Infections In Lung Transplantation Research Articles

Advances in Managing Infections in Lung Transplantation: A Review

Transplanted lung allografts are particularly susceptible to infection among SOT due to the constant exposure to the environment, aggressive immunosuppressive strategies, and impaired clearance mechanisms after denervation of the transplanted lung. Though prophylactic antimicrobial, antifungal, and antiviral regimens are used as preventive strategies to mitigate the risk of infection, complications related to allograft infection remain one of the primary causes of morbidity and mortality after lung transplantation. Here we will review the common bacterial, viral, and fungal complications after lung transplantation, and discuss some newer agents and treatment strategies that have been implemented recently.

The changing landscape of infections in the lung transplant recipient.

Infections in lung transplant recipients remain a major challenge and can affect lung allograft function and cause significant morbidity and mortality. New strategies for the prevention and treatment of infection in lung transplantation have emerged and are reviewed. For important vaccine preventable infections (VPIs), guidance has been updated for at risk solid organ transplant (SOT) recipients. However, data on the efficacy of newer vaccines in lung transplant, including the respiratory syncytial virus (RSV) vaccine, are limited. Studies demonstrate improved vaccination rate with Infectious Diseases consultation during pretransplant evaluation. Two new antiviral agents for the treatment and prevention of cytomegalovirus (CMV) in SOT, letermovir and maribavir, are being incorporated into clinical care. CMV-specific cell-mediated immune function assays are more widely available. Antibiotics for the management of multidrug resistant pathogens and Burkholderia cepacia complex have been described in case series and case reports in lung transplant. Although new vaccines and novel therapies for preventing and treating infections are available, larger studies evaluating efficacy in lung transplant recipients are needed.

Herpes Virus Infection in Lung Transplantation: Diagnosis, Treatment and Prevention Strategies.

Lung transplantation is an ultimate treatment option for some end-stage lung diseases; due to the intense immunosuppression needed to reduce the risk of developing acute and chronic allograft failure, infectious complications are highly incident. Viral infections represent nearly 30% of all infectious complications, with herpes viruses playing an important role in the development of acute and chronic diseases. Among them, cytomegalovirus (CMV) is a major cause of morbidity and mortality, being associated with an increased risk of chronic lung allograft failure. Epstein-Barr virus (EBV) is associated with transformation of infected B cells with the development of post-transplantation lymphoproliferative disorders (PTLDs). Similarly, herpes simplex virus (HSV), varicella zoster virus and human herpesviruses 6 and 7 can also be responsible for acute manifestations in lung transplant patients. During these last years, new, highly sensitive and specific diagnostic tests have been developed, and preventive and prophylactic strategies have been studied aiming to reduce and prevent the incidence of these viral infections. In this narrative review, we explore epidemiology, diagnosis and treatment options for more frequent herpes virus infections in lung transplant patients.

Cytomegalovirus Infection in Lung Transplantation: Importance of Specific Cellular Immune Response Assessment

Cytomegalovirus Infection in Lung Transplantation: Importance of Specific Cellular Immune Response Assessment

Multiresistant organisms: bacteria and beyond

Infections with multiresistant organisms are an emerging problem, cause early mortality post lung transplantation and are sometimes associated with graft dysfunction. Frequently they raise questions about the selection of lung transplant candidates and therapeutic management post lung transplantation. There are no guidelines and management must be individualized. This review summarizes the available therapeutic options in cases of multidrug-resistant (MDR) organisms and outcomes after lung transplant. Improvements in diagnosis, new and more effective drugs and the experience gained in the management of these infections in lung transplantation, lead to a more optimistic horizon than that found a decade ago. Update on the management of Burkholderia cepacia complex, Mycobacterium abscessus complex, Aspergillus spp., Scedosporium spp. and Lomentospora prolificans infections. This review clarifies current posttransplant outcomes and adds a little hope in these scenarios.

Bacterial infections in lung transplantation.

