Summary The billions of people with latent tuberculosis infection serve as the seedbeds for future cases of active tuberculosis. Virtually all episodes of tuberculosis disease are preceded by a ...period of asymptomatic Mycobacterium tuberculosis infection; therefore, identifying infected individuals most likely to progress to disease and treating such subclinical infections to prevent future disease provides a crucial opportunity to interrupt tuberculosis transmission and reduce the global burden of tuberculosis disease. Programmes focusing on single strategies rather than comprehensive programmes that deliver an integrated arsenal for tuberculosis control might continue to struggle. Tuberculosis preventive therapy is a poorly used method that is essential for controlling the reservoirs of disease that drive the epidemic. Comprehensive control strategies that combine preventive therapy for the most high-risk populations and communities with improved case-finding and treatment, control of transmission, and health systems strengthening could ultimately lead to worldwide tuberculosis elimination. In this Series paper we outline challenges to implementation of preventive therapy and provide pragmatic suggestions for overcoming them. We further advocate for tuberculosis preventive therapy as the core of a renewed worldwide focus to implement a comprehensive epidemic control strategy that would reduce new tuberculosis cases to elimination targets. This strategy would be underpinned by accelerated research to further understand the biology of subclinical tuberculosis infections, develop novel diagnostics and drug regimens specifically for subclinical tuberculosis infection, strengthen health systems and community engagement, and enhance sustainable large scale implementation of preventive therapy programmes.
By August, 2021, South Africa had been affected by three waves of SARS-CoV-2; the second associated with the beta variant and the third with the delta variant. Data on SARS-CoV-2 burden, ...transmission, and asymptomatic infections from Africa are scarce. We aimed to evaluate SARS-CoV-2 burden and transmission in one rural and one urban community in South Africa.
We conducted a prospective cohort study of households in Agincourt, Mpumalanga province (rural site) and Klerksdorp, North West province (urban site) from July, 2020 to August, 2021. We randomly selected households for the rural site from a health and sociodemographic surveillance system and for the urban site using GPS coordinates. Households with more than two members and where at least 75% of members consented to participate were eligible. Midturbinate nasal swabs were collected twice a week from household members irrespective of symptoms and tested for SARS-CoV-2 using real-time RT-PCR (RT-rtPCR). Serum was collected every 2 months and tested for anti-SARS-CoV-2 antibodies. Main outcomes were the cumulative incidence of SARS-CoV-2 infection, frequency of reinfection, symptomatic fraction (percent of infected individuals with ≥1 symptom), the duration of viral RNA shedding (number of days of SARS-CoV-2 RT-rtPCR positivity), and the household cumulative infection risk (HCIR; number of infected household contacts divided by the number of susceptible household members).
222 households (114 at the rural site and 108 at the urban site), and 1200 household members (643 at the rural site and 557 at the urban site) were included in the analysis. For 115 759 nasal specimens from 1200 household members (follow-up 92·5%), 1976 (1·7%) were SARS-CoV-2-positive on RT-rtPCR. By RT-rtPCR and serology combined, 749 of 1200 individuals (62·4% 95% CI 58·1–66·4) had at least one SARS-CoV-2 infection episode, and 87 of 749 (11·6% 9·4–14·2) were reinfected. The mean infection episode duration was 11·6 days (SD 9·0; range 4–137). Of 662 RT-rtPCR-confirmed episodes (>14 days after the start of follow-up) with available data, 97 (14·7% 11·9–17·9) were symptomatic with at least one symptom (in individuals aged <19 years, 28 7·5% of 373 episodes symptomatic; in individuals aged ≥19 years, 69 23·9% of 289 episodes symptomatic). Among 222 households, 200 (90·1% 85·3–93·7) had at least one SARS-CoV-2-positive individual on RT-rtPCR or serology. HCIR overall was 23·9% (195 of 817 susceptible household members infected 95% CI 19·8–28·4). HCIR was 23·3% (20 of 86) for symptomatic index cases and 23·9% (175 of 731) for asymptomatic index cases (univariate odds ratio OR 1·0 95% CI 0·5–2·0). On multivariable analysis, accounting for age and sex, low minimum cycle threshold value (≤30 vs >30) of the index case (OR 5·3 2·3–12·4) and beta and delta variant infection (vs Wuhan-Hu-1, OR 3·3 1·4–8·2 and 10·4 4·1–26·7, respectively) were associated with increased HCIR. People living with HIV who were not virally supressed (≥400 viral load copies per mL) were more likely to develop symptomatic illness when infected with SAR-CoV-2 (OR 3·3 1·3–8·4), and shed SARS-CoV-2 for longer (hazard ratio 0·4 95% CI 0·3–0·6) compared with HIV-uninfected individuals.
In this study, 565 (85·3%) SARS-CoV-2 infections were asymptomatic and index case symptom status did not affect HCIR, suggesting a limited role for control measures targeting symptomatic individuals. Increased household transmission of beta and delta variants was likely to have contributed to successive waves of SARS-CoV-2 infection, with more than 60% of individuals infected by the end of follow-up.
