A. Definition

1. Diffuse interstitial inflammatory lung disease
2. Components
   1. One of family of idiopathic pneumonias
   2. Idiopathic etiology with primarily fibrotic pathology with minimal inflammation
   3. Shortness of breath, diffuse pulmonary infiltrates are other main components
3. Epidemiology
   1. Prevalence is ~150,000 patients in USA
   2. Annual incidence is ~7/100,000 for women, ~10/100,000 for men
   3. Patients are usually age 50-70, with >65% over age 60
   4. About 10% of patients have family history of IPF
   5. Overall ~1 million persons worldwide
4. Progression of Fibrosis
   1. Diagnosis usually >6 months after onset of symptoms
   2. Usually fatal within 5 years of diagnosis
   3. Main problems are respiratory failure and Cor Pulmonale
   4. Lung volume (FVC) decline average ~20% per year
5. Synonyms [3]
   1. Usual Interstitial Fibrosis or Usual Interstitial Pneumonia
   2. Chronic Interstitial Pneumonitis
   3. Cryptogenic Fibrosing Alveolitis
   4. Rapidly progressive variant called Hammond-Rich Syndrome

B. Pathophysiology [1,2,4]

1. Most likely abnormal wound healing response to injury by alveolar epithelial cells
   1. Repeated stimulus leads to lung injury
   2. Lung injury leads to minimal inflammation but aberrant wound healing
   3. Aberrant wound healing leads to fibrosis
   4. Mutations in human telomerase (hTERT or hTR) found in 8% of familial IPF [18]
   5. Some Th2 T cell lymphocyte imbalance with IL4, IL13, and TGFß
2. Normal Lung Alveolar Structure
   1. Type I alveolar cells - very thin epithelial cells
   2. These Type I alveolar cells cover most of the alveolar surface
   3. Cuboidal Type II cells reside at corners of alveoli
   4. These Type II cells produce and recycle surfactant
   5. Type II cells proliferate and differentiate into new Type I during growth and injury
3. Pulmonary fibrosis begins with alveolar wall injury and mild or no inflammation
   1. Interstitial edema - hyaline membranes, septal exudates
   2. Alveolitis - Accumulation of mononuclear inflammatory cells
   3. Early death of Type I cells and replacement with hyperplastic Type II cells
   4. Pulmonary fibrosis is thought to be due abberrent repair after initial alveolar insult
4. Inflammation
   1. Follows alveolar wall injury in some patients but is not required for fibrosis
   2. Inflammatory cells secrete bioactive agents
   3. Neutrophils usually predominate in fibrotic diseases
   4. Alveolar macrophage may be responsible for directing fibrosis
   5. T lymphocytes are not usually found in inflammatory lesions in true fibrotic diseases
   6. Cell adhesion molecules are upregulated in areas of active disease
   7. Endothelial cells in the region increase ICAM-1 (ß2-integrin) expression
   8. Selectins and other ß2-integrin levels are increased
   9. Increased levels of PDGF, IGF-1 are also found in fibrotic areas
5. Hyperplasia of Type II pneumocytes
   1. Cuboidal, columnar Type II cells to replace dead Type I pneumocytes
   2. Believed that these Type II cells do not complete differentiation to Type I
   3. The Type II cells are particularly hyperplastic in pulmonary fibrosis
   4. These hyperplastic cells reduce oxygen diffusion across alveolar septa
   5. These cells likely involved in abnormal wound healing
   6. Production of profibrotic cytokines, particularly transforming growth factor ß1 (TGF-ß1)
6. Fibroblasts
   1. Fibroblasts are activated in areas of inflammation
   2. Fibroblast proliferation follows inflammatory cell accumulation
   3. Fibroblasts may migrate into alveolar spaces
   4. They deposit collagen directly on top of the pneumocytes
   5. Likely that collagen deposition causes pneumocyte death
   6. TGFß appears to be critical for the process
   7. All cell types express TGFß which stimulates collagen synthesis and angiogenesis [5]
   8. Thus, fibroblasts prevent re-epithlialization following injury
7. Increased collagen deposition in alveolar-vascular interstitium
   1. Alveolar septa become filled with collagen (mainly type I)
   2. Septa normally contain mainly Type IV collagen rather than type I
   3. Thickened basement membrane reduces oxygen transport
   4. Appearance is often called "honeycomb lung"
8. Overview of Pathology [2]
   1. Variation in location and age of lesions
   2. Prediliction of disease for peripheral subpleural parenchyma
   3. Fibrotic zones associated with honeycombing alternate with relatively normal areas
   4. Regions of chronic lung injury with scarring and honeycombing
   5. Regions of acute lung injury with acitvely proliferating fibroblasts, myofibroblasts
   6. Mild or absent areas of interstitial inflammation
9. Thus, IPF should be thought of as an "epithelial - fibroblastic disease" [1]

