A. Definition
- Diffuse interstitial inflammatory lung disease
- Components
- One of family of idiopathic pneumonias
- Idiopathic etiology with primarily fibrotic pathology with minimal inflammation
- Shortness of breath, diffuse pulmonary infiltrates are other main components
- Epidemiology
- Prevalence is ~150,000 patients in USA
- Annual incidence is ~7/100,000 for women, ~10/100,000 for men
- Patients are usually age 50-70, with >65% over age 60
- About 10% of patients have family history of IPF
- Overall ~1 million persons worldwide
- Progression of Fibrosis
- Diagnosis usually >6 months after onset of symptoms
- Usually fatal within 5 years of diagnosis
- Main problems are respiratory failure and Cor Pulmonale
- Lung volume (FVC) decline average ~20% per year
- Synonyms [3]
- Usual Interstitial Fibrosis or Usual Interstitial Pneumonia
- Chronic Interstitial Pneumonitis
- Cryptogenic Fibrosing Alveolitis
- Rapidly progressive variant called Hammond-Rich Syndrome
B. Pathophysiology [1,2,4]
- Most likely abnormal wound healing response to injury by alveolar epithelial cells
- Repeated stimulus leads to lung injury
- Lung injury leads to minimal inflammation but aberrant wound healing
- Aberrant wound healing leads to fibrosis
- Mutations in human telomerase (hTERT or hTR) found in 8% of familial IPF [18]
- Some Th2 T cell lymphocyte imbalance with IL4, IL13, and TGFß
- Normal Lung Alveolar Structure
- Type I alveolar cells - very thin epithelial cells
- These Type I alveolar cells cover most of the alveolar surface
- Cuboidal Type II cells reside at corners of alveoli
- These Type II cells produce and recycle surfactant
- Type II cells proliferate and differentiate into new Type I during growth and injury
- Pulmonary fibrosis begins with alveolar wall injury and mild or no inflammation
- Interstitial edema - hyaline membranes, septal exudates
- Alveolitis - Accumulation of mononuclear inflammatory cells
- Early death of Type I cells and replacement with hyperplastic Type II cells
- Pulmonary fibrosis is thought to be due abberrent repair after initial alveolar insult
- Inflammation
- Follows alveolar wall injury in some patients but is not required for fibrosis
- Inflammatory cells secrete bioactive agents
- Neutrophils usually predominate in fibrotic diseases
- Alveolar macrophage may be responsible for directing fibrosis
- T lymphocytes are not usually found in inflammatory lesions in true fibrotic diseases
- Cell adhesion molecules are upregulated in areas of active disease
- Endothelial cells in the region increase ICAM-1 (ß2-integrin) expression
- Selectins and other ß2-integrin levels are increased
- Increased levels of PDGF, IGF-1 are also found in fibrotic areas
- Hyperplasia of Type II pneumocytes
- Cuboidal, columnar Type II cells to replace dead Type I pneumocytes
- Believed that these Type II cells do not complete differentiation to Type I
- The Type II cells are particularly hyperplastic in pulmonary fibrosis
- These hyperplastic cells reduce oxygen diffusion across alveolar septa
- These cells likely involved in abnormal wound healing
- Production of profibrotic cytokines, particularly transforming growth factor ß1 (TGF-ß1)
- Fibroblasts
- Fibroblasts are activated in areas of inflammation
- Fibroblast proliferation follows inflammatory cell accumulation
- Fibroblasts may migrate into alveolar spaces
- They deposit collagen directly on top of the pneumocytes
- Likely that collagen deposition causes pneumocyte death
- TGFß appears to be critical for the process
- All cell types express TGFß which stimulates collagen synthesis and angiogenesis [5]
- Thus, fibroblasts prevent re-epithlialization following injury
- Increased collagen deposition in alveolar-vascular interstitium
- Alveolar septa become filled with collagen (mainly type I)
- Septa normally contain mainly Type IV collagen rather than type I
