Socio-economic burden of TB and its impact on child contacts in The Gambia.

OBJECTIVE: To determine the social impact of adult TB on child household contacts living in the Greater Banjul Area, The Gambia. METHODS: This was a prospective observational cohort study among adults (≥18 years) starting treatment for drug-susceptible pulmonary TB between June 2019 and July 2021 who reported having at least one child household contact. We collected data from 51 adults and 180 child contacts at the start of TB treatment (baseline) and again at 6 months of treatment. Participants were asked about expenses for school fees, healthcare, festivities and food security of child contacts. RESULTS: While school attendance of the child contacts remained largely unaffected, there was a significant drop in school performance at 6 months (P < 0.001). Furthermore, child contacts faced significant food insecurity in terms of food quantity and variety available, with up to a four-fold increase in some instances at 6 months compared to baseline (P < 0.001). CONCLUSION: Child contacts face a potential decline in school performance and risk of food insecurity. While a plethora of work is being undertaken to alleviate costs of care for TB patients, further emphasis is needed to ensure educational and social prosperity for child contacts, as adults with TB have socio-economic implications for the wider household.

OBJECTIF: Déterminer l'impact social de la TB de l'adulte sur les contacts familiaux de l'enfant vivant dans la région du Grand Banjul, en Gambie. MÉTHODES: Il s'agissait d'une étude de cohorte observationnelle prospective auprès d'adultes (≥18 ans) commençant un traitement contre la TB pulmonaire sensible aux médicaments entre juin 2019 et juillet 2021 et qui ont déclaré avoir au moins un contact domestique avec un enfant. Nous avons recueilli des données auprès de 51 adultes et 180 enfants contacts au début du traitement contre la TB, puis à nouveau après 6 mois de traitement. Les participants ont été interrogés sur les dépenses liées aux frais de scolarité, aux soins de santé, aux célébrations et à la sécurité alimentaire des enfants contacts. RÉSULTATS: Alors que la fréquentation scolaire des enfants contacts n'a pratiquement pas été affectée, on a constaté une baisse significative des résultats scolaires 6 mois plus tard (P < 0,001). Par ailleurs, les enfants contacts ont été confrontés à une insécurité alimentaire importante en termes de quantité et de variété de nourriture disponible, avec une augmentation d'au moins quatre fois après le traitement de la TB (P < 0,001). CONCLUSION: Les enfants contacts sont confrontés à une baisse potentielle de leurs résultats scolaires et à un risque d'insécurité alimentaire. Alors qu'une multitude de travaux sont entrepris pour réduire les coûts des soins pour les patients atteints de TB, il est nécessaire de mettre davantage l'accent sur la prospérité éducative et sociale des enfants contacts, étant donné que les adultes atteints de TB ont des implications socio-économiques pour l'ensemble du ménage.

Clinical standards for drug-susceptible TB in children and adolescents.

BACKGROUND: 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.

Perspectives of TB survivors and policymakers on post-TB disability.

BACKGROUND: An international multistakeholder participatory workshop was hosted in the Gambia, West Africa, in November 2021. OBJECTIVES: To explore the experiences, challenges and recommendations of workshop participants on health and wellbeing after TB treatment. METHODS: An exploratory, descriptive, qualitative approach was used for data collection through facilitator-guided group discussions. Workshop participants included adolescent and adult TB survivors, and representatives of TB advocacy groups and the policy sector. Discussions were audio-recorded and transcribed verbatim, and the data were analysed using a deductive thematic approach. RESULTS: Overall, 38 participants (22 women) from six West African countries participated in the workshop, comprising 33 TB survivors and advocacy group representatives and 5 participants from the policy sector. Although some TB survivors noted improved ability to carry out physical activities, others continued to experience detrimental effects on their family life, social interactions, physical health and ongoing stigma. Policymakers emphasised the lack of data and clear guidelines on post-TB disability. CONCLUSIONS: Some TB survivors continue to suffer detrimental effects of the illness even after treatment completion. However, available data on post-TB disability is inadequate to support policy adoption. Therefore, there is an urgent need for increased advocacy, awareness and research to bridge knowledge gaps.

