non-CF Recipients Research Articles

A shifting landscape: Practice patterns and outcomes of cystic fibrosis and non-cystic fibrosis pediatric lung transplantation.

New drugs may further decrease the need for lung transplant (LTx) in pediatric patients with cystic fibrosis (CF), but few studies highlight pediatric non-CF LTx characteristics and outcomes. The ISHLT registry was used to report morbidity, graft failure, and survival for primary pediatric (<18years) LTx performed 1990-2017. Recipient/donor characteristics and long-term outcomes were analyzed for CF and non-CF recipients. Survival was assessed using Kaplan-Meier curves. Of 2232 primary LTx, (43% in males), 918 (41%) were performed for non-CF indications; most commonly pulmonary hypertension (43%). Non-CF patients were younger (median age 11 vs. 15, p<.001), and more frequently on inotropes and/or extracorporeal membrane oxygenation (15% vs. 2.4%, p<.001) at transplant, compared to CF recipients. In-hospital major complications more commonly affected CF LTx recipients (57% vs. 48%, p=.003), but 30-day mortality was higher in the non-CF group (9% non-CF vs. 5% CF, p<.001). One-, five-, and ten-year mortality was 18%, 50%, and 65% for CF recipients, respectively, and 21%, 45%, and 58% for non-CF recipients (p=.01 at 10years). Five-year survival was significantly better for non-CF females versus CF females (56% vs. 48%, p=.013), but was similar between groups for males (55% vs. 54%, p=.305). While age was a late outcomes risk factor, pulmonary hypertension and later transplants eras were protective. Early mortality is higher and late mortality is lower in non-CF LTx. Current non-CF LTx outcomes leave room for improvement. Further study is needed to evaluate the effects of center volume and pediatric-specific experience on outcomes.

Cystic Fibrosis Lung Transplant Recipients Have Suppressed Airway Interferon Responses during Pseudomonas Infection

SummaryLung transplantation can be lifesaving in end-stage cystic fibrosis (CF), but long-term survival is limited by chronic lung allograft dysfunction (CLAD). Persistent upper airway Pseudomonas aeruginosa (PsA) colonization can seed the allograft. While de novo PsA infection is associated with CLAD in non-CF recipients, this association is less clear for CF recipients experiencing PsA recolonization. Here, we evaluate host and pathogen contributions to this phenomenon. In the context of PsA infection, brushings from the airways of CF recipients demonstrate type 1 interferon gene suppression. Airway epithelial cell (AEC) cultures demonstrate similar findings in the absence of pathogens or immune cells, contrasting with the pre-transplant CF AEC phenotype. Type 1 interferon promoters are relatively hypermethylated in CF AECs. CF subjects in this cohort have more mucoid PsA, while non-CF PsA subjects have decreased microbiome α diversity. Peri-transplant protocols may benefit from consideration of this host and microbiome equilibrium.

Lung Transplantation for Cystic Fibrosis and Non-cystic Fibrosis Bronchiectasis: A Single-Center Experience

ObjectivesLung transplantation is a well-established treatment for selected patients with advanced cystic fibrosis (CF)- and non-cystic fibrosis (non-CF)--related bronchiectasis. Because the number of lung transplants performed for patients with non-CF bronchiectasis is much smaller than for patients with CF, little data is available regarding patient selection, choice of procedure, and outcomes. MethodsBetween November 1997 and December 2013, 42 patients with CF and 33 patients with non-CF bronchiectasis underwent lung transplantation at the Rabin Medical Center, Israel. We analyzed and compared pretransplant evaluation data and short- and long-term results in both groups. ResultsMedian survival for the CF group in our study was 8.4 years, compared with 7.1 years for the non-CF group (P = .098), similarly to that reported by the International Society for Heart and Lung Transplantation Registry data. The main survival difference between groups was in the early postoperative period. Both groups achieved similar peak forced expiratory volume in 1 second values and had stable lung function at the 3-year follow-up. Biopsy-proven rates of acute cellular rejection were low for both groups. Rates of chronic lung allograft dysfunction development did not differ between CF and non-CF recipients. ConclusionOur institutional experience confirms that lung transplantation is feasible for non-CF bronchiectasis, and results are comparable to our CF cohort. The increased early mortality in this study occurred from 1999 to 2008 and was probably related to surgical techniques used at the time. Overall, 3-year and 5-year survival were comparable with the International Society for Heart and Lung Transplantation Registry data. Non-CF bronchiectasis patients achieved and maintained satisfactory lung function.

