Premature ageing of the immune system underlies immunodeficiency in ataxia telangiectasia.

ATM kinase modulates pathways implicated in premature ageing and ATM genotype predicts survival, yet immunodeficiency in ataxia telangiectasia is regarded as mild and unrelated to age. We address this paradox in a molecularly characterised sequential adult cohort with classical and mild variant ataxia telangiectasia. Immunodeficiency has the characteristics of premature ageing across multiple cellular and molecular immune parameters. This immune ageing occurs without previous CMV infection. Age predicts immunodeficiency in genetically homogeneous ataxia telangiectasia, and in comparison with controls, calendar age is exceeded by immunological age defined by thymic naïve CD4+ T cell levels. Applying ataxia telangiectasia as a model of immune ageing, pneumococcal vaccine responses, characteristically deficient in physiological ageing, are predicted by thymic naïve CD4+ T cell levels. These data suggest inherited defects of DNA repair may provide valuable insight into physiological ageing. Thymic naïve CD4+ T cells may provide a biomarker for vaccine responsiveness in elderly cohorts.

Screening of healthcare workers for tuberculosis: development and validation of a new health economic model to inform practice.

BACKGROUND: Methods for determining cost-effectiveness of different treatments are well established, unlike appraisal of non-drug interventions, including novel diagnostics and biomarkers. OBJECTIVE: The authors develop and validate a new health economic model by comparing cost-effectiveness of tuberculin skin test (TST); blood test, interferon-gamma release assay (IGRA) and TST followed by IGRA in conditional sequence, in screening healthcare workers for latent or active tuberculosis (TB). DESIGN: The authors focus on healthy life years gained as the benefit metric, rather than quality-adjusted life years given limited data to estimate quality adjustments of life years with TB and complications of treatment, like hepatitis. Healthy life years gained refer to the number of TB or hepatitis cases avoided and the increase in life expectancy. The authors incorporate disease and test parameters informed by systematic meta-analyses and clinical practice. Health and economic outcomes of each strategy are modelled as a decision tree in Markov chains, representing different health states informed by epidemiology. Cost and effectiveness values are generated as the individual is cycled through 20 years of the model. Key parameters undergo one-way and Monte Carlo probabilistic sensitivity analyses. SETTING: Screening healthcare workers in secondary and tertiary care. RESULTS: IGRA is the most effective strategy, with incremental costs per healthy life year gained of £10 614-£20 929, base case, £8021-£18 348, market costs TST £45, IGRA £90, IGRA specificities of 99%-97%; mean (5%, 95%), £12 060 (£4137-£38 418) by Monte Carlo analysis. CONCLUSIONS: Incremental costs per healthy life year gained, a conservative estimate of benefit, are comparable to the £20 000-£30 000 NICE band for IGRA alone, across wide differences in disease and test parameters. Health gains justify IGRA costs, even if IGRA tests cost three times TST. This health economic model offers a powerful tool for appraising non-drug interventions in the market and under development.