Everolimus Treatment for Chronic Lung Allograft Dysfunction in Lung Transplantation.

Our study aims to evaluate the effect of everolimus treatment on lung function in lung transplant (LT) patients with established chronic lung allograft dysfunction (CLAD). METHODS: This retrospective study included LT patients in two reference LT units who started everolimus therapy to treat CLAD from October 2008 to October 2016. We assessed the variation in the maximum forced expiratory volume in the first second (FEV1) before and after the treatment. RESULTS: Fifty-seven patients were included in this study. The variation in the FEV1 was -102.7 (149.6) mL/month before starting everolimus compared to -44.7 (109.6) mL/month within the first three months, +1.4 (63.5) mL/month until the sixth month, and -7.4 (46.2) mL/month until the twelfth month (p < 0.05). Glomerular filtrate remained unchanged after everolimus treatment [59.1 (17.5) mL/min per 1.73 m2 at baseline and 60.9 (19.6) mL/min per 1.73 m2, 57.7 (20.5) mL/min per 1.73 m2, and 57.3 (17.8) mL/min per 1.73 m2, at 1, 3, and 6 months, respectively] (p > 0.05). Everolimus was withdrawn in 22 (38.6%) patients. The median time to withdrawal was 14.1 (5.5-25.1) months. CONCLUSIONS: This study showed an improvement in FEV1 decline in patients with CLAD treated with everolimus. However, the drug was withdrawn in a high proportion of patients.

Simplified risk stratification based on cardiopulmonary exercise test: A Spanish two-center experience.

A simplified 4-strata risk stratification approach based on three variables is widespread in pulmonary arterial hypertension (PAH) at follow-up. This study aimed to assess the impact of replacing the 6-min walk test (6MWT) with the peak 02 uptake evaluated by the cardiopulmonary exercise test (CPET) on risk stratification by this scale. We included 180 prevalent patients with PAH from two reference hospitals in Spain, followed up between 2006 and 2022. Patients were included if all the variables of interest were available within a 3-month period on the Spanish Registry of Pulmonary Arterial Hypertension (REHAP): functional class (FC); NT-proBNP; 6MWT; and CPET. The original 4-strata model (NT-proBNP, 6MWT, FC) identified most patients at low or intermediate-low risk (36.7% and 51.1%, respectively). Notably, the modified scale (NT-proBNP, CPET, FC) improved the identification of patients at intermediate-high risk up to 18.9%, and at high risk up to 1.1% in comparison with the previous 12.2% and 0.0% in the original scale. This new model increased the number of patients correctly classified into higher-risk strata (positive NRI of 0.06), as well as classified more patients without events in lower-risk strata (negative NRI of 0.04). The proposed score showed a slightly superior prognostic capacity compared with the original model (Harrel's C-index 0.717 vs. 0.709). Using O2 uptake instead of distance walked in the 6MWT improves the identification of high-risk patients using the 4-strata scale. This change could have relevant prognostic implications and lead to changes in the specific treatment of PAH.

Early Postoperative Outcomes of Lung Transplant Recipients With Abdominal Adverse Events.

INTRODUCTION: Patients undergoing lung transplantation (LT) are at high risk of developing serious abdominal complications, which can lead to higher rates of morbidity and mortality. The aim of this study was to investigate the incidence and spectrum of these complications when they develop during the first 30 days after LT, as well as their possible association with possible risk factors. METHODS: A retrospective study of 552 patients undergoing LT between 01/02/2006 and 06/03/2021 was carried out. A descriptive and analytical evaluation of the patients who experienced complications and those who did not was performed comparatively. Data related to patient characteristics and the lung transplantation procedure were collected. RESULTS: Overall, 8.2% of patients developed severe abdominal complications during the first 30 days; paralytic ileus was the most frequent (31.1%), closely followed by visceral perforation (26.7%). The percentage of patients who required an invasive procedure to manage post-transplant complications was 57.8%. Surgical intervention was required in 39.8%. The variables that showed a significant relationship with the development of severe short-term abdominal complications in the univariate analysis were the time of surgery, the use of ECMO/ ECC and red blood cell transfusion during or after surgery. In the multivariate study, however, only duration of surgery remained significant (p=0.03). CONCLUSION: The incidence of severe short-term abdominal complications after LT period was 8%. The commonest complications were paralytic ileus and intestinal perforation. Most patients did not require surgery. The only risk factor found associated with these complications was the duration of the surgical intervention.

Endothelin-1 as a Biomarker of Idiopathic Pulmonary Fibrosis and Interstitial Lung Disease Associated with Autoimmune Diseases.

