Pulmonary sarcoidosis

The lung is the most common organ affected by sarcoidosis. Multiple tools are available to assist clinicians in assessing lung disease activity and in excluding alternative causes of respiratory symptoms. Improving outcomes in pulmonary sarcoidosis should focus on preventing disease progression and disability, and preserving quality of life, in addition to timely identification and management of complications like fibrotic pulmonary sarcoidosis. While steroids continue to be first-line therapy, other therapies with fewer long-term side-effects are available and should be considered in certain circumstances. Knowledge of common clinical features of pulmonary sarcoidosis and specific pulmonary sarcoidosis phenotypes is important for identifying patients who are more likely to benefit from treatment.Copyright © ERS 2022.

Haemodynamic (HD) evaluation of LIQ861 (treprostinil) inhalation powder for the treatment of pulmonary arterial hypertension (PAH)

Background: Treprostinil is a prostacyclin analogue which has been approved in the EU for intravenous (i.v.) and subcutaneous (SC) administration in patients with PAH. LIQ861 is a dry powder formulation of treprostinil which can be used for inhalation via a handheld device. Objectives and methods: LTI-201 was a multicentre, Phase 2, open-label, dose-escalation study to evaluate the HD dose-response and safety of LIQ861, followed by an open-label extension period. In "Part A" HD response was measured by right heart catheterization for 120 minutes after a single 26.5 or 53 mug dose of LIQ861. In "Part B" patients were titrated to symptomatic relief (<=159 mug QID) and were reassessed after 16 weeks using right heart catheterization and clinical assessments. Result(s): Fifteen PAH Patients (60 % female, mean age 56 +/- 14.3 years, mean pulmonary vascular resistance (PVR) 605+/-246 dynes/sec/cm-5) were included. In Part A HD measures (PVR and mean pulmonary arterial pressure) improved with a peak response after 15 minutes for both doses. The study was stopped early due to the COVID19 pandemic with only 6 patients completing Part B. At Week 16, these HD responses also improved and clinical assessments improved or remained stable for these patients. All doses of LIQ861 were generally well-tolerated with only one serious adverse event (short episode of hypoxia after inhalation). The most frequently reported adverse events were cough and throat irritation and most were assessed as mild in severity. Conclusion(s): LIQ861 was overall safe and well tolerated. An expected improvement in HD measures was seen with acute and chronic dosing.

The evolving landscape of pulmonary arterial hypertension clinical trials

Although it is a rare disease, the number of available therapeutic options for treating pulmonary arterial hypertension has increased since the late 1990s, with multiple drugs developed that are shown to be effective in phase 3 randomised controlled trials. Despite considerable advancements in pulmonary arterial hypertension treatment, prognosis remains poor. Existing therapies target pulmonary endothelial dysfunction with vasodilation and anti-proliferative effects. Novel therapies that target proliferative vascular remodelling and affect important outcomes are urgently needed. There is need for additional innovations in clinical trial design so that all emerging candidate therapies can be rigorously studied. Pulmonary arterial hypertension trial design has shifted from short-term submaximal exercise capacity as a primary endpoint, to larger clinical event-driven trial outcomes. Event-driven pulmonary arterial hypertension trials could face feasibility and efficiency issues in the future because increasing sample sizes and longer follow-up durations are needed, which would be problematic in such a rare disease. Enrichment strategies, innovative and alternative trial designs, and novel trial endpoints are potential solutions that could improve the efficiency of future pulmonary arterial hypertension trials while maintaining robustness and clinically meaningful evidence.Copyright © 2022 Elsevier Ltd

