Enteropathogen spectrum and effect on antimycobacterial pharmacokinetics among children with tuberculosis in rural Tanzania: a prospective cohort study.
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SUBMITTER: Van Aartsen D
PROVIDER: S-EPMC9174596 | biostudies-literature | 2022 Jun
REPOSITORIES: biostudies-literature
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Enteropathogen spectrum and effect on antimycobacterial pharmacokinetics among children with tuberculosis in rural Tanzania: a prospective cohort study.
Van Aartsen Daniel D Justine Museveni M Mduma Estomih E Mpagama Stellah G SG Alshaer Mohammad H MH Peloquin Charles A CA Mujaga Buliga B Maro Athanasia A Gratz Jean J Kosek Margaret M Liu Jie J Rogawski McQuade Elizabeth T ET Houpt Eric R ER Thomas Tania A TA Heysell Scott K SK
The Lancet. Microbe 20220407 6
<h4>Background</h4>Enteropathy is prevalent in tuberculosis-endemic areas, and it has been shown to impair intestinal absorptive function; therefore, enteropathogen burden might negatively affect antimycobacterial pharmacokinetics, particularly among malnourished children. We sought to quantify enteropathogen burden among children initiating tuberculosis treatment in rural Tanzania and determine the effect of enteropathogen burden on serum antimycobacterial pharmacokinetics.<h4>Methods</h4>We pe ...[more]
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Project description:BackgroundDosing recommendations for treating childhood tuberculosis (TB) were revised by the World Health Organization, yet so far, pharmacokinetic studies that have evaluated these changes are relatively limited. We evaluated plasma drug concentrations of rifampicin (RIF), isoniazid (INH), pyrazinamide (PZA), and ethambutol (EMB) among children undergoing TB treatment in Tanzania when these dosing recommendations were being implemented.MethodsAt the end of intensive-phase TB therapy, blood was obtained 2 hours after witnessed medication administration to estimate the peak drug concentration (C2h), measured using high-performance liquid chromatography or liquid chromatography-tandem mass spectrometry methods. Differences in median drug concentrations were compared on the basis of the weight-based dosing strategy using the Mann-Whitney U test. Risk factors for low drug concentrations were analyzed using multivariate regression analysis.ResultsWe enrolled 51 human immunodeficiency virus-negative children (median age, 5.3 years [range, 0.75-14 years]). The median C2hs were below the target range for each TB drug studied. Compared with children who received the "old" dosages, those who received the "revised" WHO dosages had a higher median C2h for RIF (P = .049) and PZA (P = .015) but not for INH (P = .624) or EMB (P = .143); however, these revised dosages did not result in the target range for RIF, INH, and EMB being achieved. A low starting dose was associated with a low C2h for RIF (P = .005) and PZA (P = .005). Malnutrition was associated with a low C2h for RIF (P = .001) and INH (P = .001).ConclusionsAmong this cohort of human immunodeficiency virus-negative Tanzanian children, use of the revised dosing strategy for treating childhood TB did not result in the target drug concentration for RIF, INH, or EMB being reached.
