Multidrug-resistant tuberculosis treatment failure detection depends on monitoring interval and microbiological method.

Debate persists about monitoring method (culture or smear) and interval (monthly or less frequently) during treatment for multidrug-resistant tuberculosis (MDR-TB). We analysed existing data and estimated the effect of monitoring strategies on timing of failure detection.We identified studies reporting microbiological response to MDR-TB treatment and solicited individual patient data from authors. Frailty survival models were used to estimate pooled relative risk of failure detection in the last 12 months of treatment; hazard of failure using monthly culture was the reference.Data were obtained for 5410 patients across 12 observational studies. During the last 12 months of treatment, failure detection occurred in a median of 3 months by monthly culture; failure detection was delayed by 2, 7, and 9 months relying on bimonthly culture, monthly smear and bimonthly smear, respectively. Risk (95% CI) of failure detection delay resulting from monthly smear relative to culture is 0.38 (0.34-0.42) for all patients and 0.33 (0.25-0.42) for HIV-co-infected patients.Failure detection is delayed by reducing the sensitivity and frequency of the monitoring method. Monthly monitoring of sputum cultures from patients receiving MDR-TB treatment is recommended. Expanded laboratory capacity is needed for high-quality culture, and for smear microscopy and rapid molecular tests.

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.

Incidence of multidrug-resistant tuberculosis disease in children: systematic review and global estimates.

BACKGROUND: Multidrug-resistant tuberculosis threatens to reverse recent reductions in global tuberculosis incidence. Although children younger than 15 years constitute more than 25% of the worldwide population, the global incidence of multidrug-resistant tuberculosis disease in children has never been quantified. We aimed to estimate the regional and global annual incidence of multidrug-resistant tuberculosis in children. METHODS: We developed two models: one to estimate the setting-specific risk of multidrug-resistant tuberculosis among child cases of tuberculosis, and a second to estimate the setting-specific incidence of tuberculosis disease in children. The model for risk of multidrug-resistant tuberculosis among children with tuberculosis needed a systematic literature review. We multiplied the setting-specific estimates of multidrug-resistant tuberculosis risk and tuberculosis incidence to estimate regional and global incidence of multidrug-resistant tuberculosis disease in children in 2010. FINDINGS: We identified 3403 papers, of which 97 studies met inclusion criteria for the systematic review of risk of multidrug-resistant tuberculosis. 31 studies reported the risk of multidrug-resistant tuberculosis in both children and treatment-naive adults with tuberculosis and were used for evaluation of the linear association between multidrug-resistant disease risk in these two patient groups. We identified that the setting-specific risk of multidrug-resistant tuberculosis was nearly identical in children and treatment-naive adults with tuberculosis, consistent with the assertion that multidrug-resistant disease in both groups reflects the local risk of transmitted multidrug-resistant tuberculosis. After application of these calculated risks, we estimated that around 999,792 (95% CI 937,877-1,055,414) children developed tuberculosis disease in 2010, of whom 31,948 (25,594-38,663) had multidrug-resistant disease. INTERPRETATION: Our estimates underscore that many cases of tuberculosis and multidrug-resistant tuberculosis disease are not being detected in children. Future estimates can be refined as more and better tuberculosis data and new diagnostic instruments become available. FUNDING: US National Institutes of Health, the Helmut Wolfgang Schumann Fellowship in Preventive Medicine at Harvard Medical School, the Norman E Zinberg Fellowship at Harvard Medical School, and the Doris and Howard Hiatt Residency in Global Health Equity and Internal Medicine at the Brigham and Women's Hospital.

Yield of contact investigations in households of patients with drug-resistant tuberculosis: systematic review and meta-analysis.

Contact investigations among individuals living with drug-susceptible tuberculosis patients (source cases) have shown a high yield of tuberculosis disease and latent tuberculosis, but the yield of such investigations in households of drug-resistant tuberculosis source cases is unknown. In this systematic review and meta-analysis, we found 25 studies that evaluated a median of 111 (interquartile range, 21-302) household contacts of drug-resistant tuberculosis source cases. The pooled yield was 7.8% (95% CI, 5.6%-10.0%) for active tuberculosis and 47.2% (95% CI, 30.0%-61.4%) for latent tuberculosis, although there was significant statistical heterogeneity (P < .0001). More than 50% of secondary cases with drug susceptibility test results were concordant with those of the source case. Among studies that followed household members, the majority of secondary cases were detected within 1 year of the source case's diagnosis. Household contact investigation around drug-resistant tuberculosis patients is a high-yield intervention for detection of drug-resistant tuberculosis and prevention of ongoing transmission.

