Carly A. Rodriguez

Mortality in children diagnosed with tuberculosis: a systematic review and meta-analysis

BACKGROUND Case fatality ratios in children with tuberculosis are poorly understood-particularly those among children with HIV and children not receiving tuberculosis treatment. We did a systematic review of published work to identify studies of population-representative samples of paediatric (ie, <15 years) tuberculosis cases. METHODS We searched PubMed and Embase for reports published in English, French, Portuguese, or Spanish before Aug 12, 2016, that included terms related to tuberculosis, children, mortality, and population representativeness. We also reviewed our own files and reference lists of articles identified by this search. We screened titles and abstracts for inclusion, excluding studies in which outcomes were unknown for 10% or more of the children and publications detailing non-representative samples. We used random-effects meta-analysis to produce pooled estimates of case fatality ratios from the included studies, which we divided into three eras: the pre-treatment era (ie, studies before 1946), the middle era (1946-80), and the recent era (after 1980). We stratified our analyses by whether or not children received tuberculosis treatment, age (0-4 years, 5-14 years), and HIV status. FINDINGS We identified 31 papers comprising 35 datasets representing 82 436 children with tuberculosis disease, of whom 9274 died. Among children with tuberculosis included in studies in the pre-treatment era, the pooled case fatality ratio was 21·9% (95% CI 18·1-26·4) overall. The pooled case fatality ratio was significantly higher in children aged 0-4 years (43·6%, 95% CI 36·8-50·6) than in those aged 5-14 years (14·9%, 11·5-19·1). In studies in the recent era, when most children had tuberculosis treatment, the pooled case fatality ratio was 0·9% (95% CI 0·5-1·6). US surveillance data suggest that the case fatality ratio is substantially higher in children with HIV receiving treatment for tuberculosis (especially without antiretroviral therapy) than in those without HIV. INTERPRETATION Without adequate treatment, children with tuberculosis, especially those younger than 5 years, are at high risk of death. Children with HIV have an increased mortality risk, even when receiving tuberculosis treatment. FUNDING US National Institutes of Health, Janssen Global Public Health.

Global and Regional Burden of Isoniazid-Resistant Tuberculosis

BACKGROUND: Isoniazid has been the backbone of tuberculosis chemotherapy for 6 decades. Resistance to isoniazid threatens the efficacy of treatment of tuberculosis disease and infection. To inform policies around treatment of tuberculosis disease and infection in children, we sought to estimate both the proportion of child tuberculosis cases with isoniazid resistance and the number of incident isoniazid-resistant tuberculosis cases in children, by region. METHODS: We determined the relationship between rates of isoniazid resistance among child cases and among treatment-naive adult cases through a systematic literature review. We applied this relationship to regional isoniazid resistance estimates to estimate proportions of childhood tuberculosis cases with isoniazid resistance. We applied these proportions to childhood tuberculosis incidence estimates to estimate numbers of children with isoniazid-resistant tuberculosis. RESULTS: We estimated 12.1% (95% confidence interval [CI] 9.8% to 14.8%) of all children with tuberculosis had isoniazid-resistant disease, representing 120 872 (95% CI 96 628 to 149 059) incident cases of isoniazid-resistant tuberculosis in children in 2010. The majority of these occurred in the Western Pacific and Southeast Asia regions; the European region had the highest proportion of child tuberculosis cases with isoniazid resistance, 26.1% (95% CI: 20.0% to 33.6%). CONCLUSIONS: The burden of isoniazid-resistant tuberculosis in children is substantial, and risk varies considerably by setting. The large number of child cases signals extensive ongoing transmission from adults with isoniazid-resistant tuberculosis. The risk of isoniazid resistance must be considered when evaluating treatment options for children with disease or latent infection to avoid inadequate treatment and consequent poor outcomes.

Programmatic Management of Drug-Resistant Tuberculosis: An Updated Research Agenda.

