Phylogenetic inference of inter-population transmission rates for infectious diseases.

Estimating transmission rates is a challenging yet essential aspect of comprehending and controlling the spread of infectious diseases. Various methods exist for estimating transmission rates, each with distinct assumptions, data needs, and constraints. This study introduces a novel phylogenetic approach called transRate, which integrates genetic information with traditional epidemiological approaches to estimate inter-population transmission rates. The phylogenetic method is statistically consistent as the sample size (i.e. the number of pathogen genomes) approaches infinity under the multi-population susceptible-infected-recovered model. Simulation analyses indicate that transRate can accurately estimate the transmission rate with a sample size of 200 ~ 400 pathogen genomes. Using transRate, we analyzed 40,028 high-quality sequences of SARS-CoV-2 in human hosts during the early pandemic. Our analysis uncovered significant transmission between populations even before widespread travel restrictions were implemented. The development of transRate provides valuable insights for scientists and public health officials to enhance their understanding of the pandemic's progression and aiding in preparedness for future viral outbreaks. As public databases for genomic sequences continue to expand, transRate is increasingly vital for tracking and mitigating the spread of infectious diseases.

Bioinformatics mentorship in a resource limited setting.

BACKGROUND: The two recent simultaneous developments of high-throughput sequencing and increased computational power have brought bioinformatics to the forefront as an important tool for effective and efficient biomedical research. Consequently, there have been multiple approaches to developing bioinformatics skills. In resource rich environments, it has been possible to develop and implement formal fully accredited graduate degree training programs in bioinformatics. In resource limited settings with a paucity of expert bioinformaticians, infrastructure and financial resources, the task has been approached by delivering short courses on bioinformatics-lasting only a few days to a couple of weeks. Alternatively, courses are offered online, usually over a period of a few months. These approaches are limited by both the lack of sustained in-person trainer-trainee interactions, which is a key part of quality mentorships and short durations which constrain the amount of learning that can be achieved. METHODS: Here, we pioneered and tested a bioinformatics training/mentorship model that effectively uses the available expertise and computational infrastructure to deliver an in-person hands-on skills training experience. This is done through a few physical lecture hours each week, guided personal coursework over the rest of the week, group discussions and continuous close mentorship and assessment of trainees over a period of 1 year. RESULTS: This model has now completed its third iteration at Makerere University and has successfully mentored trainees, who have progressed to a variety of viable career paths. CONCLUSIONS: One-year (intermediate) skills based in-person bioinformatics training and mentorships are viable, effective and particularly appropriate for resource limited settings.

Transmission Dynamics in Tuberculosis Patients With Human Immunodeficiency Virus: A Systematic Review and Meta-analysis of 32 Observational Studies.

BACKGROUND: There are large knowledge gaps on the transmission dynamics of Mycobacterium tuberculosis in settings where both tuberculosis and human immunodeficiency virus (HIV) are endemic. We aimed to assess the infectiousness of tuberculosis patients coinfected with HIV. METHODS: We systematically searched for studies of contacts of both HIV-positive and HIV-negative tuberculosis index cases. Our primary outcome was Mycobacterium tuberculosis infection in contacts. Data on sputum smear and lung cavitation status of index cases were extracted from each study to assess effect modification. Secondary outcomes included prevalent tuberculosis and HIV in contacts of HIV-positive and HIV-negative index cases. RESULTS: Of 5255 original citations identified, 32 studies met inclusion criteria, including 25 studies investigating M. tuberculosis infection (Nparticipants = 36 893), 13 on tuberculosis (Nparticipants = 18 853), and 12 on HIV positivity (Nparticipants = 18 424). Risk of M. tuberculosis infection was lower in contacts of HIV-positive index cases (odds ratio [OR], 0.67, 95% confidence interval [CI], .58-.77) but was heterogeneous (I2 = 75.1%). Two factors modified this relationship: the lung cavitary status of the index case and immunosuppression (measured through CD4 counts or HIV or acquired immunodeficiency syndrome diagnoses) among index people living with HIV. Rates of HIV were consistently higher in contacts of coinfected index cases (OR, 4.9; 95% CI, 3.0-8.0). This was modified by whether the study was in sub-Saharan Africa (OR, 2.8; 95% CI, 1.6-4.9) or in another global region (OR, 9.8; 95% CI, 5.9-16.3). CONCLUSIONS: Tuberculosis patients coinfected with HIV are less infectious than HIV-uninfected cases when they have severe immunosuppression or paucibacillary disease. Contacts of coinfected index cases are almost 5 times more likely to also have HIV.

