The two most common comorbidities that are associated with idiopathic pulmonary fibrosis (IPF) are emphysema and pulmonary hypertension (PH). Both worsen the prognosis of IPF. Furthermore, in one third of patients a combination of pulmonary fibrosis and emphysema (CPFE) exists. These comorbidities in IPF are a major challenge for physicians.
Which cell type drives the pathogenesis of IPF? Most would answer the fibroblasts, but many other cell types are also involved. The sequential lung injury that occurs in IPF is very heterogeneous in a spatiotemporal respect.
During his lecture about the cellular and molecular basis of IPF, Oliver Eickelberg (Munich, Germany) mentioned a ‘landmark paper’ (MW Parker e.a. J Clin Invest. 2014;124:1622-35.). This publication describes the activation of a profibrotic positive feedback loop by the fibrobrotic extracellular matrix.
‘The most important article’
The pathogenesis of IPF is characterized by very specific changes in genetic and genomic information. Changes in MUC5B mRNA and protein expression alter innate immunity and macrophage function in IPF. The most important article about IPF, according to Eickelberg, is a New England Journal of Medicine (NEJM) publication regarding the association of a common MUC5B promotor polymorphism and pulmonary fibrosis (Seibold MA et al. N Engl J Med. 2011;364:1503-12.). Eickelberg recommended that genetic screening is performed in all clinical and experimental studies to address the contribution of identified genotypes to IPF disease progression and response to therapy.
The next lecture, given by Ivana V. Yang (Denver, USA), focused on the genetic, but also on the environmental factors influencing IPF. Cigarette smoking is the main risk factor for the development of IPF, but multiple other environmental factors, such as exposure to asbestos, silica, beryllium, tungsten carbide, avian antigens, and molds, are also involved in its pathogenesis. Genes with a high effect size, but low allele frequency, include SPTPC and SPFTA. Common genes with a low effect size include DSP, FAM13A, OBFC1, APT11A and DPP9. TERC and TERT are positioned by Yang in both groups. MUC5B, which was also mentioned by Eickelberg, is quite an exception: it is a common mutation, but has a high effect size.
Emphysema in IPF
Approximately 30% of IPF patients also have emphysema, in a syndrome known as ‘combined pulmonary fibrosis and emphysema’ (CPFE). CPFE is a distinct syndrome with characteristic presentation, which may be overlooked because of subnormal spirometry. However, gas exchange and diffusion capacity are severely altered in CPFE patients. The prognosis is related to the frequent presence of pulmonary hypertension (PH). Vincent Cottin (Lyon, France) stated that the diagnostic criteria for usual interstitial pneumonia (UIP) are less applicable for the diagnosis of CPFE. As compared with centrilobular emphysema, paraseptal emphysema is more frequently associated with a UIP pattern and with a higher extent of fibrosis. However, a variety of pathologic patterns of pulmonary fibrosis have been reported in patients with CPFE. There is no specific treatment for CPFE, partly because of a paucity of specific data. Smoking cessation, bronchodilators, supportive care and oxygen supplementation are recommended. The efficacy of lung transplantation is often limited by comorbidities and age. With respect to drug therapy, anti-fibrotic drugs (pirfenidone and nintedanib) and corticosteroids with or without azathioprine could be considered
Pulmonary hypertension and IPF
Up to 100 million people worldwide are affected by PH. The mean survival rate without therapy is 2-4 years and even less than 3 months in patients with right heart decompensation. Soni Savai Pullamsetti (Bad Nauheim, Germany) talked about the relationship between PH and IPF. Even the presence of borderline PH may have prognostic relevance in IPF. The frequency of PH further increases in the presence of common comorbidities, such as right ventricular diastolic dysfunction and thromboembolism. PH is not influenced by the systemic therapy given in interstitial lung disease (ILD).
Source: Session 240: Complications and comorbidities in idiopathic pulmonary fibrosis. September 4th, 14:45-16:45, Platinum Room 1+2 Oral Presentation.