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.

[Highlights of the 55th SEPAR Congress]. / Highlights del 55.° Congreso SEPAR.

The 55th SEPAR Congress was held in Pamplona from 2 to 4 of June 2022. Once again, it was the referral scientific meeting for specialists in pulmonology, thoracic surgery, nursing, physiotherapy, paediatric respiratory diseases and other disciplines involved in respiratory care. The Spanish Society of Pulmonology and Thoracic Surgery showed its national and international leadership in the management of respiratory diseases, which was reflected in a program with an excellent content and a high scientific level. In this review, we offer a summary of some notable aspects covered in six selected areas of interest: pulmonary vascular diseases, non-invasive mechanical ventilation and sleep disorders, asthma, chronic obstructive pulmonary disease (COPD), interstitial lung diseases (ILD), and interventional pulmonolgy and lung transplant.

Usefulness of genetics for clinical reclassification and refinement of prognostic stratification in pulmonary arterial hypertension.

INTRODUCTION AND OBJECTIVES: Risk stratification in pulmonary arterial hypertension (PAH) is essential to provide more aggressive treatment for patients at higher risk. Nevertheless, recently introduced simplified prognostic tools neglect the genetic background. Additionally, pulmonary veno-oclusive disease (PVOD) has never been considered in risk assessment strategies. METHODS: We analyzed consecutive patients in the Spanish registry of PAH (REHAP) genetically tested, between 2011 and 2022. We applied the 4-strata COMPERA 2.0 model, comparing these results with an amplified score including genetics. Cox regression models were compared using Harrel c-statistics. The application of the model was specifically tested in PVOD before inclusion. RESULTS: We identified 298 patients tested genetically among the group of idiopathic, familial, drug-induced PAH and PVOD patients in the REHAP registry. When we analyzed only patients with all available variables of interest at baseline (World Health Organization functional class, 6-minute walk test, B-type natriuretic peptide or N-terminal pro-B-type natriuretic peptide) and included in the 4-strata model (n=142), after a median follow-up of 58.2 months, 17.6% of patients died and 11.3% underwent lung transplant. The application of the 4-strata model in our population demonstrated a good prognostic capacity (Harrel c of 0.689), which was not improved by the introduction of genetics (c-index 0.690). This last model showed a tendency for a better identification of patients at intermediate-low and intermediate-high risk, and no differences between intermediate-high and high-risk strata. CONCLUSIONS: In this work, the addition of genetics to the COMPERA 4-strata model achieved a similar global prognostic capacity but changed the identification of different risk strata in a cohort of young genetically tested patients.

Evaluation of a digital health system (PAHcare™) for routine care of patients with pulmonary arterial hypertension: The CBS-PAH study protocol.

Introduction: Pulmonary arterial hypertension (PAH) is a rare, multifactorial, chronic condition that requires ongoing monitoring and assessment. PAHcare™ is a novel, patient-centered digital platform that provides software intended for use on patients' mobile phones (downloadable application) and web-based dashboards for use by physicians and health coaches (HC). We describe herein the protocol of a clinical study aimed at evaluating the clinical benefit and safety of PAHcare™ for the routine management of patients with PAH. Methods and analysis: In this prospective, single cohort, multicenter study, 50 patients with PAH will be recruited at six specialized PAH units from reference hospitals of the public Spanish healthcare system. The PAHcare™ digital health platform allows patients to log health and lifestyle information while also providing structured content for patient education, medication reminders, and behavioral and lifestyle coaching from a remote HC. Evaluation will be primarily focused on the impact of the platform use on the patient's health-related quality of life (HRQoL) via questionnaires completion through electronic patient-reported outcomes. Moreover, the analysis of the impact on the patient's functional status, signs and symptoms of PAH, patient costs and healthcare resource utilization, satisfaction, knowledge of the disease and its management, and adherence to and safety of the platform will be secondary outcomes. The clinical investigation started in July 2021 and is expected to end by September 2022. Discussion: The PAHcare™ platform is anticipated to provide direct benefits to healthcare professionals, patients, and caregivers. These include the simplification of the multidisciplinary approach needed to tailor routine PAH management, enhancement of the patient/healthcare professional interaction, patient's empowerment to become more actively involved in the management and treatment of the disease, and increase of the patient's and caregiver's knowledge on PAH.