Excess Risk of Tuberculosis Infection Among Extra-household Contacts of Tuberculosis Cases in an African City.

BACKGROUND: Although households of tuberculosis (TB) cases represent a setting for intense transmission of Mycobacterium tuberculosis, household exposure accounts for <20% of transmission within a community. The aim of this study was to estimate excess risk of M. tuberculosis infection among household and extra-household contacts of index cases. METHODS: We performed a cross-sectional study in Kampala, Uganda, to delineate social networks of TB cases and matched controls without TB. We estimated the age-stratified prevalence difference of TB infection between case and control networks, partitioned as household and extra-household contacts. RESULTS: We enrolled 123 index cases, 124 index controls, and 2415 first-degree network contacts. The prevalence of infection was highest among household contacts of cases (61.5%), lowest among household contacts of controls (25.2%), and intermediary among extra-household TB contacts (44.9%) and extra-household control contacts (41.2%). The age-adjusted prevalence difference between extra-household contacts of cases and their controls was 5.4%. The prevalence of infection was similar among the majority of extra-household case contacts and corresponding controls (47%). CONCLUSIONS: Most first-degree social network members of TB cases do not have adequate contact with the index case to experience additional risk for infection, but appear instead to acquire infection through unrecognized exposures with infectious cases in the community.

Association between tuberculosis in men and social network structure in Kampala, Uganda.

BACKGROUND: Globally, tuberculosis disease (TB) is more common among males than females. Recent research proposes that differences in social mixing by sex could alter infection patterns in TB. We examine evidence for two mechanisms by which social-mixing could increase men's contact rates with TB cases. First, men could be positioned in social networks such that they contact more people or social groups. Second, preferential mixing by sex could prime men to have more exposure to TB cases. METHODS: We compared the networks of male and female TB cases and healthy matched controls living in Kampala, Uganda. Specifically, we estimated their positions in social networks (network distance to TB cases, degree, betweenness, and closeness) and assortativity patterns (mixing with adult men, women, and children inside and outside the household). RESULTS: The observed network consisted of 11,840 individuals. There were few differences in estimates of node position by sex. We found distinct mixing patterns by sex and TB disease status including that TB cases have proportionally more adult male contacts and fewer contacts with children. CONCLUSIONS: This analysis used a network approach to study how social mixing patterns are associated with TB disease. Understanding these mechanisms may have implications for designing targeted intervention strategies in high-burden populations.

Heme oxygenase-1 and neopterin plasma/serum levels and their role in diagnosing active and latent TB among HIV/TB co-infected patients: a cross sectional study.

