Pulmonary Arteriovenous Malformation

Etiology

PAVMs can be either congenital or sporadic. In most congenital cases, the malformations are secondary to HHT. PAVMs may be present from birth and continue developing in adulthood. Notably, up to 80% to 90% of individuals with PAVMs may later develop HHT.[5] On the other hand, approximately 30% to 50 % of patients with HHT will have PAVMs.[6]

Sporadic cases of PAVMs are uncommon and encompass various conditions such as hepatic cirrhosis, prior chest surgery, trauma, schistosomiasis, actinomycosis, mitral stenosis, Fanconi syndrome, hepatic cirrhosis-related hepatopulmonary syndrome, and metastatic carcinoma.[7][8][9][10] PAVMs have been reported as a complication following congenital heart disease surgery in children, where the formation of abnormal communications between the pulmonary artery and vein, characteristic of PAVMs, can occur as a consequence of these surgical procedures.[11] The remaining cases of PAVMs are thought to be idiopathic.[12]

Epidemiology

PAVMs are relatively uncommon, and their detection can vary based on the methods used for examination. Autopsy studies, such as the one at Johns Hopkins Hospital in 1953, might underestimate the prevalence of PAVMs, especially if they are small and not easily identified during routine biopsies. Subsequent case series from Mayo Clinic, have provided a more accurate estimation of the incidence of PAVMs. The reported incidence of approximately 4.3 cases per year in the Mayo Clinic series reflects a more refined understanding of the prevalence of PAVMs in the population.[13][14][15] In a large population study involving over 21,000 thoracic computed tomography (CT) scans, the reported prevalence of PAVMs was approximately 1 in 2,600, with 95% confidence intervals ranging from 1 in 1,315 to 1 in 5,555.[16] PAVMs are observed twice as often in females than in males.[17][18] Most PAVMs (over 90%) are typically unilateral and solitary.[19] 

PAVMs are commonly associated with HHT, an autosomal dominant disorder that affects approximately 1 in 5,000 to 8,000 people. This genetic condition is characterized by the development of arteriovenous malformations (AVMs) at various sites in the body, including the mucocutaneous, pulmonary, hepatic, gastrointestinal, and cerebrovascular systems. The association between PAVMs and HHT highlights the importance of considering genetic factors in developing these malformations.[20] 

In individuals with HHT, PAVMs show a more balanced distribution across genders, with approximately half affecting women. These malformations in patients with HHT are often multiple and evenly spread throughout the lungs. The distinctive features of PAVMs in the context of HHT contribute to the complex clinical manifestations associated with this genetic disorder.[21] Given the strong association between HHT and PAVMs, screening for PAVMs is recommended for individuals diagnosed with HHT. This proactive approach to screening helps in the early detection of PAVMs, enabling timely management and reducing the risk of associated complications.[22]

Pathophysiology

The exact pathogenesis of PAVMs remains uncertain, but various causes have been suggested. PAVMs are predominantly located in the pleura of the lower lobes, likely attributed to increased pulmonary blood flow. These lesions can be categorized as simple or complex, with approximately 95% being of the simple type. Simple PAVMs are characterized by perfusion from a single segmental artery and venous drainage through a single vein. In most cases (95%), the blood supply is from pulmonary arteries, while the remaining 5% receive supply from systemic arteries through the aorta, bronchial artery, or intercostal arteries. The size of these lesions can vary but typically ranges from 1 to 5 cm, with larger lesions associated with more severe complications.[8][23] 

PAVMs consist of thin-walled vascular channels constructed from elastic fibers and remnants of smooth muscle cells. The intima may exhibit thickening and partial coverage by mural thrombi.[24]

