Treatment outcomes of new tuberculosis patients hospitalized in Kampala, Uganda: a prospective cohort study.

BACKGROUND: In most resource limited settings, new tuberculosis (TB) patients are usually treated as outpatients. We sought to investigate the reasons for hospitalisation and the predictors of poor treatment outcomes and mortality in a cohort of hospitalized new TB patients in Kampala, Uganda. METHODS AND FINDINGS: Ninety-six new TB patients hospitalised between 2003 and 2006 were enrolled and followed for two years. Thirty two were HIV-uninfected and 64 were HIV-infected. Among the HIV-uninfected, the commonest reasons for hospitalization were low Karnofsky score (47%) and need for diagnostic evaluation (25%). HIV-infected patients were commonly hospitalized due to low Karnofsky score (72%), concurrent illness (16%) and diagnostic evaluation (14%). Eleven HIV uninfected patients died (mortality rate 19.7 per 100 person-years) while 41 deaths occurred among the HIV-infected patients (mortality rate 46.9 per 100 person years). In all patients an unsuccessful treatment outcome (treatment failure, death during the treatment period or an unknown outcome) was associated with duration of TB symptoms, with the odds of an unsuccessful outcome decreasing with increasing duration. Among HIV-infected patients, an unsuccessful treatment outcome was also associated with male sex (P = 0.004) and age (P = 0.034). Low Karnofsky score (aHR = 8.93, 95% CI 1.88 - 42.40, P = 0.001) was the only factor significantly associated with mortality among the HIV-uninfected. Mortality among the HIV-infected was associated with the composite variable of CD4 and ART use, with patients with baseline CD4 below 200 cells/µL who were not on ART at a greater risk of death than those who were on ART, and low Karnofsky score (aHR = 2.02, 95% CI 1.02 - 4.01, P = 0.045). CONCLUSION: Poor health status is a common cause of hospitalisation for new TB patients. Mortality in this study was very high and associated with advanced HIV Disease and no use of ART

An airway epithelial IL-17A response signature identifies a steroid-unresponsive COPD patient subgroup

© 2019 American Society for Clinical Investigation. All rights reserved. BACKGROUND. Chronic obstructive pulmonary disease (COPD) is a heterogeneous smoking-related disease characterized by airway obstruction and inflammation. This inflammation may persist even after smoking cessation and responds variably to corticosteroids. Personalizing treatment to biologically similar "molecular phenotypes" may improve therapeutic efficacy in COPD. IL-17A is involved in neutrophilic inflammation and corticosteroid resistance, and thus may be particularly important in a COPD molecular phenotype. METHODS. We generated a gene expression signature of IL-17A response in bronchial airway epithelial brushings from smokers with and without COPD (n = 238), and validated it using data from 2 randomized trials of IL-17 blockade in psoriasis. This IL-17 signature was related to clinical and pathologic characteristics in 2 additional human studies of COPD: (a) SPIROMICS (n = 47), which included former and current smokers with COPD, and (b) GLUCOLD (n = 79), in which COPD participants were randomized to placebo or corticosteroids. RESULTS. The IL-17 signature was associated with an inflammatory profile characteristic of an IL-17 response, including increased airway neutrophils and macrophages. In SPIROMICS the signature was associated with increased airway obstruction and functional small airways disease on quantitative chest CT. In GLUCOLD the signature was associated with decreased response to corticosteroids, irrespective of airway eosinophilic or type 2 inflammation. CONCLUSION. These data suggest that a gene signature of IL-17 airway epithelial response distinguishes a biologically, radiographically, and clinically distinct COPD subgroup that may benefit from personalized therapy

Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.

BACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function

The pharmacogenomics of inhaled corticosteroids and lung function decline in COPD.

Inhaled corticosteroids (ICS) are widely prescribed for patients with chronic obstructive pulmonary disease (COPD), yet have variable outcomes and adverse reactions, which may be genetically determined. The primary aim of the study was to identify the genetic determinants for forced expiratory volume in 1 s (FEV1) changes related to ICS therapy.In the Lung Health Study (LHS)-2, 1116 COPD patients were randomised to the ICS triamcinolone acetonide (n=559) or placebo (n=557) with spirometry performed every 6 months for 3 years. We performed a pharmacogenomic genome-wide association study for the genotype-by-ICS treatment effect on 3 years of FEV1 changes (estimated as slope) in 802 genotyped LHS-2 participants. Replication was performed in 199 COPD patients randomised to the ICS, fluticasone or placebo.A total of five loci showed genotype-by-ICS interaction at p<5×10-6; of these, single nucleotide polymorphism (SNP) rs111720447 on chromosome 7 was replicated (discovery p=4.8×10-6, replication p=5.9×10-5) with the same direction of interaction effect. ENCODE (Encyclopedia of DNA Elements) data revealed that in glucocorticoid-treated (dexamethasone) A549 alveolar cell line, glucocorticoid receptor binding sites were located near SNP rs111720447. In stratified analyses of LHS-2, genotype at SNP rs111720447 was significantly associated with rate of FEV1 decline in patients taking ICS (C allele β 56.36 mL·year-1, 95% CI 29.96-82.76 mL·year-1) and in patients who were assigned to placebo, although the relationship was weaker and in the opposite direction to that in the ICS group (C allele β -27.57 mL·year-1, 95% CI -53.27- -1.87 mL·year-1).The study uncovered genetic factors associated with FEV1 changes related to ICS in COPD patients, which may provide new insight on the potential biology of steroid responsiveness in COPD

