The diagnostic evaluation of children with a clinical suspicion of PAH is based on the European Society of Cardiology (ESC)/ European Respiratory Society (ERS) guidelines for adult patients [19
]; the recommendation to use the same diagnostic work-up proposed for adults is ranked Class IIa (i.e.
the weight of evidence/opinion is in favour of usefulness/efficacy) and the level of evidence is grade C (i.e.
it corresponds to a consensus of opinion of the experts and/or small retrospective studies or registries). The diagnosis of IPAH/HPAH is made when all other known causes of pulmonary hypertension have been excluded [110
]. The nonspecificity and the subtle presentation of PAH symptoms present difficulties in establishing a diagnosis in adults [112
], and even more so in children [113
]. Children are not always reliable in reporting symptoms and it is often necessary to rely on parental observations. PAH is often not diagnosed until after an upper respiratory tract infection: the patient does not appear to fully recover from the illness and a chest radiograph is obtained, revealing an enlarged heart. Because children are more exposed to upper respiratory tract infections and are more physically active than adults, they may be more likely to present with symptoms at an earlier stage of the disease. As a consequence, they tend to be diagnosed earlier, prior to the development of right heart failure, than adults who may not be aware of their slowly increasing physical limitations. This is supported by results from the US multicentre, observational REVEAL registry indicating that, upon diagnosis, adults with IPAH/HPAH or APAH-CHD have worse functional class and haemodynamics than their paediatric counterparts [106
is illustrative of a diagnostic algorithm. Routine investigations include a chest radiograph, surface electrocardiogram and transthoracic two-dimensional echocardiography. The patient should be evaluated for lung disease, an important cause of pulmonary hypertension. Chest computed tomographic scan and ventilation–perfusion lung scintigraphy are useful in the evaluation of thromboembolic disease (although rare in children), pulmonary interstitial lung disease and pulmonary fibrosis. Serological evaluation includes routine biochemistry and haematology tests. Thyroid function should be checked, as thyroid disease is not infrequently associated with PAH in both paediatric and adult patients [115
]. Certain conditions, such as autoimmune disorders and liver disease, are less common in paediatric patients than in adults [117
], yet still warrant assessment. Evaluation for a hypercoagulable state should be performed and includes screening for disseminated intravascular coagulation, deficiencies of antithrombin III, and proteins C and S, presence of factor V Leiden, anticardiolipin antibodies, lupus anticoagulant, and/ or prothrombin gene mutation 20210 G/A [119
]. Serological testing for autoimmune disorders involves measuring antinuclear antibodies (ANA), anti-DNA antibody, Sjögren’s syndrome-associated antibodies A and B, anticentromere antibody, scleroderma antibody, rheumatoid factor, complement factor and erythrocyte sedimentation rate [120
]. Children are not infrequently ANA-negative at the time of IPAH/HPAH diagnosis but seroconvert over several years with increased environmental antigen exposure [122
]. Thus, although the incidence of positive ANA tests in adult IPAH/HPAH patients approaches 40% in some series [123
], its incidence is also significant in paediatric IPAH/HPAH patients (18%) [122
]. Furthermore, there is an increased incidence of positive ANA tests in the parents of IPAH/HPAH children and, in particular, in their mothers (in the absence of a diagnosed CTD) [122
]. Clinically significant chronic CTD can develop years after the diagnosis of IPAH/HPAH in both paediatric and adult patients. HIV infection is associated with an increased incidence of PAH [124
] and should be assessed in PAH patients. A toxicology screen should also be included as several exogenous substances (e.g.
amphetamines, cocaine, metamphetamines, fenfluramines, St. John’s wort and phenylpropanolamine) have been identified as risk factors (or potential risk factors) for PAH in adults and children [126
]. Portopulmonary hypertension should be ruled out by performing abdominal ultrasonography and liver function tests [128
FIGURE 1 Paediatric pulmonary arterial hypertension (PAH) diagnostic work-up. CXR: chest radiography; PH: pulmonary hypertension; DL,CO: diffusing capacity of the lung for carbon monoxide; CT: computed tomography. #: if unable to obtain a reliable test in a young (more ...)
Noninvasive methods are valuable when PAH is suspected but right heart catheterisation is necessary, in both children and adults, to confirm the diagnosis of PAH (i.e.
the elevation in PVR and pa
, and the absence of left-sided heart disease), and to determine the acute vasoreactivity of the pulmonary vasculature. An acute response to vasodilator testing is currently defined for adult PAH patients as a decrease of ≥10 mmHg in pa
to an absolute level of ≤40 mmHg with a normal or increased cardiac output [129
]. Whether this is the correct definition for children, and whether it can be used to predict efficacy with long-term calcium channel blockers in infants and young children, remains unclear. One of the objectives in ongoing PAH registries, including REVEAL and the paediatric multicentre, international observational Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension (TOPP) Registry, is to analyse the utility of definitions for acute reactivity and their ability to predict response to calcium channel blockers and/or long term outcomes regardless of treatment. Furthermore, whether the severity of the pulmonary vascular disease, as indicated by the PVR at diagnosis or after 3–12 months of a given PAH therapy, will predict prognosis is critical to determine in order to develop treatment algorithms for PAH in children. Douwes et al.
