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.

Scale-Up of Rifapentine and Isoniazid for Tuberculosis Prevention Among Household Contacts in 2 Urban Centers: An Effectiveness Assessment.

BACKGROUND: Scaling up a shorter preventive regimen such as weekly isoniazid and rifapentine (3HP) for 3 months is a priority for tuberculosis (TB) preventive treatment (TPT). However, there are limited data on 3HP acceptability and completion from high-burden-TB countries. METHODS: We scaled up 3HP from 2018 to 2021 in 2 cities in Pakistan. Eligible participants were household contacts of persons diagnosed with TB disease. Participants were prescribed 3HP after ruling out TB disease. Treatment was self-administered. We analyzed the proportion who completed 3HP. RESULTS: In Karachi, we verbally screened 22 054 household contacts of all ages. Of these, 83% were clinically evaluated and 3% were diagnosed with TB. Of household contacts without TB disease, 59% initiated the 3HP regimen, of which 69% completed treatment. In Peshawar, we verbally screened 6389 household contacts of all ages. We evaluated 95% of household contacts, of whom 2% were diagnosed with TB disease. Among those without TB disease, 65% initiated 3HP, of which 93% completed. Factors associated with higher 3HP completion included residence in Peshawar (risk ratio [RR], 1.35 [95% confidence interval {CI}: 1.32-1.37]), index patient being a male (RR, 1.03 [95% CI: 1.01-1.05]), and index patient with extrapulmonary TB compared to bacteriologically positive pulmonary TB (RR, 1.10 [95% CI: 1.06-1.14]). The age of the index patient was inversely associated with completion. CONCLUSIONS: We observed a high level of acceptance and completion of 3HP in programs implemented in 2 cities in Pakistan, with differences observed across the cities. These findings suggest that 3HP can be effectively scaled up in urban settings to improve the reach and impact of TPT.

Development of treatment-decision algorithms for children evaluated for pulmonary tuberculosis: an individual participant data meta-analysis.

BACKGROUND: Many children with pulmonary tuberculosis remain undiagnosed and untreated with related high morbidity and mortality. Recent advances in childhood tuberculosis algorithm development have incorporated prediction modelling, but studies so far have been small and localised, with limited generalisability. We aimed to evaluate the performance of currently used diagnostic algorithms and to use prediction modelling to develop evidence-based algorithms to assist in tuberculosis treatment decision making for children presenting to primary health-care centres. METHODS: For this meta-analysis, we identified individual participant data from a WHO public call for data on the management of tuberculosis in children and adolescents and referral from childhood tuberculosis experts. We included studies that prospectively recruited consecutive participants younger than 10 years attending health-care centres in countries with a high tuberculosis incidence for clinical evaluation of pulmonary tuberculosis. We collated individual participant data including clinical, bacteriological, and radiological information and a standardised reference classification of pulmonary tuberculosis. Using this dataset, we first retrospectively evaluated the performance of several existing treatment-decision algorithms. We then used the data to develop two multivariable prediction models that included features used in clinical evaluation of pulmonary tuberculosis-one with chest x-ray features and one without-and we investigated each model's generalisability using internal-external cross-validation. The parameter coefficient estimates of the two models were scaled into two scoring systems to classify tuberculosis with a prespecified sensitivity target. The two scoring systems were used to develop two pragmatic, treatment-decision algorithms for use in primary health-care settings. FINDINGS: Of 4718 children from 13 studies from 12 countries, 1811 (38·4%) were classified as having pulmonary tuberculosis: 541 (29·9%) bacteriologically confirmed and 1270 (70·1%) unconfirmed. Existing treatment-decision algorithms had highly variable diagnostic performance. The scoring system derived from the prediction model that included clinical features and features from chest x-ray had a combined sensitivity of 0·86 [95% CI 0·68-0·94] and specificity of 0·37 [0·15-0·66] against a composite reference standard. The scoring system derived from the model that included only clinical features had a combined sensitivity of 0·84 [95% CI 0·66-0·93] and specificity of 0·30 [0·13-0·56] against a composite reference standard. The scoring system from each model was placed after triage steps, including assessment of illness acuity and risk of poor tuberculosis-related outcomes, to develop treatment-decision algorithms. INTERPRETATION: We adopted an evidence-based approach to develop pragmatic algorithms to guide tuberculosis treatment decisions in children, irrespective of the resources locally available. This approach will empower health workers in primary health-care settings with high tuberculosis incidence and limited resources to initiate tuberculosis treatment in children to improve access to care and reduce tuberculosis-related mortality. These algorithms have been included in the operational handbook accompanying the latest WHO guidelines on the management of tuberculosis in children and adolescents. Future prospective evaluation of algorithms, including those developed in this work, is necessary to investigate clinical performance. FUNDING: WHO, US National Institutes of Health.

