Continuing Education Activity

Pulmonary veno-occlusive disease is a rare cause of group 1 pulmonary hypertension. It is characterized by having significant venous and capillary involvement, as opposed to other causes of group 1 pulmonary hypertension, in which the arteries are primarily involved. This disease has significant mortality, and early recognition remains paramount in its management. This activity reviews the evaluation and management of patients with pulmonary veno-occlusive disease and highlights the role of the interprofessional team in managing patients with this condition.

Objectives:

• Describe the pathophysiology of pulmonary veno occlusive disease (PVOD).
• Discuss the risk factors associated with pulmonary veno occlusive disease.
• Outline the typical imaging findings associated with pulmonary veno occlusive disease.
• Summarize the management of pulmonary veno occlusive disease.

Introduction

Pulmonary hypertension (PH) is defined as a resting mean pulmonary arterial pressure (mPAP) of more than 20 mmHg.[1] Pulmonary hypertension is a complex, heterogeneous disease with multiple etiologies, subtypes, and various methods were used to classify the disease.[2] WHO has categorized pulmonary hypertension into five broad clinical groups based on the underlying etiologies, similarities in pathophysiology, and treatment approach.[2][3] 

WHO group 1 is generally referred to as pulmonary arterial hypertension (PAH).[2][3] WHO group 2 PH is caused by left heart disease. WHO group 3 is PH related to lung disease and/or hypoxia. WHO group 4 is PH due to pulmonary artery obstructions such as chronic thromboembolic pulmonary hypertension (CTEPH). WHO group 5 PH has unclear and/or multifactorial mechanisms.[3][4]

Pulmonary veno-occlusive disease (PVOD) is a rare subtype of PAH characterized by progressive obstruction of small pulmonary veins leading to elevated pulmonary arterial pressure and right-sided heart failure.[3][5] Although PVOD was first described in 1934, the understanding of the disease remains poor.[6] 

The clinical features are very non-specific and can resemble congestive heart failure, idiopathic pulmonary arterial hypertension (IPAH), and restrictive lung diseases such as pulmonary fibrosis. The gold standard for diagnosis is a biopsy, which is risky and not advisable in pulmonary hypertension due to a high risk of procedure-related complications such as life-threatening bleeding.[5][7][8] 

No medical therapy is supported by evidence, and the only curative option is lung transplantation.[7][8] The prognosis is poor, and life expectancy is two years after symptom onset.[9] This review aims to educate clinicians on this rare, less emphasized, and poorly understood disease.

Etiology

Both familial and sporadic cases of PVOD have been reported in humans. Description of familial cases of PVOD dates back to 1977.[10] In 2013, a French investigative group studied PVOD and found that 13/13 familial PVOD and 5/20 sporadic cases have had a loss of function mutations of EIF2AK4.[11] The exact mechanism of how this deletion leads to PVOD is unknown, but several other reports suggest this association.[12][13][14][15] The other gene that was found in association with PVOD is BMPR2.[16][17][18] 

Sporadic cases were linked to chemotherapeutic drugs such as mitomycin, occupational exposure to organic solvents such as trichloroethylene, autoimmune and connective tissue disorders such as systemic sclerosis, human immunodeficiency virus (HIV) infection, radiation, and bone marrow transplants.

Mitomycin C (MMC) is a relatively well-studied association with PVOD in both animal and human studies.[19][20][21][22] A French investigative group demonstrated that intraperitoneal mitomycin C administration in rats leads to pulmonary hypertension and right ventricular hypertrophy, and histological changes were consistent with PVOD.[19] 

The same study has retrospectively identified 7 cases of PVOD in humans with squamous cell anal cancer, taking MMC between June 2012 and December 2014. 4 out of 7 patients were screened negative for genetic mutations, including EIF2AK4 and BMPR2; only one was HIV positive. Of these seven patients, two were exclusively treated with MMC, and five were treated with MMC and fluorouracil (FU). In this case series, the meantime for the development of PH after initiation of chemotherapy was four months (range 2 to 12 months).