| S-EPMC7317157 | biostudies-literature
Project description:BACKGROUND:In sub-Saharan Africa, diagnosis and management of extrapulmonary tuberculosis (EPTB) in people living with HIV (PLHIV) remains a major challenge. This study aimed to characterize the epidemiology and risk factors for poor outcome of extrapulmonary tuberculosis in people living with HIV (PLHIV) in a rural setting in Tanzania. METHODS:We included PLHIV >18 years of age enrolled into the Kilombero and Ulanga antiretroviral cohort (KIULARCO) from 2013 to 2017. We assessed the diagnosis of tuberculosis by integrating prospectively collected clinical and microbiological data. We calculated prevalence- and incidence rates and used Cox regression analysis to evaluate the association of risk factors in extrapulmonary tuberculosis (EPTB) with a combined endpoint of lost to follow-up (LTFU) and death. RESULTS:We included 3,129 subjects (64.5% female) with a median age of 38 years (interquartile range [IQR] 31-46) and a median CD4+ cell count of 229/μl (IQR 94-421) at baseline. During the median follow-up of 1.25 years (IQR 0.46-2.85), 574 (18.4%) subjects were diagnosed with tuberculosis, whereof 175 (30.5%) had an extrapulmonary manifestation. Microbiological evidence by Acid-Fast-Bacillus stain (AFB-stain) or Xpert® MTB/RIF was present in 178/483 (36.9%) patients with pulmonary and in 28/175 (16.0%) of patients with extrapulmonary manifestations, respectively. Incidence density rates for pulmonary Tuberculosis (PTB and EPTB were 17.9/1000person-years (py) (95% CI 14.2-22.6) and 5.8/1000 py (95% CI 4.0-8.5), respectively. The combined endpoint of death and LTFU was observed in 1058 (33.8%) patients, most frequently in the subgroup of EPTB (47.2%). Patients with EPTB had a higher rate of the composite outcome of death/LTFU after TB diagnosis than with PTB [HR 1.63, (1.14-2.31); p = 0.006]. The adjusted hazard ratios [HR (95% CI)] for death/LTFU in EPTB patients were significantly increased for patients aged >45 years [HR 1.95, (1.15-3.3); p = 0.013], whereas ART use was protective [HR 0.15, (0.08-0.27); p <0.001]. CONCLUSIONS:Extrapulmonary tuberculosis was a frequent manifestation in this cohort of PLHIV. The diagnosis of EPTB in the absence of histopathology and mycobacterial culture remains challenging even with availability of Xpert® MTB/RIF. Patients with EPTB had increased rates of mortality and LTFU despite early recognition of the disease after enrollment.
| S-EPMC7055864 | biostudies-literature
Project description:PurposeNeurocysticercosis is common in regions endemic for Taenia solium. Active-stage neurocysticercosis can be treated with antiparasitic medication, but so far no study on efficacy and safety has been conducted in Africa.MethodsWe conducted a prospective cohort study on treatment of neurocysticercosis in Tanzania between August 2018 and January 2022. Patients were initially treated with albendazole (15 mg/kg/d) for 10 days and followed up for 6 months. Additionally in July 2021, all participants who then still had cysts were offered a combination therapy consisting of albendazole (15 mg/kg/d) and praziquantel (50 mg/kg/d). Antiparasitic treatment was accompanied by corticosteroid medication and anti-seizure medication if the patient had experienced epileptic seizures before treatment.ResultsSixty-three patients were recruited for this study, of whom 17 had a complete follow-up after albendazole monotherapy. These patients had a total of 138 cysts at baseline, of which 58 (42%) had disappeared or calcified by the end of follow-up. The median cyst reduction was 40% (interquartile range 11-63%). Frequency of epileptic seizures reduced considerably (p < 0.001). Three patients had all active cysts resolved or calcified and of the remaining 14, eight received the combination therapy which resolved 63 of 66 cysts (95%). Adverse events were infrequent and mild to moderate during both treatment cycles.ConclusionCyst resolution was unsatisfactory with albendazole monotherapy but was very high when it was followed by a combination of albendazole and praziquantel.