The aim of this study was to determine the role of endothelin-1 (ET-1), a molecule involved in multiple vascular and fibrosing abnormalities, as a biomarker of interstitial lung disease (ILD), as well as its use for the differential diagnosis between idiopathic pulmonary fibrosis (IPF) and ILD associated with autoimmune diseases (AD-ILD), using a large and well-defined cohort of patients with ILD. A total of 112 patients with IPF, 91 patients with AD-ILD (28 rheumatoid arthritis (RA), 26 systemic sclerosis, 20 idiopathic inflammatory myositis and 17 interstitial pneumonia with autoimmune features) and 44 healthy controls were included. ET-1 serum levels were determined by enzyme-linked immunosorbent assay. A significant increase in ET-1 levels was found in patients with IPF compared to controls. Likewise, AD-ILD patients also showed higher ET-1 levels than controls when the whole cohort was stratified by the type of AD. Similar ET-1 levels were found in IPF and AD-ILD patients, regardless of the underlying AD. Interestingly, increased ET-1 levels were correlated with worse lung function in IPF and RA-ILD patients. Our study supports that serum ET-1 may be useful as a biomarker of ILD, although it could not help in the differential diagnosis between IPF and AD-ILD. Moreover, ET-1 levels may be associated with ILD severity.

Early onset of azithromycin to prevent CLAD in lung transplantation: Promising results of a retrospective single centre experience.

INTRODUCTION: Azithromycin (AZI) may be an effective immune modulator in lung transplant (LT) recipients, and can decrease chronic lung allograft dysfunction (CLAD) rates, the leading cause of mortality after the 1st year post-LT. The aim of the study is to assess the effect of AZI initiation and its timing on the incidence and severity of CLAD in LT recipients. METHODS: Single-center retrospective study, including LT recipients from 01/01/2011 to 30/06/2020. Four groups were established: those who started AZI at the 3rd week post-LT (group A), those who received AZI later than the 3rd week post-LT and had preserved FEV1 (B), those who did not receive AZI (C) and those who started AZI due to a decline in FEV1 (D). The dosage of AZI prescribed was 250 mg three times per week. CLAD was defined and graduated according to the 2019 ISHLT criteria. RESULTS: We included 358 LT recipients: 139 (38.83%) were in group A, 94 (26.25%) in group B, 91 (25.42%) in group C, and 34 (9.50%) in group D. Group A experienced the lowest CLAD incidence and severity at 1 (p = .01), 3 (p < .001), and 5 years post-LT, followed by Group B. Groups C and D experienced a higher incidence and severity of CLAD (p = .015). Initiation of AZI prior to FEV1 decline (Groups A and B) proved to be protective against CLAD after adjusting for differences between the treatment groups. CONCLUSIONS: Early initiation of AZI in LT recipients could have a role in decreasing the incidence and severity of CLAD. In addition, as long as FEV1 is preserved, initiating AZI at any time could also be useful to prevent the incidence of CLAD and reduce its severity.

Lung transplantation for emphysema: only emphysema or something else?

Background: Some studies have reviewed lung explants histology to determine the frequency of pretransplant non-identified neoplasms or explore its diagnostic correlation with a previous diagnosis of interstitial lung disease (ILD). This study aims to review the histopathology of explants from patients who underwent lung transplantation (LT). Methods: A retrospective, single-center study that included patients who underwent LT for emphysema between 01 January 2011 and 31 October 2021. The control group was composed of patients with lung cancer who underwent a lung resection between 01 November 2011 and 31 December 2019 and had a previous diagnosis of chronic obstructive pulmonary disease (COPD) prior to lung resection surgery. A systematic review was performed of histological findings to compare the frequency of additional histological diagnoses. Results: The study sample included 160 patients (43.8%) who received a lung transplant for emphysema and 205 patients with COPD and lung cancer treated surgically. Although the patients in the cancer group were significantly older and had more comorbidities and higher cumulative tobacco consumption, transplant recipients received an additional significative histologic diagnosis more frequently (58.1% vs. 12.7%; P<0.001) including ILD, pneumoconiosis and others. Conclusions: Significant additional histological findings were more frequent in the group of lung transplant recipients with emphysema. Notably, these findings were not explained by tobacco use, and they were significantly more frequent in transplant recipients than in patients with a previous diagnosis of COPD and higher cumulative tobacco consumption but with a better respiratory functional status.

Calcineurin inhibitors' impact on cardiovascular and renal function, a descriptive study in lung transplant recipients from the North of Spain.

