RARE DISEASE
Pulmonary venoocclusive disease
Pulmonary venoocclusive disease
Pulmonary venoocclusive disease
Drug discovery
0
drugs
With orphan designations
Overview
Pulmonary veno-occlusive disease (PVOD) is a rare, progressive form of pulmonary hypertension caused by fibrous occlusion of pulmonary venules and capillaries, leading to elevated pulmonary arterial pressure and right heart failure. It is associated with EIF2AK4 mutations in heritable cases and chemotherapy/occupational exposures in sporadic forms. Diagnosis relies on CT findings (ground-glass opacities, septal thickening) and clinical suspicion, though biopsy remains definitive. Prognosis is poor, with median survival of ~2 years; lung transplantation is the only curative option. Vasodilator therapies risk pulmonary edema and require cautious use [1][3][6][16].
Population
Affects 0.1–0.5 cases per million annually, with heritable forms linked to EIF2AK4 mutations (younger adults/children) and sporadic cases in older adults exposed to chemotherapy, radiation, or organic solvents [1][6][16].
Represents 3–12% of idiopathic pulmonary arterial hypertension diagnoses, often misdiagnosed initially [2][6].
Therapies
Lung transplantation: Definitive treatment, though limited by donor availability and post-transplant complications [1][14][16].
Cautious vasodilators: Low-dose epoprostenol with diuretics may bridge to transplant but risks pulmonary edema [3][7][16].
Supportive care: Oxygen, anticoagulation, and diuretics for symptom management [1][7].
Categories: rare genetic diseases, rare respiratory diseases
Research Papers
179 drug discovery papers about Pulmonary venoocclusive disease, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
179 drug discovery papers about Pulmonary venoocclusive disease, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-06-22 | Survival Improvement With Steroid Use for Pulmonary Veno-Occlusive Disease With the Aid of Pulmonary Vasodilators and Tyrosine-Kinase Inhibitor, a Retrospective Study.
Steroids are effective in patients with heart failure, connective tissue disease, and interstitial lung disease, which are conditions often associated with Pulmonary veno-occlusive disease (PVOD). This study assessed the efficacy of steroid treatment combined with pulmonary vasodilators and tyrosine kinase inhibitors in patients with PVOD. This retrospective study aims to explore the effect of steroids on patient condition and survival, and the hypothesis that steroids may improve the survival of patients with PVOD was verified. The study involved two facilities in Tokyo with the same supervisors. Ten patients were diagnosed with PVOD from April 2006 to May 2018, divided into two categories: the patients not receiving (PNS, n = 5) and those receiving steroids (PRS, n = 5). The difference in survival between the two groups was evaluated with log-rank test. Based on the Kaplan-Meier curve, median survival length after symptom onset in pulmonary hypertension was 3.3 [1.3-4.3] years (outcome: all died) for PNS (n = 5) and 7.1 [5.2-11.0] years (outcome: three were alive, one had lung transplant, and one died) for PRS (n = 5). Although steroids did not necessarily improve patients' conditions, PRS had relatively stable conditions for a remarkably extended time compared to PNS. While the sample set is relatively small and this is a non-controlled retrospective study, the results indicate that a combination of steroids with pulmonary vasodilators and tyrosine-kinase inhibitors appears to be a promising treatment, especially for the purpose of extending patient survival until lung transplantation; however, this warrants further large-scale investigation.
2026-06-01 | B77-25 Pirfenidone Analogs Induce the Integrated Stress Response via Gcn2-eif2α-atf4 to Inhibit Fibroblast Proliferation
Abstract Introduction Pirfenidone exhibits pleiotropic antifibrotic and anti-inflammatory properties in experimental models and was the first ever antifibrotic medicine to reach patients in 2008. However, after more than 30 years of research, the drug’s mechanism of action (MOA) remains elusive because its poor potency precludes rigorous target identification. Until its MOA is understood, efforts to develop more effective drugs in this class will be difficult. Methods We establish structure-activity relationship assays (SAR) for the more potent pirfenidone analog GDC-3280 and its inactive analogs using quantitative live cell imaging and global proteomics. Based on robust SAR, we deploy a genome-wide CRISPR-knock-out screen in immortalized human foreskin fibroblasts. Results While GDC-3280 inhibits expression of several myofibroblast markers as previously reported, unbiased global proteomics reveal suppression of E2F targets, a G0/1 cell cycle arrest signature, and upregulation of ATF4 target genes. A CRISPR-KO screen identified EIF2AK4 (GCN2), a major stress-sensing kinase of the integrated stress response (ISR) pathway, as a key dependency for GDC-3280’s effect on fibroblast proliferation. Genetic deletion of GCN2 and co-treatment with an ISR inhibitor (ISRIB) alleviate the drug’s effect on fibroblast growth at concentrations near the clinically achievable range. Conclusion Our study suggests that Pirfenidone analog GDC-3280 may exert its therapeutic effect by inducing the integrated stress response through activation of GCN2, eIF2α and ATF4. Loss of EIF2AK4 (GCN2) leads to pulmonary veno-occlusive disease in humans, and, in animals, to worsening pulmonary fibrosis and pulmonary hypertension. GCN2 protein levels are reduced in the endothelium of diseased lungs with idiopathic pulmonary fibrosis and pulmonary hypertension, suggesting diseased lungs lack fully functional GCN2-mediated ISR activity. Therefore, restoration of the integrated stress response via activation of GCN2 may be of therapeutic benefit for fibrosing pulmonary disease. This abstract is funded by: Anonymous donation to the Section of Molecular Medicine, Department of Radiation Oncology at UT Southwestern Medical Center
2026-06-01 | P.135 Clinical and hemodynamic profile of patients with SSc-PAH with and without pulmonary veno-occlusive disease: a single-center study
Signs of pulmonary veno-occlusive disease (PVOD) may be found in patients with pulmonary arterial hypertension (PAH), particularly in systemic sclerosis (SSc)1. This association (PVOD/PAH) remains poorly characterized in SSc. We aimed to compare the clinical, echocardiographic and hemodynamic profile of patients with SSc-PAH with and without a concomitant diagnosis of PVOD, and their potential response to vasodilators. We retrospectively analyzed 23 patients with SSc-PAH diagnosed by right heart catheterization, followed at our center between 2017 and 2023. Data collected at diagnosis and after 12 months included clinical, laboratory, functional and imaging parameters. Multidisciplinary assessment allowed the identification of cases with clinical and radiological features suggestive of PVOD/PAH1. Patients were divided into two groups (PVOD/PAH and non-PVOD/PAH) and data were compared at baseline and 12-month follow-up. Twenty-three patients with SSc-PAH were enrolled in the study, of whom 6 (26%) had signs of PVOD/PAH. At PAH diagnosis, PVOD/PAH patients had higher values of mean pulmonary arterial pressure compared to non-PVOD/PAH (47.5±5.3 vs. 36.7±8.8 mmHg, p=0.011), but similar pulmonary vascular resistance. Age, sex, cardiovascular risk factors, SSc features, echo findings as well as cardiac biomarker values were similar between the two groups (table 1). At follow-up, most PVOD/PAH patients (67%) were on monotherapy with endothelin receptor antagonists (ERA), and 33% on dual therapy (ERA + phosphodiesterase inhibitors). Only one case of pulmonary edema was recorded. In the non-PVOD/PAH group, most patients (53%) were on dual vasodilator therapy. On echocardiography, PVOD/PAH patients showed higher tricuspid regurgitation velocity (4.10±0.68 vs. 3.07±0.91 m/s; p=0.035) and worse right ventricular function (FAC 25.6±8.4% vs. 33.9±6.8%; p=0.046). Changes in NT-proBNP levels from baseline differed between groups (p=0.012), showing a trend toward increase in PVOD/PAH (p=0.076) and reduction in non-PVOD/PAH (p=0.069). At 12 months, 5 hospitalizations for heart failure in each group, and a total of 5 deaths (2 PVOD/PAH and 3 non-PVOD/PAH) were recorded, with similar event-free survival (p=0.101). PVOD is frequently associated with PAH in SSc and does not seem to be associated with specific SSc features. Vasodilators, at least on monotherapy, should be considered in PVOD/PAH, as they seem to be well tolerated. Nevertheless, at follow-up these patients exhibit unfavorable laboratory and echo profiles compared to those with SSc-PAH alone, highlighting the importance of early referral for lung transplantation.