BACKGROUND: Tuberculosis (TB) diagnosis in the context of HIV co-infection remains challenging. Heme oxygenase 1 (HO-1) and neopterin have been validated as potential biomarkers for TB diagnosis. Latent TB infection (LTBI) is diagnosed using tuberculin skin test (TST) and interferon gamma release assays (T-Spot and QuantiFERON TB gold tests, respectively). However, these tests have shown challenges and yet diagnosing LTBI is important for the overall control of TB. This study was conducted to determine the levels of H0-1 and neopterin, and their role in the diagnosis of TB among individuals enrolled in the Community Health and Social Network of Tuberculosis (COHSONET) study and the Kampala TB Drug Resistance Survey (KDRS). METHODS: This was a nested cross-sectional study. Plasma and serum samples collected from 140 patients at Mulago National Referral Hospital, Kampala Uganda were used. M.tb culture was performed on sputum to confirm active TB(ATB) and QuantiFERON TB gold test to confirm latent TB infection (LTBI). ELISAs were performed to determine the levels of HO-1 and neopterin. Data analysis was done using t-test and Receiver Operating Characteristic curves to determine the diagnostic accuracy. RESULTS: HO-1 levels among active tuberculosis (ATB)/HIV-infected patients and LTBI/HIV-infected patients were 10.7 ng/ml (IQR: 7.3-12.7 ng/ml) and 7.5 ng/ml (IQR: 5.4-14.1 ng/ml) respectively. Neopterin levels among ATB/HIV-positive patients and LTBI/HIV-positive patients were 11.7 ng/ml (IQR: 5.2.4 ng/ml) and 8.8 ng/ml (IQR: 2.4-19.8 ng/ml), respectively. HO-1 showed a sensitivity of 58.57% and a specificity of 67.14% with area under the curve (AUC) of 0.57 when used to discriminate between ATB and LTB. Neopterin showed an AUC of 0.62 with a sensitivity of 57.14% and a specificity of 60.0% when used to distinguish ATB from LTB. CONCLUSION: There was no in significant difference in HO-1 concentration levels of ATB individuals compared to LTB individuals. There was a significant difference in neopterin concentrations levels of ATB individuals compared to latently infected individuals. Findings from this study, show that HO-1 and neopterin have poor ability to distinguish between ATB and LTB.

Modeling Approaches to Predicting Persistent Hotspots in SCORE Studies for Gaining Control of Schistosomiasis Mansoni in Kenya and Tanzania.

BACKGROUND: Some villages, labeled "persistent hotspots (PHS)," fail to respond adequately in regard to prevalence and intensity of infection to mass drug administration (MDA) for schistosomiasis. Early identification of PHS, for example, before initiating or after 1 or 2 years of MDA could help guide programmatic decision making. METHODS: In a study with multiple rounds of MDA, data collected before the third MDA were used to predict PHS. We assessed 6 predictive approaches using data from before MDA and after 2 rounds of annual MDA from Kenya and Tanzania. RESULTS: Generalized linear models with variable selection possessed relatively stable performance compared with tree-based methods. Models applied to Kenya data alone or combined data from Kenya and Tanzania could reach over 80% predictive accuracy, whereas predicting PHS for Tanzania was challenging. Models developed from one country and validated in another failed to achieve satisfactory performance. Several Year-3 variables were identified as key predictors. CONCLUSIONS: Statistical models applied to Year-3 data could help predict PHS and guide program decisions, with infection intensity, prevalence of heavy infections (≥400 eggs/gram of feces), and total prevalence being particularly important factors. Additional studies including more variables and locations could help in developing generalizable models.

Defining adequate contact for transmission of Mycobacterium tuberculosis in an African urban environment.

BACKGROUND: The risk of infection from respiratory pathogens increases according to the contact rate between the infectious case and susceptible contact, but the definition of adequate contact for transmission is not standard. In this study we aimed to identify factors that can explain the level of contact between tuberculosis cases and their social networks in an African urban environment. METHODS: This was a cross-sectional study conducted in Kampala, Uganda from 2013 to 2017. We carried out an exploratory factor analysis (EFA) in social network data from tuberculosis cases and their contacts. We evaluated the factorability of the data to EFA using the Kaiser-Meyer-Olkin Measure of Sampling Adequacy (KMO). We used principal axis factoring with oblique rotation to extract and rotate the factors, then we calculated factor scores for each using the weighted sum scores method. We assessed construct validity of the factors by associating the factors with other variables related to social mixing. RESULTS: Tuberculosis cases (N = 120) listed their encounters with 1154 members of their social networks. Two factors were identified, the first named "Setting" captured 61% of the variance whereas the second, named 'Relationship' captured 21%. Median scores for the setting and relationship factors were 10.2 (IQR 7.0, 13.6) and 7.7 (IQR 6.4, 10.1) respectively. Setting and Relationship scores varied according to the age, gender, and nature of the relationship among tuberculosis cases and their contacts. Family members had a higher median setting score (13.8, IQR 11.6, 15.7) than non-family members (7.2, IQR 6.2, 9.4). The median relationship score in family members (9.9, IQR 7.6, 11.5) was also higher than in non-family members (6.9, IQR 5.6, 8.1). For both factors, household contacts had higher scores than extra-household contacts (p < .0001). Contacts of male cases had a lower setting score as opposed to contacts of female cases. In contrast, contacts of male and female cases had similar relationship scores. CONCLUSIONS: In this large cross-sectional study from an urban African setting, we identified two factors that can assess adequate contact between tuberculosis cases and their social network members. These findings also confirm the complexity and heterogeneity of social mixing.

