Michael Eisenhut

Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis

Objectives To determine whether BCG vaccination protects against Mycobacterium tuberculosis infection as assessed by interferon γ release assays (IGRA) in children. Design Systematic review and meta-analysis. Searches of electronic databases 1950 to November 2013, checking of reference lists, hand searching of journals, and contact with experts. Setting Community congregate settings and households. Inclusion criteria Vaccinated and unvaccinated children aged under 16 with known recent exposure to patients with pulmonary tuberculosis. Children were screened for infection with M tuberculosis with interferon γ release assays. Data extraction Study results relating to diagnostic accuracy were extracted and risk estimates were combined with random effects meta-analysis. Results The primary analysis included 14 studies and 3855 participants. The estimated overall risk ratio was 0.81 (95% confidence interval 0.71 to 0.92), indicating a protective efficacy of 19% against infection among vaccinated children after exposure compared with unvaccinated children. The observed protection was similar when estimated with the two types of interferon γ release assays (ELISpot or QuantiFERON). Restriction of the analysis to the six studies (n=1745) with information on progression to active tuberculosis at the time of screening showed protection against infection of 27% (risk ratio 0.73, 0.61 to 0.87) compared with 71% (0.29, 0.15 to 0.58) against active tuberculosis. Among those infected, protection against progression to disease was 58% (0.42, 0.23 to 0.77). Conclusions BCG protects against M tuberculosis infection as well as progression from infection to disease. Trial registration PROSPERO registration No CRD42011001698 (www.crd.york.ac.uk/prospero/).

BCG vaccination reduces risk of infection with Mycobacterium tuberculosis as detected by gamma interferon release assay

AIMS To investigate whether BCG vaccination, in addition to a reduction of active tuberculosis, leads to a reduction of Mycobacterium tuberculosis infection during an outbreak of tuberculosis. METHODS Pupils (n=199) of a Junior School exposed to a pupil with active pulmonary tuberculosis were screened using a gamma interferon release assay for detection of M. tuberculosis infection (ex vivo ELISPOT assay). Relative risk of M. tuberculosis infection and pulmonary tuberculosis associated with BCG vaccination were calculated and adjusted for exposure risk. RESULTS Twenty-nine percent of children with previous BCG vaccination had a reactive gamma interferon release assay compared with 47% of unvaccinated children (unadjusted RR 0.61, 95%CI 0.39, 0.96). The protective effect of BCG vaccination persisted following adjustment for other risk factors for infection like ethnicity and proximity to the source case reflected in membership of class and activity groups (corrected relative risk 0.26, 95%CI 0.09, 0.69 and risk reduction of 74%, 95%CI 31%, 91%). A higher proportion of unvaccinated children (11%) were diagnosed with active pulmonary tuberculosis compared with 5% of vaccinated children (RR 0.51 95%CI 0.15, 1.70). CONCLUSION BCG vaccination was associated with a reduction of M. tuberculosis infection diagnosed by gamma interferon release assay testing in school children during a point source outbreak.

IBD immunopathogenesis: A comprehensive review of inflammatory molecules

Inflammatory molecules play a crucial role in the pathogenesis of inflammatory bowel disease (IBD) such as ulcerative colitis and Crohns disease, both of which are chronic inflammatory conditions of the gastrointestinal tract. Abnormal expressions of pro- and anti-inflammatory molecules have been described to cause an imbalance to the gut innate and adaptive immunity, and recently a large portion of research in IBD has been geared towards identifying novel molecules that may be used as potential therapeutic targets. Understanding of these inflammatory molecules has suggested that although ulcerative colitis and Crohns disease share many common clinical symptoms and signs, they are in fact two separate clinical entities characterized by different immunopathogenesis. In this review, we comprehensively discuss the roles of numerous inflammatory molecules including but not limited to cytokines, chemokines, inflammasomes, microRNAs and neuropeptides and their expression status in ulcerative colitis and Crohns disease in relation to their effects on the overall intestinal inflammatory process.

