Rany Condos, M.D.

Delivery and safety of aerosolized INF-g in IPF
Diaz K.T.; Lau S.; Bauer K.; Skaria S.; Harris K.; Solomita M.; Smaldone G.C.; Condos R.
2011 ;24(3):8-8, Journal of Aerosol Medicine & Pulmonary Drug Delivery
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
— id: 134742, year: 2011, vol: 24, page: 8, stat: Journal Article,

The effect of inhaled IFN-on the cytokine profile in the alveolar space in Idiopathic Pulmonary Fibrosis (IPF)
Lau S.; Diaz K.; Smaldone G.; Condos R.
2011 ;140(4):?-?, Chest
PURPOSE: To evaluate how a novel treatment for idiopathic pulmonary fibrosis (IPF) changes the cytokine profile in the bronchoalveolar lavage (BAL) fluid of IPF patients after 28 weeks of treatment with inhaled interferon-gamma (IFN- ). METHODS: 10 patients with a diagnosis of IPF made within one year of enrollment were treated with 100 mcg of interferon-gamma via the I-Neb AAD device three times a week for 70 weeks. Patients had blood work and a bronchoscopy with BAL of the middle lobe at enrollment and then again after 28 weeks of treatment with inhaled IFN- . Cytokines and chemokines were measured from BAL fluid, 24-hour cell culture supernatant and plasma samples by Luminex Beadlyte ELISA assay. RESULTS: The mean BAL fluid level of IFN- corrected for protein increased from a baseline value of 5.23+/-3.16 to 320.0+/-79.5 pg/mg, P=0.002 after 24 weeks of inhaled IFN- . Mean 24-hour cell culture supernatant levels of IFN- also increased from 8.25+/-5.40 to 36.9+/-11.0 pg/ml, P=0.027. Mean 24-hour cell culture supernatant levels of FGP-2, Flt-3 ligand and IL-5 were significantly decreased (12.00+/-1.80 to 9.60+/-1.66 pg/ml, p= 0.031; 5.48+/-1.01 to 3.61+/-0.83 pg/ml, p= 0.039; 0.81+/-0.04 to 0.74+/-0.03 pg/ml, p= 0.049, respectively). CONCLUSIONS: IFN- can be effectively aerosolized to the lung parenchyma achieving high concentrations in BAL fluid. In IPF, targeted therapy with inhaled I
— id: 149976, year: 2011, vol: 140, page: ?, stat: Journal Article,

Immunomodulation with recombinant interferon-gamma1b in pulmonary tuberculosis
Dawson, Rod; Condos, Rany; Tse, Doris; Huie, Maryann L; Ress, Stanley; Tseng, Chi-Hong; Brauns, Clint; Weiden, Michael; Hoshino, Yoshihiko; Bateman, Eric; Rom, William N
2009 ;4(9):e6984-e6984, PLoS ONE
BACKGROUND: Current treatment regimens for pulmonary tuberculosis require at least 6 months of therapy. Immune adjuvant therapy with recombinant interferon-gamma1b (rIFN-gammab) may reduce pulmonary inflammation and reduce the period of infectivity by promoting earlier sputum clearance. METHODOLOGY/PRINCIPAL FINDINGS: We performed a randomized, controlled clinical trial of directly observed therapy (DOTS) versus DOTS supplemented with nebulized or subcutaneously administered rIFN-gamma1b over 4 months to 89 patients with cavitary pulmonary tuberculosis. Bronchoalveolar lavage (BAL) and blood were sampled at 0 and 4 months. There was a significant decline in levels of inflammatory cytokines IL-1beta, IL-6, IL-8, and IL-10 in 24-hour BAL supernatants only in the nebulized rIFN-gamma1b group from baseline to week 16. Both rIFN-gamma1b groups showed significant 3-fold increases in CD4+ lymphocyte response to PPD at 4 weeks. There was a significant (p = 0.03) difference in the rate of clearance of Mtb from the sputum smear at 4 weeks for the nebulized rIFN-gamma1b adjuvant group compared to DOTS or DOTS with subcutaneous rIFN-gamma1b. In addition, there was significant reduction in the prevalence of fever, wheeze, and night sweats at 4 weeks among patients receiving rFN-gamma1b versus DOTS alone. CONCLUSION: Recombinant interferon-gamma1b adjuvant therapy plus DOTS in cavitary pulmonary tuberculosis can reduce inflammatory cytokines at the site of disease, improve clearance of Mtb from the sputum, and improve constitutional symptoms. TRIAL REGISTRATION: ClinicalTrials.gov NCT00201123
— id: 104334, year: 2009, vol: 4, page: e6984, stat: Journal Article,

Case series report of a linezolid-containing regimen for extensively drug-resistant tuberculosis
Condos, Rany; Hadgiangelis, Nicos; Leibert, Eric; Jacquette, Germaine; Harkin, Timothy; Rom, William N
2008 Jul;134(1):187-192, Chest
OBJECTIVE: To determine whether linezolid is safe and well tolerated in the treatment of extensively drug-resistant tuberculosis (XDR-TB). MATERIALS AND METHODS: The was conducted in a specialized tuberculosis ward for multidrug-resistant tuberculosis (MDR-TB) on the Chest Service of Bellevue Hospital Center, which is a 768-bed public hospital in New York City. Seven patients with confirmed MDR-TB or XDR-TB who were still culture positive despite appropriate directly observed therapy were treated with a regimen containing linezolid and at least one other active agent. RESULTS: The linezolid-containing regimen led to sustained negative conversion of sputum cultures and radiographic improvement in all patients. Long-term therapy (longest duration of therapy, 28 months) was well tolerated in most patients. Neutropenia developed in three patients, but was reversible, and peripheral neuropathy developed in two patients. CONCLUSIONS: Linezolid remains a promising possible addition to our therapeutic armamentarium against XDR-TB. Linezolid is associated with side effects that can be adequately managed. Further studies to define the mechanism of action and optimum dose should be performed
— id: 81065, year: 2008, vol: 134, page: 187, stat: Journal Article,

