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Interrupting transmission events is critical to tuberculosis control. Cough-generated aerosol cultures predict tuberculosis transmission better than microbiological or clinical markers. We hypothesize that highly infectious individuals with pulmonary tuberculosis (positive for cough aerosol cultures) have elevated inflammatory markers and unique transcriptional profiles compared to less infectious individuals. We performed a prospective, longitudinal study using cough aerosol sampling system. We enrolled 142 participants with treatment-naïve pulmonary tuberculosis in Kenya and assessed the association of clinical, microbiologic, and immunologic characteristics with Mycobacterium tuberculosis aerosolization and transmission in 129 household members. Contacts of the forty-three aerosol culture-positive participants (30%) are more likely to have a positive interferon-gamma release assay (85% vs 53%, P = 0.006) and higher median IFNγ level (P < 0.001, 4.28 IU/ml (1.77-5.91) vs. 0.71 (0.01-3.56)) compared to aerosol culture-negative individuals. We find that higher bacillary burden, younger age, larger mean upper arm circumference, and host inflammatory profiles, including elevated serum C-reactive protein and lower plasma TNF levels, associate with positive cough aerosol cultures. Notably, we find pre-treatment whole blood transcriptional profiles associate with aerosol culture status, independent of bacillary load. These findings suggest that tuberculosis infectiousness is associated with epidemiologic characteristics and inflammatory signatures and that these features may identify highly infectious persons. Using cough-generated aerosol cultures, authors probe the inflammatory markers and epidemiological characteristics of individuals with pulmonary tuberculosis, in association with infection state.

Exposure to pulmonary tuberculosis (PTB) culminates in heterogeneous outcomes, including variation in Mtb antigen-specific interferon-gamma (IFN-γ) T-cell responses. IFN-γ-independent cytokines, including tumor necrosis factor (TNF) and interleukin (IL-2), offer potential diagnostic improvements and insights into pathogenesis. We hypothesized that ESAT6/CFP10 TNF and IL-2 responses improve Mtb infection detection among exposed household contacts (HHCs) and are associated with index case Mtb aerosolization (i.e., cough aerosol culture positive for Mtb growth, CAC+) and HIV co-infection. We enrolled individuals with PTB and their HHCs in a longitudinal study in Nairobi, Kenya. We measured TNF and IL-2 in HHCs from QuantiFERON-TB Plus TB1 tube supernatants. An additional 9.2% (25) HHCs beyond the 58.6% (129) with an IFN-γ response demonstrated an antigen-specific increase in IL-2 and TNF. HHCs of CAC + participants were more likely to have positive IL-2 (84.6% vs. 53.8%, p  = 0.02) and IFN-γ (88.0% vs. 54.9%, p  = 0.01), but not TNF responses, compared to CAC-negative individuals. While HIV co-infection in the index was negatively associated with IFN-γ responses in HHCs (35.7% vs. 62.3%, p  = 0.03), IL-2 and TNF responses did not differ. Antigen-specific ESAT6/CFP10 IL-2 and TNF may increase rates of Mtb infection detection and provide insights into Mtb transmission and pathogenesis.

Background Though persons of African descent have one of the widest genetic variability, genetic polymorphisms of drug-metabolising enzymes such as N-Acetyltransferase-2 ( NAT2 ) are understudied. This study aimed to identify prevalent NAT2 single nucleotide polymorphisms (SNPs) and infer their potential effects on enzyme function among Kenyan volunteers with tuberculosis (TB) infection. Genotypic distribution at each SNP and non-random association of alleles were evaluated by testing for Hardy-Weinberg Equilibrium (HWE) and Linkage Disequilibrium (LD). Methods We isolated genomic DNA from cryopreserved Peripheral Blood Mononuclear Cells of 79 volunteers. We amplified the protein-coding region of the NAT2 gene by polymerase chain reaction (PCR) and sequenced PCR products using the Sanger sequencing method. Sequencing reads were mapped and aligned to the NAT2 reference using the Geneious software (Auckland, New Zealand). Statistical analyses were performed using RStudio version 4.3.2 (2023.09.1 + 494). Results The most frequent haplotype was the wild type NAT2 * 4 (37%). Five genetic variants: 282C > T ( NAT2 * 13 ), 341 T > C ( NAT2 * 5 ), 803A > G ( NAT2*12 ), 590G > A ( NAT2*6 ) and 481C > T ( NAT2*11 ) were observed with allele frequencies of 29%, 18%, 6%, 6%, and 4% respectively. According to the bimodal distribution of acetylation activity, the predicted phenotype was 76% rapid (mainly consisting of the wildtype NAT2 * 4 and the NAT2*13A variant). A higher proportion of rapid acetylators were female, 72% vs 28% male ( p  = 0.022, odds ratio [OR] 3.48, 95% confidence interval [CI] 1.21 to 10.48). All variants were in HWE. NAT2 341 T > C was in strong complete LD with the 590G > A variant (D′ = 1.0, r 2  = − 0.39) but not complete LD with the 282C > T variant (D′ = 0.94, r 2  = − 0.54). Conclusion The rapid acetylation haplotypes predominated. Despite the LD observed, none of the SNPs could be termed tag SNP. This study adds to the genetic characterisation data of African populations at NAT2, which may be useful for developing relevant pharmacogenomic tools for TB therapy. To support optimised, pharmacogenomics-guided TB therapy, we recommend genotype-phenotype studies, including studies designed to explore gender-associated differences.

