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Background : Invasive fungal infection (IFI) remains a common complication after lung transplantation, causing significant morbidity and mortality. We have attempted to quantify systematically risk factors of IFI in lung transplant recipients. Methods : Studies were retrieved from Ovid MEDLINE, Ovid Embase, Cochrane database of systematic reviews and Cochrane central register of controlled trials. All case-control and cohort studies evaluating the risk factors of IFI in adult lung transplant recipients were screened. Two researchers reviewed and assessed all studies independently. We pooled the estimated effect of each factor associated with IFI by using a random effect model. Results : Eight studies were included in the systematic review and five studies were eligible for the meta-analysis. Rates of IFI range from 8-33% in lung transplant recipients. Independent risk factors for invasive aspergillosis (IA) in lung transplantation include previous fungal colonization (OR 2.44; 95% CI 0.08-0.47), cytomegalovirus infection (OR 1.96; 95% CI 1.08-3.56) and single lung transplantation (OR 1.77; 95% CI 1.08-2.91). Pre-emptive antifungal therapy (OR 0.20; 95% CI 0.09-0.48) is a protective factor for IA in lung transplant (OR 0.2; 95% CI 0.08-0.47). Conclusion : Cytomegalovirus infection, previous fungal colonization and single lung transplantation independently increase the risk of IA in lung transplant recipients. Pre-emptive antifungal therapy is a protective factor for IA in the lung transplant population.

Antimicrobial stewardship programs (ASPs) have made immense strides in optimizing antibiotic, antifungal, and antiviral use in clinical settings. However, although ASPs are required institutionally by regulatory agencies in the United States and Canada, they are not mandated for transplant centers or programs specifically. Despite the fact that solid organ transplant recipients in particular are at increased risk of infections from multidrug-resistant organisms, due to host and donor factors and immunosuppressive therapy, there currently are little rigorous data regarding stewardship practices in solid organ transplant populations, and thus, no transplant-specific requirements currently exist. Further complicating matters, transplant patients have a wide range of variability regarding their susceptibility to infection, as factors such as surgery of transplant, intensity of immunosuppression, and presence of drains or catheters in situ may modify the risk of infection. As such, it is not feasible to have a “one-size-fits-all” style of stewardship for this patient population. The objective of this white paper is to identify opportunities, risk factors, and ASP strategies that should be assessed with solid organ transplant recipients to optimize antimicrobial use, while producing an overall improvement in patient outcomes. We hope it may serve as a springboard for development of future guidance and identification of research opportunities.

Supplemental Digital Content is available in the text., Background. Several studies have described the clinical features of COVID-19 in solid-organ transplant recipients. However, many have been retrospective or limited to more severe cases (hospitalized) and have not routinely included serial virological sampling (especially in outpatients) and immunologic assessment. Methods. Transplant patients diagnosed with COVID-19 based on a respiratory sample PCR were prospectively followed up to 90 d. Patients provided consent for convalescent serum samples and serial nasopharyngeal swabs for SARS-CoV-2 antibody (antinucleoprotein and anti-RBD) and viral load, respectively. Results. In the 161 SOT recipients diagnosed with COVID-19, the spectrum of disease ranged from asymptomatic infection (4.3%) to hospitalization (60.6%), supplemental oxygen requirement (43.1%), mechanical ventilation (22.7%), and death (15.6%). Increasing age (OR, 1.031; 95% CI, 1.001-1.062; P = 0.046) and ≥2 comorbid conditions (OR, 3.690; 95% CI, 1.418-9.615; P = 0.007) were associated with the need for supplemental oxygen. Allograft rejection was uncommon (3.7%) despite immunosuppression modification. Antibody response at ≥14 d postsymptoms onset was present in 90% (anti-RBD) and 76.7% (anti-NP) with waning of anti-NP titers and stability of anti-RBD over time. Median duration of nasopharyngeal positivity was 10.0 d (IQR, 5.5–18.0) and shedding beyond 30 d was observed in 6.7% of patients. The development of antibody did not have an impact on viral shedding. Conclusions. This study demonstrates the spectrum of COVID-19 illness in transplant patients. Risk factors for severe disease are identified. The majority form antibody by 2 wk with differential stability over time. Prolonged viral shedding was observed in a minority of patients. Reduction of immunosuppression was a safe strategy.

The incidence and impact of de novo fungal airway colonization and infection in lung transplant recipients (LTRs) with known chronic lung allograft dysfunction (CLAD) has not been established. We aimed to determine the 1-year cumulative incidence and risk factors of de novo fungal colonization or infection in LTRs with CLAD and assess the impact of colonization or infection on post-CLAD survival.Prospectively collected Toronto Lung Transplant Program database and chart review were used for double-LTRs who were diagnosed with CLAD from January 1, 2016 to January 1, 2020 and who were free of airway fungi within 1 year prior to CLAD onset. International Society for Heart and Lung Transplantation definitions were used to define clinical syndromes. Cox-Proportional Hazards Models were used for risk-factor analysis. Survival analysis could not be completed secondary to low number of fungal events; therefore, descriptive statistics were employed for survival outcomes.We found 186 LTRs diagnosed with CLAD meeting our inclusion criteria. The 1-year cumulative incidence for any fungal event was 11.8% (7.0% for infection and 4.8% for colonization). Aspergillus fumigatus was a causative pathogen in eight of 13 (61.5%) patients with infection and six of nine (66.7%) patients with colonization. No patients with fungal colonization post-CLAD developed fungal infection. Peri-CLAD diagnosis (3 months prior or 1 month after) methylprednisolone bolus (hazards ratio: 8.84, p = .001) increased the risk of fungal events. Most patients diagnosed with fungal infections (53.8%) died within 1-year of CLAD onset.De novo IFIs and fungal colonization following CLAD onset were not common. Fungal colonization did not lead to fungal infection. Methylprednisolone bolus was a significant risk factors for post-CLAD fungal events.

BK viremia is endemic among kidney transplant recipients (KTRs). Incidence, risk factors, outcomes, and clinical management of detectable versus high BK viremia have not been considered previously in KTR in the modern era. This observational study examined KTR transplanted between January 1, 2009 and December 31, 2016. Any BK viral load in the serum constituted detectable BK viremia and ≥10

BACKGROUND MicroRNAs (miRNAs) are small non-coding RNAs of ∼22 nucleotides that play a crucial role in post-transcriptional regulation of gene expression. Dysregulation of miRNA expression has been shown during microbial infections. We sought to identify miRNAs that distinguish invasive aspergillosis (IA) from non-IA in lung transplant recipients (LTRs). METHODS We used NanoString nCounter Human miRNA, version 3, panel to measure miRNAs in bronchoalveolar lavage (BAL) samples from LTRs with Aspergillus colonization (ASP group) (n = 10), those with Aspergillus colonization and chronic lung allograft dysfunction (CLAD) (ASPCLAD group) (n = 7), those with IA without CLAD (IA group) (n = 10), those who developed IA with CLAD (IACLAD group) (n = 9), and control patients (controls) (n = 9). The miRNA profile was compared using the permutation test of 100,000 trials for each of the comparisons. We used mirDIP to obtain their gene targets and pathDIP to determine the pathway enrichment. RESULTS We performed pairwise comparisons between patient groups to identify differentially expressed miRNAs. A total of 5 miRNAs were found to be specific to IA, including 4 (miR-145-5p, miR-424-5p, miR-99b-5p, and miR-4488) that were upregulated and the pair (miR-4454 + miR-7975) that was downregulated in IA group vs controls. The expression change for these miRNAs was specific to patients with IA; they were not significantly differentiated between IACLAD and IA groups. Signaling pathways associated with an immunologic response to IA were found to be significantly enriched. CONCLUSIONS We report a set of 5 differentially expressed miRNAs in the BAL of LTRs with IA that might help in the development of diagnostic and prognostic tools for IA in LTRs. However, further investigation is needed in a larger cohort to validate the findings.

