Continuing Education Activity

A pulmonary arteriovenous malformation (PAVM) is a rare pulmonary condition described as a pathologic right-to-left shunt which impairs gas exchange and normal filtration of venous blood through the pulmonary circulation. PAVMs are most commonly associated with hereditary hemorrhagic telangiectasia (HHT). This activity reviews the evaluation and management of PAVM to prevent complications and highlights the role of the interprofessional team in evaluating and improving care for patients with this condition.

Objectives:

• Identify the etiology of pulmonary arteriovenous malformation.
• Describe the physical exam findings of pulmonary arteriovenous malformation.
• Summarize the treatment options for patients with pulmonary arteriovenous malformation.
• Review pulmonary arteriovenous malformation and summarize the importance of improving care coordination among the interprofessional team to enhance patient care and improve outcomes for patients affected by this condition.

Introduction

Pulmonary arteriovenous malformation (PAVM), a rare pulmonary condition, is defined as a structurally abnormal communication between the pulmonary artery and pulmonary vein, creating a pathologic intrapulmonary right-to-left shunt.[1] This, in turn, impairs regular gas exchange and filtration of systemic venous blood. PAVMs are also known as pulmonary arteriovenous fistulae, pulmonary arteriovenous aneurysms, and pulmonary hemangiomas.[2] These lesions were initially described by Churton in 1897 and were later identified to be associated with hereditary hemorrhagic telangiectasia (HHT) in 1938.[3]

A vast majority of patients with PAVMs can be asymptomatic; however, patients that remain undiagnosed can later present with life-threatening complications such as ischemic stroke, myocardial infarctions, cerebral abscesses, massive hemoptysis, and hemothorax.[1][4] Although there is a relatively low incidence of this condition, it is essential to consider in the differential diagnosis for patients presenting with epistaxis, hypoxemia, and dyspnea with exertion.

Etiology

Pulmonary arteriovenous malformations (PAVMs) can either be congenital or sporadic, with the majority of congenital cases being secondary to HHT. PAVMs can be present from birth and ultimately develop by adult life. Up to 80 to 90% of individuals with PAVMs will later go on to develop HHT.[5]

Sporadic causes of PAVMs are rare and include prior chest surgery, trauma, schistosomiasis, actinomycosis, mitral stenosis, Fanconi’s syndrome, hepatic cirrhosis related hepatopulmonary syndrome, and metastatic carcinoma.[6][7][8][9] They have also been demonstrated to be a complication from congenital heart disease surgery in children.[10] The remainder of PAVMs is thought to be idiopathic.[11]

Epidemiology

Pulmonary arteriovenous malformations (PAVMs) are generally uncommon in the population. In 1953 Johns Hopkins hospital performed an autopsy study with 15,000 cases with only 3 cases of PAVM detected.[2] Investigators believed that small PAVMs could easily be missed during routine biopsies after that new case series by Mayo clinic revealed an incidence of approximately 4.3 cases per year.[12][13][14]

PAVMs are seen twice as often in females than males with a male predominance in newborns.[15][16]

PAVMs are largely associated with hereditary hemorrhagic telangiectasia (HHT), which itself affects approximately 1 in 5,000 to 8,000 people. HHT is an autosomal dominant disorder characterized by the development of AVMs at multiple sites, including mucocutaneous, pulmonary, hepatic, gastrointestinal, and cerebrovascular systems.[17] Approximately 80 to 90% of individuals with PAVMs will have HHT. On the contrary, approximately 15% to 35% of individuals with HHT will develop PAVMs.[18][19]

Pathophysiology

Pulmonary arteriovenous malformations (PAVMs) are predominantly found in the pleura of the lower lobes likely due to increased pulmonary blood flow. Bosher and colleagues reviewed the pathologic anatomy in 350 patients with PAVMs and found that 75% had unilateral disease, whereas 36% had bilateral disease.[20] These lesions can further be classified into simple versus complex, with up to 95% being simple type. A simple type is defined as perfusion by a single segmental artery and venous drainage by a single vein. About 95% of cases are supplied by pulmonary arteries, with the remaining 5% supplied by systemic arteries by way of the aorta, bronchial artery, or intercostal arteries.[7][21] Sizes of these lesions can also vary considerably but are typically 1 to 5 cm in size, with more extensive lesions being the culprit of more severe complications. 

