Hypersensitivity pneumonitis is an inflammatory lung disease caused by exposure to various organic antigens via inhalation. Clinical presentation and natural history are heterogeneous and, therefore, the disease is most commonly classified with the temporal designations of acute, subacute, and chronic.1 Pulmonary fibrosis most clearly identifies patients with hypersensitivity pneumonitis that will be chronic and progressive and who will have a poor prognosis.2 The clinical presentation of fibrotic hypersensitivity pneumonitis is often similar to that for idiopathic pulmonary fibrosis (IPF), which is the most deadly form of idiopathic interstitial pneumonia and is associated with progressive pulmonary fibrosis and reduced survival.2, 3
The development of pulmonary fibrosis in hypersensitivity pneumonitis is thought to be due to persistent lung injury resulting from ongoing exposure to antigens and persistent inflammation. Epidemiological studies confirm that only a subset of individuals exposed to an inciting antigen develop hypersensitivity pneumonitis, which suggests a genetic contribution,4, 5, 6, 7 although no predisposing genomic factors have been identified.1 Several single-nucleotide polymorphisms (SNPs) have been associated with predisposition to IPF,8, 9, 10, 11, 12 two of which, MUC5B rs35705950 and TOLLIP rs5743890, have also been associated with altered survival risk in people with established disease.8, 9 Variants in genes associated with telomere maintenance have also been linked to IPF,11, 13, 14, 15, 16, 17, 18, 19 with short telomere lengths in peripheral blood leucocytes (PBLs) being associated with reduced survival.20 In families in which multiple members have pulmonary fibrosis, some might be diagnosed clinically as having chronic hypersensitivity pneumonitis, which suggests that telomere dysfunction could also be a risk factor for this disorder.13, 14, 15, 16, 17, 18, 19, 21
Research in context
Evidence before this study
We searched PubMed for studies published before Jan 14, 2017, with the search terms “MUC5B”, “TOLLIP”, “telomere length”, “hypersensitivity pneumonitis”, and “alveolitis, extrinsic allergic”. We found no studies reporting associations between the MUC5B rs35705950 or TOLLIP rs5743890 single-nucleotide polymorphisms and hypersensitivity pneumonitis. Two studies reported peripheral blood leucocyte telomere length in people with hypersensitivity pneumonitis, but did not assess associations with clinical features or outcomes.
Added value of this study
We found associations between MUC5B rs35705950 minor alleles and risk of chronic hypersensitivity pneumonitis and extent of fibrosis, but none with the TOLLIP rs5743890 single-nucleotide polymorphism. Additionally, short telomere length was associated with extent of fibrosis, histopathological features of usual interstitial pneumonia, and reduced survival in people with chronic hypersensitivity pneumonitis.
Implications of all the available evidence
MUC5B rs35705950 minor alleles and short telomere length in peripheral blood lymphocytes might be useful for risk stratification in patients with chronic hypersensitivity pneumonitis. Our findings also suggest shared pathobiology between idiopathic pulmonary fibrosis and chronic hypersensitivity pneumonitis.
We did an observational study to test the theory that the genomic risk factors associated with the development and progression of IPF—MUC5B rs35705950 and TOLLIP rs5743890 SNPs and PBL telomere length—are also associated with the development of fibrosis and reduced survival in people with chronic hypersensitivity pneumonitis. We specifically assessed associations between these factors and risk, radiographic and histopathological features of lung remodelling (eg, honeycombing and traction bronchiectasis) and fibrosis (eg, reticulation and fibroblast foci), and survival in patients with chronic hypersensitivity pneumonitis.