operative period, the frequency of invasive fungal (Aspergillus and Candida) and cytomegalovirus (CMV) infections appears to be less then 10% due to prophylactic amphotericin inhalation and systemic valganciclovir administration for 100 days. After withdrawing these drugs, these infections became more common. In the late post-transplant period, the development of bronchiolitis obliterans syndrome (BOS) may predispose to infections. BOS may be manifested in approximately 50% of patients 5 years post-transplant. Routinely or urgently performed screening tests (laboratory and radiological investigations, lung function tests, sputum culture, bronchoscopy) and specific treatments are of central importance in the management of infections. In this review we discuss the clinical manifestation, the diagnosis and the treatment possibilities of the most common pulmonary infections in lung transplant recipients.

BK virus‐associated hemorrhagic cystitis in a pediatric lung transplant recipient

BKV was first postulated to be a potential pathogen in 1971 when it was isolated in the urine of a renal transplant recipient. The pathology of BKV is generally confined to the urinary tract. In renal transplant recipients, BKV has been associated with hemorrhagic cystitis, urethral stenosis, and interstitial nephritis. Reports of BKV infection in lung transplant recipients are limited to a few case reports in adult patients. A recent report revealed that up to 32% of adult lung transplant recipients may shed BKV in their urine without symptoms or renal dysfunction. To our knowledge, there are no published reports of pediatric lung transplant recipients with BKV-associated hematuria. We hereby report a case of BKV-induced hemorrhagic cystitis in a pediatric lung transplant recipient.

Airway infection in stable lung transplant patients is associated with decreased intracellular T‐helper type 1 pro‐inflammatory cytokines in bronchoalveolar lavage T‐cell subsets

Current immunosuppression protocols to prevent lung transplant rejection reduce pro-inflammatory and T-helper type 1 (Th1) cytokines. However, Th1 T-cell pro-inflammatory cytokine production is important in host defense against bacterial infection in the lungs. Excessive immunosuppression of Th1 T-cell pro-inflammatory cytokines leaves patients susceptible to infection. To investigate whether pulmonary infection in lung transplant recipients is associated with reduced Th1 T-cell pro-inflammatory cytokines, whole blood and bronchoalveolar lavage (BAL) fluid from 13 stable lung transplant patients with 'culture-negative' BAL and 13 patients with 'culture-positive' BAL was stimulated in vitro, and cytokine production by CD8+ and CD4+ T-cell subsets was determined using multiparameter flow cytometry. In BAL samples, there was a significant decrease in interleukin-2 (IL2) in CD3+ T cells and tumor necrosis factor-alpha (TNF-alpha) in CD8+ T cells (but not CD4+) in 'culture-positive' compared with 'culture-negative' transplant patients. There was no difference in blood Th1 T-cell cytokines between 'culture-positive' compared with 'culture-negative' transplant patients. A decrease in Th1 cytokines IL-2 and TNF-alpha in BAL T-cell subsets is associated with isolation of potentially pathogenic organisms in the lungs in stable lung transplant patients. Excessive immunosuppression of these Th1 T-cell pro-inflammatory cytokines in stable transplant patients may leave them susceptible to infection. Modifying immunosuppression by monitoring intracellular Th1 pro-inflammatory cytokines in BAL T cells may help to improve morbidity and infection rates in stable lung transplant patients.

The incidence of cytomegalovirus infection in lung transplant recipients under universal prophylaxis with intravenous ganciclovir

The best strategy for control of cytomegalovirus (CMV) infection in lung transplant patients is still not determined. The aim of this study was to document the incidence of CMV infection in a cohort of lung transplant recipients under universal prophylaxis with intravenous ganciclovir. All patients received immunosuppressive regimens consisting of cyclosporine, azathioprine, and prednisone. Regardless of CMV serostatus, intravenous ganciclovir was prescribed for every patient in the first 3 months post-transplantation. CMV infection was defined as the detection of CMV pp65 in leukocytes. Eighty-two lung transplant patients were included over a 5-year period. The incidence of CMV infection in the first year post-transplantation was 68.3%, occurring after a median length of 114 days (range, 26-343 days). This study revealed a high incidence of CMV infection in the first year following lung transplantation despite prolonged universal ganciclovir prophylaxis.