BACKGROUND Invasive pulmonary aspergillosis (IPA) is a significant cause of morbidity and mortality in lung transplant recipients (LTRs). It is unclear how a targeted prophylaxis/ preemptive antifungal therapy strategy impacts the incidence of IPA beyond the first-year posttransplant. METHODS This is a retrospective cohort of LTRs from January 2010 to December 2014. We included all LTRs who survived beyond the first year and followed them until death or 4 years postoperatively. Incidence of probable/proven IPA and Aspergillus colonization were assessed as per International Society for Heart and Lung Transplantation (ISHLT) criteria. Patients with risk factors, positive Aspergillus cultures, or galactomannan (GM) received targeted prophylaxis/preemptive therapy within the first-year posttransplant. RESULTS During the study period, 350 consecutive LTRs underwent 1078 bronchoscopies. Positive bronchoalveolar lavage for GM or Aspergillus cultures was reported for 15% (52/350) of LTRs between 2 and 4 years after transplantation. Among them, the median time to positive Aspergillus culture or GM positivity was 703 days (interquartile range, 529-754 d). The incidence rate of IPA and Aspergillus colonization was 30 of 1000 patient-y, and 63 of 1000 patient-y, respectively. The mortality rate was significantly higher in patients with IPA than without IPA (107/1000 patient-years versus 18/1000 patient-years; P

Bronchoalveolar lavage (BAL) is a key clinical and research tool in lung transplantation (LTx). However, BAL collection and processing are not standardized across LTx centers. This International Society for Heart and Lung Transplantation-supported consensus document on BAL standardization aims to clarify definitions and propose common approaches to improve clinical and research practice standards. The following 9 areas are covered: (1) bronchoscopy procedure and BAL collection, (2) sample handling, (3) sample processing for microbiology, (4) cytology, (5) research, (6) microbiome, (7) sample inventory/tracking, (8) donor bronchoscopy, and (9) pediatric considerations. This consensus document aims to harmonize clinical and research practices for BAL collection and processing in LTx. The overarching goal is to enhance standardization and multicenter collaboration within the international LTx community and enable improvement and development of new BAL-based diagnostics. ispartof: JOURNAL OF HEART AND LUNG TRANSPLANTATION vol:39 issue:11 pages:1171-1190 ispartof: location:United States status: published

Invasive fungal infections (IFI), particularly invasive aspergillosis (IA), cause significant morbidity and mortality in lung transplant (LTx) recipients. The optimum strategy and antifungal agents for prevention are unclear.We performed a comprehensive literature search, systematic review, and network meta-analysis using a frequentist framework to compare the efficacy of various antifungal drugs on the incidence of IA/IFI in the setting of universal prophylaxis or no prophylaxis following lung transplantation.We included 13 eligible studies comprising of 1515 LTx recipients and 12 different prophylaxis strategies/antifungal combinations. The greatest number of direct comparisons were between the inhaled amphotericin formulations. The top three ranked treatments were inhaled liposomal amphotericin B (L-AmB), inhaled amphotericin deoxycholate (AmBd), and itraconazole plus inhaled amphotericin B (AmB). Among the azoles, isavuconazole ranked highest. The certainty of the evidence, assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework, was very low.Although universal antifungal prophylaxis post lung transplantation is commonly used, robust data from randomized controlled trials (RCTs) to inform the choice of antifungal agent and prophylaxis strategy are lacking. This exploratory network meta-analysis provides insight into the probable relative effectiveness of various antifungal agents in preventing IA, and this analysis should serve as a guide when selecting antifungals to be assessed in a RCT.

Lung transplant recipients are at increased risk of candidemia, especially in the early posttransplant period. However, the specific predisposing factors have not been established. The natural history of candidemia after lung transplantation, in the absence of universal antifungal prophylaxis, is not known.We retrospectively examined the epidemiology of candidemia at any time posttransplant in patients who underwent lung transplantation at our center between 2016 and 2019. We undertook a case-control study and used logistic regression to evaluate the risk factors for candidemia during the first 30 days posttransplantation.During the study period 712 lung transplants were performed on 705 patients. Twenty-five lung transplant recipients (LTRs) (3.5%) experienced 31 episodes of candidemia. The median time to candidemia was 19.5 days (IQR 10.5-70.5), with 61.2% (n = 19) episodes of candidemia occurring within the first 30 days posttransplantation. Pretransplant hospitalization, posttransplant ECMO, and posttransplant renal replacement therapy were associated with an increased risk of candidemia in the first 30 days posttransplant. Of those with candidemia in the first 30 days, 31.2% died within 30 days of the index positive blood culture. Candidemia was associated with decreased survival within 30 days posttransplant.This study highlights the greatest risk period of lung transplant recipients for development of candidemia and identifies several factors associated with increased risk of candidemia. These findings will help guide future studies on antifungal prophylaxis.

Invasive fungal infections (IFIs) remain one of the most common infectious complications after organ transplantation, and liver transplant recipients (LTRs) have the highest mortality rate. However, risk factors associated with IFIs have only been evaluated in small single-center studies. We performed a meta-analysis by conducting a comprehensive search using Ovid MEDLINE, Ovid Embase, Cochrane database of systematic reviews, and Cochrane central register of controlled trials. All case-control and cohort studies evaluating risk factors for IFIs in adult LTRs were screened. Utilizing a random-effects model, a multivariate analysis was completed, and 28 studies were eligible for meta-analysis. Rates of IFIs ranged from 1.4% to 32.7%. Previous antibiotic use (OR 9.3; 95% CI 3.2-27.0) and bacterial infection (OR 4.3; 95% CI 2.1-8.6) were risk factors of invasive candidiasis. Yet for invasive aspergillosis, posttransplant renal replacement therapy (OR 9.2; 95% CI 4.2-20.4), reoperation (OR 8.0; 95% CI 2.9-21.7), and cytomegalovirus infection (OR 6.2; 95% CI 2.0-19.3) were risk factors. The top independent risk factors for IFIs during studies from 2010 to 2019 were previous fungal colonization (OR 9.19; 95% CI 4.92-17.16), reoperation (OR 5.45; 95% CI 2.93-10.15), and previous bacterial infections (OR 3.81; 95% CI 2.13-6.83). These risk factors may be targeted by antifungal prophylaxis in LTRs.

