High prevalence of diabetes before and after lung transplantation: target for improving outcome?

BACKGROUND: Diabetes increases morbidity and mortality of lung transplantation. However, the reported prevalence of diabetes varies post-transplantation partly due to lack of detection protocols. AIM: To determine the prevalence of diabetes in patients (i) waitlisted for lung transplant and (ii) early post-transplantation. METHODS: We analysed patients on the St Vincent's Heart Lung database from 1 April 2014 to 30 September 2015 on the waitlist (Study 1) and those transplanted (Study 2). Standard of care required all non-diabetic patients to have an oral glucose tolerance test (modified for patients with cystic fibrosis (CF) to screen for CF-related hyperglycaemia (CFRH) (plasma glucose ≥8.2 mmol/L at 60 or 90 min). RESULTS: Study 1 included 114 patients (32 with CF and 82 without CF). Of 30 CF patients with glycaemic data, 27 (90%) had abnormal glucose metabolism: 18 had diabetes and nine had CFRH. In 50 patients without CF, 20 (40%) had abnormal glucose metabolism: eight had diabetes and 12 had impaired fasting glucose and/or impaired glucose tolerance. Study 2 included 78 transplanted patients (25 with CF and 53 without CF). Fourteen CF patients had pre-existing diabetes and seven had pre-existing CFRH. All but one patient were diagnosed with diabetes post-transplantation. Hence, diabetes prevalence in CF patients post-transplantation was 96%. Among 53 transplanted patients without CF, seven (13%) had abnormal glucose metabolism but 30 (57%) were diagnosed with post-transplant diabetes. CONCLUSION: There is a high prevalence of diabetes in lung transplant patients. Earlier endocrine participation in lung transplant services is likely to lower diabetes-related morbidity and mortality further.

The Relationship Between Rehabilitation and Frailty in Advanced Heart or Lung Disease.

Background: Frailty increases morbidity and mortality in patients with advanced heart and lung disease. Emerging evidence shows that postoperative cardiac or pulmonary rehabilitation can improve the frailty status of these patients. The aim of this hypothesis-generating study was to test the relationship between prehabilitation and frailty in patients with advanced heart or lung disease referred for heart and lung transplantation. Methods: The study was a retrospective audit of consecutive patients with advanced heart or lung disease referred for transplant assessment between January 2021 and December 2022. Frailty scores were recorded using Fried's frailty phenotype (range, 0-5), and rehabilitation status of patients at the time of frailty assessment was recorded. Results: Of 286 patients, 124 patients had advanced heart disease (mean age 53 ±â€…12 y; 82% men) and 162 patients had advanced lung disease (mean age 55 ±â€…12 y; 43% men). Sixty-nine (24%) patients were robust (score 0), 156 (55%) were prefrail (score, 1-2), and 61 (21%) were frail (score, 3-5). Eighty-two (29%) patients participated in hospital-based rehabilitation, 72 (25%) in home-based rehabilitation, and 132 (46%) in no rehabilitation. Frailty scores were significantly lower in patients participating in hospital-based or home-based rehabilitation compared with patients not participating in rehabilitation (0.8 ± 1.0 versus 0.8 ± 0.9 versus 2.3±1.2, P < 0.0001). Conclusions: This study shows that patients participating in cardiac or pulmonary rehabilitation are less frail compared with patients not participating in rehabilitation. These findings suggest that prehabilitation could be beneficial for patients awaiting heart or lung transplantation.

Rapid cytological analysis of endobronchial ultrasound-guided aspirates in sarcoidosis.

Rapid on-site evaluation (ROSE) of endobronchial ultrasound-guided transbronchial needle aspirates (EBUS-TBNA) has not been compared to final detailed cytological analysis in patients with suspected sarcoidosis. To assess the diagnostic accuracy of EBUS-TBNA with ROSE in patients with suspected sarcoidosis, a prospective two-centre study performed EBUS-TBNA with ROSE of cellular material followed by transbronchial lung biopsy (TBLB) and endobronchial biopsy (EBB). The diagnostic accuracy of EBUS-TBNA with ROSE was compared to the final cytological assessment and to TBLB and EBB. Analysis confirmed 49 out of 60 cases of sarcoidosis. ROSE sensitivity was 87.8% (specificity 91%, positive predictive value 97.7%). ROSE slide interpretation in combination with the final fixed slide and cell block preparations had a sensitivity of 91.8% (specificity 100%, positive predictive value 100%). 67% of patients were confirmed as having sarcoidosis on TBLB and 29% on EBB. Interobserver agreement between cytotechnologists and pathologists was very good (κ=0.91, 95% CI 0.80-1.0 and κ=0.91, 95% CI 0.79-1.0, respectively). EBUS-TBNA with ROSE has high diagnostic accuracy and interobserver agreement and informs the bronchoscopist in theatre whether additional diagnostic procedures need to be undertaken. EBUS-TBNA with ROSE should therefore be considered as the first-line investigation of sarcoidosis.