CONTEXTE: Un atelier participatif international multipartite a été organisé en Gambie, Afrique de l'Ouest, en novembre 2021. OBJECTIFS: Analyser les expériences, les défis et les recommandations des participants à l'atelier en matière de santé et de bien-être après un traitement antituberculeux. MÉTHODES: Une approche exploratoire, descriptive et qualitative a été utilisée pour le recueil des données par le biais de discussions de groupe encadrées par un animateur. Les participants à l'atelier étaient des adolescents et des adultes ayant survécu à une TB, ainsi que des représentants de groupes de plaidoyer de la TB et du secteur politique. Les discussions ont été enregistrées sur support audio et transcrites textuellement, et les données ont été analysées en utilisant une approche thématique déductive. RÉSULTATS: Au total, 38 participants (22 femmes) de six pays d'Afrique de l'Ouest ont participé à l'atelier, dont 33 représentants de groupes de plaidoyer ayant eux-mêmes survécu à une TB et 5 participants issus du secteur politique. Bien que certaines personnes ayant survécu à une TB aient constaté une amélioration de leur capacité à mener des activités physiques, d'autres ont continué à subir les effets néfastes sur leur vie familiale, leurs interactions sociales, leur santé physique et la stigmatisation permanente. Les responsables politiques ont souligné le manque de données et de directives claires sur le handicap post-TB. CONCLUSIONS: Certaines personnes ayant survécu à une TB continuent de subir les effets néfastes de la maladie, et ce même après la fin du traitement. Cependant, les données disponibles sur le handicap post-TB sont insuffisantes pour soutenir l'adoption de politiques. Il est donc urgent de renforcer le plaidoyer, la sensibilisation et la recherche pour combler les lacunes en matière de connaissances.

Diagnosis of paediatric TB using Xpert® MTB/RIF Ultra on fresh respiratory samples.

OBJECTIVE: To evaluate the diagnostic accuracy of Xpert® MTB/RIF Ultra (Ultra) on fresh respiratory samples for the diagnosis of pulmonary TB (PTB) in children.METHODS: Between July 2017 and December 2019, children with presumed TB were prospectively enrolled at clinical sites in three African countries. Children were assessed using history, physical examination and chest X-ray. Sputum or gastric aspirate samples were analysed using Ultra and culture. The diagnostic accuracy of Ultra was calculated against culture as the reference standard.RESULTS: In total, 547children were included. The median age was 4.7 years, 77 (14.1%) were HIV infected and 77 (14.1%) had bacteriologically confirmed TB. Ultra detected an additional 20 cases in the group of children with negative culture results. The sensitivity of Ultra was 66.3% (95% CI 47-82), and the specificity was 95.4% (95% CI 89-99) when assessed against culture as the reference standard.CONCLUSION: Despite the improved performance of Ultra as compared to Xpert as was previously reported, its sensitivity remains sub-optimal for the detection of TB in children. Ultra detected additional 20 cases which otherwise could not have been detected by culture alone, suggesting that the latter is an imperfect reference standard.

Isoniazid preventive therapy in child household contacts of adults with active TB in Bamako, Mali.

BACKGROUND AND OBJECTIVE: Isoniazid preventive therapy (IPT) is known to reduce the risk of developing active TB in about 59% in children aged ⩽15 years. We assessed adherence, completion and adverse events among children who were household contacts of a newly diagnosed adult with smear-positive TB in Bamako, Mali. METHODS: Children aged <15 years living in the same house with an adult smear-positive index case were enrolled in the study in the Bamako Region after consent was obtained from the parent or legal guardian. Adherence was assessed based on the number of tablets consumed during 6 months. RESULTS: A total of 260 children aged <15 years were identified as household contacts of 207 adult patients with smear-positive TB during the study period. Among all child contacts, 130/260 (50.0%) were aged 0-4 years and were eligible for IPT; 128/130 (98.5%) were started on IPT and 83/128 (64.8%) completed with good adherence at the end of the 6 months, and without any significant adverse events. CONCLUSION: We successfully implemented IPT with good acceptance, but low completion rate. The Mali National TB Program and partners should expand this strategy to reach more children in Bamako and the whole country and create greater awareness in the population.

CADRE ET OBJECTIF: Le traitement préventif par isoniazide (IPT) réduit le risque de développer une TB active chez environ 59% des enfants ⩽15 ans. Nous avons évalué l'observance, l'achèvement du traitement et les évènements indésirables chez des enfants qui étaient contacts domestiques d'un adulte ayant récemment reçu un diagnostic de TB à microscopie positive à Bamako, Mali. MÉTHODES: Les enfants âgés <15 ans vivant sous le même toit qu'un cas index adulte de TB à microscopie positive ont été inclus dans l'étude dans la région de Bamako, après obtention du consentement des parents ou du tuteur légal. L'observance a été évaluée en fonction du nombre de comprimés consommés au cours d'une période de 6 mois. RÉSULTATS: Au total, 260 enfants âgés <15 ans ont été identifiés comme contacts domestiques de 207 patients adultes atteints de TB à microscopie positive pendant la période d'étude. Parmi tous les contacts pédiatriques, 130/260 (50,0%) étaient âgés de 0­4 ans et étaient éligibles à l'IPT ; 128/130 (98,5%) ont été mis sous IPT et 83/128 (64,8%) ont achevé leur traitement avec une bonne observance à la fin de la période de 6 mois, sans évènement indésirable significatif. CONCLUSION: Nous avons mis en place l'ITP avec succès. L'acceptation était bonne mais le taux d'achèvement du traitement était faible. Le programme national de lutte contre la TB du Mali et ses partenaires devraient élargir cette stratégie afin d'inclure davantage d'enfants de Bamako et du pays, et d'accroître la sensibilisation de la population.

