Patients Post-lung Transplantation Research Articles

A novel approach to reducing hepatotoxicity related to fungal prophylaxis in pediatric lung transplant recipients.

Pediatric lung transplant patients are at risk for developing invasive fungal infections post-transplant. No consensus exists on optimal antifungal regimens and voriconazole, a common first-line agent, has been shown to cause hepatotoxicity. We describe a single-center experience utilizing a novel antifungal regimen of intravenous micafungin and nebulized amphotericin B immediately post-transplant with conversion to an azole at the time of hospital discharge and compare it to a historical cohort of patients who received voriconazole monotherapy throughout their immediate post-operative course. This is a retrospective review of patients in the age 0-18 who received a lung transplant from June 2016-May 2021. Data points collected included: demographic data, transplant date and discharge date, Aspergillus colonization, type of lung transplant, hospitalization and level of care information, induction and antifungal medication regimen; AST, ALT, GGT, bilirubin, and direct bilirubin at various timepoints; and respiratory and blood culture results. The two patient groups were compared by assessment of changes in LFTs and culture results. Forty-two patients were included in the analysis, with 24 patients receiving micafungin and nebulized amphotericin and 18 patients receiving voriconazole. All patients in both groups experienced a post-operative elevation in at least one transaminase or bilirubin. More patients in the micafungin/amphotericin group had resolution of all abnormal LFTs by 1 month post-transplant (p = .036). Additionally, patients in the micafungin/amphotericin group experienced faster normalization of their LFTs compared with the voriconazole group (p < .001). Ten patients in the micafungin/amphotericin group and five patients in the voriconazole group were found to have fungal growth on culture post-transplant, but this difference was not found to be statistically significant (p = .507). An antifungal regimen of micafungin and nebulized amphotericin B liposomal may be useful at decreasing the duration of elevated liver enzymes in pediatric patients in the immediate post-lung transplant period when compared with voriconazole monotherapy. Larger prospective studies looking at antifungal regimens in pediatric patients post-lung transplant are warranted.

The Utility of the Sit-to-Stand Test for Inpatients in the Acute Hospital Setting After Lung Transplantation.

Measurement of physical function is important to guide physical therapy for patients post-lung transplantation (LTx). The Sit-to-Stand (STS) test has proven utility in chronic disease, but psychometric properties post-LTx are unknown. The study aimed to assess reliability, validity, responsiveness, and feasibility of the 60-second STS post-LTx. This was a measurement study in 62 inpatients post-LTx (31 acute postoperative; 31 medical readmissions). Interrater reliability was assessed with 2 STS tests undertaken by different assessors at baseline. Known group validity was assessed by comparing STS repetitions in postoperative and medical groups. Content validity was assessed using comparisons to knee extensor and grip strength, measured with hand-held dynamometry. Criterion validity was assessed by comparison of STS repetitions and 6-minute walk distance postoperatively. Responsiveness was assessed using effect sizes over inpatient admission. Median (interquartile range) age was 62 (56-67) years; time post-LTx was 5 (5-7) days postoperative and 696 (244-1849) days for medical readmissions. Interrater reliability was excellent (intraclass correlation coefficient type 2,1 = 0.96), with a mean learning effect of 2 repetitions. Repetitions were greater for medical at baseline (mean 18 vs 8). More STS repetitions were associated with greater knee extensor strength (postoperative r=0.57; medical r=0.47) and 6-minute walk distance (postoperative r=0.68). Effect sizes were 0.94 and 0.09, with a floor effect of 23% and 3% at baseline (postoperative/medical) improving to 10% at discharge. Patients incapable of attempting a STS test were excluded, reducing generalizability to critical care. Physical rehabilitation was not standardized, possibly reducing responsiveness. The 60-second STS demonstrated excellent interrater reliability and moderate validity and was responsive to change postoperatively. The 60-second STS represents a safe, feasible functional performance tool for inpatients post-LTx. Two tests should be completed at each time point.