PAVM consists of thin-walled vascular channels that are built by elastic fibers and remnants of smooth muscle cells. The intima can be thickened and partly covered by mural thrombi.[22]

Although the etiology of PAVM is unknown, recent discoveries in genetic mutations of hereditary hemorrhagic telangiectasias have shown relevance in the potential causes. Mutations in the endoglin (ENG) gene, activin receptor-like-kinase-1 (ACVRLI/ALK1) gene, and SMAD4 gene have all been associated with inheritance of HHT. These proteins are components involved in transforming growth factor-β (TGF-β) signaling pathways. Vascular abnormalities seen in PAVM are thought to arise from mutations in these proteins and the resultant imbalances in response to angiogenic factors like vascular endothelial growth factor and defective vascular repair.[23] It has been postulated that mutations in endoglin may result in an abnormal response to TGF-β during vascular remodeling, resulting in the formation of arteriovenous malformations.[24]

There have been numerous proposed theories on the pathogenesis of these lesions. Anabtawi and colleagues hypothesized that lesions were the result of incomplete resorption of the vascular septae that separate arterial and venous plexuses during fetal development.[25] Others have hypothesized that the lesions are due to a defect in terminal arterial loops that allow dilatation of thin-walled capillary sacs.[26]

History and Physical

Congenital cases of pulmonary arteriovenous malformations (PAVMs), although rare, usually present at birth with cyanosis, murmur, and congestive heart failure.[16]

The majority of cases often develop by the fourth and sixth decades of life. However, patients with hereditary hemorrhagic telangiectasia (HHT) typically develop symptoms by the second decade of life.

The most common complaint in patients with underlying HHT is epistaxis, caused by bleeding from mucosal telangiectasias.[1]

Dyspnea is the second most common symptom, with an incidence of 13% to 56%. It is most common among patients that have clubbing or whose PAVMs are large or multiple.[27] Some patients have platypnea, which is thought to be secondary to decreased blood flow through PAVM in the dependent lung portions while supine.[28]

Other features include hypoxemia, exercise intolerance, chest pain, cough, murmurs, bruits, clubbing, and cyanosis.

Evaluation

Patients presenting with radiographic evidence of pulmonary nodules, suspected or known diagnosis of hereditary hemorrhagic telangiectasia or unexplained findings such as hypoxemia, dyspnea, hemoptysis, cyanosis, clubbing, or brain abscess should prompt further investigation.

Shunt Fraction Measurement

The normal fraction of cardiac output that shunts from right-to-left is less than 5%. In patients with pulmonary arteriovenous malformations (PAVMs), this fraction is increased. Dines and colleagues found that out of 21 patients with PAVM who underwent shunt determination were found to have shunts between 9.5 and 42%.[13] Shunt fraction is done by breathing 100% oxygen for 15 to 20 minutes, then measuring the PaO2 and SaO2.[29] Those measurements are then used to determine the shunt fraction-a shunt fraction of more than 5% warrants further evaluation.

Chest Radiography

Chest radiography is a simple, inexpensive, low radiation technique that should be used for the initial screening of a PAVM. Frontal and lateral views should be obtained. Typical PAVMs should appear as well-defined lesions with feeding vessels on radiography. This imaging modality, however, has a low sensitivity for detecting smaller sized PAVMs.[30]

Transthoracic Contrast Echocardiography (TTCE)

The screening test of choice is transthoracic contrast echocardiography (TTCE), which has a sensitivity of 95%-100%.[31] This test is simple, non-invasive, and associated with low false-negative rates, in one study, positive and negative predictive values of 96% and 100%, respectively.[32] It involves introducing 10 mL of agitated saline into the peripheral circulation and observing its course through the cardiac system with echocardiography. A positive result is seen with the presence of bubbles in the left cardiac chamber after three to eight cardiac cycles.[33] TTCE can also provide information on the likelihood of future neurologic events based on pulmonary shunt grading. Pulmonary shunt grade 1 or (<30 microbubbles), is not associated with an increased prevalence of CNS events, whereas grade 2 (30-100 microbubbles) and grade 3 (>100 microbubbles) are predictors of CNS events.[34]

Radionuclide Perfusion Lung Scanning

This test can be useful in situations where echocardiography or the 100 percent oxygen method is not readily available. It involves the peripheral injection of macro aggregated albumin labeled with technetium-99m (99mTc). In healthy individuals, the radiolabeled particles will be filtered by pulmonary capillaries. When a right-to-left shunt is present, such as a pulmonary arteriovenous malformation, the radiolabeled particles pass through the lungs and are subsequently filtered by capillary beds in other organs such as the brain and kidneys.[1] The shunt fraction is calculated by quantifying the renal uptake as a percentage of the total dose given. The disadvantages are that it is an expensive test and not routinely available at most institutions. Besides, this test is unable to differentiate between intrapulmonary and intracardiac shunts.

