Infections In Lung Transplantation Research Articles

Update on viral infections in lung transplantation

Lung transplantation is an established therapeutic option for patients with severe respiratory insufficiency. Graft dysfunction or rejection depends on the orchestrated prevention of infection(s) and the level of immune suppression. More recent reports underlined the role and pathogenicity of cytomegalovirus (CMV) infection in lung transplant recipients and the double-edged sword of maintaining antiviral immune responses versus guided immune suppression to avoid graft rejection. We present data concerning the nature of the cellular response to Epstein-Barr virus (EBV) and CMV, the subsequent use of cellular therapy in antiviral treatment modalities and discuss the role of H1N1 infection and other viral infections in lung transplantation recipients. Patients after lung transplantation showed a similar susceptibility to H1N1 infections as compared to the local, healthy community. After initial recovery and oseltamivir treatment, lung transplantation patients developed bronchiolitis obliterans syndrome. The genetic background of lung transplant recipients, defined by polymorphism in immune molecules, contributes to increased risk of CMV disease; CMV induces local pro-inflammatory chemokines (CXCL10). Anti-CMV prophylaxis does not impact on anti-CMV-directed cellular immune responses, defined by IFNγ and TNFα production. Asymptomatic EBV carriers showed higher numbers of EBV-reactive T cells. High EBV load carriers showed T cells with immune-exhaustion markers and decreased IFNγ production. Anti-CMV-directed cellular therapy may aid to better manage CMV-associated complications after lung transplantation. Pharmacological immune suppression, the genetic makeup of the patient as well as concurrent viral infections impact on the successful outcome of lung transplantation and call for more detailed immune-guided diagnostics and therapy.

67 Donor-Derived Infections in Lung Transplantation

Donor-derived infections (DDIs) are an adverse consequence of solid-organ transplantation. Potential donor-derived transmission events (PDDTEs) reviewed by the OPTN Disease Transmission Advisory Committee (DTAC) were evaluated to determine the impact of DDIs on lung transplant recipients (LTR).

Feasibility, tolerability, and outcomes of nebulized liposomal amphotericin B for Aspergillus infection prevention in lung transplantation

Nebulized amphotericin B deoxycholate (n-ABD) is used to prevent Aspergillus infection in lung transplantation. Nebulized liposomal amphotericin B (n-LAB) is another option; however, no clinical data are available on the results of n-LAB for this purpose. In an observational study performed in 2 centers to assess the feasibility, tolerability, and outcomes of n-LAB prophylaxis, 104 consecutive patients undergoing prophylaxis with n-LAB were compared with 49 historical controls who received n-ABD. Patient follow-up lasted 12 months. The n-LAB prophylaxis regimen was 25 mg thrice weekly starting on the first post-operative day and continuing to 60 days, 25 mg once weekly from 60 to 180 days, and the same dose once every 2 weeks thereafter. Aspergillus infection developed in 8 of 104 patients (7.7%) with n-LAB prophylaxis (5 colonization, 1 simple tracheobronchitis, 1 ulcerative tracheobronchitis, and 1 invasive pulmonary infection). Ulcerative tracheobronchitis and invasive pulmonary aspergillosis were regarded as invasive disease; hence, the rate of invasive disease was 1.9% (2 patients). The control group had similar rates of Aspergillus infection (10.2%; p = 0.6) and invasive disease (4.1%; p = 0.43). In 3 patients (2.9%), n-LAB was withdrawn due to bronchospasm in 2 and nausea in 1. In the control group, prophylaxis was stopped in 2 patients (4.1%) because of bronchospasm (p = 0.7). At the dose and frequency described, n-LAB seems effective, safe, and convenient for the prevention of Aspergillus infection in lung transplant patients.