Lung transplantation has lower survival rates compared to other than other solid organ transplants (SOT) due to higher rates of infection and rejection-related complications, and bacterial infections (BI) are the most frequent infectious complications. Excess morbidity and mortality are not only a direct consequence of these BI, but so are subsequent loss of allograft tolerance, rejection, and chronic lung allograft dysfunction due to bronchiolitis obliterans syndrome (BOS). A wide variety of pathogens can cause infections in lung transplant recipients (LTRs), including a number of nosocomial pathogens and other multidrug-resistant (MDR) pathogens. Although pneumonia and intrathoracic infections predominate, LTRs are at risk of a number of types of infections. Risk factors include altered anatomy and function of airways, impaired immunity, the microbial flora of the donor and recipient, underlying medical conditions, and genetic factors. Further work on immune monitoring has the potential to improve outcomes. The infecting agents can be derived from the donor lung, pre-existing recipient flora, or acquired from the environment over time. Certain infections may preclude lung transplantation, but this varies from center to center, and more recent studies suggest fewer patients should be disqualified. New molecular methods allow microbiome studies of the lung, gut, and other sites that may further our knowledge of how airway colonization can result in infection and allograft loss. Surveillance, early diagnosis, and aggressive antimicrobial therapy of BI is critical in LTRs. Antibiotic resistance is a major barrier to successful management of these infections. The availability of new agents for MDR Gram-negatives may improve outcomes. Other new therapies, such as bacteriophage therapy, show promise for the future. Finally, it is important to prevent infections through peri-transplant prophylaxis, vaccination, and infection control measures.

Viral infections in lung transplantation.

Viral infections account for up to 30% of all infectious complications in lung transplant recipients, remaining a significant cause of morbidity and even mortality. Impact of viral infections is not only due to the direct effects of viral replication, but also to immunologically-mediated lung injury that may lead to acute rejection and chronic lung allograft dysfunction. This has particularly been seen in infections caused by herpesviruses and respiratory viruses. The implementation of universal preventive measures against cytomegalovirus (CMV) and influenza (by means of antiviral prophylaxis and vaccination, respectively) and administration of early antiviral treatment have reduced the burden of these diseases and potentially their role in affecting allograft outcomes. New antivirals against CMV for prophylaxis and for treatment of antiviral-resistant CMV infection are currently being evaluated in transplant recipients, and may continue to improve the management of CMV in lung transplant recipients. However, new therapeutic and preventive strategies are highly needed for other viruses such as respiratory syncytial virus (RSV) or parainfluenza virus (PIV), including new antivirals and vaccines. This is particularly important in the advent of the COVID-19 pandemic, for which several unanswered questions remain, in particular on the best antiviral and immunomodulatory regimen for decreasing mortality specifically in lung transplant recipients. In conclusion, the appropriate management of viral complications after transplantation remain an essential step to continue improving survival and quality of life of lung transplant recipients.

Fungal infections in lung transplantation.

Lung transplant is a potential life-saving procedure for chronic lung diseases. Lung transplant recipients (LTRs) are at the greatest risk for invasive fungal infections (IFIs) among solid organ transplant (SOT) recipients because the allograft is directly exposed to fungi in the environment, airway and lung host defenses are impaired, and immunosuppressive regimens are particularly intense. IFIs occur within a year of transplant in 3–19% of LTRs, and they are associated with high mortality, prolonged hospital stays, and excess healthcare costs. The most common causes of post-LT IFIs are Aspergillus and Candida spp.; less common pathogens are Mucorales, other non-Aspergillus moulds, Cryptococcus neoformans, Pneumocystis jirovecii, and endemic mycoses. The majority of IFIs occur in the first year following transplant, although later onset is observed with prolonged antifungal prophylaxis. The most common manifestations of invasive mould infections (IMIs) include tracheobronchial (particularly at anastomotic sites), pulmonary and disseminated infections. The mortality rate of tracheobronchitis is typically low, but local complications such as bronchomalacia, stenosis and dehiscence may occur. Mortality rates associated with lung and disseminated infections can exceed 40% and 80%, respectively. IMI risk factors include mould colonization, single lung transplant and augmented immunosuppression. Candidiasis is less common than mould infections, and manifests as bloodstream or other non-pulmonary invasive candidiasis; tracheobronchial infections are encountered uncommonly. Risk factors for and outcomes of candidiasis are similar to those of non lung transplant recipients. There is evidence that IFIs and fungal colonization are risk factors for allograft failure due to chronic rejection. Mould-active azoles are frontline agents for treatment of IMIs, with local debridement as needed for tracheobronchial disease. Echinocandins and azoles are treatments for invasive candidiasis, in keeping with guidelines in other patient populations. Antifungal prophylaxis is commonly administered, but benefits and optimal regimens are not defined. Universal mould-active azole prophylaxis is used most often. Other approaches include targeted prophylaxis of high-risk LTRs or pre-emptive therapy based on culture or galactomannan (GM) (or other biomarker) results. Prophylaxis trials are needed, but difficult to perform due to heterogeneity in local epidemiology of IFIs and standard LT practices. The key to devising rational strategies for preventing IFIs is to understand local epidemiology in context of institutional clinical practices.