Drug-Resistant Tuberculosis Treatment Outcomes among Children and Adolescents in Karachi, Pakistan.

BACKGROUND: Significant data gaps exist for children and adolescents with drug-resistant (DR) TB, particularly from high TB incidence settings. This report provides a descriptive analysis of programmatic outcomes among children and adolescents treated for DR-TB in Pakistan. METHODS: We extracted programmatic data from January 2014 to December 2019 from a tertiary care hospital with specialised child and adolescent DR-TB services. A physician assessed all children and adolescents (0-19 years) with presumptive DR-TB, including details of exposure to DR-TB, medical history, radiology, and laboratory results. All patients received treatment as per national DR-TB management guidelines based on WHO recommendations. RESULTS: There were 262 treatment episodes for 247 patients enrolled during the study period. The median age of the cohort was 16 years (IQR: 13-18 years) with 16 (6.1%) children being under 5 years; 237 (90.5%) patients had pulmonary TB. The majority of the patients (194 or 74.1%) experienced a favourable treatment outcome and 26 (9.9%) died while on treatment. Female patients (78.5%) were more likely to experience favourable outcomes compared to males (64.7%; chi-sqr p-value = 0.02). CONCLUSIONS: We found high rates of favourable outcomes in children and adolescents treated for DR-TB. However, there were few young children in our cohort and there was a considerable gender gap that enhanced efforts to diagnose DR-TB in young children and to elucidate and mitigate the reasons for poor outcomes amongst males.

Improving Tuberculosis Case Detection in Children: Summary of Innovations and Findings From 18 Countries.

Despite a growing focus on the plight of tuberculosis (TB) among children, 56% of the 1.2 million children who develop TB annually are not detected and notified. TB REACH is a platform of the Stop TB Partnership that supports innovative interventions to improve TB case detection and preventative treatment. We present summary findings from 27 TB REACH-supported projects in 18 countries. Interventions were designed around intensified case-finding approaches (facility-based systematic screening and contact investigation), capacity building (including decentralized care delivery and supported decision-making), and improving diagnostic methods (ie, introduction of alternative respiratory specimens and new tools to aid the diagnosis). These interventions were evaluated on how they worked to identify children with TB, prevent further transmission of TB among children, and strengthen the health system involved with childhood TB care. Overall, 13 715 children were detected with TB, improving case notifications by 34%. In addition, nearly 5000 eligible contacts were enrolled on TB preventive treatment through these interventions. Focusing efforts and funding on childhood TB can produce marked improvements in case detection.

Chronic kidney disease causes and outcomes in children: Perspective from a LMIC setting.

BACKGROUND AND OBJECTIVE: Chronic kidney disease (CKD) constitutes a major public health challenge, with a global prevalence of 15-74.7 cases /million children. Preventing CKD in children, slowing its progression and management of complications are essential, especially in challenged health systems in low middle income countries (LMIC). We conducted a retrospective review to assess the underlying cause and stage of CKD at presentation and clinical outcomes in children and adolescents at the Indus Hospital and Health Network (IHHN) in Karachi, Pakistan. METHODS: Children 0-16 years with CKD stage 1 and/or higher at presentation were included. Data including demographics, clinical status and lab results at presentation and during follow-up, surgical intervention if any, kidney function at last visit and outcome at last follow-up was recorded. RESULTS: A total of 229 children diagnosed with CKD are included in our study. The median age at diagnosis was 10 years with male: female ratio of 1.8:1. Only 5% children presented in stage 1 CKD. The rate of adverse outcomes is 4.5 times higher in children with CKD stage 3-5 compared to early CKD. Congenital anomaly of kidney and urinary tract (CAKUT) was the underlying cause in 49% children. Children with glomerular disease had comparatively worse outcome. Proteinuria, hypertension, anemia and bone disease were associated with high morbidity and mortality. CONCLUSION: The true epidemiology of childhood CKD is unknown in Pakistan. Our cohort showed better CKD outcomes in children diagnosed early with appropriate surgical and medical follow-up. Prompt diagnosis, treatment and prevention of progression can be life-saving in our setting. CKD registry data can inform policy changes that can prevent poor outcomes.