Introduction There are numerous challenges in delivering appropriate treatment for multidrug-resistant tuberculosis (MDR-TB) and the evidence base to guide those practices remains limited. We present the third updated Research Agenda for the programmatic management of drug-resistant TB (PMDT), assembled through a literature review and survey. Methods Publications citing the 2008 research agenda and normative documents were reviewed for evidence gaps. Gaps were formulated into questions and grouped as in the 2008 research agenda: Laboratory Support, Treatment Strategy, Programmatically Relevant Research, Epidemiology, and Management of Contacts. A survey was distributed through snowball sampling to identify research priorities. Respondent priority rankings were scored and summarized by mean. Sensitivity analyses explored weighting and handling of missing rankings. Results Thirty normative documents and publications were reviewed for stated research needs; these were collapsed into 56 research questions across 5 categories. Of more than 500 survey recipients, 133 ranked priorities within at least one category. Priorities within categories included new diagnostics and their effect on improving treatment outcomes, improved diagnosis of paucibacillary and extra pulmonary TB, and development of shorter, effective regimens. Interruption of nosocomial transmission and treatment for latent TB infection in contacts of known MDR−TB patients were also top priorities in their respective categories. Results were internally consistent and robust. Discussion Priorities retained from the 2008 research agenda include shorter MDR-TB regimens and averting transmission. Limitations of recent advances were implied in the continued quest for: shorter regimens containing new drugs, rapid diagnostics that improve treatment outcomes, and improved methods of estimating burden without representative data. Conclusion There is continuity around the priorities for research in PMDT. Coordinated efforts to address questions regarding shorter treatment regimens, knowledge of disease burden without representative data, and treatment for LTBI in contacts of known DR-TB patients are essential to stem the epidemic of TB, including DR-TB.

Drug-Resistant Tuberculosis Clinical Trials: Proposed Core Research Definitions in Adults

Drug-resistant tuberculosis (DR-TB) is a growing public health problem, and for the first time in decades, new drugs for the treatment of this disease have been developed. These new drugs have prompted strengthened efforts in DR-TB clinical trials research, and there are now multiple ongoing and planned DR-TB clinical trials. To facilitate comparability and maximise policy impact, a common set of core research definitions is needed, and this paper presents a core set of efficacy and safety definitions as well as other important considerations in DR-TB clinical trials work. To elaborate these definitions, a search of clinical trials registries, published manuscripts and conference proceedings was undertaken to identify groups conducting trials of new regimens for the treatment of DR-TB. Individuals from these groups developed the core set of definitions presented here. Further work is needed to validate and assess the utility of these definitions but they represent an important first step to ensure there is comparability in clinical trials on multidrug-resistant TB.

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. Monthly culture monitoring is crucial to earlier detection of treatment failure in MDR-TB patients http://ow.ly/w2MI301mK8M

Map the gap: missing children with drug-resistant tuberculosis

BACKGROUND The lack of published information about children with multidrug-resistant tuberculosis (MDR-TB) is an obstacle to efforts to advocate for better diagnostics and treatment. OBJECTIVE To describe the lack of recognition in the published literature of MDR-TB and extensively drug-resistant TB (XDR-TB) in children. DESIGN We conducted a systematic search of the literature published in countries that reported any MDR- or XDR-TB case by 2012 to identify MDR- or XDR-TB cases in adults and in children. RESULTS Of 184 countries and territories that reported any case of MDR-TB during 2005-2012, we identified adult MDR-TB cases in the published literature in 143 (78%) countries and pediatric MDR-TB cases in 78 (42%) countries. Of the 92 countries that reported any case of XDR-TB, we identified adult XDR-TB cases in the published literature in 55 (60%) countries and pediatric XDR-TB cases for 9 (10%) countries. CONCLUSION The absence of publications documenting child MDR- and XDR-TB cases in settings where MDR- and XDR-TB in adults have been reported indicates both exclusion of childhood disease from the public discourse on drug-resistant TB and likely underdetection of sick children. Our results highlight a large-scale lack of awareness about children with MDR- and XDR-TB.

A systematic review of national policies for the management of persons exposed to tuberculosis

OBJECTIVE To describe mandates and policy gaps in tuberculosis (TB) contact investigation and management. DESIGN We conducted a systematic review of national TB policy documents obtained using a systematic internet search and by contacting national TB programs. We included policies published in English, Spanish, and French, and abstracted data using a standardized form. RESULTS We reviewed policy documents for 68 of 216 (31%) countries and territories. All countries recommended performing contact investigations, but 40% did not specify how contacts enter the health system for evaluation or who was responsible for this process. All countries recommended preventive therapy for contacts, but in 14 (21%) countries only young children were eligible. While four preventive therapy regimens exist, 48 (71%) countries recommended only isoniazid monotherapy. In addition, 28 (41%) countries lacked guidance on whether to give preventive therapy to contacts exposed to drug-resistant TB. Policies in 28 (41%) countries lacked recommendations for managing contacts with the human immunodeficiency virus (HIV) after new TB exposure. CONCLUSION Policies recommending contact investigation and preventive therapy for contacts are widespread, but policy gaps exist in the areas of ensuring accountability and the management of vulnerable populations such as people living with HIV and those exposed to drug-resistant TB.