Fungal Infection in Lung Transplantation.

Invasive fungal infections threaten lung transplant outcomes with high associated morbidity and mortality. Pharmacologic prophylaxis may be key to prevent posttransplant invasive fungal infections, but cost, adverse effects, and absorption issues are barriers to effective prophylaxis. Trends in fungal infection diagnostic strategies utilize molecular diagnostic methodologies to complement traditional histopathology and culture techniques. While lung transplant recipients are susceptible to a variety of fungal pathogens, Candida spp. and Aspergillus spp. infections remain the most common. With emerging resistant organisms and multiple novel antifungal agents in the research pipeline, it is likely that treatment strategies will continue to evolve.

Multidrug-resistant bacteria in lung transplantation.

The review of infections in lung transplantation is beyond the scope of this article as it is a comprehensive topic, however we aim to focus on infections with multidrug-resistant (MDR) microorganisms in this patient population. New emerging clinical studies have provided data regarding outcomes in lung transplant recipients with MDR bacterial infections. Isolation of MDR bacteria from lung donors preoperatively has not been associated with worse outcomes in recipients. Patients with cystic fibrosis colonized with MDR bacteria do not have increased 1 year mortality rates compared to those without MDR bacteria.

Respiratory viral infection in lung transplantation induces exosomes that trigger chronic rejection

BACKGROUNDRespiratory viral infections can increase the risk of chronic lung allograft dysfunction after lung transplantation, but the mechanisms are unknown. In this study, we determined whether symptomatic respiratory viral infections after lung transplantation induce circulating exosomes that contain lung-associated self-antigens and assessed whether these exosomes activate immune responses to self-antigens.METHODSSerum samples were collected from lung transplant recipients with symptomatic lower- and upper-tract respiratory viral infections and from non-symptomatic stable recipients. Exosomes were isolated via ultracentrifugation; purity was determined using sucrose cushion; and presence of lung self-antigens, 20S proteasome, and viral antigens for rhinovirus, coronavirus, and respiratory syncytial virus were determined using immunoblot. Mice were immunized with circulating exosomes from each group and resulting differential immune responses and lung histology were analyzed.RESULTSExosomes containing self-antigens, 20S proteasome, and viral antigens were detected at significantly higher levels (p < 0.05) in serum of recipients with symptomatic respiratory viral infections (n = 35) as compared with stable controls (n = 32). Mice immunized with exosomes from recipients with respiratory viral infections developed immune responses to self-antigens, fibrosis, small airway occlusion, and significant cellular infiltration; mice immunized with exosomes from controls did not (p < 0.05).CONCLUSIONSCirculating exosomes isolated from lung transplant recipients diagnosed with respiratory viral infections contained lung self-antigens, viral antigens, and 20S proteasome and elicited immune responses to lung self-antigens that resulted in development of chronic lung allograft dysfunction in immunized mice.