Recent research has uncovered genetic mutations in proteins involved in vascular development, particularly in individuals with HHT. Mutations in the endoglin gene, activin receptor-like-kinase-1 (ACVRL1/ALK1) gene, and SMAD4 gene, all associated with HHT inheritance, play roles in transforming growth factor-β (TGF-β) signaling pathways. PAVM-related vascular abnormalities are thought to arise from these mutations, leading to imbalances in responses to angiogenic factors like vascular endothelial growth factor and defective vascular repair.[25] Mutations in endoglin, in particular, may result in abnormal responses to TGF-β during vascular remodeling, contributing to AVMs.[26] Mainly, mutations in endoglin may result in abnormal responses to TGF-β during vascular remodeling, contributing to AVMs. These mutations can lead to incomplete resorption of vascular septae during fetal development, forming PAVMs.

Additionally, there may be a failure of capillary development in fetal stages, causing dilation of favored limbs within smaller plexuses, leading to the formation of multiloculated sacs and eventual rupture of intervening vascular walls. This complex process contributes to developing numerous small PAVMs with a single artery-to-vein connection without an intervening plexus.[1][27] Others have hypothesized that the lesions are due to a defect in terminal arterial loops that allow dilatation of thin-walled capillary sacs.[28]

History and Physical

The majority of individuals with PAVMs are asymptomatic, and these anomalies are often discovered incidentally during chest imaging or as part of screening for individuals with known or suspected HHT. Congenital cases of PAVMs, though rare, typically manifest at birth with symptoms such as cyanosis, murmur, and congestive heart failure.[18] Most cases of PAVMs develop between the fourth and sixth decades of life, but individuals with HHT tend to experience symptoms by the second decade.

The most common symptom in those with underlying HHT is epistaxis, resulting from bleeding from mucosal telangiectasias.[1] Dyspnea is the second most common symptom, with an incidence of 13% to 56%. It is more prevalent among patients with clubbing or those with large or multiple PAVMs.[29]] The mechanism of dyspnea in individuals with PAVMs is not fully understood but may be associated with hypoxemia resulting from shunting or airflow limitation.[30]

Some patients exhibit platypnea, a classic but rare symptom attributed to increased blood flow through PAVMs in the dependent lung portions when upright.[31] This positional symptom is often relieved when the patient assumes a recumbent position, highlighting the dynamic nature of the vascular abnormalities associated with PAVMs.

Hemoptysis can occur due to the rupture of endobronchial or intraparenchymal PAVMs and is observed in nearly a third of patients with PAVM. This complication can be life-threatening, necessitating urgent evaluation.[32] PAVMs should be considered in patients experiencing unexplained dyspnea or hypoxemia. Furthermore, in individuals with nodules and a history of stroke or brain abscess, common complications of PAVMs, suspicion for the presence of PAVMs should be raised. The likely mechanism of stroke in PAVMs is paradoxical embolization.[33] 

Other associated features include hypoxemia, exercise intolerance, chest pain, cough, murmurs, bruits, clubbing, and cyanosis. These symptoms and signs contribute to the diverse clinical presentation of individuals with PAVMs, emphasizing the importance of a comprehensive evaluation for timely diagnosis and management.

Approximately one-third of patients with PAVMs may have orthodeoxia, defined as a decrease in oxyhemoglobin saturation by 2% or more when transitioning from the supine to the upright position.[34] Orthodeoxia and platypnea may also be present in other conditions, such as hepatopulmonary syndrome and atrial septal defects.

Symptoms may exacerbate during pregnancy, especially in the third trimester, due to increased blood volume, elevated cardiac output, and heightened vascular distensibility. These physiological changes lead to augmented blood flow through PAVMs, potentially exacerbating symptoms in affected individuals.