High-flow Nasal Oxygen Versus Standard Oxygen During Flexible Bronchoscopy in Lung Transplant Patients: A Randomized Controlled Trial.

BACKGROUND: Diagnostic and interventional flexible bronchoscopy (FB) is increasingly utilized in complex and high-risk patients. Patients are often sedated for comfort and procedure facilitation and hypoxia is commonly observed in this setting. We hypothesized that high-flow nasal oxygen (HFNO) would reduce the incidence of patients experiencing oxygen desaturation. METHODS: In this randomized controlled trial, postlung transplant patients booked for FB with transbronchial lung biopsy were assigned to either HFNO or low-flow nasal oxygen (LFNO). The patient and bronchoscopist were blinded to group allocation. The primary endpoint was the proportion of patients experiencing mild desaturation [peripheral oxygen saturation (SpO2)<94%]. Secondary endpoints included desaturation (SpO2<90%), the number of airway interventions required and procedure interruptions, the duration of oxygen desaturation and patient, bronchoscopist and anesthesiologist satisfaction scores. RESULTS: The trial analyzed data from 76 patients (LFNO, n=39; HFNO, n=37). HFNO reduced the proportion of patients experiencing SpO2<94% (43.2% vs. 89.7%, P<0.001) and SpO2<90% (16.2% vs. 69.2%, P<0.001). The FB was interrupted 11 times in 9 patients in the LFNO group, whereas there were no interruptions in the HFNO group. There were no differences in patient and bronchoscopist satisfaction scores between groups, anesthesiologists had higher satisfaction scores when using HFNO (P<0.001). CONCLUSION: Hypoxia occurred less commonly in postlung transplant patients receiving HFNO during FB. Further studies are warranted in other high-risk populations undergoing longer duration FB.

Frailty as a Predictor of Mortality in Patients With Interstitial Lung Disease Referred for Lung Transplantation.

BACKGROUND: Frailty is a clinically recognized syndrome of decreased physiological reserve and a key contributor to suboptimal clinical outcomes in various lung disease groups. Interstitial lung disease (ILD) is fast approaching chronic obstructive pulmonary disease as the number one indication for lung transplantation worldwide. Our aim was to assess whether frailty is a predictor of mortality in patients with ILD referred for lung transplantation in an Australian cohort. METHODS: Consecutive patients with ILD referred or on the waiting list for lung transplantation from May 2013 to December 2017 underwent frailty assessment using the modified Fried's frailty phenotype. Frailty was defined as a positive response to ≥3 of the following 5 components: weak grip strength, slowed walking speed, poor appetite, physical inactivity, and exhaustion. RESULTS: One hundred patients (82 male:18 female; age, 59 ± 7 y; range, 30-70) underwent frailty assessment. Twenty-four of 100 (24%) were assessed as frail. Frailty was associated with anemia, hypoalbuminemia, low creatinine, and the use of supplemental oxygen (all P < 0.05). Frailty was independent of age, gender, measures of pulmonary dysfunction (PaO2, forced vital capacity percentage predicted, total lung capacity, total lung capacity percentage predicted, DLCO, or DLCO percentage predicted), cognitive impairment, or depression. Frailty and DLCO % predicted were independent predictors of increased all-cause mortality: 1-year actuarial survival was 86 ± 4% in the nonfrail group compared with 58 ± 10% for the frail group (P = 0.002). CONCLUSIONS: Frailty is common among patients referred for lung transplant with a diagnosis of ILD and is associated with a marked increase in mortality.

Severity of lymphocytic bronchiolitis predicts long-term outcome after lung transplantation.