Mycobacterium tuberculosis induces CCL18 expression in human macrophages
Ferrara, G; Bleck, B; Richeldi, L; Reibman, J; Fabbri, L M; Rom, W N; Condos, R
2008 Dec;68(6):668-674, Scandinavian journal of immunology
The interaction of Mycobacterium tuberculosis (MTB) with the immune system is mediated by cytokine and chemokine responses of macrophages and/or dendritic cells. Chemokine (C-C motif) ligand 18 (CCL18) and interleukin (IL)-10 are major factors secreted by phagocytes, postulated to recruit naive T lymphocytes and inhibit pro-inflammatory cells. Our study investigated the role of CCL18 and IL-10 in an in vitro model of infection by MTB in human macrophages. CD14(+) monocytes, obtained from the peripheral blood of eight healthy donors, differentiated in monocyte-derived macrophages (MDM) with monocyte-colony stimulating factor (100 ng/ml) for 6 days, were stimulated in vitro with lipopolysaccharide (LPS) (1 microg/ml) and with heat killed MTB Hv37Ra (multiplicity of infection 1:5) for 24 h. Alveolar macrophages from five healthy donors were infected with MTB Hv37RA. CCL18 protein and mRNA were detected by enzyme-linked immunosorbent assay (ELISA) and real-time PCR, IL-10 levels by ELISA. Stimulation of MDM with LPS or MTB led to a significant increase in CCL18 protein (control 2.67 +/- 0.46 ng/ml, LPS 4.05 +/- 0.56 ng/ml, with MTB 6.70 +/- 1.59 ng/ml, n = 5, P < 0.05) and specific mRNA levels (control 0.09 +/- 0.01, LPS 0.24 +/- 0.11, with MTB 0.34 +/- 0.08 CCL18/Glyceraldehyde 3-phosphate dehydrogenase (GAPDH), n = 3, P < 0.05). A significant increase of the production of CCL18 was observed in infected alveolar macrophages. IL-10 levels increased from 38.52 +/- 26.38 pg/ml in control cells to 1129.32 +/- 235.00 and 974.25 +/- 164.46 pg/ml in LPS and MTB treated cells, respectively (P < 0.05). Up-regulation of CCL18 and IL-10 in macrophages by MTB may be involved in the recruitment of naive T cells in association with local suppressive immunity against intracellular pathogens. This could represent a mechanism of tolerance during the early phases of infection
— id: 91453, year: 2008, vol: 68, page: 668, stat: Journal Article,

The burden of exposure-related diffuse lung disease
Goldyn, Sheryl R; Condos, Rany; Rom, William N
2008 Dec;29(6):591-602, Seminars in respiratory & critical care medicine
Estimating the burden of exposure-related diffuse lung disease in terms of health effects and economic burden remains challenging. Labor statistics are inadequate to define the scope of the problem, and few studies have analyzed the prevalence of exposure-related illnesses and the subsequent health care cost. Well-defined exposures, such as those associated with coal mines, asbestos mines, and stonecutting, have led to more accurate assessment of prevalence and cost. As governmental regulation of workplace exposure has increased, the prevalence of diseases such as silicosis and coal workers' pneumoconiosis has diminished. However, the health and economic effects of diseases with long latency periods, such as asbestosis and mesothelioma, continue to increase in the short term. Newer exposures, such as those related to air pollution, nylon flock, and the World Trade Center collapse, have added to these costs. As a result, estimates of cost for occupational diseases, including respiratory illnesses, exceed $26 billion annually, and the true economic burden is likely much higher
— id: 94493, year: 2008, vol: 29, page: 591, stat: Journal Article,

Evaluation of subjective effects of aripiprazole and methamphetamine in methamphetamine-dependent volunteers
Newton, Thomas F; Reid, Malcolm S; De La Garza, Richard; Mahoney, James J; Abad, Antonio; Condos, Rany; Palamar, Joseph; Halkitis, Perry N; Mojisak, Jurji; Anderson, Ann; Li, Shou-Hua; Elkashef, Ahmed
2008 Dec;11(8):1037-1045, International journal of neuropsychopharmacology
A variety of neuropharmacological strategies are being pursued in the search for an effective treatment for methamphetamine (Meth) addiction. In this study, we investigated the safety and potential efficacy of aripiprazole, an antipsychotic agent acting on both dopamine and serotonin systems. We conducted a double-blind in-patient clinical pharmacology study to assess potential interactions between intravenous (i.v.) Meth (15 mg and 30 mg) and oral aripiprazole (15 mg). In addition, the effects of aripiprazole treatment on abstinence-related craving and cue-induced craving were evaluated. Participants included non-treatment-seeking, Meth-dependent patients (n=16), aged 18-45 yr, currently using Meth. Following baseline Meth dosing (15 mg and 30 mg), participants received 2 wk treatment with aripiprazole (n=8) or placebo (n=8). Participants then completed cue exposure sessions using neutral and Meth-related cues. Meth dosing (15 mg and 30 mg) was then repeated. Aripiprazole treatment had no effect on cue-induced Meth craving, or on daily baseline craving assessed over the course of medication treatment, although aripiprazole treatment was associated with increased craving independent of Meth dosing. Aripiprazole treatment was associated with significantly higher ratings on Addiction Research Center Inventory (ARCI) subscales reflecting euphoria and amphetamine-like effects following Meth dosing. Aripiprazole treatment was also associated with significant reductions in ratings of 'bad effects' and reductions on the ARCI subscale for sedation effects following Meth dosing. Aripiprazole treatment reduced the increase in systolic blood pressure following Meth dosing, but had no other effects on cardiovascular responses to Meth. Aripiprazole treatment did not alter the pharmacokinetics of Meth. These findings indicate that aripiprazole treatment appears to be safe in volunteers with Meth dependence, although the finding that aripiprazole increased some of the rewarding and stimulatory effects produced by acute Meth suggests that 15 mg aripiprazole is unlikely to be efficacious for the treatment of Meth dependence. Further research with lower doses of aripiprazole, possibly using study designs aimed at evaluating efficacy for relapse prevention, are needed before ruling out aripiprazole as a treatment for Meth dependence
— id: 96227, year: 2008, vol: 11, page: 1037, stat: Journal Article,