Tracking Progress Toward Elimination of Mother to Child Transmission of HIV in Zambia: Findings from the Early Infant Diagnosis of HIV Program (2009-2017).

BACKGROUND: We carried out analyses of early infant testing results at Livingstone Central Hospital in Zambia to assess time of testing, linkages to care and availability of test results for clinical decision making. METHODS: We abstracted data from registers of HIV-exposed infants who had dried blood spots cards (DBS) collected for DNA-PCR from January 2009 to December 2017. Only those tested from 2014 to 2017 had additional data which were used to estimate risk factors for mother-to-child HIV transmission using logistic regression models. RESULTS: DBS were collected from 2630 children. The proportion of HIV-positive tests decreased from 21% in 2009 to 2% in 2016 and 2017. Median turnaround time for results was 9 weeks (IQR: 5, 15) for HIV-negative, 7 weeks (IQR: 5, 13) for HIV-positive children. Only 2% of infants whose mothers took antiretroviral therapy (ART) were HIV positive, while 18% of infants whose mothers took short course antiretroviral drugs (ARVs) were infected. Infants of mothers who did not take ARVs had 9 times the odds of an HIV positive test (OR = 8.9, 95% CI: 3.6, 22.6). Infants of mothers who received short course ARVs were 40% less likely to get an HIV test within the first 2 months of life (OR = 0.6, 95% CI: 0.4, 0.9) compared to infants of mothers who received ART. Only 52% had a third test at median age 52 weeks (IQR: 50, 54). CONCLUSIONS: Long turnaround time for test results and low retention in care after the initial HIV test were critical challenges to clinical decision making.

Urban-rural disparities in treatment outcomes among recurrent TB cases in Southern Province, Zambia.

BACKGROUND: At least 13-20% of all Tuberculosis (TB) cases are recurrent TB. Recurrent TB has critical public health importance because recurrent TB patients have high risk of Multi-Drug Resistant TB (MDR-TB). It is critical to understand variations in the prevalence and treatment outcomes of recurrent TB between different geographical settings. The objective of our study was to estimate the prevalence of recurrent TB among TB cases and compare risk of unfavorable treatment outcomes between rural and urban settings. METHODS: In a retrospective cohort study conducted in southern province of Zambia, we used mixed effects logistic regression to asses associations between explanatory and outcome variables. Primary outcome was all-cause mortality and exposure was setting (rural/urban). Data was abstracted from the facility TB registers. RESULTS: Overall 3566 recurrent TB cases were diagnosed among 25,533 TB patients. The prevalence of recurrent TB was 15.3% (95% CI: 14.8 15.9) in urban and 11.3% (95% CI: 10.7 12.0) in rural areas. Death occurred in 197 (5.5%), 103 (2.9%) were lost to follow-up, and 113 (3.2%) failed treatment. Rural settings had 70% higher risk of death (adjusted OR: 1.7; 95% CI: 1.2 2.7). Risk of lost to follow-up was twice higher in rural than urban (adjusted OR: 2.0 95% CI: 1.3 3.0). Compared to HIV-uninfected, HIV-infected individuals on Antiretroviral Treatment (ART) were 70% more likely to die (adjusted OR: 1.7; 95% CI: 1.2 3.1). CONCLUSION: Recurrent TB prevalence was generally high in both urban and rural settings. The risk of mortality and lost to follow-up was higher among rural patients. We recommend a well-organized Directly Observed Therapy strategy adapted to setting where heightened TB control activities are focused on areas with poor treatment outcomes.

Clinical management decisions for adults with prolonged acute cough: Frequency and associated factors.

