Outcomes in children treated for tuberculosis with the new dispersible fixed-dose combinations in Port Moresby.

SETTING: The new child-friendly fixed dose combinations (FDCs) were introduced at Port Moresby General Hospital, Papua New Guinea, in 2016 for the first-line treatment of children (aged <15 years) with tuberculosis (TB) who weighed <25 kg. OBJECTIVE: To describe the characteristics and outcomes for children treated with the new FDCs, and to identify risk factors for unfavourable treatment outcomes. DESIGN: This was a retrospective cohort study of all children treated for TB with the FDCs from August 2016 to August 2017. RESULTS: Of 713 children included, 488 (68%) were diagnosed with pulmonary TB. Only 6 (0.8%) TB cases were bacteriologically confirmed and human immunodeficiency virus (HIV) status was known in 50%. Treatment outcomes were favourable in 425 (60%) children. Of 288 children with unfavourable outcomes, there were 242 (84%) with loss to follow-up (LTFU) and 25 (8.4%) were known to have died. Children who were severely underweight (weight-for-age Z score <-3) on presentation were at greater risk of LTFU compared to children of normal weight on multivariable analysis (aRR 1.3, 95%CI 1.0-1.6, P < 0.05). CONCLUSION: Alternative models of care to decrease LTFU during treatment are needed, including integration with nutritional support. Improving diagnosis through microbiological confirmation of TB and HIV are major challenges to be addressed.

Management of patients with multidrug-resistant tuberculosis.

The emergence of multidrug-resistant tuberculosis (MDR-TB; defined as resistance to at least rifampicin and isoniazid) represents a growing threat to public health and economic growth. Never before in the history of mankind have more patients been affected by MDR-TB than is the case today. The World Health Organization reports that MDR-TB outcomes are poor despite staggeringly high management costs. Moreover, treatment is prolonged, adverse events are common, and the majority of affected patients do not receive adequate treatment. As MDR-TB strains are often resistant to one or more second-line anti-TB drugs, in-depth genotypic and phenotypic drug susceptibility testing is needed to construct personalised treatment regimens to improve treatment outcomes. For the first time in decades, the availability of novel drugs such as bedaquiline allow us to design potent and well-tolerated personalised MDR-TB treatment regimens based solely on oral drugs. In this article, we present management guidance to optimise the diagnosis, algorithm-based treatment, drug dosing and therapeutic drug monitoring, and the management of adverse events and comorbidities, associated with MDR-TB. We also discuss the role of surgery, physiotherapy, rehabilitation, palliative care and smoking cessation in patients with MDR-TB. We hope that incorporating these recommendations into patient care will be helpful in optimising treatment outcomes, and lead to more MDR-TB patients achieving a relapse-free cure.

Development of tuberculosis infection control guidelines in a pediatric HIV clinic in sub-Saharan Africa.

SETTING: A well-established pediatric human immunodeficiency virus (HIV) clinic in Lesotho with initial infection control (IC) measures prioritizing blood-borne disease. In line with international recommendations, services have been expanded to include the management of patients with tuberculosis (TB). The creation of comprehensive IC guidelines with an emphasis on TB has become a priority. OBJECTIVE: To provide a model for developing and implementing IC guidelines in ambulatory care facilities in limited-resource settings with high HIV and TB prevalence. Activities: An IC plan that includes guidance covering both general IC measures and TB-specific guidelines was created by integrating local and international recommendations and emphasizing the importance of administrative measures, environmental controls, and disease-specific precautions. An interdisciplinary committee was established to oversee its implementation, monitoring, and evaluation. DISCUSSION: Development and implementation of IC guidelines in resource-limited settings are feasible and should be a priority in high HIV and TB prevalence areas. Education should be the cornerstone of such endeavors. Many interventions can be implemented with minimal expertise and material resources. Administrative support and institutional investment are essential to the sustainability of an effective IC program.