- Thickened basement membrane reduces oxygen transport
- Appearance is often called "honeycomb lung"
- Overview of Pathology [2]
- Variation in location and age of lesions
- Prediliction of disease for peripheral subpleural parenchyma
- Fibrotic zones associated with honeycombing alternate with relatively normal areas
- Regions of chronic lung injury with scarring and honeycombing
- Regions of acute lung injury with acitvely proliferating fibroblasts, myofibroblasts
- Mild or absent areas of interstitial inflammation
- Thus, IPF should be thought of as an "epithelial - fibroblastic disease" [1]
C. Diagnosis
- Patients present with increasing dyspnea on exertion, cough, hypoxemia, or cyanosis
- Physical Examination
- Rales (crackles) may be present on auscultation
- Evidence of right sided congestive heart failure
- Radiologic Findings
- Reticular markings on chest radiograph, usually lower lung fields in periphery
- Progressive fibrosis may lead to dilated distal air spaces, appear as honeycombing
- CT Scan may show diffuse alveolar septal thickening, small cysts
- White Blood Cell (Gallium) scanning may be demonstrate lung inflammation
- Echocardiography
- Pulmonary Hypertension
- Right Ventricular Dilatatation (tricuspid regurgitation) and Cor Pulmonale
- Arterial blood gas - hypoxemia without hypercarbia
- Pulmonary Function Tests (PFTs)
- Restrictive without obstructive defects (FVC decline)
- Reduced pulmonary compliance
- DLCO reduction is felt to be best predictor of disease course
- Bronchoalveolar Lavage (BAL) and Lung Biopsy
- These invasive diagnostic tests should be considered to help rule out other causes
- Thickened intra-alveolar septa often with inflammatory cells, small cysts
- Inflammatory cells include macrophages, neutrophils, mast cells, T lymphocytes
- High levels of eosinophils are atypical of IPF
- Lymphoid hyperplasia
- Intimal thickening of pulmonary arteries
- Elevated procollagen III levels in BAL fluid are a poor prognostic indicator
- Since lesions are usually peripheral, bonchoscopic biopsy rarely makes diagnosis
- No serological markers currently useful
- Erythrocyte sedimentation rate or C-reactive protein elevated in majority of patients
- Antinuclear antibodies and/or rheumatoid factor in ~30% of cases
- Lung biopsy is the standard for making the diagnosis
- Large piece of peripheral parenchymal tissue is typically required
- Thracotomy or less invasive thoracoscopic or video-assisted scopes
- Biopsy from several sites is often required to insure diagnosis
- Progression of Mild-Moderate IPF [6]
- Defined as IPF with FVC 50-90% and DLCO >25% predicted
- High resolution CT at least "probably" diagnostic of IPF
- Progression of mild-moderate IPF is not characterized by gradual, progressive decline
- Rather, acute deterioration, often fatal, occurs in mild-moderate patients
- Over a period of ~76 weeks, 23% required hospitalization, 21% died
- 90% of deaths were due to IPF
- Therefore, patients must be carefully monitored for acute deterioration
- Rapidly Progressive IPF [3,7]
- Also called Hamman-Rich Syndrome
- Progression over a period of weeks
- Considered an accelerated end-stage phase of usual interstitial pneumonitis
- Diffuse alveolar damage is present
- Most patients die within weeks to months
- Some patients are able to live with mechanical ventilation
D. Differential Diagnosis [3,8]
- Pneumoconiosis
- Systemic Sclerosis (Scleroderma)
- Hypersensitivity Pneumonitis
- Radiation Injury
- Oxygen Toxicity Pneumonitis
- Late Stage Sarcoidosis (Stage III or IV)
- Pre-lymphoma or associated with pulmonary lymphoma [9]
- Desquamative Interstitial Pneumonitis (DIP) [10]
- Some histological overlap with usual interstitial pneumonitis and other pneumonitis
- Highly inflammatory with lesions typically of similar age
- Reaction to asbestos, silica, organic dusts, mycotoxins, drugs, other agents
