Health seeking behavior among individuals presenting with chronic cough at referral hospitals in Uganda; missed opportunity for early tuberculosis diagnosis

Funding: This study was conducted with funding from the World Bank under the East African Public Health Laboratory Networking Project (EAPHLNP).Background: Tuberculosis (TB) is the 9th leading cause of death from a single infectious agent. Patients live in a complex health care system with both formal and informal providers, and it is important that a TB diagnosis is not missed at the first interaction with the health care system. In this study, we highlight the health seeking behavior of patients and missed opportunities for early TB diagnosis for which interventions could be instituted to ensure early TB diagnosis and prompt TB treatment initiation. Methods: This study was nested in a cross-sectional study that assessed the accuracy of different Xpert MTB/Rif implementation strategies in programmatic settings at the referral hospitals in Uganda. We documented the symptom profile of presumptive TB patients and assessed the health seeking behavior of those with chronic cough by calculating proportion of patients that visited each type of health facility and further calculated the odds of being TB positive given the type of health facility initially visited for consultation. Results: A total of 1,863 presumptive TB patients were enrolled of which 979 (54.5%) were male, and 1795 (99.9%) had chronic cough. A total of 1352 (75.4%) had previously sought care for chronic cough, with 805 (59.6%) seeking care from a public health facility followed by private health facility (289; 21.4%). Up to 182 (13.5%) patients visited a drug store for chronic cough. Patients whose first contact was a private health facility were more likely to have a positive GeneXpert test (adjOR 1.4, 95% CI: 1.0-1.9; p = 0.047). Conclusions: Chronic cough is a main symptom for many of the presumptive TB patients presenting at referral hospitals, with several patients having to visit the health system more than once before a TB diagnosis is made. This suggests the need for patients to be thoroughly evaluated at first interface with the health care system to ensure prompt diagnosis and treatment initiation. Improved TB diagnosis possibly with the GeneXpert test, at first contact with the health care system has potential to increase TB case finding and break the transmission cycle in the community.Publisher PDFPeer reviewe

Burden of tuberculosis disease among adolescents in a rural cohort in Eastern Uganda

BACKGROUND: The world health organization (WHO) declared tuberculosis (TB) a global emergency, mainly affecting people in sub-Saharan Africa. However there is little data about the burden of TB among adolescents. We estimated the prevalence and incidence of TB and assessed factors associated with TB among adolescents aged 12–18 years in a rural population in Uganda in order to prepare the site for phase III clinical trials with novel TB vaccines among adolescents. METHODS: In a prospective cohort study, we recruited 5000 adolescents and followed them actively, every 6 months, for 1–2 years. Participants suspected of having TB were those who had any of; TB signs and symptoms, history of TB contact or a positive tuberculin skin test (TST) of ≥10 mm. Laboratory investigations included sputum smear microscopy and culture. RESULTS: Of the 5000 participants, eight culture confirmed cases of TB were found at baseline: a prevalence of 160/100,000 (95% confidence interval (CI), 69–315). There were 13 incident TB cases detected in an average of 1.1 person years: an incidence of 235/100,000 person years (95% CI, 125–402). None of the confirmed TB cases were HIV infected. Predictors for prevalent TB disease were: a history of TB contact and a cough ≥ 2 weeks at baseline and being out of school, while the only predictor for incident TB was a positive TST during follow-up. CONCLUSION: The TB incidence among adolescents in this rural part of Uganda seemed too low for a phase III TB vaccine trial. However, the study site demonstrated capability to handle a large number of participants with minimal loss to follow-up and its suitability for future clinical trials. Improved contact tracing in TB program activities is likely to increase TB case detection among adolescents. Future studies should explore possible pockets of higher TB incidence in urban areas and among out of school youth

Do Xpert MTB/RIF Cycle Threshold Values Provide Information about Patient Delays for Tuberculosis Diagnosis?