Contexte : Une consultation pour le virus de l'immunodéficience humaine (VIH) pédiatrique bien établie au Lesotho avec des mesures de lutte initialement dirigées en priorité contre les maladies à transmission sanguine. En accord avec les recommandations internationales, les services se sont élargis pour inclure la prise en charge des patients tuberculeux. L'élaboration de directives complètes de lutte contre les infections (IC), avec un accent particulier sur la tuberculose (TB), est devenue une priorité.Objectif : Fournir un modèle d'élaboration et de mise en œuvre de directives d'IC dans des structures de soins ambulatoires aux ressources limitées mais dans un contexte de prévalence élevée du VIH et de la TB.Activités : Un plan d'IC, qui inclut une guidance couvrant à la fois les mesures d'IC en général et les directives spécifiques à la TB, a été élaboré en intégrant les recommandations locales et internationales et en mettant l'accent sur l'importance des mesures administratives, du contrôle de l'environnement et des précautions spécifiques aux différentes maladies. Un comité interdisciplinaire a été établi afin de superviser sa mise en œuvre, son suivi et son évaluation.Discussion : L'élaboration et la mise en œuvre de directives d'IC dans un contexte de ressources limitées sont faisables et devraient être une priorité dans des zones de prévalence élevée de la TB et du VIH. L'éducation devrait être la pierre angulaire de tels projets. De nombreuses interventions peuvent être mises en œuvre avec une expertise et des ressources matérielles minimales. Le soutien administratif et l'investissement des institutions sont essentiels à la pérennité d'un programme efficace d'IC.

Marco de referencia: Un consultorio reconocido de atención de la infección por el virus de la inmunodeficiencia humana (VIH) en los niños en Lesoto, cuyas medidas de control de las infecciones (IC) daban prelación a las enfermedades transmitidas por vía sanguínea. En concordancia con las recomendaciones internacionales, se ampliaron los servicios a fin de incluir el tratamiento de los pacientes con diagnóstico de tuberculosis (TB). En este contexto, la elaboración de directrices exhaustivas de IC con una atención especial en la TB se convirtió en una prioridad.Objetivo: Aportar un modelo que facilite la elaboración y la ejecución de directrices sobre el IC en los establecimientos de atención ambulatoria cuyos recursos son limitados, en entornos con una alta prevalencia de infección por el VIH y TB.Método: Se elaboró un plan de IC con orientaciones sobre las medidas generales de control además de las medidas específicas de la TB, mediante la integración de las recomendaciones locales e internacionales y destacando la importancia de las medidas administrativas, los controles medioambientales y las precauciones específicas de determinadas enfermedades. Se estableció un comité interdisciplinario que supervisó la ejecución, el seguimiento y la evaluación del plan.Conclusión: Es factible elaborar directrices sobre el IC y ponerlas en práctica en los entornos con recursos limitados. Esta iniciativa debe constituir una prioridad en las regiones con alta prevalencia de infección por el VIH y TB. La educación debe constituir la piedra angular de este tipo de iniciativas. Se pueden llevar a cabo muchas intervenciones con un mínimo de conocimientos técnicos y recursos materiales. El respaldo administrativo y la inversión institucional son elementos primordiales en la sostenibilidad de un programa eficaz de IC.

Novel application of NIH case definitions in a paediatric tuberculosis contact investigation study.

BACKGROUND: International (National Institutes of Health [NIH]) case definitions have been proposed for paediatric tuberculosis (TB) diagnostic studies. The relevance of these definitions for contact tracing studies is unknown. METHODS: We developed case definitions for a community-based contact tracing diagnostic study. We compare disease certainty using protocol-defined and NIH case definitions and describe TB disease spectrum and severity. RESULTS: There were 111 potential disease episodes in 109 (21% human immunodeficiency virus [HIV] infected) of 1093 children enrolled. Based on NIH definitions, there were 8 confirmed, 12 probable, 17 possible and 3 unlikely TB and 2 non-TB episodes. Using protocol case definitions, there were 23 episodes of confirmed, 36 probable, 27 possible and 0 unlikely TB and 21 non-TB. Of 111 potential episodes, 69 were unclassifiable using the NIH definition, while 4 were unclassifiable using the protocol definition. Agreement between definitions was 0.30 (95%CI 0.23-0.38). There were 62 episodes (72%) of non-severe and 24 (28%) of severe TB. CONCLUSIONS: The NIH definition had limited applicability to household contact studies, despite the wide spectrum of disease observed. Further research is needed to develop case definitions relevant to different research settings, including contact investigation to capture the wide spectrum of paediatric TB in clinical research.

