Post-tuberculosis lung disease in children and adolescents: A scoping review of definitions, measuring tools, and research gaps.

Tuberculosis (TB) survivors, especially children and adolescents, can develop chronic respiratory problems called post-tuberculosis lung disease (PTLD). We conducted a scoping review to identify the current knowledge gaps on PTLD definitions, measuring tools, and research specific to this age group. We searched MEDLINE, EMBASE, Global Health, CINAHL, and Web of Science for studies published between January 1, 2000, and March 1, 2024, and identified 16 studies. Our review found that no consistent definition of PTLD was used in the studies, and the measurement tools used varied widely. Moreover, there was a lack of research on children under five years old, who are disproportionately affected by TB. Also, symptom screening tools designed for adults were frequently used in these studies, raising concerns about their accuracy in detecting PTLD in children and adolescents. Several critical research gaps require attention to improve our understanding and treatment of PTLD. Firstly, the use of inconsistent definitions of PTLD across studies makes it challenging to compare research findings and gain a clear understanding of the condition. Therefore, we need to include an objective measurement of respiratory health, such as a comprehensive post-TB lung function assessment for children and adolescents. It is also crucial to determine the optimal timing and frequency of post-TB assessments for effective PTLD detection. Furthermore, we need more knowledge of the modifiable risk factors for PTLD. The scarcity of prospective studies makes it difficult to establish causality and track the long-term course of the disease in children and adolescents. Finally, current approaches to PTLD management often fail to consider patient-reported outcomes and strategies for social support. Addressing these research gaps in future studies can improve our understanding and management of paediatric PTLD, leading to better long-term health outcomes for this vulnerable population.

Barriers to childhood tuberculosis case detection and management in Cambodia: the perspectives of healthcare providers and caregivers.

BACKGROUND: Diagnosis and treatment of tuberculosis (TB) in children remain challenging, particularly in resource-limited settings. Healthcare providers and caregivers are critical in improving childhood TB screening and treatment. This study aimed to determine the barriers to childhood TB detection and management from the perspectives of healthcare providers and caregivers in Cambodia. METHOD: We conducted this qualitative study between November and December 2020. Data collection included in-depth interviews with 16 healthcare providers purposively selected from four operational districts and 28 caregivers of children with TB and children in close contact with bacteriologically confirmed pulmonary TB residing in the catchment areas of the selected health centers. Data were analyzed using thematic analyses. RESULTS: Mean ages of healthcare providers and caregivers were 40.2 years (standard deviation [SD] 11.9) and 47.9 years (SD 14.6), respectively. Male was predominant among healthcare providers (93.8%). Three-fourths of caregivers were female, and 28.6% were grandparents. Inadequate TB staff, limited knowledge on childhood TB, poor collaboration among healthcare providers in different units on TB screening and management, limited quality of TB diagnostic tools, and interruption of supplies of childhood TB medicines due to maldistribution from higher levels to health facilities were the key barriers to childhood TB case detection and management. Caregivers reported transportation costs to and from health facilities, out-of-pocket expenditure, time-consuming, and no clear explanation from healthcare providers as barriers to childhood TB care-seeking. Aging caregivers with poor physical conditions, lack of collaboration from caregivers, ignorance of healthcare provider's advice, and parent movement were also identified as barriers to childhood TB case detection and management. CONCLUSIONS: The national TB program should further invest in staff development for TB, scale-up appropriate TB diagnostic tools and ensure its functionalities, such as rapid molecular diagnostic systems and X-ray machines, and strengthen childhood TB drug management at all levels. These may include drug forecasting, precise drug distribution and monitoring mechanism, and increasing community awareness about TB to increase community engagement.

Epidemiology of childhood tuberculosis and predictors of death among children on tuberculosis treatment in central Ethiopia: an extended Cox model challenged survival analysis.

BACKGROUND: Childhood tuberculosis (TB) was poorly studied in Ethiopia. This study aimed to describe the epidemiology of childhood TB and identify predictors of death among children on TB treatment. METHODS: This is a retrospective cohort study of children aged 16 and younger who were treated for TB between 2014 and 2022. Data were extracted from TB registers of 32 healthcare facilities in central Ethiopia. Phone interview was also conducted to measure variables without a space and not recorded in the registers. Frequency tables and a graph were used to describe the epidemiology of childhood TB. To perform survival analysis, we used a Cox proportional hazards model, which was then challenged with an extended Cox model. RESULTS: We enrolled 640 children with TB, 80 (12.5%) of whom were under the age of two. Five hundred and fifty-seven (87.0%) of the enrolled children had not had known household TB contact. Thirty-six (5.6%) children died while being treated for TB. Nine (25%) of those who died were under the age of two. HIV infection (aHR = 4.2; 95% CI = 1.9-9.3), under nutrition (aHR = 4.2; 95% CI = 2.2-10.48), being under 10 years old (aHR = 4.1; 95% CI = 1.7-9.7), and relapsed TB (aHR = 3.7; 95% CI = 1.1-13.1) were all independent predictors of death. Children who were found to be still undernourished two months after starting TB treatment also had a higher risk of death (aHR = 5.64, 95% CI = 2.42-13.14) than normally nourished children. CONCLUSIONS: The majority of children had no known pulmonary TB household contact implying that they contracted TB from the community. The death rate among children on TB treatment was unacceptably high, with children under the age of two being disproportionately impacted. HIV infection, baseline as well as persistent under nutrition, age < 10 years, and relapsed TB all increased the risk of death in children undergoing TB treatment.

