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.

To compare the diagnostic performance of the GenoType MRBDRplus assay with the gold standard phenotypic drug susceptibility testing in the detection of drug resistance among culture isolates obtained from patients in Karachi, Pakistan. Mycobacterium tuberculosis isolates were obtained from 96 consecutive tuberculosis patients found to have resistance to isoniazid from two health centers in Karachi (January-November 2017). Isolates were tested for drug resistance against rifampin and isoniazid using the MTBDRplus assay. Results were compared with conventional drug-susceptibility testing and the frequency of specific mutations were reported. The MTBDRplus assay had a sensitivity for rifampin resistance of 98.8% (95% CI: 93.4–100) and for isoniazid resistance of 90.6% (95% CI: 83.0–95.6). The MTBDRplus assay showed mutations in rpoB in 81 of the 96 (84.4%) isolates. Of the 87 isolates showing resistance to isoniazid via the MTBDRplus assay, 71 (74.0%) isolates had mutations in the katG gene only, 15 (15.6%) isolates had mutations in the inhA promoter region, and 1 (1.0%) showed mutations in both genes. The GenoType MTBDRplus assay in Pakistan can identify subgroups at high-risk of having isolates with mutations in the katG and/or inhA genes. Understanding the local burden of these mutations have implications for local diagnostic and treatment guidelines.

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.

Background: The diagnosis of tuberculosis (TB) in children and adolescents is often delayed. We conducted a study to understand the barriers and facilitators to the diagnosis of TB in children and adolescents in a not-for-profit private hospital in Karachi, Pakistan. Methods: We conducted a convergent mixed-methods study comprising quantitative surveys with caregivers of 100 TB patients < 18 years old and 40 semi-structured interviews with caregivers and healthcare providers. Results: Among TB patients whose caregivers were surveyed, 82% were adolescents 10–17 years old. Caregivers reported a median of 91 days (IQR 58–160) between symptom onset and treatment initiation. Time was divided relatively evenly between symptom onset and the first visit to a healthcare provider (median 73, IQR 42–130 days), and between this visit and TB diagnosis (median 65 days, IQR 30–114). While 69% of caregivers initially visited general physicians, many felt that these general physicians did not provide satisfactory healthcare. Caregivers mentioned financial constraints as a major barrier affecting all stages of the journey to diagnosis and treatment. Conclusions: Interventions that overcome financial barriers and strategies that enhance the capacity of private sector general physicians are necessary to reduce delays in TB diagnosis and treatment initiation for children and adolescents.