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Twelve-monthly versus six-monthly radiological screening for active case-finding of tuberculosis: a randomised controlled trial

Background

The incidence of tuberculosis has increased among South African gold miners despite comprehensive control programmes, including a radiological screening programme. No data are available as to the optimal frequency of screening. The aim of this study was to compare 6-monthly and 12-monthly radiological screening for active tuberculosis case-finding.

 Methods

Employees of a gold mining company were randomly assigned to the control arm (screening at baseline, 12 and 24 months) or the intervention arm (additional ‘intervention’ radiographs at 6 and 18 months after baseline). Study outcomes included proportion of tuberculosis cases detected by screening, proportion smear-positive, extent of disease and mortality.

 Results

22 634 miners were randomised. Compared with 12-monthly screening, 6-monthly screening detected more tuberculosis suspects but not more cases, partly due to greater attrition between screening and further investigation after ‘intervention’ compared with routine radiographs. Tuberculosis cases detected in the 6-monthly versus the 12-monthly screening arm had less extensive disease (p=0.05) and a lower tuberculosis-specific mortality (death on tuberculosis treatment) (2.1 and 2.8 per 1000 person-years respectively, HR 0.73, 95% CI 0.50 to 1.08, p=0.1), which was most marked in the first 2 months of treatment (HR 0.48, 95% CI 0.23 to 0.98, p=0.04) when death from tuberculosis is most likely.

 Discussion

In settings with a high prevalence of HIV and tuberculosis despite standard tuberculosis control measures, more frequent case-finding may reduce the extent of disease, tuberculosis mortality and tuberculosis transmission through earlier detection of active tuberculosis cases. To be effective, however, all tuberculosis suspects identified through screening must be investigated for tuberculosis.

Lung function, airway remodelling and inflammation in symptomatic infants: outcome at 3 years

Background

Relationships between early deficits of lung function, infant airway pathology and outcome in symptomatic infants are unclear. A study was undertaken to determine the associations between early lung function, airway histology and inflammation in symptomatic infants with the continuance of respiratory symptoms, lung function and subsequent use of inhaled asthma medication at the age of 3 years.

 Methods

53 children who underwent lung function measurements and bronchoscopy following referral to a specialist children's hospital for recurrent lower respiratory symptoms at a mean age of 1 year were followed up at 3 years of age. Assessments were made of respiratory symptoms during the previous year, lung function by oscillometry and atopy by skin prick testing. Individual data on the purchase of asthma medications were obtained from the Social Insurance Institution for the 12 months preceding the follow-up visit.

 Results

50 children (94%) were re-evaluated, of whom 40 had ongoing airway symptoms. 11/39 (28%) who underwent successful oscillometry had reduced lung function, 31/50 (62%) used inhaled corticosteroids (ICS) regularly and 12/50 (24%) used ICS intermittently. Abnormal lung function at infancy was associated with ongoing airway symptoms (p<0.001) and with the purchase of ICS (p=0.009) and β agonists (p=0.002). Reticular basement membrane thickness in infancy and the numbers of mucosal mast cells, but not eosinophils, correlated significantly with the amount of ICS purchased at 3 years (p=0.003 and p=0.018, respectively).

 Conclusions

Reduced lung function, thickening of the reticular basement membrane and increased density of mucosal mast cells in infancy are associated with respiratory morbidity and treatment needs at age 3 years in this highly selected group of children.

Novel human genetic variants associated with extrapulmonary tuberculosis: a pilot genome wide association study.

Approximately 5-10% of persons infected with M. tuberculosis develop tuberculosis, but the factors associated with disease progression are incompletely understood. Both linkage and association studies have identified human genetic variants associated with susceptibility to pulmonary tuberculosis, but few genetic studies have evaluated extrapulmonary disease. Because extrapulmonary and pulmonary tuberculosis likely have different underlying pathophysiology, identification of genetic mutations associated with extrapulmonary disease is important.