Patients undergoing lung transplantation (LTx) need administration of immunosuppressive therapy following the procedure to prevent graft rejection. However, these drugs are not exempt from potential risks. The development of cardiovascular risk factors and impaired renal function in the post-transplantation period are conditions that may be favoured by the use of calcineurin inhibitor (CNI) drugs which could have repercussions on the quality of life and the post-transplantation evolution. To evaluate the cardiovascular and renal toxicity following the administration of CNI as maintenance immunosuppression in lung transplant recipients (LTRs) we reviewed a total number of 165 patients undergoing LTx between 01/01/2015 and 08/12/2018. They were divided into two groups according to the CNI drug administrated: cyclosporine (CsA-group) with 11 patients or tacrolimus (Tac-group), with 154 patients. We evaluated the de novo occurrence of arterial hypertension (HTN), diabetes mellitus (DM), hyperlipidemia and impaired renal function after initiation of CNI administration. In addition to that, the time until each of these events was assessed. A higher rate for developing HTN (p < 0.001) and impaired renal function (p = 0.047) was observed within the CsA-group. The new onset of hyperlipidemia was similar between both CNI groups and de novo appearance of DM was only documented in those LTRs receiving tacrolimus. In this LTRs retrospective study, it was observed that having ≥ 4 tacrolimus trough levels above the upper limit of the proposed interval for each specific post-LTx period was associated with an increased risk for developing renal impairment. No other statistically significant association was found between supratherapeutic CNIs blood levels and the evaluated toxicities.

Antifibrotics and lung transplantation: A Spanish multicentre case-controlled study.

BACKGROUND AND OBJECTIVE: Antifibrotic drugs are the standard treatments for patients with idiopathic pulmonary fibrosis (IPF). This study aims to assess the safety of antifibrotic treatment in IPF patients undergoing lung transplantation. METHODS: Patients with a diagnosis of IPF who received a lung transplant between January 2015 and June 2019 at four Spanish hospitals specialized in lung transplantation were retrospectively recruited. Cases were defined as patients receiving antifibrotic treatments at time of transplant. Each case was matched with a control who did not receive antifibrotic treatment. RESULTS: A total of 164 patients were included in the study cohort (103 cases and 61 controls). There were no statistically significant differences between the cases and controls in any of the items studied related to transplantation except the time until the appearance of chest wall dehiscence: although there were no differences in the incidence of wall dehiscence in either group (12.3% vs. 13.7%; p = 0.318), the patients on antifibrotic drugs experienced it earlier (21 days [IQR = 12.5-41.5] vs. 63 days [IQR = 46.75-152.25]; p = 0.012). There were no differences in overall post-transplant survival between the two groups (p = 0.698) or in conditional survival at 30 days, 90 days, 3 years or 5 years. However, 1 year survival was significantly greater among controls (80.6% vs. 93.3%; p = 0.028). CONCLUSION: There was evidence that chest wall dehiscences appeared earlier post-transplant in patients using antifibrotics, even though this factor did not significantly impact survival.

Lung Rapid Recovery Procurement Combined with Abdominal Normothermic Regional Perfusion in Controlled Donation after Circulatory Death.

Controlled donation after circulatory death (cDCD) has contributed to increasing donor numbers all over the world. Experiences published in the last years confirm that the outcomes after lung transplantation from cDCD are similar to those from brain death donors; however, the utilization of lungs from asystole donors remains low. Several reasons may be involved: different legal frameworks among countries and centers with different premortem interventions, inadequate lung donor care before procurement, or even poor experience with cDCD procedures and protocols. Initially, the rapid recovery technique was commonly employed for the procurement of thoracic and abdominal organs in cDCD, but, in the last decade, abdominal normothermic regional perfusion (ANRP) with extracorporeal membrane oxygenation devices has become a useful method to restore blood flow to abdominal organs, allowing their quality improvement and their functional assessment prior to transplantation. This makes the donation procedure more complex and generates doubts about injury to the grafts due to dual temperature. The aim of this article is to describe a protocol based on a single center experience with Maastricht III donors combining lung cooling rapid recovery in the thorax and abdominal normothermic regional perfusion. Tips and tricks focused on premortem interventions and lung procurement procedure techniques are explained. This may help to minimize the reluctance among professionals to use this combined technique and encourage other donor centers to use it, despite the increased complexity of the procedure.

Imaging findings of neurologic complications in lung transplantation: Review of a 9-year cohort.