| S-EPMC10037392 | biostudies-literature
Project description:BACKGROUND:Poor adherence to antiretroviral drugs and viral resistance are the main drivers of treatment failure in HIV-infected patients. In sub-Saharan Africa, avoidance of treatment failure on second-line protease inhibitor therapy is critical as treatment options are limited. METHODS:In the prospective observational study of the Kilombero & Ulanga Antiretroviral Cohort in rural Tanzania, we assessed virologic failure (viral load ≥1,000 copies/mL) and drug resistance mutations in bio-banked plasma samples 6-12 months after initiation of a protease inhibitor-based treatment regimen. Additionally, viral load was measured before start of protease inhibitor, a second time between 1-5 years after start, and at suspected treatment failure in patients with available bio-banked samples. We performed resistance testing if viral load was ≥1000 copies/ml. Risk factors for virologic failure were analyzed using logistic regression. RESULTS:In total, 252 patients were included; of those 56% were female and 21% children. Virologic failure occurred 6-12 months after the start of a protease inhibitor in 26/199 (13.1%) of adults and 7/53 of children (13.2%). The prevalence of virologic failure did not change over time. Nucleoside reverse transcriptase inhibitors drug resistance mutation testing performed at 6-12 months showed a positive signal in only 9/16 adults. No cases of resistance mutations for protease inhibitors were seen at this time. In samples taken between 1-5 years protease inhibitor resistance was demonstrated in 2/7 adults. In adult samples before protease inhibitor start, resistance to nucleoside reverse transcriptase inhibitors was detected in 30/41, and to non-nucleoside reverse-transcriptase inhibitors in 35/41 patients. In 15/16 pediatric samples, resistance to both drug classes but not for protease inhibitors was present. CONCLUSION:Our study confirms high early failure rates in adults and children treated with protease inhibitors, even in the absence of protease inhibitors resistance mutations, suggesting an urgent need for adherence support in this setting.
| S-EPMC6957142 | biostudies-literature
Project description:IntroductionScarce data are available on the epidemiology of hypertension among HIV patients in rural sub-Saharan Africa. We explored the prevalence, incidence and risk factors for incident hypertension among patients who were enrolled in a rural HIV cohort in Tanzania.MethodsProspective longitudinal study including HIV patients enrolled in the Kilombero and Ulanga Antiretroviral Cohort between 2013 and 2015. Non-ART naïve subjects at baseline and pregnant women during follow-up were excluded from the analysis. Incident hypertension was defined as systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg on two consecutive visits. Cox proportional hazards models were used to assess the association of baseline characteristics and incident hypertension.ResultsAmong 955 ART-naïve, eligible subjects, 111 (11.6%) were hypertensive at recruitment. Ten women were excluded due to pregnancy. The remaining 834 individuals contributed 7967 person-months to follow-up (median 231 days, IQR 119-421) and 80 (9.6%) of them developed hypertension during a median follow-up of 144 days from time of enrolment into the cohort [incidence rate 120.0 cases/1000 person-years, 95% confidence interval (CI) 97.2-150.0]. ART was started in 630 (75.5%) patients, with a median follow-up on ART of 7 months (IQR 4-14). Cox regression models identified age [adjusted hazard ratio (aHR) 1.34 per 10 years increase, 95% CI 1.07-1.68, p = 0.010], body mass index (aHR per 5 kg/m2 1.45, 95% CI 1.07-1.99, p = 0.018) and estimated glomerular filtration rate (aHR < 60 versus ≥ 60 ml/min/1.73 m2 3.79, 95% CI 1.60-8.99, p = 0.003) as independent risk factors for hypertension development.ConclusionsThe prevalence and incidence of hypertension were high in our cohort. Traditional cardiovascular risk factors predicted incident hypertension, but no association was observed with immunological or ART status. These data support the implementation of routine hypertension screening and integrated management into HIV programmes in rural sub-Saharan Africa.
| S-EPMC5342176 | biostudies-literature
Project description:AIMS: To define the pharmacokinetics of isoniazid (INH) in children with tuberculosis in relation to the N-acetyltransferase 2 (NAT2) genotype. METHODS: The first order elimination rate constant (k) and area under the concentration curve (AUC) were calculated in 64 children <13 years of age (median 3.8) with respiratory tuberculosis from INH concentrations determined 2-5 hours after a 10 mg/kg INH dose. The NAT2 genotype was determined; 25 children were classified as homozygous slow (SS), 24 as heterozygous fast (FS), and 15 as homozygous fast (FF) acetylators. RESULTS: The mean (SD) k values of the genotypes differed significantly from one another: SS 0.254 (0.046), FS 0.513 (0.074), FF 0.653 (0.117). Within each genotype a median regression of k on age showed a significant decrease in k with age. The mean (SD) INH concentrations (mg/l) two hours after INH administration were SS 8.599 (1.974), FS 5.131 (1.864), and FF 3.938 (1.754). A within genotype regression of 2-hour INH concentrations on age showed a significant increase with age. A within genotype regression of 3-hour, 4-hour, and 5-hour concentrations on age also showed a significant increase with age in each instance. In ethnically similar adults, mean (SD) 2-hour INH concentrations (mg/l) for each genotype were significantly higher than the children's: SS 10.942 (1.740), FS 8.702 (1.841), and FF 6.031 (1.431). CONCLUSIONS: Younger children eliminate INH faster than older children and, as a group, faster than adults, and require a higher mg/kg body weight INH dose to achieve serum concentrations comparable to adults.
