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Fibrosis
OBJECTIVES
“Death occurred about three months and a half after the onset of the acute
disease and the lung was two thirds of the normal size, grayish in color, and hard
as cartilage. Microscopically these areas showed advanced fibrotic changes and
great thickening of the alveolar walls.”
- Sir William Osler, 1892
INTERSTIAL LUNG DISEASES
Connective Tissue Diseases Treatment-Related / Drug-Induced
Scleroderma Antibiotics – nitrofurantoin, sulfasalazine
Polymyositis-Dermatomyositis Antiarrhythmics – amiodarone, propanolol
Systemic Lupus Erythematosus Anti-inflammatories – gold, penacillamine
Rheumatoid Arthritis Anti-convulsants – dilantin
Mixed Connective Tissue Disease Chemotherapeutic agents – bleomycin, cyclophosphamide,
Ankylosing Spondyitis methotrexate, azathioprine
Therapeutic radiation
Oxygen toxicity
Primary (Unclassified)
Narcotics
Sarcoidosis
Langerhans cell histiocytosis
Occupational and Environmental Diseases
Amyloidosis
Pulmonary vasculitis
Inorganic Organic
Lipoid pneumonia
Lymphangitic carcinomatosis
Silicosis Bird breeder’s lung
Bronchoalveolar carcinoma
Asbestosis Farmer’s lung
Pulmonary lymphoma
Hard-metal pneumoconiosis Bacteria – e.g. NTB mycobacteria
Gaucher’s Disease
Coal worker’s pneumoconiosis Fungi – e.g. Aspergillus
Niemann-Pick Disease
Berylliosis Animal protein – e.g. Avian
Hermansky-Pudlak syndrome
Aluminum oxide fibrosis Chemical sensitizers -
Neurofibromatosis
Talc pneumoconiosis e.g. isocyanates
Lymphangioleiomyomatosis
Siderosis (arc welder)
Tuberous Sclerosis
Stannosis (tin)
ARDS
AIDS
Bone Marrow Transplantation Idiopathic Fibrotic Disorders
Postinfectious Acute interstitial pneumonitis (Hamman-Rich syndrome)
Eosinophilic pneumonia Idiopathic Pulmonary Fibrosis
Alveolar Proteinosis Familial Idiopathic Pulmonary Fibrosis
Diffuse Alveolar Hemorrhage Syndromes Desquamative intersitial pneumonitis
Alveolar microlithiasis Respiratory bronchiolitis
Metastatic calcification Cryptogenic organizing pneumonia
Nonspecific interstitial pneumonitis
Lymphocytic interstitial pneumonia (Sjögrens Syndrome, AIDS, Hashimoto’s)
Autoimmune pulmonary fibrosis (inflammatory bowel disease, PBC, ITP, AIHA)
ATS/ERS International Multidisciplinary Consensus Classification of the
Idiopathic Interstitial Pneumonias, Am J Respir Crit Care Med. 2002
QUICK HISTORY OF IIP
In 1969, Liebow and Carrington described 5 types of chronic interstitial
pneumonias based on histology:
UIP ≈ IPF
USUAL INTERSTITIAL PNEUMONIA PATTERN
Most cases are sporadic, but rare cases of familial IPF have
been described
Chronic aspiration?
GERD AND IPF
Tachypnea
Cyanosis
Decreased DLCO
Source: images.md
ABG
ABG = Hypoxemia, respiratory alkalosis
Elevated ESR
Hypergammaglobulinemia
Low-titer positive ANA (21% patients with IPF)
RF
Circulating immune complexes
Cryoimmunoglobulins
HIGH RES CT
Can be used to detect disease, especially in pts with no
or minimal changes on CXR
Can determine extent and severity of disease activity
Can now be used to differentiate IPF from other ILD
Honeycombing
Traction bronchiectasis
Each doubling in the neutrophil percentage was associated with a nearly 30%
increased risk of death or transplantation in adjusted analysis ([HR] 1.28;
95% CI, 1.01 to 1.62; p = 0.04). There was no association with lymphocyte or
eosinophil percentage.
Suggests that BAL fluid neutrophil percentage at the time of diagnosis of IPF is an
independent predictor of time to death.