BACKGROUND: Uncomplicated episodes of prolonged acute cough are usually viral and self-limited, but despite evidence and recommendations to the contrary, they are often treated with antibiotics. METHODS: Mixed cross-sectional and prospective observational study of adults 18 years or older presenting to two urgent care centers with a cough of 7 to 56 days as their chief complaint. Factors associated with cough duration and clinical decisions were analyzed by univariate and multivariate logistic regression. RESULTS: Of the 125 enrolled patients, 118 (94%) received an antibiotic, 97 (78%) a cough suppressant, 87 (70%) a systemic corticosteroid, and 39 (31%) a chest X-ray (CXR). Longer duration of cough was associated with the presence of self-reported wheezing or noises (adjusted odds ratio 6.29, 95% CI 1.36-29.16) while the presence of both wheezing and crackles on a clinician chest exam was associated with shorter duration (aOR 0.03, 95% CI 0.00-0.27). A clinician was more likely to order a CXR in patients with dyspnea (aOR 3.01, 95% CI 1.21-7.49), less likely to prescribe a systemic corticosteroid in patients with crackles (aOR 0.27, 95% CI 0.09-0.82), and more likely to prescribe a cough suppressant to older patients (1.04 per additional year of age, 95% CI 1.01-1.07). CONCLUSIONS: Systemic corticosteroids and cough suppressants are being prescribed at high rates in patients with uncomplicated acute cough in the urgent care setting. Additional studies to determine if similar rates are seen in other urgent care centers, or in other contemporary ambulatory settings are warranted.

Predictors of loss to follow-up among children on long-term antiretroviral therapy in Zambia (2003-2015).

BACKGROUND: Retention in care is critical for children living with HIV taking antiretroviral therapy (ART). Loss to follow-up (LTFU) is high in HIV treatment programs in resource limited settings. We estimated the cumulative incidence of LTFU and identified associated risk factors among children on ART at Livingstone Central Hospital (LCH), Zambia. METHODS: Using a retrospective cohort study design, we abstracted data from medical records of children who received ART between 2003 and 2015. Loss to follow-up was defined as no clinical and pharmacy contact for at least 90 days after the child missed their last scheduled clinical visit. Non-parametric competing risks models were used to estimate the cumulative incidence of death, LTFU and transfer. Cause-specific Cox regression was used to estimate the hazard ratios of the risk factors of LTFU. RESULTS: A total of 1039 children aged 0-15 years commenced ART at LCH between 2003 and 2015. Median duration of follow-up was 3.8 years (95% CI: 1.2-6.5), median age at ART initiation was 3.6 years (IQR: 1.3-8.6), 179 (17%) started treatment during their first year of life. At least 167 (16%) were LTFU and we traced 151 (90%). Of those we traced, 39 (26%) had died, 71 (47%) defaulted, 20 (13%) continued ART at other clinics and 21 (14%) continued treatment with gaps. The cumulative incidence of LTFU for the entire cohort was 2.7% (95% CI: 1.9-3.9) at 3 months, 4.1% (95% CI: 2.9-5.4) at 6 months and 14.1% (95% CI: 12.4-16.9) after 5 years on ART. Associated risk factors were: 1) non-disclosure of HIV status at baseline, aHR = 1.9 (1.2-2.9), 2) No phone ownership, aHR = 2.1 (1.6-2.9), 3) starting treatment between 2013 to 2015, aHR = 5.6 (2.2-14.1). CONCLUSION: Among the children LTFU mortality and default were substantially high. Children who started treatment in recent years (2013-2015) had the highest hazard of LTFU. Lack of access to a phone and non-disclosure of HIV-status to the index child was associated with higher hazards of LTFU. We recommend re-enforcement of client counselling and focused follow-up strategies using modern technology such as mobile phones as adjunct to current approaches.

Long-term survival outcomes of HIV infected children receiving antiretroviral therapy: an observational study from Zambia (2003-2015).