Vitamin D deficiency is associated with tuberculosis disease in British children.

BACKGROUND: Basic science, epidemiological and interventional research supports a link between vitamin D and tuberculosis (TB) immunity, infection and disease. We evaluated the association between vitamin D levels and TB infection and disease in UK children recruited to the National Institute for Health Research IGRA Kids Study (NIKS).METHODS: Children presenting between 2011 and 2014 were eligible if they had history of exposure to an adult case with sputum smear/culture-positive TB, or were referred and diagnosed with TB disease. Children were assessed at baseline and at 6-8 weeks for immunological evidence of TB infection (interferon-gamma release assay and/or tuberculin skin test) and evidence of TB disease. Some centres routinely measured total 25-hydroxy vitamin D (25-OHD) levels.RESULTS: A total of 166 children were included. The median 25-OHD levels were higher in non-infected children (45.5 nmol/l) than in those with tuberculous infection (36.2 nmol/l) and TB disease (20.0 nmol/l). The difference between TB infection and disease was statistically significant (P < 0.001). By logistic regression, lower vitamin D levels were associated with TB disease among participants with infection or disease, with no evidence of confounding by age, sex, bacille Calmette-Guérin vaccination status, ethnicity, non-contact referral, season or centre.CONCLUSION: Children with TB disease had lower vitamin D levels than children with infection. Implications for prevention and treatment remain to be established.

Use of resuscitation promoting factors to screen for tuberculosis infection in household-exposed children in The Gambia.

BACKGROUND: Interferon-γ release assays (IGRA) with Resuscitation promoting factor (Rpf) proteins enhanced tuberculosis (TB) screening and diagnosis in adults but have not been evaluated in children. Children often develop paucibacillary TB and their immune response differs from that of adults, which together affect TB disease diagnostics and immunodiagnostics. We assessed the ability of Rpf to identify infection among household TB-exposed children in The Gambia and investigated their ability to discriminate Mycobacterium tuberculosis complex (MTBC) infection from active TB disease in children. METHODS: Detailed clinical investigations were done on 93 household TB-exposed Gambian children and a tuberculin skin test (TST) was administered to asymptomatic children. Venous blood was collected for overnight stimulation with ESAT-6/CFP-10-fusion protein (EC), purified protein derivative and RpfA, B, C, D and E. Interferon gamma (IFN-γ) production was measured by ELISA in supernatants and corrected for the background level. Infection status was defined by IGRA with EC and TB disease by mycobacterial confirmation and/or clinical diagnosis. We compared IFN-γ levels between infected and uninfected children and between infected and TB diseased children using a binomial logistic regression model while correcting for age and sex. A Receiver Operating Characteristics analysis was done to find the best cut-off for IFN-γ level and calculate sensitivity and specificity. RESULTS: Interferon gamma production was significantly higher in infected (IGRA+, n = 45) than in uninfected (IGRA-, n = 20) children after stimulation with RpfA, B, C, and D (P = 0.03; 0.007; 0.03 and 0.003, respectively). Using RpfB and D-specific IFN-γ cut-offs (33.9 pg/mL and 67.0 pg/mL), infection was classified with a sensitivity-specificity combination of 73-92% and 77-72% respectively, which was similar to and better than 65-75% for TST. Moreover, IFN-γ production was higher in infected than in TB diseased children (n = 28, 5 bacteriologically confirmed, 23 clinically diagnosed), following RpfB and D stimulation (P = 0.02 and 0.03, respectively). CONCLUSION: RpfB and RpfD show promising results for childhood MTBC infection screening, and both performed similar to and better than the TST in our study population. Additionally, both antigens appear to discriminate between infection and disease in children and thus warrant further investigation as screening and diagnostic antigens for childhood TB.

Potential cost-effectiveness of a maternal Group B streptococcal vaccine in The Gambia.