2026-05-01 | B64-34 Pulmonary Veno-Occlusive Disease Phenotype in Diffuse Large B-Cell Lymphoma: Malignancy Biology Versus Chemotherapeutic Vascular Injury
Abstract Introduction Pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) are uncommon World Health Organization (WHO) Group 1 pulmonary arterial hypertension (PAH) phenotypes, together representing approximately 10% of group 1 PAH cases. PVOD is characterized by venular obstruction, profound hypoxemia, and a disproportionately low diffusing capacity for carbon monoxide (DLCO) often progressing rapidly despite therapy. Etiology remains incompletely defined. Cyclophosphamide, hematopoietic stem cell transplant, and primary malignancy physiology have each been implicated. This case highlights a PVOD phenotype arising before bone marrow transplant, with partial symptom responsiveness to lymphoma-directed therapy, raising the question that malignancy pathology rather than chemotherapy was the driver for the disease. Case Presentation A 72-year-old man with diffuse large B-cell lymphoma achieved complete remission after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy. Approximately one year later, he developed gradually progressive shortness of breath. Pulmonary function testing (PFTs) demonstrated preserved spirometry and lung volumes but severe isolated reduction in DLCO. Computed Tomography chest showed enlarged pulmonary vessels, mosaic ground glass opacities and mediastinal Lymphadenopathy. Echocardiography showed preserved left ventricular systolic function but moderately elevated right ventricular systolic pressures (RVSP) at 57 mmHg. As exertional dyspnea worsened, a six-minute walk test confirmed chronic desaturation requiring supplemental oxygen. He underwent right sided heart catheterization that demonstrated precapillary pulmonary hypertension with an elevated transpulmonary gradient (TPG) and normal pulmonary capillary wedge pressure (PCWP): Mean pulmonary artery pressure (mPAP) 31 mmHg, PCWP 6, TPG 25, Pulmonary vascular resistance (PVR) 5.29 wood units. He received salvage chemotherapy and was started on dual pulmonary arterial hypertension therapy with tadalafil and macitentan with symptomatic benefit. He later underwent autologous stem cell transplant and ultimately discontinued home oxygen. Follow-up imaging, two-dimensional Echocardiography and pulmonary function testing showed improvement of his elevated pulmonary pressures. Discussion This case raises two distinct etiologic possibilities: (1) cyclophosphamide-mediated endothelial injury and (2) active malignancy-driven vascular remodeling. The transient improvement during lymphoma cytoreduction is a key clue supporting cancer-related illness. While PVOD is traditionally associated with transplant, this case demonstrates development prior to transplant, reinforcing the need to consider malignancy as a causative agent. Early identification of PVOD as a cause of exertional dyspnea and hypoxemia in patients with hematological malignancy is essential, as prompt initiation of PAH-targeted therapy can enhance functional status and quality of life. This abstract is funded by: None
2026-05-01 | B64-23 Unmasking Diagnostic and Treatment Challenges in a Complex Case of Pulmonary Veno-occlusive Disease
Abstract Introduction Pulmonary veno-occlusive disease (PVOD) is a rare and life-threatening cause of pulmonary arterial hypertension (PAH) with an estimated prevalence of 1 case per 1 million. Due to its rarity and diagnostic complexity, PVOD remains a challenging entity requiring a high index of suspicion and multidisciplinary evaluation. Early recognition is critical, as lung transplantation remains the only definitive treatment. This case illustrated the diagnostic and therapeutic challenges of PVOD in a patient with multifactorial pulmonary hypertension and underscores the importance of individualized management and timely diagnosis. Description A 67-year-old man with hypertension, diabetes, obesity class II, emphysema, and severe central/obstructive sleep apnea was sent to the emergency department from his pulmonology clinic for significant hypoxia (SpO2 86%) and worsening dyspnea. Chest X-ray showed mild interstitial edema. CTA ruled out pulmonary embolism but demonstrated diffuse centrilobular ground-glass opacities, interlobular septal thickening, and mediastinal lymphadenopathy, suggestive of PVOD. Echocardiogram showed a dilated right atrium and right ventricle with pulmonary artery systolic pressure (PASP) of 85 mmHg, prompting initiation of diuretics. Right heart catheterization (RHC) showed a mean pulmonary artery pressure (MPAP) of 38 mmHg and a pulmonary vascular resistance (PVR) of 9 wood units (WU). Extensive serologic workup was negative. Following BiPAP initiation for severe sleep apnea, repeat RHC after one month showed worsening MPAP (65 mmHg) and PVR (13.5 WU). He was started on low-dose tadalafil and ambrisentan, later uptitrated with close monitoring. Despite an episode of vasodilator-induced pulmonary edema requiring dose adjustment, he showed marked clinical and echocardiographic improvement, was weaned off supplemental oxygen, and deferred lung transplant evaluation due to significant recovery in function and quality of life. Discussion Pulmonary veno-occlusive disease (PVOD) is progressive with poor prognosis, making timely recognition and management critical. Response to PAH-directed therapy is highly variable; some patients achieve meaningful improvement, while others may develop pulmonary edema or remain refractory. Recent data illustrate that carefully titrated vasodilators, balanced with diuretics and close monitoring, can benefit select patients, though long-term effects are variable and remain poorly understood. In our patient, this approach, combined with optimization of comorbidities, resulted in significant clinical and hemodynamic improvement. This case emphasizes the need for individualized care in complex PVOD and the importance of ongoing research to define which patients benefit from PAH-directed therapy and clarify its long-term safety and efficacy. This abstract is funded by: None
proteins
2026-06-22 | Activin signaling inhibitor Sotatercept in pulmonary veno-occlusive disease: building a bridge to transplantation?
Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary arterial hypertension (PAH). Its prognosis is considerably worse and no medical treatment has a proven efficacy. Vasodilating drugs for PAH may contribute to a pulmonary edema in PVOD. Sotatercept is the latest approved medical treatment for PAH with a unique mode of action and promising treatment effects. However, none of the clinical trials of sotatercept have included patients with PVOD, so the effect of sotatercept is unknown. We report two cases of hereditary PVOD that were treated with sotatercept in addition to established pulmonary arterial hypertension therapy. Under treatment with sotatercept, both patients showed stabilization of clinical condition and gas exchange, accompanied by slight improvements in DLCOc and KCOc. These two cases suggest that sotatercept may have a beneficial effect on disease stabilization in hereditary PVOD, as reflected by improvements in DLCOc and KCOc as well as stabilization of clinical status. Therefore, it may be a therapeutic option to stabilize patients with PVOD and potentially prolong the bridging time to lung transplantation.
2023-11-16 | [Genetic diagnostics and molecular approaches in pulmonary arterial hypertension].
The recently published new European guidelines for diagnosis and treatment of pulmonary hypertension now offer the so far most extensive description of genetic testing and counselling for pulmonary arterial hypertension patients. In addition, the importance of a clinical screening of healthy mutation carriers is highlighted as well as the genetic testing of patients with a suspicion of pulmonary veno-occlusive disease. We frame the respective parts of the guidelines on genetic testing and counselling in the context of recent data and provide comments. Finally, we give an outlook on novel molecular approaches starting from Sotatercept, addressing ion channels and novel therapeutic developments. Die kürzlich erschienenen, neuen Leitlinien für pulmonale Hypertonie bieten den bisher ausführlichsten Einblick in die genetische Diagnostik und Beratung von PAH-Patient*innen. Aber auch der Stellenwert des klinischen Screenings von gesunden Anlageträger*innen wird hervorgehoben sowie der genetischen Testung bei Patient*innen mit dem Verdacht auf eine pulmonal veno-okklusive Erkrankung. Die jeweiligen Abschnitte der Leitlinien werden im Folgenden in die aktuelle Datenlage eingebettet und kommentiert. Abschließend geben wir einen Ausblick auf neue molekulare Ansätze von Sotatercept über Ionenkanäle bis hin zu neuen therapeutischen Ansatzpunkten.
2022-12-23 | Real-world use of defibrotide for veno-occlusive disease/sinusoidal obstruction syndrome: the DEFIFrance Registry Study
Abstract Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of haematopoietic cell transplantation (HCT) conditioning. The DEFIFrance post-marketing registry study evaluated effectiveness and safety in patients who received defibrotide. It collected retrospective/prospective patient data from 53 French HCT centres from July 2014 to March 2020. Primary endpoints were survival and complete response (CR; total serum bilirubin <2 mg/dL, multiorgan failure resolution) at Day 100 post-HCT among patients with severe/very severe VOD/SOS. A secondary endpoint was evaluation of treatment-emergent serious adverse events (TESAEs) of interest. Of 798 patients analysed, 251 and 81 received defibrotide treatment for severe/very severe VOD/SOS and mild/moderate VOD/SOS post-HCT, respectively; 381 received defibrotide for VOD/SOS prophylaxis. In patients with severe/very severe VOD/SOS post-HCT, Kaplan–Meier–estimated CR at Day 100 was 74% (95% confidence interval [CI]: 66%, 81%). At Day 100, 137/251 (55%) were alive and in CR. Kaplan–Meier–estimated Day 100 post-HCT survival was 61% (95% CI: 55%, 67%) in patients with severe/very severe VOD/SOS. TESAEs of interest occurred in 29% of these patients; VOD/SOS-related mortality at 12 months was 15%. DEFIFrance represents the largest collection of real-world data on post-registration defibrotide use, supporting the real-world utility of defibrotide for patients with severe/very severe VOD/SOS post-HCT.