WITHDRAWN: Hyperammonemia Following Lung Transplant Is a Diagnostic and Therapeutic Challenge: A Case Report

Available online 14 February 2020. This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

The Role of Fraction of Exhaled Nitric Oxide in Allograft Dysfunction in Lung Transplant Recipients

SESSION TITLE: Transplant SESSION TYPE: Original Investigation Poster PRESENTED ON: Wednesday, November 1, 2017 at 01:30 PM - 02:30 PM PURPOSE: The reasons why some patients post lung transplantation have an increased propensity for rejection and/or infection is incompletely understood. Although surveillance testing, such as pulmonary function and bronchoscopy for culture and transbronchial biopsies, has been used effectively to identify patients with post-transplant complications, there is a need for more sensitive and non-invasive assays. Fractional exhaled nitric oxide (FeNO) is a simple, widely available, non-invasive, and inexpensive method to indirectly assess increased airway neutrophilia. The objective of this study was to evaluate the use of FeNO trajectory after lung transplantation as a predictive tool for lung function decline in patients post lung transplant. METHODS: The study included all consecutive patients who had undergone bilateral lung transplantation at a single center from January to December 2015. Serial FeNO measurements were done at week 4, 8, 12, 16, 26 and 52 post-transplant. Demographics, pre-transplant diagnosis, lung function, number of infections and instances of biopsy proven rejection on surveillance or clinically indicated bronchoscopy were collected during the 12-month study period. Primary outcome was to assess the clinical correlation between FeNO levels and lung function measured by forced expiratory volume in 1 second (FEV1) percentage change. RESULTS: 29 patients were screened for the study (2 patients died and 4 had single lung transplants). Of the 23 patients included, the most common reason for transplantation was interstitial lung disease (61%), followed by COPD (26%). Rejection and infection was identified in 14 (61%) and 21 (91%) patients, respectively. FeNO levels did not have defined trajectories over time in the whole cohort (R2=0.017), or in those patients that had rejection (R2=0.013). FeNO levels did not correlate with FEV1 in all post-transplant patients (R2=0.001) or those that had rejection (R2=0.001). CONCLUSIONS: FeNO levels were not correlated with either rejection or lung function decline in lung transplant recipients. CLINICAL IMPLICATIONS: Although limited by its sample size, the current study does not support the routine use of serial measurements of FeNO to evaluate for allograft dysfunction in lung transplant recipients. DISCLOSURE: The following authors have nothing to disclose: Diego Maselli, Nina Zatikyan, Benjamin Stephens, Maria Velez, Sergio Burguete, Holly Keyt, Stephanie Levine, Marcos Restrepo, Deborah Levine, Luis Angel No Product/Research Disclosure Information

Impaired Esophageal Motility and Clearance Post-Lung Transplant: Risk For Chronic Allograft Failure

Objectives:Gastroesophageal reflux is common in patients post-lung transplantation (LTx) and thus considered a risk factor for aspiration and consequently allograft rejection and the development of chronic allograft failure. However, evidence supporting this remains unclear and often contradictory. Our aim was to examine the role played by esophageal motility on gastroesophageal reflux exposure, along with its clearance and that of boluses swallowed, and the relationship to development of obstructive chronic lung allograft dysfunction (o-CLAD).Methods:Patients post-LTx (n=50, 26 female; mean age 55 years (range, 20–73 years)) completed high-resolution impedance manometry and 24-h pH/impedance. Esophageal motility abnormalities were classified based upon the Chicago Classification version 3.0.Results:Esophagogastric junction outflow obstruction alone (EGJOOa) (P=0.01), incomplete bolus transit (IBT) (P=0.006) and proximal reflux (P=0.042) increased the risk for o-CLAD. Patients with EGJOOa were most likely to present with o-CLAD (77%); despite being less likely to exhibit abnormal numbers of reflux events (10%) compared with those with normal motility (o-CLAD: 29%, P<0.05; abnormal reflux events: 64%, P<0.05). Patients with EGJOOa had lower total reflux bolus exposure time than those with normal motility (0.6 vs. 1.5% P<0.05). In addition, poor esophageal clearance documented by abnormal post-reflux swallow-induced peristaltic wave index associated with o-CLAD; inversely correlating with the proportion of reflux events reaching the proximal esophagus (r=−0.251; P=0.052).Conclusions:These observations support esophageal dysmotility, especially EGJOOa, and impaired clearance of swallowed bolus or refluxed contents, more so than just the presence of gastroesophageal reflux alone, as important risk factors in the development of o-CLAD.

Airway Microbiota Determines Innate Cell Inflammatory or Tissue Remodeling Profiles in Lung Transplantation.