OBJECTIVE: To estimate neonatal health benefits and healthcare provider costs of a theoretical Group B streptococcal (GBS) hexavalent maternal vaccination programme in The Gambia, a low-income setting in West Africa. METHODS: A static decision analytic cost-effectiveness model was developed from the healthcare provider perspective. Demographic data and acute care costs were available from studies in The Gambia undertaken in 2012-2015. Further model parameters were taken from United Nations and World Health Organisation sources, supplemented by data from a global systematic review of GBS and literature searches. As vaccine efficacy is not known, we simulated vaccine efficacy estimates of 50-90%. Costs are reported in US dollars. Cost-effectiveness thresholds of one (US$473, very cost effective) and three (US$1420, cost effective) times Gambian GDP were used. RESULTS: Vaccination with a hexavalent vaccine would avert 24 GBS disease cases (55%) and 768 disability adjusted life years compared to current standard of care (no interventions to prevent GBS disease). At vaccine efficacy of 70%, the programme is cost-effective at a maximum vaccine price per dose of 12 US$ (2016 US$), and very cost-effective at a maximum of $3/dose. The total costs of vaccination at $12 is $1,056,962 for one annual cohort of Gambian pregnant women. One-way sensitivity analysis showed that GBS incidence was the most influential parameter on the cost effectiveness ratio. CONCLUSION: The introduction of a hexavalent vaccine would considerably reduce the current burden of GBS disease in The Gambia but to be cost-effective, the vaccine price per dose would need to be $12/dose or less.

Antibody responses to Bordetella pertussis and other childhood vaccines in infants born to mothers who received pertussis vaccine in pregnancy - a prospective, observational cohort study from the United Kingdom.

The maternal Tdap (tetanus, diphtheria and acellular pertussis) vaccination programme in the United Kingdom has successfully reduced cases of pertussis in young infants. In addition to prevention of pertussis cases, it is also important to investigate the persistence of maternal antibodies during infancy and the possible interference of maternal antibodies with infant responses to vaccines. We recruited mother-infant pairs from vaccinated and unvaccinated pregnancies and measured concentrations of immunoglobulin (Ig)G against pertussis toxin (PTx), filamentous haemagglutinin (FHA), pertactin (Prn), diphtheria toxin (DTx), tetanus toxoid (TTx) Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae in mothers and infants at birth, and in infants at 7 weeks and at 5 months. Thirty-one mother-infant pairs were tested. Tdap-vaccinated women had significantly higher antibody against Tdap antigens, compared to unvaccinated women (DTx, P = 0·01; PTx, FHA, Prn and TTx, P < 0·001). All antibodies were actively transferred to the infants (transfer ratio  > 1) with higher transfer of DTx (P = 0·04) and TTx (P = 0·02) antibody in Tdap-vaccinated pregnancies compared to unvaccinated pregnancies. Infants from Tdap-vaccinated pregnancies had significantly elevated antibodies to all antigens at birth (P < 0.001) and at 7 weeks (FHA, Prn, TTx, P < 0·001; DTx, P = 0.01; PTx, P = 0·004) compared to infants from unvaccinated pregnancies. Infants from Tdap-vaccinated and -unvaccinated pregnancies had comparable antibody concentrations following primary pertussis immunization (PTx, P = 0·77; FHA, P = 0·58; Prn, P = 0·60; DTx, P = 0·09; TTx, P = 0·88). These results support maternal immunization as a method of protecting vulnerable infants during their first weeks of life.

The burden of non-TB lung disease presenting to TB clinics in The Gambia: preliminary data in the Xpert® MTB/Rif era.

In some low and middle-income countries, 10-20% of patients presenting with a persistent cough have tuberculosis (TB). Once TB is excluded, health service provision for alternative diagnoses is limited. We prospectively studied patients with two Xpert-negative sputum results presenting to a TB clinic in The Gambia. Of 239 patients, 108 did not have TB; 65/102 (6 were lost to follow-up) had alternative diagnoses, 24.6% of which were non-respiratory; 37/102 had no diagnosis, 27.0% of whom were HIV-1-positive; 37.8% had a history of TB and 24.3% smoked. We highlight the need for general health service integration with TB platforms and exploration of non-TB patients with chronic respiratory symptoms.

Dans certains pays à revenu faible et moyen, 10­20% des patients se présentant avec une toux persistante ont une tuberculose (TB). Une fois que la TB est exclue, la prise en charge des diagnostics alternatifs est limitée. Nous avons étudié de façon prospective les patients ayant eu deux tests de crachats négatifs à l'Xpert® MTB/RIF se présentant à un dispensaire TB en Gambie. Des 239 patients, 108 n'avaient pas de TB ; 65/102 (6 perdus de vue) ont eu un autre diagnostic (non respiratoire dans 24,6% des cas) ; 37/102 n'ont pas eu de diagnostic, dont 27,0% ont été positifs à l'infection par le virus de l'immunodéficience humaine 1, 37,8% avaient des antécédents de TB et 24,3% fumaient. Nous mettons l'accent sur le besoin d'intégration générale des services de santé avec des plateformes TB et une exploration des patients non TB ayant des symptômes respiratoires chroniques.

