Faculty Bibliography

Parenteral IFN-gamma was unsuccessful as a treatment for pulmonary fibrosis. Inhaled IFN-gamma targeted to the lungs may be more effective. Our patient, a 56-year-old male with biopsy proven usual interstitial pneumonia (UIP) and declining pulmonary function tests (PFTs) was initially diagnosed with idiopathic pulmonary fibrosis (IPF). He enrolled in a 2-year research protocol and was treated with inhaled IFN-gamma (100 mug, Actimmune, Horizon Pharma, Deerfield, IL) 3 times per week. After completion of the protocol, he was able to secure the drug and continued therapy for a total of 7 years. He felt better, returning to work. His only complaint was transient cough during inhalation. PFTs improved (e.g., DLCO, 58% at baseline, 81% at 2 years, 69% currently). Clinical monitoring showed preserved exercise tolerance and stable CT scans. He was ultimately diagnosed (year 5) with scleroderma-like connective tissue disease after he developed sclerodactyly and a positive antinuclear antibody. Inhaled IFN-gamma was well tolerated for 7 years and may stabilize fibrotic lung disease.

BACKGROUND: Using data from a previously reported phase 2 safety trial, testing inhaled interferon gamma (IFN-gamma) for IPF, we analyzed effects on full pulmonary function tests (PFTs) for efficacy before and after therapy and designed a randomized controlled trial of inhaled IFN-gamma to treat IPF. METHODS: Ten patients with IPF had received inhaled IFN-gamma (Actimmune, InterMune) for 80 weeks. Full PFTs were available 20-50 weeks before Rx and monthly during Rx. Eighty-nine observations were used in the analysis. Linear mixed models for modeling longitudinal data were used to test if the PFT change over time was significantly different before and after IFN-gamma. Autoregressive dependence structure with order one was consistently selected as the best one to model the intra-patient correlation over time. Normality assumption was confirmed. Significance level was set at 0.05. Using published literature and our data we performed a sample size calculation based on simulated data. RESULTS: The change over time in DLCO was significantly different before and after IFN-gamma treatment. DLCO decreased over time before treatment but increased after treatment (p-value=0.03). Changes in TLC, FRC, RV and FVC were not statistically significant. With a sample size of 60, a placebo controlled, randomized trial has about 90% power to detect a significant difference in the change rate of DLCO in the groups of patients treated with IFN-gamma vs placebo. CONCLUSIONS: DLCO was significantly improved following inhaled (IFN-gamma) as treatment for IPF. Our data suggest that previous studies utilizing parenteral IFN-gamma may have failed because of the mode of delivery. Future randomized, controlled, phase 3 trials, comparing the difference in PFT behavior (specifically DLCO) longitudinally may be more sensitive to drug effect and serve as a valuable clinical endpoint.

BACKGROUND: Active TB disease can destroy lung parenchyma leading to cavities. Immune responses that predispose or protect individuals from lung damage during TB are poorly defined. OBJECTIVE: To sample lung immune cells and assay bronchoalveolar lavage (BAL) cell cytokine production. DESIGN: Enrolled subjects (n = 73) had bilateral infiltrates and underwent BAL. RESULTS: All had sputum culture demonstrating Mycobacterium tuberculosis and 22/73 (30%) had cavities on their chest radiograph. Those with cavities at presentation had a higher percentage of polymorphonuclear neutrophils (PMN) in BAL as well as lower inducible protein (IP) 10 (P < 0.01) and interleukin (IL) 6 (P = 0.013) in BAL cell supernatants compared to those without cavities. There was no correlation between cavities and other BAL or serum cytokines. IP-10 was negatively associated with BAL PMN. IP-10 and IL-6 expression above median reduces the odds of cavities by 79% and 78% in logistic regression models. IP-10 and IL-6 clustered with interferon-gamma and tumour necrosis factor-alpha in a principal component analysis, while IL-4 clustered with PMN. CONCLUSION: Increasing IP-10 and IL-6 production by BAL cells is associated with non-cavitary TB in patients who present with radiographically advanced TB. IP-10 and IL-6 may reflect an effective T-helper 1 immune control pathway for TB, attenuating tuberculous lung destruction.