James A. Seddon

Burden of childhood tuberculosis in 22 high-burden countries: a mathematical modelling study

BACKGROUND Confirmation of a diagnosis of tuberculosis in children (aged <15 years) is challenging; under-reporting can result even when children do present to health services. Direct incidence estimates are unavailable, and WHO estimates build on paediatric notifications, with adjustment for incomplete surveillance by the same factor as adult notifications. We aimed to estimate the incidence of infection and disease in children, the prevalence of infection, and household exposure in the 22 countries with a high burden of the disease. METHODS Within a mechanistic mathematical model, we combined estimates of adult tuberculosis prevalence in 2010, with aspects of the natural history of paediatric tuberculosis. In a household model, we estimated household exposure and infection. We accounted for the effects of age, BCG vaccination, and HIV infection. Additionally, we tested sensitivity to key structural assumptions by repeating all analyses without variation in BCG efficacy by latitude. FINDINGS The median number of children estimated to be sharing a household with an individual with infectious tuberculosis in 2010 was 15,319,701 (IQR 13,766,297-17,061,821). In 2010, the median number of Mycobacterium tuberculosis infections in children was 7,591,759 (5,800,053-9,969,780), and 650,977 children (424,871-983,118) developed disease. Cumulative exposure meant that the median number of children with latent infection in 2010 was 53,234,854 (41,111,669-68,959,804). The model suggests that 35% (23-54) of paediatric cases of tuberculosis in the 15 countries reporting notifications by age in 2010 were detected. India is predicted to account for 27% (22-33) of the total burden of paediatric tuberculosis in the 22 countries. The predicted proportion of tuberculosis burden in children for each country correlated with incidence, varying between 4% and 21%. INTERPRETATION Our model has shown that the incidence of paediatric tuberculosis is higher than the number of notifications, particularly in young children. Estimates of current household exposure and cumulative infection suggest an enormous opportunity for preventive treatment. FUNDING UNITAID and the US Agency for International Development.

Treatment outcomes for children with multidrug-resistant tuberculosis: a systematic review and meta-analysis.

BACKGROUND Paediatric multidrug-resistant (MDR) tuberculosis is a public health challenge of growing concern, accounting for an estimated 15% of all global cases of MDR tuberculosis. Clinical management is especially challenging, and recommendations are based on restricted evidence. We aimed to assess existing evidence for the treatment of MDR tuberculosis in children. METHODS We did a systematic review and meta-analysis of published and unpublished studies reporting treatment outcomes for children with MDR tuberculosis. We searched PubMed, Ovid, Embase, Cochrane Library, PsychINFO, and BioMedCentral databases up to Oct 31, 2011. Eligible studies included five or more children (aged ≤16 years) with MDR tuberculosis within a defined treatment cohort. The primary outcome was treatment success, defined as a composite of cure and treatment completion. RESULTS We identified eight studies, which reported treatment outcomes for a total of 315 patients. We recorded much variation in the characteristics of patients and programmes. Time to appropriate treatment varied from 2 days to 46 months. Average duration of treatment ranged from 6 months to 34 months, and duration of follow-up ranged from 12 months to 37 months. The pooled estimate for treatment success was 81·67% (95% CI 72·54-90·80). Across all studies, 5·9% (95% CI 1·3-10·5) died, 6·2% (2·3-10·2) defaulted, and 39·1% (28·7-49·4) had an adverse event. The most common drug-related adverse events were nausea and vomiting. Other serious adverse events were hearing loss, psychiatric effects, and hypothyroidism. INTERPRETATION The treatment of paediatric MDR tuberculosis has been neglected, but when children are treated outcomes can be achieved that are at least as good as those reported for adults. Programmes should be encouraged to report outcomes in children to improve the knowledge base for care, especially as new drugs become available. FUNDING None.