They do not have symptoms - why do they need to take medicines? Challenges in tuberculosis preventive treatment among children in Cambodia: a qualitative study.

BACKGROUND: Latent tuberculosis (TB) infection has been known as a seedbed for TB disease later in life. The interruption from latent TB infection to TB disease can be done through TB preventive treatment (TPT). In Cambodia, only 40.0% of children under five years old who were the household contacts to bacteriologically confirmed TB cases were initiated with TPT in 2021. Scientific studies of context-specific operational challenges in TPT provision and uptake among children are scarce, particularly in high TB-burden countries. This study identified challenges in TPT provision and uptake among children in Cambodia from the perspective of healthcare providers and caregivers. METHODS: Between October and December 2020, we conducted in-depth interviews with four operational district TB supervisors, four clinicians and four nurses in charge of TB in referral hospitals, four nurses in charge of TB in health centers, and 28 caregivers with children currently or previously on TB treatment or TPT, and those who refused TPT for their eligible children. Data were audio recorded along with field notetaking. After verbatim transcription, data analyses were performed using a thematic approach. RESULTS: The mean age of healthcare providers and caregivers were 40.19 years (SD 12.0) and 47.9 years (SD 14.6), respectively. Most healthcare providers (93.8%) were male, and 75.0% of caregivers were female. More than one-fourth of caregivers were grandparents, and 25.0% had no formal education. Identified key barriers to TPT implementation among children included TPT side effects, poor adherence to TPT, poor understanding of TPT among caregivers, TPT risk perception among caregivers, TPT's child-unfriendly formula, TPT supply-chain issues, caregivers' concern about the effectiveness of TPT, being non-parental caregivers, and poor community engagement. CONCLUSION: Findings from this study suggest that the national TB program should provide more TPT training to healthcare providers and strengthen supply chain mechanisms to ensure adequate TPT drug supplies. Improving community awareness of TPT among caregivers should also be intensified. These context-specific interventions will play a crucial role in expanding the TPT program to interrupt the development from latent TB infection to active and ultimately lead to ending TB in the country.

Childhood TB sequel: evaluating respiratory function after treatment for pulmonary tuberculosis in a prospective cohort of Gambian children - a study protocol.

BACKGROUND: 1.2 million children under 15 years are estimated to have developed tuberculosis (TB) in 2021. 85% of paediatric patients achieve successful treatment outcomes if treated for the first episode of TB. However, despite so-called successful treatment, TB leaves many survivors with permanently destroyed or damaged lungs. Data from prospective paediatric cohorts to establish the burden and evolution of post-TB lung disease (PTLD) are still absent. The Childhood TB Sequel study aims to describe respiratory consequences associated with pulmonary TB in Gambian children, describe the evolution of these sequelae, and determine associated epidemiological risk factors. METHODS: We aim to recruit up to 80 subjects aged 19 years and below who have recently completed treatment for pulmonary TB. Recruitment started in April 2022 and is expected to continue until June 2024. Clinical assessment, chest X-ray, and comprehensive lung function assessment are carried out at treatment completion and again six and 12 months later. DISCUSSION: The Childhood TB Sequel study will address existing research gaps to enhance our knowledge and understanding of the burden of PTLD in Gambian children. The study will also contribute to formulating a plan for post-TB evaluation and long-term follow-up strategies. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05325125, April 13, 2022.

"It's about time they taught us": a qualitative study evaluating the barriers to finding and screening child contacts under five at risk for TB in Gauteng Province, South Africa from the provider and caregiver perspectives.