Long-term survival after Liver Transplantation (LT) is often compromised by infectious and metabolic complications. We aimed to delineate alterations in intestinal microbiome (IM) over time that could contribute to medical complications compromising long-term survival following LT. Fecal samples from LT recipients were collected at 3 months (3M) and 6 months (6M) post-LT. The bacterial DNA was extracted using E.Z.N.A.® Stool DNA Kit and 16S rRNA gene sequencing at V4 hypervariable region was performed. DADA2 and Phyloseq was implemented to analyze the taxonomic composition. Differentially abundant taxa were identified by metagenomeSeq and LEfSe. Piphillin, an Inferred functional metagenomic analysis tool was used to study the bacterial functional content. For comparison, healthy samples were extracted from NCBI and analyzed similarly. The taxonomic & functional profiles of LT recipients were validated with metagenomic sequencing data from animals exposed to immunosuppressants using Venny. Our findings provide a new perspective on longitudinal increase in specific IM communities post-LT along with an increase in bacterial genes associated with metabolic and infectious disease. This article is protected by copyright. All rights reserved.

This study investigated the single-center incidence and risk factors for bloodstream infections (BSIs) in 651 adults who underwent allogeneic hematopoietic cell transplantation (alloHCT) between 2015 and 2019 and explored the impact of these BSIs on post-transplantation outcomes. Antibiotic prophylaxis with ciprofloxacin was given during the aplastic phase. Overall, the median patient age was 57 years, 79.7% of patients received an alternative donor graft, and 68.7% received post-transplantation cyclophosphamide (PTCy) as part of their graft-versus-host disease (GVHD) prophylaxis. Of the 651 patients, 358 (55.0%) had at least 1 episode of BSI, and the overall mortality rate secondary to this complication was 7.5% (12.6% among those diagnosed with at least 1 episode of BSI). BSI was more often diagnosed during the first 30 days (58.7%), and gram-positive bacteria were the most prevalent microorganisms isolated during the entire post-transplantation follow-up (62%). A high Disease Risk Index (hazard ratio [HR], 1.47; P < .029) and receipt of PTCy-based GVHD prophylaxis (HR, 3.33; P < .001) were identified as risk factors for BSI. Additionally, univariate analysis showed that patients diagnosed with a BSI during post-transplantation follow-up had worse overall survival (HR, 2.48; P < .001) and higher nonrelapse mortality (HR, 2.68; P < .001) than those without BSI. In conclusion, alloHCT recipients with a BSI had a higher risk of mortality compared with those who did not develop BSI. The inclusion of PTCy as part of GVHD prophylaxis was identified as an independent risk factor for BSI during early post-transplantation follow-up. Single-center analyses focused on reporting the incidence and risk factors for BSI highlight the need for active implementation of preemptive strategies to decrease BSI incidence in the alloHCT setting. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is a major limitation in the long-term survival of lung transplant recipients (LTRs). However, the risk factors in the development of BOS remain undetermined. We conducted an international cohort study of LTRs to assess whether Aspergillus colonization with large or small conidia is a risk factor for the development of BOS.METHODS: Consecutive LTRs from January 2005 to December 2008 were evaluated. Rates of BOS and associated risk factors were recorded at 4 years. International Society of Heart and Lung Transplantation criteria were used to define fungal and other infections. A Cox proportional-hazards-model was constructed to assess the association between Aspergillus colonization and the development of BOS controlling for confounders.RESULTS: A total of 747 LTRs were included. The cumulative incidence of BOS at 4 years after transplant was 33% (250 of 747). Additionally, 22% of LTRs experienced Aspergillus colonization after transplantation. Aspergillus colonization with either large (hazard ratio [HR] = 0.6, 95% confidence interval [CI] = 0.3-1.2, p = 0.12) or small conidia (HR = 0.9, 95% CI = 0.6-1.4, p = 0.74) was not associated with the development of BOS. Factors associated with increased risk of development of BOS were the male gender (HR = 1.4, 95% CI = 1.1-1.8, p = 0.02) and episodes of acute rejection (1-2 episodes, HR = 1.5, 95% CI = 1.1-2.1, p = 0.014; 3-4 episodes, HR = 1.6, 95% CI = 1.0-2.6, p = 0.036; >4 episodes, HR = 2.2, 95% CI = 1.1-4.3, p = 0.02), whereas tacrolimus use was associated with reduced risk of BOS (HR = 0.6, 95% CI = 0.5-0.9, p = 0.007).CONCLUSIONS: We conclude from this large multicenter cohort of lung transplant patients, that Aspergillus colonization with large or small conidia did not show an association with the development of BOS.

Infections continue to be a major cause of post-transplant morbidity and mortality, requiring increased health services utilization. Estimates on the magnitude of this impact are relatively unknown. Using national administrative databases, we compared mortality, acute care health services utilization, and costs in solid organ transplant (SOT) recipients to nontransplant patients using a retrospective cohort of hospitalizations in Canada (excluding Manitoba/Quebec) between April-2009 and March-2014, with a diagnosis of pneumonia, urinary tract infection (UTI), or sepsis. Costs were analyzed using multivariable linear regression. We examined 816 324 admissions in total: 408 352 pneumonia; 328 066 UTI's; and 128 275 sepsis. Unadjusted mean costs were greater in SOT compared to non-SOT patients with pneumonia [(C$14 923 ± C$29 147) vs. (C$11 274 ± C$18 284)] and sepsis [(C$23 434 ± C$39 685) vs. (C$20 849 ± C$36 257)]. Mortality (7.6% vs. 12.5%; P < 0.001), long-term care transfer (5.3% vs. 16.5%; P < 0.001), and mean length of stay (11.0 ± 17.7 days vs. 13.1 ± 24.9 days; P < 0.001) were lower in SOT. More SOT patients could be discharged home (63.2% vs. 44.3%; P < 0.001), but required more specialized care (23.5% vs. 16.1%; P < 0.001). Adjusting for age and comorbidities, hospitalization costs for SOT patients were 10% (95% CI: 8-12%) lower compared to non-SOT patients. Increased absolute hospitalization costs for these infections are tempered by lower adjusted costs and favorable clinical outcomes.

Background: Posttransplant lymphoproliferative disorder (PTLD) is a severe complication after kidney transplantation. This study examined the incidence, risk factors, clinical management, and outcomes of PTLD in a cohort of kidney transplant recipients. Design: This single-center cohort study included 1642 patients transplanted from January 1, 2000, to December 31, 2012, with follow-up until December 31, 2013. The incidence and risk factors for PTLD were examined using a Cox proportional hazards model. A Cox model was also used to assess the association of PTLD and graft outcomes. Results: Sixteen recipients developed PTLD over follow-up. The incidence rate was 0.18 (95% confidence interval [CI]: 0.11-0.29) cases per 100 person-years. Four were from Epstein–Barr virus (EBV) mismatched (D+/R−) transplants and 12 from EBV-positive recipients (R+). Recipients with D+/R− matches were at a significantly higher risk of developing PTLD than R+ (hazard ratio [HR]: 7.52 [95% CI: 2.42-23.32]). Fifteen cases had immunosuppression reduced, 11 cases were supplemented with rituximab or ganciclovir, 6 cases required chemotherapy or radiation, and 6 cases had tumors excised. By the end of follow-up, 6 patients went into remission, 5 returned to chronic dialysis, and 5 patients died. Patients with PTLD were significantly more likely to have total graft failure (return to chronic dialysis, preemptive retransplant, or death with graft function) than patients without PTLD (HR: 3.41 [95% CI: 1.72-6.78). Discussion: Epstein–Barr virus mismatch continues to be a strong risk factor for developing PTLD after kidney transplantation. Recipients with PTLD have a poor prognosis, as the optimal management remains to be elucidated.

