Treatment Outcomes in Global Systematic Review and Patient Meta-Analysis of Children with Extensively Drug-Resistant Tuberculosis.

Extensively drug-resistant tuberculosis (XDR TB) has extremely poor treatment outcomes in adults. Limited data are available for children. We report on clinical manifestations, treatment, and outcomes for 37 children (<15 years of age) with bacteriologically confirmed XDR TB in 11 countries. These patients were managed during 1999-2013. For the 37 children, median age was 11 years, 32 (87%) had pulmonary TB, and 29 had a recorded HIV status; 7 (24%) were infected with HIV. Median treatment duration was 7.0 months for the intensive phase and 12.2 months for the continuation phase. Thirty (81%) children had favorable treatment outcomes. Four (11%) died, 1 (3%) failed treatment, and 2 (5%) did not complete treatment. We found a high proportion of favorable treatment outcomes among children, with mortality rates markedly lower than for adults. Regimens and duration of treatment varied considerably. Evaluation of new regimens in children is required.

Treatment and outcomes in children with multidrug-resistant tuberculosis: A systematic review and individual patient data meta-analysis.

BACKGROUND: An estimated 32,000 children develop multidrug-resistant tuberculosis (MDR-TB; Mycobacterium tuberculosis resistant to isoniazid and rifampin) each year. Little is known about the optimal treatment for these children. METHODS AND FINDINGS: To inform the pediatric aspects of the revised World Health Organization (WHO) MDR-TB treatment guidelines, we performed a systematic review and individual patient data (IPD) meta-analysis, describing treatment outcomes in children treated for MDR-TB. To identify eligible reports we searched PubMed, LILACS, Embase, The Cochrane Library, PsychINFO, and BioMedCentral databases through 1 October 2014. To identify unpublished data, we reviewed conference abstracts, contacted experts in the field, and requested data through other routes, including at national and international conferences and through organizations working in pediatric MDR-TB. A cohort was eligible for inclusion if it included a minimum of three children (aged <15 years) who were treated for bacteriologically confirmed or clinically diagnosed MDR-TB, and if treatment outcomes were reported. The search yielded 2,772 reports; after review, 33 studies were eligible for inclusion, with IPD provided for 28 of these. All data were from published or unpublished observational cohorts. We analyzed demographic, clinical, and treatment factors as predictors of treatment outcome. In order to obtain adjusted estimates, we used a random-effects multivariable logistic regression (random intercept and random slope, unless specified otherwise) adjusted for the following covariates: age, sex, HIV infection, malnutrition, severe extrapulmonary disease, or the presence of severe disease on chest radiograph. We analyzed data from 975 children from 18 countries; 731 (75%) had bacteriologically confirmed and 244 (25%) had clinically diagnosed MDR-TB. The median age was 7.1 years. Of 910 (93%) children with documented HIV status, 359 (39%) were infected with HIV. When compared to clinically diagnosed patients, children with confirmed MDR-TB were more likely to be older, to be infected with HIV, to be malnourished, and to have severe tuberculosis (TB) on chest radiograph (p < 0.001 for all characteristics). Overall, 764 of 975 (78%) had a successful treatment outcome at the conclusion of therapy: 548/731 (75%) of confirmed and 216/244 (89%) of clinically diagnosed children (absolute difference 14%, 95% confidence interval [CI] 8%-19%, p < 0.001). Treatment was successful in only 56% of children with bacteriologically confirmed TB who were infected with HIV who did not receive any antiretroviral treatment (ART) during MDR-TB therapy, compared to 82% in children infected with HIV who received ART during MDR-TB therapy (absolute difference 26%, 95% CI 5%-48%, p = 0.006). In children with confirmed MDR-TB, the use of second-line injectable agents and high-dose isoniazid (15-20 mg/kg/day) were associated with treatment success (adjusted odds ratio [aOR] 2.9, 95% CI 1.0-8.3, p = 0.041 and aOR 5.9, 95% CI 1.7-20.5, p = 0.007, respectively). These findings for high-dose isoniazid may have been affected by site effect, as the majority of patients came from Cape Town. Limitations of this study include the difficulty of estimating the treatment effects of individual drugs within multidrug regimens, only observational cohort studies were available for inclusion, and treatment decisions were based on the clinician's perception of illness, with resulting potential for bias. CONCLUSIONS: This study suggests that children respond favorably to MDR-TB treatment. The low success rate in children infected with HIV who did not receive ART during their MDR-TB treatment highlights the need for ART in these children. Our findings of individual drug effects on treatment outcome should be further evaluated.

