CONTENTS

• Basics
• Epidemiology
• Symptoms
• Radiology of PAVMs
• Diagnosis of HHT (hereditary hemorrhagic telangiectasia)
• Management
  • Management of PAVMs
  • Management of HHT (hereditary hemorrhagic telangiectasia)
• Other rare pulmonary vascular disorders:
  • Pulmonary artery aneurysms & pseudoaneurysms
  • Pulmonary vein thrombosis/occlusion
  • Platypnea-orthodeoxia syndrome
• Questions & discussion

---

basics

(back to contents)

---

• Pulmonary arteriovenous malformations (PAVMs) have a variety of causes, but the most common cause is HHT (hereditary hemorrhagic telangiectasia). HHT is a genetic condition that causes AVMs to form in various locations throughout the body.
• This chapter will discuss PAVMs in general, as well as HHT (hemorrhagic telangiectasia).

---

epidemiology

(back to contents)

---

causes of PAVMs

• ~95% of PAVMs are due to HHT (hereditary hemorrhagic telangiectasia).
• Less common causes of PAVMs include: (ERS handbook 3rd ed.)
  • Hepatopulmonary syndrome.
  • Trauma/surgery, especially:
    • Penetrating chest trauma.
    • Thoracic surgery for congenital heart disease.
  • Gestational trophoblastic disease.
  • Infections (actinomycosis, schistosomiasis).
  • Metastases. (Rosado-de-Christenson 2022)
  • Idiopathic.

epidemiology of HHT (hereditary hemorrhagic telangiectasia)

• HHT is transmitted in an autosomal dominant fashion with variable penetrance due to mutations in multiple genes (including endoglin (ENG) and activin receptor-like kinase 1 (ACVRL1)).
• De novo mutation or mistaken paternity may explain the absence of a parent with HHT.
• Increasing penetrance with age:
  • Manifestations increase with aging, often manifesting between 30-40 years of age.
  • 96% of individuals are affected by 40 years old.

---

symptoms

(back to contents)

---

---

symptoms of PAVMs

Only about half of patients are symptomatic. Symptoms are often less impressive than the degree of hypoxemia and physiological derangement. 

dyspnea

• Dyspnea is the most common symptom, occurring in ~40% of patients.
• Platypnea (dyspnea when upright) is a frequent question on board exams, but in practice this is rarely encountered. However, orthodeoxia (desaturation in an upright position) is a lot more common. (Differential diagnosis of orthodeoxia: 📖)

hemoptysis

• Hemoptysis occurs in ~15% of patients.
• Hemoptysis is usually mild (due to bronchial mucosal telangiectasia).
• Massive hemoptysis may occur following rupture of a PAVM into the airway.
  • This is, fortunately, rare.
  • ~25% of cases occur in pregnancy (which causes PAVMs to enlarge).
• Hemothorax may rarely occur.

neurologic manifestations

• Manifestations include:
  • Stroke or transient ischemic attack.
  • Brain abscess.
  • Migraine headaches may also be more likely.
• Right-to-left shunt facilitates paradoxical embolization of thrombus or infected material into the brain. Neurologic symptoms are more likely if the feeding artery diameter is >3 mm. (ERS handbook 3rd ed.)

other manifestations

• Digital clubbing may occur in ~15%.

---

symptoms of hereditary hemorrhagic telangiectasia (HHT)

mucosal bleeding

• Epistaxis is the most common symptom:
  • It is experienced by most patients by age 20.
  • ~90% have epistaxis by age 45.
• Recurrent gastrointestinal bleeding:
  • Recurrent bleeding may become increasingly problematic with age.
  • Endoscopy may disclose numerous lesions.
• Hematuria can occur.

telangiectasias

• These are small, dilated blood vessels near the skin surface or mucous membrane (figure below). They are small, red, and partially blanchable.
• Location is most often on the oral mucosa, tongue, lips, face, conjunctivae, and fingertips/nail beds. (Fishman 2023)
• Telangiectasias become more visible with age. Multiple telangiectasia are seen among 90% of patients >50 years old.