Background Lung transplant (LTX) recipients are at risk miscellaneous infections, among whom the clinical significance of nontuberculous mycobacteria (NTM) is increasingly recognized. Despite anti-mycobacterial therapy becoming standardized worldwide, there is a lack of data on treatment outcomes in LTX recipients who develop NTM-pulmonary disease (PD). We aimed to review the treatment outcomes of NTM-PD among LTX recipients in our center. Methods Patients who underwent LTX from January 2013 to December 2014 were consecutively enrolled in the retrospective cohort, with follow-up of data retrieved to December 2017. Clinical and radiological improvement and culture conversion after anti-mycobacterial therapy were reviewed in those who developed post-transplant NTM-PD. Results Sixteen out of 230 LTX recipients developed post-transplant NTM-PD. Ten out of 16 patients with post-transplant NTM-PD were treated with macrolide-containing anti-mycobacterial therapy, leading to clinical improvement in 5/10 (50%), radiological improvement in 5/10 (50%), and culture conversion in 6/10 (60%) patients. Conclusion Anti-mycobacterial therapy may relieve pulmonary symptoms and reduce microbial load among individuals with post-transplant NTM-PD.

BACKGROUND Complications after liver transplantation cause additional healthcare costs. The objective of this study was to contrast the length of stay (LOS) costs for recipients with and without surgical site infections (SSIs). METHODS This retrospective observational cohort study was conducted at a transplant center in Canada, between February 2011 and August 2014. The difference in the LOS costs was assessed by the Mann-Whitney U test, while multiple linear regression analysis was used to identify the variables that may have impacted on the costs. RESULTS Two hundred and twenty-nine liver transplant recipients were enrolled. Thirty-six recipients developed SSIs (36/229, 15.7%). The median LOS costs in recipients with and without SSIs were $39,456 Canadian dollars (interquartile range $25,696- 59,722) and $31,084 Canadian dollars (interquartile range $22,712-49 610), respectively (p = .072). There was a trend that the costs were higher for those recipients with versus those without SSIs (p = .088). Transfusion of ≥ 5 units of red cells and dialysis before transplantation impacted on cost. CONCLUSION There was a trend for higher healthcare facility costs for recipients with SSIs. Red cell transfusions and greater dialysis use before transplant were factors associated with the cost. Implementation of cost reduction strategies targeting high-cost recipients is necessary.

RATIONALE Cytomegalovirus (CMV)-seronegative recipients receiving a seropositive allograft (D+/R-) are at a high risk of developing CMV disease. Our program increased the duration of CMV prophylaxis from 6 to 9 months in May 2013. Here, we present the impact on the incidence of CMV infection, disease, side effects, rejection, and other factors. METHODS Retrospective cohort of 241 CMV (D+/R-) patients transplanted between January 1, 2008, and December 31, 2017. Blood CMV testing was done according to protocol. All patients received ganciclovir/valganciclovir as prophylaxis. We compared the incidence and timing of CMV infection and disease up to 6 months after cessation of prophylaxis between patients who received 9 months (May 2013 onwards) and a historical control group who received 6 months of prophylaxis (prior to May 2013). CMV infection was defined as detectable CMV viremia in the absence of symptoms. CMV disease was defined as CMV syndrome or tissue-invasive disease. Side effects of prophylaxis and CMV resistance were recorded. RESULTS A total of 116 patients were included in the 6-month group and 125 in the 9-month group. The extended 9-month CMV prophylaxis delayed the onset of CMV infection (median time to CMV infection after lung transplantation 295 vs 353 days, P

Background Invasive fungal infection (IFI) in solid organ transplant (SOT) recipients is associated with significant morbidity and mortality. The long-term probability of post-transplant IFI is poorly understood. Methods We conducted a population-based cohort study using linked administrative healthcare databases from Ontario, Canada, to determine the incidence rate; 1-, 5-, and 10-year cumulative probabilities of IFI; and post-IFI all-cause mortality in SOT recipients from 2002 to 2016. We also determined post-IFI, death-censored renal allograft failure. Results We included 9326 SOT recipients (median follow-up: 5.35 years). Overall, the incidence of IFI was 8.3 per 1000 person-years. The 1-year cumulative probability of IFI was 7.4% for lung, 5.4% for heart, 1.8% for liver, 1.2% for kidney-pancreas, and 1.1% for kidney-only allograft recipients. Lung transplant recipients had the highest incidence rate and 10-year probability of IFI: 43.0 per 1000 person-years and 26.4%, respectively. The 1-year all-cause mortality rate after IFI was 34.3%. IFI significantly increased the risk of mortality in SOT recipients over the entire follow-up period (hazard ratio: 6.50, 95% CI: 5.69-7.42). The 1-year probability of death-censored renal allograft failure after IFI was 9.8%. Conclusion Long-term cumulative probability of IFI varies widely among SOT recipients. Lung transplantation was associated with the highest incidence of IFI with considerable 1-year all-cause mortality.

Background Letermovir, a new viral terminase complex inhibitor, has been approved for the prevention of cytomegalovirus (CMV) infection in hematopoietic stem cell transplant patients. However, data on the efficacy and safety of letermovir for the treatment of CMV infection in transplant recipients remain scarce. Methods We performed a single-center retrospective study of stem cell and organ transplant recipients who received letermovir for the treatment of CMV infection from November 2017 to October 2018. Results Six patients were included and five were evaluable. All received letermovir in the context of a refractory or resistant CMV infection including asymptomatic CMV viremia (n=3), CMV syndrome (n=1) and CMV pneumonitis and colitis (n=1). The three asymptomatic patients experienced a decrease of the viral load to less than 200 IU/mL after letermovir therapy. One patient displayed a partial viral load response (2 log of viral load reduction) but a good clinical response, and one who received a suboptimal dose of letermovir experienced an increase of viremia. There were no treatment-related adverse effects. Conclusion We demonstrate mixed efficacy in patients with refractory CMV infection suggesting that letermovir may be a useful therapeutic adjunct, potentially in combination with other antivirals.