Pasting together the preventive therapy puzzle.

In children, the effectiveness of preventive therapy (PT) for tuberculosis (TB) will always be dependent upon the care giver's behaviour, as this determines adherence. We briefly describe the knowledge, attitudes and intended behaviours in care givers of young children referred for PT in a resource-constrained setting with high TB rates. These early efforts describe one critical piece of the PT puzzle: uptake. More behavioural research is needed to understand how the many pieces of this puzzle should be assembled to improve PT usage in children.

It's hard work, but it's worth it: the task of keeping children adherent to isoniazid preventive therapy.

SETTING: Isoniazid preventive therapy (IPT) offers children protection against tuberculosis (TB), but it has been difficult to implement, particularly in developing countries. OBJECTIVE: To understand what encourages or inhibits children from adhering to IPT. DESIGN: In-depth interviews were conducted with two parents of children adherent to IPT and two staff members from three primary health care clinics in high TB prevalence communities. Themes explored were knowledge and attitudes towards IPT, problems in accessing and adhering to treatment, and community responses. RESULTS: Parents administering treatment valued it positively, realised their children's risk of TB, and were positive about the clinic. Nurses acknowledged that resistance to treatment remained, with some parents not wanting to acknowledge risk nor willing to make the effort for their children; there was also considerable misinformation about IPT. Clinic nurses acknowledged problems of staff shortages, lengthy waiting times and conflict between staff and community members. Adherence was affected by social problems, stigma about TB and its link to the human immunodeficiency virus, and the extended treatment period. CONCLUSION: Parents who maintained adherence to the IPT regimen showed that it was possible even in very difficult circumstances. Further effort is required to improve some of the clinic services, correct misinformation, reduce stigma and provide support to parents.

Well-quantified tuberculosis exposure is a reliable surrogate measure of tuberculosis infection.

SETTING: Cape Town, South Africa. OBJECTIVE: To develop a standardized, reliable measure of household tuberculosis (TB) exposure that considers child-specific risk factors. DESIGN: We assessed TB exposure in 536 children. Children were considered Mycobacterium tuberculosis infected if two of three tests of infection were positive. Principal component analysis identified a discrete set of components that collectively described exposure and contributed to a composite contact score. Logistic regression assessed the odds of having M. tuberculosis infection given increasing contact score while controlling for age and past TB treatment. RESULTS: Four components described 68% of data variance: 1) maternal TB and sleep proximity, 2) index case infectivity, 3) duration of exposure, and 4) exposure to multiple index cases. Components were derived from 10 binary questions that contributed to a contact score (range 1-10, median 5, 25th-75th interquartile range [IQR] 4-7). Among children aged 3 months to 6 years with household exposure, the odds of being M. tuberculosis-infected increased by 74% (OR 1.74, 95%CI 1.42-2.12) with each 1-point increase in the contact score. CONCLUSIONS: Well-quantified TB exposure is a good surrogate measure of M. tuberculosis infection in child household contacts in a high-burden setting, and could guide targeted preventive treatment in children at highest risk of M. tuberculosis infection.

Tuberculosis contact investigation in a high-burden setting: house or household?

SETTING: A high tuberculosis (TB) burden setting, South Africa. Two frequently used definitions for 'household' are 1) 'all dwellings on the same plot of land that share the same residential address'; and 2) 'a group of persons who live together in the same dwelling unit and who have the same eating arrangements'. OBJECTIVE: To characterise a household and the outcome of investigations in household child contacts using definition 1 compared to definition 2 during a TB contact investigation. DESIGN: Access to a household (definition 1) was gained via an adult TB case. Children were assessed for TB infection and disease. RESULTS: Household enumeration indicated 25 members of three families living in a main house and a fourth family living in an adjacent structure. Three children were diagnosed with TB and two referred for isoniazid preventive therapy. Families living in the main house shared the main kitchen, while the yard house family used its own kitchen. This household would have been classified as two separate households if definition 2 had been used, and children with TB disease and infection would have been missed. CONCLUSION: The definition of household in TB contact investigation should provide a framework that is broad enough to capture the majority of children at risk.