BACKGROUND: In 2017, 64% of children living with HIV in Zambia accessed Antiretroviral Therapy (ART). Despite expanded ART coverage, there is paucity of information on effectiveness of pediatric ART in reducing mortality. The aim of this research is to describe treatment outcomes, measure mortality rates and assess predictors of mortality among children receiving ART. METHODS: Using a retrospective cohort study design, we abstracted routinely collected clinical data from medical records of children from birth to 15 years old, who had received ART for at least 6 months at Livingstone Central Hospital in Southern Province Zambia, between January 2003 and June 2015. The primary outcome was death. Cause of death was ascertained from medical records and death certificates. Distribution of survival times according to baseline covariates were estimated using Kaplan Meier and Cox Proportional Hazards methods. RESULTS: Overall, 1039 children were commenced on ART during the study period. The median age at treatment initiation was 3.6 years (IQR: 1.3-8.6) and 520 (50%) children were female. Of these, 71 (7%) died, 164 (16%) were lost to follow-up, 210 (20%) transferred and 594 (56%) were actively on treatment. After 4450 person years, mortality rate was 1.6/100 (95% CI: 1.4-1.8). Mortality was highest during the first 3 months of treatment (11.7/100 (95% CI: 7.6-16.3). In multivariable proportional hazards regression, the adjusted hazards of death were highest among children aged < 1 year (aHR = 3.1 (95% CI: 1.3-6.4), compared to those aged 6-15 years, WHO stage 4 (aHR =4.8 (95% CI: 2.3-10), compared to WHO stage 1 and 2. In the sensitivity analysis to address bias due to loss to follow-up, mortality increased 5 times when we assumed that all the children who were lost to follow up died within 90 days of their last visit. CONCLUSION: We observed low attrition due to mortality among children on ART. Loss to follow-up was high (16%). Mortality was highest during the first 3 months of treatment. Children aged less than one year and those with advanced WHO disease stage had higher mortality. We recommend effective interventions to improve retention in care and early diagnosis of HIV in children.

Resistance and Susceptibility to Mycobacterium tuberculosis Infection and Disease in Tuberculosis Households in Kampala, Uganda.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major public health problem. Household contact studies identify children and adults along the spectrum from Mtb exposure to disease. In the Kawempe Community Health Study (conducted in Kampala, Uganda), 872 culture-confirmed pulmonary TB cases and their 2,585 contacts were enrolled during 2002-2012 and followed for up to 2 years each. Risk factors identified by time-to-event analysis for secondary TB differed among children, women, and men. Younger age (P = 0.0061), human immunodeficiency virus (HIV) (P = 0.0002), thinness (P = 0.01), absent bacille Calmette-Guérin vaccination (P = 0.002), and epidemiologic risk score (P < 0.0001) were risks for children. For women, risks were HIV (P < 0.0001), thinness (World Health Organization criteria; P < 0.0001), and epidemiologic risk score (P = 0.003). For men, HIV (P = 0.0007) and low body mass index (P = 0.008) resulted in faster progression to TB. Tuberculin skin testing (TST) identified contacts with Mtb infection and those with persistently negative TST. Risks for faster time to Mtb infection were identified, and included age (P = 0.0007), baseline TST induration (P < 0.0001), and epidemiologic risk score (P < 0.0001) only in children. Those with persistently negative TST comprised 10% of contacts but had no unique epidemiologic characteristics among adults. The burden of Mtb infection and disease is high in TB households, and risk factors for progression from exposure to infection and disease differ among children, women, and men.

Glycemic Control and the Prevalence of Tuberculosis Infection: A Population-based Observational Study.