Increased risk of PTLD in lung transplant recipients with cystic fibrosis

BackgroundPost-transplant lymphoproliferative disease (PTLD) is an important cause of morbidity and mortality following lung transplantation. Recipients with cystic fibrosis (CF) may have an increased risk of PTLD although the literature is limited to single center cohorts. Our primary aim is to examine PTLD in an adult lung transplant population by utilizing the International Society for Heart and Lung Transplantation Registry. MethodsWe studied 30,598 adult recipients of lung transplants performed between 1999 and 2011. The primary outcome was development of and time to PTLD. In addition to indication for transplant, other predictors examined included Epstein–Barr virus (EBV) and cytomegalovirus (CMV) serostatus, gender, and age. Outcomes were assessed with univariable and multivariable Cox proportional hazard models to obtain hazard ratios (HR). Results17% of the cohort had a diagnosis of CF. PTLD developed in 2% of CF recipients compared to 1% for non-CF recipients (p<0.001). Compared to non-CF recipients, CF recipients had higher prevalence of EBV and CMV seronegativity and higher prevalences of high risk EBV and CMV mismatch (D+/R−). There is a significant association between CF and the development of PTLD [HR 1.66 (95% CI 1.30–2.12)]. Stratified multivariable analysis controlling for age revealed EBV negative non-CF recipients have an almost 2 fold increased risk of developing PTLD, whereas EBV negative CF recipients had an almost 6.5 fold increased risk. ConclusionsCF recipients have a higher risk for PTLD compared to non-CF recipients. Further studies are needed to account for additional risk factors and management in this population post-transplant.

Cancer risk among lung transplant recipients with cystic fibrosis

BackgroundPrevious studies demonstrated increased digestive tract cancers among individuals with cystic fibrosis (CF), particularly among lung transplant recipients. We describe cancer incidence among CF and non-CF lung recipients. MethodsWe used data from the US transplant registry and 16 cancer registries. Standardized incidence ratios (SIRs) compared cancer incidence to the general population, and competing risk methods were used for the cumulative incidence of colorectal cancer. ResultsWe evaluated 10,179 lung recipients (1681 with CF). Risk was more strongly increased in CF recipients than non-CF recipients for overall cancer (SIR 9.9 vs. 2.7) and multiple cancers including colorectal cancer (24.2 vs. 1.7), esophageal cancer (56.3 vs. 1.3), and non-Hodgkin lymphoma (61.8 vs. 9.4). At five years post-transplant, colorectal cancer was diagnosed in 0.3% of CF recipients aged <50 at transplant and 6.4% aged ≥50. ConclusionsCF recipients have increased risk for colorectal cancer, suggesting a need for enhanced screening.

Increased Incidence of PTLD in Adult Lung Transplant Recipients with Cystic Fibrosis: Analysis of the International Society for Heart and Lung Transplantation Registry

Purpose Post-transplant lymphoproliferative disease (PTLD) is a major cause of morbidity and mortality following lung transplantation. Recipients with cystic fibrosis (CF) may have an increased incidence of PTLD although the literature is limited to single center cohort studies. Our primary aim was to examine the rate of PTLD in an adult population with CF by utilizing the ISHLT Registry. Methods and Materials We studied 30,549 adult recipients of lung transplants performed between 1999-2011. The primary outcome was development of PTLD. In addition to indication for transplant, other variables examined included: EBV serostatus, gender, age, and CMV status. Statistical analyses performed included chi-square, independent t-tests, and multivariable logistic regression model to obtain odds ratios (OR). Results 17.4% of the cohort had a diagnosis of CF. PTLD developed in 1.8% of CF recipients compared to 1.0% for non-CF recipients (p Conclusions There is a higher rate of PTLD in CF recipients compared to non-CF recipients; this association held when controlling for other variables associated with PTLD. Additional factors that may impact the association between CF and PTLD need to be examined, including induction and maintenance immunosuppression, rejection, and donor EBV status.