2022 Annual World Congress of the Pulmonary Vascular Research Institute

Pulmonary hypertension (PH) is a severe disease that can progress to clinical decompensation, risk of hospitalization and death owing to disease-related or other diseases. In the context of coronavirus disease 2019 (COVID-19), PH was considered a risk factor for complications. The purpose of the study was to assess the mortality rate of COVID-19 in PH patients from a PH Center in Brazil. We conducted a telephone survey between June and August 2021 among all patients or relatives from the PH referral center who were followed after the first case of COVID- 19 in Brazil. Only patients with a confirmed diagnosis of PH were included in the analysis. Of the 426 patients followed in the first 18 months of the pandemic, 115 patients were excluded (lost to follow-up, post-acute PE or unconfirmed PH). Among 311 patients included, 39 had a confirmed diagnosis of COVID-19 (COVID-19 + ), and 38.5% of patients were hospitalized. The estimated incidence rate was 12.5%. Comparing the COVID-19+ versus patients without infection (COVID-19 - ) in the period, the mean age was similar (55 +/- 17 vs. 54 +/- 16 years) and the majority in the COVID-19+ group were female (85% vs. 69%, p = 0.039), respectively. There was no difference in the proportion of patients diagnosed with pulmonary arterial hypertension (PAH;49% and 42%) and chronic thromboembolic pulmonary hypertension (CTEPH;24% and 33%) between groups. All PAH patients and the majority of CTEPH patients were treated on specific therapy (combination/triple therapy, 70%). The case fatality rate in the PH-COVID-19+ group was 23%. Considering only PAH and CTEPH, the case fatality rate was 21,9%, while COVID-19 mortality was 2.9% and overall lethality in Brazil was 2.8%. In the COVID-19+ group, the mean pulmonary artery pressure was 48 +/- 14 mmHg, cardiac index 2.7 +/- 0.6 L/min/m2 and pulmonary vascular resistance 730 +/- 424 dyn.s/cm5. In conclusion, among PH patients there was high incidence and mortality from COVID-19, even in those with PHspecific therapy. Further studies are needed to evaluate the prognostic predictors in PH-COVID-19 patients.

Development of a Comprehensive, Integrated Patient Data Repository of US Pulmonary Arterial Hypertension (PAH) Patients to Assess the Impact of Clinical Care on Patient Outcomes

RATIONALE: Advances in PAH management and well-established treatment guidelines have improved the prognosis for patients. However, the extent to which guidelines are implemented in real-world practice and the relationship between guidelines and real-world patient outcomes remain in question. To assess real-world treatment and outcomes, a new type of comprehensive, integrated patient data repository (CIPDR) was created. Here, we describe the process to create this repository to enable interpretation of the collected data. METHODS: The TRIO CIPDR was created with guidance from six pulmonologists who have experience in design of and/or participation in PH registries (e.g. REVEAL). The CIPDR includes data elements of demographics, disease, comorbidities, laboratory data, pulmonary function testing, functional status, PAH treatment, reasons for treatment discontinuation/switch, hospitalizations, and death, which are collected through HIPAA-secure online forms. To minimize entry errors, participating sites received form training and ongoing support, and each form contained logic to identify improbable entries. All data were deidentified prior to storage in secure, redundant servers. The site engagement, data collection forms, data storage, and data output processes were all designed to allow both retrospective and prospective data collection and for near-immediate repository expansion through addition of other PAH-treating centers. Eleven Pulmonary Hypertension Association-certified care centers initially contributed to the CIPDR though two centers were unable to continue participation due to COVID19 impact. Central IRB approval was obtained though many sites independently received approval for the repository protocol by their IRBs. To facilitate enrollment, specialty pharmacy data corresponding to each site were used to identify potential patients and pre-populate qualification forms. Each site reviewed and qualified patients who met repository criteria: age >18 years, prescribed PAH-specific medications, and confirmation of PAH diagnosis by right heart catheterization (mean Pulmonary Arterial Pressure ≥25mmHg, Pulmonary Capillary Wedge Pressure ≤15 mmHg, and Pulmonary Vascular Resistance ≥3.0 Wood Units at rest). The initial data collection included care encounters between Jan 2019 and Dec 2020 and data concerning diagnosis, onset of symptoms, procedures, and laboratory values closest to enrollment. After completion of data collection, all data were reviewed by Trio Health and adjudicated with each site. RESULTS: Of 3200 patients identified as potentially qualified, 1009 were initially enrolled and their retrospective data encompassing 4489 visits collected. Descriptive measures of the repository are presented in the TABLE. CONCLUSION: The Trio CIPDR is an important step forward to uniquely characterize the patient journey ,treatment patterns, and outcomes for patients with PAH.