RATIONALE: Severe and recurrent acute vascular rejection of the pulmonary allograft is an accepted major risk factor for obliterative bronchiolitis. OBJECTIVES: We assessed the role of lymphocytic bronchiolitis as a risk factor for bronchiolitis obliterans syndrome (BOS) and death after lung transplantation. METHODS: Retrospective analysis of 341 90-day survivors of lung transplant performed in 1995-2005 who underwent 1,770 transbronchial lung biopsy procedures. MEASUREMENTS AND MAIN RESULTS: Transbronchial biopsies showed grade B0 (normal) (n = 501), B1 (minimal) (n = 762), B2 (mild) (n = 176), B3 (moderate) (n = 70), B4 (severe) (n = 4) lymphocytic bronchiolitis, and Bx (no bronchiolar tissue) (n = 75). A total of 182 transbronchial biopsies were ungraded (8 inadequate, 142 cytomegalovirus, 32 other diagnoses). Lung transplant recipients were grouped by highest B grade before diagnosis of BOS: B0 (n = 12), B1 (n = 166), B2 (n = 89), and B3-B4 (n = 51). Twenty-three were unclassifiable. Cumulative incidence of BOS and death were dependent on highest B grade (Kaplan-Meier, P < 0.001, log-rank). Multivariable Cox proportional hazards analysis showed significant risks for BOS were highest B grade (relative risk [RR], 1.62; 95% confidence interval [CI], 1.31-2.00) (P < 0.001), longer ischemic time (RR, 1.00; CI, 1.00-1.00) (P < 0.05), and recent year of transplant (RR, 0.93; CI, 0.87-1.00) (P < 0.05), whereas risks for death were BOS as a time-dependent covariable (RR, 19.10; CI, 11.07-32.96) (P < 0.001) and highest B grade (RR, 1.36; CI, 1.07-1.72) (P < 0.05). Acute vascular rejection was not a significant risk factor in either model. CONCLUSIONS: Severity of lymphocytic bronchiolitis is associated with increased risk of BOS and death after lung transplantation independent of acute vascular rejection.

Deep multi-region whole-genome sequencing reveals heterogeneity and gene-by-environment interactions in treatment-naive, metastatic lung cancer.

Our understanding of genomic heterogeneity in lung cancer is largely based on the analysis of early-stage surgical specimens. Here we used endoscopic sampling of paired primary and intrathoracic metastatic tumors from 11 lung cancer patients to map genomic heterogeneity inoperable lung cancer with deep whole-genome sequencing. Intra-patient heterogeneity in driver or targetable mutations was predominantly in the form of copy number gain. Private mutation signatures, including patterns consistent with defects in homologous recombination, were highly variable both within and between patients. Irrespective of histotype, we observed a smaller than expected number of private mutations, suggesting that ancestral clones accumulated large mutation burdens immediately prior to metastasis. Single-region whole-genome sequencing of from 20 patients showed that tumors in ever-smokers with the strongest tobacco signatures were associated with germline variants in genes implicated in the repair of cigarette-induced DNA damage. Our results suggest that lung cancer precursors in ever-smokers accumulate large numbers of mutations prior to the formation of frank malignancy followed by rapid metastatic spread. In advanced lung cancer, germline variants in DNA repair genes may interact with the airway environment to influence the pattern of founder mutations, whereas similar interactions with the tumor microenvironment may play a role in the acquisition of mutations following metastasis.

Lung Ultrasound After Transbronchial Biopsy for Pneumothorax Screening in Post-Lung Transplant Patients.

BACKGROUND: Lung ultrasound has been suggested as an alternative to routine chest radiography (CXR) to screen for pneumothorax after transbronchial lung biopsy. In post-lung transplant patients, who may have altered anatomy and pleural adhesions, the validity of lung ultrasound to screen for postbiopsy pneumothoraces has not been investigated. METHODS: Lung ultrasound using an ultraportable handheld device was performed in a standardized manner 2-hour after biopsy in post-lung transplant patients. Ultrasound assessment was then compared with CXR performed immediately after lung ultrasound. RESULTS: In total, 165 patients were enrolled in the study. Eight pneumothoraces were diagnosed by image intensifier or CXR before lung ultrasound. There were 8 pneumothoraces diagnosed on CXR 2-hour postbiopsy. Lung ultrasound had a sensitivity of 75% and specificity of 93%. Positive predictive value was 35% and negative predictive value was 99%. The mean number of biopsies taken in patients with and without a pneuomothorax on CXR was 10.6 (±3.1) and 10.9 (±2.1), respectively (P=0.79). The overall pneumothorax rate was 9.7%. CONCLUSIONS: Lung ultrasound is a valid tool in excluding penumothoraces after lung biopsy. Ultrasound scans with features of a pneumothorax or patients with symptoms should still undergo CXR. The high false positive rate may be due to small pneumothoraces being seen or the presence of pleural adhesions and altered lung anatomy in post-lung transplant patients.

