Prophylaxis In Lung Transplant Recipients Research Articles

Omega-3 fatty acid supplement skin cancer prophylaxis in lung transplant recipients: A randomized, controlled pilot trial.

Lung transplant recipients (LTRs) are at very high risk of skin cancer. Omega-3 fatty acids (FAs) are anti-inflammatory and immune-modulating and could potentially reduce this risk. We assessed the feasibility of omega-3 FA supplementation to reduce skin cancer among these patients. LTRs aged 18+ years, at least 1 year post-transplant, were recruited from the outpatient clinic of The Prince Charles Hospital, Brisbane. Participants were randomly allocated to 4-times-daily supplements containing either omega-3 FA (3.36 eicosapentaenoic acid [EPA] + docosahexaenoic acid) or placebo (4 g olive oil) for 12 months. Primary outcomes were rates of recruitment, retention, adherence (assessed by plasma omega-3 FA), and safety. Secondary outcomes were incident skin cancers. Among 106 eligible lung transplant recipients, 49 consented to take part (46%) with 25 allocated to omega-3 FA and 24 to placebo supplements. Of these, 22 (88%) and 20 (83%), respectively, completed the trial. After 12 months, median plasma EPA increased substantially in the intervention group (125.0 to 340.0 µmol/L), but not the placebo group (98.0 to 134.5 µmol/L). In the intervention group, 6 patients developed skin cancers compared with 11 in the placebo group, giving an odds ratio (95% confidence interval) of 0.34 (0.09 to 1.32). There were no serious, active intervention-related adverse events. This pilot trial among LTRs showed acceptable recruitment and high retention and adherence. We demonstrated a signal for reduction of new skin cancer cases in those taking omega-3 FA supplements, which supports the notion that a larger, more definitive trial is warranted.

Post-operative antifungal prophylaxis in lung transplant recipients: Unprecedented evidence

Introduction/objectives Despite recent advances in lung transplantation, Aspergillus infections are still a major concern in lung transplant (LT) recipients. The genus Aspergillus may manifest as colonization or infection forms. The latter being associated with significant mortality and morbidity. Colonization, defined as bronchoalveolar lavage or bronchial aspirate, or positive bronchoalveolar lavage galactomannan test, or at least two positive sputum cultures, or tracheal aspirate for Aspergillus spp. in asymptomatic patients with normal-appearing respiratory mucosa or absence of endobronchial lesions, usually precedes infectious forms and complicates transplantation course. While several antifungal prophylactic strategies have been used to limit this deadly disease that mess with this complex endeavor, evidence from retrospective or prospective studies is lacking. In a recent international survey, only 50% of lung transplants’ centers use antifungal prophylaxis, yet, substantial differences regarding the duration and the modality of antifungal prophylaxis exist among centers and, hence, increase the unmet need for clear recommendations. Since airways’ colonization usually precedes Aspergillus infections and LT recipients are most vulnerable, in particular, during the early post-operative period due to anastomotic ischemia, Aspergillus’ eradication seems to be a plausible solution to prevent or minimize Aspergillus colonization/infections post-transplantation. Consequently, all patients who underwent single or double lung transplantation in our center after 2014 received antifungal prophylaxis started on day 1 post-transplantation and carried on till healing of bronchial anastomosis. We report our 4-year experience with antifungal prophylaxis in LT recipients. Methods A retrospective analysis was conducted and compared LT recipients who systematically received inhaled amphotericin B deoxycholate (6 mg twice daily) and 200 mg twice daily oral voriconazole (2014–2017) to those who did not (2008–2013). Only non-cystic fibrosis LT recipients were included in the analysis given that cystic fibrosis patients usually harbor aspergillus species in their sino-nasal/respiratory tract, a fact that may underestimate such therapeutic strategy benefit and Aspergillus’ eradication may not be achieved. The data showed in this analysis was traced till hospital discharge. Results A total of 142 non-cystic fibrosis patients had undergone single/double lung transplantation. Between 2014 and 2017, 59 LT recipients received antifungal prophylaxis and Aspergillus spp. was found in 20 patients (incidence of 33%), while in the control group (n = 83) Aspergillus spp. was recovered from 42 patients (incidence of 50%). The difference between these 2 groups was statistically significant (P = 0.04) suggesting a potential beneficial effect of prompt post-operative antifungal prophylaxis in reducing Aspergillus colonization. Aspergillus fumigatus, A. niger, and A. flavus were most commonly found. Conclusions Immediate post-operative antifungal prophylaxis using amphotericin B deoxycholate and oral voriconazole significantly reduced nosocomial Aspergillus colonization in non-cystic fibrosis LT recipients. A finding that might decrease subsequent Aspergillus related complications and reduce unnecessary morbidity. However, prospective controlled randomized trials with long-term follow-up are eagerly awaited.

