Pulmonary Veno-Occlusive Disease and/or Pulmonary Capillary Haemangiomatosis

1. Disease Information

1.1 Concise overview

PVOD is an ultra‑rare pulmonary microvascular vasculopathy characterized by fibrotic obstruction/obliteration of small pulmonary veins and venules, producing pre‑capillary pulmonary hypertension, severe gas‑exchange impairment, and progressive right‑heart failure. PCH (pulmonary capillary haemangiomatosis) is characterized by prominent pulmonary capillary congestion/proliferation and is widely regarded as part of the same clinicopathologic spectrum as PVOD; the entities often coexist and are frequently grouped as PVOD/PCH. (lechartier2024pulmonaryvenoocclusivedisease pages 3-5, deshwal2025pulmonaryvenoocclusivedisease pages 2-3)

A recent authoritative ERS review explicitly frames PVOD as “pulmonary arterial hypertension (PAH) with overt features of venous/capillary involvement” and stresses that distinguishing PVOD from idiopathic PAH is critical because of poor response and risk of life‑threatening pulmonary edema with PAH vasodilators. (lechartier2024pulmonaryvenoocclusivedisease pages 1-2, lechartier2024pulmonaryvenoocclusivedisease pages 3-5)

Direct abstract quotes (for definition/importance): - Lechartier et al. (Jan 2024) state PVOD is “a rare cause of PAH characterised by substantial small pulmonary vein and capillary involvement, leading to increased pulmonary vascular resistance and right ventricular failure.” (Published 2024‑01; https://doi.org/10.1183/16000617.0156-2023) (lechartier2024pulmonaryvenoocclusivedisease pages 1-2) - Deshwal et al. (Jan 2025) describe PVOD as “a progressive and fatal spectrum of pulmonary vascular disorders” and note PVOD and PCH “can be clinically indistinguishable and often coexist… referred to together as PVOD/PCH.” (Published 2025‑01; https://doi.org/10.1183/20734735.0098-2024) (deshwal2025pulmonaryvenoocclusivedisease pages 1-2)

1.2 Key identifiers (availability)

Not available in the retrieved full‑text evidence for this run: - MONDO ID: not retrieved - OMIM / Orphanet / ICD‑10 / ICD‑11 / MeSH IDs: not retrieved

1.3 Common synonyms / alternative names (from literature)

• “PAH with features of venous/capillary involvement” (classification term used in ESC/ERS context) (lechartier2024pulmonaryvenoocclusivedisease pages 1-2, lechartier2024pulmonaryvenoocclusivedisease pages 5-6)
• “PVOD/PCH” (combined term used in multiple reviews) (deshwal2025pulmonaryvenoocclusivedisease pages 1-2, deshwal2025pulmonaryvenoocclusivedisease pages 2-3)

1.4 Evidence source type

• Aggregated disease‑level resources: ERS/European Respiratory Review and Breathe clinical reviews (lechartier2024pulmonaryvenoocclusivedisease pages 1-2, deshwal2025pulmonaryvenoocclusivedisease pages 1-2)
• Individual patient evidence: genetic case report with compound heterozygous EIF2AK4 variants (park2023differentialdiagnosisof pages 2-3)
• Experimental/model organism evidence: rat and mouse mechanistic models (mitomycin C; amino‑acid deprivation) including RNA‑seq/scRNA‑seq (bignard2023tcelldysregulationand pages 1-5, prabhakar2024mechanismsunderlyingageassociated pages 2-4)

2. Etiology

2.1 Disease causal factors

Genetic (causal): EIF2AK4 (GCN2) biallelic pathogenic variants cause heritable PVOD/PCH. (lechartier2024pulmonaryvenoocclusivedisease pages 2-3, emanuelli2024functionalvalidationof pages 3-5)

Direct abstract quote (genetic causality): - Emanuelli et al. (Apr 2024) state: “Biallelic mutations of EIF2AK4… are causal in… pulmonary veno-occlusive disease and pulmonary capillary haemangiomatosis.” (Published 2024‑04; https://doi.org/10.17863/cam.108223) (emanuelli2024functionalvalidationof pages 1-3)

Environmental/iatrogenic: Epidemiologic associations include occupational exposure to organic solvents (notably trichloroethylene) and chemotherapy (notably mitomycin C and other alkylating agents). (lechartier2024pulmonaryvenoocclusivedisease pages 2-3)

2.2 Risk factors (with quantitative data)

• Occupational organic solvents / trichloroethylene: Lechartier et al. report strong association; trichloroethylene exposure occurred in 42% of PVOD vs 3% of PAH with adjusted OR 8.2, and organic solvents overall had adjusted OR 12.8. (lechartier2024pulmonaryvenoocclusivedisease pages 2-3)
• Chemotherapy (alkylating agents): Mitomycin C (MMC), cyclophosphamide, cisplatin are repeatedly associated; MMC has experimental support for endothelial toxicity and PVOD induction in rats. (lechartier2024pulmonaryvenoocclusivedisease pages 2-3)
• Tobacco: Tobacco co‑exposure is common and may be additive with solvent exposure, with permeability effects. (lechartier2024pulmonaryvenoocclusivedisease pages 2-3)

2.3 Protective factors

No protective genetic or environmental factors were identified in the retrieved evidence.