INTRODUCTION: Early diagnosis and initiation to appropriate treatment is vital for tuberculosis (TB) control. The XpertMTB/RIF (Xpert) assay offers rapid TB diagnosis and quantitative estimation of bacterial burden through Cycle threshold (Ct) values. We assessed whether the Xpert Ct value is associated with delayed TB diagnosis as a potential monitoring tool for TB control programme performance. MATERIALS AND METHODS: This analysis was nested in a prospective study under the routine TB surveillance procedures of the National TB Control Program in Manhica district, Maputo province, Mozambique. Presumptive TB patients were tested using smear microscopy and Xpert. We explored the association between Xpert Ct values and self-reported delay of Xpert-positive TB patients as recorded at the time of diagnosis enrolment. Patients with >60 days of TB symptoms were considered to have long delays. RESULTS: Of 1,483 presumptive TB cases, 580 were diagnosed as TB of whom 505 (87.0%) were due to pulmonary TB and 302 (94.1%) were Xpert positive. Ct values (range, 9.7-46.4) showed a multimodal distribution. The median (IQR) delay was 30 (30-45) days. Ct values showed no correlation with delay (R2 = 0.001, p = 0.621), nor any association with long delays: adjusted odds ratios (AOR) (95% confidence interval [CI]) comparing to >28 cycles 0.99 (0.50-1.96; p = 0.987) for 23-28 cycles, 0.93 (0.50-1.74; p = 0.828) for 16-22 cycles; and 1.05 (0.47-2.36; p = 0.897) for <16 cycles. Being HIV-negative (AOR [95% CI]), 2.05 (1.19-3.51, p = 0.009) and rural residence 1.74 (1.08-2.81, p = 0.023), were independent predictors of long delays. CONCLUSION: Xpert Ct values were not associated with patient delay for TB diagnosis and cannot be used as an indicator of TB control program performance

Cardiovascular risk factors among people with drug-resistant tuberculosis in Uganda

This work was funded by the National Institute for Health Research through the Royal Society of Tropical Medicine and Hygiene.Background Tuberculosis (TB) and its risk factors are independently associated with cardiovascular disease (CVD). We determined the prevalence and associations of CVD risk factors among people with drug-resistant tuberculosis (DRTB) in Uganda. Methods In this cross-sectional study, we enrolled people with microbiologically confirmed DRTB at four treatment sites in Uganda between July to December 2021. The studied CVD risk factors were any history of cigarette smoking, diabetes mellitus (DM) hypertension, high body mass index (BMI), central obesity and dyslipidaemia. We used modified Poisson regression models with robust standard errors to determine factors independently associated with each of dyslipidaemia, hypertension, and central obesity. Results Among 212 participants, 118 (55.7%) had HIV. Overall, 196 (92.5%, 95% confidence interval (CI) 88.0-95.3) had ≥ 1 CVD risk factor. The prevalence; 95% CI of individual CVD risk factors was: dyslipidaemia (62.5%; 55.4–69.1), hypertension (40.6%; 33.8–47.9), central obesity (39.3%; 32.9–46.1), smoking (36.3%; 30.1–43.1), high BMI (8.0%; 5.0–12.8) and DM (6.5%; 3.7–11.1). Dyslipidaemia was associated with an increase in glycated haemoglobin (adjusted prevalence ratio (aPR) 1.14, 95%CI 1.06–1.22). Hypertension was associated with rural residence (aPR 1.89, 95% CI 1.14–3.14) and previous history of smoking (aPR 0.46, 95% CI 0.21–0.98). Central obesity was associated with increasing age (aPR 1.02, 95%CI 1.00–1.03), and elevated diastolic blood pressure (aPR 1.03 95%CI 1.00–1.06). Conclusion There is a high prevalence of CVD risk factors among people with DRTB in Uganda, of which dyslipidaemia is the commonest. We recommend integrated services for identification and management of CVD risk factors in DRTB.Publisher PDFPeer reviewe

Sputum microbiota profiles of treatment-naïve TB patients in Uganda before and during first-line therapy