BACKGROUND: Invasive aspergillosis (IA) is a frequent complication in lung transplant recipients (LTRs). Clinical risk factors for IA have not been fully characterized, especially in the era of extensive anti-fungal prophylaxis. The primary objective of this study was to evaluate the clinical risk factors associated with IA in LTRs. The secondary objective was to assess the mortality in LTRs who had at least 1 episode of IA compared with LTRs who never had experienced IA.METHODS: We conducted an international, multicenter, retrospective cohort study of 900 consecutive adults who received lung transplants between 2005 and 2008 with 4years of follow-up. Risk factors associated with IA were identified using univariate and multiple regression Cox proportional hazards models.RESULTS: Anti-fungal prophylaxis was administered to 61.7% (555 of 900) of patients, and 79 patients developed 115 episodes of IA. The rate to development of the first episode was 29.6 per 1,000 person-years. Aspergillus fumigatus was the most common species isolated (63% [72 of 115 episodes]). Through multivariate analysis, significant risk factors identified for IA development were single lung transplant (hazard ratio, 1.84; 95% confidence interval, 1.09-3.10; p = 0.02,) and colonization with Aspergillus at 1 year post-transplantation (hazard ratio, 2.11; 95% confidence interval, 1.28-3.49; p = 0.003,). Cystic fibrosis, pre-transplant colonization with Aspergillus spp, and use of anti-fungal prophylaxis were not significantly associated with the development of IA. Time-dependent analysis showed IA was associated with higher mortality rates.CONCLUSION: Incidence of IA remains high in LTRs. Single-lung transplant and airway colonization with Aspergillus spp. within 1 year post-transplant were significantly associated with IA.

Background 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. Methods 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. Results 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. Conclusions 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.

Ureteral stents are routinely used in renal transplant and are associated with reduced urological complications but increased urinary tract infections (UTIs). There is no agreement on the preferred time to removal of stents after transplantation. We performed a systematic review and meta-analysis of all randomized controlled trials (RCTs) comparing stent duration of =14 days. Electronic databases were searched to identify RCTs that compared early vs late stent removal. Primary outcome was urinary tract infections. Secondary outcomes included various urological complications. No significant difference in UTI rates was demonstrated between short and long stent duration (relative risk (RR) 0.85, 95% confidence interval (CI) 0.44-1.64), with significant heterogeneity (I2 = 86%). Sensitivity analysis evaluating studies with low risk of bias for allocation concealment demonstrated statistically significant lower rates of UTI with short stent duration (RR 0.48, 95% CI 0.32-0.71) with no heterogeneity. No significant difference was demonstrated for the outcome of major urological complications (RR 0.72, 95% CI 0.50-1.05), without heterogeneity. Ureteral stenosis rates were significantly lower in the short duration arm (RR 0.42, 95% CI 0.18-0.98). Early removal of ureteral stents after renal transplant may be associated with reduced rates of UTI and ureteral stenosis. Additional RCTs are needed.

Background Invasive aspergillosis is the most common invasive fungal infection in lung transplant recipients. The use of galactomannan testing in bronchoalveolar lavage (BAL) fluid has improved diagnosis of invasive aspergillosis; however, false-positive results can lead to overdiagnosis and unnecessary treatment. The use of proinflammatory markers such as pentraxin 3 (PTX3) may help differentiate between Aspergillus colonization and disease. Methods BAL PTX3 concentrations were measured by enzyme-linked immunosorbent assay in 151 lung transplant recipients and 9 healthy control subjects. Patients were characterized as having Aspergillus colonization or invasive disease according to International Society of Heart and Lung Transplantation criteria. Concomitant PTX3values were compared using Mann-Whitney U and Kruskal-Wallis tests. Results We analyzed 322 BAL stored samples and identified 15 invasive aspergillosis events, 38 Aspergillus colonizations, and 17 positive galactomannan with negative Aspergillus cultures. Median BAL PTX3 level was significantly higher in patients with invasive aspergillosis compared with patients with Aspergillus colonization and healthy control subjects (439.20 pg/ml [interquartile range (IQR) 168.18–778.90], 68.93 pg/ml [IQR 13.67–156.74], and 13.67 pg/ml [IQR 13.67–121.18]; p 319 pg/ml with positive galactomannan and patients with BAL PTX3 value >312 pg/ml with positive Aspergillus culture were 4.5 and 5.5 times more likely to have invasive pulmonary aspergillosis, respectively. Conclusions Our study shows that PTX3 measurements in BAL samples were significantly higher among patients with invasive aspergillosis and may help to identify patients with Aspergillus colonization and false-positive galactomannan in BAL samples.

Solid organ transplantation (SOT) outcomes have continued to improve, although long-term use of immunosuppressants can lead to complications such as diabetes, compromising post-transplant outcomes. In this study, we have characterized the intestinal microbiome (IM) composition at the metagenomic level in the context of hyperglycemia induced by immunosuppressants. Sprague-Dawley rats were subjected to doses of tacrolimus and sirolimus that reliably induce hyperglycemia and an insulin-resistant state. Subsequent exposure to probiotics resulted in reversal of hyperglycemia. 16S rRNA and metagenomic sequencing of stool were done to identify the bacterial genes and pathways enriched in immunosuppression. Bacterial diversity was significantly decreased in sirolimus-treated rats, with 9 taxa significantly less present in both immunosuppression groups: Roseburia, Oscillospira, Mollicutes, Rothia, Micrococcaceae, Actinomycetales and Staphylococcus. Following probiotics, these changes were reversed to baseline. At the metagenomic level, the balance of metabolism was shifted towards the catabolic side with an increase of genes involved in sucrose degradation, similar to diabetes. Conversely, the control rats had greater abundance of anabolic processes and genes involved in starch degradation. Immunosuppression leads to a more catabolic microbial profile, which may influence development of diabetes after SOT. Modulation of the microbiome with probiotics may help in minimizing adverse long-term effects of immunosuppression.

OBJECTIVETo evaluate the incidence of surgical-site infections (SSIs) in a cohort of liver transplant recipients and to assess risk factors predisposing patients to these infections.DESIGNProspective observational cohort study.SETTINGSingle transplant center in Canada.PATIENTSPatients who underwent liver transplantation between February 2011 and August 2014.METHODSMultivariate logistic regression was used to identify independent risk factors for SSIs in liver transplant patients.RESULTSWe enrolled 250 liver transplant recipients. The recipients’ median age at the time of transplantation was 56 years (range, 19–70 years), and 166 patients (66.4%) were male. Moreover, 47 SSIs were documented in 43 patients (17.2%). Organ-space, superficial, and deep SSIs were noted in 29, 7, and 3 patients, respectively. In addition, 2 patients developed superficial and organ-space SSIs, and another 2 patients were found to have deep as well as organ-space infections. In total, we identified 33 organ-space SSIs (70.2%), 9 superficial SSIs (19.1%), and 5 deep SSIs (10.6%). Factors predictive of SSIs by multivariate analysis were duct-to-duct anastomosis (odds ratio [OR], 3.88; 95% CI, 1.85–8.13; PP=.046). Of the 66 organisms isolated in both deep and organ-space SSIs, 55 (83%) were resistant to cefazolin.CONCLUSIONSOrgan-space SSIs are a common complication after liver transplantation. Duct-to-duct anastomosis and dialysis were independent risk factors associated with SSIs. Appropriate perioperative prophylaxis targeting patients with duct-to-duct anastomosis and dialysis while simultaneously providing optimum coverage for the potential pathogens causing SSIs is warranted.Infect Control Hosp Epidemiol 2017;38:1084–1090