Low dose posaconazole delayed release tablets for fungal prophylaxis in lung transplant recipients.

In November 2013, posaconazole delayed release (DR) tablets were approved by the FDA with the labeled dose of 300mg daily for fungal prophylaxis. There are no studies demonstrating the appropriate dose in lung transplant recipients (LTR). We performed a 2-center retrospective cohort study of LTR taking posaconazole DR tablets for prophylaxis between January 2014 and January 2017. Mean serum trough concentrations and percentage of measurements ≥0.7mcg/mL were compared by daily dose. Forty-nine subjects with 156 steady state serum posaconazole concentrations were included. There was a significant difference in percentage of first measured concentration ≥0.7mcg/mL by initial daily dose (P=.04). The mean serum posaconazole concentration by dose was 0.9 (±0.42)mcg/mL for 100mg daily, 1.66 (±0.91)mcg/mL for 200mg daily, 2.39 (±1.49)mcg/mL for 300mg daily, and 1.75 (±0.21)mcg/mL for 400mg daily (P<.001). Mean concentrations were at goal in 63.3%, 96.9%, 94.9%, and 100% of subjects taking 100mg, 200mg, 300mg, and 400mg daily respectively (P=.04). Our results suggest that doses less than 300mg daily of posaconazole DR tablets may be adequate to achieve target serum concentrations in LTR. Larger studies are needed to confirm these findings.

Antifungal Prophylaxis in Lung Transplant Recipients.

Invasive fungal infection remains a serious postoperative complication in lung transplant recipients and is associated with significant morbidity and mortality. Although most lung transplant centers use antifungal prophylaxis, consensus on the strategy, choice of antifungal agent(s), route of administration, and duration of prophylaxis have not been established. This review provides an overview of the epidemiology and risk factors for common fungal infections seen in lung transplant recipients, evaluates the clinical efficacy and toxicity of the various antifungal agents used to prevent infection, and offers recommendations and opportunities for future research. Currently available data evaluating the efficacy of antifungal prophylaxis strategies is limited by a lack of prospective, randomized clinical trial data and variability in patient populations, prophylactic and immunosuppressive strategies, dosing, durations of use of antifungal agents, and definitions of invasive infection. There is controversy regarding significant risk factors for invasive fungal infection, which has limited the development and validation of targeted prophylactic strategies. Inhaled formulations of amphotericin B remain the most widely studied option for universal prophylaxis and have been shown to be effective in reducing the incidence of invasive Aspergillosis as compared with no prophylaxis. Concern over early postoperative extrapulmonary infection may suggest a benefit of initial prophylaxis with a systemic azole. Long-term use of systemic antifungals is not optimal due to emerging evidence of long-term toxicities. Multicenter, randomized trials are needed to ascertain the optimal prophylactic strategy in lung transplant recipients. New agents and delivery mechanisms may offer additional opportunities for comparative research.

(651) - Posaconazole Delayed Release Tablets for Antifungal Prophylaxis in Lung Transplant Patients

In November 2013, a delayed release (DR) tablet formulation of posaconazole was approved with improved absorption compared to suspension. There have not been studies demonstrating the appropriate dose for antifungal prophylaxis in lung transplant recipients (LTR). The current labeled dose for prophylaxis is 300mg daily. Our goal is to determine the most appropriate dose of posaconazole for prophylaxis in LTR and correlate serum concentrations with different dosing regimens.

Rate of cyp51A mutation in Aspergillus fumigatus among lung transplant recipients with targeted prophylaxis.

The most common mechanism of azole (itraconazole and voriconazole) resistance in Aspergillus fumigatus is a mutation at the cyp51A locus. The aim of our study was to determine the rate of cyp51A mutations in lung transplant recipients (LTR) undergoing targeted antifungal prophylaxis with 12 weeks of voriconazole. We conducted a prospective study that included 22 LTR with A. fumigatus between October 2008 and November 2011. Of those, 10 LTR were colonized with A. fumigatus and 12 had invasive pulmonary aspergillosis. Four patients were found to have A. fumigatus isolates with a cyp51A mutation, two had colonization and two had invasive pulmonary aspergillosis. The remaining 18 LTR had WT cyp51A A. fumigatus isolates. All A. fumigatus isolates (except one due to mixed growth) were tested for antifungal susceptibility. A total of nine LTR were exposed to azoles prior to A. fumigatus isolation for a median duration of 249 (IQR 99-524) days. Azole exposure preceded the isolation of two mutant isolates and seven WT isolates. None of the cyp51A mutant isolates conferred phenotypic resistance to azoles. Targeted antifungal prophylaxis in LTR did not lead to cyp51A resistance mutations in this cohort. Data on larger cohorts who receive universal antifungal prophylaxis are needed.

