Interstitial Lung Disease Diffuse Parenchymal Lung Disease

Interstitial Lung Disease/Diffuse Parenchymal Lung Disease(DPLD) • • • • Case/ Pretest Pathogenesis/Classifications Patient Evaluation Idiopathic Pulmonary Fibrosis (IPF) as an example • Complications and Management of DPLD • Conclusion My Patient • Mr. RL is a 71 y.o man presented in 10/1998 with worsening dry cough (especially at church choir) and DOE for 3 months, CXR and CT scan showed increased peripheral interstitial markings, mild honey combing • PMH: DM, HTN, clinical diagnosis of sarcoidosis 11 years ago without biopsy, no need for treatment • • • • • What history is important? What to look for on examination? How is CXR/CT/PFT going to help? How to confirm the diagnosis? What treatment options are there? DPLD-Introduction • • • >200 diagnoses R/O infection and cancer Prevalence estimated 20-40/100,000 V Alveolar sac A L Basement membrane DPLD-Pathogenesis • Alveolar injury/insult through airways or vasculatures and lymphatics • Single vs. continuous (ongoing injury) • Alveolitis (inflammation vs. fibrogenesis) • Interstitial architecture deranged • Repair (recruit/removal/resolution), granuloma formation, fibrotic changes DPLD-Classification DPLD Known causes e.g. drugs, CT ds Post-RT, occupation, HP Idiopathic Interstitial pneumonias Granulomatous e.g. sarcoidosis Other forms e.g. LAM, HX IPF DIP AIP NSIP Other than IPF RB-ILD COP LIP Etiologic Classification: Environmental causes Occupational, environmental exposures (partial list) Inorganic dust Silica, silicates (asbestos, talc), hard metal, beryllium Thermophilic bacteria (e.g. farmer’s lung); animal proteins (e.g. bird fancier’s lung) Organic dust Chemicals, gases, vapors, fumes, radiation Drugs, poisons (partial list) Chemotherapy Busulfan, bleomycin,methotrexate, rituximab (rituxan), ?thalidomide Nitrofurantoin, sulfasalazine Drug-induced lupus Amiodarone Antibiotics Procainamide Miscellaneous Etiologic Classification: associated diseases Connective tissue diseases SLE, RA, systemic sclerosis, Sjogren’s syndrome, polymyositis Other systemic Sarcoidosis, WG, GPS, diseases lymphangitic carcinomatosis, alveolar proteinosis Etiology IPF unknown Infections Residue of chronic aspiration/ infection Acute DPLD • • • • • • ARDS (DAD) AIP (Hamman-Rich syndrome) AEP (>25% Eo from BAL) DAH ?Acute BOOP ?Acute sarcoidosis DPLD-Patient Evaluation • History – fever, hemoptysis, sinus, swallow – muscle, joint – PMH of asthma, malignancy, chemotherapy or radiotherapy, CTD, IBD – present and prior medications – family history (3% IPF are familial) DPLD-Patient Evaluation • Detailed Occupational History- exposures, duration, exact role in work place, protective gears use, coworkers’ symptoms • work place- site visit • pets, hobbies, home environment • HIV risk, illicit drugs and cocaine use DPLD- Physical Exam • Lung exam- end inspiratory “Velcro” or “cellophane” crackles, check for pleural effusion • Heart exam- P2, RV heave, TR murmur • HJR, liver enlargement • Clubbing- up to 50% of IPF • Skin changes- E. nodosum, Raynaud’s • Eye changes- scleritis, uveitis • Salivary glands enlargement • O2 saturation- resting and ambulating, overnight DPLD-PFT • Restrictive pattern with decrease in TLC and decrease in DLCO • May be obstructive in some patients, e.g. LAM, BO, EG, sarcoidosis, IPF or BOOP in smokers – CEP, AEP, Churg-Strauss DPLD-CXR and HRCT • • • • Upper lobes vs. lower lobes vs. diffuse Peripheral (sub-pleural)- IPF Ground glass changes, traction bronchiectasis Pleural involvement is rare- CTD, asbestosis, LAM, post-RT • Ass. pneumothorax or bullae disease- HX, LAM • Lymph nodes enlargement • Early cases may have normal CXR DPLD- Bronchoalveolar lavage and lung biopsy • R/O infection and cancer • cell differential may help in some situation but lack specificity • transbronchial biopsy- limited diagnostic yield (helpful in sarcoidosis, lymphangitic spread of cancer) • VATS open lung biopsy for definitive diagnosis DPLD-other tests • • • • • • • • Hct, Eos, ESR, Urinalysis HCO3 ABG serology e.g. ANA, RF, ANCA, anti-GBM, HP panel EKG, holter monitor, echo PPD, HIV eye exam Ca, 24 hr urine Ca Idiopathic Pulmonary Fibrosis (IPF) as a classical example • IPF= Cryptogenic fibrosing alveolitis in Europe • Most common DPLD (~35% in male and 25% in female), most deadly, with average life expectancy between 2 to 5 years • Prevalence 20.2/100,000 male (incidence 10/100,000), 13.2/100,000 female (incidence 7/100,000), more common in older people (>60 years old) • Median survival~ 3 years, 50% died within 5 years, no real proven treatment still • ? Role of steroid and cytotoxic drugs targeted at inflammation (<20% respond to steroid) IPF- refined diagnosis (UIP) • Need to exclude all diseases that can lead to possible UIP pathologically: asbestosis, scleroderma and other CT ds, chronic HP, drug, CEP, rarely sarcoidosis • Histological hallmarks: temporal heterogeneity signifying ongoing injury (transition from normal lung to alveolar organization/inflammation to dense fibrosis) and abundant fibroblastic foci (?fibroblast playing the central role in pathogenesis) • 1.6-2.3 times more common in smoker • Increase lung cancer risk IPF- clinical features • Hx: usually > 60 y.o., DOE, dry cough, velcro-type crackles • CXR: diffuse interstitial infiltrate – Peripheral, sub-pleural, bibasilar – Can be patchy – Honey comb changes in later stage • PFT: restrictive impairment, decrease DLCO, hypoxemia worse on exercise IPF- Antifibrotic Agents • Rodent Models: Bleomycin/ Radiationinduced Injury • New Agents: act on Fibroblast, Macrophage and T-cells Use of Interferon gamma-1b with Prednisolone • IPF patients have decrease IFN gamma level • IFN gamma decrease fibroblast proliferation, collagen I and III synthesis IFN gamma-1b and PrednisoloneAustria Experience NEJM 1999;341:1264-9 • Design: open/randomized, comparing Pred. Vs Pred. +IFN gamma-1b • Inclusion: biopsy-confirmed IPF, decrease TLC > 10% in prior 12 months, no response to “conventional” treatments • Exclusion: “end-stage” IPF with TLC <45% IFN gamma-1b and PrednisoloneAustria Experience NEJM 1999;341:1264-9 • 50 mg pred. for 4 wks. run-in, taper to 10 mg in 2 wks. • Time zero and 6 month bronchoscopic biopsy from same area, 3/6/9/12th month PFT, resting and max. exercise ABG • 9 patients in each arm for 12 months: 200ug INF gamma-1b SQ TIW plus pred. 7.5mg (gp.1) vs pred. 7.5mg only (gp.2, may titrate to max. of 50mg) IFN gamma-1b and PrednisoloneAustria Experience NEJM 1999;341:1264-9 • Biopsy samples for TGF beta-1, connective tissue growth factor, INF gamma levels by PCR technique • Follow for 1 year IFN gamma-1b and PrednisoloneAustria Experience: Result • Gp.1: TLC increase (70 to 79%) at 12th month, increase resting PaO2 (64 to 76), increase max. exercise PaO2 (55 to 65), patients requiring O2 decrease from 3 to 1. NEJM 1999;341:1264-9 • Gp.2: TLC decrease (66 to 62%) at 12th month, decrease resting PaO2 (65 to 62), decrease max. exercise PaO2 (55 to 52), patients requiring O2 increase from 2 to 4. IFN gamma-1b and PrednisoloneAustria Experience: Comments • Not very sick population-- no death in 1 year • Un-blinded, small, lack placebo group • Quality of life not monitored • Undefined role of prednisolsone • Encouraging results NEJM 1999;341:1264-9 Interferon Gamma-1b Multinational trial NEJM 1/8/2004;350:125-33 • 58 centers, 330 patients unresponsive to 1.8 gm corticosteroid therapy, placebo-controlled • Median follow up for 58 weeks • Subcutaneous INF gamma-1b TIW vs. placebo • Progression or death, lung function, gas exchange and quality of life- no difference • More constitutional symptoms and non life-threatening pneumonias in treatment group • Subgroup analysis showed survival benefit in compliant patients, especially in those with less severe lung function impairment • New education initiative PILOT (Pulmonary Fibrosis Identification: Lessons for Optimizing Treatment) and new study INSPIRE (International Study of Survival Outcomes in IPF with Interferon gamma-1b) DPLD-Complications • Disease-related – RV failure – Cor pulmonale – LV failure • Treatment-related – Prolonged steroid use leading to myopathy, PUD, cataracts, osteoporosis, infections – Cytotoxic drugs increase susceptibility to infections, bone marrow suppression, hemorrhagic cystitis • Pulmonary infection • Acute PE • Malignancy esp. adenocarcinoma • Pneumothorax DPLD-Management Issues • • • • • Removal from known exposures Cough, home O2 (high flow trans-tracheal), travel pulmonary rehabilitation, nutrition depression, social work, insurance Steroid side effects, osteoporosis, cytotoxic drugs toxicity • pneumovax, flu, PPD, ?PCP prophylaxis • Get enrolled into research studies • Transplant Evaluation/ end of life issues DPLD-Conclusion • • • • Not all crackles are due to CHF Pleural involvement is rare in DPLD Patient evaluation discussed Early biopsy if seriously considering Rx or transplant referral, may also guide prognosis • IPF new treatment discussed • Management of disease and side effects from treatments My patient- Mr. RL • Open Lung Biopsy on 2/28/2001– UIP confirmed • Enrolled into Interferon study, got active treatment since 5/25/2001 (after 1.8gm of prednisone) • FVC stable at 68-73% predicted for almost 3 years and died subsequently on 4/14/2004 after about 4 weeks of rapid deterioration • Post-Mortem showed UIP with honeycomb, bilateral pneumonia, multiple sub-segmental PE