Evaluation

Patients presenting with radiographic evidence of pulmonary nodules, a suspected or known diagnosis of HHT, or unexplained findings such as hypoxemia, dyspnea, hemoptysis, cyanosis, clubbing, or brain abscess should prompt further investigation. Several noninvasive methods are available to assess PAVMs, including quantitative right-to-left shunt studies using the 100% oxygen method or radionuclide perfusion scanning. Contrast echocardiography and thoracic imaging studies, such as chest roentgenograms and contrast-enhanced CT scans, are also employed. However, the gold standard for diagnosing PAVMs has traditionally been pulmonary angiography.[35]

Shunt Fraction Measurement

The normal fraction of cardiac output that shunts from right to left is less than 5%. In patients with PAVMs, this fraction is increased.[14] Shunt fraction measurement is conducted by having the patient breathe 100% oxygen for 15 to 20 minutes, then measuring the PaO2 and SaO2. A more than 5% shunt fraction indicates abnormal shunting, warranting further evaluation.[36] 

Chest Radiography

Chest radiography is a simple, inexpensive, low-radiation technique for initial screening. However, it is not as sensitive for detecting smaller-sized PAVMs, and in such cases, additional imaging modalities with higher sensitivity may be warranted for a more comprehensive assessment.[37]

Transthoracic Contrast Echocardiography 

The screening test of choice is transthoracic saline bubble contrast echocardiography (TTCE), which has a sensitivity of 95% to 100%.[38] This involves introducing agitated saline (10 mL) into the peripheral circulation and observing its course through the cardiac system with echocardiography.[39] Positive results indicate the presence of bubbles in the left cardiac chamber.[40] TTCE can also provide information on the likelihood of future neurologic events based on pulmonary shunt grading. Pulmonary shunt grade 1 (<30 microbubbles) is not associated with an increased prevalence of central nervous system (CNS) events, whereas grade 2 (30 to 100 microbubbles) and grade 3 (>100 microbubbles) are predictors of CNS events.[41]

Radionuclide Perfusion Lung Scanning

This test involves the injection of macro aggregated albumin labeled with technetium-99m (99mTc). It can be helpful when other methods are not readily available. In healthy individuals, the radiolabeled particles will be filtered by pulmonary capillaries. When a right-to-left shunt is present, such as a PAVM, 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. This process involves injecting macro aggregated albumin labeled with 99mTc) and then measuring how much radiolabeled particles pass through the lungs and are subsequently filtered by capillary beds in other organs.

There are some disadvantages associated with this test:

1. Expense: The test is considered expensive, which can limit its routine use, and it may not be readily available at all institutions.

2. Differentiation between shunt types: The test cannot differentiate between intrapulmonary and intracardiac shunts. 

Despite these limitations, when other methods, such as echocardiography or the 100% oxygen method, are not readily available or feasible, radionuclide perfusion lung scanning can be a helpful alternative for detecting right-to-left shunts indicative of PAVMs. The choice of diagnostic method often depends on factors such as availability, cost, and the specific clinical context.

Computed Tomography 

A contrast-enhanced chest CT scan is the imaging modality of choice for confirming the presence and visualization of the PAVMs. 

• Indications for CT:
  • High suspicion of PAVMs: CT is recommended in patients with a high suspicion of PAVMs, especially when they present with symptoms or have abnormal findings on screening tests.
  • Positive TTCE: If TTCE shows grade 2 or 3 shunts (indicating a significant right-to-left shunt), CT is often performed for further evaluation.

• Criteria for referral for pulmonary angiography:
  • Feeding artery diameter: The decision to refer a patient for pulmonary angiography is often based on the size of the feeding artery observed on CT.
  • Threshold diameter: If the CT scan shows ≥1 PAVM with a feeding artery diameter ≥2 to 3 mm, this may be considered a threshold for referral for pulmonary angiography.

• Considerations for pulmonary angiography:
  • Feeding artery diameter <2 mm: If the feeding artery diameter is <2 mm, pulmonary angiography may be deferred unless there are clinical features suggestive of symptomatic PAVM.
  • Clinical features: Symptoms or clinical features that may prompt referral for angiography could include conditions like unexplained dyspnea, hypoxemia, or other signs of PAVM-related complications. 