En algunos países de recursos bajos y medianos, 10­20% de pacientes que acuden a la consulta con tos persistente presentan tuberculosis (TB). Una vez que se ha excluido el diagnóstico de TB, la provisión de servicios de salud para otras afecciones es escasa. En el presente estudio se analizaron de manera prospectiva los pacientes con dos resultados negativos de la prueba Xpert® MTB/RIF en muestras de esputo, que acudían a un consultorio de TB en Gambia. Ciento ocho de los 239 pacientes no presentaban TB. En 65 de 102 pacientes (seis perdidos durante el seguimiento) se definió un diagnóstico diferente de TB y en 24,6% de los casos se trataba de una afección no respiratoria. En 37 de los 102 pacientes no se formuló un diagnóstico y de estos el 27,0% eran positivos frente al virus de la inmunodeficiencia humana, 37,8% tenían antecedente de TB y 24,3% eran fumadores. Los resultados del estudio destacan la necesidad de integrar los servicios generales de salud con las plataformas de atención de la TB y de explorar a los pacientes con síntomas respiratorios crónicos que no presentan TB.

The impact of timing of maternal influenza immunization on infant antibody levels at birth.

Pregnant women and infants are at an increased risk of severe disease after influenza infection. Maternal immunization is a potent tool to protect both these at-risk groups. While the primary aim of maternal influenza vaccination is to protect the mother, a secondary benefit is the transfer of protective antibodies to the infant. A recent study using the tetanus, diphtheria and acellular pertussis (Tdap) vaccine indicated that children born to mothers immunized in the second trimester of pregnancy had the highest antibody titres compared to children immunized in the third trimester. The aim of the current study was to investigate how the timing of maternal influenza immunization impacts infant antibody levels at birth. Antibody titres were assessed in maternal and cord blood samples by both immunoglobulin (Ig)G-binding enzyme-linked immunosorbent assay (ELISA) and haemagglutination inhibition assay (HAI). Antibody titres to the H1N1 component were significantly higher in infants born to mothers vaccinated in either the second or third trimesters than infants born to unvaccinated mothers. HAI levels in the infant were significantly lower when maternal immunization was performed less than 4 weeks before birth. These studies confirm that immunization during pregnancy increases the antibody titre in infants. Importantly, antibody levels in cord blood were significantly higher when the mother was vaccinated in either trimesters 2 or 3, although titres were significantly lower if the mother was immunized less than 4 weeks before birth. Based on these data, seasonal influenza vaccination should continue to be given in pregnancy as soon as it becomes available.

Management of child MDR-TB contacts across countries in the WHO European Region: a survey of current practice.

The World Health Organization European Region has one of the highest rates of multidrug-resistant tuberculosis (MDR-TB) in the world, resulting in many vulnerable children being exposed each year. Evidence for preventive therapy following MDR-TB exposure is limited and current guidance is conflicting. An internet-based survey was performed to determine clinical practice in this region. Seventy-two clinicians from 25 countries participated. Practices related to screening and decision-making were highly variable. Just over half provided preventive therapy for children exposed to MDR-TB; the only characteristic associated with provision was practice within the European Union (adjusted OR 4.07, 95%CI 1.33-12.5).

Identifying children with tuberculosis among household contacts in The Gambia.

SETTING: Greater Banjul Area of the Gambia. OBJECTIVES: To identify co-prevalent tuberculosis (TB) among child contacts of adults with smear-positive TB. DESIGN: Child contacts aged <15 years in the immediate household and compound were prospectively enrolled and evaluated for TB disease using screening questionnaires and the tuberculin skin test (TST). Symptomatic and/or TST-positive (10 mm) contacts were further investigated. RESULTS: Of 4042 child contacts who underwent symptom screening and TST, 3339 (82.6%) were diagnosed as TB-exposed but not infected, 639 (15.8%) were latently infected and 64 (1.6%) had co-prevalent TB. Of the 64 TB cases, 50 (78.1%) were from within the immediate household of the index case, and 14 (21.9%) from within the same compound. Of the 27 asymptomatic but TST-positive children diagnosed with TB, 7 were microbiologically confirmed. The median age of the TB cases was 4.4 years (interquartile range 1.9-6.9); 53.1% were aged <5 years. Of the 4042 child contacts, 206 (5%) slept in the same bed as the index case; 28.1% of all TB cases occurred in this group. Symptom screening alone would have detected only 57.8% of the co-prevalent cases. CONCLUSION: In our community setting, if contact tracing is restricted to symptom screening and immediate households only, nearly half of all co-prevalent TB disease in child contacts would be missed.

The impact of HIV and antiretroviral therapy on TB risk in children: a systematic review and meta-analysis.

