BACKGROUND
There are few data on the treatment of children and adolescents with multidrug-resistant (MDR) or rifampicin-resistant (RR) tuberculosis, especially with more recently available drugs and regimens. We aimed to describe the clinical and treatment characteristics and their associations with treatment outcomes in this susceptible population.
METHODS
We conducted a systematic review and individual participant data meta-analysis. Databases were searched from Oct 1, 2014, to March 30, 2020. To be eligible, studies must have included more than five children or adolescents (0-19 years of age) treated for microbiologically confirmed or clinically diagnosed MDR or RR tuberculosis within a defined treatment cohort, and reported on regimen composition and treatment outcomes. Abstracts were screened independently by two authors to identify potentially eligible records. Full texts were reviewed by two authors independently to identify studies meeting the eligiblity criteria. For studies meeting eligiblity criteria, anonymised individual patient data was requested and individiual level data included for analysis. The main outcome assessed was treatment outcome defined as treatment success (cure or treatment completed) versus unfavourable outcome (treatment failure or death). Multivariable logistic regression models were used to identify associations between clinical and treatment factors and treatment outcomes. This study is registered with Prospero (CRD42020187230).
FINDINGS
1417 studies were identified through database searching. After removing duplicates and screening for eligibility, the search identified 23 369 individual participants from 42 studies, mostly from India and South Africa. Overall, 16 825 (72·0%) were successfully treated (treatment completed or cured), 2848 died (12·2%), 722 (3·1%) had treatment failure, and 2974 (12·7%) were lost to follow-up. In primary analyses, the median age was 16 (IQR 13-18) years. Of the 17 764 (87·1%) participants with reported HIV status, 2448 (13·8%) were living with HIV. 17 707 (89·6%) had microbiologically confirmed tuberculosis. After adjusting for significant factors associated with treatment outcome, the use of two (adjusted odds ratio [OR] 1·41 [95% CI 1·09-1·82]; p=0·008) or three (2·12 [1·61-2·79]; p<0·0001) WHO-classified group A drugs (bedaquiline, moxifloxacin, levofloxacin, and linezolid) compared with the use of no group A drugs at all was positively associated with treatment success.
INTERPRETATION
Younger and clinically diagnosed children are underrepresented among those treated for MDR and RR tuberculosis and should be a focus for case-finding efforts. Overall treatment outcomes in our analysis were better than in adults but lower than the international targets of 90% or more individuals successfully treated. Treatment with more group A drugs was associated with better treatment outcomes in children and adolescents, highlighting the need for more rapid access to these drugs and improved regimens.
BACKGROUND
Humanitarian crises bring unique, and potentially growing challenges to people with type 1 diabetes (T1D). We aimed to determine, in youth with T1D (mean age (± 1SD) 0–17.9 years) within and coming from humanitarian crises settings (HCS), the reported prevalence that meet international consensus targets for glycaemic, blood pressure and lipid management, and incidence of severe hypoglycaemia or diabetic ketoacidosis.
METHODS
A narrative review of quantitative data was conducted, using a systematic process. MEDLINE (Ovid), Global Health, Web of Science, Scopus, Embase, CINAHL, APA PsycINFO, Cochrane trials, and the reference lists of eligible records were searched (January 2014-February 2024); ten records covering ten separate studies were retrieved.
RESULTS
Glycaemic management was consistently suboptimal in HCS. However, among individuals coming from HCS, glycaemia varied. Across both groups, data relating to blood pressure, lipids, severe hypoglycaemia or diabetic ketoacidosis were either unavailable or limited.
CONCLUSION
Findings expose the dearth of data relating to defined youth with T1D within and coming from HCS, leaving the status of this population largely uncharacterised. With limited data indicating suboptimal T1D management, there is a pressing need for the development of a consensus guideline on, and core indicators relating to such youth within and coming from HCS, plus monitoring systems and outcome data.
Children and adolescents with multidrug-resistant and rifampicin-resistant tuberculosis (MDR/RR-TB) are under diagnosed and under treated. Few reports exist on the treatment of children and adolescents with newer TB drugs. We assessed the safety and effectiveness of MDR/RR-TB regimens containing bedaquiline and delamanid among children and adolescents.
METHODS
The endTB observational study is a prospective, multi-site study. Children and adolescents aged 19 years and below are included in this analysis. We report the frequency and outcomes of clinically relevant adverse events of special interest (AESI) and end of treatment outcomes.
RESULTS
A total of 190 children and adolescents from 14 countries were included (< 5 years: 4, 5-14 years: 20, 15- 19 years: 166), 47% had BMI < 18.5 Kg/m2, 6% were HIV positive, 68% previously treated with second-line drugs, 52% had fluoroquinolone resistance, 71% cavity or bilateral disease on chest Xray. Initial treatment contained bedaquiline only (51%), delamanid only (39%) or both (10%) as part of a multidrug regimen. Other frequently used drugs were linezolid (82%), cycloserine (71%), clofazimine (70%) and fluoroquinolones (69%). End of treatment outcomes were 85% success, 5% death, 4% failure, 4% lost to follow and 2% not evaluated. Most common clinically relevant AEIs were peripheral neuropathy, electrolyte depletion and hearing loss with 26 (16%), 24 (15%) and 11 (7%) patients experiencing at least one event respectively. Two patients (1%) experienced clinically relevant QT interval prolongation which resolved without sequelae. Among patients experiencing hearing loss 4 (36%) resolved, 4 (36%) resolved with sequelae, 1 (9%) did not resolve, and 2 (18%) had unknown outcomes. Among patients experiencing peripheral neuropathy, 14 (54%) resolved, 9 (35%) resolved with sequelae, 3 (11%) did not resolve.