Opportunities for chemoprophylaxis in children with culture-confirmed tuberculosis.

BACKGROUND AND OBJECTIVES: Chemoprophylaxis is an effective strategy to prevent progression of tuberculosis (TB) in vulnerable children who have had contact with an infectious source of TB. However, many operational gaps prevent implementation of routine chemoprophylaxis in high-burden settings. The TB exposure status and disease spectrum in children diagnosed with culture-confirmed TB are described and missed opportunities for chemoprophylaxis are highlighted. METHODS: All children <13 years of age diagnosed with culture-confirmed TB at a tertiary referral hospital between March 2003 and February 2007 were included. Clinical data were collected from retrospective review of files. TB was classified as pulmonary and extra-pulmonary; disseminated TB included miliary disease and TB meningitis. RESULTS: During the study period, 614 children (327, 53·3% boys, median age 32 months) were diagnosed with culture-confirmed TB. Contact with an infectious adult source case was documented in 333 (54·2%), 237 (71·2%) of whom were <5 years of age, and 24 (7·2%) were HIV-infected and ≥5 years of age. Of those eligible for chemoprophylaxis, missed opportunities were identified in 156/221 (70·6%) children; 127 (81·4%) were <3 years of age, 39 (25%) had disseminated TB and 8 (5·1%) died. The TB source case was the mother or father in 74/156 (47·4%) children. CONCLUSION: Opportunities for initiation of chemoprophylaxis in vulnerable children following TB exposure are often missed. Awareness should be increased among health-care workers and in the community at large regarding the importance of chemoprophylaxis in young and HIV-infected children. Health system strengthening is required to improve delivery of chemoprophylaxis to vulnerable children in close contact with newly diagnosed infectious TB cases.

Environmental tobacco smoke exposure increases Mycobacterium tuberculosis infection risk in children.

BACKGROUND: Data on the association between exposure to environmental tobacco smoke (ETS) and Mycobacterium tuberculosis infection in children are limited. OBJECTIVE: To examine the dose-response effect of ETS exposure on the risk of M. tuberculosis infection in children in a high tuberculosis (TB) burden setting. METHODS: This cross-sectional study included healthy South African children from impoverished urban communities. Data were collected on household ETS and M. tuberculosis exposure, demographics, socio-economic and anthropometric data, M. tuberculosis infection, human immunodeficiency virus and TB disease status. RESULTS: Among 196 children (median age 6.8 years, range 0.3-15.9), 97 (49.5%) were M. tuberculosis - i nfected (tuberculin skin test [TST] ≥ 10 mm) and 128 (65.3%) reported ETS exposure; of these, 81/128 (63.3%) were exposed to ≥ 2 household smokers. The presence of ≥ 2 household smokers was associated with M. tuberculosis infection in univariate analysis, irrespective of TST cut-off point. In analysis adjusting for M. tuberculosis exposure, socio-economic status, age and previous TB treatment, ETS exposure remained associated with M. tuberculosis infection. In univariate and multivariate analysis, pack-years of exposure were associated with risk of TB infection. DISCUSSION: Exposure to ETS is associated with M. tuberculosis infection in children after adjustment for multiple variables, with a dose-response relationship between the degree of ETS exposure and risk of infection. Public health interventions to reduce exposure to tobacco smoke among children in high TB burden settings are urgently needed.

Interferon-gamma release assays and childhood tuberculosis: systematic review and meta-analysis.