AVMs

• PAVMs:
  • This occurs in about half of patients with HHT.
  • Symptoms of PAVMs are described above (including dyspnea, hemoptysis).
• Brain or spinal AVMs occur in 10-20% of patients.
• Hepatic AVMs may cause high-output heart failure, portal hypertension, and cirrhosis. Eventually this may lead to pulmonary hypertension. (35000713)

phenotypes of HHT

• HHT1 (mutation of ENG gene encoding endoglin): Higher incidence of PAVMs and cerebral malformations.
• HHT2 (mutation of ACVRL1 encoding activin receptor-like kinase 1): Higher incidence of pulmonary hypertension and hepatic AVMs.

---

radiology of pulmonary AVMs

(back to contents)

---

---

bubble-contrast echocardiography to screen for PAVMs

• An intrapulmonary shunt causes microbubbles to appear in the left-sided heart chambers after >3 cardiac cycles (appearance sooner suggests an intracardiac shunt).
• Sensitivity for PAVMs is excellent (~97%). (Fishman 2023)
• Specificity depends on the number of microbubbles seen. If only a few microbubbles are seen (Grade 1 shunting; figure below), this may not represent a clinically significant shunt.
• For patients with orthodeoxia, performing echocardiography in a more upright position improves sensitivity.

---

chest radiography 

• Sensitivity for PAVMs is ~50-70%. (Rosado-de-Christenson 2022)
• AVMs may appear as well-defined, round opacities 1-5 cm in size.
• Most are in the lower lobes.
• Occasionally, it may be possible to see the feeding artery and/or vein.

---

CT scan

basic findings

• PAVMs appear as well-defined nodular lesion(s), that are rounded or multilobulated.
• The aneurysmal sac is typically ~0.5 – 5 cm in size.
• One or more feeding artery and vein may be seen. Feeding vessels fail to taper normally. In a noncontrast scan, these vessels may be a key clue to the diagnosis of AVMs. (Fishman 2023)
• Type of CT scan:
  • Noncontrast scan is adequate to diagnose PAVMs. Multidetector CT with three-dimensional reconstruction is equivalent to CT angiography for detection of small AVMs. (Shepard 2019)
  • Contrast CT angiography is needed for pre-embolotherapy planning. (Walker 2019)
  • MIP (maximal intensity projection) reformatted images may help visualize feeding vessels.

classification of AVMs

• Simple (80%): Single feeding artery and single draining vein.
• Complex (20%): Multiple feeding arteries, or multiple draining veins.

---

diagnosis of HHT

(back to contents)

---

differential diagnosis: disorders that cause oral telangiectasia & lung dysfunction:

• HHT (hereditary hemorrhagic telangiectasia).
• GPA (granulomatosis with polyangiitis).
• Scleroderma (especially limited scleroderma).
• Lupus.
• TEMPI syndrome:
  • Telangiectasias, erythrocytosis, monoclonal gammopathy, and intrapulmonary shunting.
  • Caused by a rare plasma cell dyscrasia causing a paraneoplastic syndrome. (de Moraes 2024)

Curacao criteria for HHT:

• Four clinical criteria:
  • [1] Recurrent and spontaneous epistaxis.
  • [2] Multiple telangiectasias on the skin of the hands, face, or inside the nose or mouth.
  • [3] AVMs or telangiectasias in one or more internal organs (including the lungs, brain, liver, intestines, stomach, or spinal cord).
  • [4] Family history of HHT in a first-degree relative.
• Interpretation:
  • Three criteria: definite HHT.
  • Two criteria: suspicion for HHT.
  • One criterion: HHT is unlikely.