MMC is often used in combination with other antineoplastic drugs, and it is unclear if other chemotherapeutic medications have a role in pathogenesis. For instance, in the French study mentioned above, five patients were also receiving fluorouracil, and the authors concluded that it is impossible to study the role of fluorouracil in the pathogenesis of PVOD. There are a few other case reports of MMC-induced PVOD in patients with different types of cancers, such as breast and cervical cancers. Other chemotherapeutic agents commonly reported to be associated with PVOD include cyclophosphamide, cisplatin, carmustine, doxorubicin, vincristine, etoposide, and methotrexate.

Chemical exposure to organic solvents, especially trichloroethylene, is also implicated in the development of PVOD.[23] A case-control study from 2015 evaluated the occupational exposures using a questionnaire in patients with PVOD (cases, n=33) and PAH (controls, n=65) and found that exposure to organic solvents was significantly associated with PVOD (odds ratio 12.8, 95% confidence interval 2.7 to 60.8). Trichloroethylene was the main agent implicated, with an odds ratio of 8.2 and a 95% confidence interval of 1.4 to 49.4.[23] 

The study identifies that the patients with EIF2AK4 mutations have very low exposure to trichloroethylene, and these patients are typically younger than patients with no mutation. This suggests an aggressive phenotypic response to the chemical agent in patients with EIF2AK4 mutation and suggests that the disease carries a long latency in patients with no mutation.

Autoimmune and connective disorders such as systemic sclerosis (SSc) are well-known causes of PAH and pulmonary hypertension from interstitial lung disease (PH-ILD).[24] Recently, PVOD has been hypothesized to be the reason for the treatment-refractory nature of these patients. A study from 2007 compared lung samples from 8 cases (5 autopsy samples and three explant samples after lung transplant) with connective tissue diseases to 29 patients with no history of connective tissue diseases. The study found that 6 out of 8 patients (75%) with connective tissue diseases had histology consistent with PVOD as opposed to 5 out of 29 patients (17.2%) with no connective tissue disease.[24] 

A different study from the University of Pittsburgh in 2019 analyzed 18 samples from patients with a history of SSc-PH-ILD, and 15 had histological findings consistent with PVOD, suggesting a strong association.[25] The association of PVOD with systemic sclerosis is found in patients with both systemic sclerosis and limited scleroderma.[26][27]

Cigarette smoking is seen more in patients with PVOD compared to PAH.[23]

Other risk factors anecdotally reported in case reports include radiation therapy for cancers, bone marrow transplants, and HIV infection.[28][29][30][31]

Epidemiology

The real incidence and prevalence of PVOD are unknown. Estimates of prevalence range from less than 1 to 2 cases per 10 million population.[32][33] It is also thought that PVOD accounts for 3 to 12% of previously diagnosed idiopathic or primary pulmonary hypertension cases.[32][34][35] 

Compared to PAH, which has female sex predominance, PVOD has been reported to present at similar rates in both sexes.[36] However, non-familial cases reportedly occur in males more than in females. Bimodal age distribution has been identified in PVOD, with familial cases affecting children and younger adult populations compared to sporadic cases in elderly patients.[23]

Pathophysiology

The pathophysiology of PVOD is multifactorial and has not been clearly established. It is hypothesized that PVOD may be an aberrant response to endothelial injury leading to widespread fibrosis of the pulmonary venous system.[37]

Two particular genes have been implicated in the pathogenesis of pulmonary veno-occlusive disease; BMPR2 and EIF2AK4. 

