Pulmonary Veno-Occlusive Disease

What is Pulmonary Veno-Occlusive Disease?

Pulmonary hypertension (PH) is a health condition in which the blood pressure in the arteries that carry blood from your heart to your lungs is higher than 20 mmHg at rest. It’s a complex and varied disease that can come from different causes, fall into different types, and be classified in various ways. The World Health Organization (WHO) has grouped pulmonary hypertension into five main types depending on the cause, common symptoms, and how it’s usually treated.

The first group is known as pulmonary arterial hypertension (PAH), while the second type is due to heart disease. The third group is related to lung disease or low oxygen levels, and the fourth is caused by blockages in the pulmonary artery, like Chronic Thromboembolic Pulmonary Hypertension (CTEPH). The fifth type has unclear causes or can be due to multiple factors.

Pulmonary veno-occlusive disease (PVOD) is a rare form of PAH, where the small veins in the lungs get blocked, causing an increase in blood pressure in the lungs and possibly right-sided heart failure. Despite being first described in 1934, our understanding of this disease remains limited.

Its signs and symptoms can be quite vague and can resemble conditions like congestive heart failure, idiopathic pulmonary arterial hypertension (a type of PAH without a known cause), and restrictive lung diseases such as pulmonary fibrosis. The best way to diagnose it is through a biopsy, but this is often too risky for patients with pulmonary hypertension due to the high risk of complications from the procedure, such as severe bleeding.

There is currently no medically supported treatment, and the only cure is a lung transplant. Unfortunately, the outlook for patients with PVOD is not good, with an average life expectancy of two years after symptoms start showing.

What Causes Pulmonary Veno-Occlusive Disease?

Both inherited (familial) and individual (sporadic) cases of a lung condition called pulmonary veno-occlusive disease (PVOD) have been identified in people. The first reported cases of familial PVOD were documented in 1977. In 2013, a group of French researchers found that all the familial cases of PVOD they studied, and a quarter of the individual ones, have a type of gene change, or mutation, which stops a gene called EIF2AK4 from working correctly. It’s not clear how this mutation leads to PVOD, but it has been seen in several reports.

Another gene linked to PVOD is BMPR2. Individual cases of PVOD have been connected to a variety of factors, including chemotherapy drugs like mitomycin, exposure to certain chemicals like trichloroethylene, autoimmune and connective tissue disorders such as systemic sclerosis, HIV infection, radiation, and bone marrow transplants.

Mitomycin C (MMC), a chemotherapy drug, has been closely studied in relation to PVOD. Research has shown that applying MMC inside the abdomen of rats results in the animals developing high blood pressure in the lungs, right-side heart enlargement, and other changes consistent with PVOD.

The same research team found seven recent human cases of PVOD in patients who received MMC treatment for squamous cell anal cancer. Most of these patients tested negative for the EIF2AK4 and BMPR2 gene mutations; only one was HIV positive. Of these patients, two were treated only with MMC, and five were treated with MMC and another chemotherapy drug, fluorouracil (FU).

MMC is often used alongside other cancer drugs, and it remains uncertain if these other medications have any role in causing PVOD. For instance, the French researchers found that five patients were also using fluorouracil, but stated it was not possible to test the role of this drug in causing PVOD. There are other reports of MMC-linked PVOD in patients with different types of cancers, such as breast and cervical cancers. Other chemotherapy drugs frequently associated with PVOD include cyclophosphamide, cisplatin, carmustine, doxorubicin, vincristine, etoposide, and methotrexate.

Being exposed to certain chemicals, predominantly trichloroethylene, has also been implicated in causing PVOD. A study in 2015 that surveyed people with PVOD and another lung condition, pulmonary arterial hypertension (PAH), found that exposure to organic solvents was significantly more prevalent in people with PVOD.

The study also identified that those with EIF2AK4 mutations had been exposed to very little trichloroethylene, and were typically younger than those without this mutation. This suggests that the disease is more aggressive in those with the EIF2AK4 mutation, and can take a long time to develop in people without this mutation.

Autoimmune and connective disorders like systemic sclerosis are already known to trigger PAH and a type of high lung blood pressure caused by lung disease (PH-ILD). Recently, it’s been suggested that PVOD might be the cause of these conditions being resistant to treatment. One research project compared lung samples from patients with connective tissue diseases to patients without such a history and found that these diseases were linked to PVOD far more often.

Another study, conducted at the University of Pittsburgh in 2019, found even stronger evidence of this link amongst a group of patient lung samples. The link between PVOD and systemic sclerosis has been found in patients with both systemic and limited scleroderma, a condition that leads to skin hardening and tightening.

Smoking is seen more often in PVOD patients compared with PAH ones. Other risk factors mentioned in various reports include radiation therapy for cancers, bone marrow transplants, and HIV infection.

Risk Factors and Frequency for Pulmonary Veno-Occlusive Disease

Pulmonary veno-occlusive disease (PVOD) isn’t very common, and the exact numbers of people affected is unknown. The estimates suggest that PVOD could impact between 1 to 2 people out of 10 million population. It’s estimated that PVOD makes up about 3 to 12% of all cases initially diagnosed as primary or unexplained high blood pressure in the lungs.