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.

From Health-Related Quality of Life (HRQoL) of Patients with Pulmonary Hypertension to Patient Experience with the Care Received: Should We Be More Aware of Current Patient Needs?

INTRODUCTION: Self-perceived health-related quality of life (HRQoL) of patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) and their experience with the care received are important for improving their management. We conducted a study to assess both patient-reported outcomes (PROs) and how they interrelate. METHODS: This was a cross-sectional, observational study of consecutive patients with PAH and CTEPH attending pulmonary hypertension (PH)-specialized units at 25 hospitals in Spain. PRO measurements used included CAMPHOR/EQ-5D-5L questionnaires (HRQoL) and IEXPAC (healthcare experience). Patient characteristics were collected. Relationships were analysed with Pearson's correlation coefficient and linear regression analyses. RESULTS: A total of 185 patients with PAH and 93 patients with CTEPH aged 54.4 ± 14.4 and 64.8 ± 13.4 years were included: 63.6% and 72% were functional class (FC) I-II; median time from diagnosis was 3 and 2 years, respectively. Most patients with PAH received combination oral therapy. CAMPHOR scores indicated moderate-to-high impairment in the "activity" scale (PAH 21.6 ± 6.8; CTEPH 21.0 ± 6.3). EQ-5D-5L index and visual analogue scale (VAS) score (PAH 0.59 ± 0.15 and 65.55 ± 21.54; CTEPH 0.59 ± 0.13 and 66.95 ± 18.71, respectively) indicated moderate HRQoL impairment. HRQoL was mostly affected by FC. IEXPAC scores (PAH 7.08 ± 1.56 and CTEPH 7.13 ± 1.61) indicated good healthcare experience. In patients with PAH, the CAMPHOR "symptom" and "QoL" domains inversely correlated with the IEXPAC "patient self-management" factor. CONCLUSION: In patients with long-standing PAH and CTEPH with good disease control, functional limitations greatly impact HRQoL while symptoms and generic QoL were less affected. Healthcare received was perceived as good; however, use of information and communication technologies, patient associations and promotion of self-management should improve for enhanced patient experience.

Chronic thromboembolic pulmonary hypertension in Spain: a decade of change.

INTRODUCTION AND OBJECTIVES: Chronic thromboembolic pulmonary hypertension (CTEPH) treatment has evolved in the last decade. However, there is scarce information on the long-term impact of this progress in a real-life population at a national level. This study was designed to analyze the characteristics of CTEPH patients in Spain over the last decade. METHODS: We prospectively collected epidemiological, clinical, and prognostic data from CTEPH patients consecutively included in the Spanish REHAP registry from January 1, 2007, to December 31, 2018. We evaluated differences over time, establishing 2013 as the reference date for analysis. Propensity scores for interventional treatment were calculated using a multivariable logistic regression model. RESULTS: A total of 1019 patients were included; 659 (64.4%) were evaluated at a national CTEPH center. Overall, 350 patients (34.3%) were selected for surgery and 97 (9.6%) for percutaneous treatment. Patients diagnosed between 2007 and 2012 died more frequently than those diagnosed from 2013 onward (HR, 1.83; 95%CI, 1.07-3.15; P=.027). Within the subgroup of patients adjusted by propensity score, baseline pulmonary vascular resistance and the 6-minute walk test distance also determined the outcome (HR, 1.24; 95%CI, 1.15-1.33; P=.011; and HR, 0.93; 95%CI, 0.90-0.97; P=.001, respectively). High survival rates were found in patients who underwent an invasive procedure (pulmonary endarterectomy or balloon pulmonary angioplasty). CONCLUSIONS: CTEPH diagnosis and prognosis have consistently improved in the last decade. Baseline disease severity determines the risk profile. Patients who undergo pulmonary endarterectomy or balloon pulmonary angioplasty have better outcomes.

Clinical heterogeneity of Pulmonary Arterial Hypertension associated with variants in TBX4.