BMPR2, or bone morphogenetic protein receptor type II, has long been known as the implicated gene in familial PAH. It has been implicated in at least half of all familial PAH cases and possibly 25% of nonfamilial PAH cases. Mutations in BMPR2 have also been shown in some patients with PVOD.[17] The function of this gene is to prevent the proliferation of smooth muscle cells and neointimal formation. Reduced function of BMPR2 leads to remodeling of the vasculature.[38]

EIF2AK4, or eukaryotic translation initiation factor 2-alpha kinase, has been implicated as the major gene in the pathogenesis of PVOD. Up to 25% of sporadic cases of PVOD have been shown to have mutations in this gene.[11] Phenotypically, these patients present similarly to patients without the mutation. However, they tend to present at a younger age.[39] 

The function of this gene is to encode serine-threonine kinase, which induces changes in gene expression in response to amino acid deprivation.[11] It is also involved in the phosphorylation of eIF2α, which is involved in the early stages of protein synthesis of some mRNAs. This phosphorylation inactivates eIF2α and results in the activation of stress proteins.[40] With this being said, the link between EIF2AK4 and the beginnings of PVOD remains unclear.

Histopathology

The hallmark histological features in PVOD include intimal fibrosis, luminal narrowing, recanalized thrombi, and obliteration of preseptal venules within the pulmonary circulation.[32][6] Diffuse involvement of preseptal and septal venules must be demonstrated to confirm the diagnosis. Other histologic findings include capillary congestion, alveolar edema and siderophages, dilated lymphatics, and pleural and septal edema.[41]

History and Physical

The history and physical findings for the pulmonary veno-occlusive disease are most similar to the clinical presentation of other forms of pulmonary arterial hypertension. Most patients will present with signs of right-sided heart failure, such as leg edema, ascites, and volume overload. They often will complain of dyspnea on exertion and orthopnea. Physical findings in these patients may include a split S2, loud P2, crackles, and cyanosis.[6] This reflects the worsening right ventricular dysfunction. Right-sided murmurs (tricuspid regurgitation) may be auscultated as the clinical course progresses.[42]

Evaluation

The evaluation of these patients is similar to the usual progression of a patient with dyspnea and signs of right heart failure. 

Chest radiographs will typically be performed and can note enlargement of central pulmonary arteries and signs of vascular congestion. 

Computed tomography of the chest (CT chest) will typically be performed with evidence of elevated pulmonary pressures, such as the increased diameter of pulmonary vessels and possible right ventricular enlargement with bowing of the interventricular septum into the left ventricular lumen. Additionally, there will be signs of pulmonary venous congestion such as mosaicism with centrilobular ground glass opacities, scattered pulmonary nodules, mediastinal lymph node enlargement, and smooth thickening of interlobular septa.[43]

Spirometry typically shows normal values, though mild restrictive defects may be seen.[44] DLCO is typically reduced.[44] 

Echocardiography shows signs of pulmonary hypertension, such as elevated pulmonary arterial systolic pressure (PASP), right ventricular strain/dilation, and right ventricular dysfunction. Echocardiography will also be useful to exclude left-sided heart disease as a cause of pulmonary edema.  

Ventilation and perfusion scanning (V/Q scanning) is typically performed in the workup of patients with suspected PAH. It is of poor utility in diagnosing PVOD because it is usually normal or leads to a misdiagnosis of CTEPH. It can sometimes show mismatched perfusion defects in PVOD patients.[45] However, a recent study demonstrated that the prevalence of mismatched perfusion defects from V/Q Scanning in PVOD was low and was not significantly different from PAH (7.1% vs. 10%, p>0.05). Therefore it is not a useful test for differentiating PVOD from PAH.[46]

Right heart catheterization is necessary for the diagnosis of pulmonary hypertension. Patients with PVOD will have the typical hemodynamic features of pulmonary arterial hypertension, which are elevated mean pulmonary arterial pressures (mPAP) >20 mmHg, normal pulmonary capillary wedge pressure (PCWP) ≤15 mmHg, and elevated pulmonary vascular resistance (PVR) ≥3 Wood Units.[6]

There are no particular findings in right heart catheterization specific for the pulmonary veno-occlusive disease, although some may point toward the diagnosis. The first would be developing pulmonary edema during vasoreactivity testing. Vasoreactivity testing is generally done to evaluate the viability of calcium channel blockers in treating pulmonary arterial hypertension. This is typically done using short-acting pulmonary vasodilators such as adenosine, epoprostenol, or inhaled nitric oxide.

