Two Clinical Prediction Tools to Inform Rapid Tuberculosis Treatment Decision-making in Children.

Background: In the absence of bacteriologic confirmation to diagnose tuberculosis (TB) in children, it is suggested that treatment should be initiated when sufficient clinical evidence of disease is available. However, it is unclear what clinical evidence is sufficient to make this decision. To identify children who would benefit from rapid initiation of TB treatment, we developed 2 clinical prediction tools. Methods: We conducted a secondary analysis of a prospective intensified TB patient-finding intervention conducted in Pakistan in 2014-2016. TB disease was determined through either bacteriologic confirmation or a clinical diagnosis. We derived 2 tools: 1 uses classification and regression tree (CART) analysis to develop decision trees, while the second uses multivariable logistic regression to calculate a risk score. Results: Of the 5162 and 5074 children included in the CART and prediction score, respectively, 1417 (27.5%) and 1365 (26.9%) were eligible for TB treatment. CART identified abnormal chest radiographs and family history of TB as the most important predictors (area under the receiver operating characteristic curve [AUC], 0.949). The final prediction score model included age group (0-4, 5-9, 10-14), weight <5th percentile, cough, fever, weight loss, chest radiograph suggestive of TB disease, and family history of TB; the identified best cutoff score was 9 (AUC, 0.985%). Conclusions: Use of clinical evidence was sufficient to accurately identify children who would benefit from treatment initiation. Our tools performed well compared with existing algorithms, though these results need to be externally validated before operationalization.

Age-specific Clinical Presentation and Risk Factors for Extrapulmonary Tuberculosis Disease in Children.

BACKGROUND: Clinical presentation for extrapulmonary tuberculosis (EPTB) in children can be variable and nonspecific, leading to delayed diagnosis, disease and death. We describe the age-specific clinical presentation and identify risk factors for EPTB among children in Pakistan. METHODS: In 2015-2016 in 4 facilities in Sindh, Pakistan, children were diagnosed with TB either through bacteriologic confirmation or clinical-radiologic criteria. EPTB comprised any form of TB disease that did not involve the lungs. Among children with TB disease, we report demographics, clinical characteristics and symptoms, family medical history and diagnostic test results for children with and without EPTB. We conduct age-specific regression analyses to identify factors associated with an EPTB diagnosis among children age 0-4, 5-9 and 10-14 years. RESULTS: A total of 1163 children were diagnosed with TB disease, of which 157 (13.5%) had EPTB. Of those, 46 (29.3%) were 0-4, 53 (33.8%) were 5-9 and 58 (36.9%) were 10-14 years old. Of children with EPTB, the most frequently reported sites were lymph node (113, 72.4%) and abdominal (31, 19.9%). Weight loss was associated with an increased risk of EPTB in the 0-4-year-old (adjusted odds ratio: 2.80, 95% confidence interval: 1.05-7.47) and 10-14-year-old (adjusted odds ratio: 2.79, 95% confidence interval: 1.28-6.07) groups, and the presence of cough was associated with a decreased risk of EPTB. CONCLUSIONS: This study provides new knowledge about age-specific clinical presentation and risk factors of EPTB in children in Pakistan. Our results can help to optimize clinical algorithms designed to achieve a timely diagnosis in children with EPTB along with improved treatment outcomes.

Age-specific effectiveness of a tuberculosis screening intervention in children.

OBJECTIVE: To apply a cascade-of-care framework to evaluate the effectiveness-by age of the child-of an intensified tuberculosis patient-finding intervention. DESIGN: From a prospective screening program at four hospitals in Pakistan (2014-2016) we constructed a care cascade comprising six steps: screened, positive screen, evaluated, diagnosed, started treatment, and successful outcome. We evaluated the cascade by each year of age from 0 to 14 and report the age-specific mean proportion and standard deviation. RESULTS: On average across all ages, only 12.5% (standard deviation: 2.0%) of children with a positive screen were not evaluated. Among children who had a complete evaluation, the highest percentages of children diagnosed with tuberculosis were observed in children 0-4 (mean: 31.9%; standard deviation: 4.8%), followed by lower percentages in children 5-9 (mean: 22.4%; standard deviation: 2.2%), and 10-14 (mean: 26.0%; standard deviation:5.4%). Nearly all children diagnosed with tuberculosis initiated treatment, and an average of 93.3% (standard deviation: 3.3%) across all ages had successful treatment outcomes. CONCLUSIONS: This intervention was highly effective across ages 0-14 years. Our study illustrates the utility of applying operational analyses of age-stratified cascades to identify age-specific gaps in pediatric tuberculosis care that can guide future, novel interventions to close these gaps.

