Schistosomiasis-associated Pulmonary Arterial Hypertension

Schistosomiasis associated pulmonary arterial hypertension is pre-capillary pulmonary hypertension caused by chronic infection with Schistosoma species, usually in patients with hepatosplenic disease and portal hypertension. It is one of the commonest causes of pulmonary arterial hypertension worldwide.

About 200 million people are infected, mostly in sub-Saharan Africa, with more in Brazil, the Middle East and Asia. Pulmonary hypertension develops in about 5 to 10% of those with hepatosplenic Schistosoma mansoni infection, and it is also seen with S. haematobium and S. japonicum.

Typical patients are young to middle aged adults with long standing exposure to fresh water. Presentation is years after infection, and clinical features are often mistaken for heart failure.

Haemodynamics are often milder than in IPAH, with higher cardiac output, and survival is better than in IPAH, but untreated disease progresses and causes right heart failure.

Pathophysiology.

Eggs are carried by portal blood. With portal hypertension, portosystemic collaterals allow eggs to bypass the liver and lodge in pulmonary arterioles, where they cause granulomatous inflammation.

Inflammatory cytokines (interleukin-13 and transforming growth factor beta) drive vascular remodelling with plexiform like lesions, medial hypertrophy and thrombosis. Cirrhosis does not occur, so liver synthetic function is preserved, and this separates the condition from portopulmonary hypertension.

Portal hypertension also raises cardiac output, which adds to the pulmonary load.

Exertional dyspnoea, fatigue, cough, syncope, chest pain, abdominal swelling, haematemesis from varices and oedema. Signs: splenomegaly, hepatomegaly (left lobe predominance), ascites, signs of pulmonary hypertension (loud second heart sound, right ventricular heave, tricuspid regurgitation) and clubbing is uncommon. A history of swimming or washing in freshwater in an endemic area is key.

• Parasitology: stool (Kato-Katz for S. mansoni and S. japonicum) or urine filtration (S. haematobium) for eggs, rectal snip biopsy, and serology or circulating antigen (urine point-of-care test where available). A negative stool does not exclude disease.
• Abdominal ultrasound: periportal fibrosis, splenomegaly, portal vein dilatation and collaterals. Upper gastrointestinal endoscopy for varices.
• Liver tests (usually near normal), albumin and INR to exclude cirrhosis. Hepatitis B and C serology, HIV test.
• Echocardiography and ventilation perfusion scan, high resolution CT, pulmonary function tests and NT-proBNP.
• Right heart catheterisation: mean pulmonary artery pressure over 20 mmHg, wedge pressure of 15 mmHg or less, pulmonary vascular resistance over 2 Wood units, often with normal or high cardiac output.
• Risk stratum: low (functional class I or II, 6-minute walk over 440 m, NT-proBNP under 300 ng/L), intermediate (class III, 165 to 440 m, 300 to 1100 ng/L), high (class IV, under 165 m, over 1100 ng/L, syncope).

Differential diagnosis.

• Portopulmonary hypertension from cirrhosis, and idiopathic pulmonary arterial hypertension.
• Pulmonary hypertension from rheumatic mitral disease, left heart disease or chronic lung disease.
• Chronic thromboembolic pulmonary hypertension and pulmonary hypertension from HIV or sickle cell disease.
• Hepatopulmonary syndrome and tuberculosis sequelae.

Antiparasitic treatment.

• Praziquantel 40 mg/kg orally as a single dose with food (S. mansoni and S. haematobium), or 60 mg/kg orally in 2 to 3 divided doses over 1 day (S. japonicum and S. mekongi). Repeat after 4 to 6 weeks if eggs persist. Avoid with strong CYP inducers (rifampicin, carbamazepine); reduce dose or give under specialist advice in Child-Pugh B or C hepatic impairment. Dizziness, abdominal pain and nausea are common. It does not reverse established pulmonary hypertension but stops further egg deposition.
• Prevent re-infection: avoid contact with freshwater in endemic areas, with community treatment programmes.

Pulmonary hypertension therapy (evidence comes from small observational series, so practice follows IPAH with caution). All drugs are continued long term.

• Sildenafil 20 mg orally three times daily (most experience; contraindicated with nitrates and riociguat; avoid with ritonavir) or tadalafil 40 mg once daily (start 20 mg in mild to moderate renal or hepatic impairment; avoid when creatinine clearance is under 30 mL/min).
• Ambrisentan 5 mg once daily increased to 10 mg (maximum 10 mg), macitentan 10 mg once daily or bosentan 62.5 mg twice daily for 4 weeks then 125 mg twice daily, added for functional class III or inadequate response. Liver tests monthly on bosentan, and at baseline and when indicated on the others. Avoid in significant hepatic impairment. Teratogenic: exclude pregnancy before starting and monthly.
• High risk: epoprostenol intravenously from 2 ng/kg/min or treprostinil subcutaneously or intravenously from 1.25 ng/kg/min. Selexipag 200 microgram twice daily titrated weekly to a maximum of 1600 microgram twice daily.
• Calcium channel blockers are not used because acute vasoreactivity is rare.

Portal hypertension and varices.

• Endoscopic band ligation is preferred to non-selective beta blockers for primary and secondary prevention of variceal bleeding, because beta blockers can worsen right ventricular output.
• Acute variceal bleeding: octreotide 50 microgram intravenous bolus then 50 microgram/h for 2 to 5 days, ceftriaxone 1 g daily intravenously for up to 7 days, and endoscopy within 12 hours. Transfuse to a haemoglobin of 7 to 8 g/dL.
• Splenectomy and surgical portosystemic shunts can worsen pulmonary hypertension, and are avoided unless essential.

General measures. Diuretics (furosemide 40 to 120 mg orally daily, spironolactone 25 to 100 mg daily; potassium under 5.0 mmol/L, eGFR over 30), oxygen for PaO2 under 8 kPa, vaccination, iron correction and avoidance of pregnancy. Anticoagulation is not used routinely because of variceal bleeding risk.

Monitoring. NT-proBNP, 6-minute walk and clinical review every 3 to 6 months. Echocardiography every 6 to 12 months. Stool or urine egg count 4 to 6 weeks after praziquantel and then yearly. Endoscopy for varices every 1 to 2 years. Right heart catheterisation with deterioration.

Referral and escalation. Refer to a pulmonary hypertension centre or physician experienced in the condition. Urgent referral for variceal bleeding, syncope, or high risk status.

Special groups.

• Pregnancy: pregnancy is advised against. Praziquantel is considered acceptable in pregnancy on limited data when infection is active.
• Children: praziquantel 40 mg/kg orally as a single dose with food for S. mansoni and S. haematobium (60 mg/kg in 2 to 3 divided doses over 1 day for S. japonicum and S. mekongi); screen school age children in endemic areas.
• Kidney or liver impairment: adjust praziquantel and avoid hepatotoxic pulmonary hypertension drugs when liver function is impaired.
• Region specific: coexisting HIV, hepatitis B and tuberculosis are common, and should be tested for. Sildenafil is often the only pulmonary vasodilator available.