Diagnosis of tuberculosis infection in children with a novel skin test and the traditional tuberculin skin test: An observational study.

BACKGROUND: A novel skin test-called Diaskintest (DT)-containing specific M. tuberculosis antigens is in clinical use in the Russian Federation (RF). This test may improve diagnosis of tuberculosis (TB) infection. The use and performance of the DT was described and compared to the tuberculin skin test (TST). METHODS: Data on children <18 years referred to a TB reference centre (Jan/2018- Dec/2019) with ≥1 DT and TST result available were analysed. An immune correlate of TB infection was defined as a positive TST (≥10 mm induration) or a positive DT (any induration). RESULTS: Of 2710 included cases, the median age was 9.0 (IQR 5.7-13.1) years and 97.5% were BCG immunised. Overall, 1976 (79.9%) were TB uninfected, 724 (26.7%) had an immune correlate of TB infection and 10 (0.4%) TB disease. Reasons for referral were: positive or increasing skin test results in routine screening (992, 36.6%), screening before admission to a health care institution (501, 18.5%) and TB contact (457, 16.9%). DT was positive in 11.7% (308/2625) and TST in 63.1% (467/740) (Kappa 0.08, 95% CI:0.013-0.14). A positive DT was associated with older age (OR 1.16 (95% CI: 1.13-1.19) per year). Among TB contacts DT positivity was associated with contagiousness: highest proportion of positivity of 12.0% was observed when the index case was smear positive. CONCLUSION: In a setting with universal BCG vaccination and regular screening with TST, DT was used to rule out TB infection as TST was commonly positive. We found an association of DT positivity and contagiousness of the index case in children contacts. These observations may suggest improved specificity and sensitivity of DT compared to TST.

Prevention of bronchial fistulas after pneumonectomies for selected cavitary drug resistant lung tuberculosis.

Background: The World Health Organization guidelines for management drug resistant tuberculosis include surgery as an additional method in selected cases. Pneumonectomies have higher risk of morbidity such as bronchial fistulas which may be prevented by bronchial stump covering. We compare two methods of bronchial stump reinforcement. Methods and materials: A retrospective single center follow-up study was done in 52 patients who underwent pneumonectomy for drug resistant pulmonary tuberculosis. Between 2000 and 2017 we performed pneumonectomies with pericardial fat reinforcement of bronchial stump in group 1 (n = 42), and between 2017 and 2021 in group 2 with pedicled muscle flap reinforcement group 2 (n = 10). Results: Bronchial fistulas occurred in 17/42 (41%) of patients group 1 and there was no fistula in group 2, and this was statistically different (Fisher's test p = 0.02). Post-operative complications were seen in 24/42 (57%) of the patients in Group 1, and 4/10 (40%) patients in Group 2 (Fischer's test p = 0.53). In group 1 positive bacteriology decreased from 74% to 24% just after surgery, and in group 2 it decreased from 90% to 10%, but this was not statistically different (Fisher's test p = 0.63). In group 1 no-one died the first month, but 8/42 (19%) died within a year; in group 2 one died within a month, and only this death (10%) within a year. This difference in case fatality was not statistically significant. Conclusions: The use of pedicle muscle flap for bronchial stump coverage during the pneumonectomies for destructive drug resistant tuberculosis can prevent severe postoperative fistulas and improve postoperative life.

Treatment of Rifampicin-Resistant Tuberculosis Disease and Infection in Children: Key Updates, Challenges and Opportunities.

Children affected by rifampicin-resistant tuberculosis (RR-TB; TB resistant to at least rifampicin) are a neglected group. Each year an estimated 25,000-30,000 children develop RR-TB disease globally. Improving case detection and treatment initiation is a priority since RR-TB disease is underdiagnosed and undertreated. Untreated paediatric TB has particularly high morbidity and mortality. However, children receiving TB treatment, including for RR-TB, respond well. RR-TB treatment remains a challenge for children, their caregivers and TB programmes, requiring treatment regimens of up to 18 months in duration, often associated with severe and long-term adverse effects. Shorter, safer, effective child-friendly regimens for RR-TB are needed. Preventing progression to disease following Mycobacterium tuberculosis infection is another key component of TB control. The last few years have seen exciting advances. In this article, we highlight key elements of paediatric RR-TB case detection and recent updates, ongoing challenges and forthcoming advances in the treatment of RR-TB disease and infection in children and adolescents. The global TB community must continue to advocate for more and faster research in children on novel and repurposed TB drugs and regimens and increase investments in scaling-up effective approaches, to ensure an equitable response that prioritises the needs of this vulnerable population.