The role of active case-finding (ACF) in improving tuberculosis (TB) prevention and care depends on the infectiousness of persons with undiagnosed TB and the accuracy of screening strategies. To compare undiagnosed community dwellers to persons presenting for healthcare, we evaluated clinicodemographic and microbiologic characteristics, cough aerosol culture (CAC) status, and household contact (HHC) QuantiFERON-Plus (QFT) status by case-finding approach in adults with pulmonary TB. We enrolled 388 Kenyan adults with GeneXpert (excluding trace) and/or culture-confirmed, untreated TB through healthcare presentation (passive case-finding [PCF]; 87%) or ACF (community-based prevalence survey). Interventions included cough aerosol sampling and HHC QFT testing. We performed mixed-effect logistic regression to predict transmission, clustered on index participants. World Health Organization-recommended screening symptoms (W4SS) were more common in the PCF cohort (99% vs 73%, < .001). Traditional makers of infectiousness were less frequent in the ACF cohort. Higher symptom burden (number of reported World Health Organization-recommended 4-symptom screen) associated with higher bacillary burden (lower GeneXpert Ct) (estimate -0.55; 95% confidence interval [CI], -.98 to -.13; = .01). Among 263 participants with CAC, 21% were CAC-positive, none of whom enrolled through ACF. Among 270 HHCs, QFT positivity differed by index CAC status (89% vs 56% in HHCs of CAC-positive and negative participants, respectively; < .001) but not by traditional infectiousness makers or case-finding approach. Index CAC-positive status (adjusted odds ratio [aOR], 11.2; CI, 2.2-58.3), HIV-positive status (aOR, 0.1; CI, .0-.6), and HHCs age (aOR, 1.04; CI, 1.01-1.08), independently predicted HHC QFT positivity. Our findings suggest that ACF may detect a smaller proportion of CAC-positive persons with TB than PCF.

Understanding trends in patient profiles and identifying predictors for adverse outcomes are key to improving the effectiveness of HIV care and treatment programs. Previous work in Kenya has documented findings from a rural setting. This paper describes trends in demographic and clinical characteristics of antiretroviral therapy (ART) treatment cohorts at a large urban, referral HIV clinic and explores treatment outcomes and factors associated with attrition during 12 years of follow-up. This was a retrospective cohort analysis of HIV-infected adults who started ART between January 1, 2004, and September 30, 2015. ART-experienced patients and those with missing data were excluded. The Cochran-Armitage test was used to determine trends in baseline characteristics over time. Cox proportional hazards models were used to determine the effect of baseline characteristics on attrition. ART uptake among older adolescents (15-19 years), youth, and young adults increased over time ( =0.0001). Independent predictors for attrition included (adjusted hazard ratio [95% CI]) male sex: 1.30 (1.16-1.45), =0.0001; age: 15-19 years: 1.83 (1.26-2.66), =0.0014; 20-24 years: 1.93 (1.52-2.44), =0.0001; and 25-29 years: 1.31 (1.11-1.54), =0.0012; marital status - single: 1.27 (1.11-1.44), =0.0005; and divorced/separated: 1.56 (1.30-1.87), =0.0001; urban residence: 1.40 (1.20-1.64), =0.0001; entry into HIV care following hospitalization: 1.31 (1.10-1.57), =0.0026, or transfer from another facility: 1.60 (1.26-2.04), =0.0001; initiation of ART more than 12 months after the date of HIV diagnosis: 1.36 (1.19-1.55), =0.0001, and history of a current or past opportunistic infection (OI): 1.15 (1.02-1.30), =0.0284. Although ART uptake among adolescents and young people increased over time, this group was at increased risk for attrition. Single marital status, urban residence, history of hospitalization or OI, and delayed initiation of ART also predicted attrition. This calls for focused evidence-informed strategies to address attrition and improve outcomes.