---

management of pulmonary AVMs

(back to contents)

---

basics

• Antibiotic prophylaxis may be considered for procedures with a risk of bacteremia.
• Air filters should be utilized for intravenous lines, to avoid small air embolism (which would be benign for most patients, but could cause stroke in a patient with PAVMs).

decision to treat PAVMs

• Rationales for treatment include: prevention of hemoptysis, paradoxical embolism causing stroke, or brain abscess.
• Indications for therapy may include:
  • Symptomatic disease.
  • Lesion >2 cm.
  • Feeder vessel >2-3 mm.
  • Enlarging lesions.
• Pulmonary hypertension is a potential contraindication:
  • Rare patients with hereditary hemorrhagic telangiectasia and specific mutations (ACVRL1 gene) may develop pulmonary arterial hypertension with a small vessel vasculopathy similar to idiopathic pulmonary arterial hypertension. (Fishman 2023) 
  • Ligation of PAVMs will increase pulmonary pressures. If there is intercurrent severe pulmonary hypertension, ligation could worsen it. When in doubt, balloon angioplasty may be performed to determine how AVM obliteration would affect pulmonary pressures (prior to proceeding further).

percutaneous (IR-guided) embolization

• Interventional radiology has replaced surgery for the vast majority of cases.
• Complications may include:
  • Pleuritic chest pain occurs in 30%. This may reflect some degree of pulmonary infarction.
  • Hemoptysis (~5%)
  • Rarely: stroke, angina, or transient ischemic attack (TIA).
• Over time, ~7-30% of AVMs recanalize, so follow-up is necessary to determine if re-embolization is needed. (Murray 2022)

surgery

• Surgery could be considered for AVMs not amenable to interventional radiology embolization. However, with ongoing advances in interventional radiology, the utility of surgery is decreasing.

---

management of hereditary hemorrhagic telangiectasia

(back to contents)

---

---

management of PAVMs

• Screening:
  • Patients should be screened periodically for PAVMs. Contrast echocardiography seems to be the best technique for screening of asymptomatic patients.
  • The optimal frequency of screening might be every 5-10 years, in addition to evaluation before and after pregnancy.
• Management of PAVMs is as discussed in the section above.

---

bleeding

• For single lesions, local therapy may be utilized (e.g., gastrointestinal endoscopy with cautery or laser therapy).
• Coagulopathy should be managed appropriately.
• Iron deficiency may occur, which should be treated:
  • Patients with significant shunting and hypoxemia may normally develop a compensatory polycythemia. Iron deficiency may rob them of this compensatory mechanism.
  • There should be a low threshold to consider testing for iron deficiency and replacement with intravenous iron if detected. Note that a “normal” hemoglobin may be inappropriately low in the context of chronic hypoxemia.
• Bevacizumab (a VEGF inhibitor) may have a role in refractory gastrointestinal or nasal hemorrhages.

---

hepatic AVMs & high-output heart failure

basics

• Hepatic involvement is common but usually not symptomatic.
• Hepatic AVMs may cause:
  • High-output heart failure.
  • Pulmonary hypertension.
  • Portal hypertension and cirrhosis.

treatment

• Standard management strategies for portal hypertension, cirrhosis, and/or hepatic encephalopathy are the first step.
• Embolization of AVMs?
  • This is generally not recommended due to the risk of fatal hepatic necrosis.
  • Embolization may be undertaken in unusual situations wherein very large AVMs are causing instability. (35000713)
• VEGF (vascular endothelial growth factor)-inhibitor therapy
  • Treatment may impair the growth of further AVMs and potentially reduce the cardiac output. (35000713)
  • Many patients fail to respond, or have only temporary improvement.
• Liver transplantation:
  • This is the definitive therapy.
  • Indications include:
    • Progressive high-output heart failure that is refractory to medical management.
    • Portal hypertension.

---

pregnancy

• Pregnancy is associated with growth of AVMs.
• Evaluation before pregnancy should ideally include assessment for PAVMs and cerebral AVMs (e.g., with brain MRI).
• If AVMs expand, then embolization may be considered in the third trimester to facilitate safe delivery.

