Faiz Ahmad Khan

Treatment outcomes of childhood tuberculous meningitis: a systematic review and meta-analysis.

BACKGROUND Tuberculous meningitis disproportionately affects young children. We aimed to characterise treatment outcomes for this deadliest and most debilitating form of tuberculosis. METHODS We did a systematic review and meta-analysis of childhood tuberculous meningitis studies published up to Oct 12, 2012. We included study reports that applied predefined diagnostic criteria and described treatment regimens and outcomes. We pooled risks of death during treatment and neurological sequelae among survivors. As secondary objectives, we assessed study-level characteristics as sources of heterogeneity, and we pooled frequencies of presenting symptoms and diagnostic findings. For all meta-analyses we used random-effects models with the exact binomial likelihood method. FINDINGS 19 studies met our inclusion criteria, with reported treatment outcomes for 1636 children. Risk of death was 19·3% (95% CI 14·0-26·1) and probability of survival without neurological sequelae was 36·7% (27·9-46·4). Among survivors, risk of neurological sequelae was 53·9% (95% CI 42·6-64·9). Diagnosis in the most advanced disease stage (3) occurred in 307 (47%) of 657 patients and was associated with worse outcomes than was earlier diagnosis. The most common findings at presentation were cerebrospinal fluid (CSF) leucocytosis (frequency 99·9%, 95% CI 68·5-100·0), CSF lymphocytosis (97·9%, 51·9-100·0), fever (89·8%, 79·8-95·2), and hydrocephalus (86·1%, 68·6-94·6). Frequency of CSF acid-fast-bacilli smear positivity was 8·9% (95% CI 5·0-15·4), and frequency of CSF culture positivity for Mycobacterium tuberculosis was 35·1% (16·8-59·2). INTERPRETATION Despite treatment, childhood tuberculous meningitis has very poor outcomes. Poor prognosis and difficult early diagnosis emphasise the importance of preventive therapy for child contacts of patients with tuberculosis and low threshold for empirical treatment of tuberculous meningitis suspects. Implementation of consensus definitions, standardised reporting of data, and high-quality clinical trials are needed to clarify optimum therapy. FUNDING None.

Performance of symptom-based tuberculosis screening among people living with HIV: not as great as hoped.

Objective:The objective of the present study was to determine the diagnostic performance of the symptom-based tuberculosis (TB) screening questionnaire recommended by WHO for people living with HIV (PLWH) in resource-limited settings, among adults off and on antiretroviral therapy (ART). Design:Cross-sectional study at two HIV clinics in South Africa. Methods:A total of 825 PLWH completed the screening questionnaire and underwent investigations [chest radiography (CXR) and microbiologic testing of sputa]. A positive screen was defined as presence of cough, fever, night sweats, or weight loss. Pulmonary tuberculosis (PTB) was defined as sputum smear positive for acid-fast bacilli or growth of Mycobacterium tuberculosis. Results:Of 737 participants with at least one diagnostic sputum specimen, PTB was diagnosed in 31 of 522 (5.9%) on ART, and 34 of 215 (15.8%) not on ART. The questionnaire missed 15 of 31 (48.4%) PTB cases on ART, and three of 34 (8.8%) not on ART. Among participants on ART, post-test probability of PTB diagnosis (95% confidence interval) was 6.8% (4.0–10.9%) if screening positive, and 5.2% (2.9–8.4%) if screening negative, whereas among participants not on ART, post-test probabilities were 20.3% (14.2–27.5%) and 4.8% (1.0–13.5%), respectively. Among participants diagnosed with PTB, those on ART were significantly less likely to screen positive (adjusted odds ratio 0.04, 95% confidence interval: 0.01–0.39). In both groups (ART and no ART), screening was more sensitive when CXR was incorporated. Conclusion:For case detection and exclusion of PTB, the WHO-recommended questionnaire performed adequately among PLWH not on ART, and poorly among those on ART. Further research is needed to identify feasible and effective TB screening strategies for PLWH in resource-limited settings.

Using JavaScript and WebCL for numerical computations: a comparative study of native and web technologies

From its modest beginnings as a tool to validate forms, JavaScript is now an industrial-strength language used to power online applications such as spreadsheets, IDEs, image editors and even 3D games. Since all modern web browsers support JavaScript, it provides a medium that is both easy to distribute for developers and easy to access for users. This paper provides empirical data to answer the question: Is JavaScript fast enough for numerical computations? By measuring and comparing the runtime performance of benchmarks representative of a wide variety of scientific applications, we show that sequential JavaScript is within a factor of 2 of native code. Parallel code using WebCL shows speed improvements of up to 2.28 over JavaScript for the majority of the benchmarks.