BACKGROUND: Inadequate numbers of children under five years of age who are exposed to tuberculosis (TB) in the home (child contact) are initiated on TB preventive treatment (TPT) in South Africa. We assessed barriers of initiating isoniazid preventive therapy (IPT) in this age group. METHODS: We conducted a qualitative study at two primary health clinics in the Ekurhuleni district in Gauteng Province. Between April and July 2019, we enrolled facility managers, TB staff and parents or legal guardians of child contacts (caregivers) attending for care, at the two facilities. Semi-structured questionnaires, facility observations and in-depth interviews using a semi-structured interview guide were used to collect data. Findings from the semi-structured questionnaires with facility staff and facility observations were summarized. Thematic analysis with a deductive approach was used to analyse the data from the in-depth interviews with caregivers. RESULTS: Two facility managers took part in the study and were assisted to complete the semi-structured questionnaires by TB staff. Fifteen caregivers aged between 18 and 43 years were interviewed of which 13 (87%) were female. Facility managers and TB staff (facility staff) felt that even though caregivers knew of family members who were on TB treatment, they delayed bringing their children for TB screening and TPT. Facility staff perceived caregivers as not understanding the purpose and benefits of TB prevention strategies such as TPT. Caregivers expressed the desire for their children to be screened for TB. However, caregivers lacked knowledge on TB transmission and the value of TB prevention in children at high risk of infection. CONCLUSION: While facility staff perceived caregivers to lack responsibility, caregivers expressed limited knowledge on the value of screening their children for TB as reasons for not accessing TB preventive services. Health education on TB transmission, screening, and TB prevention strategies at a community level, clinics, creches, schools and via media are important to achieve the global end TB goal of early detection and prevention of TB.

Detection of pulmonary tuberculosis in children using the Xpert MTB/RIF Ultra assay on sputum: a multicenter study.

Microbiological confirmation is rare in children with active tuberculosis; therefore, a more accurate test is needed to detect pulmonary tuberculosis in children. In this multicenter study, we evaluated the utility of the Xpert MTB/RIF Ultra (Ultra) on sputum, an assay recommended by the World Health Organization to test for childhood tuberculosis in high-burden settings. Children with symptoms suggestive of tuberculosis were enrolled at three hospitals in China and categorized as having active tuberculosis or nontuberculosis. The sensitivity and specificity of Ultra were 42.1% (48/114) and 99.0% (208/210), respectively. Using three MTB culture results as the reference, the sensitivity of Ultra in the subset of 38 children with culture-positive and 76 children with culture-negative was 68.4% (26/38) and 28.9% (22/76), respectively(p < 0.001). A single MTB culture combined with a single Ultra could detect 54 (54/114,47.4%) cases with active TB, while repeated MTB culture combined with a single Ultra detected 60 (60/114, 52.6%) cases with active TB(p = 0.427). Among 155 children (58 with TB and 97 with RTIs) simultaneously tested with the Ultra and Xpert MTB/RIF (Xpert), the sensitivity of the Xpert (24.1%, 14/58) was lower than that of the Ultra (41.4%, 24/58; p = 0.048). Eight children were found to have rifampin-resistant MTB strains. The Xpert MTB/RIF Ultra assay should be implemented to test for pulmonary tuberculosis in children to achieve higher confirmation rates.

Knowledge, attitude, and practices regarding childhood tuberculosis detection and management among health care providers in Cambodia: a cross-sectional study.

BACKGROUND: The World Health Organization (WHO) estimated that 29% of global tuberculosis (TB) and almost 47% of childhood TB cases were not reported to national TB programs in 2019. In Cambodia, most childhood TB cases were reported from health facilities supported by the Global Fund to Fight AIDS, Tuberculosis, and Malaria in 2019. This study aimed to compare the healthcare providers' knowledge, attitude, and practices (KAP) on childhood TB case detection in operational districts (ODs) with high and low childhood TB case detection in Cambodia. METHODS: We conducted a cross-sectional study between November and December 2020 among healthcare providers in 10 purposively selected ODs with high childhood TB case detection and 10 ODs with low childhood TB case detection. A total of 110 healthcare providers from referral hospitals (RHs) and 220 from health centers (HCs) were interviewed. We collected information on socio-demographic characteristics, training, and KAP on childhood TB. Pearson's Chi-square or Fisher's exact and Student's t-tests were performed to explore the differences in KAP of healthcare providers from ODs with low vs. high childhood TB detection. RESULTS: Of the 330 respondents, 193 were from ODs with high childhood TB case detection, and 66.67% were from HCs. A significantly higher proportion (46.11%) of respondents from ODs with high childhood TB case detection received training on childhood TB within the past two years than those from low childhood TB case detection ODs (34.31%) (p = 0.03). Key knowledge on childhood TB was not significantly different among respondents from ODs with high and low childhood TB case detection. A significantly higher proportion of respondents from ODs with high childhood TB case detection had a good attitude (98.96 vs. 97.08%, p = 0.002) and performed good practices (58.55 vs. 45.26%, p = 0.02) on contact investigation in the community than those from low childhood TB case detection ODs. CONCLUSIONS: Healthcare providers from ODs with high childhood TB detection had better attitudes and practices towards childhood TB. The attitudes and practices need to be improved among healthcare providers in ODs with low case detection. Further investment in training and experience sharing on childhood TB case detection among healthcare providers is needed to improve childhood TB case detection.