Gene expression profiles of bronchoalveolar cells in pulmonary TB
Raju, Bindu; Hoshino, Yoshihiko; Belitskaya-Levy, Ilana; Dawson, Rod; Ress, Stanley; Gold, Jeffrey A; Condos, Rany; Pine, Richard; Brown, Stuart; Nolan, Anna; Rom, William N; Weiden, Michael D
2008 Jan;88(1):39-51, Tuberculosis (Edinburgh, Scotland)
The host response to Mycobacterium tuberculosis includes macrophage activation, inflammation with increased immune effector cells, tissue necrosis, and cavity formation, and fibrosis, distortion, and bronchiectasis. To evaluate the molecular basis of the immune response in the lungs of patients with active pulmonary tuberculosis (TB), we used bronchoalveolar lavage to obtain cells at the site of infection. Affymetrix GeneChip microarrays and cDNA nylon filter microarrays interrogated gene expression in bronchoalveolar lavage (BAL) cells from 11 healthy controls and 17 patients with active pulmonary TB. We found altered gene expression for 69 genes in TB versus normal controls that included cell surface markers, cytokines, chemokines, receptors, transcription factors, and complement components. In addition, TB BAL cell gene expression patterns segregated into 2 groups: one suggestive of a T helper type 1 (Th1) cellular immune response with increased signal transducer and activator of transcription-4 (STAT-4), interferon-gamma (IFN-gamma receptor), and monokine induced by IFN-gamma (MIG) expression with increased IFN-gamma protein levels in BAL fluid; the other group displayed characteristics of Th2 immunity with increased STAT-6, CD81, and IL-10 receptor expression. We were able to demonstrate that a Th2 presentation could change to a Th1 pattern after anti-tuberculous treatment in 1 TB patient studied serially. These gene expression data support the conclusion that pulmonary TB produces a global change in the BAL cell transcriptome with manifestations of either Th1 or Th2 immunity
— id: 74211, year: 2008, vol: 88, page: 39, stat: Journal Article,

Volatile biomarkers of pulmonary tuberculosis in the breath
Phillips, Michael; Cataneo, Renee N; Condos, Rany; Ring Erickson, Gerald A; Greenberg, Joel; La Bombardi, Vincent; Munawar, Muhammad I; Tietje, Olaf
2007 Jan;87(1):44-52, Tuberculosis (Edinburgh, Scotland)
Pulmonary tuberculosis may alter volatile organic compounds (VOCs) in breath because Mycobacteria and oxidative stress resulting from Mycobacterial infection both generate distinctive VOCs. The objective of this study was to determine if breath VOCs contain biomarkers of active pulmonary tuberculosis. Head space VOCs from cultured Mycobacterium tuberculosis were captured on sorbent traps and assayed by gas chromatography/mass spectroscopy (GC/MS). One hundred and thirty different VOCs were consistently detected. The most abundant were naphthalene, 1-methyl-, 3-heptanone, methylcyclododecane, heptane, 2,2,4,6,6-pentamethyl-, benzene, 1-methyl-4-(1-methylethyl)-, and cyclohexane, 1,4-dimethyl-. Breath VOCs were assayed by GC/MS in 42 patients hospitalized for suspicion of pulmonary tuberculosis and in 59 healthy controls. Sputum cultures were positive for Mycobacteria in 23/42 and negative in19/42 patients. Breath markers of oxidative stress were increased in all hospitalized patients (p<0.04). Pattern recognition analysis and fuzzy logic analysis of breath VOCs independently distinguished healthy controls from hospitalized patients with 100% sensitivity and 100% specificity. Fuzzy logic analysis identified patients with positive sputum cultures with 100% sensitivity and 100% specificity (95.7% sensitivity and 78.9% specificity on leave-one-out cross-validation); breath VOC markers were similar to those observed in vitro, including naphthalene, 1-methyl- and cyclohexane, 1,4-dimethyl-. Pattern recognition analysis identified patients with positive sputum cultures with 82.6% sensitivity (19/23) and 100% specificity (18/18), employing 12 principal components from 134 breath VOCs. We conclude that volatile biomarkers in breath were sensitive and specific for pulmonary tuberculosis: the breath test distinguished between 'sick versus well' i.e. between normal controls and patients hospitalized for suspicion of pulmonary tuberculosis, and between infected versus non-infected patients i.e. between those whose sputum cultures were positive or negative for Mycobacteria
— id: 96228, year: 2007, vol: 87, page: 44, stat: Journal Article,

Mycobacterium tuberculosis malate synthase- and MPT51-based serodiagnostic assay as an adjunct to rapid identification of pulmonary tuberculosis
Achkar, Jacqueline M; Dong, Yuxin; Holzman, Robert S; Belisle, John; Kourbeti, Irene S; Sherpa, Tsering; Condos, Rany; Rom, William N; Laal, Suman
2006 Nov;13(11):1291-1293, Clinical & vaccine immunology
The 81-kDa malate synthase (MS; Rv 1837c) and the 27-kDa MPT51 (Rv 3803c) of Mycobacterium tuberculosis are immunodominant antigens recognized by serum antibodies from approximately 80% of human immunodeficiency virus-negative smear-positive tuberculosis patients from India. We now provide evidence that the use of the MS/MPT51-based serodiagnostic assay can serve as an adjunct to sputum microscopy in the rapid diagnosis of pulmonary tuberculosis
— id: 70310, year: 2006, vol: 13, page: 1291, stat: Journal Article,

Quality assurance in a large clinical trials consortium: the experience of the Tuberculosis Trials Consortium
Sandman, Laurie; Mosher, Ann; Khan, Awal; Tapy, Jan; Condos, Rany; Ferrell, Scott; Vernon, Andrew
2006 Dec;27(6):554-560, Contemporary clinical trials
Quality assurance (QA) is essential for data accuracy and proper evaluation of study objectives in clinical trials. The Tuberculosis Trials Consortium (TBTC)-a collaboration of 28 clinical sites and the Centers for Disease Control and Prevention-has developed a comprehensive QA program that provides quantitative assessments of performance based on clearly defined standards that are communicated to data collectors through a feedback process. The Implementation and Quality Committee of the TBTC developed a Site Evaluation Report (SER) that assesses performance measures (PMs) critical to the accomplishment of study objectives. PMs are defined, quantified, and evaluated, and goals and minimum acceptable scores are specified. Sites not meeting a PM minimum must provide an explanation and develop a plan to meet the goal. Site-specific and system-wide problems can be readily identified through this process. The SER is used prospectively for all TBTC treatment trials, and a Web site has been developed to maximize the availability and usefulness of performance data. The TBTC's comprehensive QA program is an example of a successful method for ensuring high quality, evaluable data
— id: 70873, year: 2006, vol: 27, page: 554, stat: Journal Article,