Extensive transmission of Mycobacterium tuberculosis from 9 year old child with pulmonary tuberculosis and negative sputum smear

A negative sputum smear does not exclude substantial risk of infection from patients with pulmonary tuberculosis

Tuberculosis—diagnosis, management, prevention, and control: summary of updated NICE guidance

#### What you need to know Tuberculosis (TB) incidence in the UK remains high compared with other Western European countries.1 It disproportionately affects underserved groups, including homeless people, people in poor housing or affected by poverty, people with problem drug use, and people born in countries with a high incidence of TB.2 However, many cases are preventable with public health measures, and, when disease does occur, most people can be cured. This article summarises the updated recommendations on diagnosing, managing, and preventing TB from the National Institute for Health and Care Excellence (NICE).1 This guidance updates the 2011 clinical guideline3 and incorporates the public health guidance on the identification and management of TB in under-served groups.4 #### What’s new in this guidance NICE recommendations are based on systematic reviews of best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on the Guideline Development Group’s experience and opinion of …

Changes in renal sodium transport during a systemic inflammatory response.

Sirs, Watanabe et al. [1] reported on the clinical characteristics of patients with hyponatremia in Kawasaki disease (KD). They noted that hyponatremia was associated with a more severe systemic inflammatory response reflected in prolonged pyrexia and higher C-reactive protein levels. We have recently published the result of a prospective study investigating changes in systemic sodium and chloride transport in meningococcal septicemia. Severe meningococcal septicemia was associated with increased fractional renal sodium excretion [2]. Both meningococcal septicemia and Kawasaki disease are associated with an intensive systemic inflammatory response with high circulating levels of interleukin-1 (IL-1) and tumor necrosis factor (TNF) [3– 6]. The mechanism by which these inflammatory mediators are able to induce hyponatremia has been investigated in both animal studies and in vitro. It involves increased renal sodium loss by a reduction in renal tubular sodium absorption. Inflammatory mediators like IL-1 and TNF have been shown to reduce epithelial sodium transport in epithelial cells by a reduction of the expression and function of the apical epithelial sodium channel (ENaC) and/or the sodium potassium ATPase (Na/K ATPase) at the basolateral membrane [7]. IL-1 was hereby found to induce natriuresis in the rat model [8]. The mechanism was investigated in cultures of inner medullary, cortical collecting duct and proximal tubular renal cells in vitro and it was found to involve a reduction of the Na/K ATPase function. The effect was mediated by prostaglandin E2 and inhibitable by the cyclooxygenase inhibitor indomethacin [9–13]. Another pathway by which IL-1 and TNF are involved in a reduction of renal sodium absorption is by increasing tissue levels of nitric oxide, which is a potent suppressor of the epithelial Na/K ATPase function mediated by the intracellular messenger cGMP and via modification of protein kinase G [14, 15]. Future studies into the etiology of hyponatremia in KD need to investigate the effects of therapies directed at a reduction of effects of IL-1 and TNF and their mediators PGE2 and NO on renal fractional sodium excretion and hyponatremia.

Insight into the role of TSLP in inflammatory bowel diseases.

Proinflammatory cytokines are thought to modulate pathogeneses of various inflammatory bowel diseases (IBDs). Thymic stromal lymphopoietin (TSLP), which has been studied in various allergic diseases such as asthma, atopic dermatitis (AD) and eosinophilic esophagitis (EoE), has been less considered to be involved in IBDs. However, mucosal dendritic cells (DCs) induced by various cytokines including TSLP were reported to cause polarization of T cell toward Th2 response, the differentiation of regulatory T-cell (Treg), and secretion of IgA by B cells. In this review, we discuss the concept that decreased TSLP has the potential to accelerate the development of Th1 response dominant diseases such as the Crohns disease (CD) while increased TSLP has the potential to lead to a development of Th2 cell dominant diseases such the ulcerative colitis (UC). To examine TSLPs role as a potential determining factor for differentiating UC and CD, we analyzed the effects of other genes regulated by TSLP in regards to the UC and CD pathogeneses using data from online open access resources such as NetPath, GeneMania, and the String database. Our findings indicate that TSLP is a key mediator in the pathogenesis of IBDs and that further studies are needed to evaluate its role.