2022-06-14 | A Systematic Review and Meta-Analysis of Studies of Defibrotide Prophylaxis for Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome.
Defibrotide is approved to treat severe veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) after haematopoietic cell transplantation in patients aged > 1 month in the European Union and for VOD/SOS with renal/pulmonary dysfunction post-haematopoietic cell transplantation in the United States. This meta-analysis estimated the incidence and risk of VOD/SOS after intravenous defibrotide prophylaxis using the published literature. PubMed, Embase and Web of Science were searched through 30 November 2021 for defibrotide studies in VOD/SOS "prevention" or "prophylaxis," excluding phase I studies, case reports, studies with fewer than ten patients and reviews. The search identified 733 records; 24 met inclusion criteria, of which 20 (N = 3005) evaluated intravenous defibrotide for VOD/SOS prophylaxis. Overall VOD/SOS incidence with intravenous defibrotide was 5%, with incidences of 5% in adults and 8% in paediatric patients. In eight studies with data on intravenous defibrotide prophylaxis vs controls (e.g. heparin, no prophylaxis), VOD/SOS incidence in controls was 16%. The risk ratio for developing VOD/SOS with defibrotide prophylaxis vs controls was 0.30 (95% confidence interval 0.12-0.71; p = 0.006). This analysis suggests a low incidence of VOD/SOS following intravenous defibrotide prophylaxis, regardless of age group, and a lower relative risk for VOD/SOS with defibrotide prophylaxis vs controls in patient populations at high risk of VOD/SOS.
2019-02-25 | Systematic review of defibrotide studies in the treatment of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS)
Veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT) conditioning or high-dose nontransplant chemotherapy. VOD/SOS with multi-organ dysfunction (MOD) is associated with a mortality rate of > 80%. Defibrotide (25 mg/kg/day) is approved to treat hepatic VOD/SOS with renal or pulmonary dysfunction post HSCT in the United States and to treat severe hepatic VOD/SOS in patients > 1 month of age in the European Union. A random effects model was used for pooling data from 17 systematically chosen defibrotide studies. For patients in these reports (n = 2598), and those in the subset of 10 reports of patients treated with ~ 25 mg/kg/day (n = 1691), estimated Day + 100 survival rates were 54% and 56%, respectively. Among those patients treated with ~ 25 mg/kg/day, estimated Day + 100 survival was 44% among patients with MOD and 71% in patients without MOD; survival was 41% and 70%, respectively, for the population of patients receiving any dose of defibrotide. Safety results were not pooled owing to differences in reporting methodology but were generally consistent with the known tolerability profile of defibrotide. This analysis provides the largest assessment of survival in patients treated with defibrotide for VOD/SOS with or without MOD.
cell therapies
2026-03-06 | Differential Diagnosis of Veno-Occlusive Pulmonary Hypertension is Challenge in Diagnosing the Child with Restricitive Cardiomyopathy
We present the report of disease in a child with severe restrictive cardiomyopathy (RCM) resulting in the development of veno-occlusive pulmonary arterial hypertension (PAH) and cardiopulmonary insufficiency with NYHA II-III. Due to borderline criteria for heart transplantation (HT), it was difficult to find justification for the procedure, although it was the only way to save the child’s life. The boy was monitored for hepatomegaly one year before admission. At the age of 11, significant dilatation in both atria, accompanied by a reduced cavity of both ventricles led to the recognition that the clinical symptoms were attributed to restrictive cardiomyopathy (RCM) with preserved left ventricular ejection fraction (LVpEF – LV with preserved EF). Because of the evidence suggesting that it is a secondary development of veno-occlusive PAH, before the HT decision it was required to clarify distinguish from reactive PH, in accordance with the latest 6WSPH criteria (6th World Symposium on pulmonary hypertension) [1]. Pulmonary hypertension is considered when the mean pulmonary artery pressure (mPA) is >20 mmHg, transcapillary gradient (PAWP) > 15 mmHg and pulmonary vascular resistance (PVR) ≥ 3 iWJ. Since the patient did not meet the criteria for passive (isolated) precapillary PAH (mPA>20 mmHg, PAWP >15 mmHg and PVR < 3iWJ) with preserved LVEF /IpcPH/LVpEF=Isolated precapillary PH with LVpEF/, but according to the same criteria, he had reactive, or combined veno-occlusive pulmonary hypertension (PVR ≥ 3iWJ) /CpcPH/LVpEF= Combined precapillary PH with LV preserved EF)/. Diagnosis indicated that it was a contraindication for HT. This position is valid only if the discussion about possible reversible changes in PAS (Pulmonary artery small – the former name of arteriole) are ignored. Aware of the fact that HT is risky, but also of the probability that changes caused by the Kitajew phenomenon are reversible [2] contrary to precapillary PH caused by CHD (Euler Ljiljestrand fenomen) [3], we decided to proceed with HT. We are predicting a difficult postoperative course but which can be overcome with adequate measures (strict supervision of the Frank-Starling law) [4] with mechanical and pharmacology support. Encouraged by reports from the literature indicating a significantly higher incidence of passive postcapillary than reactive pulmonary hypertension as well as rapid regression of pulmonary hypertension after elimination of the cause of PAS self perpetuation [5-7], we decided on HT as the only perspective for the survival of a severely ill child. Our arguments also included a discussion on the irreversibility of PAH before the development of Eisenman’s syndrome (ES) (“gray area”, 6-8 iWJ) [8,9]. HT decision despite the inconsistency of the criteria for defining pulmonary hypertension and the type of pulmonary vascular resistance according to the previous international criteria’s [10-13], including the 6WSPH criteria [1,8,14,15]. Our arguments were accepted by the EUROTRANSPLANT committee. A HT was successfully performed and boy was discharged home with good follow up more than > 10 years in good condition (NYHA I).
2025-09-12 | Management of Pulmonary Granulomatous Venulitis by Lung Transplantation.
Granulomatous venulitis is an exceedingly rare condition characterized by granulomatous inflammation and obliteration of small pulmonary veins, leading to the development of pulmonary venoocclusive disease. The prognosis is poor, with most patients surviving less than 1 year after diagnosis. We present the first case, to our knowledge, of successful management of this disease by lung transplantation.
2025-05-29 | Intravenous mesenchymal stem cell transplantation mitigates pulmonary vascular remodeling but poses dose related risks in a pulmonary veno-occlusive disease model.
Pulmonary veno-occlusive disease (PVOD) is a rare subtype of disease that causes pulmonary hypertension with vascular involvement of postcapillary structures of pulmonary vasculature. The disease has a poor prognosis with no effective therapy. The study aimed to determine whether adipose-derived mesenchymal stem cells (ASCs) alleviate pulmonary hypertension and right ventricular hypertrophy in a rat model of PVOD. Allogeneic ASCs were intravenously administered to a rat model of PVOD induced by mitomycin C. Then, muscularization in pulmonary microvessels, right ventricular systolic pressure (RVSP), and right ventricular hypertrophy were assessed using immunohistochemistry, right heart catheterization, heart weight, and hematoxylin-eosin (HE) staining. Body weight over time and survival rates were assessed. ASC transplantation substantially contributed to the reduction of pulmonary microvascular muscularization in the PVOD rat model but not to the decrease in RVSP. Furthermore, it led to the attenuation of right ventricular hypertrophy and a considerable decrease in wall thickness. However, repeated ASC administration increased the mortality rate in the PVOD rat models. To the best of our knowledge, this is the first study to analyze the effects of ASC transplantation in a rat model of PVOD. While intravenous ASC transplantation exerts beneficial effects on the lungs and right ventricle, adverse events may occur depending on the administration method. Therefore, intravenous ASC transplantation should be performed with caution.
