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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.

BACKGROUND: Tuberculosis (TB) causes 1.45 million deaths annually world wide, the majority of which occur in the developing world. Active TB disease represents immune failure to control latent infection from airborne spread. Acid-fast bacillus (AFB) seen on sputum smear is a biomarker for contagiousness. METHODS: We enrolled 73 tuberculosis patients with extensive infiltrates into a research study using bronchoalveolar lavage (BAL) to sample lung immune cells and assay BAL cell cytokine production. All patients had sputum culture demonstrating Mycobacterium tuberculosis and 59/73 (81%) had AFB identified by microscopy of the sputum. Compared with smear negative patients, smear positive patients at presentation had a higher proportion with smoking history, a higher proportion with temperature >38.5(0) C, higher BAL cells/ml, lower percent lymphocytes in BAL, higher IL-4 and IL-12p40 in BAL cell supernatants. There was no correlation between AFB smear and other BAL or serum cytokines. Increasing IL-4 was associated with BAL PMN and negatively associated with BAL lymphocytes. Each 10-fold increase in BAL IL-4 and IL-12p40 increased the odds of AFB smear positivity by 7.4 and 2.2-fold, respectively, in a multi-variable logistic model. CONCLUSION: Increasing IL-4 and IL-12p40 production by BAL cells are biomarkers for AFB in sputum of patients who present with radiographically advanced TB. They likely reflect less effective immune control of pathways for controlling TB, leading to patients with increased infectiousness.

Abstract Background: Inhaled interferon-gamma aerosol (aINF-gamma) may be effective treatment for idiopathic pulmonary fibrosis (IPF). We evaluated safety and delivery of aIFN-gamma (100 mug 3 times/week) in 10 IPF patients using the I-neb (Philips Respironics, Parsippany, NJ). Methods: IFN-gamma activity in the aerosol was confirmed by viral inhibition. Ten patients with an average age of 68 diagnosed with IPF (American Thoracic Society/European Respiratory Society consensus guidelines) were enrolled. In vivo deposition was measured via a gamma camera. The nebulizer recorded patient adherence to therapy. Pulmonary function tests [PFTs, forced vital capacity (FVC), total lung capacity (TLC), diffusing capacity for carbon monoxide (DLCO)] and the 6-min walk test were measured at baseline, and every 12-14 weeks for 80 weeks. Bronchoalveolar lavage (BAL) of the middle lobe was performed at baseline and 28 weeks. BAL and plasma samples were analyzed for chemokines and cytokines, including INF-gamma. Results: All 10 patients tolerated 80 weeks of inhaled IFN-gamma well, with no systemic side effects. True adherence with aerosol treatment averaged 96.7+/-4.81% (+/-SEM). In vivo lung deposition averaged 65.4+/-4.8mug and oropharyngeal deposition 12.6+/-3.0 mug. BAL IFN-gamma increased 60-fold and profibrotic cytokines (FGP-2, Flt-3 ligand, IL-5) were significantly decreased; IFN-gamma plasma levels were unchanged. PFTs showed minimal change in FVC. Post hoc analysis indicated that the slope of decline in TLC and DLCO reversed after beginning therapy. The 6-min walk was unchanged. Conclusions: IFN-gamma is safe in IPF and can be effectively delivered to lung parenchyma. PFTs remained stable throughout the trial. Reversal of pretherapy PFT decline may define an end-point for future clinical trials.

Introduction: We propose aerosolized INF-g as targeted therapy to the lungs in idiopathic pulmonary fibrosis (IPF). We studied 10 patients using the I-neb AAD System (Philips Re- spironics, Parsippany, NJ) interactive nebulizer in Targeted Inhalation Mode (TIM). Methods: Particle distribution was measured by cascade im- paction, lung deposition of radiolabeled IFN-g by gamma camera. Pulmonary function (PFT) was measured quarterly, before and during therapy. Bronchoscopy with BAL of the middle lobe was performed 1 hr after aerosol, at baseline and at 4 months. Levels of INF-g were normalized for protein and correlated with middle lobe deposition. Cytokines were measured by ELISA assay. Results: Except for cough, aerosol therapy was well tolerated. Lung deposition averaged 64.4% (SE +/- 5.01) and oropharyngeal deposition 15.3% (SE +/- 3.81). Central to peripheral distribution averaged 0.854 (SE +/- 0.052), and when corrected for lung volume 1.20 (SE +/- 0.269), demonstrating peripheral deposition. The pre-aerosol decline in lung function was reversed by aerosol therapy. Lung volumes and diffusion capacity were unchanged over 70 weeks of therapy. Cytokine analysis was performed on BAL fluid, significant changes were obtained for IFN-g. Conclusion: IFN-g can be effectively aerosolized to the deep lung in patients with IPF achieving high concentrations in BAL fluid. Aerosol INF-g appears safe and may be effective