Pharmacokinetics of Isoniazid, Rifampin, and Pyrazinamide in Children Younger than Two Years of Age with Tuberculosis: Evidence for Implementation of Revised World Health Organization Recommendations

ABSTRACT The World Health Organization (WHO) recently issued revised first-line antituberculosis (anti-TB) drug dosage recommendations for children. No pharmacokinetic studies for these revised dosages are available for children <2 years. The aim of the study was to document the pharmacokinetics of the first-line anti-TB agents in children <2 years of age comparing previous and revised WHO dosages of isoniazid (INH; 5 versus 10 mg/kg/day), rifampin (RMP; 10 versus 15 mg/kg/day), and pyrazinamide (PZA; 25 versus 35 mg/kg/day) and to investigate the effects of clinical covariates, including HIV coinfection, nutritional status, age, gender, and type of tuberculosis (TB), and the effect of NAT2 acetylator status. Serum INH, PZA, and RMP levels were prospectively assessed in 20 children <2 years of age treated for TB following the previous and the revised WHO dosage recommendations. Samples were taken prior to dosing and at 0.5, 1.5, 3, and 5 h following dosing. The maximum drug concentration in serum (Cmax), the time to Cmax (tmax), and the area under the concentration-time curve (AUC) were calculated. Eleven children had pulmonary and 9 had extrapulmonary TB. Five were HIV infected. The mean Cmax (μg/ml) following the administration of previous/revised dosages were as follows: INH, 3.19/8.11; RMP, 6.36/11.69; PZA, 29.94/47.11. The mean AUC (μg·h/ml) were as follows: INH, 8.09/20.36; RMP, 17.78/36.95; PZA, 118.0/175.2. The mean Cmax and AUC differed significantly between doses. There was no difference in the tmax values achieved. Children less than 2 years of age achieve target concentrations of first-line anti-TB agents using revised WHO dosage recommendations. Our data provided supportive evidence for the implementation of the revised WHO guidelines for first-line anti-TB therapy in young children.

Preventive Therapy for Child Contacts of Multidrug-Resistant Tuberculosis: A Prospective Cohort Study

BACKGROUND Evidence is limited to guide the management of children exposed to multidrug-resistant (MDR) tuberculosis. We aimed to study the tolerability and toxicity of a standard preventive therapy regimen given to children exposed to infectious MDR tuberculosis, and explore risk factors for poor outcome. METHODS In this prospective cohort study in the Western Cape, South Africa, children <5 years of age, or human immunodeficiency virus (HIV)-positive children aged <15 years, were recruited from May 2010 through April 2011 if exposed to an ofloxacin-susceptible, MDR tuberculosis source case. Children were started on preventive therapy as per local guidance: ofloxacin, ethambutol, and high-dose isoniazid for 6 months. Standardized measures of adherence and adverse events were recorded; poor outcome was defined as incident tuberculosis or death from any cause. RESULTS One hundred eighty-six children were included, with a median age of 34 months (interquartile range, 14-47 months). Of 179 children tested for HIV, 9 (5.0%) were positive. Adherence was good in 141 (75.8%) children. Only 7 (3.7%) children developed grade 3 adverse events. One child (0.5%) died and 6 (3.2%) developed incident tuberculosis during 219 patient-years of observation time. Factors associated with poor outcome were age <1 year (rate ratio [RR], 10.1; 95% confidence interval [CI], 1.65-105.8; P = .009), HIV-positive status (RR, 10.6; 95% CI, 1.01-64.9; P = .049), exposure to multiple source cases (RR, 6.75; 95% CI, 1.11-70.9; P = .036) and poor adherence (RR, 7.50; 95% CI, 1.23-78.7; P = .026). CONCLUSIONS This 3-drug preventive therapy regimen was well tolerated and few children developed tuberculosis or died if adherent to therapy. The provision of preventive therapy to vulnerable children following exposure to MDR tuberculosis should be considered.

