Idiopathic Pulmonary Fibrosis Signs and Symptoms

Cập nhật: 05 December 2023
Được đánh giá bởi

Giới thiệu

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

Definition

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

Nguyên nhân

  • Exposure to agents like smoke, environmental pollutants and dust, viral infections, gastroesophageal reflux disease (GERD) and 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 IPF
    • 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) and mutant human telomerase RNA
  • Respiratory viruses
    • Common cause of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF)

Signs and Symptoms

  • Exertional dyspnea
  • Nonproductive cough
  • Finger clubbing
  • Bilateral inspiratory crackles
  • Systemic symptoms (eg arthralgia, fatigue, low-grade fever, myalgia, weight loss)
  • Exertional dyspnea and nonproductive cough are the two most common presenting symptoms in patients with IPF
    • Dyspnea is the most prominent symptom
  • Symptoms are nonspecific as it may present in patients with cardiac and pulmonary disease
  • Approximately 5% of the patients are asymptomatic
    • Asymptomatic patients develop their symptoms approximately 1000 days after the diagnosis of IPF on routine chest radiograph and usual interstitial pneumonia on lung biopsy
  • It would take about 1-2 years (median duration of symptoms) before a diagnosis of IPF is established

Yếu tố nguy cơ

  • Cigarette smoking
  • Environmental exposure to metal dust (brass, lead, steel) and wood dust
  • Occupational exposure (eg farming, livestock, salon waste, stone cutting/polishing, vegetable dust)
  • Infections (eg Epstein-Barr virus, Hepatitis C, cytomegalovirus)
  • GERD 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 and -B, immunomodulatory genes, and matrix metalloproteinase and IPF

Dịch tễ học

  • Prevalence and incidence rates of IPF varies and depends on:
    • Ascertainment
    • Methods of reporting
    • Age
      • Incidence increases as the age advances especially on the 6th and 7th decade of life
      • Rarely seen in patients <50 years old
    • Geographic location of the population
  • Cases are higher in men than in women

Sinh lý bệnh

Histopathology

  • Characteristic histopathologic features of UIP include:
    • Presence of abnormal proliferation of mesenchymal cells
    • Varying degrees of fibrosis
    • Overproduction and disorganized disposition of collagen and extracellular matrix
    • Honeycomb cysts
  • The histological hallmark of UIP is the presence of a subepithelial fibroblast foci
  • Inflammation, aberrant fibroblast and 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 IPF
  • The initiation and perpetuation of a fibrotic response, which is considered a trigger for the development of IPF, will depend on:
    • Genetic factors
    • Environmental triggers
    • Imbalance of oxidants and anti-oxidants
    • Imbalance of Th1 and Th2 cell-derived cytokines
  • Marked proliferation of type II epithelial cells and loss of type 1 epithelial cells may be present
  • Serum concentrations of lung surfactant proteins SP-A and SP-D, and 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, and impaired regenerative capacity of the epithelium
    • On electron microscopy, the space between the alveolar epithelium and 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 and TNF-alpha gene polymorphisms have been linked to excessive collagen synthesis
  • Cytokines and growth factors that stimulates fibroblast proliferation and matrix synthesis include resident epithelial cells, endothelial cells and fibroblasts located within the lungs
  • TNF-α may be increased in patients with IPF 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 and MMP-1)
    • Surfactant protein A1
    • Cyclin A2 (CCNA2)
    • Alpha-defensins
  • Gamma interferon is deficient in patients with IPF

Genetic Factors

  • Several gene mutations that may possibly play a role in the development of IPF:
    • Mutation surfactant proteins A2 (SP-A2) and 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 and TERC telomerase gene 3q26 were confirmed
      • Other associated genes: Loci FAM13A (4q22), DSP (6p24), OBFC1 (10q24), ATP11A (13q34), DPP9 (19p13), and chromosomal regions 7q22 and 15q14-15
      • TOLLIP and SPPL2C are additional genes that were recently identified and 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 and replication of a telomere, were identified