BACKGROUND: Several cohort studies demonstrate that diabetics are at increased risk for active tuberculosis, and poor glycemic control may exacerbate this risk. A higher prevalence of tuberculosis infection at baseline among diabetics may partially explain these results; however, no population-based studies have investigated this association. Furthermore, whether glycemic control modifies the relationship between diabetes and tuberculosis infection, as it does with active tuberculosis, is unknown. METHODS: Diabetics were diagnosed through physician evaluation and using 3 laboratory tests including hemoglobin A1C (HbA1C), fasting plasma glucose (FPG), or 2-hour plasma glucose (PG). Tuberculosis infection was diagnosed through tuberculin skin tests, and glycemic control was assessed linearly and categorically using recommended targets. RESULTS: Among 4215 participants, the prevalence of tuberculosis infection was 4.1%, 5.5%, and 7.6% in nondiabetic, prediabetic, and diabetic participants (Ptrend = .012). In multivariate analysis, diabetes was associated with tuberculosis infection (adjusted odds ratio [AOR], 1.5; 95% confidence interval [CI], 1.0-2.2). Compared to nondiabetics, diabetics who were undiagnosed (AOR, 2.2 and 1.2 in diagnosed diabetics), FPG >130 mg/dL (AOR, 2.6 and 1.3 in diabetics with FPG ≤130 mg/dL), or not on insulin (AOR, 1.7 and 0.8 in diabetics on insulin) had elevated tuberculosis infection rates. In a linear dose-response analysis, increasing values of FPG (AOR, 1.02 per 1-mg/dL; 95% CI, 1.01-1.03), PG (AOR, 1.02 per 1-mg/dL; 95% CI, 1.01-1.04), and HbA1C (AOR, 1.13 per 1%; 95% CI, 1.04-1.22) all predicted tuberculosis infection. CONCLUSIONS: Our results suggest glycemic control may modify the relationship between tuberculosis infection and diabetes.

Transmission of Mycobacterium Tuberculosis in Households and the Community: A Systematic Review and Meta-Analysis.

The individual- and population-level impact of household tuberculosis exposure on transmission is unclear but may have implications for the effectiveness and implementation of control interventions. We systematically searched for and included studies in which latent tuberculosis infection was assessed in 2 groups: children exposed and unexposed to a household member with tuberculosis. We also extracted data on the smear and culture status of index cases, the age and bacillus Calmette-Guérin vaccination status of contacts, and study design characteristics. Of 6,176 citations identified from our search strategy, 26 studies (13,999 children with household exposure to tuberculosis and 174,097 children without) from 1929-2015 met inclusion criteria. Exposed children were 3.79 (95% confidence interval (CI): 3.01, 4.78) times more likely to be infected than were their community counterparts. Metaregression demonstrated higher infection among children aged 0-4 years of age compared with children aged 10-14 years (ratio of odds ratios = 2.24, 95% CI: 1.43, 3.51) and among smear-positive versus smear-negative index cases (ratio of odds ratios = 5.45, 95% CI: 3.43, 8.64). At the population level, we estimated that a small proportion (<20%) of transmission was attributable to household exposure. Our results suggest that targeting tuberculosis prevention efforts to household contacts is highly effective. However, a large proportion of transmission at the population level may occur outside the household.

Protocol and baseline data for a multi-year cohort study of the effects of different mass drug treatment approaches on functional morbidities from schistosomiasis in four African countries.

BACKGROUND: The Schistosomiasis Consortium for Operational Research and Evaluation (SCORE) focus is on randomized trials of different approaches to mass drug administration (MDA) in endemic countries in Africa. Because their studies provided an opportunity to evaluate the effects of mass treatment on Schistosoma-associated morbidity, nested cohort studies were developed within SCORE's intervention trials to monitor changes in a suite of schistosomiasis disease outcomes. This paper describes the process SCORE used to select markers for prospective monitoring and the baseline prevalence of these morbidities in four parallel cohort studies. METHODS: In July 2009, SCORE hosted a discussion of the potential impact of MDA on morbidities due to Schistosoma infection that might be measured in the context of multi-year control. Candidate markers were reviewed and selected for study implementation. Baseline data were then collected from cohorts of children in four country studies: two in high endemic S. mansoni sites (Kenya and Tanzania), and two in high endemic S. haematobium sites (Niger and Mozambique), these cohorts to be followed prospectively over 5 years. RESULTS: At baseline, 62% of children in the S. mansoni sites had detectable eggs in their stool, and 10% had heavy infections (≥ 400 eggs/g feces). Heavy S. mansoni infections were found to be associated with increased baseline risk of anemia, although children with moderate or heavy intensity infections had lower risk of physical wasting. Prevalence of egg-positive infection in the combined S. haematobium cohorts was 27%, with 5% of individuals having heavy infection (≥50 eggs/10 mL urine). At baseline, light intensity S. haematobium infection was associated with anemia and with lower scores in the social domain of health-related quality-of-life (HRQoL) assessed by Pediatric Quality of Life Inventory. CONCLUSIONS: Our consensus on practical markers of Schistosoma-associated morbidity indicated that height, weight, hemoglobin, exercise tolerance, HRQoL, and ultrasound abnormalities could be used as reference points for gauging treatment impact. Data collected over five years of program implementation will provide guidance for future evaluation of morbidity control in areas endemic for schistosomiasis. TRIAL REGISTRATION: These cohort studies are registered and performed in conjunction with the International Standard Randomised Controlled Trial Registry trials ISRCTN16755535 , ISRCTN14117624 , ISRCTN95819193 , and ISRCTN32045736 .

