Correlation Between Tacrolimus Levels in Blood Samples Obtained from Central Catheter and Peripheral Venipuncture in Lung Transplant Patients (Ven-Cat Study).

BACKGROUND: Following lung transplantation (LT), receiving immunosuppressive therapy is crucial. Tacrolimus is considered a drug with a narrow therapeutic range and its use requires constant monitoring. This study aimed to evaluate the correlation between tacrolimus levels obtained from central venous catheter and direct venipuncture in adult patients undergoing LT. METHODS: This prospective study included LT patients hospitalized in conventional ward carrying a central catheter through which no intravenous tacrolimus was administered. Trough samples were obtained through direct puncture and from the central catheter. Pearson correlation coefficient was calculated to quantify the mean difference between the 2 measures. RESULTS: A total of 54 sample pairs from 16 LT patients were obtained, mostly male (81.3%) and bilateral transplant recipients (93.8%); the transplant procedure was the primary reason for admission (81.3%). The difference in tacrolimus levels between both samples was 0.3 (0.1-0.6) mcg/L, with the measurement for the samples obtained through venipuncture being mostly higher than that for those obtained from the catheter. A strong correlation was observed between the tacrolimus levels in the samples obtained from the catheter and through venipuncture (Pearson correlation coefficient, 0.991; P < 0.001; R2 = 0.982). CONCLUSIONS: There is an excellent correlation between tacrolimus levels obtained from venipuncture and those obtained from central venous catheter in LT patients undergoing oral tacrolimus therapy.

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.

Osteopontin as a Biomarker in Interstitial Lung Diseases.

Osteopontin (OPN) is a glycoprotein involved in Th1 and Th17 differentiation, and inflammation and tissue remodeling. OPN is a biomarker of disease activity in patients with autoimmune inflammatory conditions. This study aimed to assess the diagnostic and prognostic value of OPN in interstitial lung diseases (ILDs). Between May 2016 and October 2019, 344 patients with ILD were recruited at the Hospital Universitario Marqués de Valdecilla (Spain) and were prospectively followed-up. This study involved the determination of OPN serum levels by ELISA and OPN RNA expression quantified using qPCR. Six genetic polymorphisms in OPN (rs28357094, rs2853749, rs2853750, rs11728697, rs7695531, and rs1126616) were genotyped using TaqMan assays. OPN serum levels were also assessed in 140 healthy controls. OPN serum levels (median [interquartile range]) were significantly higher in ILD patients than in controls (1.05 [0.75-1.51] ng/mL versus 0.81 [0.65-0.98] ng/mL in healthy controls; p < 0.01). OPN serum levels were inversely correlated with the forced vital capacity. OPN serum levels were also higher in ILD patients who died or underwent lung transplantation when compared with the remaining ILD patients (1.15 [0.80-1.72] ng/mL versus 0.99 [0.66-1.32] ng/mL; p = 0.05). Survival worsened in ILD patients with OPN > 1.03 ng/mL at 1, 3, and 5 years. No statistically significant differences in the genetic frequencies of OPN polymorphisms or the RNA expression were found among the different ILD groups. Elevated levels of OPN in the serum may be a useful indicator in identifying patients with ILD who are more likely to experience poor outcomes.

The impact of time from ILD diagnosis to referral to the transplant center on the probability of inclusion in the transplant waiting list.

BACKGROUND: Lung transplant is a therapeutic option for patients with progressive interstitial lung disease (ILD). OBJECTIVES: The objective of this study was to determine whether time from ILD diagnosis to referral to a transplant center influences the probability of being included in the transplant waiting list. METHODS: We performed a retrospective cohort study including all ILD patients evaluated as lung transplantation (LT) candidates at a lung transplant center between 01/01/2017 and 31/12/2022. The primary endpoint was the probability of being included in the lung transplant waiting list according to the time elapsed from diagnosis to referral to the transplant center. RESULTS: A total of 843 lung transplant requests were received, of which 367 (43.5%) were associated with ILD. Thirteen patients were excluded because they did not attend the first visit, whereas another 11 were excluded because some information was missing. As a result, our final sample was composed of 343 patients. The median time from diagnosis to referral was 29.4 (10.9 - 61.1) months. The overall probability of inclusion in the waiting list was 29.7%. By time from diagnosis to referral, the probability of inclusion in the waiting list was 48.1% for the patients referred 〈 6 months from diagnosis; 27.5% for patients referred 6 to 24 months from diagnosis; and 25.8% for patients referred 〉 24 months from diagnosis (p = 0.007). CONCLUSIONS: Early referral to a lung transplant center seemed to increase the probability of being included in the lung transplant waiting list. Further research is needed in this topic.

