Caregivers' perspectives on health-related quality of life in young children with TB and respiratory illnesses.

BACKGROUND: There is a lack of holistic health-related quality of life (HRQoL) measures for young children with respiratory disease, especially in low- and middle-income countries (LMICs). We aimed to understand caregivers' perceptions of the relevance of common HRQoL domains for children with respiratory diseases, including TB. METHODS: This study was nested in a prospective observational cohort of children presenting with respiratory symptoms presumptive of pulmonary TB. We conducted 10 semi-structured interviews to explore caregivers' perceptions of the five commonly measured HRQoL domains: physical health, social support, emotional and psychological wellbeing, and schooling. We used case descriptive analysis and thematic coding. RESULTS: Caregivers considered all five domains to be relevant. The socio-economic context framed their responses, with QoL requiring sufficient basic resources for children. HRQoL experiences varied according to the severity of the child's symptoms, but not between TB and non-TB illnesses. Manifestations in the psychological domain were difficult to distinguish from the emotional domain. Social support included broad support for family members, indirectly benefiting the children. Caregivers were concerned about their children's early developmental milestones and future schooling. CONCLUSION: This exploratory study shows that HRQoL domains are relevant but require adaptation to be applicable for young children affected by respiratory illnesses living in LMICs.

CONTEXTE: Il existe un manque de mesures holistiques de la qualité de vie liée à la santé (HRQoL) pour les jeunes enfants atteints de maladies respiratoires, en particulier dans les pays à revenu faible ou intermédiaire (LMIC). Nous avons cherché à comprendre la perception qu'ont les soignants de la pertinence des domaines communs de la HRQoL pour les enfants atteints de maladies respiratoires, dont la TB. MÉTHODES: Cette étude était imbriquée dans une cohorte observationnelle prospective d'enfants présentant des symptômes respiratoires présomptifs de TB pulmonaire. Nous avons mené 10 entretiens semi-structurés pour explorer les perceptions des soignants sur les cinq domaines de la HRQoL communément mesurés : santé physique, soutien social, bien-être émotionnel et psychologique, et scolarité. Nous avons utilisé une analyse descriptive des cas et un codage thématique. RÉSULTATS: Les soignants considèrent que les cinq domaines sont pertinents. Le contexte socio-économique encadrait leurs réponses, la QoL nécessitant des ressources de base suffisantes pour les enfants. Les expériences de QoL variaient en fonction de la gravité des symptômes de l'enfant, mais pas entre les maladies TB et non TB. Les manifestations dans le domaine psychologique étaient difficiles à distinguer du domaine émotionnel. Le soutien social comprenait un large soutien aux membres de la famille, ce qui profitait indirectement aux enfants. Les soignants étaient préoccupés par les premiers stades de développement de leurs enfants et par leur future scolarité. CONCLUSION: Cette étude exploratoire montre que les domaines de la QoL sont pertinents mais nécessitent une adaptation pour être applicables aux jeunes enfants atteints de maladies respiratoires vivant dans les LMIC.

Fungal diversity in the gut microbiome of young South African children.

BACKGROUND: The fungal microbiome, or mycobiome, is a poorly described component of the gut ecosystem and little is known about its structure and development in children. In South Africa, there have been no culture-independent evaluations of the child gut mycobiota. This study aimed to characterise the gut mycobiota and explore the relationships between fungi and bacteria in the gut microbiome of children from Cape Town communities. METHODS: Stool samples were collected from children enrolled in the TB-CHAMP clinical trial. Internal transcribed spacer 1 (ITS1) gene sequencing was performed on a total of 115 stool samples using the Illumina MiSeq platform. Differences in fungal diversity and composition in relation to demographic, clinical, and environmental factors were investigated, and correlations between fungi and previously described bacterial populations in the same samples were described. RESULTS: Taxa from the genera Candida and Saccharomyces were detected in all participants. Differential abundance analysis showed that Candida spp. were significantly more abundant in children younger than 2 years compared to older children. The gut mycobiota was less diverse than the bacterial microbiota of the same participants, consistent with the findings of other human microbiome studies. The variation in richness and evenness of fungi was substantial, even between individuals of the same age. There was significant association between vitamin A supplementation and higher fungal alpha diversity (p = 0.047), and girls were shown to have lower fungal alpha diversity (p = 0.003). Co-occurrence between several bacterial taxa and Candida albicans was observed. CONCLUSIONS: The dominant fungal taxa in our study population were similar to those reported in other paediatric studies; however, it remains difficult to identify the true core gut mycobiota due to the challenges set by the low abundance of gut fungi and the lack of true gut colonising species. The connection between the microbiota, vitamin A supplementation, and growth and immunity warrants exploration, especially in populations at risk for micronutrient deficiencies. While we were able to provide insight into the gut mycobiota of young South African children, further functional studies are necessary to explain the role of the mycobiota and the correlations between bacteria and fungi in human health.

Pharmacokinetics of Rifampin, Isoniazid, Pyrazinamide, and Ethambutol in Infants Dosed According to Revised WHO-Recommended Treatment Guidelines.