C. Diagnosis

1. Patients present with increasing dyspnea on exertion, cough, hypoxemia, or cyanosis
2. Physical Examination
   1. Rales (crackles) may be present on auscultation
   2. Evidence of right sided congestive heart failure
3. Radiologic Findings
   1. Reticular markings on chest radiograph, usually lower lung fields in periphery
   2. Progressive fibrosis may lead to dilated distal air spaces, appear as honeycombing
   3. CT Scan may show diffuse alveolar septal thickening, small cysts
   4. White Blood Cell (Gallium) scanning may be demonstrate lung inflammation
4. Echocardiography
   1. Pulmonary Hypertension
   2. Right Ventricular Dilatatation (tricuspid regurgitation) and Cor Pulmonale
5. Arterial blood gas - hypoxemia without hypercarbia
6. Pulmonary Function Tests (PFTs)
   1. Restrictive without obstructive defects (FVC decline)
   2. Reduced pulmonary compliance
   3. DLCO reduction is felt to be best predictor of disease course
7. Bronchoalveolar Lavage (BAL) and Lung Biopsy
   1. These invasive diagnostic tests should be considered to help rule out other causes
   2. Thickened intra-alveolar septa often with inflammatory cells, small cysts
   3. Inflammatory cells include macrophages, neutrophils, mast cells, T lymphocytes
   4. High levels of eosinophils are atypical of IPF
   5. Lymphoid hyperplasia
   6. Intimal thickening of pulmonary arteries
   7. Elevated procollagen III levels in BAL fluid are a poor prognostic indicator
   8. Since lesions are usually peripheral, bonchoscopic biopsy rarely makes diagnosis
8. No serological markers currently useful
   1. Erythrocyte sedimentation rate or C-reactive protein elevated in majority of patients
   2. Antinuclear antibodies and/or rheumatoid factor in ~30% of cases
9. Lung biopsy is the standard for making the diagnosis
   1. Large piece of peripheral parenchymal tissue is typically required
   2. Thracotomy or less invasive thoracoscopic or video-assisted scopes
   3. Biopsy from several sites is often required to insure diagnosis
10. Progression of Mild-Moderate IPF [6]
    1. Defined as IPF with FVC 50-90% and DLCO >25% predicted
    2. High resolution CT at least "probably" diagnostic of IPF
    3. Progression of mild-moderate IPF is not characterized by gradual, progressive decline
    4. Rather, acute deterioration, often fatal, occurs in mild-moderate patients
    5. Over a period of ~76 weeks, 23% required hospitalization, 21% died
    6. 90% of deaths were due to IPF
    7. Therefore, patients must be carefully monitored for acute deterioration
11. Rapidly Progressive IPF [3,7]
    1. Also called Hamman-Rich Syndrome
    2. Progression over a period of weeks
    3. Considered an accelerated end-stage phase of usual interstitial pneumonitis
    4. Diffuse alveolar damage is present
    5. Most patients die within weeks to months
    6. Some patients are able to live with mechanical ventilation

D. Differential Diagnosis [3,8]

1. Pneumoconiosis
2. Systemic Sclerosis (Scleroderma)
3. Hypersensitivity Pneumonitis
4. Radiation Injury
5. Oxygen Toxicity Pneumonitis
6. Late Stage Sarcoidosis (Stage III or IV)
7. Pre-lymphoma or associated with pulmonary lymphoma [9]
8. Desquamative Interstitial Pneumonitis (DIP) [10]
   1. Some histological overlap with usual interstitial pneumonitis and other pneumonitis
   2. Highly inflammatory with lesions typically of similar age
   3. Reaction to asbestos, silica, organic dusts, mycotoxins, drugs, other agents
   4. Predominance of activated alveolar macrophages
   5. These macrophages were originally thought to be desquamated pneumocytes
   6. Bilateral lower lobe grown-glass infiltrates
9. IPF itself