| S-EPMC1720436 | biostudies-other
Project description:BackgroundSub-Saharan Africa has the highest rates of child mortality worldwide. Little is known about post-hospital outcomes after an index hospitalization for older children. We determined 12-month post-hospital mortality rate and identified factors associated with higher mortality.MethodsIn this prospective cohort study, we enrolled children 2-12 years of age admitted to the pediatric wards of two public hospitals in northwestern Tanzania. Participants or proxies were contacted at 3, 6 and 12 months post-hospitalization. The primary outcome measured was mortality. Factors associated with mortality were determined using Cox regression analysis.ResultsA total of 506 participants were enrolled. In-hospital mortality rate was 7.7% (39/506). Of the 467 participants discharged, the post-hospital mortality rate was 10.1% (47/467). Sickle cell disease (Hazard Ratio (HR) 3.32, 95% CI 1.44-7.68), severe malnutrition (HR 3.19, 95% CI 1.18-8.57), neurologic diseases (HR 3.51, 95% CI 1.35-9.11), heart disease (HR 7.11, 95% CI, 2.89-17.51), cancer (HR 11.79, 95% CI 4.95-28.03), and septic shock (HR 4.64, 95% CI 1.42-15.08) had higher association with mortality compared to other diagnoses. The risk factors significantly associated with mortality included older age (HR 1.01, 95% CI 1.00-1.08), lower hemoglobin level (HR 0.83, 95% CI 0.76-0.90), lower Glasgow Coma Scale (HR 0.66, 95% CI 0.59-0.74), history of decreased urine output (HR 2.87, 95% CI 1.49-5.53), higher respiratory rate (HR 1.02, 95% CI 1.00-1.03), estimated glomerular filtration rate less than 60 ml/min/1.73m2 (binary) (HR 1.84, 95% CI 1.10-3.10), and lower oxygen saturation (HR 0.96, 95% CI 0.92-0.99).ConclusionsPost-hospital mortality is disturbingly high among children 2-12 years of age in Tanzania. Post-hospital interventions are urgently needed especially for older children with chronic illnesses.
| S-EPMC6091952 | biostudies-literature
Project description:BackgroundGeophagia or soil-eating behavior is common among pregnant women in sub-Saharan Africa, however its relationship with nutritional status demands further investigation. Using a prospective pregnancy cohort from north-eastern Tanzania, we examined the characteristics of geophagia and its association with nutritional status parameters (mid-upper arm circumference (MUAC), vitamin B12, folate, ferritin, and hemoglobin) before conception and throughout the gestational period.MethodsPregnant women (n = 530) were interviewed in each trimester regarding their soil-eating habits. Serum concentrations of vitamin B12, folate, ferritin, and hemoglobin, and MUAC were measured before conception and in each trimester. Cross-sectional comparisons between women who ate and did not eat soil were analyzed using Welch's t-test for continuous variables and χ2-test for categorical variables. The association between changes in nutritional status parameters and the initiation of geophagia was investigated using multivariable logistic regression.ResultsThe prevalence of geophagia in this cohort was 27% (n = 143) with most women initiating geophagia in the third trimester. Pregnant women that ate soil had significantly lower ferritin (p = 0.001) prior to conception and at concentrations diagnostic of iron deficiency (p = 0.022) compared to women who did not eat soil. Geophagia was associated with lower ferritin (p ≤ 0.001) and lower hemoglobin (p < 0.05) in each trimester and lower folate in the third trimester (p = 0.007). A smaller decline in hemoglobin and folate across the gestational period was associated with reduced odds of initiating geophagia in the third trimester (hemoglobin: OR 0.71, p = 0.008; folate: OR 0.97, p = 0.008). There was no significant association between a change in MUAC, serum B12 or ferritin and the initiation of geophagia during pregnancy.ConclusionsPrenatal geophagia is closely related to iron and folate status. A greater decrease in hemoglobin and folate is associated with the initiation of geophagia during pregnancy. These findings are particularly relevant to low- and middle-income settings where geophagia is practiced and the prevalence of anemia in pregnancy is high.