2022-04-01 | Pulmonary Capillary Hemangiomatosis and Refractory Hypoxemia During PH Therapy
Pulmonary capillary hemangiomatosis (PCH), a rare cause of pulmonary hypertension (PH), presents clinically with right heart dysfunction and may be indistinguishable from typical pulmonary arterial hypertension. Vasodilator therapy exacerbates hypoxemia in PCH despite improvement in heart failure symptoms. Lung transplant is the only definitive therapy. We present the case of a patient succumbing to progressive hypoxemia on PH therapy during lung transplant evaluation. Autopsy revealed PCH. A 42-year-old female with PH due to undifferentiated connective tissue disease presented with acute respiratory distress. She was diagnosed 2 years prior and initially treated with macitentan, tadalafil and diuretics with clinical improvement; however, worsening shortness of breath and new finding of hypoxemia developed after 1 year. Imaging revealed faint patchy nodular opacities initially attributed to UCTD-associated pneumonitis. Steroids and mycophenolate failed to achieve radiographic improvement. Repeat right heart catheterization showed continued elevation in pulmonary artery pressure and stably reduced cardiac output. Subcutaneous infusion of Treprostinil was initiated 2 months prior to admission, which worsened hypoxemia. Clinical diagnosis of pulmonary veno-occlusive disease (PVOD) vs PCH was suspected and lung transplant evaluation initiated. On admission, patient presented with syncope and was found to have refractory hypoxemia despite high-flow oxygen supplementation. Cardiogenic shock and hypoxemic respiratory failure ensued, resulting in hepatic and renal failure, leading to cardiac arrest and unsuccessful resuscitation. Autopsy showed PCH. Refractory hypoxemia during up-titration of vasodilator therapy for PH should prompt clinical suspicion for atypical causes of PH such as PCH. Early lung transplant referral is essential if PCH/PVOD is suspected given its poor prognosis and potentially harmful responses associated with traditional PH therapy.
2019-02-01 | Pulmonary veno-occlusive disease is highly prevalent in scleroderma patients undergoing lung transplantation
There is an unexpectedly high incidence of PVOD in patients with SSc-PH-ILD. Presence of PVOD may be an unrecognised contributor to the dismal prognosis of these patients. Early transplant referral should be considered for those with SSc-PH-ILD. http://ow.ly/vPvc30neJZV.
antibodies
2026-06-16 | Interleukin-6 is critical in the development of pulmonary vascular disease in Gcn2-deficient mice.
Biallelic mutations in EIF2AK4, encoding Eukaryotic Translation Initiation Factor 2α kinase 4 or General Control Nonderepressible 2 (GCN2), cause pulmonary veno-occlusive disease (PVOD), a fatal form of pulmonary hypertension. The mechanisms linking GCN2 deficiency with pulmonary vascular pathology are poorly understood. To investigate this, we developed two mouse models: genetic ablation of Gcn2, to mirror GCN2-mutation positive PVOD, and a pharmacological model using mitomycin C, a drug which can cause PVOD as an idiosyncratic drug reaction. Both models were phenotyped, and lungs from wild-type and Gcn2-deficient mice were analyzed using single-cell RNA sequencing. We show that homozygous loss of Gcn2 is sufficient to induce mild pulmonary hypertension in mice. Single-cell transcriptomic profiling identified adventitial fibroblasts as the cell population exhibiting the most Gcn2-dependent transcriptional changes. Pathway analysis revealed upregulation of inflammatory signaling in Gcn2-/- adventitial fibroblasts. Consistent with this, we demonstrate a proinflammatory phenotype in Gcn2-/- mouse fibroblasts and in Gcn2-/- mice. Using a mitomycin C-induced murine model, genetic deletion of interleukin-6 (Il6) rescued the pulmonary vascular phenotype. Furthermore, chronic lipopolysaccharide exposure exaggerated pulmonary hypertension in Gcn2-/- mice, and Il6 ablation rescued both baseline and lipopolysaccharide-exacerbated disease. Pharmacological inhibition or genetic ablation of the Integrated Stress Response, which can be driven by GCN2-activation, phenocopies Gcn2 deficiency. Therefore, we establish a regulatory effect of an intact GCN2-Integrated Stress Response on IL-6 signaling. Together, we show that interleukin-6 is a critical mediator of both Gcn2 deficiency-associated and mitomycin C-triggered pulmonary vascular disease in mice and highlight IL-6-dependent pathways as potential therapeutic targets.
2025-04-19 | Interleukin-6 is critical in the development of gcn2- mutation associated pulmonary vascular disease in mice
Abstract Biallelic mutations in eukaryotic translation initiation factor 2 α kinase 4, EIF2AK4 (which encodes general control nonderepressible 2, GCN2) underpin heritable forms of pulmonary veno-occlusive disease (PVOD), a rare and fatal form of pulmonary hypertension. The mechanisms linking these are mostly uncharacterised. We demonstrate for the first time that homozygous loss of gcn2 is sufficient to cause mild pulmonary hypertension in mice. Single-cell transcriptomics of mouse lungs identified adventitial fibroblasts as having the greatest GCN2-dependent transcriptional differences, implicating them as key players in this model of PVOD. The most significantly upregulated pathways in gcn2 -/- adventitial fibroblasts were inflammatory. Therefore, we went on to demonstrate a pro-inflammatory phenotype in gcn2 -/- mouse embryonic fibroblasts and gcn2 -/- mice. In a novel murine model of pulmonary hypertension induced by exposure to mitomycin C, deletion of interleukin-6 rescued the pulmonary vascular phenotype. When chronically exposed to lipopolysaccharide, the pulmonary hypertensive phenotype of gcn2 -/- mice is exaggerated. Genetic ablation of interleukin-6 completely rescues both the baseline and LPS-exaggerated pulmonary hypertensive phenotype. Targeting Il6 -dependent pathways may be useful in treating this deadly disease.
2023-11-01 | S37 Mutations in GCN2 cause pulmonary vascular disease via dysfunctional inflammatory pathways
Mutations in eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4, or General Control Nonderepressible 2 [GCN2]) cause deadly forms of pulmonary hypertension such as pulmonary veno-occlusive disease (PVOD). GCN2 is a serine/threonine protein kinase, one of a family of 4 kinases that phosphorylate the α-subunit of the translation initiation factor eIF2, which activates a common adaptive pathway known as the Integrated Stress Response. We phenotyped the gcn2-/- mouse at baseline and created 2 independent mouse models of PVOD- the first using an inflammatory driver (lipopolysaccharide) on a background of genetic gcn2 loss, and the second using mitomycin-c (which has an idiosyncratic side-effect of causing PVOD in patients). GCN2 deficiency causes a mild pulmonary hypertensive phenotype, with a right ventricular systolic pressure (RVSP) of 28.1(±3.4)mmHg in gcn2-/- mice versus 24.7(±3.7)mmHg in the wild-type at baseline. Exposure to acute LPS creates a higher level of IL-6 and KC in gcn2-/- mice. Chronic administration of LPS exaggerates the RVSP response in gcn2-/- mice (32.6±4.3mmHg) but not in the wild-type. Genetic ablation of IL-6 ameliorated the development of pulmonary hypertension, with the gcn2-/-IL6-/- mouse having a mean RVSP of 20.4 (±0.6)mmHg despite chronic exposure to LPS. Administration of mitomycin-c raises the RVSP from 19.23(±4.3)mmHg to 26.6(±3.8)mmHg in wild-type mice but not in the IL6-/- mouse. Single-cell RNA sequencing of wild-type and gcn2-deficient mouse lungs has allowed us to identify the specific cell-types responsible for the inflammatory phenotype. Serum samples from patients with GCN2-mutation-positive PVOD confirm increased IL-6 levels compared to healthy volunteers. Proteomics studies have shown that there is a heightened inflammatory response in GCN2-mutation-positive PVOD compared to healthy volunteers and that aspects of this response may differ from other kinds of mutation-driven pulmonary vascular disease. Mutations in GCN2 cause a hyper-inflammatory phenotype and a baseline pulmonary hypertensive phenotype which is worsened by persistent inflammation. Genetic deletion of IL-6 ameliorates the pulmonary vascular disease in 2 independent mouse models of disease. We propose that IL-6 is a central pathway for the pathogenesis of heritable pulmonary veno-occlusive disease and anti-IL6 therapies may be clinically useful in treating PVOD patients.
other
2025-06-05 | Pulmonary veno-occlusive disease: a paradigm of diagnosis and therapeutic challenges in pulmonary hypertension.
