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Background Limited data are available on the association between clinically measured disease severity markers and quality of life (QOL) in idiopathic pulmonary fibrosis (IPF). The study examined the associations between objective disease severity metrics and QOL in a contemporary IPF population. Methods This study evaluated baseline data from patients enrolled in the multicenter, US-based Idiopathic Pulmonary Fibrosis Prospective Outcomes Registry between June 2014 and July 2018. Disease severity metrics included FVC % predicted, diffusing capacity for carbon monoxide (Dlco) % predicted, supplemental oxygen use with activity, supplemental oxygen use at rest, and two summary scores (the Gender-Age-Lung Physiology index, based on gender, age, and % predicted values for Dlco and FVC; and the Composite Physiologic Index, based on % predicted values for Dlco, FVC, and FEV1). Multivariable adjusted regression models were used to examine cross-sectional associations between each severity measure and St. George's Respiratory Questionnaire (SGRQ) total score. Results Among 829 patients with complete SGRQ data, the median (interquartile range) SGRQ score at enrollment was 40 (26-53), with higher scores indicating worse QOL. Modest SGRQ impairments were observed with increasing Gender-Age-Lung Physiology score (2.9 [1.8-4.0] per 1-point increase] and with increasing Composite Physiologic Index scores (3.0 [2.4-3.6] per 5-point increase). Substantial SGRQ impairments were observed for oxygen use with activity (15.6 [12.9-18.2]), oxygen use at rest (16.2 [13.0-19.4]), and decreasing Dlco (5.0 [4.0-6.1] per 10% decrease in % predicted). Conclusions Objective measures of disease severity, including severity scores, physiologic parameters, and supplemental oxygen use, are associated with worse QOL in patients with IPF. Trial Registry ClinicalTrials.gov; No.: NCT01915511; URL: www.clinicaltrials.gov.

Background Hospitalizations are common among patients with idiopathic pulmonary fibrosis (IPF). We investigated the impact of hospitalizations on outcomes in patients with IPF. Methods The IPF-PRO Registry is an observational US registry that enrolled patients with IPF that was diagnosed or confirmed at the enrolling center in the previous 6 months. Associations between patient characteristics and hospitalization, and between hospitalization and mortality, were analyzed using Cox regression models. Results A total of 1002 patients with IPF were enrolled into the IPF-PRO Registry. Over a median follow-up time of 23.7 months (maximum: 67.0 months), 568 patients (56.7%) had at least one hospitalization. Of these patients, 319 (56.2%) had at least one respiratory-related hospitalization and 120 (21.1%) had at least one hospitalization with ventilatory support. Younger age (HR 0.68 [95% CI 0.55, 0.84] per 5-year increase for patients Conclusions Data from the IPF-PRO Registry demonstrate that hospitalizations are common among patients with IPF. The risk of mortality during hospitalization or within 90 days of discharge was high, particularly among patients who were hospitalized for a respiratory cause or received ventilatory support. Trial registration ClinicalTrials.gov, NCT01915511. Registered 5 August 2013, https://clinicaltrials.gov/ct2/show/NCT01915511

Background Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease for which diagnosis and management remain challenging. Defining the circulating proteome in IPF may identify targets for biomarker development. We sought to quantify the circulating proteome in IPF, determine differential protein expression between subjects with IPF and controls, and examine relationships between protein expression and markers of disease severity. Methods This study involved 300 patients with IPF from the IPF-PRO Registry and 100 participants without known lung disease. Plasma collected at enrolment was analysed using aptamer-based proteomics (1305 proteins). Linear regression was used to determine differential protein expression between participants with IPF and controls and associations between protein expression and disease severity measures (percent predicted values for forced vital capacity [FVC] and diffusion capacity of the lung for carbon monoxide [DLco]; composite physiologic index [CPI]). Multivariable models were fit to select proteins that best distinguished IPF from controls. Results Five hundred fifty one proteins had significantly different levels between IPF and controls, of which 47 showed a |log2(fold-change)| > 0.585 (i.e. > 1.5-fold difference). Among the proteins with the greatest difference in levels in patients with IPF versus controls were the glycoproteins thrombospondin 1 and von Willebrand factor and immune-related proteins C-C motif chemokine ligand 17 and bactericidal permeability-increasing protein. Multivariable classification modelling identified nine proteins that, when considered together, distinguished IPF versus control status with high accuracy (area under receiver operating curve = 0.99). Among participants with IPF, 14 proteins were significantly associated with FVC % predicted, 23 with DLco % predicted, 14 with CPI. Four proteins (roundabout homolog-2, spondin-1, polymeric immunoglobulin receptor, intercellular adhesion molecule 5) demonstrated the expected relationship across all three disease severity measures. When considered in pathways analyses, proteins associated with the presence or severity of IPF were enriched in pathways involved in platelet and haemostatic responses, vascular or platelet derived growth factor signalling, immune activation, and extracellular matrix organisation. Conclusions Patients with IPF have a distinct circulating proteome and can be distinguished using a nine-protein profile. Several proteins strongly associate with disease severity. The proteins identified may represent biomarker candidates and implicate pathways for further investigation. Trial registration ClinicalTrials.gov (NCT01915511).