• PVOD affects both males and females equally, which is different from PAH that primarily affects females.
• However, when it comes to cases that aren’t inherited, males are more likely to be affected than females.
• The disease tends to affect people in two age groups – children and younger adults who inherited it, and older adults who did not.

Signs and Symptoms of Pulmonary Veno-Occlusive Disease

Pulmonary veno-occlusive disease is a condition that usually shows similar signs and symptoms to other types of pulmonary arterial hypertension. Most people with this disease will show signs of right-sided heart failure. This might mean they have swollen legs (edema), fluid in their abdomen (ascites), and too much blood and other fluids in the body (volume overload). They often experience difficulty breathing when active (dyspnea on exertion) and discomfort when lying flat (orthopnea).

During a physical examination, doctors might hear various abnormalities when listening to the patient’s heart. These could include a specific type of heart sound (split S2), an unusually loud sound (loud P2), or a crackling noise. Patients might also show signs of a blue or purple tint to their skin, lips, or fingernails (cyanosis), indicating a lack of oxygen. These symptoms are signs of increasing dysfunction in the right ventricle of the heart, which pumps blood to the lungs.

As the condition progresses, doctors might hear heart murmurs on the right side of the patient’s chest from issues with the tricuspid valve (tricuspid regurgitation).

• Swollen legs (edema)
• Fluid accumulation in the abdomen (ascites)
• Volume overload
• Difficulty breathing during physical activity
• Discomfort when lying flat
• Split S2 heart sound
• Loud P2 heart sound
• Crackling noise from the heart
• A blue or purple tint to the skin, lips, or fingernails
• Heart murmurs on the right side of the chest due to tricuspid valve issues

Testing for Pulmonary Veno-Occlusive Disease

If you’re feeling short of breath and have symptoms like those associated with heart failure, doctors will use a variety of methods to figure out what’s causing it.

The first step is usually an x-ray of your chest, which can show whether your central lung arteries have grown larger and if there’s too much blood in your blood vessels.

A Computed Tomography (CT scan) of your chest may also be performed. This scan can provide more detailed images and evidence of high pressure in your lungs. This can show up as larger lung arteries, or even an enlarged right side of the heart. The scan might also show signs of lung congestion such as uneven lung tissue with patches of dense opacity (like a foggy window), scattered lung nodules, enlarged lymph nodes in the chest, and a smooth thickening of the walls between lung lobules [43].

Lung function tests known as spirometry may also be performed. While these tests usually show normal results, sometimes they might indicate mild restrictions in your lung capacity [44]. Another test called DLCO, which measures how well your lungs take up oxygen, is generally found to be lower than normal [44].

An ultrasound of your heart, or echocardiogram, may also reveal signs of pulmonary hypertension (high blood pressure in the lungs). This could include high pressure in your lung’s arteries, an enlarged and strained right side of your heart, and poor functioning of the right side of your heart. This test will also help rule out diseases of the left side of the heart being the cause of lung saturation.

A ventilation and perfusion scanning (V/Q scan) is often used to evaluate patients with suspected pulmonary arterial hypertension (PAH), a type of high blood pressure that affects the arteries in the lungs. However, this test is not very useful for diagnosing pulmonary veno-occlusive disease (PVOD) as it usually shows normal results or incorrectly diagnoses another condition [45].

A procedure, known as right heart catheterization is necessary to diagnose high blood pressure in the lungs. With this procedure, doctors measure the average pressure in your lung arteries, the pressure in the capillaries of the lungs and the resistance of the blood vessels in your lungs [6].

While there are no specific findings on a heart catheterization test for PVOD, some findings could indicate its presence. One example is if you suddenly develop lung congestion (accumulation of fluid) during a vasoreactivity test. This test is often done to see if certain medications used for pulmonary arterial hypertension treatment could be helpful. Another possible sign of PVOD may be an unusual rise and drop in the pressure of lung capillaries when saline is flushed through a port at the end of the instrument used during the testing process [47].

Examining lung tissue under a microscope is the most surefire way to diagnose PVOD; however, this is generally avoided due to the high risk of serious bleeding. Doctors recommend using a combination of your symptoms and noninvasive tests to diagnose PVOD [32].

If you have a family history of PVOD or idiopathic pulmonary arterial hypertension (IPAH), genetic testing for certain BMPR2 or EIF2AK4 mutations might also be done at some centers.

Supportive measures are important when treating people with pulmonary veno-occlusive disease (PVOD). This includes giving them extra oxygen if they’re not getting enough, to prevent their condition from getting worse. Doctors may also prescribe water pills, also known as diuretics, to help regulate the patient’s fluid levels. However, blood thinners are usually not recommended for people with PVOD.

Standard medicines that open up the blood vessels in the lungs do not usually help people with PVOD. They were originally thought to increase the risk of fluid build-up in the lungs. This happens because these medicines open up the blood vessels near the heart faster than those near the lungs. This creates a pressure imbalance, forcing fluid into the lungs.