Importance of Controlling Drug-resistant Pseudomonas aeruginosa Infection: Experience from Lung Transplantation in a Cystic Fibrosis Case

Cystic fibrosis (CF) is rare in Japan. We encountered a CF case with drug-resistant Pseudomonas aeruginosa infection and successfully performed lung transplant from living related donors. A combination of beta-lactams and aminoglycosides for drug-resistant P. aeruginosa infection was administered before lung transplantation. Intravenous colistin was also used immediately before and after transplant surgery. Gram staining of respiratory specimens was performed every day after surgery and it was useful in monitoring infection status. Strict monitoring of infections by the Gram staining and culture of respiratory specimens is considered to be effective in preventing lower respiratory infection in lung transplantation.

Clinical spectrum of gram‐positive infections in lung transplantation

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. Data were collected from 202 patients undergoing 208 LT procedures at a single institution between November 1990 and November 2005. Data were retrospectively analyzed according to timing, location, and causative pathogen. In the median follow-up period of 2.7 years (range, 0-13.6 years), 137 GP infections were confirmed in 72 patients. Sites of infection included respiratory tract (42%), blood (27%), skin, wound and catheter (21%), and other (10%). GP pathogens identified were Staphylococcus species (77%), Enterococcus species (12%), Streptococcus species (6%), Pneumococcus (4%), and Eubacterium lentum (1%). The likelihood of SAC and BOS was increased in lung allograft recipients with GP pneumonia as compared with those without (hazard ratio 2.1; 95% confidence interval=1.5-3.1). GP organisms were responsible for infections in 40% of lung allograft recipients and most commonly isolated from the respiratory tract and blood stream. Staphylococcal species were most frequently identified, 42% of which were methicillin-resistant Staphylococcus aureus (MRSA). Given the strong association of respiratory tract infections with the development of SAC and BOS, empiric antimicrobial strategies after LT should include agents directed against GP organisms, especially MRSA.

Infections in lung transplantation: new insights

Infections represent a major source of complications in lung transplant recipients (LTR), especially when compared with recipients of other solid organ transplants. Within the past year, new data on the impact and prevention of specific pathogens in the setting of lung transplant have been published. Specifically, this review will assess the effect of Burkholderia infection on cystic fibrosis (CF) patients following lung transplant (LTx), the role that Gram-negative bacilli (GNB) play in the development of bronchiolitis obliterans syndrome (BOS), and the optimal duration of cytomegalovirus (CMV) prophylaxis in LTR. Recent data support the hypothesis that certain Burkholderia species, potentially B. gladioli and specific B. cenocepacia subtypes, pose a greater risk for death in CF LTR than do other Burkholderia species. Additionally, recent data suggest that colonization with GNB, particularly Pseudomonas species, may play a role in the pathogenesis of BOS, the leading cause of late-term mortality in LTR. Finally, recent studies suggest that extended prophylactic regimens may be more efficacious in reducing CMV-related events. Recent data have broadened our understanding of the role that infections play in affecting LTR outcomes. Prospective multicenter studies are needed to further optimize pathogen specific prevention strategies.

Methicillin-resistant Staphylococcus aureus Infection After Lung Transplantation: 5-year Review of Clinical and Molecular Epidemiology

Data on the epidemiology of MRSA infection in lung transplantation is limited. We performed a 5-year retrospective study to assess the incidence and microbiologic and clinical characteristics of methicillin-resistant Staphylococcus aureus (MRSA) infection in a cohort of 163 lung transplant recipients. Seventeen patients with MRSA colonization and/or infection were identified, for a calculated incidence rate of 76.1 cases per 1,000 transplanted-years. Pulsed-field gel electrophoresis identified 3 different distinct MRSA profiles, all of them consistent with hospital-associated MRSA infection. Despite negative polymerase chain reaction (PCR) for the virulence factor Panton-Valentine leukocidin, MRSA infections resulted in significant disease and morbidity.

