Laparoscopic nissen fundoplication for treating reflux in lung transplant recipients

Gastroesophageal reflux disease may contribute to pulmonary injury and the development of bronchiolitis obliterans syndrome in lung transplant patients. As a result, such individuals are increasingly likely to undergo corrective gastrointestinal surgery. The present study collected outcome data for 28 lung transplant patients with documented reflux who underwent an uncomplicated laparoscopic Nissen fundoplication at our institution. The results were compared to data from 63 nontransplant reflux patients who had undergone the procedure over the same time period. All Nissen fundoplications were conducted by the same surgeon. There were no intraoperative or perioperative deaths in either patient group. Operative parameters did not differ but the postoperative hospital stay was significantly greater for the lung transplant patients (P < 0.05). Seven transplant patients (25%) were readmitted within 30 days compared to two readmissions (3.2%) in the reflux group. Five transplant patients (17.9%) have died, all from pulmonary complications; on average, death occurred 15.5 months after the Nissen surgery. There have been no deaths in the reflux group. These data indicate that laparoscopic Nissen fundoplication can be performed on lung transplant recipients to treat reflux. The average hospital stay is longer and there are more frequent readmissions in this population, but this does not appear to be due to any Nissen-related morbidity. Presented at the Forty-Third Annual Meeting of The Society for Surgery of the Alimentary Tract, San Francisco, California, May 19–22, 2002 (poster presentation). Presented at the Forty-Third Annual Meeting of The Society for Surgery of the Alimentary Tract, San Francisco, California, May 19–22, 2002 (poster presentation).     

Outbreak of aspergillosis infections among lung transplant recipients

Aspergillus infections have been associated with building constructions. We reported, for the first time, an outbreak of aspergillosis in lung transplant recipients exposed to heavy building construction work during hospitalization. We reviewed the files of 115 patients who underwent lung transplantation between May 1994 and June 2005. Patients operated on from May 1994 to December 2003 (group 1) were compared with those operated on between January 2004 and June 2005 (group 2) for findings of aspergillosis on follow up. Thirty-six transplant recipients (31%) had evidence of Aspergillus colonization, including six of the 64 patients (9.4%) operated on from 1994 to 2003 and 30 of the 51 patients (59%) operated on in 2004-2005 (P=0.0001). Eight had aspergillosis, in all group 2 (P=0.001) compared with group 1. All infections occurred within the first 4 month after the transplantation. On comparison of the two groups for background and medical factors, the only difference found was the initiation of building construction at the hospital, close to the transplant ward, in early 2004. We concluded that lung transplant recipients are prone to Aspergillus colonization following exposure to building construction work, despite prophylactic treatment. Established guidelines for the prevention of aspergillosis should be implemented and enforced during construction activities in hospitals.     

Feasibility of sputum induction in lung transplant recipients

Sputum induction (SI) is nowadays being applied as a non-invasive and safe method to investigate airway inflammation in pulmonary diseases. We investigated the feasibility of SI after lung transplantation (LTX), and compared sputum and bronchoalveolar lavage (BAL) cellular characteristics and interleukin-8 (IL-8) levels. Results were also compared with 11 healthy subjects. SI as performed between 26 and 1947 d after LTX in 19 recipients, was successful in 16 of 22 attempts (73%). Six patients failed to produce sputum after induction, mostly just post-LTX and with having a lower forced expiratory volume in 1 s (FEV1). The success rate in clinically stable patients after the first month post-LTX was 93%. Side-effects were absent. Sputum recovery, viability and squamous cell contamination were comparable between LTX patients and healthy subjects. In the LTX group, total cell counts, neutrophil percentages and IL-8 levels were much higher in SI than BAL (1.6 x 10(6)/mL, 65.5% and 54.2 ng/mL vs. 0.1 x 10(6)/mL, 3.0% and 0.01 ng/mL; p < 0.001). Although LTX-neutrophil percentages in SI and BAL correlated properly (rho=0.72, p=0.04), both techniques are not interchangeable. We conclude that sputum induction is feasible, well tolerated, and without major side-effects in stable patients after the first month post-LTX. Induced sputum may be a useful tool to study inflammatory changes of the airways after LTX, and because of the large quantity of neutrophils sampled, especially for further studies on the pathogenesis of bronchiolitis obliterans.     