2.4 Gene–environment interactions

The 2024 ERS review links solvent exposure (trichloroethylene), tobacco, and chemotherapy to endothelial permeability/barrier injury, and separately identifies EIF2AK4 (GCN2) as a stress‑response kinase—supporting a convergent model in which genetically reduced stress‑response capacity and/or environmentally induced endothelial injury contribute to PVOD/PCH pathogenesis. (lechartier2024pulmonaryvenoocclusivedisease pages 2-3)

3. Phenotypes

3.1 Core clinical phenotypes (with suggested HPO terms)

PVOD/PCH cannot be reliably distinguished from idiopathic PAH on symptoms or routine hemodynamics alone; diagnostic suspicion rests on gas‑exchange impairment and imaging patterns. (deshwal2025pulmonaryvenoocclusivedisease pages 1-2, lechartier2024pulmonaryvenoocclusivedisease pages 3-5)

Symptoms/signs - Progressive exertional dyspnea → Dyspnea (HP:0002094) (lechartier2024pulmonaryvenoocclusivedisease pages 2-3) - Hypoxemia (often disproportionate) → Hypoxemia (HP:0012418); severe resting hypoxemia highlighted as a red flag (foster2025pulmonaryvenoocclusivedisease pages 4-6) - Right‑heart failure manifestations (peripheral edema, hepatomegaly, ascites) → Peripheral edema (HP:0000969); Hepatomegaly (HP:0002240); Ascites (HP:0001541) (foster2025pulmonaryvenoocclusivedisease pages 4-6)

Pulmonary function / lab abnormalities - Markedly reduced diffusion capacity → Decreased DLCO (HP:0045051) (threshold examples below) (deshwal2025pulmonaryvenoocclusivedisease pages 8-9)

Radiology/pathology manifestations - HRCT: centrilobular ground‑glass opacities → Ground-glass opacity on pulmonary imaging (HP:0031969) - Smooth interlobular septal thickening → Interlobular septal thickening (HP:0031944) - Mediastinal lymphadenopathy → Mediastinal lymphadenopathy (HP:0030111) (lechartier2024pulmonaryvenoocclusivedisease pages 3-5, deshwal2025pulmonaryvenoocclusivedisease pages 8-9)

3.2 Phenotype characteristics (age, severity, progression)

• Age of onset: heritable EIF2AK4‑associated cases present younger (median 26 vs 60 years in one series) (lechartier2024pulmonaryvenoocclusivedisease pages 2-3)
• Course: rapid progression with poor prognosis; median survival often cited as 2–3 years after diagnosis (prabhakar2024mechanismsunderlyingageassociated pages 1-2)

3.3 Frequencies / quantitative thresholds reported

• Suggested clinical criteria in one review include PaO2 <70 mmHg and DLCO <55% predicted along with ≥2 HRCT features. (deshwal2025pulmonaryvenoocclusivedisease pages 8-9)
• Another review notes DLCO often “below 40% predicted” and mean ≈35% in studies. (foster2025pulmonaryvenoocclusivedisease pages 4-6)

3.4 Quality-of-life impact

No disease‑specific QoL instrument results (e.g., SF‑36/EQ‑5D) were identified in the retrieved evidence; functional limitation is implied by severe dyspnea, hypoxemia, and CPET impairment. (deshwal2025pulmonaryvenoocclusivedisease pages 7-8)

4. Genetic / Molecular Information

4.1 Causal genes

• EIF2AK4 (GCN2): biallelic pathogenic variants are causal for PVOD/PCH and can establish diagnosis without histology. (emanuelli2024functionalvalidationof pages 3-5, emanuelli2024functionalvalidationof pages 1-3)

4.2 Pathogenic variant examples (HGVS where available)

Case‑level PVOD/PCH genetic diagnosis (whole‑exome sequencing): - Park et al. 2023 reported compound heterozygous EIF2AK4 variants: NM_001013703.3:c.2137_2138dup (p.Ser714Leufs*78) and c.3358-1G>A, both described as absent from gnomAD; parental segregation supported biallelic inheritance. (Published 2023‑02; https://doi.org/10.1159/000527524) (park2023differentialdiagnosisof pages 2-3)

Variant spectrum and functional interpretation (2024): Emanuelli et al. 2024 list pathogenic/likely pathogenic EIF2AK4 missense examples (protein notation) including p.R585Q, p.G599R, p.V607G, p.L643R, p.S909R, p.G1109R, p.P1115L, p.H1202L, p.L1295R and also note that some alleles represent common polymorphisms (e.g., I441L, E556G, G1306C), highlighting the need for functional validation of VUS. (emanuelli2024functionalvalidationof pages 1-3)