Pilot study to identify missed opportunities for prevention of childhood tuberculosis.

Tuberculosis (TB) in exposed children can be prevented with timely contact tracing and preventive treatment. This study aimed to identify potential barriers and delays in the prevention of childhood TB in a low-incidence country by assessing the management of children subsequently diagnosed with TB. A pilot retrospective cohort study included children (< 15 years) treated for TB between 2009 and 2016 at a tertiary care hospital in Berlin, Germany. Clinical data on cases and source cases, information on time points of the diagnostic work up, and preventive measures were collected and analyzed. Forty-eight children (median age 3 years [range 0.25-14]) were included; 36 had been identified through contact tracing, the majority (26; 72.2%) being < 5 years. TB source cases were mostly family members, often with advanced disease. Thirty children (83.3%) did not receive prophylactic or preventive treatment, as TB was already prevalent when first presented. Three cases developed TB despite preventive or prophylactic treatment; in three cases (all < 5 years), recommendations had not been followed. Once TB was diagnosed in source cases, referral, assessment, TB diagnosis, and treatment were initiated in most children in a timely manner with a median duration of 18 days (interquartile range 6-60, range 0-252) between diagnosis of source case and child contact (information available for 35/36; 97.2%). In some cases, notable delays in follow-up occurred. CONCLUSION: Prompt diagnosis of adult source cases appears to be the most important challenge for childhood TB prevention. However, improvement is also needed in the management of exposed children. WHAT IS KNOWN: • Following infection with Mycobacterium tuberculosis, young children have a high risk of progression to active and severe forms of tuberculosis (TB). • The risk of infection and disease progression can be minimized by prompt identification of TB-exposed individuals and initiation of prophylactic or preventive treatment. WHAT IS NEW: • We could show that there are avoidable time lags in diagnosis in a relevant proportion of children with known TB exposure. • Delayed diagnosis of adult source cases, losses in follow-up examinations, and delay in referral to a specialized TB clinic of TB-exposed children, especially among foreign-born children, appear to be the main issue in this German pediatric study cohort.

An evaluation of childhood tuberculosis program in Chegutu District, Zimbabwe, 2020: a descriptive cross-sectional study.

BACKGROUND: Childhood tuberculosis (TB) is a major global public health concern contributing to significant child morbidity and mortality. A records review of the TB notification for Chegutu District Health Information System 2 (DHIS2) showed a low childhood TB case detection rate. For 2018 and 2019, childhood TB notifications were 4% and 7% respectively against the annual national childhood 12% case detection rate. We evaluated the performance of the childhood TB program in Chegutu. METHODS: We conducted a descriptive cross-sectional study. Sixty-six health workers (HW) participated in the study. Interviewer-administered questionnaires and checklists were used to collect data on reasons for low TB case detection, HW childhood TB knowledge, program inputs, processes, and outputs. Strengths, Weaknesses, Opportunities and Threats analysis was used to assess the childhood TB processes. We analyzed the data using Epi Info 7™ to generate frequencies, proportions and means. A Likert scale was used to assess health worker knowledge. RESULTS: The majority 51/66(77%) of HW were nurses and 51/66(67%) of respondents were females. Reasons for the low childhood TB case detection were lack of HW confidence in collecting gastric aspirates 55/66(83%) and HW's negative attitudes towards gastric aspirate collection 23/66(35%). HW 24/66 (37%) had a fair knowledge of childhood TB notification. The district had only one functional X-ray machine for 34 health facilities. Only 6/18 motorcycles were functional with inadequate fuel supply. No desk guide for the management of TB in children for HW (2018) was available in 34 health facilities. Ethambutol 400 mg was out of stock and adult 800 mg tablets were used. Funds allocated for motor vehicle and motorcycles service ($1612USD/year) were inadequate. The district failed to perform planned quarterly TB review meetings, contact tracing and childhood TB training due to funding and COVID-19 lockdown restrictions. CONCLUSION: The childhood TB program failed to meet its targets due to inadequate inputs, HW suboptimal knowledge and COVID-19 lockdown measures. Case detection and notification can be improved through on-job training, mentorship, support and supervision and adequate resources.

Childhood Tuberculosis in Mongolia: Trends and Estimates, 2010-2030.