Diagnosis and treatment of patients with pulmonary nontuberculous mycobacterial diseases in Arkhangelsk, Russia.

BACKGROUND: Nontuberculous mycobacteria (NTM) are acid-fast bacilli (AFB) that can cause disease in human. Patients with NTM pulmonary disease can be falsely diagnosed with pulmonary tuberculosis (TB) due detection of AFB in sputum and similar clinical and chest X-ray picture. Laboratory detection of NTM is complicated and does not always mean presence of the disease, but can be attributed to colonization or sample contamination. Molecular tests, such as Genotype Mycobacterium CM/AS, allow quick and reliable detection of NTM. OBJECTIVE: To assess the NTM identification rate, to estimate the incidence of pulmonary NTM disease and to report the treatment outcomes among patients with NTM disease. DESIGN: Retrospective cohort design. RESULTS: NTM were detected among 92 (0.98 per 100,000 population) presumptive pulmonary TB patients in Arkhangelsk region in 2010-2017 among who 39 (0.42 per 100,000 population) patients were diagnosed with NTM disease. The most prevalent species found in our study were M. avium (33%) and M.intracellulare (11%). 69% of patients with NTM disease completed their treatment, 15% died, 13% were lost to follow up and 3% failed treatment. CONCLUSION: A system of diagnostics and treatment for NTM disease was set up in the Arkhangelsk region in Russia. Average NTM identification rate and incidence of pulmonary NTM disease were 0.98 per 100,000 and 0.42 per 100,000 population accordingly and were lower than reported in other studies. Treatment success rate in our study was 69% encouraging further improvements in diagnostics and treatment of patients with NTM.

The Impact of a Line Probe Assay Based Diagnostic Algorithm on Time to Treatment Initiation and Treatment Outcomes for Multidrug Resistant TB Patients in Arkhangelsk Region, Russia.

BACKGROUND: In the Arkhangelsk region of Northern Russia, multidrug-resistant (MDR) tuberculosis (TB) rates in new cases are amongst the highest in the world. In 2014, MDR-TB rates reached 31.7% among new cases and 56.9% among retreatment cases. The development of new diagnostic tools allows for faster detection of both TB and MDR-TB and should lead to reduced transmission by earlier initiation of anti-TB therapy. STUDY AIM: The PROVE-IT (Policy Relevant Outcomes from Validating Evidence on Impact) Russia study aimed to assess the impact of the implementation of line probe assay (LPA) as part of an LPA-based diagnostic algorithm for patients with presumptive MDR-TB focusing on time to treatment initiation with time from first-care seeking visit to the initiation of MDR-TB treatment rather than diagnostic accuracy as the primary outcome, and to assess treatment outcomes. We hypothesized that the implementation of LPA would result in faster time to treatment initiation and better treatment outcomes. METHODS: A culture-based diagnostic algorithm used prior to LPA implementation was compared to an LPA-based algorithm that replaced BacTAlert and Löwenstein Jensen (LJ) for drug sensitivity testing. A total of 295 MDR-TB patients were included in the study, 163 diagnosed with the culture-based algorithm, 132 with the LPA-based algorithm. RESULTS: Among smear positive patients, the implementation of the LPA-based algorithm was associated with a median decrease in time to MDR-TB treatment initiation of 50 and 66 days compared to the culture-based algorithm (BacTAlert and LJ respectively, p<0.001). In smear negative patients, the LPA-based algorithm was associated with a median decrease in time to MDR-TB treatment initiation of 78 days when compared to the culture-based algorithm (LJ, p<0.001). However, several weeks were still needed for treatment initiation in LPA-based algorithm, 24 days in smear positive, and 62 days in smear negative patients. Overall treatment outcomes were better in LPA-based algorithm compared to culture-based algorithm (p = 0.003). Treatment success rates at 20 months of treatment were higher in patients diagnosed with the LPA-based algorithm (65.2%) as compared to those diagnosed with the culture-based algorithm (44.8%). Mortality was also lower in the LPA-based algorithm group (7.6%) compared to the culture-based algorithm group (15.9%). There was no statistically significant difference in smear and culture conversion rates between the two algorithms. CONCLUSION: The results of the study suggest that the introduction of LPA leads to faster time to MDR diagnosis and earlier treatment initiation as well as better treatment outcomes for patients with MDR-TB. These findings also highlight the need for further improvements within the health system to reduce both patient and diagnostic delays to truly optimize the impact of new, rapid diagnostics.