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.

A hole lot of trouble: Severe bilateral anastomotic dehiscence following bilateral single sequential lung transplant.

Airway complications post lung transplant including ischaemia and dehiscence have a significant associated mortality (2%-4%) and morbidity. We describe a case of a 22-year-old female who developed significant bilateral anastomotic dehiscence with severe ischaemia following a bilateral single sequential lung transplant (BSSLTx). Following an intensive antimicrobial regimen, judicious bronchoscopic surveillance, and a prolonged inpatient stay, the dehiscence resolved without requiring further surgical intervention. Our case highlights a space in the literature for further research with regard to airway complications post-lung transplant and their management.

Specific human leucocyte antigen-DQ risk epitope mismatches are associated with chronic lung allograft dysfunction after lung transplantation.

A high-risk epitope mismatch (REM) (found in DQA1∗05 + DQB1∗02/DQB1∗03:01) is associated with de novo donor specific antibodies after lung transplantation (LTx). Chronic lung allograft dysfunction (CLAD) remains a barrier to LTx survival. This study aimed to measure the association between DQ REM and the risk of CLAD and death after LTx. A retrospective analysis of LTx recipients at a single center was conducted between January 2014 and April 2019. Molecular typing at human leucocyte antigen-DQA/DQB identified DQ REM. Multivariable competing risk and Cox regression models were used to measure the association between DQ REM, time-to-CLAD, and time-to-death. DQ REM was detected in 96/268 (35.8%), and DQ REM de novo donor specific antibodies were detected in 34/96 (35.4%). CLAD occurred in 78 (29.1%), and 98 (36.6%) recipients died during follow-up. When analyzed as a baseline predictor, DQ REM status was associated with CLAD (subdistribution hazard ratio (SHR), 2.19; 95% confidence interval [CI], 1.40-3.43; P = .001). After adjustment for time-dependent variables, DQ REM dn-DSA (SHR, 2.43; 95% CI, 1.10-5.38; P = .029) and A-grade rejection score (SHR, 1.22; 95% CI, 1.11-1.35; P = <.001), DQ REM status was not independently associated with CLAD. DQ REM was not associated with death (hazard ratio, 1.18; 95% CI, 0.72-1.93; P = .51). Classification of DQ REM may identify patients at risk of poor outcomes and should be incorporated into clinical decision-making.

Frailty Measures in Patients Listed for Lung Transplantation.

BACKGROUND: The study aimed to determine whether the addition of cognitive impairment, depression, or both, to the assessment of physical frailty (PF) is associated with the risk of lung transplant (LTX) waitlist mortality. METHODS: Since March 2013, all patients referred for LTX evaluation underwent PF assessment. Cognition was assessed using the Montreal Cognitive Assessment and depression assessed using the Depression in Medical Illness questionnaire. We assessed the association of 4 composite frailty measures: PF ≥3 of 5 = frail, cognitive frailty (CogF ≥3 of 6 = frail), depressive frailty (DepF ≥3 of 6 = frail), and combined frailty (ComF ≥3 of 7 = frail) with waitlist mortality. RESULTS: The prevalence of PF was 78 (22%), CogF 100 (28%), DepF 105 (29%), and ComF 124 (34%). Waitlist survival in the non-PF group was 94% ± 2% versus 71% ± 7% in the PF group (P < 0.001). Cox proportional hazards regression analysis demonstrated that PF (adjusted hazard ratio [HR], 4.88; 95% confidence interval [CI], 2.06-11.56), mild cognitive impairment (adjusted HR, 3.03; 95% CI, 1.05-8.78), and hypoalbuminemia (adjusted HR, 0.89; 95% CI, 0.82-0.97) were independent predictors of waitlist mortality. There was no significant difference in the area under the curve of the 4 frailty measures. CONCLUSIONS: The addition of cognitive function and depression variables to the PF assessment increased the number of patients classified as frail. However, the addition of these variables does not strengthen the association with LTX waitlist mortality compared with the PF measure.

Reversibility of Frailty after Lung Transplantation.

BACKGROUND: Frailty contributes to increased morbidity and mortality in patients referred for and undergoing lung transplantation (LTX). The study aim was to determine if frailty is reversible after LTX in those classified as frail at LTX evaluation. METHODS: Consecutive LTX recipients were included. All patients underwent modified physical frailty assessment during LTX evaluation. For patients assessed as frail, frailty was reassessed on completion of the post-LTX rehabilitation program. Frailty was defined by the presence of ≥ 3 domains of the modified Fried Frailty Phenotype (mFFP). RESULTS: We performed 166 lung transplants (frail patients, n = 27, 16%). Eighteen of the 27 frail patients have undergone frailty reassessment. Eight frail patients died, and one interstate recipient did not return for reassessment. In the 18 (66%) patients reassessed, there was an overall reduction in their frailty score post-LTX ((3.4 ± 0.6 to 1.0 ± 0.7), p < 0.001) with 17/18 (94%) no longer classified as frail. Improvements were seen in the following frailty domains: exhaustion, mobility, appetite, and activity. Handgrip strength did not improve posttransplant. CONCLUSIONS: Physical frailty was largely reversible following LTX, underscoring the importance of considering frailty a dynamic, not a fixed, entity. Further work is needed to identify those patients whose frailty is modifiable and establish specific interventions to improve frailty.