Mongolia was listed among the 30 countries with a high tuberculosis burden in 2021. Approximately 10-11% of the tuberculosis cases are of children, which is higher than the global average (6.0%). As children are a vulnerable population, it is important to understand the current situation and prioritize the development of tuberculosis prevention strategies. However, only few studies have addressed childhood tuberculosis in Mongolia. Therefore, we aimed to describe the characteristics of childhood tuberculosis and to show its trends and estimates in Mongolia. We performed descriptive and trend analyses on secondary data from the National Center for Communicable Diseases from 2010 to 2020. A total of 4,242 childhood tuberculosis cases, compiled from nine districts of the capital city and 21 provinces, were analyzed. We found that tuberculosis occurred more frequently in school-age children, and 71.8% of the all cases were an extrapulmonary tuberculosis. Trend analysis revealed that childhood tuberculosis continuously increased with fluctuations from 2018 onwards. The central region, including the capital city of Ulaanbaatar, is the most tuberculosis-burdened. Childhood tuberculosis is estimated to increase in the central region and decrease in the others from 2021 to 2030. Our findings showed that the national childhood tuberculosis trend is increasing, although there are differences in the pattern between regions. Further studies are needed to identify the determinant factors of regional differences, and age-specific public health interventions, such as scale-up screening and preventive treatment, are in demand in high-prevalence areas.

Tuberculosis prevalence, incidence and prevention in a south african cohort of children living with HIV.

BACKGROUND: We describe tuberculosis (TB) disease among antiretroviral treatment (ART) eligible children living with HIV (CLHIV) in South Africa to highlight TB prevention opportunities. METHODS: In our secondary analysis among 0- to 12-year-old ART-eligible CLHIV in five Eastern Cape Province health facilities from 2012 to 2015, prevalent TB occurred 90 days before or after enrollment; incident TB occurred >90 days after enrollment. Characteristics associated with TB were assessed using logistic and Cox proportional hazards regression with generalized estimating equations. RESULTS: Of 397 enrolled children, 114 (28.7%) had prevalent TB. Higher-income proxy [adjusted odds ratio (aOR) 1.8 [95% confidence interval (CI) 1.3-2.6] for the highest, 1.6 (95% CI 1.6-1.7) for intermediate]; CD4+ cell count <350 cells/µl [aOR 1.6 (95% CI 1.1-2.2)]; and malnutrition [aOR 1.6 (95% CI 1.1-2.6)] were associated with prevalent TB. Incident TB was 5.2 per 100 person-years and was associated with delayed ART initiation [hazard ratio (HR) 4.7 (95% CI 2.3-9.4)], malnutrition [HR 1.8 (95% CI 1.1-2.7)] and absence of cotrimoxazole [HR 2.3 (95% CI 1.0-4.9)]. Among 362 children with data, 8.6% received TB preventive treatment. CONCLUSIONS: Among these CLHIV, prevalent and incident TB were common. Early ART, cotrimoxazole and addressing malnutrition may prevent TB in these children.

BACKGROUND: We describe tuberculosis (TB) in children living with HIV (CLHIV) eligible for HIV treatment in South Africa to highlight opportunities to prevent TB. METHODS: We analyzed additional data from our original study of CLHIV who were 0­12 years old and due to start HIV treatment in five health facilities in Eastern Cape Province from 2012 to 2015 and assessed characteristics associated with existing and new TB. RESULTS: Of 397 enrolled children, 114 (28.7%) had existing TB. Children with a higher measure of household income had higher odds of existing TB. CD4+ cell count <350 cells/µl and malnutrition were also associated with existing TB. There were 5.2 new cases of TB for every 100 child-years. New TB was 4.7 times more likely for children with delayed HIV treatment start, 1.8 times more likely for children with malnutrition and 2.3 times more likely for children who did not get cotrimoxazole. Among 362 children with data, 8.6% received treatment to prevent TB. CONCLUSIONS: Among these CLHIV, existing and new TB were common. Early HIV treatment, cotrimoxazole and addressing malnutrition may prevent TB in these children.

Impact of Xpert MTB/RIF in the Diagnosis of Childhood Tuberculosis in Rural Ethiopia.

