Idiopathic Pulmonary Fibrosis
OBJECTIVESKnow the definitions of ILD, IIP, and IPFUnderstand the pathogenesis of IPFAppreciate the clinical features Realize how the diagnosis of IPF is madeKnow current therapiesBecome aware of areas of current research and novel therapeutic approaches Be able to summarize current thinking about IPF
Interstitial Lung Disease (ILD) orDiffuse Parenchymal Lung Disease (DPLD)Mason: Murray & Nadel's Textbook of Respiratory Medicine, 4th ed. Any process that results in inflammatory-fibrotic infiltration of the alveolar septa resulting in effects on the capillary endothelium and alveolar epithelium.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 Generic term used to describe many conditions that cause breathlessness and/or cough and are associated with radiographic bilateral lung abnormalities.
INTERSTIAL LUNG DISEASESConnective Tissue DiseasesSclerodermaPolymyositis-DermatomyositisSystemic Lupus ErythematosusRheumatoid ArthritisMixed Connective Tissue DiseaseAnkylosing SpondyitisTreatment-Related / Drug-InducedAntibiotics nitrofurantoin, sulfasalazineAntiarrhythmics amiodarone, propanololAnti-inflammatories gold, penacillamineAnti-convulsants dilantinChemotherapeutic agents bleomycin, cyclophosphamide, methotrexate, azathioprineTherapeutic radiationOxygen toxicityNarcoticsPrimary (Unclassified) SarcoidosisLangerhans cell histiocytosisAmyloidosisPulmonary vasculitisLipoid pneumoniaLymphangitic carcinomatosisBronchoalveolar carcinomaPulmonary lymphomaGauchers DiseaseNiemann-Pick DiseaseHermansky-Pudlak syndromeNeurofibromatosisLymphangioleiomyomatosisTuberous SclerosisARDSAIDSBone Marrow TransplantationPostinfectiousEosinophilic pneumoniaAlveolar ProteinosisDiffuse Alveolar Hemorrhage SyndromesAlveolar microlithiasisMetastatic calcificationOccupational and Environmental Diseases
SilicosisBird breeders lungAsbestosisFarmers lungHard-metal pneumoconiosisBacteria e.g. NTB mycobacteriaCoal workers pneumoconiosisFungi e.g. AspergillusBerylliosisAnimal protein e.g. AvianAluminum oxide fibrosisChemical sensitizers - Talc pneumoconiosis e.g. isocyanatesSiderosis (arc welder)Stannosis (tin)Idiopathic Fibrotic DisordersAcute interstitial pneumonitis (Hamman-Rich syndrome)Idiopathic Pulmonary FibrosisFamilial Idiopathic Pulmonary FibrosisDesquamative intersitial pneumonitisRespiratory bronchiolitisCryptogenic organizing pneumoniaNonspecific interstitial pneumonitisLymphocytic interstitial pneumonia (Sjgrens Syndrome, AIDS, Hashimotos)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:
Usual interstitial pneumonia (UIP)Bronchiolitis obliterans interstitial pneumonia and diffuse alveolar damage (BIP)Desquamative interstitial pneumonia (DIP)Lymphocytic interstitial pneumonia (LIP)Giant cell interstitial pneumonia (GIP) In 2002, the ATS/ERS published their consensus classification of IIP based on Clinical-Radiologic-Pathologic categories:
Clinical-Radiologic-Pathologic DiagnosisHistologic PatternIdiopathic Pulmonary Fibrosis (Cryptogenic fibrosing alveolitis)Usual interstitial pneumoniaNonspecifiic interstitial pneumonia (provisional)Nonspecific interstitial pneumoniaCryptogenic organizing pneumoniaOrganizing pneumoniaAcute interstitial pneumoniaDiffuse alveolar damageRespiratory bronchiolitis ILDRespiratory bronchiolitisDesquamative interstitial pneumoniaDesquamative interstitial pneumoniaLymphoid interstitial pneumoniaLymphoid interstitial pneumonia
ATS/ERS International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias, Am J Respir Crit Care Med.