Pulmonary veno-occlusive disease (PVOD) is a rare and life-threatening form of precapillary pulmonary hypertension. This review aims to outline its genetic and environmental risk factors, highlight key diagnostic challenges, and discuss current treatment options. PVOD can occur sporadically or as a hereditary autosomal recessive condition with biallelic eukaryotic translation initiation factor 2 alpha kinase 4 ( EIF2AK4) mutations, leading to nearly complete disease penetrance. Known risk factors include specific drug/toxin and environmental exposures, such as mitomycin C and trichloroethylene, respectively. PVOD is characterized by progressive pulmonary venous and capillary remodelling, severe hypoxemia, and right ventricular failure. Diagnosis remains difficult due to overlapping features with pulmonary arterial hypertension (PAH), but high-resolution computed tomography (HRCT) findings, low lung diffusion capacity for carbon monoxide (DLCO), and genetic testing can aid differentiation. Initiation of PAH-approved drugs in patients with PVOD requires careful consideration due to limited evidence of long-term clinical benefits and the high risk of developing pulmonary oedema in this population. Lung transplantation remains the only curative treatment, with posttransplant survival rates comparable to idiopathic PAH. PVOD is a progressive and fatal disease requiring early recognition and specific management. Due to its poor prognosis and lack of effective medical therapies, early referral for lung transplantation is crucial. Advances in genetic and molecular research may lead to novel treatment strategies.
small molecules
2026-06-22 | Survival Improvement With Steroid Use for Pulmonary Veno-Occlusive Disease With the Aid of Pulmonary Vasodilators and Tyrosine-Kinase Inhibitor, a Retrospective Study.
Steroids are effective in patients with heart failure, connective tissue disease, and interstitial lung disease, which are conditions often associated with Pulmonary veno-occlusive disease (PVOD). This study assessed the efficacy of steroid treatment combined with pulmonary vasodilators and tyrosine kinase inhibitors in patients with PVOD. This retrospective study aims to explore the effect of steroids on patient condition and survival, and the hypothesis that steroids may improve the survival of patients with PVOD was verified. The study involved two facilities in Tokyo with the same supervisors. Ten patients were diagnosed with PVOD from April 2006 to May 2018, divided into two categories: the patients not receiving (PNS, n = 5) and those receiving steroids (PRS, n = 5). The difference in survival between the two groups was evaluated with log-rank test. Based on the Kaplan-Meier curve, median survival length after symptom onset in pulmonary hypertension was 3.3 [1.3-4.3] years (outcome: all died) for PNS (n = 5) and 7.1 [5.2-11.0] years (outcome: three were alive, one had lung transplant, and one died) for PRS (n = 5). Although steroids did not necessarily improve patients' conditions, PRS had relatively stable conditions for a remarkably extended time compared to PNS. While the sample set is relatively small and this is a non-controlled retrospective study, the results indicate that a combination of steroids with pulmonary vasodilators and tyrosine-kinase inhibitors appears to be a promising treatment, especially for the purpose of extending patient survival until lung transplantation; however, this warrants further large-scale investigation.
2026-06-01 | B77-25 Pirfenidone Analogs Induce the Integrated Stress Response via Gcn2-eif2α-atf4 to Inhibit Fibroblast Proliferation
Abstract Introduction Pirfenidone exhibits pleiotropic antifibrotic and anti-inflammatory properties in experimental models and was the first ever antifibrotic medicine to reach patients in 2008. However, after more than 30 years of research, the drug’s mechanism of action (MOA) remains elusive because its poor potency precludes rigorous target identification. Until its MOA is understood, efforts to develop more effective drugs in this class will be difficult. Methods We establish structure-activity relationship assays (SAR) for the more potent pirfenidone analog GDC-3280 and its inactive analogs using quantitative live cell imaging and global proteomics. Based on robust SAR, we deploy a genome-wide CRISPR-knock-out screen in immortalized human foreskin fibroblasts. Results While GDC-3280 inhibits expression of several myofibroblast markers as previously reported, unbiased global proteomics reveal suppression of E2F targets, a G0/1 cell cycle arrest signature, and upregulation of ATF4 target genes. A CRISPR-KO screen identified EIF2AK4 (GCN2), a major stress-sensing kinase of the integrated stress response (ISR) pathway, as a key dependency for GDC-3280’s effect on fibroblast proliferation. Genetic deletion of GCN2 and co-treatment with an ISR inhibitor (ISRIB) alleviate the drug’s effect on fibroblast growth at concentrations near the clinically achievable range. Conclusion Our study suggests that Pirfenidone analog GDC-3280 may exert its therapeutic effect by inducing the integrated stress response through activation of GCN2, eIF2α and ATF4. Loss of EIF2AK4 (GCN2) leads to pulmonary veno-occlusive disease in humans, and, in animals, to worsening pulmonary fibrosis and pulmonary hypertension. GCN2 protein levels are reduced in the endothelium of diseased lungs with idiopathic pulmonary fibrosis and pulmonary hypertension, suggesting diseased lungs lack fully functional GCN2-mediated ISR activity. Therefore, restoration of the integrated stress response via activation of GCN2 may be of therapeutic benefit for fibrosing pulmonary disease. This abstract is funded by: Anonymous donation to the Section of Molecular Medicine, Department of Radiation Oncology at UT Southwestern Medical Center
2026-06-01 | P.135 Clinical and hemodynamic profile of patients with SSc-PAH with and without pulmonary veno-occlusive disease: a single-center study
Signs of pulmonary veno-occlusive disease (PVOD) may be found in patients with pulmonary arterial hypertension (PAH), particularly in systemic sclerosis (SSc)1. This association (PVOD/PAH) remains poorly characterized in SSc. We aimed to compare the clinical, echocardiographic and hemodynamic profile of patients with SSc-PAH with and without a concomitant diagnosis of PVOD, and their potential response to vasodilators. We retrospectively analyzed 23 patients with SSc-PAH diagnosed by right heart catheterization, followed at our center between 2017 and 2023. Data collected at diagnosis and after 12 months included clinical, laboratory, functional and imaging parameters. Multidisciplinary assessment allowed the identification of cases with clinical and radiological features suggestive of PVOD/PAH1. Patients were divided into two groups (PVOD/PAH and non-PVOD/PAH) and data were compared at baseline and 12-month follow-up. Twenty-three patients with SSc-PAH were enrolled in the study, of whom 6 (26%) had signs of PVOD/PAH. At PAH diagnosis, PVOD/PAH patients had higher values of mean pulmonary arterial pressure compared to non-PVOD/PAH (47.5±5.3 vs. 36.7±8.8 mmHg, p=0.011), but similar pulmonary vascular resistance. Age, sex, cardiovascular risk factors, SSc features, echo findings as well as cardiac biomarker values were similar between the two groups (table 1). At follow-up, most PVOD/PAH patients (67%) were on monotherapy with endothelin receptor antagonists (ERA), and 33% on dual therapy (ERA + phosphodiesterase inhibitors). Only one case of pulmonary edema was recorded. In the non-PVOD/PAH group, most patients (53%) were on dual vasodilator therapy. On echocardiography, PVOD/PAH patients showed higher tricuspid regurgitation velocity (4.10±0.68 vs. 3.07±0.91 m/s; p=0.035) and worse right ventricular function (FAC 25.6±8.4% vs. 33.9±6.8%; p=0.046). Changes in NT-proBNP levels from baseline differed between groups (p=0.012), showing a trend toward increase in PVOD/PAH (p=0.076) and reduction in non-PVOD/PAH (p=0.069). At 12 months, 5 hospitalizations for heart failure in each group, and a total of 5 deaths (2 PVOD/PAH and 3 non-PVOD/PAH) were recorded, with similar event-free survival (p=0.101). PVOD is frequently associated with PAH in SSc and does not seem to be associated with specific SSc features. Vasodilators, at least on monotherapy, should be considered in PVOD/PAH, as they seem to be well tolerated. Nevertheless, at follow-up these patients exhibit unfavorable laboratory and echo profiles compared to those with SSc-PAH alone, highlighting the importance of early referral for lung transplantation.