If a patient develops pulmonary edema during this testing, it can be suggestive of PVOD. Another finding suggesting this diagnosis would be an abnormal rise and fall in PCWP when flushing the distal port. Due to the narrowing of pulmonary veins, there may be a steep rise in the PCWP and a slow fall after flushing saline.[47]

Histology remains the gold standard for making a definite diagnosis. However, lung biopsy is contraindicated as it increases the risk of life-threatening bleeding. It is recommended to use a noninvasive diagnostic approach based on clinical features and noninvasive tests to support the diagnosis.[32]

For patients with a family history of PVOD or IPAH, some centers may test for BMPR2 or EIF2AK4 mutations.

Treatment / Management

General and supportive measures include oxygen supplements in hypoxemic patients to prevent worsening PH from hypoxic pulmonary vasoconstriction. Diuretics should be used to optimize volume status. There is no proposed recommendation for anticoagulation in PVOD patients.

The standard pulmonary vasodilators will not help with the disease and traditionally have been thought to increase the risk of pulmonary edema. The development of pulmonary edema in these patients with the initiation of therapy is due to the early rise in arterial vasodilation and slower rise in venodilation. This leads to increased hydrostatic pressures in the pulmonary capillary bed, resulting in fluid translocation to the alveolar space.[6] 

However, recent case reports have noted the possible safety of pulmonary vasodilators in these patients. In a systematic review published in 2019, Ogawa et al. identified 20 case reports of patients with PVOD, which demonstrated the potential efficacy of pulmonary vasodilators in these patients, but with marked difficulties and risks of complications.[48] Additionally, Montani et al. noted that cautious use of pulmonary vasodilators improved hemodynamic parameters at 3 or 4 months and was a useful bridge to transplant.[49]

If vasodilator therapy is considered, it is recommended to start with a single agent at lower doses with close monitoring and the availability of high-dose diuretic therapy. It can be administered as a palliative measure to decrease the rate of decline in patients who will not be transplant candidates or as a bridge to transplant itself. 

There were some reports of the benefit of immunosuppressive agents in patients with idiopathic and heritable PVOD and patients with connective tissue disease-associated PVOD.[50][51] This is thought to be from alleviating the inflammatory process implicated in PVOD.

A lung transplant is the only curative option. If suspected, these patients should be referred for lung transplant evaluation early in the course of the disease, as lung transplantation is the only therapy shown to increase life expectancy in patients with PVOD.[52]

Differential Diagnosis

Congestive heart failure (CHF): PVOD patients have a similar presentation to CHF patients, such as shortness of breath, dyspnea on exertion, and leg swelling. Moreover, chest imaging findings are similar in both PVOD and CHF, with signs of congestion such as ground glass opacities (GGOs), septal thickening, pleural effusion, and mediastinal lymphadenopathy. Echocardiography can differentiate CHF from PVOD, which typically shows left heart dysfunction, and right heart catheterization (RHC) shows postcapillary pulmonary hypertension with elevated PCWP ≥ 15 mmHg in CHF patients. 

Chronic thromboembolic pulmonary hypertension (CTEPH): PVOD and CTEPH patients have similar symptoms. V/Q Scanning of PVOD can show mismatched perfusion defects, leading to misdiagnosis of CTEPH. Hemodynamic findings from RHC also show precapillary pulmonary hypertension (mPAP >20 mmHg, PCWP ≤15 mmHg, and PVR ≥3 Wood Units) in both PVOD and CTEPH. However, CTEPH patients are unlikely to have signs of venous congestion on chest imaging.

Idiopathic pulmonary arterial hypertension: Both IPAH and PVOD will have similar symptoms and similar RHC findings. However, IPAH patients usually do not have congestion on chest imaging. 

Interstitial lung diseases (ILD): Chest imaging of GGOs and septal thickening in PVOD can mimic certain ILDs such as sarcoidosis. However, ILD patients may report other respiratory symptoms related to ILD, such as chronic productive or dry cough, wheezing, or systemic symptoms (fever, night sweats, weight loss).