Computed Tomography (CT)

CT is the imaging modality of choice for confirmation of PAVM and should be performed in patients with either high suspicion of PAVM or grade 2 or 3 shunts by TTCE. Contrast enhancement will show a PAVM sac with both feeding and draining vessels. Generally, if the CT scan shows one or more PAVM with a feeding artery diameter ≥ 2 to 3 mm, the patient should be referred for pulmonary angiography. If the feeding artery diameter is < 2 mm, pulmonary angiography can be deferred unless there are clinical features suggestive of symptomatic PAVM.[35]

Pulmonary Angiography

Pulmonary angiography is the gold standard for diagnosis of PAVM and is utilized to define the vascular anatomy for cases that are suitable for embolization therapy. Contrast is directly introduced into the feeding artery to determine the vasculature of the lesion accurately. Contrast is also injected into the left and right main pulmonary arteries to detect additional lesions that are also amenable to embolization therapy.[1]

Other Diagnostic Tests

Contrast-enhanced magnetic resonance angiography (MRA) is not currently used for screening of PAVM. This modality is accurate in the detection of PAVM; however, it is expensive, not routinely available, and requires specialized expertise in the interpretation of imaging.

Screening for HHT

In patients without a known diagnosis of HHT with high suspicion of a PAVM, it is vital to perform a thorough history and physical exam for supporting evidence of the diagnosis. Family members of patients with HHT should also be routinely screened, as there is a high incidence of unsuspected pulmonary and cerebral AVM in family members of patients with HHT.[18] It has been reported that in HHT families in which one person has PAVM, the incidence of another family member having PAVMs in about 35%.[36]

If available, routine genetic screening is preferred in all family members. In patients found to have HHT genotype, further investigation would include chest radiography and shunt fraction measurement. In those instances where genetic testing is not available, screening protocols can be used as described by Haitjema and colleagues.[37]

Treatment / Management

The main implication for the treatment of pulmonary arteriovenous malformations (PAVMs) is to prevent cerebral abscesses, stroke, and improve exercise tolerance and hypoxemia.

Patients are best managed at facilities such as hereditary hemorrhagic telangiectasia centers, where there are experts in PAVM treatment.[38] This is done to facilitate the best outcome possible, given the potential complexity of each case.

Deciding whether treatment should be offered to patients is dependent on factors such as the presence of symptoms, the feeding artery diameter, and if the patient is capable of tolerating the procedure. Patients who are asymptomatic with a feeding artery diameter (FAD) of less than 2 mm can be observed clinically, whereas patients who are symptomatic with lesions less than 2 mm or presence of grade 3 shunting warrant further treatment.

Embolization Therapy

The most widely used and successful form of treatment is percutaneous transcatheter embolization, which involves the occlusion of the feeding artery of the PAVM. Previously in the 1990s, only lesions with a feeding artery diameter of 3 mm or more were considered for embolization therapy. Since then, it has been reported that paradoxical emboli can occur independently of the FAD. Given these findings, embolization is now being recommended in lesions with a feeding artery diameter of less than 3 mm.[38][39]

Embolotherapy can be done using either a coil or a balloon. Both techniques involve the localization of the feeding artery via angiography. A steel coil or balloon is advanced through the catheter and released at the site of the artery to disrupt blood flow. A pulmonary angiogram is repeated to ensure PAVM occlusion.[40]

The most common complication of embolization therapy is self-limiting pleuritic chest pain, reported in 5% to 13% of cases. Less common complications include stroke, transient ischemic attack, and transient air embolization.[1][4]

Follow-up is recommended three to six months post-embolization with contrast-enhanced chest computed tomography and transthoracic echocardiography and is used to confirm closure of the PAVM. If a PAVM persists at one year following initial treatment, repeat pulmonary angiography, and transcatheter embolization are indicated.[41] Patients can develop new pulmonary hypertension or a worsening of baseline pulmonary hypertension after embolization or extensive PAVM resection.[42]

Alternative Treatment

Surgical excision is recommended in patients who fail embolization therapy or in patients with life-threatening pulmonary hemorrhage from a ruptured PAVM.