Direct quote (diagnostic impact of biallelic EIF2AK4): - Emanuelli et al. 2024: “Detection of biallelic pathogenic EIF2AK4 mutations establishes the diagnosis of PVOD or PCH without the need for histological confirmation.” (emanuelli2024functionalvalidationof pages 3-5)

4.3 Inheritance

Autosomal recessive/biallelic inheritance is supported by: - Parent‑of‑origin segregation consistent with compound heterozygosity (Park 2023) (park2023differentialdiagnosisof pages 2-3) - Statement that PVOD due to EIF2AK4 is a “recessive form of pulmonary hypertension” (park2023differentialdiagnosisof pages 4-4)

4.4 Modifier genes / epigenetics / chromosomal abnormalities

Not identified in the retrieved evidence.

5. Environmental Information

5.1 Environmental factors

• Organic solvents, especially trichloroethylene (occupational exposure) (lechartier2024pulmonaryvenoocclusivedisease pages 2-3)

5.2 Lifestyle factors

• Tobacco exposure is commonly reported and may act cumulatively with solvent exposure, potentially via permeability effects. (lechartier2024pulmonaryvenoocclusivedisease pages 2-3)

5.3 Infectious agents

No specific infectious etiologies were identified in the retrieved evidence.

6. Mechanism / Pathophysiology (with causal chains and ontology suggestions)

6.1 Pathologic substrate (vascular remodeling)

PVOD is defined pathologically by diffuse fibrous thickening/obliteration of septal veins and pre‑septal venules, with characteristic involvement of small venules (<100 µm). PCH is part of the same spectrum with capillary congestion/proliferation. (lechartier2024pulmonaryvenoocclusivedisease pages 3-5)

Causal chain (high‑level): Trigger(s) (biallelic EIF2AK4 loss and/or endothelial toxic exposures such as MMC/solvents) → endothelial stress response/barrier dysfunction → increased permeability, microvascular remodeling and venular obstruction → increased pulmonary vascular resistance → pre‑capillary PH → RV hypertrophy/failure and hypoxemia due to impaired gas exchange. (prabhakar2024mechanismsunderlyingageassociated pages 2-4, lechartier2024pulmonaryvenoocclusivedisease pages 2-3)

6.2 Integrated stress response (ISR) and PKR/PP1 axis (recent 2023–2024 developments)

A key 2024 mechanistic study reports that MMC induces PVOD‑like disease in rats via activation of PKR and the integrated stress response (ISR), with sustained eIF2α phosphorylation due to reduced protein phosphatase 1 (PP1), leading to endothelial junction disruption and barrier dysfunction. (prabhakar2024mechanismsunderlyingageassociated pages 1-2, prabhakar2024mechanismsunderlyingageassociated pages 2-4)

Quantitative findings in the MMC rat model include increased RV systolic pressure and RV hypertrophy after MMC, with greater severity in aged animals; pharmacologic PKR or ISR blockade mitigated PVOD phenotypes. (prabhakar2024mechanismsunderlyingageassociated pages 2-4)

Direct abstract quote (2024): - Prabhakar et al. 2024: “We previously showed that… mitomycin C (MMC) in rats mediates PVOD through the activation of… protein kinase R (PKR) and the integrated stress response (ISR), resulting in the impairment of vascular endothelial junctional structure and barrier function.” (Published 2024‑09; https://doi.org/10.1172/jci.insight.181877) (prabhakar2024mechanismsunderlyingageassociated pages 1-2)

GO term suggestions (processes): - Integrated stress response → GO:0140749 (integrated stress response) (conceptually aligned with eIF2α‑ATF4 pathway described) (prabhakar2024mechanismsunderlyingageassociated pages 1-2) - Regulation of endothelial barrier / permeability → GO:0035633 (maintenance of barrier function) (conceptual) (prabhakar2024mechanismsunderlyingageassociated pages 1-2) - Vascular remodeling/fibrosis → GO:0001525 (angiogenesis); GO:0045766 (positive regulation of angiogenesis) (supported by angiogenesis mentions and remodeling) (bignard2023tcelldysregulationand pages 16-19)

Cell Ontology (CL) suggestions (cell types implicated): - Pulmonary vascular endothelial cells → Endothelial cell (CL:0000115), supported by CD31+ endothelial localization of ISR markers (prabhakar2024mechanismsunderlyingageassociated pages 2-4) - T cells (LAG3+ and proliferative populations) → T cell (CL:0000084); regulatory/exhausted‑like subsets conceptually consistent with LAG3+ population (bignard2023tcelldysregulationand pages 1-5) - Neutrophils → Neutrophil (CL:0000775) (bignard2023tcelldysregulationand pages 1-5) - Macrophages/mononuclear phagocytes involved in inflammation signals (supported by infiltration language) → Macrophage (CL:0000235) (bignard2023tcelldysregulationand pages 1-5)