Effectiveness and Safety of Standardised Shorter Regimens for Multidrug-Resistant Tuberculosis: Individual Patient Data and Aggregate Data Meta-Analyses

We assessed the effectiveness and safety of standardised, shorter multidrug-resistant tuberculosis (MDR-TB) regimens by pooling data from observational studies. Published studies were identified from medical databases; unpublished studies were identified from expert consultation. We conducted aggregate data meta-analyses to estimate pooled proportions of treatment outcomes and individual patient data (IPD) meta-regression to identify risk factors for unsuccessful treatment in patients treated with 9- to 12-month MDR-TB regimens composed of a second-line injectable, gatifloxacin/moxifloxacin, prothionamide, clofazimine, isoniazid, pyrazinamide and ethambutol. We included five studies in which 796 out of 1279 (62.2%) individuals with confirmed MDR-TB (98.4%) or rifampin-resistant TB (1.6%), and not previously exposed to second-line drugs, were eligible for shorter regimens. 669 out of 796 participants were successfully treated (83.0%, 95% CI 71.9–90.3%). In IPD meta-regression (three studies, n=497), failure/relapse was associated with fluoroquinolone resistance (crude OR 46, 95% CI 8–273), pyrazinamide resistance (OR 8, 95% CI 2–38) and no culture conversion by month 2 of treatment (OR 7, 95% CI 3–202). Two participants acquired extensive drug resistance. Four studies reported grade 3 or 4 adverse events in 55 out of 304 (18.1%) participants. Shorter regimens were effective in treating MDR-TB; however, there is uncertainty surrounding the generalisability of the high rate of treatment success to less selected populations, to programmatic settings and in the absence of drug susceptibility tests to key component drugs. Shorter TB regimens were effective, but generalisability of success rates to less selected populations is uncertain http://ow.ly/ptI630b3xxT

Use of chest radiography in the 22 highest tuberculosis burden countries

An estimated 9 million new tuberculosis (TB) cases and 1.5 million deaths were caused by Mycobacterium tuberculosis in 2013 [1], more than 80% of which occurred in the 22 highest TB burden countries (HBCs). Among the confirmed incident cases, 4.9 million were pulmonary TB (PTB), of which 58% were bacteriologically confirmed. For many of these cases, chest radiography (CXR) was used as an important tool for triaging, particularly in smear-negative patients, to select patients for further microbiological workup with culture or Xpert MTB/RIF (Cepheid, Sunnyvale, CA, USA) [2, 3]. For the diagnosis of 42% of PTB cases who were microbiologically negative, CXR was often used to support the clinical decision, particularly in children [1, 4]. CXR is used widely in the 22 highest TB burden countries but we need strategies for cost and human resources http://ow.ly/RT7fq

Reducing relapse in tuberculosis treatment: is it time to reassess WHO treatment guidelines?

LIKE MANY in the tuberculosis (TB) community, we were disappointed by the results of recent clinical trials showing 4-month first-line regimens for TB to be inferior to the 6-month standard of care.1–3 On examination of the control arms of these trials, however, we were reminded of the high relapse rates associated with indiscriminate use of a regimen that has become the global standard for every single adult with drug-susceptible pulmonary TB. All three trials reported results from control arms using the standard 6-month regimen of isoniazid, rifampin, pyrazinamide, and ethambutol. Risk of relapse was 2.8% in REMoxTB and 3.2% in RIFAQUIN, with an 18-month follow-up in each study. OFLOTUB reported a recurrence risk of 7.1% over a 24-month follow-up. Unfortunately, such high rates are not unusual: a 2009 systematic review by Menzies et al. reported relapse in 3.8% of TB patients after treatment with a 6-month rifampin-containing regimen, compared with 1% relapse with 78 month regimens.4 Current World Health Organization (WHO) TB treatment guidelines recommend this same regimen for all adult patients with new or drug-susceptible pulmonary TB,5 meaning that we as a TB control community are accepting a 4% probability of recurrent disease in ideal conditions. In the real world, this proportion is undoubtedly higher. Proponents of the 6-month standard regimen note that extending therapy is challenging in high-burden settings, and that identification of high-risk populations is often imprecise.5 On the other hand, we know that patients with cavitary disease or smear positivity at 2 months are at high risk of relapse;4,5 indeed it is common practice in many high-income regions to extend therapy in high-risk patients (e.g., culture positive at 2 months). Our community has committed to a post-2015 TB elimination plan that prioritizes prevention. Considering the significant effort required to engage, screen and treat high-risk groups of people without known TB, we feel that appropriately treating people with TB who are at high risk of relapse represents a tremendous missed opportunity for TB prevention. Assuming a 4% probability of relapse over 2 years, patients being treated today have an expected TB incidence of 2000 per 100 000 person-years—and these people are already engaged in TB care. This is not to mention the toll relapse takes on individual patients, including transmission to their families and a ‘retreatment’ regimen that often includes toxic injectable second-line medications. If we in the TB community are serious in our commitment to eliminate TB, we must move beyond a ‘one-size-fits-all’ approach to TB treatment. We cannot consider as ‘cured’ a population that has an expected TB incidence 20 000 times higher than the elimination target of 1 per million per year. The WHO and the international TB community should urgently consider a more nuanced guideline that includes treatment monitoring and extended therapy in well-defined high-risk groups. Such guidelines would certainly place further demands on cashstrapped TB programs, but we believe that patients with drug-susceptible pulmonary TB deserve to be cured, with a ,1% chance of relapse, regardless of where they live.