Impact of the New Definition of Pulmonary Hypertension on the Prevalence of Primary Graft Dysfunction in Lung Transplant Recipients.

BACKGROUND & AIM: Pulmonary hypertension (PH) secondary to lung disease (Group-3 PH) is the second leading cause of PH. The role of PH as a risk factor for primary graft dysfunction (PGD) following lung transplant (LT) is controversial. OBJECTIVE: To assess the impact that the new definition of PH had on the prevalence of PH in patients with advanced lung disease-candidate for LT, and its association with the occurrence of PGD. METHOD: A retrospective study was performed in all patients undergoing cardiac catheterisation referred for consideration as candidates to LT in a centre between 1 January 2017 and 31 December 2022. The baseline and haemodynamic characteristics of patients were analysed, along with the occurrence of PGD and post-transplant course in those who ultimately underwent transplantation. RESULTS: A total of 396 patients were included. Based on the new 2022 European Society of Cardiology/European Respiratory Society definitions, as many as 70.7% of patients met PH criteria. Since the introduction of the 2022 definition, a significant reduction was observed in the frequency of severe Group-3 PH (41.1% vs 10.3%; p<0.001), with respect to the 2015 definition. As many as 236 patients underwent transplantation. None of the variables associated with PH was identified as a risk factor for PGD. CONCLUSION: The new classification did not have any impact on the prevalence of PGD after transplantation. These results exclude that any significant differences exist in the baseline characteristics or post-transplant course of patients with Group-3 PH vs unclassified PH.

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.

E-Selectin, ICAM-1, and ET-1 Biomarkers Address the Concern of the Challenging Diagnosis of Interstitial Lung Disease in Patients with Autoimmune Diseases.

Interstitial lung disease (ILD) constitutes the most critical comorbidity in autoimmune diseases (ADs) and its early diagnosis remains a challenge for clinicians. Accordingly, we evaluated whether E-selectin, ICAM-1, and ET-1, key molecules in endothelial damage, could be useful biomarkers for the detection of AD-ILD+. We recruited patients with rheumatoid arthritis (RA)-ILD+ (n = 21) and systemic sclerosis (SSc)-ILD+ (n = 21). We included comparison groups of patients: RA-ILD- (n = 25), SSc-ILD- (n = 20), and idiopathic pulmonary fibrosis (IPF) (n = 21). Serum levels of these proteins were determined by ELISA. E-selectin, ICAM-1, and ET-1 serum levels were increased in RA-ILD+ and IPF patients in comparison to RA-ILD- patients. Additionally, SSc-ILD+ and IPF patients exhibited higher ICAM-1 levels than those with SSc-ILD-. The ability of E-selectin, ICAM-1, and ET-1 to discriminate RA-ILD+ from RA-ILD- patients, and ICAM-1 to distinguish SSc-ILD+ from SSc-ILD- patients was confirmed using ROC curve analysis. Furthermore, elevated levels of ET-1 and E-selectin correlated with lung function decline in RA-ILD+ and SSc-ILD+ patients, respectively. In conclusion, our findings support the relevant role of E-selectin, ICAM-1, and ET-1 in RA-ILD+ patients as well as of ICAM-1 in SSc-ILD+ patients, constituting potential screening blood biomarkers of ILD in AD. Moreover, this study suggests ET-1 and E-selectin as possible indicators of worsening lung function in RA-ILD+ and SSc-ILD+ patients, respectively.

DQA1 Eplet Mismatch Load As an Independent Risk Factor of CLAD After Lung Transplantation.