Lower incidence of CMV infection and acute rejections with valganciclovir prophylaxis in lung transplant recipients

BackgroundCytomegalovirus (CMV) is the most common opportunistic infection following lung transplantation. CMV replication in the lung allograft is described as accelerating the development of bronchiolitis obliterans syndrome (BOS). Finding a strategy to prevent CMV infection is an important issue.MethodsWe performed a retrospective, single-centre study of 114 lung transplant recipients (LTRs) who underwent lung transplantation from January 2001 to December 2006. In a smaller cohort of 88 CMV seropositive (R+) LTRs, three months of valganciclovir prophylaxis (2004-2006) was compared to three months of oral ganciclovir (2001-2003) with respect to the incidence of CMV infection/disease, the severity of CMV disease, acute rejection, BOS-free 4 year survival and 4 year survival. In the whole group of 114 LTRs the impact of CMV infection on long-term survival (BOS free 4 year survival and 6 year survival) was assessed.ResultsFor the cohort of 88 CMV seropositive LTRs, the incidence of CMV infection/disease at one year was lower in the valganciclovir group compared to the ganciclovir group (24% vs. 54%, p = 0.003). There was a tendency towards reduced CMV disease, from 33% to 20% and a significant lower incidence of asymptomatic CMV infection (22% vs. 4%, p = 0.005). A lower incidence of acute rejection was observed in the valganciclovir group. However, there was no significant difference between the two groups in BOS free 4 year survival and 4 year survival.For the entire group of 114 LTRs, BOS-free 4 year survival for recipients with CMV disease was (32%, p = 0.005) and among those with asymptomatic CMV infection (36%, p = 0.061) as compared with patients without CMV infection (69%). Six year survival was lower among patients with CMV disease, (64%, p = 0.042) and asymptomatic CMV infection (55%, p = 0.018) than patients without CMV infection (84%).ConclusionsA lower incidence of CMV infection/disease and acute rejections was observed with valganciclovir (3 months) when compared to oral ganciclovir (3 months). The long-term impact of CMV infection/disease was significant for BOS-free survival and survival.

Anti-Aspergillus Prophylaxis in Lung Transplantation: A Systematic Review and Meta-analysis

Aspergillus is the most common cause of invasive fungal infection in lung transplant recipients. Most transplant centers employ routine antifungal prophylaxis to prevent the development of invasive aspergillosis (IA). We identified 22 studies from the literature to perform a systematic review and meta-analysis, in order to assess the development of IA and Aspergillus colonization with and without antifungal prophylaxis. Similarly, differences in the toxicities of different formulations of amphotericin-B and azoles were analyzed. Nineteen of 235 (8.1%) and 28 of 196 (14.3%) developed IA in the universal prophylaxis and no-prophylaxis arms, respectively (RR: 0.36, CI: 0.05-2.62). We did not find a significant reduction in IA or Aspergillus colonization with universal anti-aspergillus prophylaxis. There was no difference in the adverse events of inhaled amphotericin-B deoxycholate and lipid formulations of inhaled amphotericin-B. However, voriconazole was more hepatotoxic than itraconazole. These results should be interpreted with caution due to heterogeneity of the studies. A multicenter randomized controlled trial is warranted to assess the efficacy of anti-aspergillus prophylaxis in lung transplant recipients.

Anti-Fungal Prophylaxis in Lung Transplant Recipients (LTRs): A Meta-Analysis of Cohort Studies