Although initial therapy for cytomegalovirus (CMV) is usually successful, a significant subset of patients may have recurrent viremia. However, the epidemiology and risk factors for recurrence have not been fully defined, as well as the utility of prolonged antivirals after initial clearance.Solid organ transplant patients with first episode of CMV disease or asymptomatic viremia (≥1000 IU/mL) requiring treatment were identified by chart review. Clinical and virologic data were collected. The primary outcome was recurrence of CMV viremia or disease within 6 months of treatment discontinuation.The first episode of CMV viremia requiring antiviral therapy was assessed in 282 patients (147 CMV disease and 135 asymptomatic viremia). Cytomegalovirus occurred at 5.6 (0.63-27.7) months posttransplant. Recurrent CMV occurred in 30.5% patients at a median of 51 (0-160) days after discontinuation of therapy. Factors predictive of recurrence were treatment phase viral kinetics (P = 0.005), lung transplant (P = 0.002), CMV donor (D)+/recipient (R)- serostatus(P = 0.04) and recent acute rejection(P = 0.02). Prolonged antiviral therapy was given to 226 (80.1%) of 282 patients. Recurrence occurred in 73 (32.3%) of 226 patients that received prolonged antivirals versus 13 (23.2%) of 56 in those with no prolonged antivirals (P = 0.19).Recurrent CMV occurs in a significant percentage of patients after treatment of the first episode of CMV viremia/disease. CMV D+/R- serostatus, lung transplant, and treatment phase viral kinetics were significant predictors of recurrence. Continuation of prolonged antivirals beyond initial clearance was not associated with a reduced risk of recurrence.

The role of antiviral prophylaxis for the prevention of posttransplant lymphoproliferative disease (PTLD) remains controversial for solid organ transplantation (SOT) recipients who are seronegative for Epstein-Barr virus (EBV) but who received organs from seropositive donors. We performed a systematic review and meta-analysis to address this issue. Two independent assessors extracted data from studies after determining patient eligibility and completing quality assessments. Overall, 31 studies were identified and included in the quantitative synthesis. Nine studies were included in the direct comparisons (total 2366 participants), and 22 were included in the indirect analysis. There was no significant difference in the rate of EBV-associated PTLD in SOT recipients among those who received prophylaxis (acyclovir, valacyclovir, ganciclovir, valganciclovir) compared with those who did not receive prophylaxis (nine studies; risk ratio 0.95, 95% confidence interval 0.58-1.54). No significant differences were noted across all types of organ transplants, age groups, or antiviral use as prophylaxis or preemptive therapy. There was no significant heterogeneity in the effect of antiviral prophylaxis on the incidence of PTLD. In conclusion, the use of antiviral prophylaxis in high-risk EBV-naive patients has no effect on the incidence of PTLD in SOT recipients.

There are limited data on blastomycosis in solid organ transplant recipients with the subsequent development of the immune reconstitution inflammatory syndrome (IRIS). Herein we describe a case of pulmonary blastomycosis in a renal transplant recipient with the development of concomitant IRIS. Keywords: Transplantation, Immune Reconstitution Inflammatory Syndrome (IRIS), Blastomycosis

BACKGROUND Scedosporium species and Lomentospora prolificans (S/L) are the second most common causes of invasive mold infections following Aspergillus in lung transplant recipients. METHODS We assessed the current practices on management of S/L colonization/infection of the lower respiratory tract before and after lung transplantation in a large number of lung transplant centers through an international practice survey from October 2016 to March 2017. RESULTS A total of 51 respondents from 45 lung transplant centers (17 countries, 4 continents) answered the survey (response rate 58%). S/L colonization was estimated to be detected in candidates by 48% of centers. Only 18% of the centers used a specific medium to detect S/L colonization. Scedosporium spp. colonization was a contraindication to transplantation in 10% of centers whereas L prolificans was a contraindication in 31%; 22% of centers declared having had 1-5 recipients infected with S/L in the past 5 years. CONCLUSIONS This survey gives an overview of the current practices regarding S/L colonization and infection in lung transplant centers worldwide and underscores the need of S/L culture procedure standardization before implementing prospective studies.

INTRODUCTION The significance of granuloma in explanted lungs of lung transplant recipients (LTR) on the development of post-transplant mycobacterial infection is unclear. METHODS A retrospective review comparing LTRs and heart-lung transplant (H-LTR) recipients with granuloma in the explanted lungs between 2000 and 2012 (excluding those LTRs with granuloma due to sarcoidosis) and LTRs or H-LTRs without granuloma. Patients were followed for 2 years post-transplant. RESULTS A total of 144 LTRs and 4 H-LTRs with granulomas (75 necrotizing and 73 non-necrotizing) and a comparator cohort of 144 LTRs and 4 H-LTRs without granuloma were analyzed. In LTRs with granulomas, identification of infectious organisms was more common by histopathology (35 AFB and 22 fungal) compared to cultures (six NTM and seven fungal) taken around time of the transplant. LTRs with granulomas were more likely to have pre-transplant non-tuberculous mycobacteria (NTM) infection compared to LTRs without granuloma; P

Cytomegalovirus (CMV) infection and development of CMV drug resistance can cause significant morbidity and mortality in patients with lung transplantation (LTX). We investigated the incidence of CMV drug resistance in adult patients with LTX and characterized this patient group and its outcomes.We analyzed a single-center retrospective cohort of 735 patients who received LTX between January 2012 and October 2017. We assessed the incidences of CMV UL97 and UL54 genotyping for clinically suspected drug resistance and confirmed drug resistance. Case-matched controls (3 control patients for each resistant patient) were identified by matching for CMV serological status, development of CMV disease or significant viremia (≥3,000 IU/ml), and transplantation date.The incidence of drug-resistant CMV was 1.98% (11/556) in donor and/or recipient CMV-positive patients and 4.7% (7/150) in donor-positive/recipient-negative patients. Altogether, 27 patients were tested for drug resistance, and 11 strains were resistant, 8 sensitive, and 8 inconclusive. No differences in immunosuppression, acute rejection, or pre-transplant sensitization were seen between case-matched groups. The peak CMV viral load and mean duration of viremia were significantly higher in the resistant group (324,000 vs. 117,000 mean IU/ml, p = 0.048 and 140 vs. 55 days, p0.001, respectively). The resistant group had increased overall mortality after onset of viremia compared with controls (3-year mortality 70% vs. 30%; p = 0.01).Drug-resistant CMV infection is rare, but patients who develop it have decreased overall survival. Peak CMV viral load and duration of CMV viremia were associated with development of resistant CMV infection.

BACKGROUND Low-level CMV DNAemia is common and in the absence of treatment may either progress to higher viral loads that require therapy, or may spontaneously resolve. The clinical predictors of progression and spontaneous viral clearance are not well defined. METHODS We performed a retrospective cohort study of organ transplant recipients who had untreated low-level CMV DNAemia (

These updated AST-IDCOP guidelines provide information on epidemiology, diagnosis, and management of Aspergillus after organ transplantation. Aspergillus is the most common invasive mold infection in solid-organ transplant (SOT) recipients, and it is the most common invasive fungal infection among lung transplant recipients. Time from transplant to diagnosis of invasive aspergillosis (IA) is variable, but most cases present within the first year post-transplant, with shortest time to onset among liver and heart transplant recipients. The overall 12-week mortality of IA in SOT exceeds 20%; prognosis is worse among those with central nervous system involvement or disseminated disease. Bronchoalveolar lavage galactomannan is preferred for the diagnosis of IA in lung and non-lung transplant recipients, in combination with other diagnostic modalities (eg, chest CT scan, culture). Voriconazole remains the drug of choice to treat IA, with isavuconazole and lipid formulations of amphotericin B regarded as alternative agents. The role of combination antifungals for primary therapy of IA remains controversial. Either universal prophylaxis or preemptive therapy is recommended in lung transplant recipients, whereas targeted prophylaxis is favored in liver and heart transplant recipients. In these guidelines, we also discuss newer antifungals and diagnostic tests, antifungal susceptibility testing, and special patient populations.