Infectiousness of HIV-Seropositive Patients with Tuberculosis in a High-Burden African Setting.

RATIONALE: Policy recommendations on contact investigation of HIV-seropositive patients with tuberculosis have changed several times. Current epidemiologic evidence informing these recommendations is considered low quality, and few large studies investigating the infectiousness of HIV-seropositive and -seronegative index cases have been performed in sub-Saharan Africa. OBJECTIVES: We assessed the infectiousness of HIV-seropositive and -seronegative patients with tuberculosis to their household contacts and examined potential modifiers of this relationship. METHODS: Adults suffering from their first episode of pulmonary tuberculosis were identified in Kampala, Uganda. Field workers visited index households and enrolled consenting household contacts. Latent tuberculosis infection was measured through tuberculin skin testing, and relative risks were calculated using modified Poisson regression models. Standard assessments of interaction between latent tuberculosis infection, the HIV serostatus of index cases, and other variables were performed. MEASUREMENTS AND MAIN RESULTS: Latent tuberculosis infection was found in 577 of 878 (65.7%) and 717 of 974 (73.6%) household contacts of HIV-seropositive and -seronegative tuberculosis cases (relative risk, 0.89; 95% confidence interval, 0.82-0.97). On further stratification, cavitary lung disease (P < 0.0001 for interaction) and smear status (P = 0.02 for interaction) of tuberculosis cases modified the infectiousness of HIV-seropositive indexes. Cough duration of index cases did not display interaction (P = 0.499 for interaction). CONCLUSIONS: This study suggests that HIV-seropositive tuberculosis cases may be less infectious than HIV-seronegative patients only when they are smear-negative or lack cavitary lung disease. These results may explain heterogeneity between prior studies and provide evidence suggesting that tuberculosis contact investigation should include HIV-seropositive index cases in high disease burden settings.

Antiretroviral therapy improves survival among TB-HIV co-infected patients who have CD4+ T-cell count above 350cells/mm3.

BACKGROUND: Co-infection with Mycobacterium tuberculosis remains a leading cause of morbidity and mortality among HIV infected individuals especially in developing countries. Early initiation of cART in these patients when CD4+ T cell count is less than 200cells/mm3 has reduced disease progression and mortality. However for patients with higher CD4+ T cell counts greater than 350cells/mm3 evidence is conflicting. In this study we seek to evaluate the effectiveness of cART in reducing mortality among TB-HIV co-infected patients with CD4 + T cells above 350cells/mm3 at the time of TB diagnosis. METHOD: In a retrospective cohort study we analyzed 337 HIV-TB co-infected patients with CD4+ T cells above 350cells/mm3 at baseline who were diagnosed between 2006 and 2012 in the southern province of Zambia. The primary outcome was all-cause mortality. We estimated the effect of cART by comparing survival according to cART and controlling for differential loss to follow-up. RESULTS: Of the 257 patients on cART, 22 died (9 %) and 20 (8 %) were lost to follow-up; of 80 patients not on cART, 20 died (25 %) and 19 (24 %) were lost to follow-up. Patients treated with cART had better survival compared to those not treated (P < 0 · 0001, log-rank test). In a proportional hazard regression adjusting for Cotrimoxazole, the risk of death was reduced by 78 % with cART (95 % CI: 0 · 47, 0 · 91). In a propensity score analysis, the effect of cART was still beneficial. CONCLUSION: In patients with HIV-associated TB and CD4+ T cells above 350cells/mm3, treatment with cART reduced mortality for up to 4 years as compared to no cART and was associated with better retention in care.