| S-EPMC11881378 | biostudies-literature
Project description:Identification of blood biomarkers that prospectively predict progression of Mycobacterium tuberculosis infection to tuberculosis disease might lead to interventions that combat the tuberculosis epidemic. We aimed to assess whether global gene expression measured in whole blood of healthy people allowed identification of prospective signatures of risk of active tuberculosis disease. RESULTS:Between July 6, 2005, and April 23, 2007, we enrolled 6363 from the ACS study and 4466 from independent South African and Gambian cohorts. 46 progressors and 107 matched controls were identified in the ACS cohort. A 16 gene signature of risk was identified. The signature predicted tuberculosis progression with a sensitivity of 66·1% (95% CI 63·2–68·9) and a specificity of 80·6% (79·2–82·0) in the 12 months preceding tuberculosis diagnosis. The risk signature was validated in an untouched group of adolescents (p=0·018 for RNA sequencing and p=0·0095 for qRT-PCR) and in the independent South African and Gambian cohorts (p values <0·0001 by qRT-PCR) with a sensitivity of 53·7% (42·6–64·3) and a specificity of 82·8% (76·7–86) in 12 months preceding tuberculosis. Interpretation: The whole blood tuberculosis risk signature prospectively identified people at risk of developing active tuberculosis, opening the possibility for targeted intervention to prevent the disease.
2016-03-22 | GSE79362 | GEO
Project description:BackgroundCryptosporidium epidemiology is poorly understood, but infection is suspected of contributing to childhood malnutrition and diarrhea-related mortality worldwide.Methods/findingsA prospective cohort of 108 women and their infants in rural/semi-rural Tanzania were followed from delivery through six months. Cryptosporidium infection was determined in feces using modified Ziehl-Neelsen staining. Breastfeeding/infant feeding practices were queried and anthropometry measured. Maternal Cryptosporidium infection remained high throughout the study (monthly proportion = 44 to 63%). Infection did not differ during lactation or by HIV-serostatus, except that a greater proportion of HIV-positive mothers were infected at Month 1. Infant Cryptosporidium infection remained undetected until Month 2 and uncommon through Month 3 however, by Month 6, 33% of infants were infected. There were no differences in infant infection by HIV-exposure. Overall, exclusive breastfeeding (EBF) was limited, but as the proportion of infants exclusively breastfed declined from 32% at Month 1 to 4% at Month 6, infant infection increased from 0% at Month 1 to 33% at Month 6. Maternal Cryptosporidium infection was associated with increased odds of infant infection (unadjusted OR = 3.18, 95% CI 1.01 to 9.99), while maternal hand washing prior to infant feeding was counterintuitively also associated with increased odds of infant infection (adjusted OR = 5.02, 95% CI = 1.11 to 22.78).ConclusionsBoth mothers and infants living in this setting suffer a high burden of Cryptosporidium infection, and the timing of first infant infection coincides with changes in breastfeeding practices. It is unknown whether this is due to breastfeeding practices reducing pathogen exposure through avoidance of contaminated food/water consumption; and/or breast milk providing important protective immune factors. Without a Cryptosporidium vaccine, and facing considerable diagnostic challenges and ineffective treatment in young infants, minimizing the overall environmental burden (e.g. contaminated water) and particularly, maternal Cryptosporidium infection burden as a means to protect against early infant infection needs prioritization.
| S-EPMC4183438 | biostudies-literature