Lung transplantation remains the treatment of choice for end-stage lung diseases, and recipient selection is currently based on clinical urgency, ABO compatibility, and donor size. The risk of allosensitization is classically based on HLA mismatch, but eplet mismatch load is increasingly seen to be important in long-term outcomes in solid organ transplantation. Chronic lung allograft dysfunction (CLAD) is relatively common and relevant, affecting almost 50% of patients 5 y after transplantation and being the first cause of death from the first year after transplantation. The overall class-II eplet mismatch load has been associated with CLAD development. Methods: Based on clinical data, 240 lung transplant recipients were eligible for CLAD, and HLA and eplet mismatch was analyzed using the HLAMatchmaker 3.1 software. Results: A total of 92 (38.3%) lung transplant recipients developed CLAD. The time free-of-CLAD was significantly decreased in patients with presence of DQA1 eplet mismatches (P = 0.015). Furthermore, when other previously described CLAD risk factors were studied in a multivariate analysis, the presence of DQA1 eplet mismatches was found to be independently associated with the early onset of CLAD. Conclusions: The concept of epitope load has arisen as a new tool to better define donor-recipient immunologic compatibility. The presence of DQA1 eplet mismatches potentially would increase the likelihood of developing CLAD.

Bronchial Stenosis After Lung Transplantation From cDCD Donors Using Simultaneous Abdominal Normothermic Regional Perfusion: A Single-center Experience.

BACKGROUND: Controlled donation after circulatory death (cDCD) has increased the number of lung donors significantly. The use of abdominal normothermic regional perfusion (A-NRP) during organ procurement is a common practice in some centers due to its benefits on abdominal grafts. This study aimed to assess whether the use of A-NRP in cDCD increases the frequency of bronchial stenosis in lung transplant (LT) recipients. METHODS: A single-center, retrospective study including all LTs was performed between January 1, 2015, and August 30, 2022. Airway stenosis was defined as a stricture that leads to clinical/functional worsening requiring the use of invasive monitoring and therapeutic procedures. RESULTS: A total of 308 LT recipients were included in the study. Seventy-six LT recipients (24.7%) received lungs from cDCD donors using A-NRP during organ procurement. Forty-seven LT recipients (15.3%) developed airway stenosis, with no differences between lung recipients with grafts from cDCD (17.2%) and donation after brain death donors (13.3%; P = 0.278). A total of 48.9% of recipients showed signs of acute airway ischemia on control bronchoscopy at 2 to 3 wk posttransplant. Acute ischemia was an independent risk factor for airway stenosis development (odds ratio = 2.523 [1.311-4.855], P = 0.006). The median number of bronchoscopies per patient was 5 (2-9), and 25% of patients needed >8 dilatations. Twenty-three patients underwent endobronchial stenting (50.0%) and each patient needed a median of 1 (1-2) stent. CONCLUSIONS: Incidence of airway stenosis is not increased in LT recipients with grafts obtained from cDCD donors using A-NRP.

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.

Lack of concordance between the different exercise test measures used in the risk stratification of patients with pulmonary arterial hypertension.

In pulmonary arterial hypertension (PAH) patients it is essential to perform a prognostic assessment to optimize the treatment. The aim of this study is to evaluate the risk stratification concordance assessed with different exercise test variables in a cohort of PAH patients. A retrospective analysis was performed using patient data registered in the PAH unit. Only those patients in whom the mean time elapsed between the 6-min walking test (6MWT) and the cardiopulmonary exercise test (CPET) was a maximum of 6 months were selected. A total of 140 records from 40 patients were finally analyzed. When it came to assessing the concordance between the two exercise tests in the guidelines (CPET and 6MWT), up to 84.3% of the records did not coincide in terms of the risk stratification. Exclusively considering the CPET parameters, most of the records (75%) failed to include all three variables in the same risk category. When analyzing the VO2 alone, up to 40.7% of the tests yielded different risk classifications depending on whether the parameter was expressed. In conclusion, there is a low concordance between the two proposed exercise tests. These results should be a call for reflection on whether the cut-off points set for the exercise tests proposed for the current risk stratification are adequate to achieve a correct risk stratification or whether they require an appropriate revision.

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.