Tobacco and alcohol use in lung transplant candidates and recipients

Tobacco and alcohol use among lung transplant candidates and recipients is unknown. Our first goal was to describe tobacco and alcohol use before and after lung transplant in patients with cystic fibrosis (CF) and other pulmonary diseases (non-CF). Our second goal was to determine whether demographic variables, depression, anxiety and social support predicted tobacco and alcohol use. Self-report data from transplant candidates and recipients, and transplant nurse coordinator ratings of post-transplant smoking and drinking were utilized. Data from two samples were analyzed. Sample 1 comprised 219 patients being evaluated for lung transplant, and sample 2 comprised 45 transplant recipients who were 1-7 yrs post-transplant. The results from analyzing sample 1 indicated that 72% of non-CF patients and 16% of CF patients had a history of smoking cigarettes, and the majority of patients in both groups had consumed alcohol in the past. For CF patients, past smoking was related to higher depression scores, and past drinking was related to higher education and lower social support. For non-CF patients, a history of smoking was associated with being Caucasian and older. For CF patients, a history of drinking was associated with being older and less depressed, and for non-CF patients a history of drinking was associated with higher education and lower social support. Post-transplant 100% of recipients reported abstinence from tobacco, and over 60% reported abstinence from alcohol. Transplant coordinator ratings corroborated that no transplant recipients were using tobacco products or consuming alcohol in an excessive or problematic manner. For both groups, consuming alcohol after transplant was related to lower levels of social support. In conclusion, lung recipients remain abstinent from tobacco, and although over 30% of patients consume alcohol after transplant, it is not at problematic levels. Smoking and drinking behaviors were related to demographic variables, depression, and low social support.     

A contemporary analysis of induction immunosuppression in pediatric lung transplant recipients

There is an increasing trend in the use of induction immunosuppression in children undergoing lung transplantation (LTx). To evaluate the effect of this practice on survival, the United Network for Organ Sharing (UNOS) was queried from 1987 to 2012, restricting analysis to transplant patients 6–17 years old from 2001 to 2012, who received no induction (NONE) or induction (INDUCED) with the contemporary agents of basiliximab, alemtuzumab, thymoglobulin, antilymphocyte globulin (ALG), or antithymocyte globulin (ATG). Of 23 951 lung transplants, 330 met inclusion criteria with 177 (54%) being INDUCED. Of the INDUCED agents, 121 (68%) were basiliximab, 3 (2%) alemtuzumab, and 53 (30%) ALG/ATG/thymoglobulin. The mean patient age was 13.6 (SD = 3.2) and 14 (SD = 3.0) years for the INDUCED and NONE groups, respectively. The median survival in the INDUCED group was 77.4 months (95% CI: 46.1, 125.6) compared with 50.8 months (95% CI: 42.9, 61.3) for the NONE (log‐rank P‐value = 0.3601). The most common cause of death was due to allograft failure or pulmonary complications with only one patient dying from post‐transplant lymphoproliferative disorder. The estimated hazard ratio for INDUCED versus NONE was 0.859 (95% CI: 0.620, 1.191; P = 0.3618); there were no significant confounders or effect modifiers among the demographic and clinical variables. In conclusion, antibody‐based induction immunosuppression with contemporary agents had a trend toward a protective, but not statistically significant, effect in 6‐ to 17‐year‐old patients.     

