Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive disease with high mortality. CC-chemokine ligand 18 (CCL18) is predictive of survival in IPF. We described correlation of CCL18 serum levels with the genotype of rs2015086 C > T polymorphism the CCL18-gene, which was associated with survival in a pre-antifibrotic cohort (Part-A). Herein (Part-B), we aimed to validate these findings and to study the effects of antifibrotics. Two cohorts were prospectively recruited, cohort-A (n = 61, pre-antifibrotic) and cohort B (n = 101, received antifibrotics). Baseline CCL18 serum level measurement by enzyme-linked immunosorbent assay (ELISA, serially in cohort B) and genotyping of rs2015086 was performed and correlated with clinical outcomes. The CT genotype was present in 15% and 31% of patients. These patients had higher CCL18 levels compared to the TT-genotype (cohort-A: 234 vs. 115.8 ng/mL, p < 0.001; cohort B: 159.5 vs. 120 ng/mL, p = 0.0001). During antifibrotic therapy, CCL18 increased (p = 0.0036) regardless of rs2015086-genotype and antifibrotic-agent. In cohort-A, baseline CCL18-cutoff (>120 ng/mL) and CT-genotype were associated with mortality (p = 0.041 and p = 0.0051). In cohort-B, the CCL18-cutoff (>140 ng/mL) was associated with mortality (p = 0.003) and progression (p = 0.004), but not the CT/CC-genotype. In conclusion, we validated the correlation between rs2015086-genotype and CCL18 serum levels, which was predictive of (progression-free)-survival in two prospective validation cohorts.
Highlights
Idiopathic pulmonary fibrosis (IPF) is the most common type of idiopathic interstitial pneumonias
In the more recent validation in cohort B from Hannover Medical School, 126 patients had a confident diagnosis of IPF and available serum samples (2014–2018) which were used for the CC chemokine ligand 18 (CCL18) measurements and genotyping, and of which 101 with complete follow-up data were included in the survival analysis
We show the predictive value of CCL18 serum levels with respect to outcome in patients treated with antifibrotics
Summary
Idiopathic pulmonary fibrosis (IPF) is the most common type of idiopathic interstitial pneumonias. It is characterized by a radiologic and histopathological “usual interstitial pneumonia (UIP)” pattern and dismal prognosis with a median survival of 3 years following diagnosis if untreated [1,2]. Despite antifibrotics and numerous agents being investigated at present, there is an unmet need for development of personalized treatment options considering the significant morbidity and mortality in IPF [8]. The serum level of CCL18 has been shown to predict survival in IPF and systemic sclerosis, including in depth analyses from data of two randomized controlled trials [11,12,13,14,15,16]. There are two single nucleotide polymorphisms (SNPs) in the promotor region of CCL18 gene, rs2015086 and rs712040 which are presumably functional in gene regulation [10,17]
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