FINDINGS: We performed a pilot genome-wide association study among 24 persons with previous extrapulmonary tuberculosis and well-characterized immune defects; 24 pulmonary tuberculosis patients and 57 patients with M. tuberculosis infection served as controls. The Affymetrix GeneChip Human Mapping Xba Array was used for genotyping; after careful quality control, genotypes at 44,175 single nucleotide polymorphisms (SNPs) were available for analysis. Eigenstrat quantified population stratification within our sample; logistic regression, using results of the Eigenstrat analysis as a covariate, identified significant associations between groups. Permutation testing controlled the family-wise error rate for each comparison between groups. Four SNPs were significantly associated with extrapulmonary tuberculosis compared to controls with M. tuberculosis infection; one (rs4893980) in the gene PDE11A, one (rs10488286) in KCND2, and one (rs2026414) in PCDH15; one was in chromosome 7 but not associated with a known gene. Two additional variants were significantly associated with extrapulmonary tuberculosis compared with pulmonary tuberculosis; one (rs340708) in the gene FAM135B and one in chromosome 13 but not associated with a known gene. The function of all four genes affects cell signaling and activity, including in the brain.

CONCLUSIONS: In this pilot study, we identified 6 novel variants not previously known to be associated with extrapulmonary tuberculosis, including two SNPs more common in persons with extrapulmonary than pulmonary tuberculosis. This provides support for the hypothesis that the pathogenesis and genetic predisposition to extrapulmonary tuberculosis differs from pulmonary tuberculosis. Further study of these novel SNPs, and more well-powered genome-wide studies of extrapulmonary tuberculosis, is warranted.

Assessment of Five Antigens from Mycobacterium tuberculosis for Serodiagnosis of Tuberculosis.

Tuberculosis (TB) caused by Mycobacterium tuberculosis is a major public health issue, particularly in developing countries, and thus effective diagnostic methods for TB remain a central theme in basic and clinical research.

To evaluate five antigens (38kDa, Rv3621c, Rv3618, 38kDa-ESAT-6 (38E6), and Ag85B-HBHA (AH)) in serological tests for TB patients, we recruited 288 patients and 201 healthy controls. The median IgG reactivity to 38kDa, 38E6 and AH was higher than that to Rv3618 and Rv3621c in pulmonary TB. 38kDa and 38E6 provided high sensitivity in pulmonary TB, but low sensitivity in extra-pulmonary TB (EPTB). The specificity achieved by 38kDa and 38E6 ranged from 82.0% to 93.9% in patients with non-TB respiratory disease (PD) and in controls. 38kDa and 38E6 exhibited lower sensitivity and higher specificity than their combinations with Rv3618.

These findings provide useful information on the relative importance of the above five antigens and suggest that combinations of Rv3618 with 38kDa and 38E6 can increase the sensitivity, but their specificity needs to be further increased.

Klebsiella pneumoniae outer membrane protein A is required to prevent the activation of airway epithelial cells.

Outer membrane protein A (OmpA) is a class of proteins highly conserved among the Enterobacteriaceae family and throughout evolution. Klebsiella pneumoniae is a capsulated Gram negative pathogen. It is an important cause of community-acquired and nosocomial pneumonia.

Evidence indicates that K. pneumoniae infections are characterized by lacking an early inflammatory response. Data from our laboratory indicates that K. pneumoniae CPS helps to suppress the host inflammatory response. However, it is unknown whether K. pneumoniae employs additional factors to modulate host inflammatory responses.

Here, we report that K. pneumoniae OmpA is important for immune evasion in vitro and in vivo. Infection of A549 and normal human bronchial cells with 52OmpA2, ompA mutant, increased the levels of IL-8. 52145-ΔwcaK2ompA, which does not express CPS and ompA, induced the highest levels of IL-8. Both mutants could be complemented. In vivo, 52OmpA2 induced higher levels of tnf α, kc and il6 than the wild type. ompA mutants activated NF-κB and the phosphorylation of p38, p44/42 and JNK MAPKs and IL-8 induction was via NF-κB and p38 and p44/42-dependent pathways. 52OmpA2 engaged TLR 2 and 4 to activate NF-κB whereas 52145-ΔwcaK2ompA activated not only TLR2 and TLR4 but also NOD1. Finally, we demonstrate that ompA mutant is attenuated in the pneumonia mouse model.

The results of this study indicate that K. pneumoniae OmpA contributes to attenuate airway cell responses. This may facilitate pathogen survival in the hostile environment of the lung.

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