Body mass index and its effect on outcome in children after lung transplantation

Malnutrition is common in children undergoing lung transplantation, particularly among those with cystic fibrosis (CF). However, the effect of body habitus on outcome after pediatric lung transplantation is unknown. We studied body mass index (BMI) and its effect on outcome in pediatric lung transplantation. The International Society for Heart and Lung Transplantation Registry on Pediatric Lung Transplantation was queried for primary pediatric lung transplant recipients (aged<18 years) between 1990 and 2008. BMI cohorts were defined according to International Obesity Task Force cutoffs: thinness grade 3, BMI<16 kg/m(2); thinness grade 2, 16 to<17 kg/m(2); thinness grade 1, 17 to<18.5 kg/m(2); normal, 18.5 to<25 kg/m(2); overweight, 25 to<30 kg/m(2); and obese, ≥ 30 kg/m(2). Survival was compared among BMI cohorts within CF and non-CF recipient groups. Included were 897 recipients. The median age at transplantation was 14 years (interquartile, 11, 16 years) and 63% had CF. The incidence of thinness was 59% in CF vs 39% in non-CF patients (p<0.001). A significant proportion of CF patients were underweight, whereas more non-CF patients were obese. Cox regression showed neither underweight nor overweight CF recipients differed in survival compared with recipients of normal-weight recipients. Grade of thinness was not related to outcome after transplantation. For non-CF recipients, being overweight/obese increased risk of death compared with normal-weight recipients (hazard ratio, 2.05; 95% confidence interval, 1.28-3.26; p = 0.002). The incidence of underweight status amongst pediatric lung transplant recipients with CF is high. However, we did not find a significant negative effect of underweight body habitus on survival in CF children after lung transplantation. Overweight pediatric recipients appear to have poorer survival after transplant.

Exhaled Nitric Oxide: A Valuable Tool for Early Diagnosis and Phenotyping of Bronchiolitis Obliterans Syndrome

To the Editor: Thank you very much for the opportunity to write a letter of response with respect to the letter of Antus et al. regarding possible limitations of fraction of nitric oxide in exhaled breath (FeNO) for the early detection of chronic graft dysfunction after lung transplantation (LTX; Ref. 1). We speculate that several factors might have contributed to the lack of demonstration of clinical utility for FeNO in this relatively small cohort of LTX recipients. In our study, population underlying disease was not identified as a variable contributing to the variance of FeNO. However, the percentage of cystic fibrosis (CF) patients in our study cohort was only 16.7% in comparison to 43.3% in the Hungarian cohort. Although subgroup analysis of FeNO performance is limited because of the overall small sample size, we cannot definitely rule out a significant impact of the underlying disease on FeNO performance as a marker for bronchiolitis obliterans syndrome (BOS; Ref. 2). Despite the fact that FeNO readings of recipients with overt infection were excluded from the analysis, a significant rate of colonization and subclinical infections in CF patients may be important confounders for the interpretation of FeNO measurements (3). In accordance with the findings of Antus et al., our data demonstrated that a relevant percentage of patients displayed only slightly elevated FeNO values in spite of developing BOS. We suggest that dividing BOS patients on the basis of BAL neutrophilia into neutrophilic reversible allograft dysfunction and fibroproliferative BOS (fBOS) could reveal a lack of detectable FeNO increase in fBOS patients because FeNO is mainly a marker of airway inflammation (4). Moreover, Antus and colleagues do not report the prophylactic or therapeutic use of azithromycin in CF and nonCF recipients which is the standard of care in many centers for patients during early stages of BOS that might result in a significant reduction of FeNO (5). The authors report an impressively high number of FeNO measurements without finding an unambiguous association of FeNO and BOS during long-term follow-up. However, assessment of FeNO readings as a mean of all values recorded during 6-month intervals as depicted by Antus and colleagues might hamper the performance of FeNO as a predictive marker because the average time from FeNO readingto onsetofBOSwas only 117 ±9 days in ourstudy. In this respect, we wish to emphasize the high negative predictive value of elevated FeNO (96.9%) in comparison to its rather intermediate positive predictive value (69.0%) in our cohort. In summary, we clearly recognize the relevant limitations of FeNO as a predictive marker in the context of the overall highly variable course of BOS. Nevertheless, FeNO is a valuable tool to improve our understanding for different phenotypes of BOS with potentially important clinical applications.