In lung transplant recipients, long-term graft survival relies on the control of inflammation and tissue remodeling to maintain graft functionality and avoid chronic lung allograft dysfunction. Although advances in clinical practice have improved transplant success, the mechanisms by which the balance between inflammation and remodeling is maintained are largely unknown. To assess whether host-microbe interactions in the transplanted lung determine the immunologic tone of the airways, and consequently could impact graft survival. Microbiota DNA and host total RNA were isolated from 203 bronchoalveolar lavages obtained from 112 patients post-lung transplantation. Microbiota composition was determined using 16S ribosomal RNA analysis, and expression of a set of genes involved in prototypic macrophage functions was quantified using real-time quantitative polymerase chain reaction. We show that the characteristics of the pulmonary microbiota aligned with distinct innate cell gene expression profiles. Although a nonpolarized activation was associated with bacterial communities consisting of a balance between proinflammatory (e.g., Staphylococcus and Pseudomonas) and low stimulatory (e.g., Prevotella and Streptococcus) bacteria, "inflammatory" and "remodeling" profiles were linked to bacterial dysbiosis. Mechanistic assays provided direct evidence that bacterial dysbiosis could lead to inflammatory or remodeling profiles in macrophages, whereas a balanced microbial community maintained homeostasis. The crosstalk between bacterial communities and innate immune cells potentially determines the function of the transplanted lung offering novel pathways for intervention strategies.

232 Consulting the experts: engaging pre-adolescent children and their parents in the development of a study proposal

With increasing life expectancy patients with CF are encountering medical complications that historically have never been an issue. Over the last 10 years three patients with CF have been diagnosed with skin malignancy at the Leeds Adult CF unit. Specific risk factors in CF include photosensitive medication, such as ciprofloxacin and anti-fungals, as well as immune suppression post-transplant. In view of this we undertook a questionnaire based survey of our adult patients’ behaviours regarding sun health. The questionnaire was handed out to patients at routine outpatient appointments. Results to date indicate that two thirds of our patients have been sunburnt in the last 12 months. Over half of patients never use any form of sun protection when going out in the sun and only 17% use sun cream most or all of the time. Over 40% of patients had used tanning beds in the past with a third of these using them regularly over the past 12 months. These high risk behaviours were also seen in patients post-lung transplant. In terms of medications almost 60% were able to name medications that increased the risk of sunburn; however, 20% did not know that medications increased the risk. Once the study is completed we plan to implement an educational programme for patients. Particular attention will be paid to high risk groups such as post-transplant patients, patients who have had skin cancer, and patients who have a family history of cancer.

231 Are adult cystic fibrosis patients aware of the importance of skin health and sun protection?

With increasing life expectancy patients with CF are encountering medical complications that historically have never been an issue. Over the last 10 years three patients with CF have been diagnosed with skin malignancy at the Leeds Adult CF unit. Specific risk factors in CF include photosensitive medication, such as ciprofloxacin and anti-fungals, as well as immune suppression post-transplant. In view of this we undertook a questionnaire based survey of our adult patients’ behaviours regarding sun health. The questionnaire was handed out to patients at routine outpatient appointments. Results to date indicate that two thirds of our patients have been sunburnt in the last 12 months. Over half of patients never use any form of sun protection when going out in the sun and only 17% use sun cream most or all of the time. Over 40% of patients had used tanning beds in the past with a third of these using them regularly over the past 12 months. These high risk behaviours were also seen in patients post-lung transplant. In terms of medications almost 60% were able to name medications that increased the risk of sunburn; however, 20% did not know that medications increased the risk. Once the study is completed we plan to implement an educational programme for patients. Particular attention will be paid to high risk groups such as post-transplant patients, patients who have had skin cancer, and patients who have a family history of cancer

Continued Smoking in Lung Transplant Patients: A Cross Sectional Survey.

IntroductionSmoking is associated with a higher incidence of post-lung transplantation complications and mortality. Prior to inclusion on the lung transplant waiting list in the Czech Republic, patients are supposed to be tobacco free for at least 6 months. Our aim was to determine the prevalence of smoking, validated by urinary cotinine, among patients post lung transplantation and prior to inclusion on the transplant waiting list.MethodsBetween 2009 and 2012, we conducted a cross-sectional survey of urinary cotinine to assess tobacco exposure in 203 patients in the Lung Transplant Program in the Czech Republic. We measured urinary cotinine in 163 patients prior to inclusion on the transplantation waiting list, and 53 patients post bilateral lung transplantation.Results15.1% (95% CI 0.078 to 0.269) of all lung transplant recipients had urinary cotinine levels corresponding to active smoking; and a further 3.8% (95% CI 0.007 to 0.116) had borderline results. Compared to patients with other diagnoses, patients with COPD were 35 times more likely to resume smoking post- transplantation (95% CI 1.92 to 637.37, p-value 0.016). All patients who tested positive for urinary cotinine levels were offered smoking cessation support. Only one Tx patient sought treatment for tobacco dependence, but was unsuccessful.ConclusionSmoking resumption may be an underrecognized risk for lung transplantation recipients, particularly among patients with chronic obstructive pulmonary disease. More rigorous screening, as well as support and treatment to stop smoking among these patients are needed.