Background Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a variable clinical course and high mortality. We used data from a large national US registry of patients with IPF to investigate relationships between patient characteristics, including markers of disease severity, and mortality. Methods The analysis cohort comprised patients enrolled in the IPF-PRO Registry from its inception on 5 June 2014 to 26 October 2017. The primary criterion for inclusion in this registry is that patients must be diagnosed or confirmed with IPF at the enrolling centre within 6 months. Associations between patient characteristics and markers of disease severity at enrolment and mortality outcomes were investigated using univariable, multivariable and adjustment models. Results Among 662 patients enrolled, 111 patients died or had a lung transplant over a follow-up period of 30 months. The probability of being free of both events at month 30 was 50.6% (95% CI: 40.0, 60.2). When patient characteristics and markers of disease severity were jointly examined in a multivariable analysis, oxygen use at rest (hazard ratio [HR] 2.44 [95% CI: 1.45, 4.10]), lower forced vital capacity (FVC) % predicted (HR 1.28 [95% CI: 1.10, 1.49] per 10% decrease) and diffusion capacity for carbon monoxide (DLco) % predicted (HR 1.25 [95% CI: 1.04, 1.51] per 10% decrease) were significantly associated with increased risk of death or lung transplant. The risk of death or lung transplant increased with increasing age in patients ≥62 years old (HR 1.18 [95% CI: 0.99, 1.40] per 5-year increase), and decreased with increasing age in patients

The acute course of coronavirus disease 2019 (COVID-19) is variable and ranges from asymptomatic infection to fulminant respiratory failure. Patients recovering from COVID-19 can have persistent symptoms and computed tomography (CT) abnormalities of variable severity. At 3 months after acute infection, a subset of patients will have CT abnormalities that include ground glass abnormalities (GGO) and subpleural bands with concomitant pulmonary function abnormalities. At 6 months after acute infection, some patients have persistent CT changes to include the resolution of GGOs seen in the early recovery phase and the persistence or development of changes suggestive of fibrosis such as reticulation with or without parenchymal distortion. Predictors of post-COVID lung disease include need for intensive care unit (ICU) admission, mechanical ventilation, higher inflammatory markers, longer hospital stay and a diagnosis of acute respiratory distress syndrome (ARDS). Treatments of post-COVID lung disease are being investigated with anti-fibrotic agents being investigated for the prevention of post-COVID lung fibrosis. The etiology of post-COVID lung disease may be a sequela of prolonged mechanical ventilation, COVID-induced ARDS or direct injury from the virus. Future research is needed to determine the long-term persistence of post-COVID lung disease, its impact on patients and ways to prevent or treat it.

People with cystic fibrosis (pwCF) may be at risk of complications from COVID-19 but the impact of COVID-19 on pwCF remains unknown.We conducted a multicenter retrospective cohort study to assess the impact of the COVID-19 pandemic first wave on pwCF in the New York metropolitan area (NY) from March 1, 2020 to August 31, 2020. Objectives were to determine (1) the prevalence of COVID-19 by PCR and IgG antibody testing, (2) the clinical characteristics of COVID-19, (3) delay in routine outpatient care, and (4) the effect on anxiety and depression in pwCF.There were 26 COVID-19 cases diagnosed by PCR or antibody testing among the study cohort of 810 pwCF. The prevalence of COVID-19 by PCR (1.6%) and IgG antibody (12.2%) testing was low. 58% of cases were asymptomatic and 82% were managed at home. 8% were hospitalized and 1 person died. 89% of pwCF experienced delay in care. The prevalence of anxiety increased from 43% baseline to 58% during the pandemic (P0.01). In post-hoc analysis, the proportion of patients with diabetes (38% versus 16%, P0.01) and pancreatic insufficiency (96% versus 66%, P0.01) were higher while CFTR modulator use was lower (46% versus 65%, P = 0.05) in pwCF who tested positive for COVID-19.The prevalence of COVID-19 among pwCF in NY during the pandemic first wave was low and most cases were managed at home. CFTR modulators may be protective. PwCF experienced delay in routine care and increased anxiety.