Abdominal involvement in pediatric heart and lung transplant recipients with posttransplant lymphoproliferative disease increases the risk of mortality

Background

Posttransplant lymphoproliferative disease (PTLD) is a serious complication in transplant recipients. Abdominal PTLD has been reported, but the prognosis remains undefined. The purpose of this study was to identify the incidence, predisposing factors, and outcome of abdominal PTLD in pediatric cardiothoracic transplant patients.

Methods

Retrospective chart review of 134 transplant patients (50 heart, 77 lung, 7 heart/lung) at our institution (1995-2005).

Results

Posttransplant lymphoproliferative disease was diagnosed in 14 patients. Most were Epstein-Barr virus naive initially, but all had seroconverted when diagnosed with PTLD. Eight had abdominal involvement; 4 required surgical interventions—1 for intussusception and for bowel perforation, 2 for bowel perforation, and 1 for tumor debulking. All had lifelong follow-up, with an average follow-up of 3 years. Of 8 patients with abdominal PTLD, 4 died of complications related to PTLD, whereas 1 of 6 patients with extraabdominal PTLD died of PTLD.

Conclusions

Epstein-Barr virus infection after transplantation is a major risk factor for PTLD. Pediatric patients with PTLD who present with abdominal involvement are more likely to die of PTLD than those without abdominal disease. Delay in diagnosis may contribute to the high mortality. Therefore, prompt evaluation and surveillance for possible abdominal PTLD may decrease mortality associated with this devastating problem.     

Extracorporeal membrane oxygenation for lung transplant recipients with primary severe donor lung dysfunction

Primary severe donor lung dysfunction (DLD) is a significant complication after lung transplantation (LTx), and a high mortality is reported with conventional therapy. The purpose of this report is to review the experience of the University of Pittsburgh with extracorporeal membrane oxygenation (ECMO) for primary severe DLD after LTx. From September 1991 to May 1995, 220 LTx were performed at our center. Eight patients (8/220=3.6%) with severe DLD after LTx required ECMO support. The age of LTx recipients was 44±5 years (mean±SD); seven patients were female and one was male. Indications for LTx were: chronic obstructive pulmonary disease in four patients, bronchiectasis in two, and pulmonary hypertension in two. There were three single LTx and five bilateral LTx. The interval from LTx to institution of ECMO was 5.6±3.2 h (range 0–10 h). Three patients were supported with veno-venous (v-v) ECMO and five had veno-arterial (v-a) ECMO. The duration of ECMO support was 7.3±4.8 days (range 3–15 days). activated glotting time (ACT) was maintained between 110 and 180 s with intermittent use of heparin. Seven patients (7/8=87%) were successfully weaned from ECMO and six patients (6/8=75%) were discharged home; they are currently alive after a follow-up of 17±10.1 months. One patient died on ECMO support for refractory DLD and another died 2 months after ECMO wean from multisystem organ failure. At 6 months follow-up, forced expiratory volume in 1 s (FEV1) is 2.35±0.91 (75%±17.4% predicted) and mean forced vital capacity (FVC) is 2.53±0.81 (64%±14% predicted). We conclude that ECMO can be lifesaving when instituted early after primary severe DLD. The v-v ECMO support is preferred when the patient is hemodynamically stable and adequate long-term function of the allograft is anticipated.     

Vascular resistance and endothelial function in cyclosporine-treated lung transplant recipients