BACKGROUND: The knowledge of hereditary predisposition has changed our understanding of Pulmonary Arterial Hypertension. Genetic testing has been widely extended and the application of Pulmonary Arterial Hypertension specific gene panels has allowed its inclusion in the diagnostic workup and increase the diagnostic ratio compared to the traditional sequencing techniques. This is particularly important in the differential diagnosis between Pulmonary Arterial Hypertension and Pulmonary Venoocclusive Disease. METHODS: Since November 2011, genetic testing is offered to all patients with idiopathic, hereditable and associated forms of Pulmonary Arterial Hypertension or Pulmonary Venoocclusive Disease included in the Spanish Registry of Pulmonary Arterial Hypertension. Herein, we present the clinical phenotype and prognosis of all Pulmonary Arterial Hypertension patients with disease-associated variants in TBX4. RESULTS: Out of 579 adults and 45 children, we found in eight patients from seven families, disease-causing associated variants in TBX4. All adult patients had a moderate-severe reduction in diffusion capacity. However, we observed a wide spectrum of clinical presentations, including Pulmonary Venoocclusive Disease suspicion, interstitial lung disease, pulmonary vascular abnormalities and congenital heart disease. CONCLUSIONS: Genetic testing is now essential for a correct diagnosis work-up in Pulmonary Arterial Hypertension. TBX4-associated Pulmonary Arterial Hypertension has marked clinical heterogeneity. In this regard, a genetic study is extremely useful to obtain an accurate diagnosis and provide appropriate management.

Long-term survival of lung transplantation for interstitial lung disease associated with connective tissue diseases: a study of 26 cases from a referral centre.

OBJECTIVES: Interstitial lung disease (ILD) is a leading cause of mortality in patients with connective tissue diseases (CTD). Lung transplantation has become a viable option for patients with end-stage CTD-ILD. However, patients with CTD are often considered suboptimal candidates for lung transplantation because of concerns of worse outcomes. We assessed post-transplant survival of patients with CTD-ILD compared to patients with idiopathic pulmonary fibrosis (IPF). METHODS: Medical records of patients who underwent lung transplantation for CTD-ILD at a single referral centre for lung transplantation in Northern Spain between 1998 and 2018 were reviewed. This cohort was compared with patients with IPF (group-matched for age ±3.3 years, transplant year and use of basiliximab induction previous to transplant). Cumulative survival rates after transplantation were estimated by the Kaplan-Meier method and compared between groups using the log-rank test. RESULTS: We studied 26 patients with CTD-ILD and 26 patients with IPF. The underlying diseases of CTD-ILD patients were rheumatoid arthritis (n=9), scleroderma (n=6), Sjögren's syndrome (n=4), ANCA-associated vasculitis (n=3), anti-synthetase syndrome (n=2), and dermatomyositis, systemic lupus erythematosus (1 each). Baseline characteristics were similar in both groups. CTD-ILD patients experienced acute graft rejection less commonly than those with IPF (32.0% vs. 62.5%; p=0.032). However, a non-statistically significant increased frequency of chronic graft rejection was observed in CTD-ILD patients (20.0% vs. 8.3%; p=0.417). In this regard, the 5-year cumulative survival rates after transplantation was reduced in CTD-ILD (42.4% vs. 65.8%) but the difference did not achieve statistical significance (p=0.075). CONCLUSIONS: Long-term post-transplant survival in Northern Spanish patients with CTD-ILD is reduced compared with IPF.

Real-life experience of inhaled iloprost for patients with pulmonary arterial hypertension: Insights from the Spanish REHAP registry.

INTRODUCTION: REHAP is a voluntary, observational Spanish registry of patients with pulmonary arterial hypertension. We analyzed the experience (use and effectiveness) with inhaled iloprost (inh-ILO) in real-life conditions during a 3-year period. METHODS: Patients included were those with PAH ≥14 years recruited during 1998-2016 who had received inh-ILO. Variables were collected at the beginning of treatment (0 ±â€¯3 months) and 12 ±â€¯3/36 ±â€¯6 months follow-up. Effectiveness was assessed in the intent-to-treat population as changes in functional class and/or physical performance and transplant-free survival from the beginning of treatment. Stopping inh-ILO-related survival was also assessed. Subanalyses included treatment strategy (first-line therapy -monotherapy or upfront combination- or sequential therapy) and risk of clinical worsening/death. RESULTS: Inh-ILO was the most frequently used prostanoid in Spain, rendering 267 patients eligible for analysis. Median age was 54 years; 61% were WHO FC III. Sixty (23%) patients started inh-ILO as monotherapy, 27 (10%) as upfront combination and 180 (67%) sequentially. At 3-year follow-up significant clinical improvements were observed; however, transplant-free survival rate was 54%, being poorer in patients at high risk (63% vs. 85% in low risk patients; P < 0.001) and similar in the three treatment strategies. Only 25% patients remained on inh-ILO. Three-year after stopping inh-ILO-related survival rate was 24.7%. CONCLUSION: Data from the REHAP collected during 3 years shows that inh-ILO has low effectiveness independently of the treatment strategy used, with a 3-year survival rate of 54% despite significant clinical improvements, probably due to the use in high-risk patients. Discontinuation rate was as high as 75%.