] have suggested that, regardless of the response with acute vasodilator testing, the PVR to systemic vascular resistance ratio, as well as the pa
to mean systemic blood pressure ratio at diagnosis, appear predictive of outcome in patients with IPAH/HPAH and APAH. In general, the younger the children are at the time of diagnosis, the more likely they are to respond to acute vasodilator testing; however, there is wide variability, consistent with wide biological variability in paediatric, as well as in adult, patients [10
]. We have observed that children with symptoms suggestive of severe pulmonary vascular disease for several years may be acute responders to acute vasodilator testing and manifest near-complete reversibility with chronic oral calcium channel blockers, while others with only a brief duration of symptoms may have what appears to be irreversible pulmonary vascular obstructive disease [90
]. The incidence of responders to acute vasodilator testing ranges from 11 to 40% in children with IPAH/HPAH [10
] and from 6 to 27% in adult patients [130
]. Although patients (paediatric or adult) with IPAH/ HPAH or repaired APAH-CHD may respond to acute vasodilator testing, patients with APAH-CTD, HIV or portal hypertension, tend to be nonresponders.
The assessment of WHO functional class for patients with pulmonary hypertension developed at the 2nd World Conference on Pulmonary Hypertension in Evian, France (1998) [125
] remains widely used in adult PAH patients to evaluate functional impairment. It can also be useful in older children, but less so in infants or young children, for whom a specific scoring system for heart failure [134
] may be more appropriate. WHO functional class may also be inadequate to characterise a child with preserved cardiac output and no, or limited, functional impairment at rest, but with syncope upon over-exertion or with even mild exercise. Whether such a child should be considered as functional class IV is a matter of controversy, but the consensus is that aggressive treatment should be considered to manage recurrent syncope. Standardised guidelines are needed for the physicians taking care of paediatric pulmonary hypertension so that WHO functional class is used reproducibly in children.
The 6-min walk test is another tool to assess disease severity that is widely used in adults and is in the process of being standardised in children. Standard references are now available in healthy children [135
]. The 6-min walk test assesses exercise endurance. It is useful in PAH patients, both adults and older children, who have symptoms such as dyspnoea with walking. However, the test procedure is not always followed by younger children, who walk at whatever pace they choose. This results in data that may not be reproducible nor reliable, especially in children <7 yrs of age [134
]. Moreover, for a child who can carry out normal daily activities but has syncope with over-exertion, the 6-min walk test may be “normal” for the child’s age and sex and, thus, underestimate the child’s exercise limitations; in this instance, it is less useful as a tool to assess exercise endurance.
Noninvasive cardiopulmonary exercise testing (CPET) with gas exchange can be utilised to evaluate ventilatory responses to exercise in adult [138
] and most paediatric PAH patients over 7–8 yrs of age [139
]. This maximal exercise test may allow the detection of patients in whom pulmonary artery pressures are normal at rest but increase abnormally during exercise (e.g.
“asymptomatic” obligate carriers of BMPR2 mutations); CPET may prove useful to diagnose these patients based on abnormal ventilatory efficiency [143
]. In our experience, CPET, in contrast to the 6-min walk test, may be particularly relevant to identify those children who have an exaggerated response of the pulmonary vascular bed to exercise and appear to have good exercise capacity with normal activities of daily living, but have a history of syncopal episodes with over-exertion or in response to mild hypoventilation with sleep [90
Various markers used in adults such as serum N-terminal pro-brain natriuretic peptide (NT-proBNP), brain natriuretic peptide (BNP), uric acid, noradrenaline and C-reactive protein may also provide additional information on both disease severity and prognosis in children [145
]. Lower NT-proBNP and BNP concentrations have been reported in children [145
] compared with adults [147
], consistent with right heart failure being less frequent in children as compared with adult patients.
In summary, noninvasive disease severity assessment tools used in adults, such as WHO functional class and CPET, can be difficult to perform and are, therefore, less reliable in infants and young children; thus, haemodynamic evaluation remains the gold standard for assessing disease severity and evaluating treatment responses in PAH children. Nevertheless, as the goals of treatment for paediatric and adult patients are to improve overall quality of life in addition to increasing survival, we need to develop and validate quality of life tools that can be utilised in children of all ages.