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 pulmonary arterial hypertension (PAH), and those with underlying connective tissue disease or congenital heart defects.

Paediatric pulmonary arterial hypertension

Pulmonary hypertension in children is most commonly idiopathic or hereditary PAH or caused by congenital heart disease. However, PH associated with respiratory disease may go underreported and is an important cause. 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 2015 guidelines, even though some disease associations are rare and should be excluded before a definite diagnosis of IPAH is made. Performance of a 6MWT depends on whether the child can cooperate. The definitive investigation is cardiac catheterisation and vasoreactivity testing, although probably only about 10% of children are responders.

A similar treatment algorithm to that used in adults 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

  • Paediatric PH is most commonly caused by IPAH, HPAH and PAH associated with congenital heart disease. However, PH due to respiratory diseases and rare causes need to be investigated
  • These children are often sicker than adults, and have poorer outcomes

PAH associated with adult congenital heart disease

A significant proportion of patients with congenital heart disease (CHD) develop PAH if left untreated, especially those with systemic-to-pulmonary shunts.3 This is thought to be around 5–10%. The clinical classification is discussed earlier in the handbook. Increased blood flow to the pulmonary vessels and increased pressure may lead to obstructive arteriopathy 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.

Shunt closure in patients with CHD associated PAH can be considered in those who are suitable. Table 1 below outlines the current recommendations for shunt closure based on PVR. While there is interest, the approach to treat medically to achieve operability criteria is not supported by available data.

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 in FC III and IV.6 These data need to be confirmed in other studies. Anecdotal experience using endothelin receptor antagonists, PDE5-i and IV epoprostenol have shown improved functional and haemodynamic results in patients with PAH associated with CHD and Eisenmenger syndrome. There are few published data on the use of combination therapy and the approach is the same as in idiopathic PAH.

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

Learning points

  • Bosentan is recommended in WHO FC III patients with Eisenmenger syndrome

PAH associated with connective tissue diseases

PAH is a complication of various connective tissue diseases (CTD), including scleroderma (affecting roughly 10% of patients), systemic lupus erythematosus (SLE), mixed CTD, dermatomyositis, Sjogren’s syndrome 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 In these patients, pulmonary hypertension can occur in association with interstitial lung disease, left heart disease, pulmonary vascular disease affecting the post-capillary venules (PVOD) or pre-capillary arterioles. Hence, it is important to determine the predominant mechanism so treatment can be initiated appropriately.

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.

Treatment of these patients is more complex than that of IPAH. Immunosuppression may be indicated in active SLE or mixed CTD. Subgroup analyses from controlled trials (predominantly in scleroderma patients) suggest benefit from endothelin receptor antagonists, PDE5 inhibitors, riociguat and subcutaneous treprostinil. Disease targeted therapy should follow the same treatment algorithm as in IPAH.

Learning point

  • PAH is a complication of connective tissue diseases
  • Immunosuppression and disease targeted therapy need to be considered