A module-based analytical strategy to identify novel disease-associated genes shows an inhibitory role for interleukin 7 Receptor in allergic inflammation

<p>Abstract</p> <p>Background</p> <p>The identification of novel genes by high-throughput studies of complex diseases is complicated by the large number of potential genes. However, since disease-associated genes tend to interact, one solution is to arrange them in modules based on co-expression data and known gene interactions. The hypothesis of this study was that such a module could be a) found and validated in allergic disease and b) used to find and validate one ore more novel disease-associated genes.</p> <p>Results</p> <p>To test these hypotheses integrated analysis of a large number of gene expression microarray experiments from different forms of allergy was performed. This led to the identification of an experimentally validated reference gene that was used to construct a module of co-expressed and interacting genes. This module was validated in an independent material, by replicating the expression changes in allergen-challenged CD4⁺cells. Moreover, the changes were reversed following treatment with corticosteroids. The module contained several novel disease-associated genes, of which the one with the highest number of interactions with known disease genes, <it>IL7R</it>, was selected for further validation. The expression levels of <it>IL7R </it>in allergen challenged CD4⁺cells decreased following challenge but increased after treatment. This suggested an inhibitory role, which was confirmed by functional studies.</p> <p>Conclusion</p> <p>We propose that a module-based analytical strategy is generally applicable to find novel genes in complex diseases.</p

Deaths among tuberculosis cases in Shanghai, China: who is at risk?

<p>Abstract</p> <p>Background</p> <p>Information about the risk factors associated with death caused by tuberculosis (TB) or death with TB would allow improvements in the clinical care of TB patients and save lives. The present study sought to identify characteristics associated with increased risk of death during anti-TB treatment in Shanghai, a city in China with one of the country's highest TB mortality rates.</p> <p>Methods</p> <p>We evaluated deaths among culture positive pulmonary TB cases that were diagnosed in Shanghai during 2000–2004 and initiated anti-TB therapy. Demographic, clinical, mycobacteriological information and treatment outcomes were routinely collected through a mandatory reporting system.</p> <p>Results</p> <p>There were 7,999 culture positive pulmonary cases reported during the study period. The overall case fatality rate was 5.5% (440 cases), and approximately half (50.5%) of the deaths were attributed to causes other than TB. Eighty-six percent of the deaths were among TB cases age ≥ 60 years. The significant independent risk factors for mortality during anti-TB treatment were advancing age, male sex, sputum smear positivity, and the presence of a comorbidity.</p> <p>Conclusion</p> <p>More vigorous clinical management and prevention strategies by both the TB control program and other public health programs are essential to improve TB treatment outcomes. Earlier suspicion, diagnosis and treatment of TB, especially among persons older than 60 years of age and those with a comorbid condition, could reduce deaths among TB patients.</p

Personal and Societal Health Quality Lost to Tuberculosis

BACKGROUND: In developed countries, tuberculosis is considered a disease with little loss of Quality-Adjusted Life Years (QALYs). Tuberculosis treatment is predominantly ambulatory and death from tuberculosis is rare. Research has shown that there are chronic pulmonary sequelae in a majority of patients who have completed treatment for pulmonary tuberculosis (PTB). This and other health effects of tuberculosis have not been considered in QALY calculations. Consequently both the burden of tuberculosis on the individual and the value of tuberculosis prevention to society are underestimated. We estimated QALYs lost to pulmonary TB patients from all known sources, and estimated health loss to prevalent TB disease. METHODOLOGY/PRINCIPAL FINDINGS: We calculated values for health during illness and treatment, pulmonary impairment after tuberculosis (PIAT), death rates, years-of-life-lost to death, and normal population health. We then compared the lifetime expected QALYs for a cohort of tuberculosis patients with that expected for comparison populations with latent tuberculosis infection and without tuberculosis infection. Persons with culture-confirmed tuberculosis accrued fewer lifetime QALYs than those without tuberculosis. Acute tuberculosis morbidity cost 0.046 QALYs (4% of total) per individual. Chronic morbidity accounted for an average of 0.96 QALYs (78% of total). Mortality accounted for 0.22 QALYs lost (18% of total). The net benefit to society of averting one case of PTB was about 1.4 QALYs. CONCLUSIONS/SIGNIFICANCE: Tuberculosis, a preventable disease, results in QALYs lost owing to illness, impairment, and death. The majority of QALYs lost from tuberculosis resulted from impairment after microbiologic cure. Successful TB prevention efforts yield more health quality than previously thought and should be given high priority by health policy makers. (Refer to Abstracto S1 for Spanish language abstract)