BACKGROUND: Children (<15 years) are vulnerable to TB disease following infection, but no systematic review or meta-analysis has quantified the effects of HIV-related immunosuppression or antiretroviral therapy (ART) on their TB incidence. OBJECTIVES: Determine the impact of HIV infection and ART on risk of incident TB disease in children. METHODS: We searched MEDLINE and Embase for studies measuring HIV prevalence in paediatric TB cases ('TB cohorts') and paediatric HIV cohorts reporting TB incidence ('HIV cohorts'). Study quality was assessed using the Newcastle-Ottawa tool. TB cohorts with controls were meta-analysed to determine the incidence rate ratio (IRR) for TB given HIV. HIV cohort data were meta-analysed to estimate the trend in log-IRR versus CD4%, relative incidence by immunological stage and ART-associated protection from TB. RESULTS: 42 TB cohorts and 22 HIV cohorts were included. In the eight TB cohorts with controls, the IRR for TB was 7.9 (95% CI 4.5 to 13.7). HIV-infected children exhibited a reduction in IRR of 0.94 (95% credible interval: 0.83-1.07) per percentage point increase in CD4%. TB incidence was 5.0 (95% CI 4.0 to 6.0) times higher in children with severe compared with non-significant immunosuppression. TB incidence was lower in HIV-infected children on ART (HR: 0.30; 95% CI 0.21 to 0.39). Following initiation of ART, TB incidence declined rapidly over 12 months towards a HR of 0.10 (95% CI 0.04 to 0.25). CONCLUSIONS: HIV is a potent risk factor for paediatric TB, and ART is strongly protective. In HIV-infected children, early diagnosis and ART initiation reduces TB risk. TRIAL REGISTRATION NUMBER: CRD42014014276.

Oral azithromycin given during labour decreases bacterial carriage in the mothers and their offspring: a double-blind randomized trial.

Bacterial sepsis remains a leading cause of death among neonates with Staphylococcus aureus, group B streptococcus (GBS) and Streptococcus pneumoniae identified as the most common causative pathogens in Africa. Asymptomatic bacterial colonization is an intermediate step towards sepsis. We conducted a phase III, double-blind, placebo-controlled randomized trial to determine the impact of giving one oral dose of azithromycin to Gambian women in labour on the nasopharyngeal carriage of S. aureus, GBS or S. pneumoniae in the newborn at day 6 postpartum. Study participants were recruited in a health facility in western Gambia. They were followed for 8 weeks and samples were collected during the first 4 weeks. Between April 2013 and April 2014 we recruited 829 women who delivered 843 babies, including 13 stillbirths. Sixteen babies died during the follow-up period. No maternal deaths were observed. No serious adverse events related to the intervention were reported. According to the intent-to-treat analysis, prevalence of nasopharyngeal carriage of the bacteria of interest in the newborns at day 6 was lower in the intervention arm (28.3% versus 65.1% prevalence ratio 0.43; 95% CI 0.36-0.52, p <0.001). At the same time-point, prevalence of any bacteria in the mother was also lower in the azithromycin group (nasopharynx, 9.3% versus 40.0%, p <0.001; breast milk, 7.9% versus 21.6%, p <0.001; and the vaginal tract, 13.2% versus 24.2%, p <0.001). Differences between arms lasted for at least 4 weeks. Oral azithromycin given to women in labour decreased the carriage of bacteria of interest in mothers and newborns and may lower the risk of neonatal sepsis. Trial registrationClinicalTrials.gov Identifier NCT01800942.

Risk factors for Group B Streptococcus colonisation and disease in Gambian women and their infants.

OBJECTIVES: To determine risk factors for GBS colonisation in Gambian mothers and in their infants from birth to day 60-89 of age. METHODS: Swabs and breastmilk from mothers/infant pairs were collected and cultured on selective agar. Negative samples were analysed for GBS DNA via real-time PCR. Positive isolates were serotyped using multiplex PCR and gel-agarose electrophoresis. RESULTS: Seven hundred and fifty women/infant pairs were recruited. 253 women (33.7%) were GBS-colonised at delivery. The predominant serotypes were: V (55%), II (16%), III (10%), Ia (8%) and Ib (8%). 186 infants were colonised (24.8%) at birth, 181 (24.1%) at 6 days and 96 at day 60-89 (14%). Infants born before 34 weeks of gestation and to women with rectovaginal and breastmilk colonisation at delivery had increased odds of GBS colonisation at birth. Season of birth was associated with increased odds of persistent infant GBS colonisation (dry season vs. wet season AOR 2.9; 95% CI 1.6-5.2). CONCLUSION: GBS colonisation is common in Gambian women at delivery and in their infants to day 60-89 and is dominated by serotype V. In addition to maternal colonisation, breastmilk and season of birth are important risk factors for infant GBS colonisation.