CONCLUSION
Treatment of MDR/RR-TB with bedaquiline and delamanid is effective and well tolerated amongst children and adolescents. All oral regimens should be scaled up as recommended by WHO for these age groups.
The key lessons learned from this implementation were:
▸ Schedule all adolescents on the same day(s); preferably during out-of-school hours.
▸ Ensure disclosure is a repeated and ongoing process and not an on/off one.
▸ Maintain close collaboration between clinicians and counsellors to continuously transmit information to the changing and evolving concerns of teens.
▸ Organize sessions by age band, separating the pre-pubescent adolescents from older ones. Full HIV disclosure is recommended before integrating the adolescents into group activities.
▸ Include sexual and reproductive health in the package of care. Health workers and peers must be trained to address the specific concerns of adolescents.
▸ Recognize peers are an important asset to conveying messages and sharing positive experiences. While peers are useful actors in the management of teens, they should not be solely responsible for managing the cases of adolescents failing on treatment.
▸ Perform a viral load (VL) every six months for this vulnerable age group. Point-of-care VL, with same-day results, permits a rapid management of the unsuppressed patients, and requires logistic organization in rural contexts.
▸ Utilize a multidisciplinary team – clinicians, counsellors, psychologists, social workers, and peers – to address the complex situations faced by some adolescents.
Historic South African 5-year overall survival (OS) rates for Hodgkin lymphoma (HL) from 2000 to 2010 were 46% and 84% for human immunodeficiency virus (HIV)-positive and HIV-negative children, respectively. We investigated whether a harmonised treatment protocol using risk stratification and response-adapted therapy could increase the OS of childhood and adolescent HL.
METHODS
Seventeen units prospectively enrolled patients less than 18 years, newly diagnosed with classical HL onto a risk-stratified, response-adapted treatment protocol from July 2016 to December 2022. Low- and intermediate-risk patients received four and six courses of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD), respectively. High-risk patients received two courses of ABVD, followed by four courses of cyclophosphamide, vincristine, prednisone, and dacarbazine (COPDac). Those with a slow early response and bulky disease received consolidation radiotherapy. HIV-positive patients could receive granulocyte colony-stimulating factor and less intensive therapy if stratified as high risk, at the treating clinician's discretion. Kaplan-Meier survival analysis was performed to determine 2-year OS and Cox regression to elucidate prognostic factors.
RESULTS
The cohort comprised 132 patients (19 HIV-positive, 113 HIV-negative), median age of 9.7 years, with a median follow-up of 2.2 years. Risk grouping comprised nine (7%) low risk, 36 (27%) intermediate risk and 87 (66%) high risk, with 71 (54%) rapid early responders and 45 (34%) slow early responders, and 16 (12%) undocumented. Two-year OS was 100% for low-risk, 93% for intermediate-risk, and 91% for high-risk patients. OS for HIV-negative (93%) and HIV-positive (89%) patients were similar (p = .53). Absolute lymphocyte count greater than 0.6 × 109 predicted survival (94% vs. 83%, p = .02).
CONCLUSION
In the first South African harmonised HL treatment protocol, risk stratification correlated with prognosis. Two-year OS of HIV-positive and HIV-negative patients improved since 2010, partially ascribed to standardised treatment and increased supportive care. This improved survival strengthens the harmonisation movement and gives hope that South Africa will achieve the WHO Global Initiative for Childhood Cancer goals.
These clinical standards aim to provide guidance for diagnosis, treatment, and management of drug-susceptible TB in children and adolescents.
METHODS
Fifty-two global experts in paediatric TB participated in a Delphi consensus process. After eight rounds of revisions, 51/52 (98%) participants endorsed the final document.
RESULTS
Eight standards were identified: Standard 1, Age and developmental stage are critical considerations in the assessment and management of TB; Standard 2, Children and adolescents with symptoms and signs of TB disease should undergo prompt evaluation, and diagnosis and treatment initiation should not depend on microbiological confirmation; Standard 3, Treatment initiation is particularly urgent in children and adolescents with presumptive TB meningitis and disseminated (miliary) TB; Standard 4, Children and adolescents should be treated with an appropriate weight-based regimen; Standard 5, Treating TB infection (TBI) is important to prevent disease; Standard 6, Children and adolescents should receive home-based/community-based treatment support whenever possible; Standard 7, Children, adolescents, and their families should be provided age-appropriate support to optimise engagement in care and clinical outcomes; and Standard 8, Case reporting and contact tracing should be conducted for each child and adolescent.
CONCLUSION
These consensus-based clinical standards, which should be adapted to local contexts, will improve the care of children and adolescents affected by TB.