Long‐term outcomes of cytomegalovirus infection and disease after lung or heart–lung transplantation with a delayed ganciclovir regimen

Information is limited on long-term outcomes after preemptive use of ganciclovir to control cytomegalovirus (CMV) infection in lung transplantation. We studied 78 lung recipients who received antithymocyte globulin induction from 1994 to 2000. All patients received six months of oral acyclovir (800 mg TID). This was interrupted three wk post transplantation for a two-wk course of IV ganciclovir. Additional courses of ganciclovir were administered based on serial virological monitoring. CMV-mismatched patients (R-D+) also received four doses of CMV immunoglobulin between weeks 2 and 8. The one yr cumulative risk of CMV disease was 2% (1/61) in CMV seropositive (R+) patients, but was 37% (6/17) in R-D+ patients (p < 0.0001). Over 4.3 yr of follow-up, patients with CMV infection developed more chronic graft dysfunction caused by bronchiolitis obliterans or bronchiolitis obliterans syndrome than patients without CMV infection (p = 0.012). This effect was also apparent in the subgroup of R+ recipients (p = 0.043). Acute rejection and overall survival were not associated with CMV infection. The use of prophylactic acyclovir and short preemptive courses of ganciclovir effectively controlled CMV disease in R+ patients, but was a relative failure in R-D+ patients. CMV infection was significantly associated with chronic graft dysfunction, even in R+ recipients who had good control of CMV symptoms.

651: Increased Mortality in Ganciclovir Resistant CMV Infection in Lung Transplantation

651: Increased Mortality in Ganciclovir Resistant CMV Infection in Lung Transplantation

Diagnosis and prevention of infection in lung transplantation

The lung is unique amongst solid organ transplants (SOT) for its extreme exposure to the ambient environment which leads to increased vulnerability to infection, particularly when host immune response and barrier mucosal function are impaired. Moreover, resident viruses and other microbes are invariably transplanted within the donor lung(s) which may lead to primary infection within the naive recipient. Importantly, lung allograft infection promotes both innate and adaptive immune responses with resultant chronic allograft dysfunction manifest as bronchiolitis obliterans syndrome (BOS). Infection is both a promoter and result of airway damage, particularly where mucociliary clearance is impaired. The diagnosis and prevention of infection after LTX begins with a comprehensive microbiological survey of the recipient and the potential donor to identify tolerable risks. Prophylactic therapies against identified risks as well as common important infections including herpesgroup viruses, Pneumocystis carinii pneumonia (PCP), Chlamydia species and fungi are commenced routinely with bronchoscopic graft surveillance to identify infections not diagnosed by less invasive means. While effective preventative strategies for cytomegalovirus (CMV) are now readily available, the relative importance of community acquired respiratory viruses (CARV) has increased, especially as diagnosis may be delayed by late presentation and therapies are limited in efficacy. Prevention of CARV remains a challenge.

Invasive fungal infections in lung transplantation: role of aerosolised amphotericin B

Immunocompromised patients, especially solid organ transplant (SOT) and hematopoietic stem cell transplant recipients, have a high morbidity and mortality rate as a result of invasive fungal infections (IFIs). Therefore, effective and correct prophylaxis of these IFIs continues to be an important issue in these patient populations. Fungal infections in the lung are most often due to Aspergillus spp., but other non- Aspergillus moulds such as Mucor spp. can also cause pulmonary infections. Lung transplant recipients have the highest incidence of invasive aspergillosis of all SOT patients. Prophylaxis should consider the risk factors affecting each group of patients. As the lung is the target organ of most fungal infections due to moulds, aerosolised antifungal prophylaxis has been potentially considered to be a safe and effective strategy. Administration of a nebulised antibiotic achieves high local concentration of the drug, avoiding undesirable systemic effects and drug interactions. The use of aerosolised amphotericin B (AmB) as prophylaxis or co-adjuvant treatment for pulmonary fungal infections has been reported in several groups of immunosuppressed patients. Lipid formulations of AmB penetrate the lung better and have a longer half-life than amphotericin B deoxycholate (ABD). Prophylaxis with aerosolised lipid-based AmB products has several advantages over ABD: it can be administered at much longer intervals and is equally effective and better tolerated. Although several studies have been published using aerosolised AmB both as deoxycholate and lipid formulations, available data remain inconclusive owing a lack of standardisation of administration procedures and doses.