Information on microbiota dynamics in pulmonary tuberculosis (TB) in Africa is scarce. Here, we sequenced sputa from 120 treatment-naïve TB patients in Uganda, and investigated changes in microbiota of 30 patients with treatment-response follow-up samples. Overall, HIV-status and anti-TB treatment were associated with microbial structural and abundance changes. The predominant phyla were Bacteroidetes, Firmicutes, Proteobacteria, Fusobacteria and Actinobacteria, accounting for nearly 95% of the sputum microbiota composition; the predominant genera across time were Prevotella, Streptococcus, Veillonella, Haemophilus, Neisseria, Alloprevotella, Porphyromonas, Fusobacterium, Gemella, and Rothia. Treatment-response follow-up at month 2 was characterized by a reduction in abundance of Mycobacterium and Fretibacterium, and an increase in Ruminococcus and Peptococcus; month 5 was characterized by a reduction in Tannerella and Fusobacterium, and an increase in members of the family Neisseriaceae. The microbiota core comprised of 44 genera that were stable during treatment. Hierarchical clustering of this core’s abundance distinctly separated baseline (month 0) samples from treatment follow-up samples (months 2/5). We also observed a reduction in microbial diversity with 9.1% (CI 6–14%) of the structural variation attributed to HIV-status and anti-TB treatment. Our findings show discernible microbiota signals associated with treatment with potential to inform anti-TB treatment response monitoring

Patient satisfaction with TB care clinical consultations in Kampala: a cross sectional study.

Background: Patient satisfaction towards care during encounter with clinicians is key for better treatment outcomes. We assessed patient satisfaction with TB clinical care consultations in Kampala, Uganda. Methods: This was a facility-based cross sectional study done between September 2012 and February 2013 using qualitative method of data collection. Participants consecutively completed a pre-tested structured satisfaction questionnaire. A criteria of the rating as good; &gt;75% was considered acceptable, (50-75%) as more effort is needed and &lt;50 as unacceptable and require immediate action was used to categorize data for analysis using Epi-info 7.1.4.0. Results: Of the 260 registered TB patients, 178(68.5%) completed the questionnaire. Overall, 162 (91.0%) were satisfied with the clinical consultation. Factors that contributed to high patient satisfaction, were: time spent with clinician (85.4%), explanation of what was done (87.6%), technical skills (91.6%), personal manner of the clinician seen (91.6%). Factors for low satisfaction were; waiting time before getting an appointment (61.8%), convenience of location of consultation office (53.4%), getting through to the office by phone (21.3%) and length of time waiting at the office (61.2%). Conclusion: Tuberculosis patients in Kampala are satisfied with TB clinical care consultations. Addressing factors with low patient satisfaction may significantly impact on treatment outcome

Prevalence and risk factors of latent Tuberculosis among adolescents in rural Eastern Uganda

Background: Latent Tuberculosis treatment is a key tuberculosis control intervention. Adolescents are a high risk group that is not routinely treated in low income countries. Knowledge of latent Tuberculosis (TB) burden among adolescents may influence policy. Objectives: We determined the prevalence and risk factors of latent TB infection among adolescents in rural Uganda. Methods: We analyzed baseline data from a study that assessed the prevalence and incidence of Tuberculosis disease among adolescents. We extracted socio-demographics, medical assessment information, and tuberculin skin test results and estimated prevalence ratios (PR) of latent TB infection risk factors by binomial regression. Results: The prevalence of latent TB was 16.1%, 95% CI (15.1 \u2013 17.2). Significant risk factors were: a BCG scar, APR 1.29 (95% CI 1.12 \u2013 1.48); male gender, APR 1.37 (95% CI 1.21 \u2013 1.56); age 17 -18 years, APR 1.46 (95% CI 1.24 \u2013 1.71) and 15-16 years, APR 1.25 (95% CI 1.07 \u2013 1.46) compared to 12-14 years; being out of school, APR 1.31 (95% CI 1.05 \u2013 1.62); and a known history of household TB contact in last 2 years, APR 1.91 (95% CI 1.55 \u2013 2.35) Conclusion: Targeted routine latent TB treatment among adolescents out of school may be crucial for TB disease control in low income countries

High Mycobacterium tuberculosis bacillary loads detected by tuberculosis molecular bacterial load assay in patient stool : a potential alternative for nonsputum diagnosis and treatment response monitoring of tuberculosis