Purpose Majority of lung transplant centers have adopted antifungal prophylaxis directed against Aspergillus (Asp) species based on single center cohort studies. We performed a meta-analysis to determine whether current antifungal prophylaxis strategies decrease the rate of invasive aspergillosis (IA) or Asp. colonization in LTRs. Methods and Materials The search was carried out on MEDLINE (1990-Oct 2012), EMBASE (1990-Oct 2012). For dichotomous outcomes, relative risks (RR) with 95% confidence intervals (CI) were calculated for individual studies and the summary statistics were calculated using a Random effects model (Review Manager [RevMan] Version 5.0, The Nordic Cochrane Centre, The Cochrane Collaboration, 2008). Results Of 323 references retrieved, 16 retrospective cohort studies were identified. Out of these, 8 studies had sufficient information of the comparator for the meta-analysis. These studies included a total of 1,009 LTRs. Antifungal prophylaxis significantly reduced the IA (RR, 0.45; CI, 0.21-0.97) while there was no significant effect on Asp. colonization (RR, 0.82; CI, 0.56-1.20). Antifungal prophylaxis with inhaled-Amphotericin (including lipid preparation) (3 studies), (RR, 0.47; CI, 0.18-1.22) and azoles (6 studies) (RR, 0.42; CI, 0.12-1.52) didn’t show statistically significant risk reduction. Rate of Discontinuation, cough, SOB, nausea and hepatotoxicity was not statistically significant among different antifungals. Conclusions Overall antifungal prophylaxis decreases the rate of IA however, has no effect on the Asp. colonization in LTRs. A randomized controlled trial to assess the efficacy of antifungal prophylaxis is warranted.

Low-Dose Valganciclovir for CMV Prophylaxis after Lung Transplantation

Purpose. Cytomegalovirus (CMV) remains an important pathogen following solid organ transplantation (SOT). Universal prophylaxis for CMV is adopted by most centers after lung transplantation. Various combinations studied for CMV prophylaxis include intravenous and oral ganciclovirs, oral valganciclovir, and CMV immunoglobulins. We present our experience with a low-dose of oral valganciclovir for CMV prophylaxis following lung transplantation. Methods and Materials. Our center started using 450 mg of daily oral valganciclovir for CMV prophylaxis in lung transplant recipients in Jan, 2001. A retrospective chart analysis of patients who underwent lung transplantation from January 2001 to December 2006 was done. Of 46 patients, 4 were excluded as they died within 30 days of transplant from postop complications. The mean age at transplant was 64 years, mostly single lung transplants (36/6) with a male-to-female ratio of 25/17. COPD was the most common reason for transplant (65%), and the serological CMV status of donors (D) and recipients (R) was as follows: D+/R+ 28, D+/R− 5, D−/R+ 5, and D−/R− 4. Valganciclovir was given for a total of 6 months posttransplant except for D−/R+ patients who received it for 12 months. Results. Five patients (12%) developed CMV disease with an average followup of 26 months. Only 2 (4.7%) developed CMV disease within six months of completing valganciclovir prophylaxis. This incidence is not significantly different from the best-reported results of CMV prophylaxis in lung transplant recipients. The remaining 3 patients developed the disease later in their course, one as late as 32 months posttransplant. The main side effects noted include leucopenia, neutropenia, and GI disturbances. However, the number of patients who had to temporarily stop or discontinue the medication (9.5%) was significantly lower than that reported in previous studies. Conclusions. Our experience suggests that low-dose valganciclovir is an effective method of prophylaxis for CMV disease in high-risk patients. It is a simple regimen that seems to have a better side effect profile and to improve patient compliance.

Fungi and Molds following Lung Transplantation

The landscape of fungal infections in lung transplant recipients has significantly changed over the course of time. The initial predominance of CANDIDA species has given way to the prominence of ASPERGILLUS species in the current era followed by other mold infections, namely, SCEDOSPORIUM and Zygomycetes, which are emerging as newer pathogens. CRYPTOCOCCUS NEOFORMANS is another important pathogen responsible for the morbidity in lung transplant recipients. The use of widespread antifungal prophylaxis directed against the mold infections has resulted in delayed onset of invasive aspergillosis in lung transplant recipients. In recent studies cumulative incidence rate of invasive aspergillosis was noted to be 2.4% at 12 months. Invasive mold infections in lung transplant may present as tracheobronchitis, invasive pulmonary infections, or disseminated disease. Invasive pulmonary infections are now the most common manifestations of mold infections, followed by tracheobronchitis. Pre- or posttransplant ASPERGILLUS colonization, along with preceding cytomegalovirus infections, hypogammaglobulinemia, and single-lung transplants are considered significant risk factors for invasive aspergillosis. Recently posttransplant colonization has been implicated in the development of bronchiolitis obliterans syndrome. The appropriate antimold prophylaxis strategy, by the use of either voriconazole or inhaled amphotericin, remains to be fully determined. Advances in the diagnosis and treatment of invasive aspergillosis have resulted in significant decreases in mortality. The risk factors for other mold infections such as SCEDOSPORIUM or Zygomycetes are being elucidated. Infections with these organisms, however, carry mortality up to 80%. The current article reviews the changes in the epidemiology of invasive molds and CRYPTOCOCCUS infections and other emerging fungal pathogens and highlights the controversies surrounding antifungal prophylaxis in lung transplant recipients.