Validation of Advanced Paediatric Life Support Formulas for Weight Calculation in a Multiethnic Population

Introduction. The aims of this study were to validate the new formulas for weight calculation introduced by the advanced life support group (alsg) of the United Kingdom in 2011 and compare their performance to the formula currently used by the European Resuscitation Council (ERC) and other formulas and to check whether performance of formulas for weight calculation is affected by ethnic group and gender. Methods. Prospective audit of weight versus calculated weight comparing alsg formula with ERC, Luscombe, Argall, and Best Guess formulas analysed for gender, age, and ethnic groups. Results. Prospectively 599 children were included: 157 Asian, 268 Caucasian, and 174 children from other origin. In infants there was no difference between actual weight and alsg formula calculated weight. There was a progressively increased underestimation of weight year by year from 1 to 10 years of age using the ERC formula. In the 6–10 year age group the ERC formula underestimated the weight by a mean of 6.5 kg (21.8%, P < 0.001) with the alsg and Luscombe formulas performing best. In 11-12 year old children the alsg formula estimated well. Conclusion. In one- to ten-year-old children, the Luscombe formula provided a better weight estimate than alsg and ERC formulas in a multiethnic population.

Reducing Prescribing Errors in Paediatric Patients by Assessment and Feedback Targeted at Prescribers

Prescribing errors are the most common type of medical errors and can result in harm particularly in young children. Doctors were enrolled in a programme of written assessment in prescribing skills and individualized feedback. Pharmacists audited the impact. The setting was the paediatric wards and neonatal unit of a District General Hospital. 16 doctors were tested and received feedback. A total of 110 errors were identified in this test, out of a 51 were classified as major including wrong dose and frequency, and prescribing medication the patient had an allergy to. Audit of impact of this intervention revealed a reduction of errors from 47 to 21, and patients affected from 19 to 11 per 100 (P = 0.001) emergency admissions compared to an audit before the intervention. An intervention combining a comprehensive multifaceted assessment and detailed feedback can lead to reduction of prescribing errors in paediatric trainees.

Hair Analysis for Determination of Isoniazid Concentrations and Acetylator Phenotype during Antituberculous Treatment

Background. Analysis of isoniazid (INH) uptake has been based on measurement of plasma concentrations providing a short-term and potentially biased view. Objectives. To establish hair analysis as a tool to measure long-term uptake of INH and to assess whether acetylator phenotype in hair reflects N-acetyltransferase-2 (NAT2) genotype. Design and Methods. INH and acetyl-INH concentrations in hair were determined in patients on INH treatment for M. tuberculosis infection using high pressure liquid chromatography/mass spectrometry. Acetyl-INH/INH ratios were correlated with NAT-2 genotype. Results. Hair concentrations of INH, determined in 40 patients, were not dependent on ethnic group or body mass index and were significantly higher in male compared to female patients (median (range) 2.37 ng/mg (0.76–4.9) versus 1.11 ng/mg (0.02–7.20) (P = 0.02). Acetyl-INH/INH ratios were a median of 15.2% (14.5 to 31.7) in homozygous rapid acetylator NAT-2 genotype and 37.3% (1.73 to 51.2) in the heterozygous rapid acetylator NAT-2 genotype and both significantly higher than in the slow acetylator NAT-2 genotype with 5.8% (0.53 to 14.4) (P < 0.05). Conclusions. Results of hair analysis for INH showed lower concentrations in females. Acetyl-INH/INH ratios were significantly lower in patients with slow acetylator versus rapid acetylator genotypes.