Cytokine response in tuberculosis
Condos R; Rom WN
Tuberculosis Philadelphia : Lippincott Williams & Wilkins, 2004,
— id: 3965, year: 2004, vol: , page: 285, stat: Chapter,

Regional deposition of aerosolized interferon-gamma in pulmonary tuberculosis
Condos, Rany; Hull, Frank P; Schluger, Neil W; Rom, William N; Smaldone, Gerald C
2004 Jun;125(6):2146-2155, Chest
STUDY OBJECTIVES: Aerosol interferon-gamma (IFN-gamma) is a potential immunomodulator in the treatment of pulmonary tuberculosis (TB). Previous investigations demonstrated conversion of sputum smears in five patients with multidrug-resistant TB after 12 treatments over 1 month, and induction of signaling molecules in 10 of 11 drug-sensitive TB patients using BAL. The objective of the current study was to evaluate particle size and deposition pattern in patients with TB receiving aerosol IFN-gamma treatment. DESIGN: Particle size was determined with a cascade impactor, and deposition of IFN-gamma mixed with (99m)Tc-labeled human serum albumin was assessed using a gamma camera. Local levels of IFN-gamma were measured in BAL using enzyme-linked immunosorbent assays. Study patients/intervention: Fourteen patients with pulmonary TB received IFN-gamma aerosol (500 micro g) for 12 treatments in addition to antimycobacterial therapy with BAL before and after IFN-gamma aerosol treatment. Eight patients with minimal-to-moderate parenchymal involvement underwent deposition studies. Deposited (99m)Tc-labeled IFN-gamma aerosol was partitioned between upper airways and lungs using attenuation correction measurements. (133)Xe equilibrium scanning, (133)Xe washout, and (99m)Tc- macroaggregate injection defined regional lung volume, ventilation, and perfusion. RESULTS: Upper airway deposition was significant often exceeding lung deposition (53.9 +/- 7.09 micro g vs 35.8 +/- 2.73 micro g, respectively [mean +/- SE]). IFN-gamma levels measured in BAL fluid were significantly increased with aerosol treatment (0.83 +/- 0.43 micro g before vs 24.76 +/- 8.71 micro g after, p </= 0.017), and IFN-gamma levels correlated with regional deposition of IFN-gamma aerosol (r = 0.823). Four-quadrant analysis of regional lung deposition best correlated with regional perfusion (r = 0.422, p = 0.013) with penetration of aerosol into areas of obvious radiographic infiltration on chest radiograph. CONCLUSIONS: Aerosol therapy with IFN-gamma in patients with pulmonary TB is widely distributed and results in significant enhancement of IFN-gamma levels in the lower respiratory tract. In patients without lung destruction, IFN-gamma aerosol may be an adjuvant to enhance the local immune response
— id: 44955, year: 2004, vol: 125, page: 2146, stat: Journal Article,

Surfactant protein A modulates the inflammatory response in macrophages during tuberculosis
Gold, Jeffrey A; Hoshino, Yoshihiko; Tanaka, Naohiko; Rom, William N; Raju, Bindu; Condos, Rany; Weiden, Michael D
2004 Feb;72(2):645-650, Infection & immunity
Tuberculosis leads to immune activation and increased human immunodeficiency virus type 1 (HIV-1) replication in the lung. However, in vitro models of mycobacterial infection of human macrophages do not fully reproduce these in vivo observations, suggesting that there are additional host factors. Surfactant protein A (SP-A) is an important mediator of innate immunity in the lung. SP-A levels were assayed in the human lung by using bronchoalveolar lavage (BAL). There was a threefold reduction in SP-A levels during tuberculosis only in the radiographically involved lung segments, and the levels returned to normal after 1 month of treatment. The SP-A levels were inversely correlated with the percentage of neutrophils in BAL fluid, suggesting that low SP-A levels were associated with increased inflammation in the lung. Differentiated THP-1 macrophages were used to test the effect of decreasing SP-A levels on immune function. In the absence of infection with Mycobacterium tuberculosis, SP-A at doses ranging from 5 to 0.01 micro g/ml inhibited both interleukin-6 (IL-6) production and HIV-1 long terminal repeat (LTR) activity. In macrophages infected with M. tuberculosis, SP-A augmented both IL-6 production and HIV-1 LTR activity. To better understand the effect of SP-A, we measured expression of CAAT/enhancer binding protein beta (C/EBPbeta), a transcription factor central to the regulation of IL-6 and the HIV-1 LTR. In macrophages infected with M. tuberculosis, SP-A reduced expression of a dominant negative isoform of C/EBPbeta. These data suggest that SP-A has pleiotropic effects even at the low concentrations found in tuberculosis patients. This protein augments inflammation in the presence of infection and inhibits inflammation in uninfected macrophages, protecting uninvolved lung segments from the deleterious effects of inflammation
— id: 42242, year: 2004, vol: 72, page: 645, stat: Journal Article,

Management of multidrug-resistant tuberculosis
Harkin TJ; Condos R
Tuberculosis Philadelphia : Lippincott Williams & Wilkins, 2004,
— id: 3986, year: 2004, vol: , page: 729, stat: Chapter,