Abstract 14631: Pulmonary Artery Calcification: A New Threat in Pulmonary Arterial Hypertension

Background: Pulmonary arterial hypertension (PAH) is associated with imbalance between proliferation and apoptosis of pulmonary artery (PA) smooth muscle cells (PASMCs). Recently, we uncovered a role for microRNA-204 (miR-204), whose downregulation sustains the phenotype in time. In systemic vascular disease, miR-204 downregulation increases the Runt-related transcription factor 2 (RUNX2), a key osteogenic factor inducing calcification. The fact that PAH patients live longer increases the odds of developing PA calcification lesions. Interestingly, the presence and development of calcified lesions in PAH have not been explored. We thus hypothesized that miR-204-dependent upregulation of RUNX2 triggers the development of proliferative and calcified vascular lesions within the lungs, thus worsening PAH. Methods/Results: Using CT-scan, we showed that PAH patients (n=50; p&lt;0.05) had significant increase in distal PA calcification compared to control patients matched for age, sex and comorbidities known to promote vascular calcification. This non-invasive finding was histologically confirmed in the same patients post lung transplantation using Von Kossa staining (n=10; p&lt;0.05). Finally, increase in calcification contributes to worsening of PA compliance and is associated with poorer PAH patients’ survival (n=50; p&lt;0.05). At the molecular level, enhanced calcification in PAH patients correlates (n=43; p&lt;0.05) with a miR-204-dependent up regulation of RUNX2 in lungs, distal PA and primary cultured PASMCs (n=12-40, fold change ≈ 2.5). Using gain and loss of function approaches, we demonstrated in PASMCs from PAH and healthy donors (using siRNA and adenoviruses respectively) that RUNX2, promotes PAH-PASMC proliferation (Ki67), resistance to apoptosis (Annexin-V) and calcification (Alizarin red) (p&lt;0.05). Finally, in Sugen/hypoxia rat model of PAH, we demonstrated that RUNX2 inhibition improves pulmonary hemodynamic and reduces PA remodeling and calcification (n=5-12, p&lt;0.05). Conclusion: We demonstrated for the first time the presence of significant calcification in PAH distal PA contributing to PAH worsening and identified RUNX2 as an attractive new therapeutic strategy to improve PAH. *SC and GR equally contributed.

Survival after lung transplantation in systemic sclerosis. A systematic review

Lung transplantation is a life-saving option for systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) and interstitial lung disease (SSc-ILD) patients. However, some programs may be concerned about the possibility of excess post-transplantation mortality related to the extra-pulmonary manifestations of SSc. The objective of this study was to evaluate survival of SSc patients post-lung transplantation. We secondarily evaluated SSc lung transplant recipient characteristics (age, sex, and type of SSc lung disease), and discussed post-lung transplantation survival of SSc patients and non-SSc patients (idiopathic PAH, and ILD). A systematic review of MEDLINE, EMBASE, Cochrane Central Registry of Controlled Trials and CINAHL (all inception to 2012) was performed to identify studies evaluating post-lung transplant survival in SSc compared to PAH and ILD patients. Two reviewers independently abstracted study and survival data. Two hundred twenty-six citations were screened to identify 7 observational studies reporting SSc patients who underwent single lung, double lung, or heart-lung transplantation. Mean age at transplantation ranged 46-53 years. SSc post-transplantation survival ranged 69%-91% at 30-days, 69%-85% at 6-months, 59%-93% at 1-year, 49%-80% at 2-years, and 46%-79% at 3-years. Causes of death included graft failure, infection, cardiac events, hemorrhagic stroke, respiratory failure, malignancy, pulmonary hypertension, complications of bronchiolitis obliterans syndrome, anesthetic complication, and scleroderma renal crisis. There were no reports of recurrence of SSc in the lung allograft. The short-term and intermediate-term survival post-lung transplantation are similar to IPAH and ILD patients requiring lung transplantation.