Cost-effectiveness of household contact investigation for detection of tuberculosis in Pakistan.

OBJECTIVES: Despite WHO guidelines recommending household contact investigation, and studies showing the impact of active screening, most tuberculosis (TB) programmes in resource-limited settings only carry out passive contact investigation. The cost of such strategies is often cited as barriers to their implementation. However, little data are available for the additional costs required to implement this strategy. We aimed to estimate the cost and cost-effectiveness of active contact investigation as compared with passive contact investigation in urban Pakistan. METHODS: We estimated the cost-effectiveness of 'enhanced' (passive with follow-up) and 'active' (household visit) contact investigations compared with standard 'passive' contact investigation from providers and the programme's perspective using a simple decision tree. Costs were collected in Pakistan from a TB clinic performing passive contact investigation and from studies of active contact tracing interventions conducted. The effectiveness was based on the number of patients with TB identified among household contacts screened. RESULTS: The addition of enhanced contact investigation to the existing passive mode detected 3.8 times more cases of TB per index patient compared with passive contact investigation alone. The incremental cost was US$30 per index patient, which yielded an incremental cost of US$120 per incremental patient identified with TB. The active contact investigation was 1.5 times more effective than enhanced contact investigation with an incremental cost of US$238 per incremental patient with TB identified. CONCLUSION: Our results show that enhanced and active approaches to contact investigation effectively identify additional patients with TB among household contacts at a relatively modest cost. These strategies can be added to the passive contact investigation in a high burden setting to find the people with TB who are missed and meet the End TB strategy goals.

Predictors of unsuccessful tuberculosis treatment outcomes in children from a prospective cohort study in Pakistan.

BACKGROUND: Every year, about 239 000 children die from tuberculosis (TB), despite availability of highly effective regimens. Few studies have evaluated predictors for poor treatment outcomes in children treated for TB. METHODS: We assessed predictors of unsuccessful TB treatment outcomes in a prospective cohort of children diagnosed by an intensified TB patient-finding intervention at four facilities in Pakistan between 2014 and 2016. A case of TB disease was determined through either bacteriologic confirmation of disease or a clinical diagnosis. To estimate characteristics predictive of experiencing an unsuccessful treatment outcome, we used a multi-level model with a modified Poisson approach, accounting for clustering at the facility level. We report estimated relative risks (RR) and 95% confidence intervals (CI). RESULTS: During the study period, 1404 children less than 15 years old were initiated on treatment for drug-susceptible TB. In total, 709 (50.5%) were 0-4, 406 (28.9%) were 5-9 years, and 289 (20.6%) were 10-14 years old; 614 (43.7%) were female; and of the 1377 children assessed for malnourishment, 1161 (84.3%) were malnourished. A total of 1322 (94.2%) children experienced a successful treatment outcome, 14 (1.0%) children transferred out to a different facility, and 68 (4.8%) children experienced an unsuccessful treatment outcome: 14 (1.0%) died, 20 (1.4%) failed treatment, and 34 (2.4%) were lost to follow-up. After adjustment for age group, sex, and malnutrition status, we identified increased risk of unsuccessful treatment outcome in children presenting with fever (RR = 2.56, 95% CI = 1.02-6.44; P = 0.05) or an abdominal examination suggestive of TB disease (RR = 2.34, 95% CI = 1.20-4.58; P = 0.01), and a decreased risk in children who initiated treatment at a rural facility (RR = 0.05, 95% CI = 0.00-0.74; P = 0.03). CONCLUSIONS: More than 94% of children experienced successful treatment outcomes. We identified individual-, facility-, and clinical-factors predictive of experiencing unsuccessful treatment outcomes. Children with fevers and abdominal findings suggestive of TB disease should be tested for TB and followed closely throughout treatment to ensure necessary support for successful completion of treatment.