Aerosolized gamma interferon (IFN-gamma) induces expression of the genes encoding the IFN-gamma-inducible 10-kilodalton protein but not inducible nitric oxide synthase in the lung during tuberculosis
Raju, Bindu; Hoshino, Yoshihiko; Kuwabara, Kenichi; Belitskaya, Ilana; Prabhakar, Savita; Canova, Antony; Gold, Jeffrey A; Condos, Rany; Pine, Richard I; Brown, Stuart; Rom, William N; Weiden, Michael D
2004 Mar;72(3):1275-1283, Infection & immunity
Gamma interferon (IFN-gamma) is critical in the immune response against Mycobacterium tuberculosis. In an ongoing trial of aerosol IFN-gamma in conjunction with standard drug therapy, we have observed activation of IFN signaling in bronchoalveolar lavage (BAL) cells from tuberculosis (TB) patients. We hypothesized that aerosol IFN-gamma treatment of pulmonary TB would increase expression of genes important for the control of TB. We investigated the expression of downstream genes by measuring inducible nitric oxide synthase (iNOS) and the chemokine IFN-inducible 10-kDa protein (IP-10) by real-time quantitative reverse transcription-PCR. In vitro, M. tuberculosis induced IP-10, and IFN-gamma stimulated this further, with no effect on iNOS expression. We studied 21 patients with pulmonary TB and 7 healthy subjects. Similar to the in vitro model, IP-10 mRNA was increased in BAL cells from TB patients and was augmented after treatment with aerosolized IFN-gamma. TB was also associated with elevated iNOS mRNA, but aerosolized IFN-gamma did not further enhance expression. Genomic analysis identified 1,300 of 4,058 genes expressed in BAL cells from six TB patients before and after 1 month of therapy, including aerosolized IFN-gamma. However, only 15 genes were differentially regulated by IFN-gamma. We conclude that iNOS and IP-10 mRNA expression is increased in TB but that aerosol IFN-gamma treatment increases expression of few genes in the human lung
— id: 42241, year: 2004, vol: 72, page: 1275, stat: Journal Article,

Does diabetes predispose to the development of multidrug-resistant tuberculosis?
Condos, R; Alcabes, P
2003 JAN ;123(1):309-309, Chest
— id: 55580, year: 2003, vol: 123, page: 309, stat: Journal Article,

Recombinant gamma interferon stimulates signal transduction and gene expression in alveolar macrophages in vitro and in tuberculosis patients
Condos, Rany; Raju, Bindu; Canova, Antony; Zhao, Ben-Yang; Weiden, Michael; Rom, William N; Pine, Richard
2003 Apr;71(4):2058-2064, Infection & immunity
Tuberculosis is the seventh leading cause of morbidity and mortality in the world, with eight million cases per year. Animal and human studies demonstrate an enrichment of CD4 cells at sites of disease, with a more favorable clinical course when there is a Th1 response with the presence of gamma interferon (IFN-gamma). We previously treated patients who had multidrug-resistant tuberculosis with recombinant IFN-gamma (rIFN-gamma) in aerosol form and were able to convert smear-positive cases to smear negative with 12 treatments over 1 month. We hypothesized that rIFN-gamma would induce signal transducer and activator of transcription (STAT) and interferon regulatory factor (IRF) binding activity in alveolar macrophages (AM). AM treated in vitro showed clear upregulation of STAT-1 and IRF-1 by rIFN-gamma. STAT-1 was not activated and IRF-1 was only weakly induced after 1 day of infection by Mycobacterium tuberculosis TN913. In bronchoalveolar lavage (BAL) cells obtained from 10 of 10 tuberculosis patients 10 +/- 2 days post-antituberculosis treatment, there was no detectable STAT-1 or IRF-1 DNA-binding activity. After 4 weeks of treatment with rIFN-gamma aerosol in addition to the antituberculosis drugs, 10 of 10 patients had increased STAT-1, IRF-1, and/or IRF-9 DNA-binding activity in BAL cells from lung segments shown radiographically to be involved and in those shown to be uninvolved. Symptoms and chest radiographs improved, and amounts of macrophage inflammatory cytokines and human immunodeficiency virus type 1 (HIV-1) viral loads (in five of five HIV-1-coinfected patients) declined in the second BAL specimens. rIFN-gamma aerosol induces signal transduction and gene expression in BAL cells and should be evaluated for efficacy in a randomized, controlled clinical trial
— id: 44958, year: 2003, vol: 71, page: 2058, stat: Journal Article,

Lung deposition and respirable mass during wet nebulization
Sangwan, Sanjay; Condos, Rany; Smaldone, Gerald C
2003 Winter;16(4):379-386, Journal of aerosol medicine
For metered dose inhalers (MDIs), high-flow cascade impaction with a United States Pharmacopia (USP) throat provides a useful prediction of in vivo lung and oropharyngeal aerosol deposition. Particles expected to deposit in the lung are included in the 'fine particle fraction' measured on the bench. Comparable in vitro standards are not available for nebulizers. The present study compared aerosol deposition in an in vitro model using low-flow cascade impaction with deposition in vivo in human subjects. A low-flow (1 Lmin), 10-stage cascade impactor measured aerodynamic distributions of aerosolized interferon-gamma (IFN-gamma) from two nebulizers (Misty-Neb and AeroEclipse). (99m)Technetium diethylene triaminepenta-acetic acid ((99m)Tc-DTPA) was used as the radiolabel. Two bench conditions were specified: no breathing (standing cloud) and simulated ventilation with a piston pump (tidal volume 750 mL frequency 25 per minute and duty cycle 0.5). Mass median aerodynamic diameter (MMAD) for both nebulizers was affected by ventilation (Misty-Neb vs. AeroEclipse: 5.2 vs. 4.6 microm for standing cloud and 3.1 vs. 2.2 microm during ventilation). In three subjects, measured values of oropharyngeal deposition averaged 68.1 +/- 0.08% for Misty-Neb and 30.9 +/- 0.03% for AeroEclipse. In vivo deposition patterns compared to aerosol distributions from both nebulizers indicated that, for wet nebulization, penetration of aerosol beyond the upper airways (fine particle fraction) will occur only for aerosol particles below 2.5 microm. This assessment requires that the bench aerosol distribution be measured under conditions of clinical use (i.e., during tidal breathing)
— id: 96229, year: 2003, vol: 16, page: 379, stat: Journal Article,

Correlation of PPD status of immunocompetent tuberculosis patients and bronchoalveolar lavage (BAL) cell differential
Nolan A; Rom WN; Condos R; Raju B
2002 ;165:A288-A288, American journal of respiratory & critical care medicine
— id: 101405, year: 2002, vol: 165, page: A288, stat: Journal Article,