Oral ribavirin for respiratory syncytial virus infection after lung transplantation: Efficacy and cost-efficiency.

BACKGROUND: Respiratory syncytial virus (RSV) causes serious respiratory tract infections in lung transplant (LTx) recipients, is associated with development of bronchiolitis obliterans syndrome, and has no proven effective therapy. We evaluated the efficacy, safety, and cost-effectiveness of oral ribavirin for the treatment of RSV infection after LTx. METHODS: Between December 2011 and May 2014, 52 LTx recipients developed 56 episodes of symptomatic RSV infection, which was diagnosed by positive RSV polymerase chain reaction on nasopharyngeal swabs. An intravenous (IV) loading dose of ribavirin (33 mg/kg) was given in 52 of 56 episodes; an equivalent oral loading dose was given in 2 episodes. Oral ribavirin (20 mg/kg/day) was given by day 2 in 53 of 56 episodes. Median duration of therapy was 8 days (range 6-31 days). RESULTS: Mean forced expiratory volume in 1 sec decreased from 2.38 ± 0.78 liters to 2.07 ± 0.85 liters (p < 0.001) at presentation, recovered to 2.26 ± 0.82 liters at cessation of ribavirin, and was maintained at 2.31 ± 0.81 liters within 3 months. New-onset bronchiolitis obliterans syndrome developed in 1 of 38 patients (2.6%) at 3 months. Anemia worsened in 23 episodes, and de novo anemia developed in 5 episodes. Mean hemoglobin decreased from 118 ± 16 g/liter to 113 ± 21 g/liter (p = 0.015). There were 4 late deaths. Compared with IV therapy, mean drug cost saving was US $6,035 per episode, and mean inpatient bed days was reduced by 6.7 days (p < 0.001). CONCLUSIONS: To our knowledge, we report the largest series of LTx recipients treated with oral ribavirin for RSV. Oral ribavirin appears to be an effective, well-tolerated alternative to IV or inhaled ribavirin; provides considerable cost savings and reduces length of hospital stay. Potential long-term benefits in preventing development of chronic lung allograft dysfunction are yet to be determined.

Post-transplant lymphoproliferative disease in heart and lung transplantation: Defining risk and prognostic factors.

BACKGROUND: Heart and lung transplant recipients have among of the highest incidence rates of post-transplant lymphoproliferative disease (PTLD). Despite this, there is a paucity of data specific to this group. We collated data on heart, lung and heart-lung transplant recipients with PTLD to identify disease features and prognostic factors unique to this group of patients. METHODS: Seventy cases of PTLD were identified from a single institution (41 heart, 22 lung, 6 heart-lung and 1 heart-kidney transplant) from 1984 to 2013. Demographics, immunosuppression, treatment, response, complications and survival data were analyzed. Uni- and multivariate Cox regression analyses were performed to identify prognostic factors. RESULTS: The incidence of PTLD was 7.59% in heart-lung, 5.37% in heart and 3.1% in lung transplant recipients. Extranodal disease (82%) with diffuse large B-cell lymphoma (72%) was the most common presentation. Bone marrow involvement (13%) and central nervous system disease (3%) were uncommon. Heart transplant recipients had later onset of PTLD (>1 year post-transplant), with less allograft involvement, compared with lung and heart-lung recipients. Poor prognostic markers were bone marrow involvement (HR 6.75, p < 0.001) and serum albumin <30 g/liter (HR 3.18, p = 0.006). Improved survival was seen with a complete response within 3 months of treatment (HR 0.08, p < 0.001). Five-year overall survival was 29%. CONCLUSION: This analysis is the largest to date on PTLD in heart and lung transplant recipients. It provides a detailed analysis of the disease in this group of patients and identifies unique prognostic features to aid risk stratification and guide treatment allocation.

Everolimus and mycophenolate mofetil are potent inhibitors of fibroblast proliferation after lung transplantation.