Donor to Host Transmission of Infection in Lung Transplantation

Purpose To evaluate the incidence and etiology of donor infection and donor to host transmission of infections in lung transplantation. Methods We performed a retrospective cohort study of lung transplant patients at Hospital Italiano de Buenos Aires from January 2010 to March 2017. We analyzed data from electronic medical records. Donor infection was classified as bacteremia, graft colonization or isolated contamination of preservation fluids. Donor-to-host transmission of infection was defined as any infection in the recipient due to at least one microorganism also isolated from the donor and with identical antimicrobial susceptibility pattern. Results We included 55 lung transplant patients. Mean age was 48 years (SD 16), Single lung transplantation was performed in 75% of the cases. Cause of transplantation was chronic obstructive pulmonary disease (n=19), interstitial lung disease (n= 15), cystic fibrosis (n= 16) and others (n=5). Incidence of donor infection was 92.7% (n=51, 95%CI 82-98). Isolated contamination of preservation fluids was determined in 76.4% of cases (n= 42), graft colonization in 83.6% (n= 46) and bacteremia in 12.7% (n=7). The most common microorganisms isolated were gram positive coccus. Incidence of donor to host transmission of infection was 12.7% (n= 7, 95% CI 5-24). All cases were related to graft colonization. 40% (n=3) of recipients that developed infection had inadequate antibiotic prophylaxis. The microbiological etiologies were Acinetobacter baumannii (n=2), Klebsiella pneumoniae (n=2), Citrobacter koseri (n=1), Aspergillus fumigatus (n=1) and Methicillin-Sensitive Staphylococcus Aureus (n=1). Types of host infection were pneumonia (n=5), tracheobronchitis (n=1) and empyema (n=1). Infection-related death occurred in one patient. Conclusion The incidence of donor infection was high but donor to host transmission of infection after lung transplantation was an uncommon event. Inadequate antibiotic prophylaxis was high in those with donor to host transmission of infection. The most frequent etiology for donor infection was gram positive cocci. Gram negative bacteria was the most frequent cause of donor to host transmission of infection.

Pre Transplant Interleukin 10 Levels are Higher in Lung Recipients with Post Transplant Infections

Purpose The identification of pre-transplant biomarkers to assess the risk of post transplant infections in lung transplantation is of interest. The anti-inflammatory cytokine interleukin-10 (IL-10) was investigated in this study. Higher IL-10 plasma levels have been associated with prolonged CMV clearance in lung recipients. In other clinical setings higher IL-10 levels have been found to be a predictor of clinical outcome in sepsis. In this study we evaluated the relationship between pre-transplant IL-10 serum concentration and the development of infections occurring after lung transplantation. Methods In a prospective follow-up multicenter study, 87 patients in 5 centers were included to identify potential biomarkers of risk for development of post transplant infections. 82 patients were transplanted. 41 patients (50%) developed at least one infection episode that required intravenous drug therapy during the first 6 months after transplantation. Pre-transplant IL-10 was measured with an enzyme-linked immunosorbent assay in blood. IL-10 levels were then correlated with the prevalence of infections. Results The distribution of post transplant infections was as follows: bacterial (67,35%), fungal (20,41%), viral (10,20%). Patients who developed infections disclosed significantly higher levels of pre-transplant serum IL-10: 43,26 ± 39,55 pg/ml vs. 21,70 ± 23,34 pg/ml; p 29 pg/ml were at higher risk of having post transplant infections (Logistic regression relative hazard 3.64 (p= 0.021; 95% confidence interval: 1.28- 10.87). Conclusion We demostrated that in lung recipients with pre-transplant higher levels of serum IL-10, the prevalence of post-transplant infections was higher which suggest a potential role of individual anti-inflammatory responses in the predisposition to infection.

A strategy for prevention of fungal infections in lung transplantation: Role of bronchoalveolar lavage fluid galactomannan and fungal culture

The optimal strategy for prevention of invasive fungal infections in lung transplant recipients remains undetermined. We studied strategies based on bronchoalveolar lavage fungal culture and galactomannan for prevention of invasive aspergillosis in lung transplant recipients. Consecutive lung transplant recipients were evaluated during the period January 2010 to September 2014. Rates of invasive aspergillosis and all-cause mortality were recorded at 1 year. Criteria established by the International Society for Heart and Lung Transplantation were used to define invasive fungal infections. Multivariate Cox regression analyses were performed to assess the outcomes of mortality and invasive aspergillosis. A total of 519 lung transplant recipients with 3,077 bronchoscopies were included in our study. The cumulative incidence of fungal infections was 14% (75 of 519). Of these patients, 10.6% (54 of 519) developed Aspergillus-related clinical syndromes. Using multivariate analysis, pre-emptive therapy was associated with significantly lower rates of invasive aspergillosis at 1 year post-transplantation compared with no pre-emptive therapy (hazard ratio [HR] 0.23, 95% confidence interval [CI] 0.09 to 0.58). Pre-emptive therapy and invasive aspergillosis had similar mortality rates compared with no invasive aspergillosis, or negative culture and galactomannan at 1 year (HR 0.54, 95% CI 0.23 to 1.28; and HR 0.99, 95% CI 0.44 to 2.25, respectively). During follow-up, 50% (259 of 519) of patients were negative for galactomannan and Aspergillus culture in bronchoalveolar lavage, and did not receive anti-fungal treatment. Only 2 patients developed invasive aspergillosis in this cohort. Our study suggests that use of bronchoalveolar lavage culture and a galactomannan-directed pre-emptive approach significantly decreased the risk of invasive aspergillosis, allowing a 50% reduction in anti-fungal exposure compared with a universal prophylaxis approach, without affecting mortality at 1 year.