295: Clinical spectrum of gram positive infections in lung transplantation

295: Clinical spectrum of gram positive infections in lung transplantation

Donor-To-Host Transmission of Bacterial and Fungal Infections in Lung Transplantation

The purpose of this study was to evaluate the incidence and etiology of bacterial and fungal infection or contamination in lung allograft donors and to assess donor-to-host transmission of these infections. Recipients who survived more than 24 h and their respective donors were evaluated. The overall incidence of donor infection was 52% (103 out of 197 donors). Types of donor infection included isolated contamination of preservation fluids (n = 30, 29.1%), graft colonization (n = 65, 63.1%) and bacteremia (n = 8, 7.8%). Donor-to-host transmission of bacterial or fungal infection occurred in 15 lung allograft recipients, 7.6% of lung transplants performed. Among these cases, 2 were due to donor bacteremia and 13 to colonization of the graft. Twenty-five percent of donors with bacteremia and 14.1% of colonized grafts were responsible for transmitting infection. Excluding the five cases without an effective prophylactic regimen, prophylaxis failure occurred in 11 out of 197 procedures (5.58%). Donor-to-host transmission of infection is a frequent event after lung transplantation. Fatal consequences can be avoided with an appropriate prophylactic antibiotic regimen that must be modified according to the microorganisms isolated from cultures of samples obtained from donors, grafts, preservation fluids and recipients.

Acanthamoeba infection in lung transplantation: report of a case and review of the literature

A 49-year-old woman underwent bilateral lung transplantation for advanced idiopathic pulmonary fibrosis. During the postoperative period she received immunosuppressive medications as well as corticosteroids. Aspergillus fumigatus grew from a sputum sample, and she was treated with nebulized amphotericin. She was discharged on tacrolimus and prednisone. After initially doing well, she required re-hospitalization for treatment of cytomegalovirus and Pseudomonas aeruginosa pneumonia. She was treated with ganciclovir and cefepime and, after a 2-week hospitalization, was discharged. Seven months after transplantation she developed progressive sinusitis, treated with antibiotics and sinus debridement surgery. Aspergillus organisms were recovered and, at the periphery of the tangled masses of Aspergillus hyphae, numerous amebic cysts were also identified, which were morphologically consistent with Acanthamoeba spp. Subsequent electron microscopy and immunofluorescent staining confirmed this impression. She was initially treated with intravenous amphotericin, later changed to voriconazole and caspofungin. Debridement of the sinuses 3 weeks later revealed fungal hyphae but no amebae. Infections with Acanthamoeba have rarely been reported in lung transplantation but have been recognized in bone-marrow and renal transplant patients, and have been lethal in many cases, particularly in patients with immunosuppression due to human immunodeficiency virus infection. More recently, aggressive antimicrobial therapy has resulted in successful outcomes, as discussed herein.

Risk factors for perioperative mortality and nosocomial infections in lung transplantation

Risk factors for perioperative mortality and nosocomial infections in lung transplantation

Fungal infection in lung transplantation.