BACKGROUND: Dysregulated fibroblast proliferation is thought to play an important role in the progression of bronchiolitis obliterans (BO) after lung transplantation. Augmented immunosuppression is often used to treat BO. We investigated the effect of methylprednisolone (mPRED), cyclosporine A (CsA), tacrolimus (FK506), azathioprine (AZA), mycophenolate mofetil (MMF), and everolimus (rapamycin derivative [RAD]) on the proliferative capacity of fibroblasts cultured from transbronchial biopsies of lung transplant recipients. METHODS: Primary cultures of human lung fibroblasts were obtained from 14 transbronchial biopsies of lung transplant recipients. Subconfluent cells were serum starved for 24 hr followed by growth stimulation in the presence or absence of the respective drug in six concentrations ranging as follows: 0.01 to 100 mg/L for mPRED; 0.01 to 50 mg/L for CsA and AZA; 0.001 to 5 mg/L for FK506 and MMF; and 0.00001 to 1 mg/L for RAD. Proliferation was quantified by [3H]thymidine incorporation and direct cell count. A toxic drug effect was excluded by trypan blue. RESULTS: Drug concentrations (mg/L) causing a 50% inhibition of fibroblast proliferation were mPRED 4; CsA 20; FK506 0.3; AZA 7; MMF 0.3; and RAD 0.0006. Drug concentrations (mg/L) causing inhibition of fetal bovine serum-induced proliferation were mPRED 60; CsA 45; FK506 3; AZA 35; MMF 1; and RAD 0.003. CONCLUSIONS: RAD and MMF were the most potent antifibroproliferative drugs and were effective at concentrations achieved clinically, supporting their use for the treatment of patients with early BO. Our method holds promise as an in vitro model to assess the likely in vivo responses of human lung fibroblasts to specific immunosuppressive drugs.

Spirometry values in Himalayan high altitude residents (Sherpas).

We compared the spirometric values of the isolated racial group of Himalayan Sherpas with those predicted for the European Coal and Steel Community (EC&S). 146 normal adult Sherpas (64 males, 82 females) and 103 adolescents (37 females and 66 males, age 10-18 years) resident at an altitude of 3,840 m were studied. Predicted values for each adult individual were calculated using the EC&S reference equations and separate Caucasian values for children were used, and new predictive equations for the Sherpa population derived. The FEV(1) of boys, adult male and female Sherpas are all significantly greater than predicted (% Predicted (PP) (95% Confidence Interval (CI)), 113% (110-116), 110% (107-114) and 116% (112-121), P < 0.0001 for all groups) as is forced vital capacity (FVC) (112% (111-119), 113% (109-117) and 121% (117-125) respectively, P < 0.0001 for all groups). Sherpa girls displayed a smaller difference in FEV(1) and FVC (PP(CI), 104% (99-109) P<0.1 and 108% (103-114) P = 0.005, respectively). We conclude that the Sherpa race has significantly larger spirometric values than Caucasians. We speculate that this is an adaptation in response to chronic hypoxia and high levels of habitual exercise.

Targeted case finding for OSA within the primary care setting.

STUDY OBJECTIVES: The aim was to determine the feasibility of using an unattended 2-channel device to screen for obstructive sleep apnea in a population of high-risk patients using a targeted, case-finding strategy. The case finding was based on the presence of risk factors not symptoms in the studied population. METHODS: The study took place from June 2007 to May 2008 in rural and metropolitan Queensland and New South Wales. Family doctors were asked to identify patients with any of the following: BMI > 30, type 2 diabetes, treated hypertension, ischemic heart disease. Participants applied the ApneaLink+O2 at home for a single night. The device recorded nasal flow and pulse oximetry. Data were analyzed by proprietary software, then checked and reported by either of two sleep physicians. RESULTS: 1,157 patients were recruited; mean age 53 ± 14.6, M/F% = 62/38, mean BMI = 31.8, obesity = 35%, diabetes = 16%, hypertension = 39%, IHD = 5%, Mean Epworth Sleepiness Scale score (ESS) = 8.3. The prevalence of unrecognized OSA was very high: 71% had an AHI > 5/h, 33% had an AHI > 15/h, and 16% had an AHI > 30/h. The ApneaLink+O2 device yielded technically adequate studies in 93% of cases. CONCLUSION: The study shows that a "real world" simple low cost case finding and management program, based on unattended home monitoring for OSA, can work well in a population with risk factors and comorbidities associated with OSA, independent of the presence of symptoms. The prevalence of unrecognized OSA was very high.