A Novel Next-Generation Sequencing Approach without Donor-Derived Material for Acute Rejection and Infection Monitoring in Solid Organ Transplantation

Background: Donor-derived cell free DNA (ddcf DNA) has been reported as a universal noninvasive biomarker for rejection monitoring in heart, kidney, liver, and lung transplantation. Current approaches based on next-generation sequencing for quantification of ddcf DNA, although promising, may be restricted by the requirement for donor material, as donor samples may not be available. Methods: We proposed a novel next-generation sequencing approach without donor-derived material and compared the non-donor-derived approach and the donor-derived approach using simulation testing and 69 clinical specimens. We also evaluated the performance for acute rejection and infection monitoring in lung transplantation. Results: The non-donor-derived approach reached similar efficacy as the donor-derived approach with a significant linear correlation of R2 = 0.98. Subsequent validation in clinical specimens demonstrated significant difference between the acute rejection group (4.83% ± 2.11%, mean ± SD) and the non-rejection group (1.61% ± 0.63%, mean ± SD) (P < 0.0001, Welch’s t test). With the cut-off value of 2.999, our approach had 90.48% sensitivity (95% CI, 69.62% - 98.83%), 100% specificity (95% CI, 91.59% - 100%), and AUC 0.9266 (95% CI, 0.8277 - 1.026). The test also had the ability to simultaneously detect infectious agents, especially cytomegalovirus, as compared with the clinical test. Conclusion: The proposed approach without donor-derived material could potentially be used to monitor acute rejection and infection in lung transplantation and may be applied to other types of solid organ transplantation.

10 years of prophylaxis with nebulized liposomal amphotericin B and the changing epidemiology of Aspergillus spp. infection in lung transplantation.

The aim of this study was to assess the outcome and tolerability of prophylactic nebulized liposomal amphotericin B (n-LAB) in lung transplant recipients (LTR) and the changing epidemiology of Aspergillus spp. infection and colonization. We performed an observational study including consecutive LTR recipients (2003-2013) undergoing n-LAB prophylaxis lifetime. A total of 412 patients were included (mean postoperative follow-up 2.56 years; IQR 1.01-4.65). Fifty-three (12.8%) patients developed 59 Aspergillus spp. infections, and 22 invasive aspergillosis (overall incidence 5.3%). Since 2009, person-time incidence rates of Aspergillus spp. colonization and infection decreased (2003-2008, 0.19; 2009-2014, 0.09; P = 0.0007), but species with reduced susceptibility or resistance to amphotericin significantly increased (2003-2008, 38.1% vs 2009-2014, 58.1%; P = 0.039). Chronic lung allograft dysfunction (CLAD) was associated with Aspergillus spp. colonization and infection (HR 24.4, 95% CI 14.28-41.97; P = 0.00). Only 2.9% of patients presented adverse effects, and 1.7% required discontinuation. Long-term administration of prophylaxis with n-LAB has proved to be tolerable and can be used for preventing Aspergillus spp. infection in LTR. Over the last years, the incidence of Aspergillus spp. colonization and infection has decreased, but species with reduced amphotericin susceptibility or resistance are emerging. CLAD is associated with Aspergillus spp. colonization and infection.

Therapeutic approach to respiratory infections in lung transplantation

Lung transplant recipients (LTRs) are at life-long risk for infections and disseminated diseases owing to their immunocompromised state. Besides organ failure and sepsis, infection can trigger acute and chronic graft rejection which increases mortality. Medical prophylaxis and treatment are based on comprehensive diagnostic work-up including previous history of infection and airway colonisation to reduce long-term complications and mortality. Common bacterial pathogens include Pseudomonas and Staphylococcus, whilst Aspergillus and Cytomegalovirus (CMV) are respectively the commonest fungal and viral pathogens. Clinical symptoms can be various in lung transplant recipients presenting an asymptomatic to severe progress. Regular control of infection parameters, daily lung function testing and lifelong follow-up in a specialist transplant centre are mandatory for early detection of bacterial, viral and fungal infections.After transplantation each patient receives intensive training with rules of conduct concerning preventive behaviour and to recognize early signs of post transplant complications. Early detection of infection and complications are important goals to reduce major complications after lung transplantation.