BACKGROUND: Lung transplantation (LT) requires complex multidisciplinary organization and constitutes a therapeutic option and a life-saving procedure. Although the number of lung recipients continues to increase, neurological complications and death rates following lung transplantation are still higher than desirable. PURPOSE: This study aims to analyse the neuroimaging findings in a cohort of adult patients with LT. MATERIAL AND METHODS: A retrospective cohort study of all lung transplant recipients (344 patients: 205 men and 139 women) at a single institution from January 2011 to January 2020. The collected data included demographic features, clinical data and evaluation of the imaging findings. We also recorded the date of neurological complication(s) and the underlying disease motivating lung transplantation. RESULTS: We found an elevated rate of neuroimaging findings in patients following LT with 32.6% of positive studies. In our cohort, the average time after LT to a neurological complication was 4.9 months post-transplant. Encephalopathy, critical illness polyneuropathy and stroke, in that order, were the most frequent neurological complications. Structural abnormalities in brain imaging were more often detected using MRI than CT for indications of encephalopathy and seizures. CONCLUSIONS: LT recipients constitute an especially vulnerable group that needs close surveillance, mainly during the early post-transplant period.

Role of VEGF Polymorphisms in the Susceptibility and Severity of Interstitial Lung Disease.

The search for biomarkers that can help to establish an early diagnosis and prognosis of interstitial lung disease (ILD) is of potential interest. VEGF polymorphisms have been implicated in the development of several lung disorders. Consequently, we assessed, for the first time, the role of VEGF polymorphisms in the susceptibility and severity of ILD. A total of 436 Caucasian ILD patients (244 with idiopathic interstitial pneumonias (IIPs) and 192 with non-IIP) and 536 ethnically-matched healthy controls were genotyped for VEGF rs833061, rs1570360, rs2010963, rs3025020, and rs3025039 polymorphisms by TaqMan assays. Pulmonary function tests were collected from all the patients. VEGF serum levels were determined by ELISA in a subgroup of patients. No VEGF genotype, allele, carrier, or haplotype differences were found between ILD patients and controls as well as between IIP and non-IIP patients. However, an association of rs1570360 with IIP in women and also with lung function in IIP patients was found. None of the VEGF polymorphisms were associated with VEGF levels. In conclusion, our results suggest that VEGF does not seem to play a relevant role in ILD, although rs1570360 may influence the severity of ILD in women and a worse outcome in IIP patients.

Rituximab in the Treatment of Interstitial Lung Disease Associated with Autoimmune Diseases: Experience from a Single Referral Center and Literature Review.

In the present study, we aimed to report our experience with rituximab (RTX) in the treatment of patients with ILD associated with AD (AD-ILD) at a single center. For this purpose, clinical characteristics, radiological findings, and pulmonary function tests (PFTs) of RTX-treated AD-ILD-patients seen from May 2016 until March 2020 at a referral center for individuals with ILD were retrospectively reviewed. Additionally, an updated literature review was conducted. A total of 26 patients (mean age 58.3 ± 11.1 years at ILD diagnosis) was included. The most common ADs related to ILD were systemic sclerosis, idiopathic inflammatory myositis (including anti-synthetase syndrome) and rheumatoid arthritis. Non-specific interstitial pneumonia (n = 12) and usual interstitial pneumonia (n = 11) were the predominant radiological patterns. The sustained improvement in PFTs was observed from the start of RTX, with a statistically significant increase in DLCO from basal to one year after RTX (mean + 4.2%, p = 0.024). Overall, there were no differences when comparing PFT outcome according to the radiological pattern or the specific type of AD. In conclusion, RTX constitutes a good therapeutic option to preserve lung function in patients with AD-ILD, regardless of the radiological pattern or the underlying AD.

The Spectrum of Interstitial Lung Disease Associated with Autoimmune Diseases: Data of a 3.6-Year Prospective Study from a Referral Center of Interstitial Lung Disease and Lung Transplantation.

Interstitial lung disease (ILD) may occur in patients with a rheumatic autoimmune disease (AD), increasing their risk of morbidity and mortality. However, little is known about the prevalence of AD in patients diagnosed with an ILD. In this prospective study, we determined the spectrum of ILD associated with AD (AD-ILD) among patients sent for assessment to a single clinic of ILD and lung transplantation from a referral center between May 2016 and December 2019. ILD diagnosis was made by pneumologists based on clinical and radiological findings and pulmonary function test abnormalities. All patients with ILD were also assessed by experienced rheumatologists. During the period of assessment, 338 patients were diagnosed with ILD. Among them, 32.8% fulfilled definitions for an AD. Most cases with AD-ILD had a diagnosis of rheumatoid arthritis (27.0%), systemic sclerosis (26.1%) or anti-synthetase syndrome (17.1%). Interestingly, 18% of the patients with AD-ILD were diagnosed as having an interstitial pneumonia with autoimmune features. Antinuclear antibodies and non-specific interstitial pneumonia were the most frequent positive autoantibodies and radiological pattern found in AD-ILD patients, respectively. In conclusion, our study indicates that a high number of ILD patients have a related AD. Consequently, close collaboration among rheumatologists and pneumologists is needed.