Invasive Aspergillosis in Solid Organ Transplant Recipients

This chapter discusses the current status and evolving trends in the epidemiology, risk factors, diagnostic laboratory assays, and the approach to antifungal prophylaxis and treatment of invasive aspergillosis in Solid Organ Transplant (SOT) recipients. Most invasive fungal infections in these high-risk patients occur within the first month posttransplant; the median time to onset of invasive aspergillosis after renal replacement therapy and retransplantation was 13 and 28 days, respectively, in one study. Other factors associated with invasive aspergillosis in liver transplant recipients include transplantation for fulminate hepatic failure, cytomegalovirus (CMV) infection, and prolonged intensive care unit stay. A retrospective survey documented invasive pulmonary aspergillosis in 7.5% (19/251) of lung transplant recipients, of whom 47% (9/19) had disseminated aspergillosis. In a survey of antifungal prophylactic strategies in lung transplant units in the United States, aerosolized amphotericin B was the most frequently employed antifungal prophylactic agent. In order of preference, the prophylactic agents used in lung transplant centers in this study were inhaled amphotericin B (61%), itraconazole (46%), parenteral amphotericin formulations (25%), and fluconazole (21%); many centers used more than one agent. Preemptive therapy, where antifungal prophylaxis is directed towards lung transplant recipients colonized with Aspergillus spp. immediately before or within 6 to 9 months after transplantation, is another approach to the prevention of invasive aspergillosis in lung transplant recipients.

Variation in antifungal prophylaxis strategies in lung transplantation

We conducted a survey of 50 lung transplant centers across the world to evaluate the variation in antifungal prophylaxis practices. These 50 centers performed 63% of the world's lung transplants reported in 2001. Eighty-six percent (43/50) of the centers responded to the survey. Sixty-nine percent (30/43) of centers used universal antifungal prophylaxis. Aerosolized amphotericin B deoxycholate (AmBd) alone or in combination with itraconazole was used at 56% (24/43) of centers. The median duration of prophylaxis with aerosolized AmBd and itraconazole was 30 and 90 days, respectively. Seventy-four percent of the centers surveyed agreed to participate in future research prophylaxis protocols, which they felt should include both diagnostic and therapeutic arms. Our survey is the first documentation of the international variation in antifungal prophylactic strategies in lung transplant recipients, and underscores the need for multicenter, randomized trials of antifungal prophylaxis in lung transplant recipients.

353: Decrease in incident fungal infections following discontinuation of aerosolized amphotericin B lipid complex as primary prophylaxis in lung transplant recipients

353: Decrease in incident fungal infections following discontinuation of aerosolized amphotericin B lipid complex as primary prophylaxis in lung transplant recipients

Itraconazole Prophylaxis in Lung Transplant Recipients Receiving Tacrolimus (FK 506): Efficacy and Drug Interaction

Itraconazole is often given for fungal prophylaxis to lung transplant recipients after transplantation. The aim of this study was to determine the extent of interaction between tacrolimus and itraconazole in lung transplant recipients and the efficacy of itraconazole prophylaxis. The study group included 40 lung transplant recipients followed for at least 12 months. All received prophylactic itraconazole, 200 mg twice a day, for the first 6 months after transplantation. Tacrolimus levels and dosage requirements were compared during and after itraconazole therapy. Rejection rate, fungal infection rate, and renal function were assessed. The mean cost per daily treatment of the itraconazole/tacrolimus combination and tacrolimus alone was calculated. The mean tacrolimus dose during itraconazole treatment was 3.26 +/- 2.1 mg/day compared with 5.74 +/- 2.9 mg/day after itraconazole was stopped (p < 0.0001) for a mean total daily dose elevation of tacrolimus of 76%. When the cost of itraconazole was taken into account, the average total daily cost of the combined treatment was US5.86 dollars less than the treatment with tacrolimus alone. No differences in the rejection or fungal infection rate, or in renal toxicity, were observed between the periods with and without itraconazole treatment, although less positive fungal isolates were identified during itraconazole therapy. Prophylaxis therapy with itraconazole is highly effective. Itraconazole reduces the dose of tacrolimus and therefore lowers the cost of therapy without causing an increase in rejection rate and with renal function preservation.

Dose adjustment and cost of itraconazole prophylaxis in lung transplant recipients receiving cyclosporine and tacrolimus (FK 506)

Dose adjustment and cost of itraconazole prophylaxis in lung transplant recipients receiving cyclosporine and tacrolimus (FK 506)