Rationale Two antifibrotic medications, nintedanib and pirfenidone, have been approved for the treatment of idiopathic pulmonary fibrosis (IPF) in the US. Few data have been published on the use of these medications in clinical practice. Objective To investigate patterns of use of antifibrotic medications in the US. Methods The IPF-PRO Registry, a multicenter US registry, has enrolled patients with IPF that was diagnosed or confirmed at the enrolling center in the past 6 months. Data from patients enrolled from 5 June 2014 to 4 March 2018 were used to determine antifibrotic medication use ("treatment") in the enrollment window and a follow-up window approximately 6 months later. Associations between patient characteristics and treatment status were tested using logistic regression. Results Overall, 551 of 782 eligible patients (70.5%) were treated in the enrollment window. Younger age, lower FVC % predicted, oxygen use with activity, worse self-rated health based on the Short Form-12 (SF-12) or St George's Respiratory Questionnaire score, referral to the enrolling center by a pulmonologist, use of lung biopsy in diagnosis, and carrying a diagnosis of IPF to the enrolling center were associated with being treated. Among 534 patients treated at enrollment who had follow-up data, 94.0% remained treated in follow-up. Better self-rated health based on the SF-12 mental component score or EuroQoL score, and not using oxygen with activity at enrollment, were associated with continuing treatment in follow-up. Among 172 patients who were untreated at enrollment and had follow-up data, 29.7% started treatment in follow-up. Lower DLco % predicted, a family history of ILD, a history of sleep apnea, and a definite diagnosis of IPF at enrollment were associated with starting treatment in follow-up. Conclusions The majority of patients in the IPF-PRO Registry were receiving an approved medication for IPF at enrollment. Treatment at enrollment was associated with greater disease severity, more compromised quality of life and the use of oxygen with activity. Clinical trial registered with ClinicalTrials.gov (NCT01915511).

BackgroundMatrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) play important roles in the turnover of extracellular matrix and in the pathogenesis of idiopathic pulmonary fibrosis (IPF). This study aimed to determine the utility of circulating MMPs and TIMPs in distinguishing patients with IPF from controls and to explore associations between MMPs/TIMPs and measures of disease severity in patients with IPF.MethodsThe IPF cohort (n = 300) came from the IPF-PRO Registry, an observational multicenter registry of patients with IPF that was diagnosed or confirmed at the enrolling center in the past 6 months. Controls (n = 100) without known lung disease came from a population-based registry. Generalized linear models were used to compare circulating concentrations of MMPs 1, 2, 3, 7, 8, 9, 12, and 13 and TIMPs 1, 2, and 4 between patients with IPF and controls, and to investigate associations between circulating levels of these proteins and measures of IPF severity. Multivariable models were fit to identify the MMP/TIMPs that best distinguished patients with IPF from controls.ResultsAll the MMP/TIMPs analyzed were present at significantly higher levels in patients with IPF compared with controls except for TIMP2. Multivariable analyses selected MMP8, MMP9 and TIMP1 as top candidates for distinguishing patients with IPF from controls. Higher concentrations of MMP7, MMP12, MMP13 and TIMP4 were significantly associated with lower diffusion capacity of the lung for carbon monoxide (DLCO) % predicted and higher composite physiologic index (worse disease). MMP9 was associated with the composite physiologic index. No MMP/TIMPs were associated with forced vital capacity % predicted.ConclusionsCirculating MMPs and TIMPs were broadly elevated among patients with IPF. Select MMP/TIMPs strongly associated with measures of disease severity. Our results identify potential MMP/TIMP targets for further development as disease-related biomarkers.