Funding: Emmanuel’s doctoral research is supported by European and Developing countries Clinical Trial Partnership (EDCTP)-funded PanACEA II studentship (TR1A2015-1102), and the University of St Andrews St Leonards scholarship. Funding from the Infectious Diseases Institute, Makerere University to Mr Emmanuel Musisi and Dr Abdul Sessolo through Health and Innovation Impact project supported collection of specimens. Enrolment was funded by the Lung MicroCHIP (NIH: U01 HL098964) and K24 (NIH: K24 HL087713) grants through Professor Laurence Huang. Funding from the Scottish Funding Council (SCF)-Global401 Challenges Research Fund (GCRF) supported the TB-MBLA processing of the samples.Not all patients produce sputum, yet most available TB tests use sputum. We investigated the utility of a novel RNA-based quantitative test, the tuberculosis molecular bacterial load assay (TB-MBLA), for the detection and quantification of Mycobacterium tuberculosis in stool. Stools from 100 adult individuals were treated with OMNIgene-sputum reagent and tested using Xpert MTB/RIF ultra (Xpert ultra), auramine O smear microscopy (smear), mycobacterial growth indicator tube (MGIT), and Lowenstein-Jensen (LJ) cultures. The remaining portions were frozen at −20°C and later tested by TB-MBLA. MGIT sputum culture was used as a TB confirmatory test and reference for stool tests. Sixty-one of 100 participants were already confirmed TB positive by MGIT sputum culture, 20 (33%) of whom were HIV coinfected. TB-MBLA detected M. tuberculosis in 57/100 stool samples, including 49 already confirmed for TB. The mean bacterial load measured by stool TB-MBLA was 5.67 ± 1.7 log10 estimated CFU (eCFU) per mL in HIV-coinfected participants, which was higher than the 4.83 ± 1.59 log10 eCFU per mL among the HIV-negative participants (P = 0.04). The sensitivities (95% confidence intervals [CI]) of stool assays were 80% (68 to 89) and 90% (79 to 98) for TB-MBLA and Xpert ultra, which were both higher than the 44% (32 to 58), 64% (51 to 76), and 62% (45 to 77) for smear, MGIT, and Lowenstein-Jensen (LJ) stool cultures, respectively. The specificity (95% CI) of stool assays was highest for smear, at 97% (87 to 100), followed by Xpert ultra at 91% (76 to 98), TB-MBLA at 79% (63 to 90), LJ at 80% (64 to 91), and MGIT at 62% (45 to 77). Twenty-six percent of MGIT and 21% of LJ stool cultures were indeterminate due to contamination. Detection and quantification of viable M. tuberculosis bacilli in stool raises its utility as an alternative to sputum as a sample type for TB diagnosis.Publisher PDFPeer reviewe

Accuracy of the tuberculosis molecular bacterial load assay to diagnose and monitor response to anti-tuberculosis therapy : a longitudinal comparative study with standard-of-care smear microscopy, Xpert MTB/RIF Ultra, and culture in Uganda

