DEFUNCT PAH module 4: special groups

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Some patients belong to clinical group 1 of the pulmonary hypertension classification but their underlying conditions are different, and they require a different management strategy. These include children who present with PAH, and those with underlying connective tissue disease or congenital heart defects.

Paediatric pulmonary arterial hypertension

Pulmonary hypertension in children is most commonly caused by congenital heart disease, and idiopathic or heritable PAH.  At presentation, children are often very sick and response to treatment is difficult to predict.

Common symptoms are syncope, dyspnoea, fatigue and failure to thrive. Right ventricular failure occurs late, and is uncommon.

The medical history should encompass a thorough family history and details of the pregnancy, delivery and neonatal period. A similar diagnostic workup to pulmonary hypertension in adulthood is recommended by the ESC 2009 guidelines, even though some disease associations are rare. Performance of a 6MWT depends on whether the child can cooperate. The definitive investigation is cardiac catheterization and vasoreactivity testing, although probably only about 10% of children are responders.

The PAH treatment algorithm is also used in children even though the response to therapy is difficult to predict and RCT evidence is lacking. The age of the patient is also a factor in deciding treatment. Recent survival figures from Great Ormond Street Hospital for Children, London are 84% and 76% at one and three years, respectively, for IPAH children in functional classes III and IV; combination therapy gives better results than monotherapy.1,2

Learning points

  • Most PH in children is associated with congenital heart disease
  • These children are often sicker than adults, and have poorer outcomes

PAH associated with congenital heart disease

A large proportion of patients with congenital heart disease (CHD) develop PAH if left untreated, especially those with systemic-to-pulmonary shunts.3 The clinical classification is discussed earlier in the handbook. Increased blood flow to the pulmonary vessels and increased pressure may lead to obstructive disease and will raise the pulmonary vascular resistance. The most severe form of PAH is seen in Eisenmenger’s syndrome (an initial large systemic-to-pulmonary shunt leading to pulmonary disease, with reversal of the shunt and central cyanosis), and this accounts for between one quarter and one half of cases in Europe and North America.4

Patients with Eisenmenger’s syndrome may develop haemoptysis, cerebrovascular accidents and coagulation abnormalities and may die suddenly. They have reduced life expectancy and quality of life.

Evidence for treatment of patients who have PAH associated with CHD is limited to Eisenmenger’s syndrome. The BREATHE 5 study showed improvement in 6MWT and decreased pulmonary vascular resistance.5 Open label data from a single centre suggest benefit in treating patients I FC III and IV.6 These data need to be confirmed in other studies. The use of other disease-targeted therapies for PAH is limited to anecdotal experience. There are as yet no published data on the use of combination therapy.

The use of disease-targeted therapies for PAH in managing the failing Fontan circulation is anecdotal and remains to be evaluated fully.

Bosentan is approved for WHO-FC III patients, in whom it has been shown to improve 6MWT and decrease PVR.5 Anecdotal experience supports the use of sildenafil, tadalafil and epoprostenol in patients with PAH associated with CHD and Eisenmenger’s syndrome. There are as yet no published data on the use of combination therapy. There is interest in using targeted therapy to remodel the pulmonary vascular bed, thus rendering inoperable patients suitable for intervention.

Learning points

  • Eisenmenger’s syndrome is the commonest associated congenital defect
  • Prognosis remains poor in these patients

PAH associated with connective tissue diseases

Pulmonary hypertension associated with connective tissue disease may be caused by PAH, PVOD, PH related to left heart disease, PH related to interstitial lung disease or chronic thromboembolic disease. Pulmonary arterial hypertension is a complication of various connective tissue diseases (CTD), including scleroderma (affecting roughly 10% of patients), systemic lupus erythematosus (SLE), mixed CTD and rheumatoid arthritis.7 Compared with idiopathic pulmonary hypertension patients, these patients are predominantly female, are older at the time of diagnosis of PAH and have shorter survival (the unadjusted risk of death is three times higher than in IPAH).8

Annual echocardiographic screening to detect pulmonary hypertension has been recommended for symptomatic CTD patients, and for asymptomatic patients with scleroderma. High-resolution CT is used to diagnose interstitial lung disease.

Immunosuppression may be indicated in active SLE. Subgroup analyses from controlled trials (predominantly in scleroderma patients) suggest benefit from endothelin receptor antagonists, PDE5 inhibitors and prostanoids.

Learning point

  • PAH is a complication of connective tissue diseases