Variable Expressivity of a Founder Mutation in the EIF2AK4 Gene in Hereditary Pulmonary Veno-occlusive Disease and Its Impact on Survival.

INTRODUCTION AND OBJECTIVES: Hereditary pulmonary veno-occlusive disease (PVOD) has been associated with biallelic mutations in EIF2AK4 with the recent discovery of a founder mutation in Iberian Romani patients with familial PVOD. The aims of this study were phenotypical characterization and survival analysis of Iberian Romani patients with familial PVOD carrying the founder p.Pro1115Leu mutation in EIF2AK4, according to their tolerance to pulmonary vasodilators (PVD). Familial genetic screening was conducted, as well as assessment of sociocultural determinants with a potential influence on disease course. METHODS: Observational study of Romani patients with familial PVOD included in the Spanish Registry of Pulmonary Arterial Hypertension. Genetic screening of EIF2AK4 was performed in index cases and relatives between November 2011 and July 2016 and histological pulmonary examination was carried out in patients who received a lung transplant or died. The patients were divided into 2 groups depending on their tolerance to PVD, with comparison of baseline characteristics and survival free of death or lung transplant. RESULTS: Eighteen Romani patients were included: 9 index cases and 9 relatives. The biallelic founder mutation in EIF2AK4 was found in all affected cases and 2 unaffected relatives. Family screening showed 34.2% of healthy heterozygotes, high consanguinity, young age at childbirth, and frequent multiparity. Prognosis was bleak, with significant differences depending on tolerance to PVD. CONCLUSIONS: We describe 2 phenotypes of hereditary PVOD depending on tolerance to PVD, with prognostic impact and familial distribution. Consanguinity may have a negative impact on the transmission of PVOD, with familial genetic screening showing high effectiveness.

Isolated pulmonary vasculitis: case report and literature review.

BACKGROUND AND OBJECTIVES: Single-organ vasculitis has been reported to affect the skin, kidneys, central nervous system, peripheral nerves, genitourinary tract, calf muscles, aorta, coronary arteries, retina, or gastrointestinal tract. However, isolated pulmonary vasculitis is a very rare entity. Our aims were to describe a case of localized pulmonary vasculitis affecting medium-sized vessels and review the literature. METHODS: A patient with localized pulmonary vasculitis affecting medium-sized vessels that presented as pulmonary arterial hypertension is described. A MEDLINE database search of cases with localized pulmonary vasculitis was also conducted. RESULTS: A 30-year-old man presented with pulmonary hypertension due to isolated pulmonary medium-sized vessel vasculitis that was confirmed histologically. Initially he responded to corticosteroids and vasodilator treatment, but therapy eventually lost efficacy. Treatment with rituximab was not effective, and as the clinical situation worsened, lung transplant was performed. Isolated large pulmonary vessel disease, often related to Takayasu disease or giant cell arteritis, may present as pulmonary artery hypertension, thus mimicking chronic thromboembolic disease. Medium- and small-vessel pulmonary vasculitis usually develops in the context of a systemic disease. Some cases of isolated small-vessel vasculitis have been reported presenting as diffuse alveolar hemorrhage. In contrast, our case developed pulmonary artery hypertension secondary to medium-sized vessels vasculitis. To our knowledge, this is the first case of lung transplantation in isolated pulmonary vasculitis. CONCLUSIONS: Pulmonary isolated vasculitis is a rare cause of pulmonary hypertension but it must be taken into consideration after more common disorders are excluded.