Bhanu Williams

Management of patients with multidrug-resistant/extensively drug-resistant tuberculosis in Europe: a TBNET consensus statement

The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) substantially challenges TB control, especially in the European Region of the World Health Organization, where the highest prevalence of MDR/XDR cases is reported. The current management of patients with MDR/XDR-TB is extremely complex for medical, social and public health systems. The treatment with currently available anti-TB therapies to achieve relapse-free cure is long and undermined by a high frequency of adverse drug events, suboptimal treatment adherence, high costs and low treatment success rates. Availability of optimal management for patients with MDR/XDR-TB is limited even in the European Region. In the absence of a preventive vaccine, more effective diagnostic tools and novel therapeutic interventions the control of MDR/XDR-TB will be extremely difficult. Despite recent scientific advances in MDR/XDR-TB care, decisions for the management of patients with MDR/XDR-TB and their contacts often rely on expert opinions, rather than on clinical evidence. This document summarises the current knowledge on the prevention, diagnosis and treatment of adults and children with MDR/XDR-TB and their contacts, and provides expert consensus recommendations on questions where scientific evidence is still lacking. TBNET consensus statement on the management of patients with MDR/XDR-TB has been released in the Eur Respir J http://ow.ly/uizRD

Interferon-γ release assays do not identify more children with active tuberculosis than the tuberculin skin test

Data are lacking on the performance of interferon-γ release assays (IGRAs) in children. Although IGRAs are recommended for screening for latent tuberculosis infection (LTBI), many clinicians wish to employ them as a diagnostic test for active tuberculosis (TB). The objective of the present study was to compare the performance of the two commercially available IGRAs and the tuberculin skin test (TST) side-by-side in children with active TB and LTBI. In a prospective study, 209 children were investigated for active (n = 91) or latent TB (n = 118). TST, QuantiFERON-TB Gold In-tube (QFG-IT; Cellestis, Carnegie, Australia) and T-SPOT.TB (Oxford Immunotec, Abingdon, UK) assays were simultaneously used. For culture-confirmed active TB, the sensitivity of the TST was 83%, compared with 80% for QFG-IT and 58% for T-SPOT.TB. IGRAs did not perform significantly better than TST, although QFG-IT was significantly better than T-SPOT.TB. The agreement between QFG-IT and T-SPOT.TB in culture-confirmed TB was poor at 66.7%. In LTBI, the agreement between QFG-IT and T-SPOT.TB was very good (92%) with moderate agreement between TST and T-SPOT.TB (75%) and QFG-IT and TST (77%). A negative interferon-γ release assay should not dissuade paediatricians from diagnosing and treating presumed active tuberculosis. If used for diagnosis of latent tuberculosis infection, interferon-γ release assays could significantly reduce the numbers of children receiving chemoprophylaxis. Very good concordance between both tests was found.

Vitamin D deficiency and insufficiency in children with tuberculosis.

We examined the prevalence of vitamin D deficiency and insufficiency in children attending our tuberculosis (TB) clinic during a 2-year period. Sixty-four patients were included with active TB (n = 26) or latent TB infection (n = 38). Eighty-six percent (n = 55) were either vitamin D deficient (serum 25-hydroxyvitamin D <20 nmol/L) or insufficient (serum 25-hydroxyvitamin D <75 nmol/L). Only 1 child with active TB was vitamin D replete.

The impact of BCG vaccination on tuberculin skin test responses in children is age dependent: evidence to be considered when screening children for tuberculosis infection

Background Following exposure to TB, contacts are screened to target preventive treatment at those at high risk of developing TB. The UK has recently revised its recommendations for screening and now advises a 5 mm tuberculin skin test (TST) cut-off irrespective of age or BCG status. We sought to evaluate the impact of BCG on TST responses in UK children exposed to TB and the performance of different TST cut-offs to predict interferon γ release assay (IGRA) positivity. Methods Children <15 years old were recruited from 11 sites in the UK between January 2011 and December 2014 if exposed in their home to a source case with sputum smear or culture positive TB. Demographic details were collected and TST and IGRA undertaken. The impact of BCG vaccination on TST positivity was evaluated in IGRA-negative children, as was the performance of different TST cut-offs to predict IGRA positivity. Results Of 422 children recruited (median age 69 months; IQR: 32–113 months), 300 (71%) had been vaccinated with BCG. BCG vaccination affected the TST response in IGRA-negative children less than 5 years old but not in older children. A 5 mm TST cut-off demonstrated good sensitivity and specificity in BCG-unvaccinated children, and an excellent negative predictive value but was associated with low specificity (62.7%; 95% CI 56.1% to 69.0%) in BCG-vaccinated children. For BCG-vaccinated children, a 10 mm cut-off provided a high negative predictive value (97.7%; 95% CI 94.2% to 99.4%) with the positive predictive value increasing with increasing age of the child. Discussion BCG vaccination had little impact on TST size in children over 5 years of age. The revised TST cut-off recommended in the recent revision to the UK TB guidelines demonstrates good sensitivity but is associated with impaired specificity in BCG-vaccinated children.

Management of paediatric tuberculosis in leading UK centres: unveiling consensus and discrepancies.

