• The most common type of idiopathic interstitial pneumonia (IIP)
• The most common interstitial lung disease among referrals & 2nd most common diagnosis or frequent disease for lung transplantation

• A specific form of chronic, progressive fibrosing interstitial pneumonia that occurs spontaneously & is limited to the lungs, associated with a pattern of usual interstitial pneumonia (UIP) both on high-resolution computed tomography (HRCT) or lung biopsy
• Also known as cryptogenic fibrosing alveolitis (CFA)

• Exposure to agents like smoke, environmental pollutants & dust, viral infections, gastroesophageal reflux disease (GERD) & chronic aspiration may lead to initial alveolar epithelial damage especially in susceptible hosts
• Familial pulmonary fibrosis (FPF)
  • Account for <5% of the total number of patients with idiopathic pulmonary fibrosis
  • May affect ≥2 family members of the same primary biological family
  • May be caused by a genetic mutation in serum surfactant protein C or A2 (SFTPA2)
  • Also associated with the gene encoding mucin 5B (MUC5B) & mutant human telomerase RNA

• Respiratory viruses
  • Common cause of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF)

• Exertional dyspnea
• Nonproductive cough
• Finger clubbing
• Bilateral inspiratory crackles
• Systemic symptoms (arthralgia, fatigue, low-grade fever, myalgia, weight loss)
• Exertional dyspnea & nonproductive cough are the 2 most common presenting symptoms in patients with idiopathic pulmonary fibrosis
  
  • Dyspnea is the most prominent symptom

• Symptoms are nonspecific as it may present in patients with cardiac & pulmonary disease
• Approximately 5% of the patients are asymptomatic
  
  • Asymptomatic patients develop their symptoms approximately 1000 days after the diagnosis of idiopathic pulmonary fibrosis on routine chest radiograph & usual interstitial pneumonia on lung biopsy 

• It would take about 1-2 years (median duration of symptoms) before a diagnosis of idiopathic pulmonary fibrosis is established

• Cigarette smoking
• Environmental exposure to metal dust (brass, lead, steel) & wood dust
• Occupational exposure (farming, livestock, salon waste, stone cutting/polishing, vegetable dust)
• Infections (Epstein-Barr virus, Hepatitis C, cytomegalovirus)
• Gastroesophageal reflux disease via microaspiration
• Familial pulmonary fibrosis
  
  • Further studies are needed to prove the association of the genetic polymorphisms for cytokines, enzymes, profibrotic molecules, coagulation pathway genes, surfactant protein-A & -B, immunomodulatory genes, & matrix metalloproteinase & idiopathic pulmonary fibrosis

• Prevalence & incidence rates of idiopathic pulmonary fibrosis varies & depends on:
  
  • Ascertainment
  • Methods of reporting
  • Age
    
    • Incidence increases as the age advances especially on the 6th & 7th decade of life
    • Rarely seen in patients <50 years old
  • Geographic location of the population

• Cases are higher in men than in women

Histopathology

• Characteristic histopathologic features of usual interstitial pneumonia include:
  • Presence of abnormal proliferation of mesenchymal cells
  • Varying degrees of fibrosis
  • Overproduction & disorganized disposition of collagen & extracellular matrix
  • Honeycomb cysts

• The histological hallmark of usual interstitial pneumonia is the presence of a subepithelial fibroblast foci
• Inflammation, aberrant fibroblast & epithelial cell function, or abnormal epithelial-mesenchymal interactions with little or without an inflammatory component may play a role in the development of fibrosis in idiopathic pulmonary fibrosis
• The initiation & perpetuation of a fibrotic response, which is considered a trigger for the development of idiopathic pulmonary fibrosis, will depend on:
  
  • Genetic factors
  • Environmental triggers
  • Imbalance of oxidants & anti-oxidants
  • Imbalance of Th1 & Th2 cell-derived cytokines

• Marked proliferation of type II epithelial cells & loss of type 1 epithelial cells may be present
• Serum concentrations of lung surfactant proteins SP-A & SP-D, & Kerbs von Lungren 6 antigen (KL-6) are increased in patients with idiopathic pulmonary fibrosis
  
  • A change in the concentration of KL-6 may be used as a marker for the activity of the disease

• Abnormalities of the alveolar epithelium cells (AECs) causing altered reepithelization in idiopathic pulmonary fibrosis  patients include loss of type 1 epithelial cells, proliferation of type 2 epithelial cells, & impaired regenerative capacity of the epithelium
  • On electron microscopy, the space between the alveolar epithelium & capillary endothelium is where the resident mesenchymal cells are located

• Excess collagen deposition within the extracellular matrix that may be due to decreased collagenolytic activity prevents re-expansion of collapse lung tissue
• Recurring lung tissue injury & TNF-alpha gene polymorphisms have been linked to excessive collagen synthesis
• Cytokines & growth factors that stimulates fibroblast proliferation & matrix synthesis include resident epithelial cells, endothelial cells & fibroblasts located within the lungs
• TNF-α may be increased in patients with idiopathic pulmonary fibrosis but its role in idiopathic pulmonary fibrosis is not clear
• Overexpressed molecules from a lung tissue or blood sample include:
  
  • Fibrotic cytokines
  • Matrix metalloprotein (MMP-7 & MMP-1)
  • Surfactant protein A1
  • Cyclin A2 (CCNA2)
  • Alpha-defensins

• Gamma interferon is deficient in patients with idiopathic pulmonary fibrosis

Genetic Factors

• Several gene mutations that may possibly play a role in the development of idiopathic pulmonary fibrosis:
  
  • Mutation surfactant proteins A2 (SP-A2) & C (SFTPC)
  • Risk locus for chromosome 11
  • Telomerase gene mutations (eg TERT, TERC, DKC1, TNF-2)
  • In patients with fibrotic idiopathic interstitial pneumonias, association with TERT, MUC5B & TERC telomerase gene 3q26 were confirmed
    
    • Other associated genes: Loci FAM13A (4q22), DSP (6p24), OBFC1 (10q24), ATP11A (13q34), DPP9 (19p13), & chromosomal regions 7q22 & 15q14-15
    • TOLLIP & SPPL2C are additional genes that were recently identified & both are associated with disease susceptibility
  • In patients with familial interstitial pneumonia (FIP), regulator of telomere elongation helicase 1 (RTEL 1) gene (rare variant), a DNA helicase that regulates the stability & replication of a telomere, were identified