A MULTIMODALITY IMAGING DIAGNOSIS OF A CHALLENGING CASE OF CONCOMITANT GROUP 1 PULMONARY HYPERTENSION AND PARADOXICALLY LOW- FLOW, LOW-GRADIENTAORTIC STENOSIS

A 76 year old woman was admitted to our hospital for self-limiting dyspnoea (NYHA class III) in oxygen dependence and frequent lipothymia following Valsalva manoeuvres. She was previously admitted to a Spoke Centre for heart failure (HF) with preserved ejection fraction (EF) and a new diagnosis of “pre-capillary pulmonary hypertension (PH)”. Despite a diagnosis of PH of unclear aetiology, she was started on macitentan without being reassessed for functional capacity due to Covid emergency;because of worsening symptoms, she was admitted to our Hub Centre. Resting ECG showed right axis deviation, right ventricle (RV) hypertrophy, first-degree atrioventricular block and right bundle branch block. Transthoracic echocardiography (TTE) showed reduced left ventricular (LV) volume with preserved EF (diastolic volume= 37 ml, EF=88%), severe right atrial and RV dilation with flattening of the interventricular septum, estimated pulmonary artery systolic pressure (PASP) of 124 mmHg, and moderate calcific aortic stenosis (peak aortic velocity 3.3 m/s, mean gradient 25 mmHg, valve area 1.1 cm2). Right and left heart catheterization showed severe pre-capillary PH (mean pulmonary pressure 60 mmHg, mean wedge 11 mmHg, pulmonary vascular resistance 14.41 WU), a severe aortic valve stenosis (aortic valve area 0.68 cmq and peak-to-peak gradient 25 mmHg, slight reduction of cardiac index 2.04 l/min/mq) and no significant coronary artery disease. The degree of aortic stenosis was considered as moderate-severe by integrating data of transesophageal echocardiography (planimetric area 1cm2) and assessment of calcium score (1615 Agatson units). Pneumological causes, chronic thromboembolic PH, rheumatologic diseases, HIV infection, paraneoplastic origin and veno-occlusive disease were all ruled out as potential PH causes and a diagnosis of Idiopathic pulmonary arterial hypertension (IPAH) was finally made. The Heart Team established the best therapeutic option was a transcatheter aortic valve replacement (TAVI) allowing better haemodynamic tolerability of PH therapy. The patient underwent TAVI and was started on PH therapy;a complete atrio-ventricular block developed after the procedure, requiring permanent pacemaker (PM) implantation. Unfortunately, few days later, the patient died following pacemaker's lead dislocation. Conclusion: PH has a diverse aetiology, and prognosis is generally poor, especially in patients with severe comorbidities. (Figure Presented).

THE ELDEST HEART TRANSPLANTED PATIENT IN EUROPE: 36 YEARS SURVIVAL AND STILL GOING ON

Development of endomyocardial biopsy for acute rejection monitoring in the early Seventies, and above all use of cyclosporine in the clinical practice starting from 1980, introduced the modern era of heart transplantation. Following the initial positive outcomes, the first Italian transplant was performed in Padua by V.Gallucci on November 15th 1985. This pioneering success was rapidly repeated in Pavia, where M.Viganò performed the second transplant on Novembre 17th. Recipient was 20 years old man, suffering from dilated cardiomyopathy, on urgent transplant list. Cardiac index was 1.38 l/min/m2 and pulmonary vascular resistance 1.6 WU. Donor was a 14 years old boy died of brain injury. Total ischemic time was 125 minutes. Induction immunosuppression consisted of horse anti-lymphocyte immunoglobulins, whereas maintenance therapy included cyclosporine, azathioprine and steroids. Postoperative course was complicated by pericardial effusion and cholestatic jaundice. Later pulmonary aspergillosis occurred and due to the profound immunodepression was complicated by fungal localization at L2 vertebral body. The infection was treated with surgical removal of the secondary localization and amphotericin B administration. On December 6th severe acute rejection was found at biopsy and treated with i.v. steroid pulse. Length of ICU and hospital stay was 28 and 72 days, respectively. In 1998 HCV infection was detected and eradicated in 2017 with elbasvir/grazoprevir therapy. Complications of long term immunosuppressive treatment included dyslipidemia, myeloma and basal cell carcinoma. Due to long-term calcineurin inhibitors therapy progressive chronic renal failure occurred, leading to replacement therapy in 2015 and kidney transplantation in 2016. In 2015 the patient underwent percutaneous coronary intervention with stents implantation in two marginal branches and in the anterior descending artery in 2021. Everolimus was introduced to slow down progression of cardiac allograft vasculopathy. In 2020 he suffered from Covid-19, but the course of infection was uneventful being cough the only symptom. We report the eldest survivor after heart transplant in Europe. Our case demonstrates that despite early and long-term complications of immunosuppressive therapy, a careful and patient tailored management allowed an amazing outcome. Nowadays heart transplant remains the best treatment for end stage heart failure and allows to resume a nearly normal quality of life.