SETTING Large specialist paediatric TB clinics in the UK. OBJECTIVE To evaluate clinical practice and compare with national and international guidelines. DESIGN A survey based on an electronic questionnaire on the management of latent tuberculous infection (LTBI) and tuberculosis (TB) disease was conducted in 13 specialist paediatric TB clinics. The consensus and discrepancies were evaluated by descriptive analysis. RESULTS Practice was reportedly different when choosing age limits for preventive treatment for TB contacts with initially negative tuberculin skin tests (TSTs), interpretation of TST results and use of interferon-gamma release assays (IGRAs) in the context of LTBI. In relation to management of children with TB disease, practices varied for duration of treatment of osteoarticular TB, monitoring for ethambutol ocular toxicity and use of pyridoxine. There was limited experience with multidrug-resistant TB (MDR-TB), and over half of the clinics monitored MDR-TB contacts without giving preventive treatment. CONCLUSIONS The survey showed heterogeneity in several aspects of clinical care for children with TB. Available paediatric TB guidelines differ substantially, explaining the wide variations in management of childhood TB. Prospective paediatric studies are urgently required to inform and standardise clinical practice, especially in the context of evolving drug resistance.

Evaluating UK National Guidance for Screening of Children for Tuberculosis. A Prospective Multicenter Study

Rationale: To identify infected contacts of tuberculosis (TB) cases, the UK National Institute for Health and Care Excellence (NICE) recommended the addition of IFN‐&ggr; release assays (IGRA) to the tuberculin skin test (TST) in its 2006 TB guidelines. Treatment for TB infection was no longer recommended for children who screened TST‐positive but IGRA‐negative. Objectives: We performed a cohort study to evaluate the risk of TB disease in this group. Methods: Children exposed to an infectious case of TB in their household were recruited from 11 pediatric TB clinics. TST and IGRA were performed at baseline, with IGRA repeated at 8 weeks and TST repeated if initially negative. Children were treated according to 2006 NICE guidelines and followed for 24 months. Measurements and Main Results: Of 431 recruited children, 392 completed the study. We diagnosed 48 (12.2%) cases of prevalent TB disease, 105 (26.8%) with TB infection, and 239 (60.9%) without TB infection or disease. Eighteen children aged 2 years and above had a positive TST but persistently negative IGRA. None received TB infection treatment and none developed TB disease. Ninety (26.1%) children qualified for TB infection treatment according to 2006 NICE guidelines. In contrast, 147 (42.7%) children would have qualified under revised NICE guidance, issued in 2016. Conclusions: In this low‐prevalence setting we saw no incident cases of TB disease in children who were TST‐positive but IGRA‐negative and did not receive treatment for TB infection. Following the latest NICE guidance, significantly more children will require medication.

Squaring the circle: health as a bridge to global solidarity in the Sustainable Development Goals

The Sustainable Development Goals (SDGs), launched in September 2015 to follow on from the Millennium Development Goals, require action by all countries. The new goals range from traditional areas of health and education to a newer focus on global trade and environmental protection. We discuss how all countries can be incentivised to engage and commit and argue that thoughtful target-setting and benchmarking, a more aggressive focus on equity and an emphasis on the interdependence of health and non-health development goals are key to meaningful progress. Fundamental shared values and aspirations around health, and in particular child health, within SDG3 may, we argue, offer a platform on which to build genuine global solidarity.

Antibiotics for tonsillitis: should the emergency department emulate general practice?

Objectives To determine whether antibiotics are prescribed appropriately for acute tonsillitis in an emergency department (ED). Methods Cross-sectional observational study in large district general hospital in London. Patients diagnosed and coded with ‘acute tonsillitis’ in the ED over a 3-month period in 2015. Medical records were reviewed for Centor criteria, which is a clinical scoring system to guide antibiotic prescribing in UK general practice. Drug charts were reviewed for the specific antibiotic(s) prescribed, and throat swab (TS) cultures were recorded. Results 273/389 patients with tonsillitis were analysed—186 children, 87 adults. Exclusions were missing patient records (86), patients had/awaiting tonsillectomy (22), receiving antibiotics (6) and immunocompromised (2). Centor score (CS) was not recorded for any patient. Based on derived CS from documented signs/symptoms, antibiotics were prescribed inappropriately to 196/273 patients (80%; 95% CI 74% to 85%) including broad-spectrum antibiotics to 25%. These included co-amoxiclav (18%), amoxicillin (6%), azithromycin (0.5%) and ceftriaxone (0.5%). TSs were taken in 66/273(24%) patients; 10/66 were positive for group A streptococcus (GAS). However, 48/56 GAS negative patients were prescribed antibiotics. Conclusions CS was not being used in the ED to guide antibiotic prescribing for acute tonsillitis. Antibiotic prescribing was based on clinical judgement. Based on derived CS (<3), 80% of patients were inappropriately prescribed antibiotics, particularly broad-spectrum antibiotics. Further studies need to assess use of CS to guide antibiotic prescription in ED. TSs were commonly performed in the ED but did not either improve diagnosis or guide antibiotic prescription.

A retrospective analysis of paediatric tuberculosis diagnosis in London: room for improvement?

Tuberculosis (TB) in children can be challenging to diagnose with microbiological certainty. Younger children are unable to expectorate sputum and the bacillary load is frequently low; few children with a clinical diagnosis of pulmonary TB have this confirmed microbiologically. Similarly, confirmation of extra-pulmonary TB, using other samples, can be difficult.1 Despite these challenges, 27 TB guidelines, including those produced by the National Institute for Health and Care Excellence, recommend that microbiological confirmation is attempted in all children with suspected TB, and that where pulmonary TB is suspected, three samples should be sent.2 Microbiological diagnosis is useful for a number of reasons: it confirms the diagnosis, it allows epidemiological data regarding strain …