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Pulmonary Veno-Occlusive Disease - From Clinical Ambiguity to Molecular Diagnostics

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Amresh Raina, MD, FACC
Allegheny General Hospital
Pittsburgh, PA, USA

As pulmonary hypertension (PH) clinicians, we are often faced with diagnostic challenges that force us to re-evaluate the physiology of a patient's disease. In the clinical realm, outside of randomized clinical trials, a patient's PH diagnosis can often be painted in shades of gray rather than with the clarity of black and white. Especially when patients do not respond to therapy in an expected manner, we often find ourselves reassessing the diagnosis and questioning common alternative diagnoses: I have often found myself pondering again "is it left heart disease?" "Is it chronic thromboembolic disease?" "Is it smoldering interstitial lung disease?"

Consider the recent case of a 52-year-old man with an 18-month history of progressive dyspnea, extremity edema and presyncope. He admitted to a 30 pack-year smoking history, but had only mild emphysema on CT of the chest and minimal obstructive lung disease on pulmonary function testing, but with profoundly reduced diffusion capacity for carbon monoxide (DLCO). Echocardiogram revealed a markedly dilated and dysfunctional right ventricle with compression on the left ventricle from interventricular septal flattening (Figure 1A). Left atrial size and left ventricular function were normal. Invasive hemodynamics revealed near systemic PH with profoundly reduced cardiac index and PVR of 12 WU (Figure 1B). Pulmonary capillary wedge pressure (PCWP) was normal.

The patient was admitted to the CCU and started on IV prostacyclin under careful hemodynamic monitoring. On day 2 of prostacyclin infusion, CT of the chest was repeated, showing diffuse ground glass opacity and inter-lobular septal thickening (Figure 2A), while repeat PCWP tracing remained normal (Figure 2B). On the basis of this clinical response, the patient was diagnosed with suspected pulmonary veno-occlusive disease (PVOD) and referred for urgent lung transplant evaluation.

PVOD and the related disorder, pulmonary capillary hemangiomatosis (PCH), are extremely rare clinical entities in the general population and thought to make up 10% of cases initially diagnosed as pulmonary arterial hypertension (PAH), itself a rare disorder [1]. However, in PH referral centers, PVOD is seen with increasing frequency. The pathologic hallmarks of PVOD are a fibrotic thickening of small pulmonary venules, especially in the interlobular septa, typically sparing the larger veins. Patients with PVOD will typically have a normal PCWP as the wedge pressure reflects pressure in the larger pulmonary veins rather than the small veins affected by PVOD and the disease process itself may be patchy.

The diagnosis of PVOD is often entertained due to the development of a pattern of pulmonary edema or diffuse ground glass opacities and interlobular septal thickening on X-ray and/or high resolution CT of the chest in the setting of normal PCWP and absence of left heart pathology, accompanied by hypoxemia and very low DLCO on pulmonary function testing [2]. In many cases, pulmonary edema may be provoked with the initiation of pulmonary vasodilator therapy. PVOD, like PAH, may be familial or sporadic and is associated with inflammatory disorders such as sarcoidosis and scleroderma, as well as chemotherapeutic agents, radiation and malignancy. PVOD, unlike PAH has a higher male:female preponderance and is associated with cigarette exposure [3].

Definitive diagnosis of PVOD has traditionally required surgical lung biopsy for confirmatory histopathology; however, this is rarely performed pre-mortem due to risks involved in lung biopsy in patients with severe PH, and thus most commonly the diagnosis has been made on clinical grounds alone. This is typically unsatisfying for both patients and clinicians alike; in the best-case scenario, eligible patients are referred for bilateral lung transplantation without a definitive confirmatory test or a pathologic diagnosis, and those who are not candidates are faced with a grim prognosis, with or without a trial of pulmonary vasodilator therapy, again commonly without definitive confirmation of the diagnosis.

However, recently a major step forward in the diagnosis of PVOD was the finding of biallelic mutations in the gene encoding the eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) in both familial (100%) and sporadic (20% to 25%) cases of PVOD/PCH [4, 5]. This strongly suggested an underlying genetic basis for the risk of development of PVOD.

Moreover, a recent study by Hadinnapola et al, demonstrated that in a large cohort of 864 patients with a clinical diagnosis of idiopathic or heritable PAH, 9 patients carried a biallelic mutation in EIF2AK4; these patients had a younger age at presentation, lower DLCO and worse response to therapy and prognosis. However, these patients could not be readily identified by radiographic findings and did not develop pulmonary edema with pulmonary vasodilating therapy. Indeed, many of these patients were on parenteral prostacyclin therapy as they had been classified as having PAH at major European referral centers [6]. In contrast, mutations in EIF2AK4 were almost never identified in patients with idiopathic and familial PAH in a US cohort [7].

Thus, genetic testing for biallelic mutation in EIF2AK4 may provide a means to definitively diagnose patients with PVOD earlier in their clinical course, even in patients without classic radiographic findings and may guide earlier referral for lung transplantation in eligible patients.

Though this may represent a major advance with regards to diagnostic and genetic testing, there unfortunately remains limited therapy for this progressive and fatal disease. Pulmonary vasodilators should be used with caution and with close follow up at expert centers due to risk of worsening hypoxemia and pulmonary edema. With a more detailed understanding of the genetic underpinnings of PVOD may come more specific targeted therapies short of lung transplantation.

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Disclosure Statement: I have no relevant disclosures to this article. More broadly, I report research support and consulting fees from United Therapeutics and Actelion, Consulting fees from St. Jude, and Speakers Honoraria from Bayer.


  1. Montani D, Achouh L, Dorfmuller P, Le Pavec J, Sztrymf B, Tcherakian C, et al. Pulmonary veno-occlusive disease: clinical, functional, radiologic, and hemodynamic characteristics and outcome of 24 cases confirmed by histology. Medicine (Baltimore). 2008;87(4):220-33.
  2. Gunther S, Jais X, Maitre S, Berezne A, Dorfmuller P, Seferian A, et al. Computed tomography findings of pulmonary venoocclusive disease in scleroderma patients presenting with precapillary pulmonary hypertension. Arthritis Rheum. 2012;64(9):2995-3005.
  3. Montani D, Price LC, Dorfmuller P, Achouh L, Jais X, Yaici A, et al. Pulmonary veno-occlusive disease. Eur Respir J. 2009;33(1):189-200.
  4. Best DH, Sumner KL, Austin ED, Chung WK, Brown LM, Borczuk AC, et al. EIF2AK4 mutations in pulmonary capillary hemangiomatosis. Chest. 2014;145(2):231-6.
  5. Eyries M, Montani D, Girerd B, Perret C, Leroy A, Lonjou C, et al. EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension. Nat Genet. 2014;46(1):65-9.
  6. Hadinnapola C, Bleda M, Haimel M, Screaton N, Swift A, Dorfmuller P, et al. Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension. Circulation. 2017;136(21):2022-33.
  7. Best DH, Sumner KL, Smith BP, Damjanovich-Colmenares K, Nakayama I, Brown LM, et al. EIF2AK4 Mutations in Patients Diagnosed With Pulmonary Arterial Hypertension. Chest. 2017;151(4):821-8.

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