BACKGROUND: This study assesses the impact of the Xpert MTB/RIF in the diagnosis of childhood tuberculosis (TB) in a rural hospital in a resource-constrained setting. METHODS: Retrospective cross-sectional study in children evaluated for presumptive TB from 1 June 2016 to 31 May 2017 at the Gambo General Hospital in rural Southern Ethiopia. Children were evaluated according to a defined protocol based on national guidelines. Samples were submitted for Xpert MTB/RIF assay to the nearest reference laboratory. RESULTS: Of the 201 children assessed for presumptive TB, 46.3% (93/201) were diagnosed with TB. Of these, 49.5% (46/93) were microbiologically confirmed, mostly by Xpert MTB/RIF (only one patient was diagnosed by smear alone). The rest were clinically diagnosed. Microbiologically confirmed patients had a higher mean age, longer duration of fever and cough and lymphadenopathy more frequently than those clinically diagnosed. Gastric aspirates were Xpert MTB/RIF-positive in 18.2% of the samples (26/143); none were smear-positive (0/140). Sputum samples were Xpert MTB/RIF-positive in 27.1% (13/35) of the samples and smear-positive in 8.6% (3/35). There were no HIV-positive patients and just one case of rifampicin-resistant TB. A long delay (median 15 days) was detected in returning the results. CONCLUSION: Xpert MTB/RIF serves as an important adjunctive test for diagnosing childhood TB in rural settings, with microbiological confirmation in up to half the TB cases. Processes need to be optimized to achieve an early diagnosis. The diagnosis of childhood TB in high-burden countries such as Ethiopia still relies largely upon diagnostic algorithms and the clinician's skills.Lay summaryWorld Health Organization recommends the use of Xpert MTB/RIF to improve the microbiological diagnosis of childhood tuberculosis (TB) since 2014, but the impact of this test under real conditions in rural areas of low-income countries is not clear. We conducted a cross-sectional study in children evaluated for presumptive TB from 1 June 2016 to 31 May 2017 at the Gambo General Hospital in rural Southern Ethiopia. Children were evaluated according to a clinical protocol based on national guidelines and samples were submitted for Xpert MTB/RIF assay to the nearest reference laboratory.Of the 201 children assessed, 46.3% (93/201) were diagnosed with tuberculosis. Of these, 48.4% (45/93) were microbiologically confirmed by Xpert MTB/RIF [smear microscopy only diagnosed the 5.4% (5/93)]. Patients with microbiologically confirmed tuberculosis had a higher mean age, longer duration of fever and cough and had lymphadenopathy more frequently than those clinically diagnosed. A long delay in returning the results (median 15 days) was detected. Xpert MTB/RIF serves as an important test for diagnosing childhood TB in rural settings, with microbiological confirmation in up to half the cases. Processes need to be optimized to achieve an early diagnosis. The diagnosis of childhood TB in high-burden countries still relies largely upon diagnostic algorithms and the clinician's skills.

Discontinuation of tuberculosis treatment among children in the Kampala Capital City Authority health facilities: a mixed-methods study.

INTRODUCTION: Discontinuation of tuberculosis treatment (DTT) among children in sub-Saharan Africa is a major obstacle to effective tuberculosis (TB) control and has the potential to worsen the emergence of multi-drug resistant TB and death. DTT in children is understudied in Uganda. We examined the level and factors associated with DTT among children at four large health facilities in Kampala Capital City Authority and documented the reasons for DTT from treatment supporters and healthcare provider perspectives. METHODS: We conducted a retrospective analysis of records for children < 15 years diagnosed and treated for TB between January 2018 and December 2019. We held focus group discussions with treatment supporters and key informant interviews with healthcare providers. We defined DTT as the stoppage of TB treatment for 30 or more consecutive days. We used a stepwise generalized linear model to assess factors independently associated with DTT and content analysis for the qualitative data reported using sub-themes. RESULTS: Of 312 participants enrolled, 35 (11.2%) had discontinued TB treatment. The reasons for DTT included lack of privacy at healthcare facilities for children with TB and their treatment supporters, the disappearance of TB symptoms following treatment initiation, poor implementation of the community-based directly observed therapy short-course (CB-DOTS) strategy, insufficient funding to the TB program, and frequent stock-outs of TB drugs. DTT was more likely during the continuation phase of TB treatment compared to the intensive phase (Adjusted odds ratio (aOR), 5.22; 95% Confidence Interval (CI), 1.76-17.52) and when the treatment supporter was employed compared to when the treatment supporter was unemployed (aOR, 3.60; 95% CI, 1.34-11.38). CONCLUSION: Many children with TB discontinue TB treatment and this might exacerbate TB morbidity and mortality. To mitigate DTT, healthcare providers should ensure children with TB and their treatment supporters are accorded privacy during service provision and provide more information about TB symptom resolution and treatment duration versus the need to complete treatment. The district and national TB control programs should address gaps in funding to TB care, the supply of TB drugs, and the implementation of the CB-DOTS strategy.

Treatment Outcomes of Childhood Tuberculosis in Three Districts of Balochistan, Pakistan: Findings from a Retrospective Cohort Study.