Colon cancer in lung transplant recipients with CF: Increased risk and results of screening

Objective To determine the incidence of colon cancer in lung transplant recipients with cystic fibrosis (CF) and review screening colonoscopic findings in other recipients with CF. Methods A retrospective chart review was performed for all patients with CF transplanted at the University of Wisconsin Hospital and Clinics (January 1994 through December 2010). Results Four of 70 transplant recipients with CF developed fatal colon carcinoma following transplantation, and the cancer was advanced in all 4 recipients (age 31, 44, 44, 64) at the time of diagnosis. In contrast, only one of 287 recipients transplanted for non-CF indications developed colon cancer. Of all recipients with CF who did not develop colon cancer, 20 recipients underwent screening colonoscopy at 1 to 12 years following transplantation. Seven (35%) of the screened transplant recipients (ages 36, 38, 40, 41, 43, 49, 51) had colonic polyps in locations ranging from cecum to sigmoid colon and up to 3 cm in diameter. Conclusions In contrast to non-CF recipients, patients with CF displayed a significant incidence of colon cancer (4 of 70 recipients; 5.7%) with onset ranging from 246 days to 9.3 years post-transplant, which may be due to a combination of their underlying genetic disorder plus intense, sustained immunosuppression following lung transplantation. Colonoscopic screening may identify patients with pre-malignant colonic lesions and prevent progression to colonic malignancy.

A comparison of CF and non-CF school-age children undergoing lung transplantation

Cystic fibrosis (CF) is a genetic disorder resulting in a chloride channel (CFTR) defect characterized by multi-organ damage. The primary cause of morbidity and mortality is end-stage obstructive lung disease. Lung transplantation is a treatment option, but is complicated by the risks of acute rejection, Bronchiolitis Obliterans syndrome (BOS) (graft dysfunction), and serious infection. This study sought to assess survival free from three major complications, namely BOS, acute rejection, and serious infection and also to compare overall survival among school-age CF transplantation recipients to non-CF recipients. We limited consideration to school-age children because they comprise a unique cohort in terms of linear and graft growth, immunity, pharmacokinetics and infection exposure as compared with infants, adolescents and adults. The OPTN national database was searched for period between January 1997 and August 2006 for children between 6 and 10 years of age undergoing lung transplantation. Children with CF were compared with non-CF recipients with regard to occurrence of BOS, infection-related hospitalizations, and acute rejections. Kaplan-Meier analyses were used for statistical comparisons of the two cohorts. There were 50 CF patients and 37 non-CF patients available for analysis from the OPTN database. Up to 5 years post-transplant, there were no statistically significant differences between CF and non-CF patients in overall survival, and survival free from BOS, acute rejections, or serious infections defined as those requiring hospitalization. Despite having an underlying systemic disease based on defective CFTR, CF school-age children receiving a lung transplant do not demonstrate more major complications or lower survival than non-CF children.