Increased incidence of multidrug-resistant tuberculosis in diabetic patients on the Bellevue Chest Service, 1987 to 1997
Bashar M; Alcabes P; Rom WN; Condos R
2001 Nov;120(5):1514-1519, Chest
STUDY OBJECTIVES: To investigate the characteristics of tuberculosis infection in diabetic patients at Bellevue Hospital. DESIGN: We conducted a case-control study retrospectively reviewing the records of patients at Bellevue Hospital Center from 1987 to 1997 with a discharge diagnosis of tuberculosis and diabetes mellitus. SETTING: Bellevue Hospital Center is a 1,200-bed, inner-city municipal hospital located in the Lower East Side of New York City. PATIENTS: Fifty-three identified patients had verified tuberculosis infection and diabetes; of these, 50 charts were available for review. One hundred five control cases were selected from nondiabetic patients with a discharge diagnosis of tuberculosis during the same time period. MEASUREMENTS AND RESULTS: Thirty-six percent (18 cases) of the patients with diabetes and tuberculosis had multidrug-resistant tuberculosis (MDR-TB) compared to only 10% (10 cases) in the control group (p < 0.01) Controlling for homelessness, HIV status, and directly observed therapy, the relative risk of MDR-TB was calculated to be 8.6 (confidence interval, 3.1 to 23.6) in the diabetic group compared to the control group. CONCLUSIONS: There was a significant association between diabetes and MDR-TB. Diabetes continues to be a risk factor for tuberculosis and was associated with MDR-TB in our patients
— id: 26564, year: 2001, vol: 120, page: 1514, stat: Journal Article,

In situ activation of helper t cells in the lung
Raju B; Tung CF; Cheng D; Yousefzadeh N; Condos R; Rom WN; Tse DB
2001 Aug;69(8):4790-4798, Infection & immunity
To better understand the lung and systemic responses of helper T cells mediating memory immunity to Mycobacterium tuberculosis, we used three- and four-color flow cytometry to study the surface phenotype of CD4(+) lymphocytes. Bronchoalveolar lavage (BAL) fluid and peripheral blood (PB) samples were obtained from a total of 25 subjects, including 10 tuberculosis (TB)-infected subjects, 8 purified-protein-derivative-negative subjects, and 7 purified-protein-derivative-positive subjects. In marked contrast to CD4(+) lymphocytes from PB (9% +/- 5% expressing CD45RA and CD29), the majority (55% +/- 16%) of CD4(+) lymphocytes in BAL (ALs) simultaneously expressed CD45RA, a naive T-cell marker, and CD29, members of the very late activation family. Further evaluation revealed that CD4(+) ALs expressed both CD45RA and CD45RO, a memory T-cell marker. In addition, the proportion of CD4(+) lymphocytes expressing CD69, an early activation marker, was drastically increased in BAL fluid (83% +/- 9%) compared to PB (1% +/- 1%), whereas no significant difference was seen in the expression of CD25, the low-affinity interleukin 2 receptor (34% +/- 15% versus 40% +/- 16%). More importantly, we identified a minor population of CD69(bright) CD25(bright) CD4(+) lymphocytes in BAL (10% +/- 6%) that were consistently absent from PB (1% +/- 1%). Thus, CD4(+) lymphocytes in the lung paradoxically coexpress surface molecules characteristic of naive and memory helper T cells as well as surface molecules commonly associated with early and late stages of activation. No difference was observed for ALs obtained from TB-infected and uninfected lung segments in this regard. It remains to be determined if these surface molecules are induced by the alveolar environment or if CD4(+) lymphocytes coexpressing this unusual combination of surface molecules are selectively recruited from the circulation. Our data suggest that ex vivo experiments on helper T-cell subsets that display distinctive phenotypes may be pivotal to studies on the human immune response to potential TB vaccines
— id: 21134, year: 2001, vol: 69, page: 4790, stat: Journal Article,

Lung-specific immune response in tuberculosis
Condos R; Rom WN; Weiden M
2000 Feb;4(2 Suppl 1):S11-S17, International journal of tuberculosis & lung disease
— id: 11825, year: 2000, vol: 4, page: S11, stat: Journal Article,

Diabetes mellitus and tuberculosis on the Bellevue chest service 1987-1997: A case control study
Bashar, M; Lan, A; Alcabes, P; Rom, WN; Condos, R
1999 MAR ;159(3):A748-A748, American journal of respiratory & critical care medicine
— id: 53891, year: 1999, vol: 159, page: A748, stat: Journal Article,

Induction of IRF-1 STAT-1 by IFN-gamma in tuberculosis infection
Condos, R; Raju, B; Lubin, AS; Rom, WN; Pine, RI
1999 MAR ;159(3):A740-A740, American journal of respiratory & critical care medicine
— id: 53890, year: 1999, vol: 159, page: A740, stat: Journal Article,

Cytokine-based approaches to the treatment of multidrug-resistant tuberculosis
Condos, R; Schluger, N W
1999 Mar;11(3):165-173, Biodrugs
The most disturbing aspect of the current epidemic of tuberculosis (TB) is the appearance of large numbers of strains of Mycobacterium tuberculosis that are resistant to one or more of the first-line agents used to treat the disease. Mortality associated with a multidrug-resistant strain of tuberculosis (MDR-TB) infection is reported to be extremely high, in many cases no different from the mortality of tuberculosis in the pre-antibiotic era. Infection control measures have limited the spread of MDR-TB. However, many outbreaks over the last several years have created a large reservoir of MDR-TB infection. In order to treat the cases of MDR-TB that are occurring now and which will undoubtedly occur in the future, new approaches to treatment will be needed. Recent research into the immunopathogenesis of tuberculosis has provided insight into the important constituents of the host immune system needed to control the infection in vivo. These elements include CD4+ and CD8+ T cells as well as cytokines such as interferon gamma (IFNgamma), interleukin-12 (IL-12), and tumour necrosis factor (TNF). IL-2, IFNgamma and M. vaccae vaccination have all shown promising effects in small preliminary studies. Evidence suggests that TNF antagonists and IL-12 may also prove useful in the treatment of drug-susceptible TB and MDR-TB. Further studies are needed to determine the precise role of these recombinant proteins in the treatment of TB
— id: 101868, year: 1999, vol: 11, page: 165, stat: Journal Article,