Aspiration is associated with nontuberculous mycobacterial (NTM) pulmonary disease and airway dysbiosis is associated with increased inflammation. We examined whether NTM disease was associated with a distinct airway microbiota and immune profile.297 oral wash and induced sputum samples were collected from 106 participants with respiratory symptoms and imaging abnormalities compatible with NTM. Lower airway samples were obtained in 20 participants undergoing bronchoscopy. 16S rRNA gene and nested mycobacteriome sequencing approaches characterised microbiota composition. In addition, inflammatory profiles of lower airway samples were examined.The prevalence of NTM+cultures was 58%. Few changes were noted in microbiota characteristics or composition in oral wash and sputum samples among groups. Among NTM+samples, 27% of the lower airway samples were enriched withMycobacterium. A mycobacteriome approach identifiedMycobacteriumin a greater percentage of samples, including some nonpathogenic strains. In NTM+lower airway samples, taxa identified as oral commensals were associated with increased inflammatory biomarkers.The 16S rRNA gene sequencing approach is not sensitive in identifying NTM among airway samples that are culture-positive. However, associations between lower airway inflammation and microbiota signatures suggest a potential role for these microbes in the inflammatory process in NTM disease.

Background Familial dysautonomia (Riley-Day syndrome, hereditary sensory autonomic neuropathy type-III) is a rare genetic disease caused by impaired development of sensory and afferent autonomic nerves. As a consequence, patients develop neurogenic dysphagia with frequent aspiration, chronic lung disease, and chemoreflex failure leading to severe sleep disordered breathing. The purpose of these guidelines is to provide recommendations for the diagnosis and treatment of respiratory disorders in familial dysautonomia. Methods We performed a systematic review to summarize the evidence related to our questions. When evidence was not sufficient, we used data from the New York University Familial Dysautonomia Patient Registry, a database containing ongoing prospective comprehensive clinical data from 670 cases. The evidence was summarized and discussed by a multidisciplinary panel of experts. Evidence-based and expert recommendations were then formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. Results Recommendations were formulated for or against specific diagnostic tests and clinical interventions. Diagnostic tests reviewed included radiological evaluation, dysphagia evaluation, gastroesophageal evaluation, bronchoscopy and bronchoalveolar lavage, pulmonary function tests, laryngoscopy and polysomnography. Clinical interventions and therapies reviewed included prevention and management of aspiration, airway mucus clearance and chest physical therapy, viral respiratory infections, precautions during high altitude or air-flight travel, non-invasive ventilation during sleep, antibiotic therapy, steroid therapy, oxygen therapy, gastrostomy tube placement, Nissen fundoplication surgery, scoliosis surgery, tracheostomy and lung lobectomy. Conclusions Expert recommendations for the diagnosis and management of respiratory disease in patients with familial dysautonomia are provided. Frequent reassessment and updating will be needed.

Therapies targeting inflammation reveal inconsistent results in idiopathic pulmonary fibrosis (IPF). Aerosolised interferon (IFN)-γ has been proposed as a novel therapy. Changes in the host airway microbiome are associated with the inflammatory milieu and may be associated with disease progression. Here, we evaluate whether treatment with aerosolised IFN-γ in IPF impacts either the lower airway microbiome or the host immune phenotype. Patients with IPF who enrolled in an aerosolised IFN-γ trial underwent bronchoscopy at baseline and after 6 months. 16S rRNA sequencing of bronchoalveolar lavage fluid (BALF) was used to evaluate the lung microbiome. Biomarkers were measured by Luminex assay in plasma, BALF and BAL cell supernatant. The compPLS framework was used to evaluate associations between taxa and biomarkers. IFN-γ treatment did not change α or β diversity of the lung microbiome and few taxonomic changes occurred. While none of the biomarkers changed in plasma, there was an increase in IFN-γ and a decrease in Fit-3 ligand, IFN-α2 and interleukin-5 in BAL cell supernatant, and a decrease in tumour necrosis factor-β in BALF. Multiple correlations between microbial taxa common to the oral mucosa and host inflammatory biomarkers were found. These data suggest that the lung microbiome is independently associated with the host immune tone and may have a potential mechanistic role in IPF., Lower airway microbiome and immunological tone are associated in IPF, an effect independent of IFN-γ treatment http://ow.ly/cTDo30bsJiN

Background: Therapies targeting the inflammatory process revealed inconsistent results in Idiopathic Pulmonary Fibrosis (IPF). Aerosolized Interferon Gamma (IFN-y) has been proposed as a novel therapy. Additionally, changes in the host airway microbiome have been associated with inflammatory tone and, in IPF, may be associated with disease progression. We evaluate whether …

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.