BACKGROUND: Children infected with Mycobacterium tuberculosis have significant risk of developing tuberculosis(TB) and can therefore benefit from preventive therapy. OBJECTIVE: To assess the value of interferon-gamma release assays (IGRAs) and the tuberculin skin test (TST)in the diagnosis of TB infection and disease in children. METHODS: Thirty-three studies were included, assessing commercial IGRAs (QuantiFERON®-TB [QFT] andT-SPOT.®TB) and TST. Reference standards for infection were incident TB or TB exposure. Test performance for disease diagnosis was evaluated in studies assessing children with confirmed and/or clinically diagnosed TB,compared to children where TB was excluded. RESULTS: Two small studies measured incident TB in children tested with QFT and found weak positive predictive value. Association of test response with exposure-categorized dichotomously or as a gradient-was similar for all tests. The sensitivity and specificity of all tests were similar in diagnosing the disease. Stratified analysis suggested lower sensitivity for all tests in young or human immuno deficiency virus infected children. CONCLUSIONS: Available data suggest that TST and IGRAs have similar accuracy for the detection of TB infection or the diagnosis of disease in children. Heterogeneous methodology limited the comparability of studies and the interpretation of results. A rigorous, standardized approach to evaluate TB diagnostic tests in children is needed.

Mycobacterial genotype is associated with disease phenotype in children.

OBJECTIVE: To investigate the association between mycobacterial genotype and disease phenotype in children. METHODS: We describe hospitalised children diagnosed with culture-confirmed tuberculosis (TB) in South Africa, a high TB burden setting. Disease phenotype was classified as intrathoracic or extrathoracic based on mycobacterial culture site. Mycobacterial genotyping was completed using spoligotyping. RESULTS: We analysed 421 isolates from 392 children (median age 2 years, range 0.1-12). Intrathoracic disease was present in 294 (75%) children and extrathoracic disease in 98 (25%). The Beijing genotype was the most prevalent (32.9%), followed by the Latin American Mediterranean (LAM, 28.8%), and S genotypes (6.4%). Age was significantly associated with genotype. Children with the Beijing (OR = 2.36, 95%CI 1.21- 4.60) and S genotypes (OR = 3.47, 95%CI 1.26-9.56) were more likely to have extrathoracic disease compared to children infected with the LAM genotype, in analyses adjusted for age and drug resistance. CONCLUSIONS: TB genotype and disease phenotype in children were associated. Beijing and S genotypes were more frequently cultured from extrathoracic cultures, indicating potential improved ability to disseminate. Strain-related phenotypes could explain different disease spectra in geographic settings where certain strains are successful. Studies of mycobacterial human interaction should consider host immune responses, clinical and epidemiological factors.

Recording isoniazid preventive therapy delivery to children: operational challenges.

Despite recommendations to provide isoniazid preventive therapy (IPT) to eligible children aged <5 years who are in close contact with an infectious tuberculosis (TB) case, IPT delivery in high-burden settings remains poor. To evaluate the current system supporting IPT delivery to children in an urban community, South Africa, we reviewed the recording practices of a local clinic regarding management of children exposed to a current adult TB case. No standardised IPT management tools existed. Only 21% of children eligible for IPT had documentation of IPT delivery. There is a need to implement systems that support IPT recommendations in high-burden settings.

Highly discordant T cell responses in individuals with recent exposure to household tuberculosis.

BACKGROUND: There are limited data comparing interferon-gamma release assays (IGRAs) for the detection of Mycobacterium tuberculosis infection in highly endemic settings. METHODS: A cross-sectional household contact study was conducted to measure the agreement of two IGRAs in relation to the tuberculin skin test (TST) to detect M tuberculosis infection and to assess the influence of M tuberculosis exposure and age. RESULTS: In 82 individuals in household contact, 93% of children and 42% of adults had a high M tuberculosis contact score. The TST was positive in 78% of adults and 54% of children, the T-SPOT.TB was positive in 89% of children and 66% of adults and the QuantiFERON TB Gold (QTF) was positive in a similar proportion of adults and children (38.1% and 39.6%). In children there was poor agreement between the TST and T-SPOT.TB (kappa = -0.15) and the T-SPOT.TB and the QTF (kappa = -0.03), but good agreement between the TST and the QTF (kappa = 0.78) using 10 mm cut-off. In adults there was fair to moderate agreement between the TST and T-SPOT.TB (kappa = 0.38), the TST and QTF (kappa = 0.34) and T-SPOT.TB and QTF (kappa = -0.50). High levels of exposure to M tuberculosis were associated with at least a sevenfold odds of being T-SPOT.TB positive (95% CI 7.67 to 508.69) and a threefold odds of being QTF positive (95% CI 3.02 to 30.54). There was a significant difference in the magnitude of T-SPOT.TB early secretory antigenic target (ESAT)-6 and culture filtrate protein 10 kD (CFP-10) spot counts between adults and children. CONCLUSIONS: The T-SPOT.TB may be more sensitive than the TST or QTF for detecting recent M tuberculosis infection in children. Differences between assays and the predictive utility of these findings for subsequent disease development should be prospectively assessed.