USUAL INTERSTITIAL PNEUMONIA PATTERNThe UIP pattern can be seen in the following conditions: IPF Familial IPF Collagen vascular diseases Drug toxicity Chronic hypersensitivity pneumonitis Asbestosis Hermansky-Pudlak syndromeThe term UIP is usually reserved for patients in whom the lesion is idiopathicUIP IPF
Key histologic features:Dense fibrosis with remodeling of lung architecture , frequent honeycomb fibrosisFibroblastic foci usually at the edge of scarringPatchy lung involvementUsually subpleural distributionImportant negative findings:No active lesions typical of other ILDsLackof marked interstitial chronic inflammationNo (or rare) granulomasNo evidence of inorganic dust deposits (e.g. asbestos bodies)Lack of marked eosinophiliaUSUAL INTERSTITIAL PNEUMONIA PATTERN
Mason: Murray & Nadel's Textbook of Respiratory Medicine, 4th ed. Idiopathic Pulmonary Fibrosis, Gross and Huninghake, NEJM, 2001.USUAL INTERSTITIAL PNEUMONIA PATTERN
HONEYCOMB PATTERNPictures taken from http://mediswww.meds.cwru.edu/ecsample/yeartwo/pulmonary/interstitial.html
IDIOPATHIC PULMONARY FIBROSISATS definition: IPF is a distinctive type of chronic fibrosing interstitial pneumonia of unknown cause limited to the lungs and associated with a surgical lung biopsy showing a histologic pattern of UIP.A distinct type of chronic fibrosing interstitial pneumonia Unknown cause Limited to the lungs Associated with a histologic pattern of usual interstitial pneumonia (UIP)
EPIDEMIOLOGYRaghu et. al., Am J of Resp Crit Care Med 2006 Estimated to affect approx 5 million people worldwide Most cases are sporadic, but rare cases of familial IPF have been described The most common (and deadly) interstitial lung disease
EPIDEMIOLOGYRaghu et. al., Am J of Resp Crit Care Med 2006
CLINICAL PRESENTATIONMiddle age 50-70s New onset of progressive exertional dyspnea and non-productive coughMost have symptoms for 12-18 months prior to definitive evaluationConstitutional symptoms are uncommonWeight loss, fever, fatigue, myalgias, or arthralgias occasionally presentDetailed occupational and exposure history
PHYSICAL EXAMBibasilar late inspiratory fine crackles (Velcro rales)Clubbing 40-75% - late in disease courseCardiac exam usually normal until middle-late stages- augmented P2, right-sided heave, S3 gallopCyanosisRash, arthritis, myositis should suggest an alternate diagnosisTachypnea
CXRIdiopathic Pulmonary Fibrosis, Gross and Hunninghake, NEJM, 2001.16% of patients with ILD have normal chest x-raysCourtesy of W. Richard Webb, MD.
CXRMason: Murray & Nadel's Textbook of Respiratory Medicine, 4th ed.
PFTsPFTsSource: images.mdRestrictive patternReduced TLC, VC, and/or RV (decreased compliance)
Normal or increased FEV1/FVC
ABGABG=Hypoxemia, respiratory alkalosisDecreased PaO2 with rest or exercise
Increased A-a gradientOther lab tests that might be useful?Elevated ESRHypergammaglobulinemiaLow-titer positive ANA (21% patients with IPF)RFCirculating immune complexesCryoimmunoglobulins
HIGH RES CTCan now be used to differentiate IPF from other ILDCan determine extent and severity of disease activityCan be used to detect disease, especially in pts with no or minimal changes on CXRIdiopathic Pulmonary Fibrosis, Gross and Hunninghake, NEJM, 2001.Peripheral, subpleural fibrosisAlternating areas of normal tissueHoneycombingTraction bronchiectasisLater stages - more diffuse reticular pattern prominent in lower lung zones associated with thickened interlobular septa
BAL in IPF Role and value of serial BAL in IPF previously unknown Increased inflammatory cells in IPF, but no predominant type156 subjects with biopsy proven UIP/IPF enrolled between 1982-1996
BAL within 3 weeks of lung biopsy
Linear relationship between increasing neutrophil percentage and the risk of mortality
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. Kinder et al, Chest, Jan 2008
LUNG BIOPSY Gold Standard for diagnosis of IPF (and IIPs) 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 VATSOTHER STUDIES IN IPF Gallium Scanning (67Ga)used for staging alveolitis in ILD, e.g sarcoidosisNot useful difficult to interpret, very low specificity VQ scanreveals patchy, non-segmental areas of decreased Vdecreased perfusion in lower lung zonesincreased perfusion of upper lung zones (due to PH)
ATS/ERS CRITERIA FOR DIAGNOSIS OF IPF IN ABSENCE OF SURGICAL LUNG BIOPSYMajor Criteria:Exclusion of other known causes of ILD
Abnormal PFTs that include evidence of restriction and impaired gas exchange
Bibasilar reticular abnormalities with minimal ground glass opacities on HRCT
Transbronchial lung biopsy or BAL showing no features to support alternative dxMinor Criteria:Age > 50
Insidious onset of otherwise unexplained dyspnea on exertion
Duration of illness greater than 3 months
Bibasilar inspiratory crackles (dry or Velcro-type in quality)ALL of