6.3 Immune dysregulation in EIF2AK4/GCN2 deficiency (2023)

In a 2023 rat model, Gcn2 (Eif2ak4) deficiency did not spontaneously cause PVOD but produced immune dysregulation and inflammatory signatures under metabolic stress (asparaginase‑induced amino‑acid deprivation), including expansion of specific T‑cell populations at baseline and neutrophil infiltration plus innate immune gene upregulation after stress; scRNA‑seq and RNA‑seq were used. (bignard2023tcelldysregulationand pages 1-5)

Direct abstract quote (2023): - Bignard et al. 2023: “Hereditary pulmonary veno-occlusive disease… is… due to biallelic loss-of-function of the EIF2AK4 gene… Lung mRNAS were analyzed by RNASeq and single cell RNASeq (scRNA-seq)… Under basal conditions, scRNA-seq analysis… revealed increases in two T cell populations…” (Published 2023‑05; https://doi.org/10.1152/ajplung.00460.2021) (bignard2023tcelldysregulationand pages 1-5)

6.4 Anatomical localization (UBERON suggestions)

• Lung (primary) → lung (UBERON:0002048)
• Pulmonary venules/small pulmonary veins (microvasculature) → pulmonary vein (UBERON:0002017) (approximate macro term; microvenules not explicitly mapped in retrieved evidence)
• Right ventricle (secondary) → right ventricle (UBERON:0002080) (supported by RV hypertrophy/failure) (prabhakar2024mechanismsunderlyingageassociated pages 1-2)

7. Anatomical Structures Affected

7.1 Organ level

• Primary: lung microvasculature (pulmonary venules/veins and capillary bed) (lechartier2024pulmonaryvenoocclusivedisease pages 3-5)
• Secondary: right ventricle/right heart due to increased pulmonary vascular resistance (prabhakar2024mechanismsunderlyingageassociated pages 1-2)

7.2 Tissue/cell level

• Vascular endothelium (CD31+ endothelial cells implicated in ISR signaling) (prabhakar2024mechanismsunderlyingageassociated pages 2-4)
• Perivascular inflammatory infiltrates (T cells and neutrophils highlighted in Gcn2 deficiency models) (bignard2023tcelldysregulationand pages 1-5)

7.3 Subcellular level (GO cellular component suggestions)

Not directly specified in retrieved evidence; however, ISR signaling implies involvement of cytosolic translation machinery and stress‑kinase signaling complexes.

8. Temporal Development

8.1 Onset

• Broad: children/young adults to older ages; EIF2AK4 carriers present younger (median 26 vs 60 years in one series). (lechartier2024pulmonaryvenoocclusivedisease pages 2-3)

8.2 Progression / stages

PVOD/PCH is described as rapidly progressive with poor prognosis; quantitative endpoints reported include time from diagnosis to death/transplant and 1‑year mortality. (lechartier2024pulmonaryvenoocclusivedisease pages 3-5)

9. Inheritance and Population

9.1 Epidemiology

• Incidence ~0.1–0.5 per million/year; prevalence ~1–2 per million (rare). (lechartier2024pulmonaryvenoocclusivedisease pages 1-2)

9.2 Inheritance

• EIF2AK4‑associated PVOD/PCH is recessive/biallelic (compound heterozygous or homozygous), supported by segregation in Park 2023 and explicit “recessive form” statement. (park2023differentialdiagnosisof pages 2-3, park2023differentialdiagnosisof pages 4-4)

9.3 Demographics

• In one cohort description, EIF2AK4 carriers had a near‑equal sex ratio and younger age. (lechartier2024pulmonaryvenoocclusivedisease pages 2-3)

10. Diagnostics

10.1 Clinical tests and biomarkers

Hemodynamics (gold standard for PH diagnosis): pre‑capillary PH with mPAP >20 mmHg, PAWP/PCWP ≤15 mmHg, PVR >2 WU. (lechartier2024pulmonaryvenoocclusivedisease pages 2-3, deshwal2025pulmonaryvenoocclusivedisease pages 8-9)

Pulmonary function: reduced DLCO is a key clue (e.g., <55% predicted in one suggested clinical pattern). (deshwal2025pulmonaryvenoocclusivedisease pages 8-9)

10.2 Imaging

HRCT diagnostic triad: centrilobular ground‑glass opacities + smooth interlobular septal thickening + mediastinal lymphadenopathy; parenchymal changes may precede overt PH. (lechartier2024pulmonaryvenoocclusivedisease pages 3-5)

10.3 Genetic testing

Genetic testing for EIF2AK4 is recommended in suggestive cases; biallelic pathogenic variants can confirm heritable PVOD/PCH without histology. (lechartier2024pulmonaryvenoocclusivedisease pages 5-6, emanuelli2024functionalvalidationof pages 3-5)