Aspergillus Infection in Lung Transplant Recipients With Cystic Fibrosis : Risk Factors and Outcomes Comparison to Other Types of Transplant Recipients

To characterize Aspergillus infections in lung transplant recipients with cystic fibrosis (CF). A retrospective analysis of 32 consecutive lung transplant recipients with CF who underwent bilateral lung transplant at the University of Wisconsin from 1994 to 2000 to determine the incidence, risk factors, and consequences of Aspergillus infection. The findings were compared to 101 non-CF recipients of lung transplants (93) and heart-lung transplants (8) for other transplant indications. A university hospital. Lung transplant recipients with CF or other indications for transplantation. None. Seventeen of 32 CF recipients (53%) had Aspergillus fumigatus isolated from their respiratory secretions prior to undergoing transplantation. Ten of these 17 (59%) recipients had A fumigatus persistently found in their respiratory secretions posttransplant vs 6 of 15 CF patients (40%) who had not been colonized pretransplant and 28 of 101 of the non-CF recipients (28%). Four of the preoperatively colonized CF recipients developed tracheobronchial aspergillosis (TBA) just distal to the bronchial anastomoses, and one recipient had dehiscence of the involved anastomosis. None of the CF recipients developed disseminated aspergillosis or pneumonia. Prophylactic antifungal therapy did not prevent TBA, and IV amphotericin B therapy was required to clear the infection in all four patients, with endobronchial debridement of necrotic tissue required in two of them. In contrast, 10 of the non-CF (10%) recipients developed Aspergillus infections posttransplant (TBA, 4 recipients; pneumonitis, 6 recipients), and only 3 patients had successful treatment and long-term survival (TBA, 2 patients; pneumonia, 1 patient). Donor lung ischemia time, cytomegalovirus infection or pneumonia, or pretransplant mechanical ventilation did not increase the risk of developing TBA in CF recipients. The risk of TBA for patients receiving lung transplants for CF warrants early surveillance bronchoscopy to detect TBA, particularly in recipients with pretransplant colonization.

Pulmonary Aspergillosis in Cystic Fibrosis Lung Transplant Recipients

To define the prevalence of colonization and infection of the lower respiratory tract (LRT) with Aspergillus in lung transplant recipients with and without cystic fibrosis (CF). Retrospective review. Large university lung transplant center. The postoperative course of 31 CF and 53 non-CF double lung or double lobar transplant recipients receiving allografts from April 1991 to February 1996 was reviewed. All recipients were subjected to surveillance bronchoscopy and biopsy at predetermined intervals and when clinically indicated. BAL fluid (BALF) and biopsy material were examined by appropriate fungal culture and staining techniques. Infection was defined by the finding of tissue-invasive disease on biopsy specimens. Seven of the 31 CF recipients (22%) had Aspergillus isolated from cultures of sputum prior to transplantation. Following transplantation, 15 CF recipients (48%) had Aspergillus isolated from either sputum or BALF, including 4 of the 7 recipients identified with the fungus prior to transplantation. By contrast, 21 of the 53 non-CF recipients (40%) had Aspergillus isolated from the LRT following transplantation, none having had the fungus isolated prior to transplantation. The prevalence of Aspergillus did not differ between these groups (p = 0.51). Infections with Aspergillus occurred in 4 of the CF recipients (27%) and did not differ from the 3 infections (14%) identified in the non-CF recipients (p = 0.36). However, three of the four infections in the CF recipients involved the healing bronchial anastomosis and occurred prior to postoperative day 60. All three of these recipients had Aspergillus preoperatively. Postoperative infection was more common in the CF recipients having Aspergillus preoperatively than in those CF recipients without preoperative Aspergillus (p = 0.02). Isolation of Aspergillus from the LRT following double lung transplantation is common and generally not associated with tissue-invasive disease. Those CF recipients with Aspergillus isolated in cultures of sputum preoperatively are at risk for postoperative infections with this agent. The healing bronchial anastomosis is particularly vulnerable.