---

pulmonary artery aneurysms & pseudoaneurysms

(back to contents)

---

basics

• Pulmonary artery aneurysm is defined by dilation of the pulmonary artery to >1.5 times the normal diameter with all three layers of the artery intact. If all layers of the artery are not preserved, that constitutes a pseudoaneurysm (which has a greater risk of rupture).
• In practice, it's generally impossible to biopsy a pulmonary artery, so the distinction between a pseudoaneurysm and an aneurysm is hard to make in a living patient. Consequently, the terms “aneurysm” and “pseudoaneurysm” are often used interchangeably. However, if the etiology of the disease process is known, this may point to either a pseudoaneurysm or an aneurysm.

---

epidemiology – causes of pulmonary artery aneurysms & pseudoaneurysms

infection (most common; usually pseudoaneurysm)

• Mycotic aneurysm due to bacteremia (27502994)
  • Usually in the segmental pulmonary arteries.
  • Usually multiple and bilateral.
  • Hemoptysis can be massive, with ~50% mortality.
• Necrotizing pneumonia.
• Mold infection (e.g., mucormycosis, aspergillosis). This may reflect direct invasion of the vessel wall.
• Tuberculosis (Rasmussen aneurysm is used to refer to an aneurysm adjacent to or within a tuberculous cavity).
• Syphilis (true aneurysm). (34242146)

cardiovascular (usually true aneurysm)

• Causes:
  • Pulmonary arterial hypertension (usually in long-standing, severe disease). (29641962)
  • Pulmonic valve stenosis, or post-valvular stenosis.
  • Congenital heart disease (e.g., patent ductus arteriosus).
• These usually cause true aneurysms involving the main pulmonary artery.

vasculitis

• Hughes-Stovin syndrome (which is a partially manifested form of Behcet disease that has been referred to as “a cardiovascular manifestation of Behcet disease”). (29641962)
  • Typically affects men in their 30s-40s. (27066146)
  • Clinical manifestations of Hughes-Stovin syndrome:
    • (a) Recurrent thromboembolic events occur in the vast majority of patients (most often in the legs, followed by the inferior vena cava, and sometimes a mural thrombus within the heart). (35648079)
    • (b) Multiple aneurysms. These may occur anywhere in the body, but usually involve the pulmonary and bronchial arteries. (35648079; 29641962)
    • (c) Constitutional symptoms.
  • Management includes immunosuppression. Anticoagulation therapy is often unwise, since the most common cause of death is massive hemoptysis. (35648079)
• Giant cell arteritis.
• Takayasu arteritis (usually post-stenotic dilations).

traumatic (pseudoaneurysm)

• Penetrating or blunt thoracic trauma.
• Lung biopsy.

following Swan-Ganz catheterization (pseudoaneurysm)

• The most common symptom is hemoptysis, which frequently occurs within two days. However, pseudoaneurysm formation may be initially asymptomatic, with subsequent rupture occurring within 0-60 days after the procedure. (36759122)

other

• Malignancy erodes into a pulmonary artery (pseudoaneurysm).
• Cystic medial degeneration of the artery.
• Idiopathic. (Murray 2022)

---

symptoms

• Aneurysms are usually asymptomatic.
• Rupture may cause hemoptysis.

---

diagnosis: CT angiography

• (1) Aneurysm fills with contrast.
  • In some cases, the aneurysm is obviously a focal arterial dilation.
  • In other cases, a contrast-enhancing lesion is seen close to pulmonary arteries. Based on similar contrast opacification, a pseudoaneurysm may be suggested.
• (2) Features of the aneurysm may include:
  • Arterial calcification suggests calcified intramural thrombus or chronic pulmonary hypertension. (Murray 2022)
  • Arterial wall thickening suggests vasculitis.
• (3) Focal adjacent ground-glass opacities may suggest arterial rupture has already occurred, with subsequent hemoptysis. However, parenchymal abnormalities may also reflect the underlying causative process which led to aneurysm formation (e.g., pneumonia).