10.4 Biopsy and procedure risk

ESC/ERS‑referenced guidance emphasizes clinical‑radiologic diagnosis and recommends against lung biopsy for confirmation. (lechartier2024pulmonaryvenoocclusivedisease pages 5-6, lechartier2024pulmonaryvenoocclusivedisease media a49a6475)

10.5 Differential diagnosis

Differential diagnoses include idiopathic PAH, ILD‑associated PH, and CTEPH (with V/Q scanning as key screen for CTEPH). (foster2025pulmonaryvenoocclusivedisease pages 10-12, deshwal2025pulmonaryvenoocclusivedisease pages 7-8)

11. Outcome / Prognosis

PVOD/PCH carries a very poor prognosis: - 1‑year mortality ~72% and mean time from diagnosis to death/transplant 11.8 months (lechartier2024pulmonaryvenoocclusivedisease pages 3-5) - Median survival often reported as 2–3 years after diagnosis (prabhakar2024mechanismsunderlyingageassociated pages 1-2)

A major adverse management outcome is pulmonary edema precipitated by PAH vasodilators, reported as >20% in a cohort and ~30/64 in a systematic review summarized in a clinical review. (lechartier2024pulmonaryvenoocclusivedisease pages 3-5, deshwal2025pulmonaryvenoocclusivedisease pages 9-10)

12. Treatment

12.1 Supportive care (real‑world standard)

• Supplemental oxygen and diuretics are commonly recommended supportive measures. (lechartier2024pulmonaryvenoocclusivedisease pages 3-5)
• Routine anticoagulation is not recommended unless another indication exists. (lechartier2024pulmonaryvenoocclusivedisease pages 3-5, foster2025pulmonaryvenoocclusivedisease pages 10-12)

MAXO suggestions: - Oxygen therapy → MAXO:0000861 (oxygen therapy) (conceptual) - Diuretic therapy → MAXO:0000930 (diuretic therapy) (conceptual)

12.2 PAH‑targeted therapies (caution)

PAH‑approved drugs “may be considered with careful monitoring of clinical symptoms and gas exchange” in guideline‑summarized recommendations, reflecting risk–benefit uncertainty; pulmonary edema can occur with any PAH drug class and can be life‑threatening. (lechartier2024pulmonaryvenoocclusivedisease pages 5-6, lechartier2024pulmonaryvenoocclusivedisease pages 3-5)

• Pulmonary edema incidence: >20% in a large cohort summary; systematic review summary indicates ~30/64 with edema; older series suggest 20–50% with PAH therapies and ~70% with calcium channel blockers. (lechartier2024pulmonaryvenoocclusivedisease pages 3-5, deshwal2025pulmonaryvenoocclusivedisease pages 9-10)

MAXO suggestions: - Pulmonary vasodilator therapy → MAXO:0001298 (vasodilator therapy) (conceptual)

12.3 Definitive therapy

Bilateral lung transplantation is consistently described as the definitive/curative option; early referral to a transplant center is emphasized due to rapid progression. (lechartier2024pulmonaryvenoocclusivedisease pages 3-5, lechartier2024pulmonaryvenoocclusivedisease pages 1-2)

MAXO suggestion: - Lung transplantation → MAXO:0000602 (lung transplantation) (conceptual)

12.4 Emerging/experimental (mechanism‑based)

Recent mechanistic work suggests that pharmacologic blockade of PKR/ISR pathways can mitigate disease phenotypes in MMC models, supporting investigational therapeutic directions; this is preclinical/experimental. (prabhakar2024mechanismsunderlyingageassociated pages 2-4)

13. Prevention

No established primary prevention strategies were identified in the retrieved evidence. Practical prevention in high‑risk contexts is best framed as: - Avoidance/mitigation of exposures (occupational solvents; high‑risk chemotherapies when alternatives exist) consistent with risk association evidence. (lechartier2024pulmonaryvenoocclusivedisease pages 2-3) - Genetic counseling and cascade testing in families with EIF2AK4‑associated disease. (lechartier2024pulmonaryvenoocclusivedisease pages 1-2)

14. Other Species / Natural Disease

Not identified in the retrieved evidence.

15. Model Organisms

15.1 Genetic models

• Gcn2 (Eif2ak4)‑deficient rats: phenotypically normal at baseline but show immune/inflammatory dysregulation under amino‑acid deprivation, analyzed with bulk RNA‑seq and scRNA‑seq. (bignard2023tcelldysregulationand pages 1-5)

15.2 Induced models

• Mitomycin C (MMC) rat model: induces PVOD‑like remodeling via PKR/ISR activation; aged rats show more severe remodeling and RV hypertrophy. (prabhakar2024mechanismsunderlyingageassociated pages 1-2, prabhakar2024mechanismsunderlyingageassociated pages 2-4)

15.3 Model limitations

Gcn2‑deficient rats did not spontaneously develop PVOD, suggesting additional triggers/factors are required to reproduce human disease fully. (bignard2023tcelldysregulationand pages 1-5)

Current applications / real-world implementations (registries and carrier screening)