2026-05-01 | B64-34 Pulmonary Veno-Occlusive Disease Phenotype in Diffuse Large B-Cell Lymphoma: Malignancy Biology Versus Chemotherapeutic Vascular Injury
Abstract Introduction Pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) are uncommon World Health Organization (WHO) Group 1 pulmonary arterial hypertension (PAH) phenotypes, together representing approximately 10% of group 1 PAH cases. PVOD is characterized by venular obstruction, profound hypoxemia, and a disproportionately low diffusing capacity for carbon monoxide (DLCO) often progressing rapidly despite therapy. Etiology remains incompletely defined. Cyclophosphamide, hematopoietic stem cell transplant, and primary malignancy physiology have each been implicated. This case highlights a PVOD phenotype arising before bone marrow transplant, with partial symptom responsiveness to lymphoma-directed therapy, raising the question that malignancy pathology rather than chemotherapy was the driver for the disease. Case Presentation A 72-year-old man with diffuse large B-cell lymphoma achieved complete remission after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy. Approximately one year later, he developed gradually progressive shortness of breath. Pulmonary function testing (PFTs) demonstrated preserved spirometry and lung volumes but severe isolated reduction in DLCO. Computed Tomography chest showed enlarged pulmonary vessels, mosaic ground glass opacities and mediastinal Lymphadenopathy. Echocardiography showed preserved left ventricular systolic function but moderately elevated right ventricular systolic pressures (RVSP) at 57 mmHg. As exertional dyspnea worsened, a six-minute walk test confirmed chronic desaturation requiring supplemental oxygen. He underwent right sided heart catheterization that demonstrated precapillary pulmonary hypertension with an elevated transpulmonary gradient (TPG) and normal pulmonary capillary wedge pressure (PCWP): Mean pulmonary artery pressure (mPAP) 31 mmHg, PCWP 6, TPG 25, Pulmonary vascular resistance (PVR) 5.29 wood units. He received salvage chemotherapy and was started on dual pulmonary arterial hypertension therapy with tadalafil and macitentan with symptomatic benefit. He later underwent autologous stem cell transplant and ultimately discontinued home oxygen. Follow-up imaging, two-dimensional Echocardiography and pulmonary function testing showed improvement of his elevated pulmonary pressures. Discussion This case raises two distinct etiologic possibilities: (1) cyclophosphamide-mediated endothelial injury and (2) active malignancy-driven vascular remodeling. The transient improvement during lymphoma cytoreduction is a key clue supporting cancer-related illness. While PVOD is traditionally associated with transplant, this case demonstrates development prior to transplant, reinforcing the need to consider malignancy as a causative agent. Early identification of PVOD as a cause of exertional dyspnea and hypoxemia in patients with hematological malignancy is essential, as prompt initiation of PAH-targeted therapy can enhance functional status and quality of life. This abstract is funded by: None
2026-05-01 | B64-23 Unmasking Diagnostic and Treatment Challenges in a Complex Case of Pulmonary Veno-occlusive Disease
Abstract Introduction Pulmonary veno-occlusive disease (PVOD) is a rare and life-threatening cause of pulmonary arterial hypertension (PAH) with an estimated prevalence of 1 case per 1 million. Due to its rarity and diagnostic complexity, PVOD remains a challenging entity requiring a high index of suspicion and multidisciplinary evaluation. Early recognition is critical, as lung transplantation remains the only definitive treatment. This case illustrated the diagnostic and therapeutic challenges of PVOD in a patient with multifactorial pulmonary hypertension and underscores the importance of individualized management and timely diagnosis. Description A 67-year-old man with hypertension, diabetes, obesity class II, emphysema, and severe central/obstructive sleep apnea was sent to the emergency department from his pulmonology clinic for significant hypoxia (SpO2 86%) and worsening dyspnea. Chest X-ray showed mild interstitial edema. CTA ruled out pulmonary embolism but demonstrated diffuse centrilobular ground-glass opacities, interlobular septal thickening, and mediastinal lymphadenopathy, suggestive of PVOD. Echocardiogram showed a dilated right atrium and right ventricle with pulmonary artery systolic pressure (PASP) of 85 mmHg, prompting initiation of diuretics. Right heart catheterization (RHC) showed a mean pulmonary artery pressure (MPAP) of 38 mmHg and a pulmonary vascular resistance (PVR) of 9 wood units (WU). Extensive serologic workup was negative. Following BiPAP initiation for severe sleep apnea, repeat RHC after one month showed worsening MPAP (65 mmHg) and PVR (13.5 WU). He was started on low-dose tadalafil and ambrisentan, later uptitrated with close monitoring. Despite an episode of vasodilator-induced pulmonary edema requiring dose adjustment, he showed marked clinical and echocardiographic improvement, was weaned off supplemental oxygen, and deferred lung transplant evaluation due to significant recovery in function and quality of life. Discussion Pulmonary veno-occlusive disease (PVOD) is progressive with poor prognosis, making timely recognition and management critical. Response to PAH-directed therapy is highly variable; some patients achieve meaningful improvement, while others may develop pulmonary edema or remain refractory. Recent data illustrate that carefully titrated vasodilators, balanced with diuretics and close monitoring, can benefit select patients, though long-term effects are variable and remain poorly understood. In our patient, this approach, combined with optimization of comorbidities, resulted in significant clinical and hemodynamic improvement. This case emphasizes the need for individualized care in complex PVOD and the importance of ongoing research to define which patients benefit from PAH-directed therapy and clarify its long-term safety and efficacy. This abstract is funded by: None
proteins
2026-06-22 | Activin signaling inhibitor Sotatercept in pulmonary veno-occlusive disease: building a bridge to transplantation?
Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary arterial hypertension (PAH). Its prognosis is considerably worse and no medical treatment has a proven efficacy. Vasodilating drugs for PAH may contribute to a pulmonary edema in PVOD. Sotatercept is the latest approved medical treatment for PAH with a unique mode of action and promising treatment effects. However, none of the clinical trials of sotatercept have included patients with PVOD, so the effect of sotatercept is unknown. We report two cases of hereditary PVOD that were treated with sotatercept in addition to established pulmonary arterial hypertension therapy. Under treatment with sotatercept, both patients showed stabilization of clinical condition and gas exchange, accompanied by slight improvements in DLCOc and KCOc. These two cases suggest that sotatercept may have a beneficial effect on disease stabilization in hereditary PVOD, as reflected by improvements in DLCOc and KCOc as well as stabilization of clinical status. Therefore, it may be a therapeutic option to stabilize patients with PVOD and potentially prolong the bridging time to lung transplantation.
2023-11-16 | [Genetic diagnostics and molecular approaches in pulmonary arterial hypertension].
The recently published new European guidelines for diagnosis and treatment of pulmonary hypertension now offer the so far most extensive description of genetic testing and counselling for pulmonary arterial hypertension patients. In addition, the importance of a clinical screening of healthy mutation carriers is highlighted as well as the genetic testing of patients with a suspicion of pulmonary veno-occlusive disease. We frame the respective parts of the guidelines on genetic testing and counselling in the context of recent data and provide comments. Finally, we give an outlook on novel molecular approaches starting from Sotatercept, addressing ion channels and novel therapeutic developments. Die kürzlich erschienenen, neuen Leitlinien für pulmonale Hypertonie bieten den bisher ausführlichsten Einblick in die genetische Diagnostik und Beratung von PAH-Patient*innen. Aber auch der Stellenwert des klinischen Screenings von gesunden Anlageträger*innen wird hervorgehoben sowie der genetischen Testung bei Patient*innen mit dem Verdacht auf eine pulmonal veno-okklusive Erkrankung. Die jeweiligen Abschnitte der Leitlinien werden im Folgenden in die aktuelle Datenlage eingebettet und kommentiert. Abschließend geben wir einen Ausblick auf neue molekulare Ansätze von Sotatercept über Ionenkanäle bis hin zu neuen therapeutischen Ansatzpunkten.
2022-12-23 | Real-world use of defibrotide for veno-occlusive disease/sinusoidal obstruction syndrome: the DEFIFrance Registry Study
Abstract Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of haematopoietic cell transplantation (HCT) conditioning. The DEFIFrance post-marketing registry study evaluated effectiveness and safety in patients who received defibrotide. It collected retrospective/prospective patient data from 53 French HCT centres from July 2014 to March 2020. Primary endpoints were survival and complete response (CR; total serum bilirubin <2 mg/dL, multiorgan failure resolution) at Day 100 post-HCT among patients with severe/very severe VOD/SOS. A secondary endpoint was evaluation of treatment-emergent serious adverse events (TESAEs) of interest. Of 798 patients analysed, 251 and 81 received defibrotide treatment for severe/very severe VOD/SOS and mild/moderate VOD/SOS post-HCT, respectively; 381 received defibrotide for VOD/SOS prophylaxis. In patients with severe/very severe VOD/SOS post-HCT, Kaplan–Meier–estimated CR at Day 100 was 74% (95% confidence interval [CI]: 66%, 81%). At Day 100, 137/251 (55%) were alive and in CR. Kaplan–Meier–estimated Day 100 post-HCT survival was 61% (95% CI: 55%, 67%) in patients with severe/very severe VOD/SOS. TESAEs of interest occurred in 29% of these patients; VOD/SOS-related mortality at 12 months was 15%. DEFIFrance represents the largest collection of real-world data on post-registration defibrotide use, supporting the real-world utility of defibrotide for patients with severe/very severe VOD/SOS post-HCT.
2022-06-14 | A Systematic Review and Meta-Analysis of Studies of Defibrotide Prophylaxis for Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome.