Background The success of antiretroviral therapy in resource-scarce settings is an illustration that complex healthcare interventions can be successfully delivered even in fragile health systems. Documenting the success factors in the scale-up of HIV care and treatment in resource constrained settings will enable health systems to prepare for changing population health needs. This study describes changing demographic and clinical characteristics of adult pre-ART cohorts, and identifies predictors of pre-ART attrition at a large urban HIV clinic in Nairobi, Kenya. Methods We conducted a retrospective cohort analysis of data on HIV infected adults (≥15 years) enrolling in pre-ART care between January 2004 and September 2015. Attrition (loss to program) was defined as those who died or were lost to follow-up (having no contact with the facility for at least 6 months). We used Kaplan-Meier survival analysis to determine time to event for the different modes of transition, and Cox proportional hazards models to determine predictors of pre-ART attrition. Results Over the 12 years of observation, there were increases in the proportions of young people (age 15 to 24 years); and patients presenting with early disease (by WHO clinical stage and higher median CD4 cell counts), p = 0.0001 for trend. Independent predictors of attrition included: aHR (95% CI): male gender 1.98 (1.69–2.33), p = 0.0001; age 20–24 years 1.80 (1.37–2.37), p = 0.0001), or 25–34 years 1.22 (1.01–1.47), p = 0.0364; marital status single 1.55 (1.29–1.86), p = 0.0001) or divorced 1.41(1.02–1.95), p = 0.0370; urban residency 1.83 (1.40–2.38), p = 0.0001; CD4 count of 0–100 cells/µl 1.63 (1.003–2.658), p = 0.0486 or CD4 count >500 cells/µl 2.14(1.46–3.14), p = 0.0001. Conclusions In order to optimize the impact of HIV prevention, care and treatment in resource scarce settings, there is an urgent need to implement prevention and treatment interventions targeting young people and patients entering care with severe immunosuppression (CD4 cell counts <100 cells/µl). Additionally, care and treatment programmes should strengthen inter-facility referrals and linkages to improve care coordination and prevent leakages in the HIV care continuum.

Background: Understanding trends in patient profiles and identifying predictors for adverse outcomes are key to improving the effectiveness of HIV care and treatment programs. Previous work in Kenya has documented findings from a rural setting. This paper describes trends in demographic and clinical characteristics of antiretroviral therapy (ART) treatment cohorts at a large urban, referral HIV clinic and explores treatment outcomes and factors associated with attrition during 12 years of follow-up. Methods: This was a retrospective cohort analysis of HIV-infected adults who started ART between January 1, 2004, and September 30, 2015. ART-experienced patients and those with missing data were excluded. The Cochran--Armitage test was used to determine trends in baseline characteristics over time. Cox proportional hazards models were used to determine the effect of baseline characteristics on attrition. Results: ART uptake among older adolescents (15-19 years), youth, and young adults increased over time (p=0.0001). Independent predictors for attrition included (adjusted hazard ratio [95% CI]) male sex: 1.30 (1.16-1.45), p=0.0001; age: 15-19 years: 1.83 (1.26-2.66),p=0.0014; 20-24 years: 1.93 (1.52-2.44), p=0.0001; and 25-29 years: 1.31 (1.11-1.54), p=0.0012; marital status--single: 1.27 (1.11-1.44), p=0.0005; and divorced/separated: 1.56 (1.30-1.87), p=0.0001; urban residence: 1.40 (1.20-1.64), p=0.0001; entry into HIV care following hospitalization: 1.31 (1.10-1.57), p=0.0026, or transfer from another facility: 1.60 (1.26-2.04), p=0.0001; initiation of ART more than 12 months after the date of HIV diagnosis: 1.36 (1.19-1.55), p=0.0001, and history of a current or past opportunistic infection (OI): 1.15 (1.02-1.30), p=0.0284. Conclusion: Although ART uptake among adolescents and young people increased over time, this group was at increased risk for attrition. Single marital status, urban residence, history of hospitalization or OI, and delayed initiation of ART also predicted attrition. This calls for focused evidence-informed strategies to address attrition and improve outcomes. Keywords: antiretroviral therapy, attrition, lost to follow-up, risk factors, electronic medical records, adolescents, urban