Prognosis

Overall, the prognosis is poor. The one-year mortality has been reported to be close to 72%.[52] There have been no studies performed evaluating the prognosis of PVOD patients receiving medical therapy. Most patients either die or require a lung transplant within two years of diagnosis.[53] 

Outcomes after heart-lung or lung transplant for pulmonary veno-occlusive disease patients are similar to outcomes of other patients with pulmonary arterial hypertension requiring a transplant.

Complications

The complications for these patients are similar to patients with pulmonary arterial hypertension. Elevated pulmonary vascular resistance leads to increased afterload of the right ventricle (RV). In the early phase, RV remains adapted to afterload by increasing contractility without increasing RV chamber dimension. In the more advanced phase, RV function cannot remain matched to afterload, resulting in RV dilation, myocardial fibrosis, and low RV cardiac output, eventually leading to right-sided heart failure and volume overload from systemic venous congestion.[54]

Deterrence and Patient Education

Pulmonary hypertension is defined as an increase in the blood pressure of the arteries of the pulmonary system. Pulmonary veno-occlusive disease is a rare cause of pulmonary hypertension and primarily involves the venous system. 

Early symptoms for patients typically include shortness of breath or swelling in the legs. This can eventually progress to worsening shortness of breath on exertion, abdominal swelling, and low oxygen levels.  

The workup for the pulmonary veno-occlusive disease includes obtaining an echocardiogram or ultrasound of the heart. It can also include an X-ray of the chest, CT of the chest, and eventually, a right heart catheterization. A right heart catheterization is a procedure by which a physician takes a catheter, inserts it through a vein, and advances it into the pulmonary artery, where the diagnosis of pulmonary hypertension can be made.  

The clinician may also obtain genetic markers if the patient has a family history of this disorder. 

The management of pulmonary veno-occlusive disease includes diuretics to remove fluid from the body. Lung transplantation is currently the only proven curative treatment for this disease; patients need to understand this so expectations can be realistically set.

Pearls and Other Issues

Given the rarity of this condition and the nonspecific presentation, delays in diagnosing PVOD are common. Most patients are usually presumed to have congestive heart failure due to the findings of pulmonary congestion on the CT chest.

Some patients may be misdiagnosed with CTEPH due to the mismatched perfusion defect from V/Q scanning. Suspicion of PVOD should be raised in patients with a history of familial PVOD, a history of underlying autoimmune disease, or a history of chemical/chemotherapeutic drug exposures.

Enhancing Healthcare Team Outcomes

Pulmonary veno-occlusive disease is a rare cause of pulmonary arterial hypertension. The patients typically present with signs of right ventricular dysfunction such as worsening dyspnea on exertion, lower extremity edema, and ascites. The workup of these patients is the same as the workup of pulmonary hypertension itself. This includes echocardiography, chest X-ray, computed tomography of the chest, and right heart catheterization. Given the rare nature of this disease and the complexity of diagnosis and management, a multidisciplinary and interprofessional team approach is crucial.

For patients with family history, genetic tests may be necessary. The early recognition of this disease is ideal as these patients benefit from early referral for lung transplantation. This will require all members of the health care team to be aware of the disease process and its high rate of mortality.

Early referral to a lung transplant center will require the utilization of caseworkers and nurses to facilitate this process. Though most of the initial care will be provided by a pulmonologist, there will need to be involvement of multiple specialties, including cardiology, transplant pulmonology, and radiology. For patients in which medical therapy is attempted, it will require pharmacists' cooperation, guidance, and monitoring of medications prescribed, along with thorough medication reconciliation. 

All interprofessional team members must maintain clear communication channels with all other team members and reach out when any change in patient status is noted, or any intervention may be necessary. Everyone on the management team is responsible for keeping meticulous records of all interactions and interventions so that everyone on the case can access the same accurate, up-to-date information. This interprofessional team approach will optimize patient outcomes for this rare condition. [Level 5]