Survival of patients with schistosomiasis-associated pulmonary arterial hypertension in the modern management era

To the Editor:

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterised by an elevated pulmonary vascular resistance in the absence of left ventricular disease, and increasing pulmonary artery pressure, with consequent right ventricular failure and death [1]. Several aetiologies have been associated with PAH, including connective tissue diseases, congenital heart diseases and chronic infections, such as HIV. Due to its high prevalence in developing countries, one of the most relevant forms of PAH worldwide is the one associated to schistosomiasis [2].

Schistosomiasis-associated pulmonary arterial hypertension (Sch-PAH) is present in 5% of patients with the hepatosplenic form of the disease [3]. Due to its histological and haemodynamic similarities to idiopathic PAH (IPAH), it is classified within group 1 (pre-capillary pulmonary hypertension) of the current pulmonary hypertension classification [4]. However, despite the similarities, a previous cohort has shown that Sch-PAH has a distinct, more benign course than IPAH, even in the absence of specific therapy [5].

Data regarding the efficacy of specific PAH therapy in Sch-PAH are scarce. Improvements in functional class, cardiac output and 6-min walking test distance (6MWT), using phosphodiesterase-5 inhibitors (PDE5i) or endothelin-1 receptor antagonists (ERA) were demonstrated in a small cohort of 12 Sch-PAH patients [6]. The effect of PAH treatment on hard end-points, such as clinical worsening or survival, has not been evaluated in this population, until this date.

The aim of this study was to compare the survival of newly diagnosed Sch-PAH patients treated with PAH targeted therapies against a group of untreated patients from a historical cohort.

Data from all consecutive, newly diagnosed Sch-PAH patients referred to our centre in Brazil were analysed. Sch-PAH was characterised by the presence of mean pulmonary arterial pressure ≥25 mmHg with pulmonary artery occlusion pressure ≤15 mmHg, in the absence of significant lung parenchymal disease, left ventricular dysfunction or chronic thromboembolic disease, associated with the presence of periportal fibrosis and/or left liver lobe enlargement associated with at least one of the following features: positive epidemiology, previous treatment of schistosomiasis or identification of eggs in stool or rectal biopsy [7]. Since specific PAH therapy became widely available in Brazil after 2010, patients diagnosed before this date received only supportive therapy and comprised our historical cohort. After 2010, Sch-PAH patients were regularly treated with PDE5i, ERA or both, at discretion of the attending physician, in accordance to the available guidelines [8, 9].

Baseline clinical, demographical, including New York Heart Association (NYHA) functional class (FC) assessment, 6MWT, brain natriuretic peptide (BNP) and haemodynamic data were collected.

Analysis was performed using the SPSS 21 statistical package (SPSS, Inc.). All continuous variables are expressed as mean±sd and compared using t-test. Categorical data are presented as proportions and compared using Chi-square or Fisher's exact test, as appropriate.

The 60-month survival was evaluated using Kaplan−Meier estimate. Log-rank test was used for curve comparison. A p-value <0.05 was considered statistically significant.

The study population comprised 102 Sch-PAH patients; 50 patients (49%) were diagnosed before 2010 and, therefore, did not receive specific PAH therapy (untreated group; historical control). Except for the availability of specific treatment, there was no change in the standard of care during the whole observation period. 52 patients (51%) were diagnosed after 2010 and received targeted therapies: 41 patients (40.2%) received monotherapy with PDE5i, 10 patients (9.8%) received monotherapy with ERA, and one patient (1%) received upfront combination therapy.

Sch-PAH untreated and treated patients had similar baseline clinical and demographic data. At diagnosis, the mean±sd age was 53.7±13.2 versus 52.7±13.0 years, 6MWT was 458±149 m versus 411±100 m, and BNP was 107±90 versus 142±183 pg·dL⁻¹. Among untreated patients, 68% were female, with 25 patients (55%) in FC I and II and 20 patients (45%) in FC III and IV, whilst in the treated group, 59.6% were female patients, with 26 patients (51%) in FC I and II and 25 patients (49%) in FC III and IV (p>0.05 for all comparisons).

The haemodynamic impairment was also similar between groups. Untreated and treated patients presented right atrium pressure of 9.7±4.7 and 10.8±5.7 mmHg (p=0.281); mean pulmonary arterial pressure of 52.4±16.7 versus 59.9±17.9 mmHg (p=0.033), pulmonary artery occlusion pressure of 11.7±4.1 versus 13.4±5.4 mmHg (p=0.085), cardiac output of 4.8±1.6 versus 4.4±1.4 L·min⁻¹ (p=0.208) and pulmonary vascular resistance of 10.1±7.1 versus 11.8±6.4 WU (p=0.225), respectively. No statistically significant difference was found between the groups. None of the patients presented acute vasodilator response, regardless of the group [10].

The survival rate of the untreated group at 60 months was 69.2% for the untreated and 89.1% for the treated Sch-PAH patients (p=0.029) (figure 1).

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FIGURE 1

Survival of patients with schistosomiasis-associated pulmonary arterial hypertension according to treatment.

The use of specific PAH therapy in Sch-PAH patients was associated with improved survival, in comparison with a historical control group of untreated patients. To our knowledge, this is the first time that this information is reported in medical literature.

Schistosomiasis is the third most prevalent form of chronic infection disease worldwide, possibly infecting 200 million people [11]. Considering the prevalence of 5% of PAH in patients with the hepatosplenic form of the disease [3], Sch-PAH is clearly one of the most relevant forms of PAH, particularly in developing countries [12, 13]. Nevertheless, this population is rarely included in the large trials evaluating PAH targeted therapies [14]. Despite that, current PAH guideline recommends specific treatment for schistosomiasis, in line with other entities included in group 1 of the current PH classification [9]. However, the long-term efficacy of PAH targeted therapies had never been demonstrated in Sch-PAH.

Our study has some limitations that need to be highlighted. It is a non-randomised single-centre study, using historical controls as comparators, thus limiting the availability of follow-up data regarding the effect of targeted therapies in the functional and haemodynamic variables. However, our centre is the largest referral centre in the country, receiving patients from all other regions, including those from highly endemic areas. Furthermore, survival of untreated Sch-PAH survival rate was consistent with previously published data [5, 15]. Likewise, the better survival associated with treatment is in line with the clinical and haemodynamic benefits of targeted PAH therapy in Sch-PAH previously demonstrated [6].

In conclusion, our results provide more robust evidence supporting current PAH guidelines recommendation, reinforcing the indication for targeted therapies in Sch-PAH, similarly to other forms of PAH.