Sexually dimorphic production of interleukin-6 in respiratory disease.

Diverging susceptibility and severity in respiratory diseases is prevalent between males and females. Sex hormones have inconclusively been attributed as the cause of these differences, however, strong evidence exists promoting genetic factors leading to sexual dimorphism. As such, we investigate differential proinflammatory cytokine (interleukin (IL)-6 and CXCL8) release from TNF-α stimulated primary human lung fibroblasts in vitro. We present, for the first time, in vitro evidence supporting clinical findings of differential production of IL-6 between males and females across various respiratory diseases. IL-6 was found to be produced approximately two times more from fibroblasts derived from females compared to males. As such we demonstrate sexual dimorphism in cytokine production of IL-6 outside the context of biological factors in the human body. As such, our data highlight that differences exist between males and females in the absence of sex hormones. We, for the first time, demonstrate inherent in vitro differences exist between males and females in pulmonary fibroblasts.

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.

Frailty in lung transplantation: a systematic review.

Introduction: Lung transplantation is an effective treatment for certain types of end-stage lung disease. Frailty is a complex clinical syndrome associated with decreased physiological reserve and an increased risk for suboptimal health outcomes.Area covered: This article reviews the current literature on frailty in lung transplantation, with an emphasis on frailty measures, prevalence and impact of frailty on morbidity and mortality prior to and following lung transplantation. Pubmed, EMBASE, CINAHL and Cochrane systematic review databases were searched to September 2019. The search included the MeSH terms 'frail elderly' or 'frailty' or 'sarcopenia' and 'lung disease' or 'lung transplantation'. Studies were included if: the population were undergoing evaluation for, listed for or received a lung transplant; frailty was prospectively assessed during lung transplant evaluation using systematically defined criteria; used human subjects and; published in English. The prevalence of frailty varied from 0% - 58%. The frailty phenotype and short physical performance battery were the most common measures. Frailty was associated with delisting and death pre-transplantation. Frailty was associated with an increased risk of early mortality post-lung transplantation.Expert opinion: Frailty is identified often in lung transplant candidates and is associated with adverse pre and post-transplantation outcomes. Further research is necessary to identify potential frailty interventions.

Short-chain fatty acids increase TNFα-induced inflammation in primary human lung mesenchymal cells through the activation of p38 MAPK.

Short-chain fatty acids (SCFAs), produced as by-products of dietary fiber metabolism by gut bacteria, have anti-inflammatory properties and could potentially be used for the treatment of inflammatory diseases, including asthma. The direct effects of SCFAs on inflammatory responses in primary human lung mesenchymal cells have not been assessed. We investigated whether SCFAs can protect against tumor necrosis factor (TNF)α-induced inflammation in primary human lung fibroblasts (HLFs) and airway smooth muscle (ASM) cells in vitro. HLFs and ASM cells were exposed to SCFAs, acetate (C2:0), propionate (C3:0), and butyrate (C4:0) (0.01-25 mM) with or without TNFα, and the release of proinflammatory cytokines, IL-6, and CXCL8 was measured using ELISA. We found that none of the SCFAs suppressed TNFα-induced cytokine release. On the contrary, challenge with supraphysiological concentrations (10-25 mM), as might be used therapeutically, of propionate or butyrate in combination with TNFα resulted in substantially greater IL-6 and CXCL8 release from HLFs and ASM cells than challenge with TNFα alone, demonstrating synergistic effects. In ASM cells, challenge with acetate also enhanced TNFα-induced IL-6, but not CXCL8 release. Synergistic upregulation of IL-6 and CXCL8 was mediated through the activation of free fatty acid receptor (FFAR)3, but not FFAR2. The signaling pathways involved were further examined using specific inhibitors and immunoblotting, and responses were found to be mediated through p38 MAPK signaling. This study demonstrates that proinflammatory, rather than anti-inflammatory effects of SCFAs are evident in lung mesenchymal cells.

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.

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.

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.

Physiology of sleep and breathing before and after lung transplantation.

During the past 20 years, lung transplantation (LTX) has evolved and it is now accepted as a mainstream modality for care of patients with severe life-threatening respiratory diseases that are refractory to maximal conventional therapies. Improvements in surgical techniques and in antirejection medications have resulted in prolonged survival in these patients. Several studies have explored quality of life after LTX and its improvement has been noted especially in the early period between 3 and 6 months. This article discusses the salient features of the physiology of breathing and sleep disturbances before and after LTX and its alterations during sleep.

Exhaled breath condensate (EBC) biomarkers in pulmonary fibrosis.