---

treatment

general approach 

• Identify & treat the cause: Any underlying cause should be managed (e.g., vasculitic aneurysms may regress with immunosuppressive therapy). (Murray 2022)
• When to intervene?
  • If the artery has ruptured and the patient has hemoptysis, then intervention is needed.
  • If the artery has not ruptured, it may not be clear whether lesions can be followed or should be ligated. Factors to consider may include the etiology of the lesion, size, and growth over time.
• How to intervene?
  • Interventional radiology embolization is generally preferred if possible. Depending on the geometry of the pseudoaneurysm, it might be possible to occlude the aneurysm while preserving blood flow through the artery.
  • If the aneurysm is in a proximal pulmonary artery, cardiothoracic surgery may be needed to correct the lesion without obstructing blood flow to the lung.

management of pseudoaneurysm after Swan-Ganz catheterization

• If rupture is diagnosed while the pulmonary artery catheter is still in place, the catheter may be withdrawn ~2 cm and inflated to tamponade bleeding and temporarily stabilize the patient. (36759122) 
• Pseudoaneurysm should be treated even if not actively bleeding, due to the high risk of subsequent rupture. Interventional radiology is usually utilized. (36759122)

---

pulmonary vein thrombosis or occlusion

(back to contents)

---

---

epidemiology

pulmonary vein thrombosis

• Thrombosis is very rarely idiopathic, but rather it usually has some underlying cause:
• Postprocedural, for example:
  • Lung transplantation (may occur in up to 15% of patients). (29626975)
  • Recent left upper lobectomy (~3% of patients). (29626975)
  • Atrial fibrillation ablation usually causes pulmonary vein stenosis, but this may be further complicated by pulmonary vein thrombosis.
• Metastatic cancer causing direct occlusion of a vessel.
• Hypercoagulable states.

nonthrombotic causes of pulmonary vein insufficiency

• Iatrogenic:
  • Ablation for atrial fibrillation may cause pulmonary vein stenosis. Pulmonary vein stenosis usually begins ~2-5 months after the procedure. (35809948)
  • Cardiac surgery. (30821492)
• Pulmonary vein compression: (30821492)
  • Malignancy (usually lung cancer or lymphoma).
  • Fibrosing mediastinitis.
  • Mediastinal granulomatous diseases.

---

clinical presentation

• Pulmonary venous insufficiency may cause localized pulmonary venous engorgement, leading to focal cardiogenic pulmonary edema. Symptoms may include:
  • Dyspnea.
  • Chest pain.
  • Cough, hemoptysis.
• Pulmonary vein thrombosis may additionally lead to embolization, with subsequent systemic arterial emboli (e.g., stroke, limb ischemia).
• Pulmonary hypertension with right ventricular dysfunction may eventually develop over time.

---

diagnostic studies

CT scan

• Focal cardiogenic pulmonary edema.
• Ipsilateral pleural effusion may occur.
• Dilation of bronchial veins may be seen. (30821492)
• Enlarged hilar lymph nodes may occur. (30821492)
• Evaluation of the pulmonary veins:
  • Contrasted CT scan may visualize a thrombosis. If thrombosis is suspected, the CT scan may be protocoled specifically to evaluate the pulmonary veins rather than the pulmonary arteries.

echocardiography

• May evaluate the flow through pulmonary veins.
• In the case of thrombosis, echocardiography sometimes may visualize a thrombus.
• Depending on windows, transesophageal echocardiography may be needed.

cardiac MRI

• This is another option to provide advanced imaging (especially if transthoracic echocardiography windows are suboptimal).

