Study of the Etiology and Immunological Pathogenesis in Acute Exacerbation of Idiopathic Pulmonary Fibrosis (AE-IPF)

IPF has become the focus of study in the area of pulmonary fibrosis, accounting for over 25% of all interstitial lung diseases (ILD) 1 and over 60% of all idiopathic interstitial pneumonia (IIP). The past 20 years have observed the remarkable tendency of increase of IPF incidence, accompanied by only 2-3 years of medium survival after diagnosis and 30-50% of 5-year survival2. Due to limited diagnosis method at early stage of the disease, the patients are most likely diagnosed only when they reach middle or late stage. Other issue is lack of effective treatment, except for lung transplantation. Most of the deaths are caused by acute exacerbation, which is defined by clinicians as acute exacerbation of IPF (AE-IPF) and characterized by the rapid deterioration during relatively stable period of IPF (Stable-IPF). Exacerbation may occur at all stages of IPF development (see the below figure) and is accompanied by hazardous and quick development, high mortality and very poor prognosis.

The incidence and mortality of AE-IPF varies in different studies. Kubo etc. reported that acute exacerbation occurs within 3 years in around 57% of IPF patients, with the mortality of 53%. Study by Kim etc. show that the mortality of AE-IPF reaches 78%. Study by Song etc.demonstrated that the incidence of acute exacerbation of IPF is 35.4%, with over 50% of in-hospital morality, 56% of 1-year mortality and 18.4% of 3-year mortality. Other studies showed that 1-year post-exacerbation mortality is nearly 100%. Data based on the 178 in-hospital IPF patients in the investigators' department during the latest 4 years showed that 58% (102/178) of those patients experienced acute exacerbation at certain stage of disease, with 70 deaths occurred. Among those deaths, 56 cases (83%) were caused by acute exacerbation. It is clear that the high incidence and mortality of AE-IPF is the most essential factors impacting the survival and quality of life of IPF patients, therefore lead to the poor prognosis of IPF.

Hypothesis and key scientific questions Based on analysis above, the investigators propose the following hypothesis: certain level of immunological imbalance exists in those relatively stable IPF patients, making them susceptible to infection by various pathogens. Once infected, especially by viruses (e.g. common cold related viruses), AE-IPF can be quickly triggered, leading to ARDS-like reaction. To validate this hypothesis, four key scientific questions need to be answered by studies with scrupulous design: 1) what are the characteristic changes of immunological function in IPF/AE-IPF patients so as to make the patients more susceptible to common cold viruses? 2) What kind of pathogens, especially those common cold viruses, are the key triggering factors during the development of AE-IPF? 3) What kind of inflammatory cascade reaction occurs in AE-IPF leading to ARDS-like prompt development of pulmonary inflammation? Key research direction and scientific rationale In order to address the key scientific questions above, the investigators will conduct comprehensive studies based on detailed screen and analysis of large amount of clinical cases, integrated research methods in such areas as immunology, molecular, cytology and animal model, as well as high throughput data collection and big data analysis: 1) Extensive screening and identification of those pathogens closely related with AE-IPF; 2) Comprehensive analysis of the change of immunology function, focusing on the pathological-physiological alteration in virus induced immunologic imbalance in IPF, as well as the characteristic changes in relevant cytological signal transduction, so as to identify important AE-IPF bio-markers and explain the pathological molecular mechanism and network of ARDS-like inflammatory cascade reaction, which will be significant efforts in terms of prevention of AE-IPF, reduction of mortality, improvement of quality of life, delaying of disease progression and increase of survival.

Similar clinical deterioration like AE-IPF will also occur in almost all the other types of pulmonary fibrosis, especially connective tissue disease-ILD (CTD-ILD), nonspecific interstitial pneumonia (NSIP), drug induced ILD, fibrotic allergic pneumonia and cryptogenic organizing pneumonia (COP) etc. Therefore, this program will also provide insight into the basic research and clinical management of acute exacerbation of other interstitial lung diseases, which is one common problem extensively exists in the area of interstitial lung disease and the key factor in terms of improving patients' quality of life and survival.