Acute cellular rejection (ACR) is a significant risk factor for chronic lung allograft dysfunction (CLAD). Although clinically manifest and higher grade (≥A2) ACR is generally treated with augmented immunosuppression, management of minimal (grade A1) ACR remains controversial. In our program, patients with subclinical and spirometrically stable A1 rejection (StA1R) are routinely not treated with augmented immunosuppression. We hypothesized that an untreated first StA1R does not increase the risk of CLAD or death compared to episodes of spirometrically stable no ACR (StNAR). The cohort was drawn from all consecutive adult, first, bilateral lung transplantations performed between 1999 and 2017. Biopsies obtained in the first-year posttransplant were paired with (forced expiratory volume in 1 second FEV1 ). The first occurrence of StA1R was compared to a time-matched StNAR. The risk of CLAD or death was assessed using univariable and multivariable Cox proportional hazards models. The analyses demonstrated no significant difference in risk of CLAD or death in patients with a first StA1R compared to StNAR. This largest study to date shows that, in clinically stable patients, an untreated first A1 ACR in the first-year posttransplant is not significantly associated with an increased risk for CLAD or death. Watchful-waiting approach may be an acceptable tactic for stable A1 episodes in lung transplant recipients.

Purpose Bronchiolitis obliterans syndrome (BOS), restrictive allograft syndrome (RAS), and mixed are major phenotypes of CLAD. In previous, older studies, CMV viremia has been associated with reduced survival. We hypothesized that, in a more modern era of CMV prophylaxis, CMV viremia would remain associated with death, but also represent a risk factor for CLAD and specifically RAS/mixed phenotype. Methods This is a retrospective cohort study of all consecutive adult, first, bilateral-/single-lung transplants performed 2010-2016 who had ≥4 pulmonary function tests and ≥1 CMV-PCR measurement. CMV-PCR levels were divided into 3 categories: undetectable, Results Of 645 patients, 257 developed CLAD (143 BOS, 44 RAS/mixed, 66 undefined/unclassified) and 388 were CLAD-free at last follow-up. In univariate analysis, CMV-PCR≥1000 IU/mL was a significant risk factor for CLAD (HR 1.33, p=0.05). In multivariate analysis, CMV-PCR was not a significant risk factor for CLAD, whereas CMV serostatus mismatch was (Table). CMV-PCR was not a significant risk factor for RAS/mixed (CMV-PCR Conclusion CMV viremia was significantly associated with death/re-transplantation. Conversely, CMV viremia was not strongly associated with CLAD or RAS/mixed, while CMV serostatus mismatch was. CMV serostatus mismatch may have an impact on CLAD through mechanisms independent of viremia. In light of these paradoxical results, we are further assessing the relationship between immunosuppression, immune function, and CMV.

Purpose There is a paucity of studies assessing the incidental finding of histoplasmosis in the explanted tissue from lung transplant recipients (LTRs). Thus, there are currently no recommendations for the management of Histoplasmosis in the explanted organ of LTRs. This study aims to describe our experience in the management of histopathologic evidence of Histoplasmosis, encountered unexpectedly in the explanted tissue of LTRs at the time of transplantation. Methods We retrospectively identified LTRs at the Toronto program from 2010-2017, with histopathologic evidence of Histoplasma in the lung explanted tissue. Results Of 810 LTRs, 6 recipients had Histoplasmosis in the explanted organ (incidence 0.75%, clinical characteristics shown in Table 1. None of the 6 patients had a previously known diagnosis of Histoplasmosis. All of them lived in Ontario, Canada, and only one had traveled abroad in the past five years (to Florida, USA). All 6 patients had lung parenchyma and lymph node involvement in the histopathology findings, with necrotizing granulomas and fungal spores compatible with Histoplasmosis. All patients received antifungal pre-emptive therapy after transplant: 4 (67%) Itraconazole and 2 (33%) voriconazole for a mean duration of 4.8 months (IQR, 2.82-8.1 months). No patients in this group developed posttransplant Histoplasmosis (median follow up of 3.0 years [IQR 2.0-4.1 years]). Conclusion The unexpected finding of histoplasmosis in the explanted tissue of LTRs was infrequent (0.75%) in this non-endemic area. None of the patients, all of whom received antifungal therapy, developed active Histoplasmosis post-transplant.

Purpose Infections in patients with a left ventricular assist device (LVAD) for bridge to heart transplant (HTx) do not appear to impact post-HTx survival. We evaluated the association between LVAD-related infections requiring long-term suppressive antibiotics and non-recent infections of any kind on the risk of early and late infection, rejection and mortality post-HTx in comparison to LVAD recipients without infection. Methods This is a single-center retrospective observational cohort study of consecutive adults with a durable continuous flow LVAD undergoing HTx between 2006-2019. Patients were grouped into: 1) LVAD-related infection requiring long-term antibiotic use until time of HTx; 2) any type of infection after LVAD implant in whom antibiotics were stopped at least 1 month prior to HTx; and 3) no infections between LVAD implant and HTx. LVAD-related infections included bacteremia, driveline or pocket. We evaluated the association between LVAD infection and post-HTx in-hospital infection, rejection and mortality using logistic regression, and long-term infection, rejection and mortality using Cox PH models. Results We included 75 LVAD recipients; 16 (21%) patients had an LVAD-related infection on suppressive antibiotics, 30 (40%) had a non-recent infection, and 29 (39%) had no infections. During a median post-HTx follow-up time of 4 (2-7) years, we observed 65/75 (87%) infections, 43/67 (64%) rejections, and 17/75 (23%) deaths. Both short- and long-term risk of infection, rejection, and mortality did not differ significantly among the groups (Table 1). Conclusion LVAD patients with history of infections did not have higher risk of infection, rejection or mortality at any time point after HTx. Different post-HTx management strategies may have buffered the risk of adverse events in LVAD patients with infections.

Purpose BAL GM has higher sensitivity than traditional culture methods. However, smaller studies have documented higher false positivity in the early post-transplant period. This study aimed to evaluate the rate of IA in patients who had a negative fungal culture and positive BAL GM in the first 30 days post lung transplant. Methods We retrospectively identified LTRs from January 2010 to January 2017, who had a negative Aspergillus culture and positive BAL GM with an index cutoff value of ≥1.0 in the first 30 days post-transplant. Development of IA within 30 days after the initial positivity was evaluated. ISHLT definitions were used to define IA and colonization. Results We reviewed 791 LTRs; 119 patients had negative fungal culture and a positive BAL GM in the first 30 days post-transplant. 59% (70/119) were male, mean age 53 years old, 15% (18/119) had cystic fibrosis. 3% (4/119) of the patients had IA at the time of initial positive BAL GM. Of the other 115 patients, 112 were noted to be positive only once, 3 were positive two or more times. 63% (73/115) received preemptive antifungal therapy. None of them developed IA. 37% (42/115) did not receive preemptive antifungal therapy, and only 7% (3/42) developed IA. Conclusion In the absence of antifungal therapy, 7% (3/42) of LTRs subsequently developed IA following positive BAL GM >1.0 in the first 30 days post-transplant. Further characterization of patients with positive BAL GM during the first month may be helpful in devising the pre-emptive antifungal therapy in the early period after lung transplantation.