Culture-Confirmed Multidrug-Resistant Tuberculosis in Children: Clinical Features, Treatment, and Outcome

BACKGROUND Multidrug-resistant (MDR) tuberculosis in children is frequently associated with delayed diagnosis and treatment. There is limited evidence regarding the management and outcome of children with MDR-tuberculosis. METHODS All children <15 years of age with a diagnosis of culture-confirmed MDR-tuberculosis were included in this retrospective cohort study from 1 January 2003 to 31 December 2008, with follow-up documented until 31 May 2011. We identified children from Brooklyn Hospital for Chest Diseases and Tygerberg Childrens Hospital, Western Cape Province, South Africa. Treatment outcomes were defined as 2-month sputum-culture conversion, treatment episode outcome, and survival. RESULTS A total of 111 children (median age, 50 months) were included. The diagnosis was delayed in children who had no identified MDR-tuberculosis index case (median delay, 123 vs 58 days; P < .001). Sixty-two percent of patients (53 of 85) were sputum-smear positive, and 43% of patients (43 of 100) were human immunodeficiency virus (HIV) infected. Overall, 82% had favorable treatment outcomes; total mortality was 12%. Malnutrition was associated with failure to culture-convert at 2 months (odds ratio [OR], 4.49 [95% confidence interval {CI}, 1.32-15.2]; P = .02) and death (OR, 15.0 [95% CI, 1.17-192.5]; P = .04) in multivariate analysis. HIV coinfection (OR, 24.7 [95% CI, 1.79-341.1]; P = .02) and the presence of extrapulmonary tuberculosis (OR, 37.8 [95% CI, 2.78-513.4]; P = .006) predicted death. CONCLUSIONS Despite advanced disease at presentation and a high prevalence of human immunodeficiency virus coinfection, children with MDR-tuberculosis can be treated successfully, using individualized treatment under routine conditions.

Global burden of drug-resistant tuberculosis in children: a mathematical modelling study

BACKGROUND After infection with Mycobacterium tuberculosis, children are at an increased risk of progression to tuberculosis disease; a condition that can be challenging to diagnose. New estimation approaches for children have highlighted the gap between incidence and notifications of M tuberculosis, and suggest there are more cases of isoniazid-resistant and multidrug-resistant (MDR) disease than are identified. No work has yet quantified the burden of drug-resistant infection, or accounted for other types of drug resistance or sampling uncertainty. METHODS We combined a mathematical model of tuberculosis in children with an analysis of drug-resistance patterns to produce country-level, regional, and global estimates of drug-resistant infection and disease. We determined drug resistance using data from the Global Project on Antituberculosis Drug Resistance Surveillance at WHO, from surveys and surveillance reported between 1988 and 2014. We combined 1000 sampled proportions for each country from a Bayesian approach with 10 000 sampled country estimates of tuberculosis disease incidence and M tuberculosis infection prevalence. We estimated the proportions of tuberculosis cases at a country level with isoniazid monoresistance, rifampicin monoresistance, multidrug resistance (MDR), fluoroquinolone-resistant multidrug resistance, second-line injectable-resistant multidrug resistance, and extensive multidrug resistance with resistance to both a fluoroquinolone and a second-line injectable (XDR). FINDINGS We estimated that 850 000 children developed tuberculosis in 2014; 58 000 with isoniazid-monoresistant tuberculosis, 25 000 with MDR tuberculosis, and 1200 with XDR tuberculosis. We estimate 67 million children are infected with M tuberculosis; 5 million with isoniazid monoresistance, 2 million with MDR, and 100 000 with XDR. Africa and southeast Asia have the highest numbers of children with tuberculosis, but the WHO Eastern Mediterranean region, European region, and Western Pacific region also contribute substantially to the burden of drug-resistant tuberculosis because of their much higher proportions of resistance. INTERPRETATION Far more drug-resistant tuberculosis occurs in children than is diagnosed, and there is a large pool of drug-resistant infection. This finding has implications for approaches to empirical treatment and preventive therapy in some regions of the world. FUNDING UNITAID.