Induction of STAT-1 and IRF-1 by IFN-gamma in tuberculosis patients
Condos, Rany; Zhao, Ben Yang; Raju, Bindu; Lubin, Andrew S; Canova, Antony; Rom William N; Pine, Richard
1999 Sept;19(Supl. 1):S95-S95, Journal of interferon & cytokine research
— id: 15939, year: 1999, vol: 19, page: S95, stat: Journal Article,

High levels of plasma IL-10 does not diminish purified protein derivative (PPD) skin induration size
Hull, FP; Condos, R; Rom, WN
1999 MAR ;159(3):A555-A555, American journal of respiratory & critical care medicine
— id: 53884, year: 1999, vol: 159, page: A555, stat: Journal Article,

Phenotypic analysis of alveolar helper T cells demonstrates in situ activation in the lung
Tse, DB; Raju, B; Tung, CF; Chan, DS; Condos, R; Rom, WN
1999 MAR ;159(3):A555-A555, American journal of respiratory & critical care medicine
— id: 53885, year: 1999, vol: 159, page: A555, stat: Journal Article,

Local immune responses correlate with presentation and outcome in tuberculosis
Condos R; Rom WN; Liu YM; Schluger NW
1998 Mar;157(3 Pt 1):729-735, American journal of respiratory & critical care medicine
Local cellular immune responses may affect presentation and outcome in tuberculosis (TB). To investigate this hypothesis, we performed bronchoalveolar lavage (BAL) on 30 patients with untreated pulmonary tuberculosis and assessed the type of cellular inflammatory response and cytokine production. We then correlated BAL findings and cytokine production with clinical findings. We also performed BAL on a subset of patients to examine changes in cytokine production by BAL cells over time. We found that at presentation patients with less clinically and radiographically advanced TB (smear-negative, noncavitary disease) had a local immune response characterized by a predominance of lymphocytes. Furthermore, BAL cells from these patients secreted interferon (IFNgamma), and not Interleukin-4, suggesting a Th 1-type lymphocytic response. In patients with smear-positive and/or cavitary disease, macrophages or polymorphonuclear leukocytes were the predominant BAL cell type, but with treatment and clinical improvement these patients went on to recruit IFNgamma producing cells to the lung. We conclude that the type of cellular immune response that occurs locally in the lung may affect presentation and outcome in pulmonary TB, and an understanding of the development of this response may lead to insights into pathogenesis and novel therapies for TB
— id: 7536, year: 1998, vol: 157, page: 729, stat: Journal Article,

Treatment of multidrug-resistant pulmonary tuberculosis with interferon-gamma via aerosol
Condos R; Rom WN; Schluger NW
1997 May 24;349(9064):1513-1515, Lancet
BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) is associated with substantial morbidity, despite drug therapy. Interferon-gamma, a cytokine produced mainly by CD4 T lymphocytes, can activate alveolar macrophages, important effector cells in host immunity against Mycobacterium tuberculosis. We investigated safety and tolerability of aerosolised interferon-gamma in patients with MDR-TB, and assessed its efficacy in terms of sputum-smear grades. METHODS: We did an open-label trial of aerosol interferon-gamma given to five patients with smears and cultures positive for pulmonary MDR-TB, despite documented adherence to therapy. The patients received aerosol interferon-gamma 500 micrograms three times a week for 1 month. Safety and tolerability were assessed, and, as well as routine clinical assessments, sputum samples for smear and culture were collected at entry and weekly. Computed tomography scans of the chest were done at baseline and after therapy ended. FINDINGS: Interferon-gamma was well tolerated by all patients. In all five, bodyweight stabilised or increased. Sputum acid-fast-bacillus smears became negative in all patients, and the time to positive culture increased (from 17 to 24 days, not significant), which suggested that the mycobacterial burden had decreased. The size of cavitary lesions was reduced in all patients, 2 months after treatment had ended. INTERPRETATION: Preliminary data suggest that aerosol interferon-gamma is a well-tolerated treatment that may be useful as adjunctive therapy in patients with MDR-TB who are otherwise not responding well to therapy
— id: 56933, year: 1997, vol: 349, page: 1513, stat: Journal Article,

Mycobacterium tuberculosis enhances human immunodeficiency virus-1 replication in the lung
Nakata K; Rom WN; Honda Y; Condos R; Kanegasaki S; Cao Y; Weiden M
1997 Mar;155(3):996-1003, American journal of respiratory & critical care medicine
We investigated the in vivo effect of coinfection of Mycobacterium tuberculosis on human immunodeficiency virus type 1 (HIV-1) replication using bronchoalveolar lavage (BAL) of 11 HIV-1-infected patients with pulmonary tuberculosis and 10 patients with no lung disease. Lung segments involved with pulmonary tuberculosis had significantly elevated HIV-1 branched DNA (bDNA) levels and p24 in BAL compared with lung segments uninvolved with tuberculosis or with BAL from patients with no lung disease. The BAL viral burden was higher than plasma HIV-1 in tuberculosis patients, indicating local production of virus. BAL HIV-1 bDNA declined over the course of treatment for tuberculosis in three patients who underwent serial bronchoscopies. Tumor necrosis factor-alpha (TNF-alpha) and HIV-1 bDNA particles were strongly correlated (r2 = 0.9, p < 0.01) in lung segments involved with tuberculosis. The deduced amino acid sequence of HIV-1 gp120 V3 region from involved segments of three patients with pulmonary tuberculosis showed basic substitutions associated with altered viral phenotype. Phylogenetic analysis of V3 sequences demonstrated that BAL HIV-1 RNA had diverged from plasma. These data support the conclusion that pulmonary tuberculosis enhances local HIV-1 replication in vivo
— id: 12363, year: 1997, vol: 155, page: 996, stat: Journal Article,