BACKGROUND: This study aimed to evaluate treatment outcomes and factors associated unsuccessful outcomes among pediatric tuberculosis (TB) patients (age ≤14 years). METHODS: This was a retrospective cohort study conducted at three districts (Quetta, Zhob and Killa Abdullah) of Balochistan, Pakistan. All childhood TB patients enrolled for treatment at Bolan Medical Complex Hospital (BMCH) Quetta and District Headquarter Hospitals of Zhob and Killa Abdullah from 1 January 2016 to 31 December 2018 were included in the study and followed until their treatment outcomes were reported. Data were collected through a purpose developed standardized data collection form and analyzed by using SPSS 20. A p-value <0.05 was considered statistically significant. RESULTS: Out of 5152 TB patients enrolled at the study sites, 2184 (42.4%) were children. Among them, 1941 childhood TB patients had complete medical record were included in the study. Majority of the study participants were <5 years old (66.6%) and had pulmonary TB (PTB; 65%). A total of 45 (2.3%) patients were cured, 1680 (86.6%) completed treatment, 195 (10%) lost to follow-up, 15 (0.8%) died, 5 (0.3%) failed treatment and 1 (0.1%) was not evaluated for outcomes. In multivariate binary logistic regression analysis, treatment at BMCH Quetta (OR = 25.671, p-value < 0.001), rural residence (OR = 3.126, p-value < 0.001) and extra-PTB (OR = 1.619, p-value = 0.004) emerged as risk factors for unsuccessful outcomes. CONCLUSION: The study sites collectively reached the World Health Organization's target of treatment success (>85%). Lost to follow-up was the major reason for unsuccessful outcomes. Special attention to patients with identified risk factors for unsuccessful outcomes may improve outcomes further.

Comparing Treatment Outcomes between Confirmed and Non-Confirmed Childhood TB Cases: Study from a Major Tertiary Center in Thailand.

BACKGROUND: Tuberculosis (TB) in children is challenging to diagnose due to its non-specific symptoms and difficulties in obtaining confirmatory laboratory results. This study aimed to compare the treatment outcomes of confirmed and non-confirmed TB in children. METHODS: The medical records of children aged ≤ 15 years diagnosed with TB at Songklanagarind Hospital from January 2007 to December 2018 were examined. The TB cases were classified into three groups, confirmed cases (positive culture and/or polymerase chain reaction), probable cases (positive histopathological and/or acid-fast bacilli results) and presumptive cases (clinical manifestations and imaging findings compatible with TB and good response to anti-TB drugs but without microbiological confirmation). RESULTS: Of 177 children, 66 (37.3%) had a confirmed diagnosis, 57 (32.2%) a probable diagnosis, and 54 (30.5%) a presumptive diagnosis. The successful treatment rates of the confirmed, probable and presumptive TB groups were 80.3%, 87.7% and 92.6%, respectively (p = 0.21). Of the 54 presumptive cases, a history of household contact with TB led to a diagnosis of asymptomatic pulmonary TB in 10 (18.5%) cases. Patients with a presumptive diagnosis were less likely to have disseminated and/or miliary TB (1.9% vs. 7.0% of probable vs. 22.7% of confirmed, p < 0.01). CONCLUSIONS: Only one-third of the study patients had a confirmed TB diagnosis. The successful treatment and mortality rates did not significantly differ among the three groups. To increase the detection rate of early diagnosis of childhood TB, physicians should perform active TB contact investigations in household members of the index case.

Application of whole-genome sequencing in a case study of renal tuberculosis in a child.

BACKGROUND: Urogenital tuberculosis (TB) is rare in children and usually develops due to reactivation of the foci in the genitourinary tract after the latency period following initial infection. Urogenital TB in children has no pathognomonic clinical features that can result in overlooking or misdiagnosing this clinical entity. Here, we report important findings regarding the pathogenesis and transmission of TB by using genotyping and whole-genome sequencing (WGS) in a study of renal TB case in a child. CASE PRESENTATION: A 13-year-old boy was admitted to the hospital because of high fever, severe dry cough, flank pain and painful urination. Abdominal ultrasonography and CT revealed an 8 mm calculus in the kidney, and clinical findings were initially interpreted as nephrolithiasis. Nevertheless, due to the atypical clinical presentation of kidney stone disease, additional investigations for possible TB were performed. The QuantiFERON®-TB Gold Plus test was positive, and the Mantoux test resulted in 15 mm of induration, confirming infection with Mycobacterium tuberculosis (Mtb). Chest X-ray was normal. Chest CT revealed calcified intrathoracic lymph nodes. The urine sample tested positive for acid-fast bacilli, and Mtb cultures were obtained from urine and bronchial aspirate samples, resulting in a final diagnosis of intrathoracic lymph node and renal TB. Contact investigation revealed that the child's father was diagnosed with TB when the child was 1 year old. Genotyping and WGS analysis of Mtb isolates of the child and his father confirmed the epidemiological link and pointed to the latency of infection in the child. CONCLUSIONS: This case report confirmed the development of active TB from calcified lesions in adolescent after 12 years of exposure, demonstrated the absence of microevolutionary changes in the Mtb genome during the period of latency, and proved the importance of appropriate evaluation and management to prevent the progression of TB infection to active TB disease. The use of WGS provided the ultimate resolution for the detection of TB transmission and reactivation events.

