Three distinct blood biomarker signatures in patients with pulmonary fibrosis that are linked with lung function and prognosis have been identified by a group of Australian and international researchers.
The findings could pave the way for the classification of patients and the development of therapies tailored to specific disease endotypes, as well as inform future treatments and clinical trial designs, the team noted in a paper published in The Lancet Respiratory Medicine.
The researchers analysed biomarkers in patients from the UK PROFILE study and the Australian Idiopathic Pulmonary Fibrosis Registry (AIPFR).
In a cohort of 455 patients (76% male; mean age 72 years) from the PROFILE study, the team assessed the presence of different pulmonary fibrosis endotypes against a panel of 13 circulating biomarkers.
The largest cluster identified within this group (55% of patients) – the basement membrane collagen [BM] cluster – showed high levels of collagen remodelling biomarkers such as PRO-C4 and C3M.
An epithelial injury cluster (24%) was characterised by high concentrations of epithelial-derived biomarkers including MMP-7, SP-D and CYFRA211.
They also discovered a third cluster, the crosslinked fibrin [XF] cluster (22%), in which there were high concentrations of the crosslinked fibrin degradation marker X-FIB.
Notably, the results were replicated in a separate dataset involving 117 patients from the AIPFR, which identified the same three BM (79%), EI (7%) and XF (14%) clusters.
The Australian team included Professor Yuben Moodley of the NHMRC Centre of Research Excellence in Pulmonary Fibrosis, Sydney and Professor Tamera Corte from Sydney University.
Different mortality risk and outcomes
Investigators also found that EI and XF clusters were linked with a higher mortality risk than BM – even after taking into account various potential cofounders – with results showing an adjusted hazard ratio of 1.88 (p<0·0001) for EI versus BM and 1.53 (p=0·0058) for XF versus BM.
Median survival was shortest in the EI cluster (2.5 years), followed by the XF cluster (4.0 years) and the BM cluster (4.8 years).
Patients in the EI cluster experienced the steepest annual decline in FVC%, at -12% compared for -8.5% for both BM and XF clusters.
“The stability of patient classification to a biomarker-defined cluster, and differential outcomes between patients in different clusters, raises the possibility that fundamental differences exist in the active disease biology between these groups,” said Dr Scott McCall and Professor Jonathan Kropski, both from Vanderbilt University Medical Center, in a linked comment on the findings.
“The observation that patients with the highest concentrations of epithelial-derived biomarkers had the fastest disease progression is consistent with previous reports linking epithelial-derived biomarkers to idiopathic pulmonary fibrosis outcomes, and supports the concept that active epithelial injury and dysfunction is a critical driver of idiopathic pulmonary fibrosis pathogenesis and progression,” they added.
Limitations and further questions
However, the editorialists also cautioned that the potential implications of the research should be considered against a backdrop of several limitations.
For example, the PROFILE study population was almost exclusively patients with European ancestries, “and whether this endotype architecture is preserved in more diverse populations with pulmonary fibrosis will be important to establish,” they said.
Also, cluster assignment stability was assessed over just three months, which is unlikely to be a long enough timeframe to conclude with certainty that endotype classification is maintained across the disease pathway.
The editorialists also highlighted several key points to be explored further, including the finding that antifibrotic treatment failed to improve survival outcomes in the EI endotype, which they said raises the prospect that current and experimental pulmonary fibrosis therapies might have different impacts depending on disease endotype.
“Additional study will be required to ascertain whether biomarker-defined endotypes should be used as stratifying or enriching variables in future clinical trials and to establish the feasibility of this strategy for precision therapy development in pulmonary fibrosis”, they concluded.