Inadequate Diet Is Associated with Acquiring Mycobacterium tuberculosis Infection in an Inuit Community. A Case-Control Study.

BACKGROUND Tuberculosis predominantly affects socioeconomically disadvantaged communities. The extent to which specific dietary and lifestyle factors contribute to tuberculosis susceptibility has not been established. METHODS A total of 200 residents of a village in Northern Quebec were investigated during a tuberculosis outbreak and identified to have active tuberculosis, latent tuberculosis infection, or neither. Participants completed questionnaires about their intake of food from traditional and commercial sources, and provided blood samples. Adults were asked about recent smoking and drug and alcohol intake. Nutritional adequacy was evaluated with reference to North American standards. Multiple dietary, lifestyle, and housing factors were combined in a logistic regression model evaluating the contributions of each to disease and infection. FINDINGS After adjusting for potential confounding, new infection was associated with inadequate intake of fruit and vegetables (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.03-4.3), carbohydrates (OR, 4.4; 95% CI, 1.2-16.3), and certain vitamins and minerals. A multivariable model, combining nutrition, housing, and lifestyle factors, found associations between new infection and inadequate fruit and vegetable intake (OR, 2.3; 95% CI, 1.0-5.1), living in the same house as a person with smear-positive tuberculosis (OR, 14.7; 95% CI, 1.6-137.3), and visiting a community gathering house (OR, 3.7; 95% CI, 1.7-8.3). Current smoking was associated with new infection (OR, 9.4; 95% CI, 1.2-72) among adults completing a detailed lifestyle survey. INTERPRETATION Inadequate nutrition was associated with increased susceptibility to infection, but not active tuberculosis. Interventions addressed at improving nutrition may reduce susceptibility to infection in settings where access to healthy foods is limited.

Comorbidities and treatment outcomes in multidrug resistant tuberculosis: a systematic review and meta-analysis

Little is known about the impact of comorbidities on multidrug resistant (MDR) and extensively drug resistant (XDR) tuberculosis (TB) treatment outcomes. We aimed to examine the effect of human immunodeficiency virus (HIV), diabetes, chronic kidney disease (CKD), alcohol misuse, and smoking on MDR/XDRTB treatment outcomes. We searched MEDLINE, EMBASE, Cochrane Central Registrar and Cochrane Database of Systematic Reviews as per PRISMA guidelines. Eligible studies were identified and treatment outcome data were extracted. We performed a meta-analysis to generate a pooled relative risk (RR) for unsuccessful outcome in MDR/XDRTB treatment by co-morbidity. From 2457 studies identified, 48 reported on 18,257 participants, which were included in the final analysis. Median study population was 235 (range 60–1768). Pooled RR of unsuccessful outcome was higher in people living with HIV (RR = 1.41 [95%CI: 1.15–1.73]) and in people with alcohol misuse (RR = 1.45 [95%CI: 1.21–1.74]). Outcomes were similar in people with diabetes or in people that smoked. Data was insufficient to examine outcomes in exclusive XDRTB or CKD cohorts. In this systematic review and meta-analysis, alcohol misuse and HIV were associated with higher pooled OR of an unsuccessful outcome in MDR/XDRTB treatment. Further research is required to understand the role of comorbidities in driving unsuccessful treatment outcomes.

Screening for tuberculosis in migrants and visitors from high-incidence settings: Present and future perspectives

In most settings with a low incidence of tuberculosis (TB), foreign-born people make up the majority of TB cases, but the distribution of the TB risk among different migrant populations is often poorly quantified. In addition, screening practices for TB disease and latent TB infection (LTBI) vary widely. Addressing the risk of TB in international migrants is an essential component of TB prevention and care efforts in low-incidence countries, and strategies to systematically screen for, diagnose, treat and prevent TB among this group contribute to national and global TB elimination goals. This review provides an overview and critical assessment of TB screening practices that are focused on migrants and visitors from high to low TB incidence countries, including pre-migration screening and post-migration follow-up of those deemed to be at an increased risk of developing TB. We focus mainly on migrants who enter the destination country via application for a long-stay visa, as well as asylum seekers and refugees, but briefly consider issues related to short-term visitors and those with long-duration multiple-entry visas. Issues related to the screening of children and screening for LTBI are also explored. TB screening of migrants from high to low TB incidence settings contributes to national and global TB elimination http://ow.ly/ZuRi30kb4bs

Computer-aided reading of tuberculosis chest radiography: moving the research agenda forward to inform policy

Key gaps limit the evidence base for computer-aided reading of TB on CXR. We describe a research agenda to fill them http://ow.ly/JkmQ30cynWR