Clinical implementation is active in longitudinal registries and carrier surveillance: - NCT03902353 (2019; ClinicalTrials.gov): screening of heterozygous EIF2AK4 carriers using CT, DLCO, echo, CPET, and biomarkers to identify early abnormalities and predictors of PVOD development. (NCT03902353 chunk 1) - NCT03169010 (2017; ClinicalTrials.gov): long‑term rare pulmonary hypertension registry explicitly including PVOD and PCH with planned sequencing/biobank and survival/transplant outcomes. (NCT03169010 chunk 1) - NCT01907295 (2014; ClinicalTrials.gov): UK national cohort/biorepository including PVOD/PCH, deep phenotyping, and next‑generation sequencing for natural history and predictors. (NCT01907295 chunk 1)

Visual evidence (guideline table)

The ESC/ERS 2022 PVOD/PCH recommendation summary table (diagnosis based on clinical+radiologic findings, lung biopsy not recommended, PAH drugs may be considered with careful monitoring) was retrieved as an image from Lechartier et al. 2024. (lechartier2024pulmonaryvenoocclusivedisease media a49a6475)

Expert synthesis (authoritative interpretation grounded in cited sources)

1) PVOD/PCH is best approached as a distinct PAH spectrum disorder with venous/capillary involvement, where accurate early identification matters because common PAH vasodilator strategies can be dangerous (pulmonary edema) and the therapeutic window for transplant referral is short. (lechartier2024pulmonaryvenoocclusivedisease pages 3-5, lechartier2024pulmonaryvenoocclusivedisease pages 1-2)

2) Genetic confirmation is increasingly central: biallelic EIF2AK4 pathogenic variants can establish diagnosis without lung biopsy, enabling family testing and earlier care pathway decisions (e.g., transplant evaluation, exposure avoidance). (emanuelli2024functionalvalidationof pages 3-5, park2023differentialdiagnosisof pages 2-3)

3) 2023–2024 mechanistic advances converge on stress-response and barrier biology (ISR/PKR/PP1 axis; endothelial junction disruption) and suggest tractable therapeutic targets, but these remain preclinical and not yet standard of care. (prabhakar2024mechanismsunderlyingageassociated pages 2-4)

URLs and publication dates (key sources used)

• Lechartier B. et al. 2024‑01. European Respiratory Review. https://doi.org/10.1183/16000617.0156-2023 (lechartier2024pulmonaryvenoocclusivedisease pages 1-2)
• Park J.E. et al. 2023‑02. Molecular Syndromology. https://doi.org/10.1159/000527524 (park2023differentialdiagnosisof pages 2-3)
• Prabhakar A. et al. 2024‑09. JCI Insight. https://doi.org/10.1172/jci.insight.181877 (prabhakar2024mechanismsunderlyingageassociated pages 1-2)
• Bignard J. et al. 2023‑05. AJP-Lung. https://doi.org/10.1152/ajplung.00460.2021 (bignard2023tcelldysregulationand pages 1-5)
• Emanuelli G. et al. 2024‑04. https://doi.org/10.17863/cam.108223 (emanuelli2024functionalvalidationof pages 1-3)

Limitations of this report (evidence availability)

• Standard identifiers (OMIM/Orphanet/ICD/MeSH/MONDO) and some phenotype frequency statistics were not present in the retrieved corpus for this run; the report therefore focuses on high‑confidence clinical, genetic, imaging, mechanistic, and guideline‑linked evidence available in the provided texts. (lechartier2024pulmonaryvenoocclusivedisease pages 1-2, deshwal2025pulmonaryvenoocclusivedisease pages 1-2)

References

1. (lechartier2024pulmonaryvenoocclusivedisease pages 1-2): Benoit Lechartier, Athénaïs Boucly, Sabina Solinas, Deepa Gopalan, Peter Dorfmüller, Teodora Radonic, Olivier Sitbon, and David Montani. Pulmonary veno-occlusive disease: illustrative cases and literature review. European Respiratory Review, 33:230156, Jan 2024. URL: https://doi.org/10.1183/16000617.0156-2023, doi:10.1183/16000617.0156-2023. This article has 28 citations and is from a peer-reviewed journal.

2. (deshwal2025pulmonaryvenoocclusivedisease pages 1-2): Himanshu Deshwal, Sauradeep Sarkar, Atreyee Basu, and Bilal A. Jalil. Pulmonary veno-occlusive disease: a clinical review. Breathe, 21:240098, Jan 2025. URL: https://doi.org/10.1183/20734735.0098-2024, doi:10.1183/20734735.0098-2024. This article has 4 citations.

3. (deshwal2025pulmonaryvenoocclusivedisease pages 2-3): Himanshu Deshwal, Sauradeep Sarkar, Atreyee Basu, and Bilal A. Jalil. Pulmonary veno-occlusive disease: a clinical review. Breathe, 21:240098, Jan 2025. URL: https://doi.org/10.1183/20734735.0098-2024, doi:10.1183/20734735.0098-2024. This article has 4 citations.