Mycobacterium abscessus Infections in Lung Transplant Recipients: The International Experience

The clinical significance of Mycobacterium abscessus infection in the lung transplant population is not well understood. An international survey was performed to determine the incidence and clinical outcomes of M abscessus infections before and after lung transplantation. Thirty-one (50%) of the 62 transplant centers affiliated with the International Society of Heart and Lung Transplantation responded to the survey. Of 5,200 transplants performed, 17 patients (0.33%) (M/F, 12:5) were identified with M abscessus after transplantation. Two patients had respiratory colonization before lung transplantation. Post-transplantation M abscessus infections occurred in the pulmonary allograft in 12, in skin/soft tissue in 3, or both in 2. Median time to diagnosis after transplantation was 18.5 months (range, 1-111 months). Therapies included multiple antibiotics in 16, surgical débridement in 2, interferon-gamma in 1, or no therapy owing to presumed colonization in 1. Eleven (73%) of 16 treated patients had a radiologic or microbiologic response to treatment. Concurrent infections were common, with Aspergillus (n = 8) and Pseudomonas aeruginosa (n = 5) most frequently seen. Death in 2 patients was attributed to M abscessus. Ten of 17 patients are alive and considered cured. M abscessus infection in the lung transplant recipient is uncommon and challenging; however, successful treatment can occur. Prolonged combination anti-microbial therapy is required for pulmonary involvement, and surgical débridement is recommended for cutaneous lesions. Concurrent infections are common and may contribute to mortality in this immunosuppressed population.

Chronic Rhinoviral Infection in Lung Transplant Recipients

Lung transplant recipients are particularly at risk of complications from rhinovirus, the most frequent respiratory virus circulating in the community. To determine whether lung transplant recipients can be chronically infected by rhinovirus and the potential clinical impact. We first identified an index case, in which rhinovirus was isolated repeatedly, and conducted detailed molecular analysis to determine whether this was related to a unique strain or to re-infection episodes. Transbronchial biopsies were used to assess the presence of rhinovirus in the lung parenchyma. The incidence of chronic rhinoviral infections and potential clinical impact was assessed prospectively in a cohort of 68 lung transplant recipients during 19 mo by screening of bronchoalveolar lavages. We describe 3 lung transplant recipients with graft dysfunctions in whom rhinovirus was identified by reverse transcriptase-polymerase chain reaction in upper and lower respiratory specimens over a 12-mo period. In two cases, rhinovirus was repeatedly isolated in culture. The persistence of a unique strain in each case was confirmed by sequence analysis of the 5'NCR and VP1 gene. In the index case, rhinovirus was detected in the lower respiratory parenchyma. In the cohort of lung transplant recipients, rhinoviral infections were documented in bronchoalveolar lavage specimens of 10 recipients, and 2 presented with a persistent infection. Rhinoviral infection can be persistent in lung transplant recipients with graft dysfunction, and the virus can be detected in the lung parenchyma. Given the potential clinical impact, chronic rhinoviral infection needs to be considered in lung transplant recipients.

Mycobacterium abscessus Chest Wall and Pulmonary Infection in a Cystic Fibrosis Lung Transplant Recipient

Mycobacterial infections are increasingly recognized in cystic fibrosis (CF) patients before transplant; however, knowledge about the clinical significance or spectrum of infections observed with mycobacterial infections in lung transplant recipients is still evolving. Herein, we report a case of infection with Mycobacterium abscessus in a CF lung transplant recipient. Despite aggressive treatment before and peri-operatively with anti-mycobacterial therapy, the patient developed skin and soft tissue infection of the incision and of bilateral breast implants, eventually leading to disseminated pulmonary infection and death. This report highlights the potential for M abscessus to cause post-transplant disease in CF patients undergoing lung transplant, despite peri-operative anti-mycobacterial therapy. Thus, pre-transplant colonization with M abscessus should be viewed as a strong relative, if not absolute, contraindication to lung transplantation. The combination of the virulent pre-transplant pathogen M abscessus and foreign bodies in the chest likely acted synergistically to contribute to the unfortunate outcome in this patient.