E. Treatment

1. Oxygen
   1. Generally given for resting (or exertional) arterial pO2 < 60mmHg
   2. May slow progression of right heart failure (Cor Pulmonale)
   3. Other vasodilators may be helpful if pulmonary pressures are high
2. Glucocorticoids [11,12]
   1. May have some symptomatic benefit in nearly all patients
   2. Improved disease in ~25% of patients, stabilized in another ~45%
   3. DIP may show better response than usual interstitial pneumonitis
   4. High doses intravenously are usually given, followed by oral agents
   5. Alternative dosing is prednisone 0.5mg/kg po initially for 1 month, with subsequent tapers to 10mg/d over 3 months [13]
   6. Azathioprine 2mg/kg po may be added to prednisone as a glucocorticoid sparing agent [13]
   7. Patients with good initial (3 month) response have improved survival
   8. Most effective when combined with other agents
   9. Most patients develop glucocorticoid related side effects unless dose is tapered
3. Cyclophosphamide
   1. Used in conjunction with glucocorticoids
   2. Appears to be more efficacious than glucocorticoids alone in uncontrolled studies
   3. Glucocorticoids + cyclophosphamide had no benefit on survival versus placebo in controlled retrospective study [12]
4. Interferon Gamma (IFNg) [14,15]
   1. IFNg has anti-fibrotic activities
   2. Inhibits the proliferation of lung fibroblasts
   3. Down regulates TGFß1 expression
   4. Dose 200µg sc thrice weekly added to prednisolone 7.5mg/day stabilized disease in Phase 2 clinical study [14]
   5. Combination with prednisolone improved baseline and exercise oxygenation [14]
   6. In randomized Phase 3 clinical study, IFNg had no benefit in patients with IPF whose disease was resistant to glucocorticoids [15]
   7. Therefore, IFNg can no longer be recommended in IPF
5. In patients with pulmonary hypertension, oxygen and vasodilators may help
6. Antioxidant Therapy [15]
   1. Direct oxygen toxicity and neutrophil release of reactive oxygen increase damage
   2. Oral high dose N-acetylcysteine (NAC) 600mg po tid added to prednisone + azathioprine slowed FEV1 and DLCO decline over 1 year
   3. NAC also reduced the incidence of myelotoxicity of azathioprine
   4. There is concern that azathioprine can exacerbate oxidative damage in the lung
7. Lung Transplantation [16]
   1. Transplantation may be required due to severe destruction of lung tissue
   2. Cor Pulmonale (right heart failure) has often developed as lung function declines
   3. Therefore, combination with heart transplant often required
   4. Lung transplantation cleary improves outcome in majority of these patients
   5. Infections are main cause of death after transplantation
   6. Primary non-function occurs in >15%, and malignant disorders occur in ~15%
   7. Waiting period for transplantation is ~2 years
8. Indications for Lung Transplantation in IPF [17]
   1. Symptomatic disease unresponsive to medical therapy
   2. Forced vital capacity <60-70% of predicted
   3. Resting or exercise-induced hypoxemia
9. Experimental Agents [1]
   1. ACE Inhibitor - captopril inhibits fibroblast proliferation, reduces fibrotic lung responses
   2. Interferon ß1a - reduces fibroblast migration, proliferation, and collagen I synthesis
   3. Pirfenidone - inhibits TGF-ß and PDGF gene expression
   4. Colchicine - inhibits collagen formation; no more effective than glucocorticoids alone
   5. Keratinocyte growth factor - induces proliferation of type II pneumocytes
   6. Endothelin 1 blockade with bosentan (Tracleer®) has not shown benefit in IPF

F. Prognosis

1. Mainly related to progressive lung and heart disease
2. Median survival after lung biopsy diagnosis is typically <3 years
3. Patients with rapidly Hamman-Rich Syndrome usually live <6 months

References

1. Selman M, King TE Jr, Pardo A. 2001. Ann Intern Med. 134(2):136
2. Gross TJ and Hunninghake GW. 2001. NEJM. 345(7):517
3. Gong MN and Mark EJ. 2002. NEJM. 347(26):2141 (Case Record)
4. Paine R III and Ward PA. 1999. Am J Med. 107(3):268
5. Blobe GC, Wchiemann WP, Lodish HF. 2000. NEJM. 342(18):1350
6. Martinez FJ, Safrin S, Weycker D, et al. 2005. Ann Intern Med. 142(12):963
7. Hollingsworth HM and Mark EJ. 2001. NEJM. 345(16):1193 (Case Record)
8. Ryu JH, Olson EJ, Midthun DE, Swensen SJ. 2002. Mayo Clin Proc. 77:1221
9. Reilly JJ Jr and Mark EJ. 1998. NEJM. 338(18):1293
10. Hayes BG and Mark EJ. 1998. NEJM. 338(7):453 (Case Report)
11. Flaherty KR, Toews GB, Lynch JP III, et al. 2001. Am J Med. 110(4):278
12. Collard HR, Ryu JH, Douglas WW, et al. 2004. Chest. 125(6):2169
13. Demedts M, Behr J, Buhl R, et al. 2005. NEJM. 353(21):2229
14. Ziesche R, Hofbauer E, Wittmann K, et al. 1999. NEJM. 341(17):1264
15. Raghu G, Brown KK, Bradford WZ, et al. 2004. NEJM. 350(2):125
16. Hosenpud JD, Bennett LE, Keck BM, et al. 1998. Lancet. 351(9095):24
17. Arcasoy SM and Kotloff RM. 1999. NEJM. 340(14):1081
18. Armanios MY, Chen JJ, Cogan JD, et al. 2007. NEJM.