The diffuse parenchymal lung diseases (DPLDs) are a group of clinicopathological entities which have recently undergone reclassification. The commonest type of idiopathic DPLD is interstitial pulmonary fibrosis (PF), which is histologically characterized by usual interstitial pneumonia (UIP), with inflammatory changes in the alveoli and subsequent collagen deposition. A similar type of inflammatory change can also be seen with connective tissue disorders. Many mediators are involved, but it is difficult to study these in a non-invasive manner in patients. The aim of the study detailed in this paper was to investigate inflammatory and oxidative stress biomarkers in PF and correlate these with lung function. 20 PF patients and 20 controls participated in the study. Exhaled breath condensate (EBC) was collected over 10 min using a refrigerated condenser, after fractional exhaled nitric oxide (FeNO) and carbon monoxide (eCO) measurement. EBC total nitrogen oxides (NOx), hydrogen peroxide (H(2)O(2)), 8-isoprostane (8-iso), 3-nitrotyrosine (3-NT), pH and total protein were measured. EBC biomarkers were significantly raised in PF compared with controls: EBC 3-NT (2.5 (0.7-8.9) versus 0.3 (0.1-1.1) ng ml(-1), p = 0.02); pH (7.6 ± 0.3 versus 7.4 ± 0.2, p = 0.004); 8-isoprostane (0.2 (0.1-0.4) versus 0.08 (0.04-0.2) ng ml(-1), p = 0.04) and total protein (24.7 ± 21.1 versus 10.7 ± 7.0 µg ml(-1), p = 0.008). FeNO and eCO were also increased (8.6 (7.1-10.4) versus 6.6 (5.6-7.8) ppb, p = 0.04, and 4.5 ± 1.7 versus 2.7 ± 0.7 ppm, p = 0.001, respectively), but no significant differences were found for NOx or H(2)O(2). In conclusion, inflammatory and oxidative stress biomarkers are raised in patients with PF compared with controls. EBC may be useful for detecting and monitoring lung inflammation in PF.

An investigator-driven study of everolimus in surgical lung biopsy confirmed idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: We evaluated the efficacy and safety of everolimus, a macrocyclic proliferation signal inhibitor with anti-fibroproliferative activity to prevent disease progression or death in patients with IPF, a progressive, fatal disease with no known effective therapy. METHODS: Eighty-nine patients with surgical lung biopsy confirmed IPF were enrolled in a 3-year investigator-driven, placebo-controlled, double-blinded, multicentre study of everolimus. RESULTS: The everolimus (n = 44) and placebo (n = 45) groups were matched for demographic variables (gender, P = 0.46) and baseline lung function parameters (FVC, P = 0.29; TLC, P = 0.45; DL(CO) , P = 0.41 and PaO(2) , P = 0.34). Independent risks for disease progression were everolimus (hazard ratio (HR) 2.37, 95% CI: 1.40-4.00, P < 0.01, log rank) and male gender (HR 2.76, 95% CI: 1.47-5.17, P < 0.01, log rank). Three-year transplant-free survival was 36 ± 7% (everolimus) versus 51 ± 8% (placebo) (Kaplan-Meier, P = 0.11, log rank). Independent risks for transplant-free survival were male gender (HR 2.33, 95% CI: 1.07-5.05, P = 0.03, log rank) and baseline DL(CO) (% predicted) (HR 0.96, 95% CI: 0.93-0.99, P = 0.02, log rank). CONCLUSIONS: Everolimus use was associated with more rapid disease progression in a well-defined cohort of patients with IPF confirmed by surgical lung biopsy followed for 3 years.

Sleep-disordered breathing before and after lung transplantation.

BACKGROUND: Sleep-disordered breathing (SDB) is common in patients with severe chronic respiratory failure, but there are no data describing the prevalence of SDB among patients listed for lung transplantation or the effect of transplantation on SDB. We sought to determine the prevalence and impact of SDB before and after lung transplantation. METHODS: We performed polysomnography (PSG) on 117 of 183 (64%) consecutive patients (64 males, 53 females) listed for lung transplantation between 1998 and 2001. SDB was defined as respiratory disturbance index (RDI) >or=10 or an awake oxygen saturation >90% and >or=10% of total sleep time (TST) with oxygen saturation (SaO2) or=10% of TST with SaO2 or=10. Eight of 32 had both >or=10% of TST with SaO2 or=10. Nine of 30 (30%) patients on oxygen and 1 of 7 on NIV had SDB. Post-transplant, SDB resolved in 6 of 11 patients with the condition, but 4 of 14 without previous SDB developed new SDB. SDB (treated or not) did not influence whether patients survived to transplant (p = 0.8), nor did a diagnosis of SBD prior to transplant influence post-transplant survival (p = 0.7). CONCLUSIONS: SDB is common before lung transplantation. Lung transplantation improves oxygenation, but new-onset SDB may occur after the procedure.

Use of extracorporeal membrane oxygenation as a bridge to primary lung transplant: 3 consecutive, successful cases and a review of the literature.

Many transplant centers have considered extracorporeal membrane oxygenation (ECMO) to be a contraindication to lung transplantation, due to historically poor outcomes. However, recent advances in the technical aspects of ECMO have enabled patients to be supported with relative safety for several weeks until a donor lung becomes available. We present 3 young patients with acute (in 1 case, acute on chronic), severe respiratory failure that was refractory to conventional ventilation, who were placed on venovenous ECMO. In each case, a clinical decision was made that the patient's respiratory failure was irreversible and they were successfully managed with urgent lung transplantation.