Fungal infection remains a significant cause of postoperative morbidity and mortality in lung transplant recipients. The lung recipient remains the only solid-organ allograft continuously open to the environment and to the myriad of fungal spores and pathogens. Many factors may predispose to fungal infection in these patients, including: preoperative chronic lung diseases and inherent palliative immunosuppression, intraoperative complications such as abnormalities in the bronchial anastomosis or lung injury, and postoperative complications such as enhanced immunosuppression for early rejection, graft dysfunction, concurrent viral and bacterial infections, and bronchiolitis obliterans syndrome. The risk factors and time course for fungal infection in lung transplant recipients parallel the observations in other solid-organ transplant recipients. Early fungal infections are related to surgical complications, while the period of 1-6 months reflect opportunistic, relapsed, or residual infections; fungal infections greater than 6 months and thereafter are usually associated with treatments for chronic rejection or bronchial airway mechanical abnormalities. The majority of fungal infections in lung transplant recipients involve Aspergillus species, followed by Candida, Pneumocystis, Cryptococcus, geographically-restricted agents, and newly emerging fungal pathogens. The identification of at-risk patients (preoperatively and postoperatively) is essential in implementing prophylaxis or preemptive management. Some anti-fungal strategies and future options for clinical research are discussed.

Nebulized amphotericin B prophylaxis for Aspergillus infection in lung transplantation: study of risk factors

Background Aspergillus infection remains a major cause of morbidity and mortality after lung transplantation. Therefore, some strategies have been attempted, one of which is nebulized amphotericin B (nAB); however, the efficacy of this prophylaxis has not been shown clearly. The aim is to study whether nAB can protect against Aspergillus infection in lung transplant recipients. Patients and methods A study of risk factors was conducted in 55 consecutive lung allograft recipients. Twenty-three potential risk factors were analyzed. In 44 (80%) patients, nAB was indicated as prophylaxis. Multivariate analysis using logistic regression was performed. Results Eighteen of the 55 patients (33%) developed infection due to Aspergillus spp. Multivariate analysis showed nAB to be a preventive factor (odds ratio: 0.13; 95% confidence interval [CI] 0.02–0.69; p < 0.05) and cytomegalovirus (CMV) disease was an independent risk factor for developing Aspergillus infection (odds ratio: 5.1; 95% CI 1.35–19.17; p < 0.05). Only 1 patient required withdrawal of the prophylaxis owing to bronchospasm. nAB was well-tolerated in the remaining patients with only a few, mild, easily controlled side effects. Conclusions The present results show that nAB prophylaxis may be efficient and safe in preventing Aspergillus infection in lung-transplanted patients, and CMV disease increases the probability of Aspergillus infection.

Immune and non‐immune consequences of infection in lung transplantation

Immune and non‐immune consequences of infection in lung transplantation

Adhesion molecules in patients after lung transplantation.

Leukocyte adhesion molecules, such as intercellular adhesion molecule (ICAM)-1 and its ligands, are involved in inflammatory processes of the lung. For ICAM-1, differential expression during different kinds of complications after transplantation has been proposed. We analyzed the role of ICAM-1, CD18, CD11a, CD11b, and CD11c during episodes of rejection or infection in patients after lung transplantation and compared the results to episodes without apparent complication. A total of 98 bronchoalveolar lavage (BAL) samples and 90 serum samples were analyzed. ICAM-1, CD18, CD11a, CD11b, and CD11c expressions were detected immunocytochemically on alveolar macrophages. Soluble ICAM-1 was quantified in serum and BAL. In the control group, 49.8 +/- 18% of macrophages stained positive for CD11b. During rejection, the mean of cells showing CD11b on the surface was significantly higher (64.6 +/-11.4%) with no difference compared to episodes of infection (59.7 +/-22.7). All other epitopes were not expressed differently with regard to a normal clinical course or episodes of infection and rejections. In summary, assessment of ICAM-1 and corresponding ligands did not allow for a reliable discrimination between episodes of rejection or infection in lung transplantation.

The impact of ganciclovir-resistant cytomegalovirus infection in lung transplantation: R.M. Kruger, G.A. Storch, W.D. Shannon, M.Q. Arens, J.P. Lynch, and E.P. Trulock, Washington University, St. Louis, Missouri

The impact of ganciclovir-resistant cytomegalovirus infection in lung transplantation: R.M. Kruger, G.A. Storch, W.D. Shannon, M.Q. Arens, J.P. Lynch, and E.P. Trulock, Washington University, St. Louis, Missouri