Aggressive regimens for multidrug-resistant tuberculosis decrease all-cause mortality.

RATIONALE: A better understanding of the composition of optimal treatment regimens for multidrug-resistant tuberculosis (MDR-TB) is essential for expanding universal access to effective treatment and for developing new therapies for MDR-TB. Analysis of observational data may inform the definition of an optimized regimen. OBJECTIVES: This study assessed the impact of an aggressive regimen-one containing at least five likely effective drugs, including a fluoroquinolone and injectable-on treatment outcomes in a large MDR-TB patient cohort. METHODS: This was a retrospective cohort study of patients treated in a national outpatient program in Peru between 1999 and 2002. We examined the association between receiving an aggressive regimen and the rate of death. MEASUREMENTS AND MAIN RESULTS: In total, 669 patients were treated with individualized regimens for laboratory-confirmed MDR-TB. Isolates were resistant to a mean of 5.4 (SD 1.7) drugs. Cure or completion was achieved in 66.1% (442) of patients; death occurred in 20.8% (139). Patients who received an aggressive regimen were less likely to die (crude hazard ratio [HR]: 0.62; 95% CI: 0.44,0.89), compared to those who did not receive such a regimen. This association held in analyses adjusted for comorbidities and indicators of severity (adjusted HR: 0.63; 95% CI: 0.43,0.93). CONCLUSIONS: The aggressive regimen is a robust predictor of MDR-TB treatment outcome. TB policy makers and program directors should consider this standard as they design and implement regimens for patients with drug-resistant disease. Furthermore, the aggressive regimen should be considered the standard background regimen when designing randomized trials of treatment for drug-resistant TB.

Isoniazid-resistant tuberculosis in children: a systematic review.

BACKGROUND: Isoniazid resistance is an obstacle to the treatment of tuberculosis disease and latent tuberculosis infection in children. We aim to summarize the literature describing the risk of isoniazid-resistant tuberculosis among children with tuberculosis disease. METHODS: We did a systematic review of published reports of children with tuberculosis disease who had isolates tested for susceptibility to isoniazid. We searched PubMed, Embase and LILACS online databases up to January 12, 2012. RESULTS: Our search identified 3403 citations, of which 95 studies met inclusion criteria. These studies evaluated 8351 children with tuberculosis disease for resistance to isoniazid. The median proportion of children found to have isoniazid-resistant strains was 8%; the distribution was right-skewed (25th percentile: 0% and 75th percentile: 18%). CONCLUSIONS: High proportions of isoniazid resistance among pediatric tuberculosis patients have been reported in many settings suggesting that diagnostics detecting only rifampin resistance are insufficient to guide appropriate treatment in this population. Many children are likely receiving substandard tuberculosis treatment with empirical isoniazid-based regimens, and treating latent tuberculosis infection with isoniazid may not be effective in large numbers of children. Work is needed urgently to identify effective regimens for the treatment of children sick with or exposed to isoniazid-resistant tuberculosis and to better understand the scope of this problem.

Neurocognitive predictors of objective and subjective quality of life in individuals with schizophrenia: a meta-analytic investigation.

Quality of life (QOL) has been recognized as a crucial domain of outcome in schizophrenia treatment, and yet its determinants are not well understood. Recent meta-analyses suggest that symptoms have only a modest relationship to QOL (Eack SM, Newhill CE. Psychiatric symptoms and quality of life in schizophrenia: a meta-analysis. Schizophr Bull. 2007;33:1225-1237). Individuals with schizophrenia show 1-2 SD deficits on measures of elementary neurocognition, and links between these deficits and objective measures of community functioning (eg, employment and independent living) are well established. While objective measures of community functioning and measures of QOL would appear to be closely related, studies investigating the ability of neurocognitive variables to predict QOL in individuals with schizophrenia have yielded conflicting results. One potential explanation for opposing findings in the schizophrenia literature is the interchangeable use of objective and subjective indices of QOL. This study used quantitative methods of meta-analysis to clarify the relationship between neurocognitive determinants of objective QOL (ie, observable, clinician-rated) and subjective QOL (ie, patient satisfaction) separately in individuals with schizophrenia. A total of 20 studies (10 objective and 10 subjective) consisting of 1615 clients were aggregated from relevant databases. Weighted effect size analysis revealed that there were small-moderate relationships (d ≤ 0.55) between crystallized verbal ability, working memory verbal list learning, processing speed, and executive function and objective indices of QOL. In contrast, results revealed either nonsignificant or inverse relationships for the vast majority of neurocognitive measures and measures of subjective QOL. Moderating variables and implications for future research and treatment development are discussed.