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.

Tuberculosis in Children and Adolescents: Progress and Perseverance.

Although it is an ancient pathogen, tuberculosis (TB) remains a major infectious cause of death globally, transiently displaced by COVID-19 [...].

Rapidly progressive glomerulonephritis in children.

Rapidly progressive glomerulonephritis (RPGN), characterized by a rapid development of nephritis with loss of kidney function in days or weeks, is typically associated histologically, with crescents in most glomeruli; and is a challenging problem, particularly in low resource settings. RPGN is a diagnostic and therapeutic emergency requiring prompt evaluation and treatment to prevent poor outcomes. Histopathologically, RPGN consists of four major categories, anti-glomerular basement membrane (GBM) disease, immune complex mediated, pauci-immune disorders and idiopathic /overlap disorders. Clinical manifestations include gross hematuria, proteinuria, oliguria, hypertension and edema. Diagnostic evaluation, including renal function tests, electrolytes, urinalysis/microscopy and serology including (anti GBM antibody, antineutrophil cytoplasmic antibody (ANCA)) starts simultaneously with management. An urgent renal biopsy is required to allow specific pathologic diagnosis as well as to assess disease activity and chronicity to guide specific treatment. The current guidelines for management of pediatric RPGN are adopted from adult experience and consist of induction and maintenance therapy. Aggressive combination immunosuppression has markedly improved outcomes, however, nephrotic syndrome, severe acute kidney injury requiring dialysis, presence of fibrous crescents and chronicity are predictors of poor renal survival. RPGN associated post infectious glomerulonephritis (PIGN) usually has good prognosis in children without immunosuppression whereas immune-complex-mediated GN and lupus nephritis (LN) are associated with poor prognosis with development of end stage kidney disease (ESKD) in more than 50% and 30% respectively. Given the need for prompt diagnosis and urgent treatment to avoid devastating outcomes, we conducted a review of the latest evidence in RPGN management to help formulate clinical practice guidance for children in our setting. Information sources and search strategy: The search strategy was performed in the digital databases of PubMed, Cochrane Library, google scholar, from their inception dates to December 2020. Three investigators independently performed a systematic search using the following search terms "Rapidly progressive glomerulonephritis" "children" "crescentic glomerulonephritis" "management" at the same time, backtracking search for references of related literature.

The WHO Global Tuberculosis 2021 Report - not so good news and turning the tide back to End TB.

OBJECTIVE: To review the data presented in the 2021 WHO global TB report and discuss the current constraints in the global response. INTRODUCTION AND METHODS: The WHO global TB reports, consolidate TB data from countries and provide up to date assessment of the global TB epidemic. We reviewed the data presented in the 2021 report. RESULTS: We noted that the 2021 WHO global TB report presents a rather grim picture on the trajectory of the global epidemic of TB including a stagnation in the annual decline in TB incidence, a decline in TB notifications and an increase in estimated TB deaths. All the targets set at the 2018 United Nations High Level Meeting on TB were off track. INTERPRETATION AND CONCLUSION: The sub-optimal global performance on achieving TB control targets in 2020 is attributed to the on-going COVID-19 pandemic, however, TB programs were already off track well before the onset of the pandemic, suggesting that the pandemic amplified an already fragile global TB response. We emphasize that ending the global TB epidemic will require bold leadership, optimization of existing interventions, widespread coverage, addressing social determinants of TB and importantly mobilization of adequate funding required for TB care and prevention.