However, recent findings suggest that these drugs may be safe for people with PVOD if used carefully. A review in 2019 looked at 20 cases where they seemed effective. But it’s important to note that using these drugs can be difficult and risky. Starting with a low dose of a single medicine, with close monitoring, is recommended if this approach is considered. These medicines can either slow the disease in patients who won’t have a lung transplant, or be used in preparation for a transplant.

Immunosuppressive drugs, which reduce the body’s immune response, could also help certain PVOD patients. They’re thought to work by easing the inflammation involved in the disease.

A lung transplant is the only cure for PVOD. If someone is suspected of having PVOD, a doctor should discuss a lung transplant with them early in their treatment, as it’s the only therapy proven to prolong their life.

What else can Pulmonary Veno-Occlusive Disease be?

People with Pulmonary Veno-Occlusive Disease (PVOD) often exhibit symptoms similar to other conditions, which can make diagnosis difficult. Here are some conditions that might present similarly:

• Congestive heart failure (CHF): Symptoms such as shortness of breath, difficulty breathing during physical activity, and swelling in the legs could suggest either PVOD or CHF. Chest scans can show signs of congestion in both conditions. But the use of heart imaging techniques can distinguish between the two, as CHF usually results in malfunction of the left side of the heart.
• Chronic Pulmonary Hypertension due to blood clots (CTEPH): People with PVOD and CTEPH can exhibit similar symptoms. A specific type of lung scan in PVOD might show signs that can be mistaken for CTEPH. However, people with CTEPH are less likely to have signs of congestion on chest scans.
• Idiopathic Pulmonary Arterial Hypertension (IPAH): Both PVOD and IPAH can share similar symptoms and findings from right heart catheterization (a procedure to examine how well your heart is working). However, people with IPAH usually do not show congestion in chest imaging.
• Interstitial Lung Diseases (ILD): Certain ILDs, such as sarcoidosis, can appear similar to PVOD in chest images. However, people with ILDs might experience other symptoms that could point to their condition, including chronic coughs (either dry or with mucus), wheezing, and systemic symptoms like fever, night sweats, and weight loss.

Thus, careful and thorough examination is crucial to distinguish between PVOD and these other conditions.

What to expect with Pulmonary Veno-Occlusive Disease

On the whole, the outlook isn’t optimistic. It’s been reported that around 72% of patients don’t survive past the first year after diagnosis. Unfortunately, there hasn’t been any research conducted to evaluate the potential benefits of medical therapy for these patients.

Most people diagnosed with this condition either pass away or need a lung transplant within two years. Patients who get a lung or heart-lung transplant have similar outcomes to those of other patients dealing with pulmonary arterial hypertension (a type of high blood pressure that affects arteries in the lungs and the right side of the heart) who’ve also had a transplant.

Possible Complications When Diagnosed with Pulmonary Veno-Occlusive Disease

The potential complications for these individuals can be compared to those seen in patients with high blood pressure in the lungs or pulmonary arterial hypertension. The main problem is an increase in the resistance of blood vessels in the lungs. This condition adds extra stress to the right side of the heart, which has to work harder.

At the beginning, the right ventricle, which is the lower chamber on the right side of the heart, can handle the additional load by contracting more strongly without expanding in size. As the disease progresses, however, the right ventricle is no longer able to keep up with the added pressure. It begins to stretch out and bulge, a condition known as dilation. It can even develop a condition called myocardial fibrosis, which involves the buildup of hard fibrous tissue in the heart muscle.

The heart’s output of blood, known as cardiac output, gradually decreases. Eventually, this leads to a condition called right-sided heart failure. This can result in a backed up and overloaded blood flow from the veins, which is referred to as systemic venous congestion.

To summarize, the potential complications include:

• High blood pressure in the lungs
• Increase in resistance of lung blood vessels
• Extra stress on the heart
• Right ventricle dilation
• Myocardial fibrosis in the heart muscle
• Decreased cardiac output
• Right-sided heart failure
• Systemic venous congestion or overloaded blood flow from veins

Preventing Pulmonary Veno-Occlusive Disease

Pulmonary hypertension refers to high blood pressure in the arteries that supply blood to the lungs. A rare cause of this condition is Pulmonary Veno-Occlusive Disease, which mainly affects the veins in the lungs.

The early signs for patients usually include feeling short of breath or having swollen legs. Over time, these symptoms can get worse, with increased difficulty breathing, swelling in the stomach, and low levels of oxygen in the body.

To diagnose Pulmonary Veno-Occlusive Disease, a physician often refers to tests like an echocardiogram, a test that uses ultrasound to provide a picture of the heart. Other tests could include a chest X-ray, a chest CT scan, and eventually, a procedure known as a right heart catheterization. This procedure involves a doctor inserting a thin tube (a catheter) into a vein, then advancing it into the artery that goes to the lung. Here, they can confirm if the patient has pulmonary hypertension.

If there’s a history of this disorder in the family, genetic testing may be performed as well.

If a patient is diagnosed with Pulmonary Veno-Occlusive Disease, treatment usually involves diuretics, medicines used to help the body get rid of extra fluid. Right now, a lung transplant is the only known cure for this disease. It’s essential for patients to understand this so that they can have reasonable expectations about their treatment.