Volatile organic compounds as a biomarker in immune-mediated pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive disorder involving the
pulmonary vasculature that leads to right heart failure and death. In
idiopathic PAH (IPAH) and connective tissue disease associated PAH (PAH-CTD)
(including systemic sclerosis) has the role of altered immunity and
inflammation increasingly been recognized in earlier studies. Recently also
inflammatory factors are described in chronic thromboembolic PH (CTEPH).The
role of immunosuppressive therapy is currently still unclear. Consequently, a
better understanding of inflammatory pathways and their role in the
pathogenesis of PAH may lead to targeted therapeutic approaches. In this study,
the analysis of exhaled air will be used as a biomarker of inflammation and
autoimmunity in patients with autoimmune PAH in systemic sclerosis, SLE
(together CTD-PAH), in CTEPH patients and in IPAH. The analysis of exhaled air
is known to contain a complex mixture of volatile organic compounds (VOCs). The
occurrence of inflammation, and subsequent oxidative stress, can result in the
excretion of specific volatile compounds that generate unique VOC patterns. Our
study uses VOC profiles of patients with CTD-PAH, CTPEH patients and patients
with IPAH to investigate their role as a biomarker in immune-mediated PAH.
Further, VOC profiles of PAH-CTD patients will be compared with those of
SSc/SLE patients without pulmonary hypertension.

Primary Objective:
1. to determine unique inflammatory VOC profiles that distinguish patients with
PAH-CTD, CTEPH and IPAH from SSc and SLE (CTD) patients without PAH.

Secondary objectives:
1. to test whether these unique inflammatory VOCs associates with
well-established serum biomarkers of inflammation and autoimmunity in PAH as
was demonstrated earlier. Markers which will be used:
- pro-inflammatory biomarkers (hsCRP, IL-6, CCL2, CXCL4)
- vascular biomarkers (VEGF, von Willebrand factor)
- IgG auto-antibodies against endothelial cells (AECAs)
2. to investigate whether unique inflammatory VOC products in all four groups
of patients are affected by PAH and/or immunosuppressive therapy during 12
months follow-up.

The study is performed in patients with PAH-CTD, CTEPH, IPAH and patients with
SSc or SLE (CTD) without PAH.
The first baseline phase of two weeks is a cross-sectional study where baseline
VOC profiles will be determined in patients with PAH-CTD, CTEPH, IPAH and
patients with SSc or SLE (CTD) without PAH.
In the second follow-up phase, a explorative pilot study is performed to
evaluate specific inflammatory VOC products of treated patients in all four
groups. Treatment consists of PAH medication and/or immunosuppressive therapy.

Risks of the study are related to known complications of the performed
diagnostic tests. However, blood sampling, echocardiography, six minute walking
test, pulmonary function testing, HR CT thorax and if necessary a right heart
catheterization is considered standard of care in the clinical follow up of
patients at risk for pulmonary arterial hypertension. In the noninvasive
collection of exhaled air we do not expect any adverse events.