Peripheral-blood-based PCR assay to identify patients with active pulmonary tuberculosis
Condos R; McClune A; Rom WN; Schluger NW
1996 Apr 20;347(9008):1082-1085, Lancet
BACKGROUND: There is a need for rapid diagnosis of pulmonary tuberculosis. We have previously used a PCR to detect circulating Mycobacterium tuberculosis DNA in blood samples from patients (mostly HIV-infected) with pulmonary tuberculosis. We have now prospectively investigated the role of this blood-based PCR assay for diagnosis of this disease in a clinical setting. METHODS: Our PCR assay is specific for the IS6110 insertion element of the M tuberculosis complex of organisms. We used it to test peripheral blood from 88 consecutive patients admitted to a chest ward with suspected pulmonary tuberculosis. Personnel who carried out the assay did not know the results of any clinical investigations and ultimate diagnosis, and clinicians did not know the PCR results. Results of the PCR assay were compared with the final clinical diagnosis. A subgroup of 15 patients had blood samples assayed serially to track the PCR signal over time. FINDINGS: 41 patients had a final clinical diagnosis of tuberculosis, and the cases were typical of those seen at our hospital: HIV infection was common, and most cases were not sputum-smear positive for acid-fast bacilli. The PCR assay correctly identified 39 of 41 patients with proven pulmonary tuberculosis, 26 (63%) of whom were sputum-smear negative. There were five patients in whom a positive PCR result did not accord with the final clinical diagnosis, and two of the 44 negative PCR results were classified as false negatives. The overall sensitivity and specificity of the PCR assay for a diagnosis of tuberculosis was 95% and 89%, respectively. In 15 patients with pulmonary tuberculosis and a positive blood assay,the PCR result remained positive after 1 month of therapy, but had reverted to negative in 13 of the 15 by 4 months of therapy. INTERPRETATION: We conclude that peripheral-blood-based PCR detection for the diagnosis of tuberculosis is a technically feasible approach that has a potentially important role in the diagnosis of pulmonary tuberculosis
— id: 56864, year: 1996, vol: 347, page: 1082, stat: Journal Article,

Human host response to Mycobacterium tuberculosis
Rom WN; Schluger N; Law K; Condos R; Zhang Y; Weiden M; Harkin T; Tchou-Wong KM
1995 Nov 11;125(45):2178-2185, Schweizerische medizinische wochenschrift = Journal suisse de medecine
Despite the importance of tuberculosis as the leading cause of death due to infectious disease in the world, it has only been recently that an understanding of the human host response in this infection has begun to emerge. The key components of this response are cytokines and components of cellular immunity, predominantly T-lymphocytes and macrophages. Though the relationships among the components of the immune response are complex, it seems likely that in response to mycobacterial infection associated with active disease, cytokines such as TNF-alpha and IL-1 beta are produced; these cytokines serve to recruit more lymphocytes, generally of the T(H) (T helper) phenotype, which then produces substances such as the macrophage activating factor interferon-gamma. Macrophages activated by IFN-gamma ar thus stimulating to enhance intracellular killing of mycobacteria. The role of other cytokines, such as IL-6 and IL-8, both of which are induced by M. tuberculosis or its cell was components, is less clear. Further elucidation of the human host response to tuberculosis should help in the development of new vaccines and treatment strategies
— id: 12714, year: 1995, vol: 125, page: 2178, stat: Journal Article,

Flow limitation as a noninvasive assessment of residual upper-airway resistance during continuous positive airway pressure therapy of obstructive sleep apnea
Condos R; Norman RG; Krishnasamy I; Peduzzi N; Goldring RM; Rapoport DM
1994 Aug;150(2):475-480, American journal of respiratory & critical care medicine
Many patients with obstructive sleep apnea syndrome (OSAS), despite therapy with nasal continuous positive airway pressure (CPAP), have persisting daytime somnolence that may be due to a persistently elevated upper-airway resistance associated with electroencephalographic (EEG) arousals. We tested the hypothesis that elevated upper-airway resistance can be inferred from the contour of the inspiratory flow tracing obtained from a conventional CPAP circuit. This may provide a noninvasive method for determining optimal CPAP. Data were collected during a CPAP titration of an upper-airway model and in eight patients with OSAS. Estimated inspiratory resistance was calculated from esophageal pressure, CPAP mask pressure, and inspiratory flow. At high CPAP, resistance was low and inspiratory flow contour was found to be rounded. At low CPAP, resistance was high and flow contour developed a plateau suggesting flow limitation. We also noted that the CPAP pressure at which high resistance developed, and at which flow limitation appeared, showed hysteresis. We conclude that when respiration is stable, the contour of inspiratory flow tracing from a CPAP system can be used to infer the presence of elevated upper-airway resistance and flow limitation. Optimizing flow contour may be an alternative to eliminating apneas in evaluation of the optimal therapeutic level of CPAP in OSAS
— id: 6339, year: 1994, vol: 150, page: 475, stat: Journal Article,

Amplification of DNA of Mycobacterium tuberculosis from peripheral blood of patients with pulmonary tuberculosis
Schluger NW; Condos R; Lewis S; Rom WN
1994 Jul 23;344(8917):232-233, Lancet
Sputum examination for rapid diagnosis of pulmonary tuberculosis is not always satisfactory. We examined peripheral blood with the polymerase chain reaction (PCR). Blood samples were collected from 8 consecutive patients with suspected pulmonary tuberculosis and from 18 healthy controls, half of whom were tuberculin skin-test positive. All 8 patients had evidence of circulating Mycobacterium tuberculosis DNA in the lymphocyte fraction of peripheral blood, and positive sputum cultures indicating active pulmonary tuberculosis. None of the healthy controls had positive PCR results. This PCR technique may prove useful for the rapid diagnosis of tuberculosis
— id: 56708, year: 1994, vol: 344, page: 232, stat: Journal Article,

TUBERCULOSIS INFECTIONS AMONG HOUSESTAFF AT BELLEVUE HOSPITAL IN AN EPIDEMIC PERIOD
CONDOS, R; SCHLUGER, N; LACOUTURE, R; ROM, W
1993 APR ;147(4):A124-A124, American review of respiratory disease
— id: 54154, year: 1993, vol: 147, page: A124, stat: Journal Article,