There are limited pharmacokinetic data for use of the first-line antituberculosis drugs during infancy (<12 months of age), when drug disposition may differ. Intensive pharmacokinetic sampling was performed in infants routinely receiving antituberculosis treatment, including rifampin, isoniazid, pyrazinamide, and ethambutol, using World Health Organization-recommended doses. Regulatory-approved single-drug formulations, including two rifampin suspensions, were used on the sampling day. Assays were conducted using liquid chromatography-mass spectrometry; pharmacokinetic parameters were generated using noncompartmental analysis. Thirty-nine infants were studied; 14 (36%) had culture-confirmed tuberculosis. Fifteen (38%) were premature (<37 weeks gestation); 5 (13%) were HIV infected. The mean corrected age and weight were 6.6 months and 6.45 kg, respectively. The mean maximum plasma concentrations (Cmax) for rifampin, isoniazid, pyrazinamide, and ethambutol were 2.9, 7.9, 41.9, and 1.3 µg/ml, respectively (current recommended adult target concentrations: 8 to 24, 3 to 6, 20 to 50, and 2 to 6 µg/ml, respectively), and the mean areas under the concentration-time curves from 0 to 8 h (AUC0-8) were 12.1, 24.7, 239.4, and 5.1 µg · h/ml, respectively. After adjusting for age and weight, rifampin exposures for the two formulations used differed inCmax(geometric mean ratio [GMR],2.55; 95% confidence interval [CI], 1.47 to 4.41;P= 0.001) and AUC0-8(GMR, 2.52; 95% CI, 1.34 to 4.73;P= 0.005). HIV status was associated with lower pyrazinamideCmax(GMR, 0.85; 95% CI, 0.75 to 0.96;P= 0.013) and AUC0-8(GMR, 0.79; 95% CI, 0.69 to 0.90;P< 0.001) values. No other important differences were observed due to age, weight, prematurity, ethnicity, or gender. In summary, isoniazid and pyrazinamide concentrations in infants compared well with proposed adult target concentrations; ethambutol concentrations were lower but similar to previously reported pediatric studies. The low rifampin exposures require further investigation. (This study has been registered at ClinicalTrials.gov under registration no. NCT01637558.).

Fluoroquinolones for the treatment of tuberculosis in children.

The fluoroquinolones are key components of current multidrug-resistant tuberculosis (MDR-TB) treatment regimens and are being evaluated in shortened treatment regimens as well as in the prevention of drug-resistant TB. The objective of this review was to identify existing evidence for the use of the fluoroquinolones ofloxacin, levofloxacin and moxifloxacin in the treatment of TB in children. Existing data from in vitro, animal and human studies consistently demonstrate the efficacy of the fluoroquinolones against Mycobacterium tuberculosis, with superiority of levofloxacin and moxifloxacin compared to ofloxacin. In vitro and murine studies demonstrated the potential of moxifloxacin to shorten drug-susceptible TB treatment, but in multiple randomized controlled trials shortened fluoroquinolone-containing regimens have not been non-inferior compared to standard therapy. Resistance occurs frequently via mutations in the gyrA gene, and emerges rapidly depending on the fluoroquinolone concentration, with newer more potent fluoroquinolones less likely to develop resistance. Emerging data from paediatric studies underlines the importance of fluoroquinolones in the treatment of MDR-TB in children. There is a paucity of pharmacokinetic data especially in children <5 years of age and HIV-infected children; existing studies show substantially lower serum concentrations in children compared to adults at currently recommended doses, probably due to faster elimination. This has implications for optimizing paediatric treatment and for the development of resistance. Fluoroquinolone use has been restricted in children due to concerns about drug-induced arthropathy. The available data does not demonstrate any serious arthropathy or other severe toxicity in children. Although there is limited paediatric safety data for the prolonged treatment of MDR-TB, extended administration of fluoroquinolones in adults with MDR-TB does not show serious adverse effects and there is no evidence suggesting less tolerability of fluoroquinolones in children. Additional study of moxifloxacin and levofloxacin for TB treatment and prevention in children is an urgent priority.

Ethionamide cross- and co-resistance in children with isoniazid-resistant tuberculosis.

BACKGROUND: Ethionamide (ETH) is a structural analogue of isoniazid (INH). Both are pro-drugs requiring activation by separate and common enzyme pathways, which could lead to co- and/or cross-resistance. OBJECTIVE: To characterise paediatric INH-resistant mycobacterial isolates to investigate the presence of ETH resistance and mutations in the katG gene and the inhA promoter region. METHODS: Forty-five INH-resistant and 19 INH-susceptible Mycobacterium tuberculosis control isolates from children from the Western Cape Province, South Africa, were analysed to quantify INH minimal inhibitory concentration, test for ETH resistance and investigate mutations in the katG gene and/or inhA promoter region. RESULTS: Among 45 INH-resistant children, ETH resistance was present in 19 of 39 (49%). An inhA promoter mutation was identified in 15 (33.3%); 12/14 (86%) of these isolates were also ETH-resistant. Of the 21 isolates with a katG mutation, six (29%) were ETH-resistant. No isolate had both katG and inhA promoter mutations. Nine (20%) isolates had neither inhA promoter nor katG mutations. Of 15 isolates with inhA promoter mutation, 14 (93%) displayed low- or intermediate-level INH resistance. Among the 19 INH-susceptible isolates, ETH resistance was present in 1/18 (6%) and none showed inhA or katG gene mutations. CONCLUSION: We found a high level of cross- and co-resistance with ETH among INH-resistant M. tuberculosis isolates from children in this geographic area.