Funding: Emmanuel Musisi’s doctoral research was supported by the European and Developing Countries Clinical Trial Partnership (EDCTP)-funded PanACEA II studentship (grant number TR1A2015-1102) and the University of St Andrews St Leonards scholarship. Funding from Makerere University Research and Innovation Fund (MAKRIF) by the Government of Uganda to Emmanuel Musisi and Samuel Wamutu supported collection and processing of specimens. Enrolment was funded by NIH R01 HL128156 and NIH R01 HL143998 grants.BACKGROUND: In 2018, the tuberculosis molecular bacterial load assay (TB-MBLA), a ribosomal RNA-based test, was acknowledged by WHO as a molecular assay that could replace smear microscopy and culture for monitoring tuberculosis treatment response. In this study, we evaluated the accuracy of TB-MBLA for diagnosis and monitoring of treatment response in comparison with standard-of-care tests. METHODS: For this longitudinal prospective study, patients aged 18 years or older with presumptive tuberculosis (coughing for at least 2 weeks, night sweats, and weight loss) were enrolled at China-Uganda Friendship Hospital Naguru (Kampala, Uganda). Participants were evaluated for tuberculosis by TB-MBLA in comparison with Xpert MTB/RIF Ultra (Xpert-Ultra) and smear microscopy, with Mycobacteria Growth Indicator Tube (MGIT) culture as a reference test. Participants who were positive on Xpert-Ultra were enrolled on a standard 6-month anti-tuberculosis regimen, and monitored for treatment response at weeks 2, 8, 17, and 26 after initiation of treatment and then 3 months after treatment. FINDINGS: Between Nov 15, 2019, and June 15, 2022, 210 participants (median age 35 years [IQR 27-44]) were enrolled. 135 (64%) participants were male and 72 (34%) were HIV positive. The pretreatment diagnostic sensitivities of TB-MBLA and Xpert-Ultra were similar (both 99% [95% CI 95-100]) but the specificity was higher for TB-MBLA (90% [83-96]) than for Xpert-Ultra (78% [68-86]). Ten participants were Xpert-Ultra trace positive, eight (80%) of whom were negative by TB-MBLA and MGIT culture. Smear microscopy had lower diagnostic sensitivity (75% [65-83]) but higher specificity (98% [93-100]) than TB-MBLA and Xpert-Ultra. Among participants who were smear microscopy negative, the sensitivity of TB-MBLA was 96% (95 CI 80-100) and was 100% (95% CI 86-100) in those who were HIV positive. 129 (61%) participants were identified as tuberculosis positive by Xpert-Ultra and these individuals were enrolled in the treatment group and monitored for treatment response. According to TB-MBLA, 19 of these patients cleared bacillary load to zero by week 2 of treatment and remained negative throughout the 6-month treatment follow-up. Positivity for tuberculosis decreased with treatment as measured by all tests, but the rate was slower with Xpert-Ultra. Consequently, 31 (33%) of 95 participants were still Xpert-Ultra positive at the end of treatment but were clinically well and negative on TB-MBLA and culture at 6 months of treatment. Two patients were still Xpert-Ultra positive with a further 3 months of post-treatment follow-up. The rate of conversion to negative of the DNA-based Xpert-Ultra was 3·3-times slower than that of the rRNA-based TB-MBLA. Consequently for the same patient, it would take 13 weeks and 52 weeks to reach complete tuberculosis negativity by TB-MBLA and Xpert-Ultra, respectively. Participants who were positive on smear microscopy at 8 weeks, who received an extra month of intensive treatment, had a similar TB-MBLA-measured bacillary load at 8 weeks to those who were smear microscopy negative. INTERPRETATION: TB-MBLA has a similar performance to Xpert-Ultra for pretreatment diagnosis of tuberculosis, but is more accurate at detecting and characterising the response to treatment than Xpert-Ultra and standard-of-care smear microscopy. FUNDING: European and Developing Countries Clinical Trials Partnership, Makerere University Research and Innovation Fund, US National Institutes of Health.Peer reviewe

Incremental Yield of Serial Sputum Cultures for Diagnosis of Tuberculosis among HIV Infected Smear Negative Pulmonary TB Suspects in Kampala, Uganda

Sputum culture is the gold standard for diagnosis of pulmonary tuberculosis (PTB). Although mostly used for research, culture is recommended by the World Health Organization for TB diagnosis among HIV infected smear negative PTB suspects. Even then, the number of sputum samples required remains unspecified. Here, we determined the Incremental Yield (IY) and number of samples required to diagnose an additional PTB case upon second and third serial sputum culture.This was a cross sectional study done between January and March 2011. Serial sputum samples were provided by participants within two days and cultured using Lowenstein Jensen (LJ) and Mycobacteria Growth Indicator Tube (MGIT) methods. A PTB case was defined as a positive culture on either one or both methods. The IY from the second and third serial cultures was determined and the reciprocal of the product of the fractions of IY provided the number of samples required for an additional PTB case. Of the 170 smear negative PTB suspects, 62 (36.5%) met the case definition. The IY of the second sample culture was 12.7%, 23.6% and 12.6% and for the third sample culture was 6.8%, 7.5% and 7.3% with LJ, MGIT and LJ or MGIT, respectively. The number of samples required for an additional PTB case and 95% CI upon the second sample culture were 29.9 (16.6, 156.5), 11.3 (7.6, 21.9) and 20.8 (12.5, 62.7); while for the third sample culture were 55.6 (26.4, 500.4), 35.7 (19.0, 313.8) and 36.1 (19.1, 330.9) by LJ, MGIT and LJ or MGIT respectively.Among HIV infected smear negative PTB suspects in Kampala, 93% of PTB cases are diagnosed upon the second serial sputum culture. The number of cultures needed to diagnose an additional PTB case, ranges from 11–30 and 35–56 by the second and third sputum samples, respectively