Isoniazid preventive treatment among child contacts of adults with smear-positive tuberculosis in The Gambia.

Setting: Greater Banjul area of The Gambia. Objectives: To evaluate uptake, adherence and completion of treatment among tuberculosis (TB) exposed children in The Gambia when isoniazid preventive treatment (IPT) is delivered at home Design: Child (age <5 years) contacts of adults with smear-positive TB were prospectively enrolled. Following symptom screening, tuberculin skin testing and clinical evaluation where indicated, those without disease were placed on daily isoniazid, provided monthly at home. Adherence was assessed by pill counts and IsoScreen™ urine test. Results: Of 404 contacts aged <5 years, 368 (91.1%) were offered IPT. Of the 328 (89.4%) for whom consent was received and who commenced IPT, 18 (5.5%) dropped out and 310 (94.5%) remained on IPT to the end of the 6-month regimen. Altogether, 255/328 children (77.7%, 95%CI 73.2-82.2) completed all 6 months, with good adherence. The IsoScreen test was positive in 85.3% (435/510) of all tests among those defined as having good adherence by pill count and in 16% (8/50) of those defined as having poor adherence (P < 0.001). A cascade of care analysis showed an overall completion rate with good adherence of 61% for all child contacts. Conclusion: Home-delivered IPT among child contacts of adults with smear-positive TB in The Gambia achieved verifiable high uptake and adherence rates. System rather than patient factors are likely to determine the success of IPT at national level.

Contexte : Région du Grand Banjul en Gambie.Objectifs : Evaluer la couverture, l'adhésion et l'achèvement du traitement parmi des enfants exposés à la tuberculose (TB) en Gambie quand le traitement préventif par isoniazide (TPI) est donné à domicile.Schéma : Les enfants âgés de <5 ans, contacts d'adultes atteints de TB à frottis positif, ont été enrôlés de manière prospective. Après dépistage sur les symptômes, test cutané à la tuberculine et évaluation clinique quand cela était indiqué, les enfants non malades ont été mis sous isoniazide, fourni une fois par mois à domicile. L'adhésion a été évaluée par un comptage des comprimés et par un test urinaire IsoScreen™.Résultats : Sur 404 contacts âgés de <5 ans, 368 (91,1%) ont été invités à bénéficier du TPI, et 328 (89,4%) ont consenti et commencé le TPI. Sur ces 328 enfants, 18 (5,5%) ont abandonné et 310 (94,5%) sont restés sous TPI jusqu'à la fin du 6e mois. Au total, 255/328 enfants (77,7% ; IC95% 73,2­82,2) ont achevé les 6 mois de traitement avec une bonne adhésion. Le test IsoScreen a été positif chez 85,3% (435/510) de tous les tests parmi ceux définis comme ayant une bonne adhésion par le comptage des comprimés et chez 16% (8/50) de ceux définis comme ayant une adhésion médiocre (P < 0,001). L'analyse de la « cascade des soins ¼ a montré, pour tous les enfants contacts, un taux de bonne adhésion d'ensemble de 61%.Conclusion: L'administration à domicile du TPI à des enfants contacts d'adultes atteints de TB à frottis positif en Gambie a abouti à une bonne couverture et à un bon taux d'adhésion, tous deux vérifiables. Ce sont les facteurs de système plutôt que ceux liés au patient qui sont susceptibles de déterminer le succès du TPI au niveau national.

Marco de referencia: La zona del Gran Banjul en Gambia.Objetivos: Evaluar la aceptación del tratamiento preventivo con isoniazida (TPI), su cumplimiento y su compleción por parte de los niños expuestos en Gambia, cuando se suministra el tratamiento en los hogares.Método: Se incluyeron en el estudio de manera prospectiva los niños menores de 5 años de edad que eran contactos de un adulto con diagnóstico de tuberculosis (TB) y baciloscopia positiva. Luego de la detección sistemática a partir de los síntomas, se practicaron la prueba cutánea de la tuberculina y la evaluación clínica cuando estaban indicadas; en caso de ausencia de enfermedad activa se inició el tratamiento diario con isoniazida, la cual se suministraba en el hogar cada mes. Se evaluó el cumplimiento en función del recuento de los comprimidos y la prueba IsoScreen™ en muestras de orina.Resultados: En los 404 contactos menores de 5 años de edad, se ofreció el TPI a 368 niños (91,1%) y 328 lo aceptaron y comenzaron a recibirlo (89,4%). De este grupo, 18 niños abandonaron el tratamiento (5,5%) y 310 recibían aun el medicamento al final del 6 mes (94,5%). De los 328 niños, 255 terminaron los 6 meses de tratamiento, con un cumplimiento satisfactorio (77,7%; IC del 95% de 73,2 hasta 82,2). La prueba IsoScreen fue positiva en el 85,3% (435/510) de los casos definidos con cumplimiento adecuado según el recuento de comprimidos y en el 16% (8/50) de los casos cuyo cumplimiento se consideró deficiente (P < 0,001). El análisis de la trayectoria asistencial reveló que en todos los contactos la tasa global de compleción con cumplimiento satisfactorio fue 61%.Conclusión: El TPI suministrado en el hogar a los niños que son contactos de un adulto con diagnóstico de TB y baciloscopia positiva alcanza altas tasas de aceptación y de cumplimiento que se pueden verificar. Los factores que determinan el éxito del TPI a escala nacional dependen del sistema de salud y no del paciente.