It is important to note that the decision-making process involves careful consideration of clinical and imaging findings. The goal is to identify and characterize PAVMs accurately, assess their size and hemodynamic significance, and determine the need for further intervention, such as embolization. The management approach may vary based on individual patient characteristics and the severity of PAVMs.[42] 

If the CT scan does not detect PAVMs but shunting is observed on TTCE, microscopic PAVMs may cause the shunt, and follow-up, as described above, is advisable (ie, yearly clinical evaluation and at appropriate intervals if symptomatic). The established recommendation is to repeat assessment at 3- to 5-year intervals.[35]

If the CT scan is inconclusive (eg, atypical features suggestive but not diagnostic of PAVM), further evaluation should be individualized. When clinical suspicion is high, performing contrast pulmonary angiography and indeterminate CT scans is recommended in patients with high-grade shunts. However, observation with follow-up TTCE or CT is also appropriate, especially for those with minimal symptoms or a low-grade shunt.[43]

Pulmonary Angiography

Pulmonary angiography is the gold standard for diagnosing PAVM and is utilized to define the vascular anatomy for cases suitable for embolization therapy. Contrast is directly introduced into the feeding artery to accurately determine the vasculature of the lesion. Additionally, contrast is injected into the left and right main pulmonary arteries to detect additional lesions amenable to embolization therapy.[1] For individuals who do not undergo angiography, it is recommended to conduct yearly clinical observation to monitor for the emergence of progressive symptoms. A repeat TTCE and CT scan may be warranted in case of significant changes or symptoms.

Other Diagnostic Tests

Contrast-enhanced magnetic resonance angiography (MRA) accurately detects PAVMs but is expensive and not routinely available. While it may provide detailed vascular imaging, the cost and limited accessibility may make it a less practical option than other diagnostic modalities, particularly in specific healthcare settings.

Screening for HHT

A thorough history and physical exam are vital in patients without a known diagnosis of HHT with a high suspicion of a PAVM. Screening for HHT involves genetic testing when available and routine screening protocols for family members.[44] It has been reported that in families with HHT in which 1 person has PAVM, the incidence of another family member having PAVMs is about 35%.[45] Nevertheless, the absence of findings associated with HHT does not entirely rule out the possibility of its presence.

If available, routine genetic screening is preferred for 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 unavailable, screening protocols can be used, as described by Haitjema and colleagues.[46] 

In summary, the diagnostic approach involves a combination of noninvasive methods, imaging studies, and, when necessary, the gold standard pulmonary angiography. The choice of diagnostic method depends on factors such as availability, cost, and the clinical situation. Additionally, screening for HHT is crucial, especially in patients with a suspected or confirmed diagnosis of PAVM.

Treatment / Management

The treatment of PAVMs is aimed at preventing complications such as cerebral abscesses and strokes and improving symptoms like dyspnea and hypoxemia. The decision to offer treatment depends on factors such as symptoms, the size of the feeding artery, and the patient's ability to tolerate the procedure.[47] Nonetheless, retrospective data indicate that neurovascular complications can occur with PAVMs of any size. This underscores the complexity and variability in the relationship between PAVM characteristics, particularly size, and the occurrence of neurovascular issues.[48]

Patients are best managed at facilities such as HHT centers, where there are experts in PAVM treatment.[22] This is done to facilitate the best outcome possible, given the potential complexity of each case.

