Presentation and healthcare delays among people with tuberculosis in London, and the impact on treatment outcome.

Background: A quarter of London's pulmonary tuberculosis (TB) patients have over 4 months of delay. Late diagnosis increases disease severity and the risk of transmission. We aim to classify delays, identify associated risk factors and assess treatment outcome. Methods: We conducted a retrospective cohort study using London surveillance data, 2012-2018 on adults aged ≥18 years with pulmonary TB. We defined presentation delay (days from symptom onset to first healthcare visit) and healthcare delay (first healthcare visit to treatment commencement) as dichotomous variables; positive delay being days equal or greater than the third quartile. We applied logistic regression models to identify risk factors associated with delays and treatment outcome at 12 months. Results: Of 7216 people, 4539 reported presentation and 5193 healthcare delays. The third quartiles for presentation and healthcare delay were 84 and 61 days, respectively. Presentation delay was associated with female sex (adjusted OR (aOR)=1.21; 95% CI 1.04 to 1.39), increasing age (aOR=1.004; 95% CI 1.001 to 1.008), white compared to Asian ethnicity (aOR=1.35; 95% CI 1.12 to 1.62), previous imprisonment (aOR=1.66; 95% CI 1.22 to 2.26) and alcohol misuse (aOR=1.44; 95% CI 1.04 to 1.89). Healthcare delay was associated with female sex (aOR=1.39; 95% CI 1.21 to 1.59), increasing age (aOR=1.014; 95% CI 1.009 to 1.018) and white ethnicity (aOR=1.41; 95% CI 1.19 to 1.68). 16% of 5678 people with known outcome did not complete treatment. Neither delay was associated with non-completion (p value <0.05). Conclusions: Female, white and older people with TB were more likely to experience both presentation and healthcare delays. Social risk factors were also associated with delay in presentation. Early diagnosis and treatment remain critical to reduce transmission, regardless of whether delay affected completion.

Should NICE reconsider the 2016 UK guidelines on TB contact tracing? A cost-effectiveness analysis of contact investigations in London.

BACKGROUND: In January 2016, clinical TB guidance in the UK changed to no longer recommend screening contacts of non-pulmonary, non-laryngeal (ETB) index cases. However, no new evidence was cited for this change, and there is evidence that screening these contacts may be worthwhile. The objective of this study was to estimate the cost-effectiveness of screening contacts of adult ETB cases and adult pulmonary or laryngeal TB (PTB) cases in London, UK. METHODS: We carried out a cross-sectional analysis of data collected on TB index cases and contacts in the London TB register and an economic evaluation using a static model describing contact tracing outcomes. Incremental cost-effectiveness ratios (ICERs) were calculated using no screening as the baseline comparator. All adult TB cases (≥15 years old) in London from 2012 to 2015, and their contacts, were eligible (2465/5084 PTB and 2559/6090 ETB index cases were included). RESULTS: Assuming each contact with PTB infects one person/month, the ICER of screening contacts of ETB cases was £78 000/quality-adjusted life-years (QALY) (95% CI 39 000 to 140 000), and screening contacts of PTB cases was £30 000/QALY (95% CI 18 000 to 50 000). The ICER of screening contacts of ETB cases was £30 000/QALY if each contact with PTB infects 3.4 people/month. Limitations of this study include the use of self-reported symptomatic periods and lack of knowledge about onward transmission from PTB contacts. CONCLUSIONS: Screening contacts of ETB cases in London was almost certainly not cost-effective at any conventional willingness-to-pay threshold in England, supporting recent changes to National Institute for Health and Care Excellence national guidelines.

Oxidative stress and cigarette smoke alter chromatin remodeling but differentially regulate NF-kappaB activation and proinflammatory cytokine release in alveolar epithelial cells.

Oxidative stress is implicated in lung inflammation due to its effect on proinflammatory gene transcription. Changes in gene transcription depend on chromatin remodeling and the relative activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Alterations in the nuclear histone acetylation:deacetylation balance may result in uncontrolled transcription of specific proinflammatory genes. We studied the effect of hydrogen peroxide (H2O2) and cigarette smoke condensate (CSC) on histone acetylation:deacetylation in human alveolar epithelial cells (A549). H2O2 and CSC significantly increased acetylation of histone H4 proteins and were associated with decreased HDAC activity and HDAC2 levels in A549 cells. Also, the decreased HDAC2 activity was due to protein modification by aldehydes and nitric oxide products. Pretreatment of A549 cells with N-acetyl-l-cysteine attenuated the oxidant-mediated reduction in HDAC activity. Treatment of A549 cells with CSC did not cause nuclear factor-kappaB (NF-kappaB) activation or expression and release of either interleukin (IL)-8 or IL-6. However, H2O2, tumor necrosis factor-alpha (TNF-alpha), and IL-1beta significantly increased NF-kappaB activation and expression of IL-8 compared with control cells. Interestingly, CSC dose dependently inhibited TNF-alpha- and IL-1beta-mediated NF-kappaB activation and IL-8 expression. Thus, H2O2 and CSC enhance acetylation of histone proteins and decrease histone deacetylase activity but differentially regulate proinflammatory cytokine release in alveolar epithelial cells.