Fibrosing Diseases: Idiopathic Pulmonary Fibrosis (PDF)

# Fibrosing Diseases ## Idiopathic Pulmonary Fibrosis (Usual Interstitial Pneumonia) Idiopathic pulmonary fibrosis (IPF) refers to a pulmonary disorder of unknown etiology that is characterized by patchy, progressive bilateral interstitial fibrosis. The radiologic and histologic pattern of fibrosi...

# Fibrosing Diseases ## Idiopathic Pulmonary Fibrosis (Usual Interstitial Pneumonia) Idiopathic pulmonary fibrosis (IPF) refers to a pulmonary disorder of unknown etiology that is characterized by patchy, progressive bilateral interstitial fibrosis. The radiologic and histologic pattern of fibrosis is referred to as usual interstitial pneumonia (UIP), which is required for the diagnosis of IPF. Because its etiology is unknown, it is also known as cryptogenic organizing alveolitis. Males are affected more often than females, and it is a disease of older adults, virtually never occurring before 50 years of age. Of note, similar pathologic changes in the lung may be present in entities such as asbestosis, collagen vascular diseases, and other conditions, and IPF is therefore a diagnosis of exclusion. ### Pathogenesis The interstitial fibrosis that characterizes IPF is believed to result from repeated injury and defective repair of alveolar epithelium, often in a genetically predisposed individual. The cause of the injury is obscure, a variety of sources have been proposed, including chronic gastroesophageal reflux. However, only a small fraction of individuals with reflux or who have been exposed to other proposed environmental triggers develop IPF, thus other unknown factors must have an important role. The clearest etiologic clues come from genetic studies. Germline mutations leading to loss of telomerase function are associated with increased risk, suggesting that cellular senescence contributes to a profibrotic phenotype. Approximately 35% of affected individuals have a genetic variant in the *MUC5B* gene that alters the production of mucin, while a smaller number of affected patients have germline mutations in surfactant genes. These genes are only expressed in lung epithelial cells, suggesting that epithelial cell abnormalities are key initiators of IPF. It is hypothesized that abnormal epithelial repair at the sites of chronic injury and inflammation gives rise to exuberant fibroblastic or myofibroblastic proliferation and collagen deposition. Although the mechanisms of fibrosis are incompletely understood, excessive activation of profibrotic factors such as TGF-β is likely to be involved. One school of thought holds that alveolar macrophages with an M2 phenotype have a central role in driving fibrosis due to their ability to secrete cytokines that promote fibroblast activation. ### Morphology Grossly, the pleural surfaces of the lung are cobblestoned due to retraction of scars along the interlobular septa. The cut surface shows firm, rubbery, white areas of fibrosis. Histologically, the hallmark is patchy interstitial fibrosis, which varies in amount and worsens with time. It occurs preferentially within the lower lobe, the subpleural regions, and along the interlobular septa. The earliest lesions demonstrate exuberant fibroblastic proliferation (fibroblastic foci). Over time these areas become more collagenous and less cellular. A typical finding is the coexistence of both early and late lesions. The dense fibrosis causes collapse of alveolar walls and formation of cystic spaces (honeycomb fibrosis) lined by hyperplastic type II pneumocytes or bronchiolar epithelium. The interstitial inflammation consists of alveolar septal infiltrates of lymphocytes and occasional plasma cells, mast cells, and eosinophils. Secondary pulmonary hypertensive changes (intimal fibrosis and medial thickening of pulmonary arteries) are often present. ### Clinical Features IPF usually presents with the gradual onset of a nonproductive cough and progressive dyspnea. On physical examination, most patients have characteristic "dry" or "velcro-like" crackles during inspiration. Cyanosis, cor pulmonale, and peripheral edema may develop in later stages of the disease. The characteristic clinical and radiologic findings (i.e., subpleural and basilar fibrosis, reticular abnormalities, and "honeycombing") are often diagnostic. ### Environmental Factors * Smoking * Occupational exposure * Gastroesophageal reflux * Other irritants and toxins * Viral infections ### Genetic Risk Factors * Aging * Telomerase mutations * Surfactant mutations * *MUC5B* variant ### Proposed Pathogenic Mechanisms * **At risk epithelium** → **Persistent epithelial injury/activation** → **Profibrogenic factors** → **Pathogenic activation of signaling pathways** → **Fibroblastic proliferation, collagen production** → **FIBROSIS** (Fig. 11.13) Anti-inflammatory therapies have proven to be of little use, in line with the idea that inflammation is of secondary pathogenic importance. By contrast, antifibrotic therapies such as nintedanib, a tyrosine kinase inhibitor, and pirfenidone, an inhibitor of TGF-β, are now approved for use. The overall prognosis remains poor, however: survival is only 3 to 5 years, and lung transplantation is the only definitive treatment.