Deciding whether treatment should be offered to patients depends on factors such as the presence of symptoms, the feeding artery diameter, and whether the patient can tolerate the procedure. Asymptomatic patients with a feeding artery diameter of less than 2 mm can be monitored through intermittent clinical observation, and noncontrast CT scans can be performed every 5 to 10 years to assess the status of the PAVMs. However, patients who are symptomatic with lesions less than 2 mm or the presence of grade 3 shunting warrant further treatment. For PAVMs with FAD 3 mm or greater on chest CT, pulmonary angiography is recommended to be performed.[22]

Embolization Therapy

Embolization therapy is the most widely used and successful form of treatment. The feeding artery of the PAVM is occluded using coils or balloons. The procedure is recommended for patients with symptomatic PAVMs or those with lesions less than 3 mm in diameter, especially if associated with symptoms. Follow-up with imaging is essential to confirm closure.[22][49] Embolotherapy can be done using either a coil or a balloon.[50] 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.[51](B3)

• Immediate benefits of embolization therapy:
  • Cessation of blood flow
  • Relief from symptoms such as dyspnea
  • Improved oxygenation levels in the blood

• Long-term benefits:
  • Reduce the incidence of complications associated with PAVMs, such as strokes and cerebral abscesses.

• Complications of embolization:
  • Pleuritic chest pain: Common and self-limiting complication. It is a minor and transient side effect.
  • Stroke: Less common but potential complication associated with embolization therapy. The risk must be weighed against the risks associated with untreated PAVMs.
  • Transient ischemic attack: A temporary episode of neurological dysfunction caused by a brief interruption of blood flow to the brain.
  • Transient air embolization: The introduction of air into the circulation can occur during the procedure. This is typically a transient event and is carefully managed by the medical team.

It is crucial to note that the decision to pursue embolization therapy is based on carefully assessing the individual patient's condition, including the size and characteristics of the PAVMs and the presence of symptoms. The potential benefits of embolization in preventing severe complications often outweigh the risks associated with the procedure. Regular follow-up is important to assess the treatment's effectiveness and monitor for potential complications or recurrence of PAVMs.[1][4]

Follow-up is recommended 3 to 6 months postembolization with contrast-enhanced chest CT and TTE to confirm closure of the PAVMs. If a PAVM persists at 1 year following initial treatment, repeat pulmonary angiography and transcatheter embolization are indicated.[52] Patients can develop new pulmonary hypertension or a worsening of baseline pulmonary hypertension after embolization or extensive PAVM resection.[53](B3)

Alternative Treatment

While embolization therapy is the most common and effective treatment for PAVMs, there are alternative treatments that may be considered in some instances. These alternatives are generally less common and are often reserved for specific situations. Alternative treatments include:

• Surgical excision: This is recommended in patients who fail embolization therapy or in those with life-threatening pulmonary hemorrhage from ruptured PAVMs.

• Lung transplantation: For patients refractory to repeated embolization, especially those with bilateral disease or a high risk of mortality, lung transplantation may be considered as an alternative. This option is typically reserved for severe cases where other interventions have been ineffective or are not feasible.

Adjunctive Therapy

Adjunctive therapies for PAVMs may be considered to complement primary treatments or manage associated symptoms. These therapies are not standalone treatments for PAVMs but may play a supportive role. Some adjunctive therapies include:

• Oxygen therapy: May be prescribed to manage hypoxemia associated with PAVMs

• Anticoagulation: Anticoagulant medications may be used to prevent complications such as stroke in individuals with PAVMs, mainly when there is a risk of paradoxical embolization.

• Antibiotic prophylaxis: Lifelong antibiotic prophylaxis is recommended before dental or surgical procedures to prevent bacteremia and brain abscesses, even after embolization therapy.[54][55] 
(B2)

• Bevacizumab: This medication has shown promise in decreasing the duration and number of epistaxis episodes.[56] 

Special Considerations

Treatment of PAVMs can vary on an individual basis. The following considerations should be taken into account during and after treatment:

• Pulmonary hypertension: Patients with severe pulmonary hypertension require careful evaluation. PAVM closure may be associated with an increase in pulmonary artery pressures, and the decision must consider the delicate balance between addressing PAVMs and the potential impact on pulmonary hemodynamics.[57]

• Management of pregnant women: The management of pregnant women with significant PAVMs requires careful consideration of fetal radiation exposure. To enhance safety, measures such as minimizing the field of view and fluoroscopy time are implemented, and it is advisable to delay procedures until the second trimester.[58]  

• Intravenous fluid or medication administration: Given the risk of air embolism, intravenous fluids or medications should be cautiously administered.