The majority of patients undergoing solid organ transplantation develop hypertension, to which vasoconstriction and impaired endothelial function have been suggested to contribute. We compared basal vascular resistance and nitric oxide-mediated endothelial-dependent and independent vasoreactivity between cyclosporine-treated lung transplant recipients and healthy subjects. Forearm blood flow was measured by venous occlusion plethysmography at rest and during acetylcholine, glyceryltrinitrate and N(G)-monomethyl-L-arginine acetate (L-NMMA) infusion in 11 lung transplant recipients 3-5 years after transplantation and in eight healthy subjects. Forearm vascular resistance (FVR) was calculated. Plasma levels of endothelin-1 (ET-1) and von Willebrand factor (vWf) were analysed. Basal vascular resistance was 40% lower in transplant recipients than in healthy subjects (P = 0.021). Endothelial-dependent and independent vasodilation did not differ. Plasma levels of ET-1 and vWf were higher in transplant recipients (P = 0.009 and P < 0.001 respectively). There was a significant correlation between ET-1 levels and FVR in healthy subjects (r = 0.83, P = 0.042), but not in transplant recipients (r = -0.14, P = 0.70). The findings oppose the theory of generalized vasoconstriction and impaired endothelial function in the pathogenesis of hypertension after transplantation. Increased plasma levels of ET-1 do not cause increased FVR in lung transplant recipients.     

Genotypes associated with tacrolimus pharmacokinetics impact clinical outcomes in lung transplant recipients

Most lung transplantation immunosuppression regimens include tacrolimus. Single nucleotide polymorphisms (SNPs) in genes important to tacrolimus bioavailability and clearance (ABCB1, CYP3A4, and CYP3A5) are associated with differences in tacrolimus pharmacokinetics. We hypothesized that polymorphisms in these genes would impact immunosuppression‐related outcomes. We categorized ABCB1, CYP3A4, and CYP3A5 SNPs for 321 lung allograft recipients. Genotype effects on time to therapeutic tacrolimus level, interactions with antifungal medications, concentration to dose (C₀/D), acute kidney injury, and rejection were assessed using linear models adjusted for subject characteristics and repeat measures. Compared with CYP3A poor metabolizers (PM), time to therapeutic tacrolimus trough was increased by 5.1 ± 1.6 days for CYP3A extensive metabolizers (EM, P < 0.001). In the post‐operative period, CYP3A intermediate metabolizers spent 1.2 ± 0.5 days less (P = 0.01) and EM spent 2.1 ± 0.5 days less (P < 0.001) in goal tacrolimus range than CYP3A PM. Azole antifungals interacted with CYP3A genotype in predicting C₀/D (P < 0.001). Increased acute kidney injury rates were observed in subjects with high ABCB1 function (OR 3.0, 95% CI 1.1‐8.6, P = 0.01). Lower rates of acute cellular rejection were observed in subjects with low ABCB1 function (OR 0.36, 95% CI 0.07‐0.94, P = 0.02). Recipient genotyping may help inform tacrolimus dosing decisions and risk of adverse clinical outcomes.     

Bronchoscopy in the diagnosis and surveillance of respiratory infections in lung and heart–lung transplant recipients

Fiberoptic bronchoscopy (FOB) with bronchoalveolar lavage (BAL) and transbronchial biopsies (TBB) is a widely used method to detect respiratory infections and to differentiate them from other postoperative complications in lung transplant (LTX) recipients, but the usefulness of surveillance FOBs is not yet established. The aim of this study was to evaluate the usefulness of FOB in the diagnosis and surveillance of infections in LTX recipients. We reviewed all the consecutive 609 FOBs performed on 40 lung or heart-LTX recipients between February 1994 and November 2002. The overall diagnostic yield was 115/190 (61%) and 43/282 (15%) for clinically indicated and surveillance FOBs respectively (P < 0.001). Infection was established by bronchoscopic samples in 96/190 (50.5.%) of the clinically indicated FOBs and 34/282 (12.1%) of the surveillance FOBs (P < 0.001). The diagnostic yield of the clinically indicated FOBs was highest (72%) from 1 to 6 months post-transplant (P = 0.04). Pneumocystis carinii was detected in 23 (4.9%) of the bronchoscopic specimens and 15 (65%) of the P. carinii infections were detected during adequate chemoprophylaxis. To conclude, in LTX recipients clinically indicated FOB has a good diagnostic yield in detecting infections and other postoperative complications, whereas the information received from surveillance FOB has remained less significant. With current prophylaxis and screening strategies FOB is still required to detect P. carinii infections.     

