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.

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.

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 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.

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.

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.

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.

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.