High treatment success in children treated for multidrug-resistant tuberculosis: an observational cohort study

Background Few studies have described the management of multidrug-resistant (MDR) tuberculosis (TB) in children and evidence-based guidance on management is lacking. We describe the presentation, treatment and outcome in children treated for severe and non-severe MDR-TB in Cape Town, South Africa. Methods We conducted an observational cohort study of all children (<15 years) treated for MDR-TB if routinely initiated on treatment between January 2009 and December 2010. Treatment was based on local standard of care, based on international guidelines. Data were collected through family interviews and folder review. Standardised definitions were used for diagnosis, severity of disease, adverse events and outcome. Results Of 149 children started on MDR-TB treatment, the median age was 36 months (IQR 16–66), 32 (22%; of 146 tested) had HIV infection and 59 (40%) had a confirmed diagnosis. Ninety-four (66%) children were treated with an injectable drug and the median total duration of treatment was 13 months (IQR 11–18). Thirty-six (24%) children were cured, 101 (68%) probably cured, 1 (1%) was transferred out, 8 (5%) were lost to follow-up and 3 (2%) died. Children with severe disease were older (54 months (IQR 18–142) vs 31.5 months (IQR 17.5–53.5); p=0.012), more commonly had HIV infection (OR 6.25; 95% CI 2.50 to 15.6; p<0.001) and were more likely to die (p=0.008). Discussion A confirmed diagnosis of MDR-TB is not possible in all cases but this should not impede the treatment of MDR-TB in children. More than 90% of children with MDR-TB can be successfully treated. Non-severe disease could be successfully treated with reduced treatment duration.

Hearing loss in patients on treatment for drug-resistant tuberculosis.

The treatment of drug-resistant (DR)-tuberculosis (TB) necessitates the use of second-line injectable anti-TB drugs which are associated with hearing loss. Hearing loss affects communication and the development of language and social skills in children. This review describes the pathophysiology of hearing loss and the testing methodologies that can be employed. It is the first paper to systematically review the literature regarding hearing loss in those treated for DR-TB. In the studies identified, the methodology used to test for and to classify hearing loss is inconsistent and children and those with HIV are poorly represented. This review describes existing guidelines and suggests management strategies when hearing loss is found. It describes the challenges of testing hearing in the developing world contexts where the majority of patients with DR-TB are treated. Finally it makes the recommendation that a standardised testing methodology and classification system should be used.

Paediatric use of second-line anti-tuberculosis agents: A review.

Childhood multidrug-resistant tuberculosis (MDR-TB) is an emerging global epidemic. With the imminent roll-out of rapid molecular diagnostic tests, more children are likely to be identified and require treatment. As MDR-TB is resistant to the most effective first-line drugs, clinicians will have to rely on second-line medications which are less effective and often associated with more pronounced adverse effects than first-line therapy. Despite the fact that most of these agents were discovered many years ago, robust information is lacking regarding their pharmacokinetic and pharmacodynamic properties, adverse effects and drug interactions, especially in children. Children differ from adults in the way that drugs are administered, the manner in which they are metabolised and in the adverse effects experienced. The interaction of these drugs with human immunodeficiency virus infection and antiretroviral therapy is also poorly documented. This article reviews the available second-line drugs currently used in the treatment of MDR-TB in children and discusses medication properties and adverse effects while potential interactions with antiretroviral therapy are explored.

Turning off the tap: stopping tuberculosis transmission through active case-finding and prompt effective treatment

Summary To halt the global tuberculosis epidemic, transmission must be stopped to prevent new infections and new cases. Identification of individuals with tuberculosis and prompt initiation of effective treatment to rapidly render them non-infectious is crucial to this task. However, in settings of high tuberculosis burden, active case-finding is often not implemented, resulting in long delays in diagnosis and treatment. A range of strategies to find cases and ensure prompt and correct treatment have been shown to be effective in high tuberculosis-burden settings. The population-level effect of targeted active case-finding on reducing tuberculosis incidence has been shown by studies and projected by mathematical modelling. The inclusion of targeted active case-finding in a comprehensive epidemic-control strategy for tuberculosis should contribute substantially to a decrease in tuberculosis incidence.