- Predominance of activated alveolar macrophages
- These macrophages were originally thought to be desquamated pneumocytes
- Bilateral lower lobe grown-glass infiltrates
- IPF itself
E. Treatment
- Oxygen
- Generally given for resting (or exertional) arterial pO2 < 60mmHg
- May slow progression of right heart failure (Cor Pulmonale)
- Other vasodilators may be helpful if pulmonary pressures are high
- Glucocorticoids [11,12]
- May have some symptomatic benefit in nearly all patients
- Improved disease in ~25% of patients, stabilized in another ~45%
- DIP may show better response than usual interstitial pneumonitis
- High doses intravenously are usually given, followed by oral agents
- Alternative dosing is prednisone 0.5mg/kg po initially for 1 month, with subsequent tapers to 10mg/d over 3 months [13]
- Azathioprine 2mg/kg po may be added to prednisone as a glucocorticoid sparing agent [13]
- Patients with good initial (3 month) response have improved survival
- Most effective when combined with other agents
- Most patients develop glucocorticoid related side effects unless dose is tapered
- Cyclophosphamide
- Used in conjunction with glucocorticoids
- Appears to be more efficacious than glucocorticoids alone in uncontrolled studies
- Glucocorticoids + cyclophosphamide had no benefit on survival versus placebo in controlled retrospective study [12]
- Interferon Gamma (IFNg) [14,15]
- IFNg has anti-fibrotic activities
- Inhibits the proliferation of lung fibroblasts
- Down regulates TGFß1 expression
- Dose 200µg sc thrice weekly added to prednisolone 7.5mg/day stabilized disease in Phase 2 clinical study [14]
- Combination with prednisolone improved baseline and exercise oxygenation [14]
- In randomized Phase 3 clinical study, IFNg had no benefit in patients with IPF whose disease was resistant to glucocorticoids [15]
- Therefore, IFNg can no longer be recommended in IPF
- In patients with pulmonary hypertension, oxygen and vasodilators may help
- Antioxidant Therapy [15]
- Direct oxygen toxicity and neutrophil release of reactive oxygen increase damage
- Oral high dose N-acetylcysteine (NAC) 600mg po tid added to prednisone + azathioprine slowed FEV1 and DLCO decline over 1 year
- NAC also reduced the incidence of myelotoxicity of azathioprine
- There is concern that azathioprine can exacerbate oxidative damage in the lung
- Lung Transplantation [16]
- Transplantation may be required due to severe destruction of lung tissue
- Cor Pulmonale (right heart failure) has often developed as lung function declines
- Therefore, combination with heart transplant often required
- Lung transplantation cleary improves outcome in majority of these patients
- Infections are main cause of death after transplantation
- Primary non-function occurs in >15%, and malignant disorders occur in ~15%
- Waiting period for transplantation is ~2 years
- Indications for Lung Transplantation in IPF [17]
- Symptomatic disease unresponsive to medical therapy
- Forced vital capacity <60-70% of predicted
- Resting or exercise-induced hypoxemia
- Experimental Agents [1]
- ACE Inhibitor - captopril inhibits fibroblast proliferation, reduces fibrotic lung responses
- Interferon ß1a - reduces fibroblast migration, proliferation, and collagen I synthesis
- Pirfenidone - inhibits TGF-ß and PDGF gene expression
- Colchicine - inhibits collagen formation; no more effective than glucocorticoids alone
- Keratinocyte growth factor - induces proliferation of type II pneumocytes
- Endothelin 1 blockade with bosentan (Tracleer®) has not shown benefit in IPF
F. Prognosis
- Mainly related to progressive lung and heart disease
- Median survival after lung biopsy diagnosis is typically <3 years
- Patients with rapidly Hamman-Rich Syndrome usually live <6 months
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