Contribution of Xpert® MTB/RIF to the diagnosis of pulmonary tuberculosis among TB-exposed children in The Gambia.

SETTING: Greater Banjul Area, The Gambia. OBJECTIVE: To conduct a pragmatic evaluation of the Xpert(®) MTB/RIF assay in the diagnosis of tuberculosis (TB) among child contacts. DESIGN: In this prospective study, one induced sputum sample was obtained from TB contacts aged <15 years and tested using fluorescent microscopy, culture and Xpert. The diagnostic accuracy of the microbiological tests was evaluated against culture and 'all TB diagnosis and treatment' as separate reference standards. RESULTS: Using culture as a reference standard, Xpert was positive for Mycobacterium tuberculosis in 6/14 culture-positive and 6/473 culture-negative children, giving a sensitivity and specificity of respectively 42.9% (95%CI 17.7-71.1) and 98.7% (95%CI 97.2-99.5). With 'all TB diagnosis and treatment' as a composite reference standard, combined Xpert and culture tests were positive for M. tuberculosis in 20/62 children with TB disease (32.3%, 95%CI 20.9-45.3), which was comparable to the yield from microscopy, culture and Xpert combined (33.9%, 95%CI 22.3-47.0), but significantly higher than individual yields from each test. CONCLUSION: The sensitivity of Xpert is low in actively traced child contacts, but a combination of Xpert and mycobacterial culture has incremental benefits for the bacteriological confirmation of TB disease.

Differential transcriptomic and metabolic profiles of M. africanum- and M. tuberculosis-infected patients after, but not before, drug treatment.

The epidemiology of Mycobacterium tuberculosis (Mtb) and M. africanum (Maf) suggests differences in their virulence, but the host immune profile to better understand the pathogenesis of tuberculosis (TB) have not been studied. We compared the transcriptomic and metabolic profiles between Mtb- and Maf-infected TB cases to identify host biomarkers associated with lineages-specific pathogenesis and response to anti-TB chemotherapy. Venous blood samples from Mtb- and Maf-infected patients obtained before and after anti-TB treatment were analyzed for cell composition, gene expression and metabolic profiles. Prior to treatment, similar transcriptomic profiles were seen in Maf- and Mtb-infected patients. In contrast, post treatment, over 1600 genes related to immune responses and metabolic diseases were differentially expressed between the groups. Notably, the upstream regulator hepatocyte nuclear factor 4-alpha (HNF4α), which regulated 15% of these genes, was markedly enriched. Serum metabolic profiles were similar in both group pre-treatment, but the decline in pro-inflammatory metabolites post treatment were most pronounced in Mtb-infected patients. Together, the differences in both peripheral blood transcriptomic and serum metabolic profiles between Maf- and Mtb-infected patients observed over the treatment period, might be indicative of intrinsic host factors related to susceptibility to TB and/or differential efficacy of the standard anti-TB treatment on the two lineages.

The influence of paediatric HIV infection on circulating B cell subsets and CXCR5(+) T helper cells.

Antiretroviral therapy (ART) only partially restores HIV-induced alterations in lymphocyte populations. We assessed B and T cell phenotypes in a cohort of children from a single centre in the United Kingdom with perinatally acquired HIV compared to healthy controls. The majority of HIV infected children (44 of 56) were on fully suppressive combination ART. Children with perinatally acquired HIV had significantly lower memory B and CD4(+) CD45RO(+) CXCR5(+) [follicular T helper cell (Tfh)-like] T cell percentages. Detectable viraemia was associated with higher CD21(-) (activated and exhausted/tissue-like memory) B cells. A greater proportion of life spent on suppressive ART was associated with higher memory B cell percentages. These results suggest that early and sustained suppressive ART may preserve B and T cell phenotypes in perinatally acquired HIV and limit deficits in humoral immunity. A lower proportion of circulating Tfh-like cells in HIV infected children appears to be independent of HIV treatment history and ongoing HIV viraemia and warrants further investigation.