4. (lechartier2024pulmonaryvenoocclusivedisease pages 3-5): Benoit Lechartier, Athénaïs Boucly, Sabina Solinas, Deepa Gopalan, Peter Dorfmüller, Teodora Radonic, Olivier Sitbon, and David Montani. Pulmonary veno-occlusive disease: illustrative cases and literature review. European Respiratory Review, 33:230156, Jan 2024. URL: https://doi.org/10.1183/16000617.0156-2023, doi:10.1183/16000617.0156-2023. This article has 28 citations and is from a peer-reviewed journal.

5. (prabhakar2024mechanismsunderlyingageassociated pages 1-2): Amit Prabhakar, Meetu Wadhwa, Rahul Kumar, Prajakta Ghatpande, Aneta Gandjeva, Rubin M. Tuder, Brian B. Graham, Giorgio Lagna, and Akiko Hata. Mechanisms underlying age-associated exacerbation of pulmonary veno-occlusive disease. JCI Insight, Sep 2024. URL: https://doi.org/10.1172/jci.insight.181877, doi:10.1172/jci.insight.181877. This article has 7 citations and is from a domain leading peer-reviewed journal.

6. (lechartier2024pulmonaryvenoocclusivedisease pages 2-3): Benoit Lechartier, Athénaïs Boucly, Sabina Solinas, Deepa Gopalan, Peter Dorfmüller, Teodora Radonic, Olivier Sitbon, and David Montani. Pulmonary veno-occlusive disease: illustrative cases and literature review. European Respiratory Review, 33:230156, Jan 2024. URL: https://doi.org/10.1183/16000617.0156-2023, doi:10.1183/16000617.0156-2023. This article has 28 citations and is from a peer-reviewed journal.

7. (deshwal2025pulmonaryvenoocclusivedisease pages 8-9): Himanshu Deshwal, Sauradeep Sarkar, Atreyee Basu, and Bilal A. Jalil. Pulmonary veno-occlusive disease: a clinical review. Breathe, 21:240098, Jan 2025. URL: https://doi.org/10.1183/20734735.0098-2024, doi:10.1183/20734735.0098-2024. This article has 4 citations.

8. (deshwal2025pulmonaryvenoocclusivedisease pages 7-8): Himanshu Deshwal, Sauradeep Sarkar, Atreyee Basu, and Bilal A. Jalil. Pulmonary veno-occlusive disease: a clinical review. Breathe, 21:240098, Jan 2025. URL: https://doi.org/10.1183/20734735.0098-2024, doi:10.1183/20734735.0098-2024. This article has 4 citations.

9. (foster2025pulmonaryvenoocclusivedisease pages 4-6): Brian Foster, Sikandar Khan, Ana Suarez Gonzalez, and Samantha Gillenwater. Pulmonary veno-occlusive disease: a comprehensive review of diagnostic challenges, therapeutic limitations, and evolving management. Advances in Respiratory Medicine, 93:48, Oct 2025. URL: https://doi.org/10.3390/arm93060048, doi:10.3390/arm93060048. This article has 2 citations.

10. (lechartier2024pulmonaryvenoocclusivedisease pages 5-6): Benoit Lechartier, Athénaïs Boucly, Sabina Solinas, Deepa Gopalan, Peter Dorfmüller, Teodora Radonic, Olivier Sitbon, and David Montani. Pulmonary veno-occlusive disease: illustrative cases and literature review. European Respiratory Review, 33:230156, Jan 2024. URL: https://doi.org/10.1183/16000617.0156-2023, doi:10.1183/16000617.0156-2023. This article has 28 citations and is from a peer-reviewed journal.

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12. (park2023differentialdiagnosisof pages 2-3): Jong Eun Park, Sung-A Chang, Shin Yi Jang, Kyung Soo Lee, Duk-Kyung Kim, and Chang-Seok Ki. Differential diagnosis of pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis after identification of two novel eif2ak4 variants by whole-exome sequencing. Molecular Syndromology, 14:254-257, Feb 2023. URL: https://doi.org/10.1159/000527524, doi:10.1159/000527524. This article has 6 citations and is from a peer-reviewed journal.

13. (park2023differentialdiagnosisof pages 1-2): Jong Eun Park, Sung-A Chang, Shin Yi Jang, Kyung Soo Lee, Duk-Kyung Kim, and Chang-Seok Ki. Differential diagnosis of pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis after identification of two novel eif2ak4 variants by whole-exome sequencing. Molecular Syndromology, 14:254-257, Feb 2023. URL: https://doi.org/10.1159/000527524, doi:10.1159/000527524. This article has 6 citations and is from a peer-reviewed journal.

14. (emanuelli2024functionalvalidationof pages 3-5): Giulia Emanuelli, JiaYi Zhu, Wei Li, Nicholas W Morrell, and Stefan J Marciniak. Functional validation of eif2ak4 (gcn2) missense variants associated with pulmonary arterial hypertension. JournalArticle, Apr 2024. URL: https://doi.org/10.17863/cam.108223, doi:10.17863/cam.108223. This article has 14 citations.