High level of discordant IGRA results in HIV-infected adults and children.

SETTING: Tygerberg district, Western Cape Province, South Africa. OBJECTIVE: To measure the agreement of two interferon-gamma release assays (IGRAs) and the tuberculin skin test (TST) for the detection of Mycobacterium tuberculosis infection in human immunodeficiency virus (HIV) infected adults and children in a setting highly endemic for tuberculosis (TB). DESIGN: Cross-sectional study. RESULTS: In HIV-infected adults (n=20) and children (n=23), tests yielded discordant results, with 61% of individuals testing positive with T-SPOT.TB, 41% with TST and 28% with QuantiFERON TB Gold (QTF). In children, there was poor agreement between the TST and T-SPOT.TB (kappa [kappa]=-0.02), but moderate agreement between the TST and QTF (kappa=0.44). In adults, there was moderate agreement between the TST and T-SPOT.TB (kappa=0.43), and the TST and QTF (kappa = 0.46). In children and adults, there was fair agreement between the T-SPOT.TB and QTF (kappa=0.33). Twenty per cent of adults had >or=1 indeterminate IGRA results. CONCLUSIONS: There is poor to moderate agreement between the TST and IGRAs in HIV-infected adults and children. T-SPOT.TB may have improved sensitivity for detection of M. tuberculosis infection in HIV-infected individuals compared to the QTF and the TST. In HIV-infected individuals, IGRA test properties are affected by test cut-off point and nil control responses.

Human immunodeficiency virus status and delayed-type hypersensitivity skin testing in Ugandan children.

BACKGROUND: In previous studies, delayed-type hypersensitivity (DTH) skin testing has been shown to be affected by several factors including nutritional status, intercurrent infection, host immune status, and previous exposure to the antigen being used. OBJECTIVE: To determine the effect of human immunodeficiency virus type 1 (HIV-1) status on DTH skin testing in a cohort of HIV-1-infected and noninfected Ugandan children followed prospectively from birth. DESIGN: Nested case-control study. SETTING: Primary care clinic serving study participants at Mulago Hospital, Makerere University, Kampala, Uganda. PARTICIPANTS: Thirty HIV-1-infected children and 30 age-matched, HIV-1-noninfected children. METHODS: After completion of history and physical, each child underwent Mantoux skin testing with both Candida and purified protein derivative (PPD). Results of skin testing were read in 48 to 72 hours. Complete chart reviews were performed on all children. CD4 lymphocyte counts were obtained on all HIV-1-infected children at the time the skin testing was read. RESULTS: The average age of participants was 67 months (range, 51-92 months). HIV-1-infected children (mean CD4 lymphocyte count, 1069 mL-1; range, 86-3378 mL-1), compared with noninfected, age-matched peers, developed significantly smaller PPD reaction size (mean, 1.18 mm +/- 4.3 vs 3.6 mm +/- 7.6, respectively). Candida responses were not different between the two groups of children. Among HIV-1-infected children, there was a larger Candida reaction size in children who had recently received chloroquine treatment. There was no significant correlation between Candida reactivity and PPD reactivity, progressive HIV-1 disease, or CD4 lymphocyte count. The six children diagnosed clinically with active tuberculosis had lower absolute CD4 lymphocyte counts than children without tuberculosis. Lack of reaction to PPD was associated with lower CD4 lymphocyte counts and progressive HIV-1 disease. CONCLUSIONS: In HIV-1-infected Ugandan children, DTH skin testing was influenced by the choice of antigen selected, HIV-1 infection, and recent treatment with chloroquine. Based on these findings, we believe that further prospective, longitudinal investigation into the role of chloroquine in HIV-1-infected children is needed. We emphasize the limitations of DTH skin testing in HIV-infected children as an adjunct in the diagnosis of active tuberculosis.