Defibrotide is approved to treat severe veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) after haematopoietic cell transplantation in patients aged > 1 month in the European Union and for VOD/SOS with renal/pulmonary dysfunction post-haematopoietic cell transplantation in the United States. This meta-analysis estimated the incidence and risk of VOD/SOS after intravenous defibrotide prophylaxis using the published literature. PubMed, Embase and Web of Science were searched through 30 November 2021 for defibrotide studies in VOD/SOS "prevention" or "prophylaxis," excluding phase I studies, case reports, studies with fewer than ten patients and reviews. The search identified 733 records; 24 met inclusion criteria, of which 20 (N = 3005) evaluated intravenous defibrotide for VOD/SOS prophylaxis. Overall VOD/SOS incidence with intravenous defibrotide was 5%, with incidences of 5% in adults and 8% in paediatric patients. In eight studies with data on intravenous defibrotide prophylaxis vs controls (e.g. heparin, no prophylaxis), VOD/SOS incidence in controls was 16%. The risk ratio for developing VOD/SOS with defibrotide prophylaxis vs controls was 0.30 (95% confidence interval 0.12-0.71; p = 0.006). This analysis suggests a low incidence of VOD/SOS following intravenous defibrotide prophylaxis, regardless of age group, and a lower relative risk for VOD/SOS with defibrotide prophylaxis vs controls in patient populations at high risk of VOD/SOS.
2019-02-25 | Systematic review of defibrotide studies in the treatment of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS)
Veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT) conditioning or high-dose nontransplant chemotherapy. VOD/SOS with multi-organ dysfunction (MOD) is associated with a mortality rate of > 80%. Defibrotide (25 mg/kg/day) is approved to treat hepatic VOD/SOS with renal or pulmonary dysfunction post HSCT in the United States and to treat severe hepatic VOD/SOS in patients > 1 month of age in the European Union. A random effects model was used for pooling data from 17 systematically chosen defibrotide studies. For patients in these reports (n = 2598), and those in the subset of 10 reports of patients treated with ~ 25 mg/kg/day (n = 1691), estimated Day + 100 survival rates were 54% and 56%, respectively. Among those patients treated with ~ 25 mg/kg/day, estimated Day + 100 survival was 44% among patients with MOD and 71% in patients without MOD; survival was 41% and 70%, respectively, for the population of patients receiving any dose of defibrotide. Safety results were not pooled owing to differences in reporting methodology but were generally consistent with the known tolerability profile of defibrotide. This analysis provides the largest assessment of survival in patients treated with defibrotide for VOD/SOS with or without MOD.
cell therapies
2026-03-06 | Differential Diagnosis of Veno-Occlusive Pulmonary Hypertension is Challenge in Diagnosing the Child with Restricitive Cardiomyopathy
We present the report of disease in a child with severe restrictive cardiomyopathy (RCM) resulting in the development of veno-occlusive pulmonary arterial hypertension (PAH) and cardiopulmonary insufficiency with NYHA II-III. Due to borderline criteria for heart transplantation (HT), it was difficult to find justification for the procedure, although it was the only way to save the child’s life. The boy was monitored for hepatomegaly one year before admission. At the age of 11, significant dilatation in both atria, accompanied by a reduced cavity of both ventricles led to the recognition that the clinical symptoms were attributed to restrictive cardiomyopathy (RCM) with preserved left ventricular ejection fraction (LVpEF – LV with preserved EF). Because of the evidence suggesting that it is a secondary development of veno-occlusive PAH, before the HT decision it was required to clarify distinguish from reactive PH, in accordance with the latest 6WSPH criteria (6th World Symposium on pulmonary hypertension) [1]. Pulmonary hypertension is considered when the mean pulmonary artery pressure (mPA) is >20 mmHg, transcapillary gradient (PAWP) > 15 mmHg and pulmonary vascular resistance (PVR) ≥ 3 iWJ. Since the patient did not meet the criteria for passive (isolated) precapillary PAH (mPA>20 mmHg, PAWP >15 mmHg and PVR < 3iWJ) with preserved LVEF /IpcPH/LVpEF=Isolated precapillary PH with LVpEF/, but according to the same criteria, he had reactive, or combined veno-occlusive pulmonary hypertension (PVR ≥ 3iWJ) /CpcPH/LVpEF= Combined precapillary PH with LV preserved EF)/. Diagnosis indicated that it was a contraindication for HT. This position is valid only if the discussion about possible reversible changes in PAS (Pulmonary artery small – the former name of arteriole) are ignored. Aware of the fact that HT is risky, but also of the probability that changes caused by the Kitajew phenomenon are reversible [2] contrary to precapillary PH caused by CHD (Euler Ljiljestrand fenomen) [3], we decided to proceed with HT. We are predicting a difficult postoperative course but which can be overcome with adequate measures (strict supervision of the Frank-Starling law) [4] with mechanical and pharmacology support. Encouraged by reports from the literature indicating a significantly higher incidence of passive postcapillary than reactive pulmonary hypertension as well as rapid regression of pulmonary hypertension after elimination of the cause of PAS self perpetuation [5-7], we decided on HT as the only perspective for the survival of a severely ill child. Our arguments also included a discussion on the irreversibility of PAH before the development of Eisenman’s syndrome (ES) (“gray area”, 6-8 iWJ) [8,9]. HT decision despite the inconsistency of the criteria for defining pulmonary hypertension and the type of pulmonary vascular resistance according to the previous international criteria’s [10-13], including the 6WSPH criteria [1,8,14,15]. Our arguments were accepted by the EUROTRANSPLANT committee. A HT was successfully performed and boy was discharged home with good follow up more than > 10 years in good condition (NYHA I).
2025-09-12 | Management of Pulmonary Granulomatous Venulitis by Lung Transplantation.
Granulomatous venulitis is an exceedingly rare condition characterized by granulomatous inflammation and obliteration of small pulmonary veins, leading to the development of pulmonary venoocclusive disease. The prognosis is poor, with most patients surviving less than 1 year after diagnosis. We present the first case, to our knowledge, of successful management of this disease by lung transplantation.
2025-05-29 | Intravenous mesenchymal stem cell transplantation mitigates pulmonary vascular remodeling but poses dose related risks in a pulmonary veno-occlusive disease model.
Pulmonary veno-occlusive disease (PVOD) is a rare subtype of disease that causes pulmonary hypertension with vascular involvement of postcapillary structures of pulmonary vasculature. The disease has a poor prognosis with no effective therapy. The study aimed to determine whether adipose-derived mesenchymal stem cells (ASCs) alleviate pulmonary hypertension and right ventricular hypertrophy in a rat model of PVOD. Allogeneic ASCs were intravenously administered to a rat model of PVOD induced by mitomycin C. Then, muscularization in pulmonary microvessels, right ventricular systolic pressure (RVSP), and right ventricular hypertrophy were assessed using immunohistochemistry, right heart catheterization, heart weight, and hematoxylin-eosin (HE) staining. Body weight over time and survival rates were assessed. ASC transplantation substantially contributed to the reduction of pulmonary microvascular muscularization in the PVOD rat model but not to the decrease in RVSP. Furthermore, it led to the attenuation of right ventricular hypertrophy and a considerable decrease in wall thickness. However, repeated ASC administration increased the mortality rate in the PVOD rat models. To the best of our knowledge, this is the first study to analyze the effects of ASC transplantation in a rat model of PVOD. While intravenous ASC transplantation exerts beneficial effects on the lungs and right ventricle, adverse events may occur depending on the administration method. Therefore, intravenous ASC transplantation should be performed with caution.
2022-04-01 | Pulmonary Capillary Hemangiomatosis and Refractory Hypoxemia During PH Therapy
Pulmonary capillary hemangiomatosis (PCH), a rare cause of pulmonary hypertension (PH), presents clinically with right heart dysfunction and may be indistinguishable from typical pulmonary arterial hypertension. Vasodilator therapy exacerbates hypoxemia in PCH despite improvement in heart failure symptoms. Lung transplant is the only definitive therapy. We present the case of a patient succumbing to progressive hypoxemia on PH therapy during lung transplant evaluation. Autopsy revealed PCH. A 42-year-old female with PH due to undifferentiated connective tissue disease presented with acute respiratory distress. She was diagnosed 2 years prior and initially treated with macitentan, tadalafil and diuretics with clinical improvement; however, worsening shortness of breath and new finding of hypoxemia developed after 1 year. Imaging revealed faint patchy nodular opacities initially attributed to UCTD-associated pneumonitis. Steroids and mycophenolate failed to achieve radiographic improvement. Repeat right heart catheterization showed continued elevation in pulmonary artery pressure and stably reduced cardiac output. Subcutaneous infusion of Treprostinil was initiated 2 months prior to admission, which worsened hypoxemia. Clinical diagnosis of pulmonary veno-occlusive disease (PVOD) vs PCH was suspected and lung transplant evaluation initiated. On admission, patient presented with syncope and was found to have refractory hypoxemia despite high-flow oxygen supplementation. Cardiogenic shock and hypoxemic respiratory failure ensued, resulting in hepatic and renal failure, leading to cardiac arrest and unsuccessful resuscitation. Autopsy showed PCH. Refractory hypoxemia during up-titration of vasodilator therapy for PH should prompt clinical suspicion for atypical causes of PH such as PCH. Early lung transplant referral is essential if PCH/PVOD is suspected given its poor prognosis and potentially harmful responses associated with traditional PH therapy.
