Features of a telomere syndrome in patients with idiopathic pulmonary fibrosis

Abstract

This thesis aimed to explore clinical and genetic features of a telomere syndrome in patients with idiopathic pulmonary fibrosis (IPF). IPF is thought to represent a chronic disease process, but the initial stages of disease development remain elusive. Here it is shown that in patients with IPF, abnormalities were often seen on chest X-rays even prior to the initial symptoms of pulmonary fibrosis. In 23% of patients with IPF a chest X-ray had been made a median of 50.5 months prior to the start of symptoms, and on 58% abnormalities were seen that potentially represented early stages of IPF. Even after the start of symptoms, the median time to a final diagnosis was 24 months, illustrating that there is a significant potential for earlier diagnosis of IPF.

In addition, the work presented in this thesis provides new insight into IPF as a part of the spectrum of telomere syndromes. It shows that potential manifestations of a telomere syndrome outside the lung are common in patients with IPF, with 9% and 19% of patients having a clinical history suggestive of a telomere syndrome, and laboratory abnormalities suggestive of a telomere syndrome, respectively. These factors are associated with shorter leukocyte telomere length and worse survival. It was also found that other hypothesized extrapulmonary manifestations of a telomere syndrome, namely humoral immunodeficiency and osteoporosis, were uncommon in patients with IPF, and did not associate with leukocyte telomere length. Coronary artery disease and a higher coronary artery calcification score are common, and indicate a worse prognosis, but were not associated with leukocyte telomere length and are unlikely to be manifestations of telomere dysfunction in patients with IPF. Taken together, these findings support that IPF is more than a single organ disease.

Furthermore, this thesis shows that mutations in various telomere genes can underly pulmonary disease, including mutations in ACD and TINF2. It is noted that mutations in most telomere-related genes that were first identified in patients with other manifestations of a telomere syndrome and no pulmonary fibrosis can also be found in patients with IPF. This illustrates that IPF is truly part of a spectrum of telomere dysfunction-related diseases. Specific treatments for these diseases remain to be further explored. In this context, the results are described of a prospective observational study of patients with IPF who were treated with danazol as a last resort. Patients were offered treatment with danazol in case of disease progression despite treatment with pirfenidone and/or nintedanib or intolerance to antifibrotic drugs. It was found that treatment with danazol did not lead to slowing of lung function decline. Secondary outcomes, including radiographic imaging and survival analyses, also did not point towards a beneficial effect of danazol treatment. Future studies will have to determine whether earlier treatment with danazol or treatment of subgroups of patients with IPF is beneficial. Finally, it is argued that novel treatments for patients with pulmonary fibrosis, including pulmonary fibrosis due to telomere dysfunction, can be developed in the context of the treatable traits model.