Suleman Khawaja July 31, 2002

Idiopathic Pulmonary Fibrosis

Pathogenesis: - may involve series of nonspecific insults including smoking, infection, chronic aspiration, environmental pollutants, which lead to a form of aberrant wound healing - among the implicated factors are cytokines, abnormal fibroblast activity and collagen metabolism Epidemiology: - prevalence 20/100,000 for males and 13/100,000 for females - presents at age 40-70, mean age at diagnosis 66 years - no distinct geographical or racial distribution - potential risk factors are smoking, environmental exposures (metal dust, wood dust, solvents), viruses (EBV, CMV, influenza, HCV), chronic aspiration (?GERD), drugs (?antidepressants) - familial form, probably autosomal dominant with variable penetrance, is believed to exist Clinical Features: - presents insidiously with gradual onset of dyspnea and a nonproductive, often paroxysmal dry cough; the dyspnea becomes progressive and disabling - sleep disturbance is common even in the absence of sleep apnea and other sleep disorder breathing - characteristic physical findings include dry, end-inspiratory Velcro crackles, more prominent at the bases, scattered late inspiratory squeaks, and clubbing (25-50%) - late findings include cyanosis, loud P2, RV heave, and peripheral edema from cor pulmonale Workup: - Chest X-ray typically shows diffuse bilateral opacities, worse at bases, often in reticular, nodular, or mixed pattern without significant lymphadenopathy; lung volumes are often reduced - PFTs show restrictive pattern volumes are low (TLC, VC, FRC), may be closer to normal in smokers; spirometry shows decreased FEV1 and FVC, but a preserved or increased ratio FEV1/FVC; DLCO is reduced because of mismatch - ABG reveals hypoxemia which may need to be induced by exercise or sleep; CO2 retention signifies endstage disease; exercise testing with serial measurement can be useful - HRCT is up to 90% accurate when a confident diagnosis can be made (which is in 66% of cases); will show patchy, heterogeneous findings including areas of normal parenchyma, ground glass opacity representing interstitial inflammation with alveolitis (should be <30%), and fibrotic, cystic areas of honeycombing - to establish diagnosis of an idiopathic interstitial pneumonia, must exclude collagen vascular disease and other causes scleroderma, RA, SLE, sarcoidosis, HIV, infection - see other handout for classification of idiopathic interstitial pneumonias and where IPF/UIP fit in Bronchoscopy and Lung Biopsy: - BAL is of very limited diagnostic value and is typically useful chiefly to rule out numerous infectious causes; % lymphs in fluid can be of prognostic significance - Transbronchial biopsy is good for some other disorders (sarcoid, Goodpastures, infection, tumor), but not for ILD in general because pathology is often patchy and biopsy of fibrosed, cystic areas is both low-yield and risky for pneumothorax - VATS is the preferred method for getting tissue; HRCT is helpful to the surgeons in choosing sites - Biopsies should be from multiple sites, > 2cm, and subpleural, RML, and lingular tissue should be avoided, as they often have nonspecific fibrosis Pathology: - Usual interstitial pneumonia is the usual finding the hallmark is heterogeneous, variegated appearance with alternation between normal lung, interstitial inflammation, fibrosis, and honeycombed cystic areas

UIP is a term reserved for truly idiopathic cases in which collagen vascular disease has been ruled out and there is no pathologic evidence of occupational lung disease such as asbestosis

Prognostic Factors: - a clinical staging system would be helpful, especially with transplant being an option for some; only a minority respond to therapy, and the natural history is typically a relentless downhill course - indicators of longer survival age <50, female sex, shorter symptomatic period (< 1 year), greater proportion of inflammatory findings on HRCT (ground glass, reticular opacity), greater proportion of lymphocytes (20-25%) in BAL fluid, initial response to steroids - poor prognostic factors extent of fibrosis on HRCT (especially honeycombing), poor response to initial therapy Therapy: - progression is the rule with IPF, but disease may be more responsive early, and it may be critical to prevent further worsening in patients whose pulmonary function is already severely compromised - therapy is less likely to benefit patients who are older than 70, have preexisting obesity, DM, cardiac disease, osteoporosis, endstage honeycomb lung - there is not much good data, and most trials are tiny (n=10-20) Corticosteroids: - recommended initial therapy prednisone 1.0-1.5 mg/kg/day for 4 wk, and re-evaluate patient; if patient responds, taper to 0.5-1 mg/kg/day for another 12 wk, then re-evaluate, taper again - indications of response are decreased symptoms, improved CXR, improvement in serial PFTs (FVC increase, TLC increase by > 25%, DLCO increase by >40%), and decreased exercise O2 desaturation - PPD should be placed prior to starting corticosteroids; need to anticipate possibility of steroidinduced DM, osteoporosis, neuropsychiatric changes Cytotoxic and Antifibrotic Agents: - cyclophosphamide second-line drug in those worsening despite steroids; 50mg po qd, increase in 25mg increments to max 150mg, keep WBCs 4K-7K; CBCs Q2wks x 12 wks, then Qmonth - pts need to maintain aggressive po hydration; risks are cystitis, myelosuppression, stomatitis, infertility, malignancy; response takes 3-6 mos - 1 RCT of concurrent use with steroids shows possible survival advantage (Thorax 1989; 44:280) - azathioprine roughly same role, with one small study; 2mg/kg/day to max 200mg, maintain WBCs > 4K; risks are myelosuppression, hepatotoxicity, malignancy - colchicine may block fibrosis; failed to show significant change in decline of lung function in a nonrandomized study compared to steroids, but far better tolerated at 0.6mg po qd-bid - penicillamine improved median survival vs. historical controls in population of steroid failures - cyclosporine may have some role as a steroid-sparing agent in those awaiting tx - interferon gamma 1b inhibits fibroblast proliferation and collagen synthesis in animals - trial of 18 nonresponders to steroids randomized to prednisolone alone vs. prednisolone + IFN revealed improvement in TLC and O2 status after 12 months - side effects of F/C/myalgia generally resolve after 3 months Transplantation: - for progressive deterioration in O2 and functional status despite optimal medical management - single-lung tx currently preferred; screening and waiting time are even more discouraging than for other organs because of donor availability, more involved surgery, post-op course and immunologic factors; 5-year post-transplant survival approximates 50-60% Pulmonary Rehab programs can improve exercise tolerance, improve quality of life Activity should be encouraged; O2 requirements may be higher than for COPD pts Antitussives including codeine should be used aggressively, as the cough is often the most distressing aspect of the disease to patients