Development and Validation of a Food Frequency Questionnaire to Estimate Intake among Children and Adolescents in Urban Peru

Tools to assess intake among children in Latin America are limited. We developed and assessed the reproducibility and validity of a semi-quantitative food frequency questionnaire (FFQ) administered to children, adolescents, and their caregivers in Lima, Peru. We conducted 24-h diet recalls (DRs) and focus groups to develop a locally-tailored FFQ prototype for children aged 0–14 years. To validate the FFQ, we administered two FFQs and three DRs to children and/or their caregivers (N = 120) over six months. We examined FFQ reproducibility by quartile agreement and Pearson correlation coefficients, and validity by quartile agreement and correlation with DRs. For reproducibility, quartile agreement ranged from 60–77% with correlations highest for vitamins A and C (0.31). Age-adjusted correlations for the mean DR and the second-administered FFQ were highest in the 0–7 age group, in which the majority of caregivers completed the FFQ on behalf of the child (total fat; 0.67) and in the 8–14 age group, in which both the child and caregiver completed the FFQ together (calcium, niacin; 0.54); correlations were <0.10 for most nutrients in the 8–14 age group in which the caregiver completed the FFQ on the child’s behalf. The FFQ was reproducible and the first developed and validated to assess various nutrients in children and adolescents in Peru.

Increasing isoniazid preventive therapy uptake in an HIV program in rural Papua New Guinea

Setting: Tuberculosis (TB) is the leading cause of death among people living with the human immunodeficiency virus (PLHIV) in Papua New Guinea. Despite a policy for isoniazid preventive therapy (IPT) among PLHIV, implementation has been slow. Objective: We prospectively evaluated a standardized guided screening process, including TB diagnostic support, to increase IPT initiation in adult PLHIV on antiretro-viral treatment. Design: The guided process included a paper-based IPT screening tool that prompted review of patient history and TB symptoms and sputum analysis by smear microscopy and Xpert® MTB/RIF. Chest X-ray was performed at the providers discretion. We quantified the yield of this guided process on IPT initiation and detection of TB and rifampicin resistance, and examined the contributions of each diagnostic modality. Results: Among 532 patients, TB was ruled out and IPT initiated in 450 (84%). TB was diagnosed and treatment was started in 82 (15%) patients. Xpert detected rifampicin resistance in one of 21 patients (5%, 95%CI 0.24-21.3) with a positive Xpert result. All TB cases were diagnosed by chest X-ray and/or Xpert. No cases were diagnosed by sputum smear alone. Conclusion: A standardized guided process, including TB diagnostic support, successfully enabled IPT initiation and identified a large burden of undetected TB.

Discordant Treatment Responses to Combination Antiretroviral Therapy in Rwanda: A Prospective Cohort Study

Introduction Some antiretroviral therapy naïve patients starting combination antiretroviral therapy (cART) experience a limited CD4 count rise despite virological suppression, or vice versa. We assessed the prevalence and determinants of discordant treatment responses in a Rwandan cohort. Methods A discordant immunological cART response was defined as an increase of <100 CD4 cells/mm3 at 12 months compared to baseline despite virological suppression (viral load [VL] <40 copies/mL). A discordant virological cART response was defined as detectable VL at 12 months with an increase in CD4 count ≥100 cells/mm3. The prevalence of, and independent predictors for these two types of discordant responses were analysed in two cohorts nested in a 12-month prospective study of cART-naïve HIV patients treated at nine rural health facilities in two regions in Rwanda. Results Among 382 patients with an undetectable VL at 12 months, 112 (29%) had a CD4 rise of <100 cells/mm3. Age ≥35 years and longer travel to the clinic were independent determinants of an immunological discordant response, but sex, baseline CD4 count, body mass index and WHO HIV clinical stage were not. Among 326 patients with a CD4 rise of ≥100 cells/mm3, 56 (17%) had a detectable viral load at 12 months. Male sex was associated with a virological discordant treatment response (P = 0.05), but age, baseline CD4 count, BMI, WHO HIV clinical stage, and travel time to the clinic were not. Conclusions Discordant treatment responses were common in cART-naïve HIV patients in Rwanda. Small CD4 increases could be misinterpreted as a (virological) treatment failure and lead to unnecessary treatment changes.