• Scuba diving: Scute diving is advised against due to the potential risks associated with PAVMs.

Differential Diagnosis

The differential diagnosis of PAVMs is broad and varies based on the presenting symptoms. Although PAVMs are uncommon culprits for pulmonary nodules, dyspnea, hemoptysis, stroke, and cerebral abscess, consideration should be given to them when more common causes for these symptoms and signs are ruled out.

The diagnostic approach should be tailored to the patient's symptoms and clinical context. 

• Dyspnea: Differentiating features for dyspnea include platypnea and orthodeoxia, although these can also be present in conditions such as hepatopulmonary syndrome, atrial septal defects (including patent foramen ovale), and other shunting causes. Chest imaging and pulmonary function testing can aid in the differential diagnosis.

• Hemoptysis: Causes of hemoptysis can be nasal telangiectases, endobronchial telangiectases, or PAVMs in the context of HHT. Hence, it is crucial to exercise caution if PAVMs are suspected, particularly during procedures such as biopsies, as they can result in significant bleeding. [59]

• Platypnea and orthodeoxia: Patients with hepatopulmonary syndrome typically present with platypnea and evidence of underlying chronic liver disease. This may include clinical signs and symptoms of liver dysfunction and abnormal liver function tests. In contrast, individuals with platypnea-orthodeoxia from atrial septal defects often demonstrate echocardiographic evidence of an early right-to-left shunt, a hallmark feature of atrial septal defects.[60] 

• CT imaging: Distinguishing features, such as feeding arteries and veins, play a crucial role in differentiating PAVMs from primary or metastatic lung and brain lesions.

• Brain MRI: MRI is useful for differentiating between cerebral infarcts, abscesses, and cerebral AVMs.

Given that the clinical features and radiological findings of PAVMs resemble many other diseases, the imaging considerations for PAVMs can be categorized into vascular and nonvascular lesions. This classification helps distinguish PAVMs from various conditions with similar presentations and guides appropriate diagnostic and management strategies.

Vascular:

1. Abnormal systemic vessels.
2. Vascular parenchymal mass.
3. Congenital or acquired pulmonary arterial or venous lesions (eg, pulmonary varix)[61]
4. Pulmonary artery pseudoaneurysm
5. Hepatopulmonary vessel
6. Retroperitoneal varices

Nonvascular:

1. Bronchoceles
2. Mucoceles
3. Granulomas [62][63]
4. Atelectasis
5. Primary lung malignancy
6. Carcinoid tumor
7. Metastatic disease

Prognosis

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.[13][44]

Although correct estimates of morbidity and mortality are lacking, PAVMs are known to carry high morbidity and mortality due to the development of serious complications such as stroke and brain abscess. An untreated PAVM is associated with a mortality of up to 50% compared to 3% in those that are treated.[29][64][65] 

The second and third trimesters of pregnancy are associated with a heightened risk of PAVM rupture, leading to complications such as hemothorax, hemoptysis, and life-threatening pulmonary hemorrhage.[66] Regular monitoring and timely intervention are crucial in managing PAVMs and preventing severe complications.

Complications

Complications of PAVMs are thought to be secondary to paradoxical emboli. The most common neurologic sequelae include stroke and brain abscesses, with a higher prevalence observed in patients with multiple PAVMs.[5] Other complications include:

• Syncope
• Diplopia
• Tinnitus
• Migraine
• Headache
• Transient ischemic attack
• Seizures
• Cerebral AVMs
• Congestive heart failure
• Hemoptysis
• Hemothorax or pulmonary hemorrhage
• Pulmonary hypertension
• Anemia
• Infective endocarditis
• Myocardial infarction [20]