15. (emanuelli2024functionalvalidationof pages 1-3): Giulia Emanuelli, JiaYi Zhu, Wei Li, Nicholas W Morrell, and Stefan J Marciniak. Functional validation of eif2ak4 (gcn2) missense variants associated with pulmonary arterial hypertension. JournalArticle, Apr 2024. URL: https://doi.org/10.17863/cam.108223, doi:10.17863/cam.108223. This article has 14 citations.

16. (prabhakar2024mechanismsunderlyingageassociated pages 2-4): Amit Prabhakar, Meetu Wadhwa, Rahul Kumar, Prajakta Ghatpande, Aneta Gandjeva, Rubin M. Tuder, Brian B. Graham, Giorgio Lagna, and Akiko Hata. Mechanisms underlying age-associated exacerbation of pulmonary veno-occlusive disease. JCI Insight, Sep 2024. URL: https://doi.org/10.1172/jci.insight.181877, doi:10.1172/jci.insight.181877. This article has 7 citations and is from a domain leading peer-reviewed journal.

17. (bignard2023tcelldysregulationand pages 1-5): Juliette Bignard, Fabrice Atassi, Olivier Claude, Maria-Rosa Ghigna, Nathalie Mougenot, Bahgat Soilih Abdoulkarim, Florence Deknuydt, Aurélie Gestin, Virginie Monceau, David Montani, Sophie Nadaud, Florent Soubrier, and Frédéric Perros. T-cell dysregulation and inflammatory process in gcn2 (eif2ak4^−/−)-deficient rats in basal and stress conditions. American Journal of Physiology-Lung Cellular and Molecular Physiology, 324:L609-L624, May 2023. URL: https://doi.org/10.1152/ajplung.00460.2021, doi:10.1152/ajplung.00460.2021. This article has 5 citations.

18. (bignard2023tcelldysregulationand pages 16-19): Juliette Bignard, Fabrice Atassi, Olivier Claude, Maria-Rosa Ghigna, Nathalie Mougenot, Bahgat Soilih Abdoulkarim, Florence Deknuydt, Aurélie Gestin, Virginie Monceau, David Montani, Sophie Nadaud, Florent Soubrier, and Frédéric Perros. T-cell dysregulation and inflammatory process in gcn2 (eif2ak4^−/−)-deficient rats in basal and stress conditions. American Journal of Physiology-Lung Cellular and Molecular Physiology, 324:L609-L624, May 2023. URL: https://doi.org/10.1152/ajplung.00460.2021, doi:10.1152/ajplung.00460.2021. This article has 5 citations.

19. (deshwal2025pulmonaryvenoocclusivedisease pages 9-10): Himanshu Deshwal, Sauradeep Sarkar, Atreyee Basu, and Bilal A. Jalil. Pulmonary veno-occlusive disease: a clinical review. Breathe, 21:240098, Jan 2025. URL: https://doi.org/10.1183/20734735.0098-2024, doi:10.1183/20734735.0098-2024. This article has 4 citations.

20. (foster2025pulmonaryvenoocclusivedisease pages 10-12): Brian Foster, Sikandar Khan, Ana Suarez Gonzalez, and Samantha Gillenwater. Pulmonary veno-occlusive disease: a comprehensive review of diagnostic challenges, therapeutic limitations, and evolving management. Advances in Respiratory Medicine, 93:48, Oct 2025. URL: https://doi.org/10.3390/arm93060048, doi:10.3390/arm93060048. This article has 2 citations.

21. (NCT03902353 chunk 1): Screening of Pulmonary Veino Occlusive Disease in Heterozygous EIF2AK4 Mutation Carriers. Assistance Publique - Hôpitaux de Paris. 2019. ClinicalTrials.gov Identifier: NCT03902353

22. (NCT03169010 chunk 1): Zhi-Cheng JING, MD. Registration Study for Rare Type of Pulmonary Hypertension. China National Center for Cardiovascular Diseases. 2017. ClinicalTrials.gov Identifier: NCT03169010

23. (NCT01907295 chunk 1): Nick Morrell. National Cohort Study of Idiopathic and Heritable Pulmonary Arterial Hypertension. University of Cambridge. 2014. ClinicalTrials.gov Identifier: NCT01907295

24. (park2023differentialdiagnosisof pages 4-4): Jong Eun Park, Sung-A Chang, Shin Yi Jang, Kyung Soo Lee, Duk-Kyung Kim, and Chang-Seok Ki. Differential diagnosis of pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis after identification of two novel eif2ak4 variants by whole-exome sequencing. Molecular Syndromology, 14:254-257, Feb 2023. URL: https://doi.org/10.1159/000527524, doi:10.1159/000527524. This article has 6 citations and is from a peer-reviewed journal.