Background. We sought to determine whether invasive aspergillosis (IA) during the first year after lung transplantation increased the risk of chronic lung allograft dysfunction (CLAD). Methods. We retrospectively reviewed the records of 191 patients who underwent lung transplantation at our institution between January 2013 and December 2017. Screening for Aspergillus was with bronchial aspirates, bronchoalveolar lavage if indicated or during surveillance bronchoscopy, radiography, and computed tomography. We used Fine and Gray multivariable regression to identify potential risk factors for CLAD. Results. During the first posttransplant year, 72 patients had at least 1 deep-airway sample positive for Aspergillus; 63 were classified as having IA and were included in the study. Median number of endoscopies per patient during the first year was 9 (range, 1–44). Median time from transplantation to first Aspergillus-positive sample was 121 d. Bronchial aspirate samples and bronchoalveolar lavage fluid were positive in 71 and 44 patients, respectively. Aspergillus fumigatus (n = 36, 50%) predominated; bacterial samples were also positive in 22 (31%) patients. IA within 4 mo after transplantation was independently associated with CLAD development (subdistribution hazard ratio, 3.75; 95% confidence interval [CI], 1.61-8.73; P < 0.01) by regression analysis. Survival at 3 and 5 y conditional on 1-y CLAD-free survival was 37% (95% CI, 24%-58%), and 24% (95% CI, 11%-52%) in the IA

(1,3) β-D-Glucan (BDG) is present in the cell wall of most fungi. Its detection in serum has been useful in the diagnosis of invasive aspergillosis (IA) in patients with hematologic malignancies. However, assaying for BDG did not perform well in the serum of lung transplant recipients. We undertook to study the performance of BDG in the bronchoalveolar lavage (BAL) of lung transplant recipients for the diagnosis of invasive pulmonary aspergillosis (IPA). Available and stored BAL samples from lung transplant recipients at the Toronto General Hospital between October 2007 and April 2013 were tested for BDG using the Fungitell kit from the Associates of Cape Cod Inc, Falmouth, MA, USA : The International Society for Heart and Lung transplantation (ISHLT) criteria was used for the diagnosis of IA. Of 195 samples, there were ten episodes of IA. The sensitivity and specificity of the test were 80% and 53% and 60% and 70% at 41 pg/ml and 108 pg/ml cut-offs, respectively. On excluding 52 bronchoscopies due to receipt of anti-Aspergillus therapy during specimen collection, the sensitivity and specificity improved to 75% and 91%, respectively, at a 524 pg/ml cut-off. However, only four episodes of IA remained in this analysis. Using BDG in BAL of lung transplant recipients for the diagnosis of IA, our study demonstrated moderate sensitivity and specificity.

Ex vivo lung perfusion (EVLP) is a platform to treat infected donor lungs with antibiotic therapy before lung transplantation. Human donor lungs that were rejected for transplantation because of clinical concern regarding infection were randomly assigned to two groups. In the antibiotic group (n = 8), lungs underwent EVLP for 12 h with high-dose antibiotics (ciprofloxacin 400 mg or azithromycin 500 mg, vancomycin 15 mg/kg, and meropenem 2 g). In the control group (n = 7), lungs underwent EVLP for 12 h without antibiotics. A quantitative decrease in bacterial counts in bronchoalveolar lavage (BAL) was found in all antibiotic-treated cases but in only two control cases. Perfusate endotoxin levels at 12 h were significantly lower in the antibiotic group compared with the control group. EVLP with broad-spectrum antibiotic therapy significantly improved pulmonary oxygenation and compliance and reduced pulmonary vascular resistance. Perfusate endotoxin levels at 12 h were strongly correlated with levels of perfusates tumor necrosis factor α, IL-1β and macrophage inflammatory proteins 1α and 1β at 12 h. In conclusion, EVLP treatment of infected donor lungs with broad-spectrum antibiotics significantly reduced BAL bacterial counts and endotoxin levels and improved donor lung function.

Shahid Husain, MD, MS, Amparo Sole, MD, PhD, Barbara D. Alexander, MD, MHS, Saima Aslam, MD, MS, Robin Avery, MD, Christian Benden, MD, Eliane M. Billaud, PharmD, PhD, Daniel Chambers, MBBS, MD, Lara Danziger-Isakov, MD, Savitri Fedson, MD, Kate Gould, MD, Aric Gregson, MD, Paolo Grossi, MD, PhD, Denis Hadjiliadis, MD, Peter Hopkins, MD, Me-Linh Luong, MD, Debbie J.E. Marriott, MD, Victor Monforte, MD, Patricia Munoz, MD, PhD, Alessandro C. Pasqualotto, MD, PhD, Antonio Roman, MD, Fernanda P. Silveira, MD, Jeffrey Teuteberg, MD, MS, Stephen Weigt, MD, Aimee K. Zaas, MD, MHS, Andreas Zuckerman, MD, and Orla Morrissey, MD, PhD

Purpose Allograft infection after lung transplant (LTx) has a significant impact on outcome and has been associated with chronic lung allograft dysfunction (CLAD). Commensal bacteria (CB) are commonly isolated from bronchoalveolar lavages (BAL) in LTx recipients but the clinical significance is unknown. Our objective was to evaluate the association of high growth of CB (≥106 CFU/L) in BAL cultures with subsequent infection or CLAD. Methods We conducted a single-center, retrospective, cohort study of consecutive adult, first bilateral LTx performed 2010-2017. Patients who had no evidence of BAL infection and were alive and CLAD-free throughout the first 6-months post-transplant were included. Infection was defined as the presence of treatment-requiring pathogens in BAL. Outcomes of patients with ≥1CB within the first 6-months post-transplant were compared to patients with no CB isolation episodes within the same time interval. Association of CB with subsequent clinically significant BAL infections using logistic regression models and with time to CLAD was assessed using Cox Proportional Hazards models. Results The study cohort consisted of 202 patients with a median of 7 (IQR 7, 8) bronchoscopies per patient. Seventy of the 202 (34.7%) had subsequent BAL infection at some point post-transplant. Median time to CLAD was 497 days (IQR 131, 1043). Fifty-four (26.7%) patients had at least one episode of CB within the first 6-months post-transplant. In a multivariable analysis accounting for age, sex, primary lung disease, acute rejection score and CMV-mismatch, there was no difference in risk for subsequent infections (OR=0.83, 95% CI 0.40-1.69, P=0.60) or CLAD (HR=0.97, 95% CI 0.50-1.87, P=0.92) between patients with ≥1CB episode versus none. Conclusion We found that in the absence of specific infectious pathogens, isolation of commensal bacteria from BAL of LTx recipients during the first 6-months is not associated with an increased risk of subsequent infections or development of CLAD.