Evaluation of QuantiFERON tuberculosis Gold In-Tube assay for diagnosis of active tuberculosis in children.

AIM: Tuberculin skin test (TST) is still used in diagnostic algorithms of childhood tuberculosis (TB). QuantiFERON TB Gold In-Tube assay (QFT-GIT) is an alternative test to TST based on the detection of interferon-gamma release upon in vitro induction of peripheral mononuclear cells by TB antigens. In this study, we aimed to determine the diagnostic value and performance of QFT-GIT for active childhood TB. METHODS: This retrospective study was conducted between January 2005 and December 2011 in three referral hospitals in Turkey with 124 children who were diagnosed with definite active TB. Sensitivity values of TST and QFT-GIT were determined by accepting the microbiological confirmation as the gold standard of diagnosis of TB. RESULTS: In our study, sensitivity of QFT-GIT and TST was found to be 65 and 66% respectively. However, combined usage of QFT-GIT and TST was found to be more sensitive (85%) than TST or QFT-GIT alone (P < 0.0001). Although negative results of QFT-GIT or TST did not exclude the diagnosis of active TB in children, their positivity supported the diagnosis. Specificity could not be measured as only microbiologically confirmed cases of Mycobacterium tuberculosis disease were enrolled in the study. CONCLUSION: Although sensitivities of TST and QFT-GIT are too low to exclude active TB, their positivity supports diagnosis of active TB in children concomitant with signs and symptoms. QFT-GIT and TST should be used together to enhance diagnostic sensitivity and could help exclude a diagnosis of TB if the pretest probability is low.

Bacterial Genotyping of Central Nervous System Tuberculosis in South Africa: Heterogenic Mycobacterium tuberculosis Infection and Predominance of Lineage 4.

Tuberculous meningitis (TBM), the most severe extrapulmonary manifestation of tuberculosis, is caused by the pathogen Mycobacterium tuberculosis The M. tuberculosis complex includes seven lineages, all described to harbor a unique geographical dissemination pattern and clinical presentation. In this study, we set out to determine whether a certain M. tuberculosis lineage demonstrated tropism to cause TBM in patients from Cape Town, South Africa. DNA was extracted from formalin-fixed paraffin-embedded central nervous system (CNS) tissue from a unique neuropathological cohort of 83 TBM patients, collected between 1975 and 2012. M. tuberculosis lineages 1, 2, 3, and 4 were determined using an allele-specific PCR and Sanger sequencing. Of the 83 patient specimens tested, bacterial characterization could be performed on 46 specimens (55%). M. tuberculosis lineage 4 was present in 26 patient specimens (56%), and non-lineage 4 was identified in 10 cases (22%). Moreover, genomic heterogeneity was detected in the CNS specimens of 7 adults and 3 children. We could show that infection of the CNS is not restricted to a single M. tuberculosis lineage and that even young children with rapid progression of disease can harbor more than one M. tuberculosis lineage in the CNS.

Evaluating UK National Guidance for Screening of Children for Tuberculosis. A Prospective Multicenter Study.

RATIONALE: To identify infected contacts of tuberculosis (TB) cases, the UK National Institute for Health and Care Excellence (NICE) recommended the addition of IFN-γ release assays (IGRA) to the tuberculin skin test (TST) in its 2006 TB guidelines. Treatment for TB infection was no longer recommended for children who screened TST-positive but IGRA-negative. OBJECTIVES: We performed a cohort study to evaluate the risk of TB disease in this group. METHODS: Children exposed to an infectious case of TB in their household were recruited from 11 pediatric TB clinics. TST and IGRA were performed at baseline, with IGRA repeated at 8 weeks and TST repeated if initially negative. Children were treated according to 2006 NICE guidelines and followed for 24 months. MEASUREMENTS AND MAIN RESULTS: Of 431 recruited children, 392 completed the study. We diagnosed 48 (12.2%) cases of prevalent TB disease, 105 (26.8%) with TB infection, and 239 (60.9%) without TB infection or disease. Eighteen children aged 2 years and above had a positive TST but persistently negative IGRA. None received TB infection treatment and none developed TB disease. Ninety (26.1%) children qualified for TB infection treatment according to 2006 NICE guidelines. In contrast, 147 (42.7%) children would have qualified under revised NICE guidance, issued in 2016. CONCLUSIONS: In this low-prevalence setting we saw no incident cases of TB disease in children who were TST-positive but IGRA-negative and did not receive treatment for TB infection. Following the latest NICE guidance, significantly more children will require medication.