2019-02-01 | Pulmonary veno-occlusive disease is highly prevalent in scleroderma patients undergoing lung transplantation
There is an unexpectedly high incidence of PVOD in patients with SSc-PH-ILD. Presence of PVOD may be an unrecognised contributor to the dismal prognosis of these patients. Early transplant referral should be considered for those with SSc-PH-ILD. http://ow.ly/vPvc30neJZV.
antibodies
2026-06-16 | Interleukin-6 is critical in the development of pulmonary vascular disease in Gcn2-deficient mice.
Biallelic mutations in EIF2AK4, encoding Eukaryotic Translation Initiation Factor 2α kinase 4 or General Control Nonderepressible 2 (GCN2), cause pulmonary veno-occlusive disease (PVOD), a fatal form of pulmonary hypertension. The mechanisms linking GCN2 deficiency with pulmonary vascular pathology are poorly understood. To investigate this, we developed two mouse models: genetic ablation of Gcn2, to mirror GCN2-mutation positive PVOD, and a pharmacological model using mitomycin C, a drug which can cause PVOD as an idiosyncratic drug reaction. Both models were phenotyped, and lungs from wild-type and Gcn2-deficient mice were analyzed using single-cell RNA sequencing. We show that homozygous loss of Gcn2 is sufficient to induce mild pulmonary hypertension in mice. Single-cell transcriptomic profiling identified adventitial fibroblasts as the cell population exhibiting the most Gcn2-dependent transcriptional changes. Pathway analysis revealed upregulation of inflammatory signaling in Gcn2-/- adventitial fibroblasts. Consistent with this, we demonstrate a proinflammatory phenotype in Gcn2-/- mouse fibroblasts and in Gcn2-/- mice. Using a mitomycin C-induced murine model, genetic deletion of interleukin-6 (Il6) rescued the pulmonary vascular phenotype. Furthermore, chronic lipopolysaccharide exposure exaggerated pulmonary hypertension in Gcn2-/- mice, and Il6 ablation rescued both baseline and lipopolysaccharide-exacerbated disease. Pharmacological inhibition or genetic ablation of the Integrated Stress Response, which can be driven by GCN2-activation, phenocopies Gcn2 deficiency. Therefore, we establish a regulatory effect of an intact GCN2-Integrated Stress Response on IL-6 signaling. Together, we show that interleukin-6 is a critical mediator of both Gcn2 deficiency-associated and mitomycin C-triggered pulmonary vascular disease in mice and highlight IL-6-dependent pathways as potential therapeutic targets.
2025-04-19 | Interleukin-6 is critical in the development of gcn2- mutation associated pulmonary vascular disease in mice
Abstract Biallelic mutations in eukaryotic translation initiation factor 2 α kinase 4, EIF2AK4 (which encodes general control nonderepressible 2, GCN2) underpin heritable forms of pulmonary veno-occlusive disease (PVOD), a rare and fatal form of pulmonary hypertension. The mechanisms linking these are mostly uncharacterised. We demonstrate for the first time that homozygous loss of gcn2 is sufficient to cause mild pulmonary hypertension in mice. Single-cell transcriptomics of mouse lungs identified adventitial fibroblasts as having the greatest GCN2-dependent transcriptional differences, implicating them as key players in this model of PVOD. The most significantly upregulated pathways in gcn2 -/- adventitial fibroblasts were inflammatory. Therefore, we went on to demonstrate a pro-inflammatory phenotype in gcn2 -/- mouse embryonic fibroblasts and gcn2 -/- mice. In a novel murine model of pulmonary hypertension induced by exposure to mitomycin C, deletion of interleukin-6 rescued the pulmonary vascular phenotype. When chronically exposed to lipopolysaccharide, the pulmonary hypertensive phenotype of gcn2 -/- mice is exaggerated. Genetic ablation of interleukin-6 completely rescues both the baseline and LPS-exaggerated pulmonary hypertensive phenotype. Targeting Il6 -dependent pathways may be useful in treating this deadly disease.
2023-11-01 | S37 Mutations in GCN2 cause pulmonary vascular disease via dysfunctional inflammatory pathways
Mutations in eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4, or General Control Nonderepressible 2 [GCN2]) cause deadly forms of pulmonary hypertension such as pulmonary veno-occlusive disease (PVOD). GCN2 is a serine/threonine protein kinase, one of a family of 4 kinases that phosphorylate the α-subunit of the translation initiation factor eIF2, which activates a common adaptive pathway known as the Integrated Stress Response. We phenotyped the gcn2-/- mouse at baseline and created 2 independent mouse models of PVOD- the first using an inflammatory driver (lipopolysaccharide) on a background of genetic gcn2 loss, and the second using mitomycin-c (which has an idiosyncratic side-effect of causing PVOD in patients). GCN2 deficiency causes a mild pulmonary hypertensive phenotype, with a right ventricular systolic pressure (RVSP) of 28.1(±3.4)mmHg in gcn2-/- mice versus 24.7(±3.7)mmHg in the wild-type at baseline. Exposure to acute LPS creates a higher level of IL-6 and KC in gcn2-/- mice. Chronic administration of LPS exaggerates the RVSP response in gcn2-/- mice (32.6±4.3mmHg) but not in the wild-type. Genetic ablation of IL-6 ameliorated the development of pulmonary hypertension, with the gcn2-/-IL6-/- mouse having a mean RVSP of 20.4 (±0.6)mmHg despite chronic exposure to LPS. Administration of mitomycin-c raises the RVSP from 19.23(±4.3)mmHg to 26.6(±3.8)mmHg in wild-type mice but not in the IL6-/- mouse. Single-cell RNA sequencing of wild-type and gcn2-deficient mouse lungs has allowed us to identify the specific cell-types responsible for the inflammatory phenotype. Serum samples from patients with GCN2-mutation-positive PVOD confirm increased IL-6 levels compared to healthy volunteers. Proteomics studies have shown that there is a heightened inflammatory response in GCN2-mutation-positive PVOD compared to healthy volunteers and that aspects of this response may differ from other kinds of mutation-driven pulmonary vascular disease. Mutations in GCN2 cause a hyper-inflammatory phenotype and a baseline pulmonary hypertensive phenotype which is worsened by persistent inflammation. Genetic deletion of IL-6 ameliorates the pulmonary vascular disease in 2 independent mouse models of disease. We propose that IL-6 is a central pathway for the pathogenesis of heritable pulmonary veno-occlusive disease and anti-IL6 therapies may be clinically useful in treating PVOD patients.
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2025-06-05 | Pulmonary veno-occlusive disease: a paradigm of diagnosis and therapeutic challenges in pulmonary hypertension.
Pulmonary veno-occlusive disease (PVOD) is a rare and life-threatening form of precapillary pulmonary hypertension. This review aims to outline its genetic and environmental risk factors, highlight key diagnostic challenges, and discuss current treatment options. PVOD can occur sporadically or as a hereditary autosomal recessive condition with biallelic eukaryotic translation initiation factor 2 alpha kinase 4 ( EIF2AK4) mutations, leading to nearly complete disease penetrance. Known risk factors include specific drug/toxin and environmental exposures, such as mitomycin C and trichloroethylene, respectively. PVOD is characterized by progressive pulmonary venous and capillary remodelling, severe hypoxemia, and right ventricular failure. Diagnosis remains difficult due to overlapping features with pulmonary arterial hypertension (PAH), but high-resolution computed tomography (HRCT) findings, low lung diffusion capacity for carbon monoxide (DLCO), and genetic testing can aid differentiation. Initiation of PAH-approved drugs in patients with PVOD requires careful consideration due to limited evidence of long-term clinical benefits and the high risk of developing pulmonary oedema in this population. Lung transplantation remains the only curative treatment, with posttransplant survival rates comparable to idiopathic PAH. PVOD is a progressive and fatal disease requiring early recognition and specific management. Due to its poor prognosis and lack of effective medical therapies, early referral for lung transplantation is crucial. Advances in genetic and molecular research may lead to novel treatment strategies.
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