Using data from a previously reported phase 2 safety trial, testing inhaled interferon gamma (IFN-γ) 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-γ to treat IPF.Ten patients with IPF had received inhaled IFN-γ (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-γ. 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.The change over time in DLCO was significantly different before and after IFN-γ 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-γ vs placebo.DLCO was significantly improved following inhaled (IFN-γ) as treatment for IPF. Our data suggest that previous studies utilizing parenteral IFN-γ 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.

To better understand the lung and systemic responses of helper T cells mediating memory immunity toMycobacterium 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 naı̈ve 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 CD69brightCD25brightCD4+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 naı̈ve 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.

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 ∼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.

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 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.

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.

Gamma interferon (IFN-γ) is critical in the immune response againstMycobacterium tuberculosis. In an ongoing trial of aerosol IFN-γ 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-γ 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. tuberculosisinduced IP-10, and IFN-γ 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-γ. TB was also associated with elevated iNOS mRNA, but aerosolized IFN-γ 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-γ. However, only 15 genes were differentially regulated by IFN-γ. We conclude that iNOS and IP-10 mRNA expression is increased in TB but that aerosol IFN-γ treatment increases expression of few genes in the human lung.

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 μg/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/EBPβ), 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/EBPβ. 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.

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-γ). We previously treated patients who had multidrug-resistant tuberculosis with recombinant IFN-γ (rIFN-γ) in aerosol form and were able to convert smear-positive cases to smear negative with 12 treatments over 1 month. We hypothesized that rIFN-γ 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- γ . 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-γ 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- γ aerosol induces signal transduction and gene expression in BAL cells and should be evaluated for efficacy in a randomized, controlled clinical trial.

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.

Summary Background Multidrug-resistant tuberculosis (MDR-TB) is associated with substantial morbidity, despite drug therapy. Interferon-γ, 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-γ 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-γ given to five patients with smears and cultures positive for pulmonary MDR-TB, despite documented adherence to therapy. The patients received aerosol interferon-γ 500 μg 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-γ 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-γ 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.

Summary 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.

A variety of neuropharmacological strategies are being pursued in the search for an effective treatment for methamphetamine 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 inpatient clinical pharmacology study to assess potential interactions between intravenous (IV) methamphetamine (15mg and 30mg) and oral aripiprazole (15mg). In addition, the effects of aripiprazole treatment on abstinence related craving and cue-induced craving were evaluated. Participants included non-treatment seeking, methamphetamine dependent patients (N=16), 18-45 years of age, currently using methamphetamine. Following baseline methamphetamine dosing (15mg and 30mg), participants received 2 weeks of treatment with aripiprazole (n=8) or placebo (n=8). Participants then completed cue exposure sessions using neutral and methamphetamine-related cues. Methamphetamine dosing (15mg and 30mg) was then repeated. Aripiprazole treatment had no effect on cue-induced methamphetamine craving, or on daily baseline craving assessed over the course of medication treatment, though aripiprazole treatment was associated with increased craving independent of methamphetamine dosing. Aripiprazole treatment was associated with significantly higher ratings on ARCI subscales reflecting euphoria and amphetamine-like effects following methamphetamine dosing. Aripiprazole was treatment was also associated with significant reductions in ratings of “bad effects” and reductions on the ARCI subscale for sedation effects following methamphetamine dosing. Aripiprazole treatment reduced the increase in systolic blood pressure following methamphetamine dosing, but had no other effects on cardiovascular responses to methamphetamine. Aripiprazole treatment did not alter the pharmacokinetics of methamphetamine. These findings indicate that aripiprazole treatment appears to be safe in volunteers with methamphetamine dependence, though the finding that aripiprazole increased some of the rewarding and stimulatory effects produced by acute methamphetamine suggests that 15mg aripiprazole is unlikely to be efficacious for the treatment of methamphetamine 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 methamphetamine dependence.