LUNG BIOPSY
Gold Standard for diagnosis of IPF (and IIP’s)
Large piece of lung parenchyma is required, optimally from several sites
Transbronchial biopsy is only useful for ruling out other disorders
Can be performed by thoracotomy, thorascopy, or VATS
Gallium Scanning (67Ga) used for staging “alveolitis” in ILD, e.g sarcoidosis
Not useful – difficult to interpret, very low specificity
Abnormal PFTs that include evidence of restriction and impaired gas exchange
Minor Criteria:
Age > 50
Accelerated variant
Acute exacerbation
Probability of
0.8
Side effects: Azathioprine +
leukopenia, Survival 0.6 Prednisone (n = 14)
GI-related
0.4
Prednisone (n = 13)
0.2
0
0 1 2 3 4 5 6 7 8 9
Years
Mortality, P =
NS
7/80 (9%)
NAC+Pred+Aza
Living donor lobar lung transplant (LDLLT) - Date et al, Chest 2005
The most important distinction is differentiate IPF from the other IIP’s
Biopsy is the gold standard for diagnosis, histology = UIP pattern with
fibroblast foci (hallmark of IPF)
Most common presentation is 50-60 y.o. male with progressive dyspnea
and non-productive cough
Most common physical exam findings are “Velcro” rales +/- clubbing
Most important diagnostic studies are CXR, PFT’s, ABG, and HRCT
If certain clinical criteria are met, can diagnose IPF without biopsy
American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic
Interstitial Pneumonias. Am J Respir Crit Care Med. Vol 165, pp 277-304, 2002.
Verma and Slutsky , Idiopathic Pulmonary Fibrosis – New Insights. NEJM. Vol 356, No 13: pp 1370-1372, 2007.
Gross and Hunninghake, Idiopathic Pulmonary Fibrosis. NEJM. Vol 345, No 7: pp 517-525, 2001.
Kinder BW et al. , Baseline BAL neutrophilia predicts early mortality in idiopathic pulmonary fibrosis. Chest. Vol 133(1): pp 226-32, Jan 2008.
Martinez FJ et al. (IPF Study Group). The Clinical Course of Patients with Idiopathic Pulmonary Fibrosis. Ann Intern Med. Vol 142: pp 963-967,
2005.
Kim DS et al. Acute exacerbation of idiopathic pulmonary fibrosis: frequency and clinical features. Eur Resp J. Vol 27: pp143-150, 2006.
Selman et al. Idiopathic Pulmonary Fibrosis: Prevailing and Evolving Hypotheses about Its Pathogenesis and Implications for Therapy.
Annals of Internal Medicine. Vol 134: 2, pp. 136-151, 2001.
Raghu, G et al . Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: a prospective, double-blind
randomized, placebo-controlled clinical trial. Am. Rev. Respir. Dis. 144: 291-296, 1991.
Collard et al, Combined corticosteroid and cyclophosphamide therapy does not alter survival in idiopathic pulmonary fibrosis. Chest.
125(6):2169-74, 2004.
Maurits Demedts et al, High-dose acetylcysteine in Idiopathic Pulmonary Fibrosis. NEJM, Vol 353: 2229-2242, 2005.
Armanios MY et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. NEJM 356: 1317-26, 2007.
Noth and Martinez. Recent Advances in Idiopathic Pulmonary Fibrosis. Chest 132: 637-50, 2007.
Noble PW. Idiopathic Pulmonary Fibrosis: Natural History and Prognosis. Clin Chest Med 27, S11-16, 2006.
American Thoracic Society, Idiopathic Pulmonary Fibrosis: Diagnosis and Treatment. Am. J. Respir. Crit. Care Med., Volume 161, Number 2, 646-
664, 2000.
Richeldi L, Davies HR, Ferrara G, Franco F. Corticosteroids for idiopathic pulmonary fibrosis. Cochrane Database of Systematic Reviews 2003, Iss 3.
Raghu G et al. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J. Vol 28(4): 884-5,
2006.
Orens et al. International Guidelines for the Selection of Lung Transplant Candidates: 2006 Update—A Consensus Report From the
Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. The Journal of Heart and Lung
Transplantation. Volume 25, Issue 7, Pages A1-A20, 745-868 (July 2006)
Date et al. A New Treatment Strategy for Advanced Idiopathic Interstitial Pneumonia*: Living-Donor Lobar Lung Transplantation
Chest, Sep 2005; 128: 1364 – 1370.
Noutati terapeutice in IPF
PIRFENIDON
• studiu faza 3 (ASCEND study group);
• 555 pts cu IPF- pirfenidon (2403mg/zi) sau placebo;
• End-point-uri primare – modificari FVC sau deces la 52 de
saptamani;
• End-pointu-uri secundare: testul distantei parcurse in 6 min,
supravietuire fara progresie, dispneea si deces de orice forma;