Fungal Infection by Mucorales Order in Lung Transplantation: 4 Case Reports

Mucorales is a fungus that causes systemic, highly lethal infections in immunocompromised patients. The overall mortality of pulmonary mucormycosis can reach 95%. This work is a review of medical records of 200 lung transplant recipients between the years of 2003 and 2013, in order to identify the prevalence of Mucorales in the Lung Transplantation service of Heart Institute (InCor), Hospital das Clínicas da Universidade de São Paulo, Brazil, by culture results from bronchoalveolar lavage and necropsy findings. We report 4 cases found at this analyses: 3 in patients with cystic fibrosis and 1 in a patient with bronchiectasis due to Kartagener syndrome. There were 2 unfavorable outcomes related to the presence of Mucorales, 1 by reduction of immunosuppression, another by invasive infection. Another patient died from renal and septic complications from another etiology. One patient was diagnosed at autopsy just 5 days after lung transplantation, with the Mucor inside the pulmonary vein with a precise, well-defined involvement only of donor's segment, leading to previous colonization hypothesis. There are few case reports of Mucorales infection in lung transplantation in the literature. Surveillance for the presence of Mucor can lead to timely fungal treatment and reduce morbidity and mortality in the immunocompromised patients, especially lung transplant recipients.

Decreased incidence of cytomegalovirus infection with sirolimus in a post hoc randomized, multicenter study in lung transplantation

Cytomegalovirus (CMV) is the most common opportunistic infection in lung transplantation. A recent multicenter, randomized trial (the AIRSAC study) comparing sirolimus to azathioprine in lung transplant recipients showed a decreased incidence of CMV events in the sirolimus cohort. To better characterize this relationship of decreased incidence of CMV events with sirolimus, we examined known risk factors and characteristics of CMV events from the AIRSAC database. The AIRSAC database included 181 lung transplant patients from 8 U.S.-based lung transplant centers that were randomized to sirolimus or azathioprine at 3 months post-transplantation. CMV incidence, prophylaxis, diagnosis and treatment data were all prospectively collected. Prophylaxis and treatment of CMV were at the discretion of each institution. The overall incidence of any CMV event was decreased in the sirolimus arm when compared with the azathioprine arm at 1 year after lung transplantation (relative risk [RR] = 0.67, confidence interval [CI] 0.55 to 0.82, p < 0.01). This decreased incidence of CMV events with sirolimus remained significant after adjusting for confounding factors of CMV serostatus and CMV prophylaxis. These data support results from other solid-organ transplantation studies and suggest further investigation of this agent in the treatment of lung transplant recipients at high risk for CMV events.

Study of B-Cell Subpopulations in Lung Transplant Recipients With Posttransplant Infection

BackgroundPosttransplant infection after lung transplantation is a common feature due to the immunodeficiency induced by the immunosuppressive load. AimTo assess B-cell subsets in lung transplant recipients suffering at least one episode of infection within the first year posttransplantation. MethodsTwenty-eight lung transplant recipients were enrolled in the study. Their overall mean age was 56.6 ± 10.7 years and 10 were women (35.7%). All recipients were treated with steroids, tacrolimus, and mycophenolate mofetil. B-cell subset levels were measured in peripheral blood before as well as 7, 14, 30, 60, 90, and 180 days posttransplantation. ResultsNo difference in the absolute number of B-cell subsets was observed within the first year of follow-up. However, pre–germinal center-activated naïve B cells (Bm2′), defined as IgD+CD38++, were increased among patients displaying infections within the first year. The increased Bm2′ subset was accompanied by a decrease in the double negative (CD27−IgD−) B-cell population. ConclusionInfections in lung transplant recipients were associated with an increase in the Bm2′ subset even before transplantation. It is possible that Bm2′ cells have a role in response to infection in lung transplantation.