Lung transplantation is an option for those patients who are refractory to repeated embolization, usually in those with bilateral disease or those considered to have a high risk of mortality.

Adjunctive Therapy

Given the high risk of air embolism in these patients, the administration of intravenous fluids or medications should be done with caution. Scuba diving should also be avoided in this population.

Lastly, all patients should be given lifelong antibiotic prophylaxis before dental or surgical procedures to avoid the development of bacteremia and brain abscesses. This is recommended, even after embolization therapy.[43][44] A preliminary study has shown a decrease in the duration and the number of epistaxis episodes with bevacizumab.[45]

Differential Diagnosis

The clinical features and radiological findings of pulmonary arteriovenous malformations (PAVMs) resemble many other diseases. The following differentials should be kept in mind when assessing a patient of PAVM.

• Pulmonary contusion
• Pulmonary hamartoma
• Pulmonary infarct
• Bronchogenic cyst
• Pulmonary varices
• Pulmonary bronchocele
• Pulmonary artery aneurysm
• Primary lung malignancy
• Carcinoid tumor
• Metastatic disease
• Calcified or infectious granuloma.[46][47]

Prognosis

Pulmonary arteriovenous malformations (PAVMs) do not spontaneously resolve. Most remain stable in size, although approximately 25% of PAVMs can enlarge in size at a rate of 0.2 to 0.3 mm a year.[12][18]

Although correct estimates of morbidity and mortality are lacking, PAVMs are known to carry high morbidity and mortality precisely due to the development of serious complications such as stroke and brain abscess. PAVM that remain untreated is associated with a mortality of up to 50% compared to 3% in those that are treated.[27][48][49]

Complications

Complications of pulmonary arteriovenous malformations (PAVMs) are thought to be secondary to paradoxical emboli. The most common neurologic sequelae include stroke and brain abscesses. The prevalence of these complications is seen in patients with multiple PAVMs.[5]

Other complications include:[17]

• Syncope
• Diplopia
• Tinnitus
• Migraine
• Headache
• Transient ischemic attack
• Seizures
• Cerebral arteriovenous malformations
• Congestive heart failure
• Hemoptysis
• Hemothorax or pulmonary hemorrhage
• Pulmonary hypertension
• Anemia
• Infective endocarditis
• Myocardial infarction

Deterrence and Patient Education

Given the potential for life-threatening complications, patients with pulmonary arteriovenous malformations (PAVMs) should undergo thorough evaluation including history and physical exam, along with the appropriate genetic testing for hereditary hemorrhagic telangiectasia. Clinical signs, symptoms, and complications should be reviewed with patients beforehand. Close follow-up is also recommended in order to monitor disease progression or possible complications from interventions performed.

Enhancing Healthcare Team Outcomes

The diagnosis of pulmonary arteriovenous malformation (PAVM) requires a high index of suspicion, as this a rare condition. It is crucial to consider PAVM in the differential of patients presenting with complaints of epistaxis, hemoptysis, shortness of breath, and exercise intolerance. Besides, any patient presenting with radiographic evidence of pulmonary nodules, suspected or known diagnosis of hereditary hemorrhagic telangiectasia, or unexplained findings such as hypoxemia, dyspnea, hemoptysis, cyanosis, clubbing, or brain abscess should prompt further investigation.

A thorough evaluation with history, physical exam, ancillary imaging such as contrast-enhanced CT to further support the diagnosis. As this condition is highly associated with HHT, patients should routinely undergo genetic testing, especially those with a family history. Lesions that are identified on CT should undergo further evaluation with pulmonary angiography. Although there are no clear guidelines in the definitive management of PAVMs, it has been recommended that those with a feeding artery diameter of less than 3 mm should undergo embolization therapy (Level II).[39][50] Future randomized control studies are necessary further to delineate guidelines for the management of these patients.

The importance of diagnosis and treatment in this condition is to prevent the life-threatening and debilitating complications of untreated lesions such as stroke, seizures, and brain abscesses. All patients should be educated on these complications and the importance of interval follow-up and imaging. It is recommended that patients with HHT should be followed at an HHT center.[50]