Su1061 How Many Suspected Laryngopharyngeal Reflux are Confirmed as GERD? a MII-pH Study

Background/Aims: Gastroesophageal reflux (GER) and subsequent aspiration events are hypothesized to be potential contributors to chronic allograft dysfunction in lung transplant recipients. There are limited data on changes in GER or esophageal motility post-transplantation. We hypothesized that patients who had undergone lung transplantation would be predisposed to increased reflux events. Methods: Prospective comparative series of 19 pretransplant patients (47% female) and 13 post-transplant patients (23% female) being evaluated for GER. All patients were on regular acid suppression. After informed consent, patients filled out a detailed GER symptom questionnaire. Thereafter, both groups underwent esophageal manometry and 24hour catheter pH monitoring. Results: Mean age was similar between groups (Pre: 55yrs, 95% CI: 49-60; Post: 53yrs, 95% CI: 47-58. p= 0.65) . Cause of lung disease was also similar between groups (interstitial lung disease: 9/19 patients pre, 4/13 post. COPD: 7/19 patients pre, 4/13 post). No differences in esophageal manometry, including baseline lower esophageal sphincter (LES) pressures (Pre-transplantation: 12.5 mmHg, 95% CI: 9.5-16.0. Post transplant: 9.0, 95% CI: 5.0-12.9. p=0.13) and percent LES relaxation (Pre-transplant: 76%, 95% CI: 63-88. Post transplant: 70%, 95% CI: 58-83, p= 0.28) were observed between the two groups. Patients post-lung transplantation had a significantly increased total time spent in reflux over the 24 hour study period, as well as a significantly increased number of reflux episodes over five minutes (Table). There was a trend towards an increase in the DeMeester score in patients post-lung transplantation. Conclusion: This hypothesis-generating study suggests that post-lung transplant patients have more prolonged reflux episodes and total time spent in reflux compared to pretransplant candidates, via a mechanism independent of altered esophageal motility.

Tacrolimus in lung transplantation: New strategies to optimize dose

Background: Tacrolimus (TAC) dosing in lung transplantation is traditionally based on blood trough levels (C0). Best sampling strategy for estimation of total drug exposure (area-under-the-curve, AUC) has not been determined. Methods: Thirty-one 12 hour pharmacokinetic profiles were studied in 15 patients (8 men and 7 women, 42.0 13 years) post bilateral lung transplantation (7.3 3.7 months, range 3–18 months). 12 hour AUC (AUC0-12) was calculated by trapezoidal rule. Relationships between individual concentration points or abbreviated kinetics (2–4 concentration points) and AUC0-12 was determined by linear regression analysis (R; absolute prediction error, APE). Results: Pharmacokinetic profiles showed high variability, particularly in the absorption phase. AUC was 221 47.2 ng/ml (range 156 –329.3 ng/ml at C0 10 –15 ng/ml and was independent of TAC dose (R 0.002). C0 was poorly predictive of AUC0-12 (R 0.64, APE 16.1 10.9%, range 1.4 –37.8%). Predictive performance for AUC0-12 was highest with abbreviated kinetics using four (C0/C2/ C3/C4: R 0.99, APE.2.6 2.0%, range 0.1–7%) or three concentration points (C0/C2/C4: R 0.98, APE. 2.6 2.1, range 0.1– 9.1%). Of the 2-point kinetics C2/C6 (R 0.96, 5.3 3.7%, range 0.1–12.7%) and C0/C4 (R2 0.94, APE 4.1 2.9%, range 0.5– 11.4%) performed best. Single point strategies (best was C4: R2 0.94, APE 7.1 5.5%, range 0.2–24.1%, all had unacceptably high APE (range 15%). Conclusion: True TAC exposure shows high variability in stable lung transplant patients and is poorly predicted by C0. Abbreviated kinetics covering at least two concentration points between 0 and 4 hours post drug intake are required for accurate estimation of AUC.

Utility of Inhaled Pentamidine Prophylaxis in Lung Transplant Recipients

The incidence of Pneumocystis carinii pneumonia (PCP) has been shown to be high posttransplantation in the absence of prophylaxis. For this reason, lung transplant recipients routinely receive prophylaxis. We report on our results using aerosolized pentamidine prophylaxis in nine patients post-lung transplantation (eight single lung transplants, one double). The patients received monthly treatments of 300 mg of aerosolized pentamidine for a mean of 10.6 months (range, 4 to 21 months). Patients were routinely monitored with serial pulmonary function studies and bronchoscopy as clinically indicated. Two of the patients experienced bronchospasm in response to the therapy. None of the patients experienced any episodes of PCP during the period of inhaled pentamidine prophylaxis. Inhaled pentamidine is a safe and effective form of PCP prophylaxis and may be used instead of sulfamethoxazole-trimethoprim in patients who have a sulfa allergy or other untoward sulfa side effects.