Impaired systemic oxygen extraction relates to reduced exercise capacity in post-covid-19 long hauler syndrome

Introduction: Following acute coronavirus 2019 (COVID-19) disease, at least 10% of patients report some form of residual limitation, most commonly dyspnea and fatigue. These COVID-19 “long haulers” experience symptoms that are largely unexplained by pulmonary function testing (PFT), echocardiogram and chest computed tomography (CT). Using invasive cardiopulmonary exercise testing, this pilot study characterized exercise limitation in 5 patients with persistent symptoms 1 year following mild COVID-19 illness. Methods: Following written informed consent, data were obtained in accordance with an IRBapproved protocol entailing placement of radial and pulmonary arterial catheters for pressure monitoring and blood sampling prior to and during maximum upright incremental exercise. Rest and exercise pulmonary hemodynamics, ventilation and gas exchange were recorded. Aerobic exercise capacity was estimated by peak O2 consumption (VO2 ). Results: All patients had normal biventricular and valvular function on resting echocardiogram, no evident parenchymal lung disease on CT, and normal PFTs. Resting mean pulmonary arterial pressure was ≤20 mmHg for all patients with pulmonary vascular resistance <3 Woods units. At maximum exercise, all patients exhibited normal respiratory, cardiac output (% predicted), and total pulmonary vascular resistance responses, but demonstrated clearly depressed aerobic capacity (peak VO2 <80% predicted). Reduced peak VO2 was associated with impaired systemic O2 extraction as indicated by an arterial-venous O2 content difference (adjusted for hemoglobin) of <80% (Figure 1). Conclusion: This case series provides preliminary evidence that reduced peak aerobic capacity among long haulers is primarily attributable to a peripheral (i.e., impaired systemic O2 extraction), rather than central cardiopulmonary, limitation. These results suggest that systemic microcirculatory dysfunction contributes to exercise limitation.

Increased incidence of Persistent Pulmonary Hypertension of the Newborn following third trimester maternal COVID-19 infection

Background: Novel coronavirus (COVID-19) has been a world concern since December 2019. The knowledge about vertical transmission and fetal morbidity and mortality from maternal COVID-19 infection is limited.We detected an increase in the number of cases of term and near-term neonates with persistent pulmonary hypertension (PPHN) during the COVID-19 pandemic in 2020. Methods and results: We collected data on all newborns with PPHN born between 2018 and 2020. We excluded premature infants (<34+0 weeks) and infants with other significant pathology or genetic syndromes. Compared to 5 cases of PPHN of 22930 live births in 2018, and 6 cases of PPHN of 22270 live births in 2019 (2-year average 0.02%, 95% CI 0.013%- 0.043%), there were 16 PPHN cases from 22323 live births in 2020 (0.07%, 95% CI 0.044%-0.12%), a 3 fold increase (p<0.01). We report 5 cases of term and near-term neonates born to mothers who had highly suspected (2) and PCR proven (3) COVID-19 infection during the third trimester of pregnancy, who presented with PPHN during COVID-19 pandemic in 2020. All had otherwise unexplained pulmonary hypertension, right ventricular hypertrophy (RVH) and dilatation. Two patients needed endotracheal intubation, one was supported by nasal continuous positive airway pressure (CPAP) without intubation, two needed O2 support by nasal cannula only ant two newborns (one of them was intubated) needed Nitric oxide (NO) as pulmonary vasodilator therapy. No patient required Extracorporeal membrane oxygenation (ECMO) or died, and no prolonged residual cardiovascular or pulmonary morbidity was recorded during a median follow up of 4.8 months (range 4-6 months). Conclusions: The increase in the incidence of PPHN during the COVID- 19 pandemic, and the cases presented, suggest an intrauterine effect of maternal COVID-19 infection on the fetal pulmonary circulation. It is possible that the maternal infection affected the fetal pulmonary vascular resistance, or altered the normal decline in the resistance after birth. The right ventricular hypertrophy and dilatation with reduced function may be secondary to this hypothetical increased afterload or a direct effect of the infection. Further studies are warranted to elucidate the pathogenesis and clinical implications of this phenomenon.