---

treatment

• For pulmonary venous thrombosis, anticoagulation is generally utilized.
• Pulmonary vein stenting may be an option if the vein isn't entirely occluded.
• Surgery:
  • Surgical pulmonary resection may be required for massive hemoptysis. (35809948)
  • Surgical repair of the vein may also be a possibility.
• Diuresis may cause some improvement in pulmonary edema, if possible. (30821492)

---

platypnea-orthodeoxia syndrome

(back to contents)

---

definition of platypnea-orthodeoxia syndrome

• Orthodeoxia is roughly defined as a drop in saturation of >5% when transitioning from a supine to upright position, which subsequently resolves when returning to a supine position. (35000712)
• Platypnea is defined as worsening dyspnea in a sitting position, as compared to lying supine.
• Pragmatically speaking, the presence of orthodeoxia is more important, since this is objectively measurable.

---

causes of orthodeoxia 

[#1/3] Basal-predominant parenchymal lung disease 

• Large basilar pleural effusions.
• Bibasilar atelectasis.
• ARDS.
• IPF (idiopathic pulmonary fibrosis).

[#2/3] Pulmonary vascular abnormality

• Pulmonary arteriovenous malformations located in the lung bases.
• Hepatopulmonary syndrome.

[#3/3] Positional intracardiac shunt 

• This involves a combination of patent foramen ovale or atrial septal defect PLUS a second process that causes the shunt flow to increase in an upright position. This second process may include the following:
• (#1) Various anatomic distortions may occur that direct blood flow towards the interatrial defect when in an upright position, such as: (35000712; 34935270, 30943341, 33000958) 
  • Ascending aortic aneurysm.
  • Prior cardiac surgery, especially aortic valve replacement.
  • Loculated pericardial effusion.
  • Severe pulmonary disease.
  • Cardiac cyst or mass.
  • Kyphosis.
  • Hemidiaphragmatic paralysis.
• (#2) Elevated right atrial pressures of any etiology. Upright posture increases right-sided pressure, thereby increasing the shunt fraction. Potential causes of elevated right atrial pressures could include:
  • Pericardial effusion.
  • Tricuspid regurgitation and/or stenosis.
  • Pulmonary hypertension, for example:
    • Pulmonary embolism.
    • Hypoxic lung disease causing acute hypoxic pulmonary vasoconstriction.
    • Pneumonectomy.
• Treatment generally involves closure of the interatrial communication (e.g., percutaneously). However, note that in patients with severe pulmonary hypertension, this may be contraindicated.

---

investigations of orthodeoxia 

⚠️ Investigation is often challenging because most diagnostic studies are typically performed in a supine position. However, shunting may not be detectable unless the patient is in an upright position. Consequently, studies that are performed in a supine position may be falsely negative.

echocardiography with bubble contrast is the diagnostic cornerstone

• For maximal sensitivity, this should be performed in an upright position.
  • No shunt detected –> suggests parenchymal lung disease (#1 above).
  • Delayed shunt (after >3 heartbeats) –> intrapulmonary shunt (#2 above).
  • Immediate shunting –> intracardiac shunt (#3 above).

additional studies that may be considered 

• Chest radiograph to evaluate for basilar parenchymal disease.
• CT angiogram may be considered (to evaluate for pulmonary arteriovenous malformations or vascular abnormalities).

---

management 

• Treatment depends on reversal of the underlying problem, for example:
  • Pulmonary arteriovenous malformations may be managed with embolization.
  • Intracardiac right-to-left shunting may be managed by shunt closure, if physiologically possible (discussed above).

---

questions & discussion

(back to contents)

---

To keep this page small and fast, questions & discussion about this post can be found on another page here.

Guide to emoji hyperlinks 

•  = Link to online calculator.
•  = Link to Medscape monograph about a drug.
•  = Link to IBCC section about a drug.
•  = Link to IBCC section covering that topic.
•  = Link to FOAMed site with related information.
• 📄 = Link to open-access journal article.
• = Link to supplemental media.