Nocardia infection in lung transplant recipients

Nocardia is a well-recognized pathogen in immunocompromised hosts, but the incidence of Nocardia infections in lung transplant recipients is not well defined. A chart review from 1990 to 2007 at Clarian Hospital Lung Transplant Center and Indiana University Medical Center revealed Nocardia infections in four of 410 lung transplant recipients despite prophylaxis. All infections were confined to lung and occurred at a median time of 315 d after transplantation. Nocardia nova was isolated in two patients, Nocardia farcinica in one, and unspecified Nocardia sp. in one. Nocardia isolates were susceptible to trimethoprim sulfa (TMP/SMX). Our data suggest that the dose of TMP/SMX, commonly used for Pneumocystis prophylaxis is not protective for Nocardia. Contrary to historic data reporting 40% mortality, none of the patients in our study died because of Nocardia. Nocardia infection is an under-recognized entity in lung transplant recipients, and the optimal duration of therapy and prophylaxis are unclear.     

Parenteral administration of oral medications in lung transplant recipients: An underrecognized problem

Microcrystalline cellulose (MCC) is an insoluble material commonly used as a binder and filler in oral medications. Identification of pulmonary intravascular deposition of MCC in transbronchial biopsies from lung transplant (LT) recipients following parenteral injection of oral medications has only been reported once. A search of our surgical pathology electronic database was performed from January 1, 2000 to November 1, 2017 using the text “transplant transbronchial.” The diagnosis field for all cases retrieved was then searched for the text “cellulose.” These cases were queried for patient demographics and outcomes. Between January 1, 2000 and November 1, 2017, 1558 lung transplants were performed in 1476 individual patients at our institution; 12 were identified to have MCC in their lung tissue. Patients with MCC identified on biopsies were more likely to be transplanted for cystic fibrosis versus other indications and younger versus older. MCC identified in 2 of our cases was favored to be donor derived. Of the 12 patients, 6 (50%) are deceased. MCC within the pulmonary vasculature may be an indicator of increased complications, mortality, or shortened survival in LT recipients. Detecting intravascular MCC and distinguishing it from aspirated foreign material can be challenging. Awareness of the differential diagnosis for pulmonary foreign material is of paramount importance for the pathologist.     

A review of the potential applications and controversies of non‐invasive testing for biomarkers of aspiration in the lung transplant population

Davis CS, Gagermeier J, Dilling D, Alex C, Lowery E, Kovacs EJ, Love RB, Fisichella PM. A review of the potential applications and controversies of non‐invasive testing for biomarkers of aspiration in the lung transplant population.
Clin Transplant 2010: 24: E54–E61. © 2010 John Wiley & Sons A/S. Abstract: Despite improvements in one‐yr survival following lung transplantation, five‐yr survival lags significantly behind the transplantation of other solid organs. The contrast in survival persists despite advancements in anti‐rejection regimens, suggesting a non‐alloimmune mechanism to chronic lung transplant failure. Notably, markers of aspiration have been demonstrated in bronchoalveolar lavage (BAL) fluid concurrent with bronchiolitis obliterans syndrome (BOS). This recent evidence has underscored gastroesophageal reflux (GER) and its associated aspiration risk as a non‐alloimmune mechanism of chronic lung transplant failure. Given the suggested safety and efficacy of laparoscopic anti‐reflux procedures in the lung transplant population, identifying those at risk for aspiration is of prime importance, especially concerning the potential for long‐term improvements in morbidity and mortality. Conventional diagnostic methods for GER and aspiration, such as pH monitoring and detecting pepsin and bile salts in BAL fluid, have gaps in their effectiveness. Therefore, we review the applications and controversies of a non‐invasive method of defining reflux injury in the lung transplant population: the detection of biomarkers of aspiration in the exhaled breath condensate. Only by means of assay standardization and directed collaboration may such a non‐invasive method be a realization in lung transplantation.