Pediatric Tuberculosis Research and Development: Progress, Priorities and Funding Opportunities.

In this article, we highlight technological pediatric TB research advances across the TB care cascade; discuss recently completed or ongoing work in adults and corresponding significant research gaps for children; and offer recommendations and opportunities to increase investments and accelerate pediatric TB R&D.

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.

Quantified TB Exposure Can Predict Prevalent TB Disease in Child Contacts.

In a matched case-control study in Pakistan, we found that quantified tuberculosis (TB) exposure using a 10-point score is associated with prevalent TB disease in pediatric household contacts. A 1 unit increase in TB exposure score increased the odds of TB disease by 44% (conditional odds ratio: 1.44, 95% confidence interval: 1.33-1.56). Collecting well-documented exposure history can help TB diagnosis in resource-limited settings.

Safety and feasibility of 1 month of daily rifapentine plus isoniazid to prevent tuberculosis in children and adolescents: a prospective cohort study.

BACKGROUND: Shorter regimens for tuberculosis prevention can improve completion rates and protection against developing active tuberculosis disease after tuberculosis exposure. We aimed to assess the safety and feasibility of 1 month of daily isoniazid and rifapentine (1HP) in children and adolescents in a low-resource setting in south Asia with low prevalence of HIV. METHODS: This prospective cohort study was done in eight tuberculosis facilities in Karachi, Pakistan. Eligible participants were aged 2-19 years and were household contacts of patients with drug-susceptible tuberculosis infection. After clinical, radiological, and laboratory evaluation to rule out tuberculosis disease, participants were prescribed 1HP as a preventive regimen. Isoniazid was administered as 100 mg or 300 mg oral tablets and rifapentine was administered as 150 mg oral tablets. Dosing was according to participant bodyweight. The primary endpoints were the cumulative probability of a household contact completing all stages of the preventive care cascade, assessed in all eligible participants, and the proportion of household contacts completing 1HP, assessed among all those who initiated the regimen. Safety was assessed in all household contacts who initiated the 1HP regimen. FINDINGS: Between Dec 21, 2019, and March 20, 2020, 1395 household contacts of 253 patients with tuberculosis were identified, including 678 household contacts who were eligible to participate. 628 (93%) completed evaluation, of whom ten (2%) had active tuberculosis disease. Of the 618 individuals eligible for tuberculosis prevention, 408 (66%) initiated 1HP, 385 (94%) of whom completed the regimen. The median duration of 1HP was 31 days (IQR 30-32) in those who completed the regimen. The cumulative probability of completing all steps of the tuberculosis prevention cascade was 58%. A girl aged 11 years developed tuberculosis disease within 6 months of completing 1HP. A boy aged 14 years developed a burning sensation during 1HP therapy and discontinued the regimen. No other adverse events were observed. INTERPRETATION: 1HP can be safely and feasibly implemented as tuberculosis prevention in children and adolescents in programmatic settings. FUNDING: The Global Fund to Fight AIDS, Tuberculosis and Malaria.

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.

Paediatric tuberculosis - new advances to close persistent gaps.

Young children are most vulnerable to develop severe forms of tuberculosis (TB) and are over-represented among TB deaths. Almost all children estimated to have died from TB were never diagnosed or offered TB treatment. Improved access to TB preventive treatment (TPT) requires major upscaling of household contact investigation with allocation of adequate resources. Symptom-based screening is often discouraged in adults for fear of generating drug resistance, if TB cases are missed. However, the situation in vulnerable young children is different, as they present minimal risk of drug resistance generation. Further, the perceived need for additional diagnostic evaluation presents a major barrier to TPT access and underlies general reluctance to consider pragmatic decentralised models of care. Widespread roll-out of Xpert MTB/RIF Ultra® represents an opportunity for improved case detection in young children, but attaining full impact will require the use of non-sputum specimens. The new Fujifilm SILVAMP TB LAM® urine assay demonstrated good diagnostic accuracy in HIV-positive and malnourished children, but further validation is required. Given the limited accuracy of all available tests and the excellent tolerance of TB drugs in children, the global community may have to accept some over-treatment if we want to close the persistent case detection gap in young children.