US CDC, South Africa National Institute for Communicable Diseases, and Wellcome Trust.
People with tuberculosis (TB) are often lost to follow-up during treatment transition to another facility. These losses may result in substantial morbidity and mortality but are rarely recorded. We ...conducted a record review on adults diagnosed with TB at 11 hospitals in Limpopo, South Africa, who were subsequently transferred to a local clinic to initiate or continue treatment. We then performed in-depth record reviews at the primary care clinic to which they were referred and called participants who could not be identified as starting treatment. Between August 2017 and April 2018, we reviewed records of 778 individuals diagnosed with TB in-hospital and later referred to local clinics for treatment. Of the 778, 88 (11%) did not link to care, and an additional 43 (5.5%) died. Compared to people without cough, those with cough had higher odds of linking to care (aOR = 2.01, 95% CI: 1.26-3.25, p = 0.005) and were also linked more quickly adjusted Time Ratio (aTR) = 0.53, 95% CI:0.36-0.79, p<0.001, as were those diagnosed microbiologically (aOR = 1.86, 95% CI: 1.16-3.06, p = 0.012; aTR = 0.58, 95% CI: 0.34-0.98, p = 0.04). People diagnosed with TB in hospitals often disengage following referral to local clinics. Interventions to identify and re-engage people who do not present to local clinics within days of referral might close an important gap in the TB treatment cascade.
South Africa was among the first countries to detect the SARS-CoV-2 Omicron variant. However, the size of its Omicron BA.1 and BA.2 subvariants (BA.1/2) wave remains poorly understood. We analyzed ...sequential serum samples collected through a prospective cohort study before, during, and after the Omicron BA.1/2 wave to infer infection rates and monitor changes in the immune histories of participants over time. We found that the Omicron BA.1/2 wave infected more than half of the cohort population, with reinfections and vaccine breakthroughs accounting for > 60% of all infections in both rural and urban sites. After the Omicron BA.1/2 wave, we found few (< 6%) remained naïve to SARS-CoV-2 and the population immunologic landscape is fragmented with diverse infection/immunization histories. Prior infection with the ancestral strain, Beta, and Delta variants provided 13%, 34%, and 51% protection against Omicron BA.1/2 infection, respectively. Hybrid immunity and repeated prior infections reduced the risks of Omicron BA.1/2 infection by 60% and 85% respectively. Our study sheds light on a rapidly shifting landscape of population immunity in the Omicron era and provides context for anticipating the long-term circulation of SARS-CoV-2 in populations no longer naïve to the virus.
Symptom screening is a recommended component of intensified case-finding (ICF) for pulmonary tuberculosis (TB) among HIV-infected individuals. Symptomatic individuals are further investigated to ...either exclude or diagnose pulmonary TB, thus reducing the number of individuals requiring costly laboratory investigation. Those with laboratory evaluations negative for pulmonary TB or who lack symptoms may be eligible for antiretroviral therapy (ART) and/or TB isoniazid preventive therapy (IPT). A four-part symptom screen has been recommended by the World Health Organization (WHO) for identifying TB suspects and those unlikely to have TB. A meta-analysis of studies among HIV-infected individuals calculated a sensitivity of 90.1% for the four-part symptoms screen--of any of cough, fever, night sweats, or weight loss--among patients in clinical care, making it an effective tool for identifying most patients with TB. An important population for intensified case-finding not included in that meta-analysis was HIV-infected pregnant women. We undertook a cross-sectional survey among HIV-infected pregnant women receiving prenatal care at community clinics in South Africa. We obtained a four-symptom review and sputum smear microscopy and mycobacterial culture on all participants. Among 1415 women, 226 (16%) had a positive symptom screen, and 35 (2.5%) were newly diagnosed with culture-positive TB. Twelve were on TB treatment at the time of screening, yielding 47 (3.3%) women with prevalent TB. Symptom screening among women without known TB had a sensitivity of 28% and specificity of 84%. The poor performance of symptom screening to identify women with TB suggests that other approaches may be needed for intensified case-finding to be effective for this population.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections may be underestimated because of limited access to testing. We measured SARS-CoV-2 seroprevalence in South Africa every 2 ...months during July 2020–March 2021 in randomly selected household cohorts in 2 communities. We compared seroprevalence to reported laboratory-confirmed infections, hospitalizations, and deaths to calculate infection–case, infection–hospitalization, and infection–fatality ratios in 2 waves of infection. Post–second wave seroprevalence ranged from 18% in the rural community children <5 years of age, to 59% in urban community adults 35–59 years of age. The second wave saw a shift in age distribution of case-patients in the urban community (from persons 35–59 years of age to persons at the extremes of age), higher attack rates in the rural community, and a higher infection–fatality ratio in the urban community. Approximately 95% of SARS-CoV-2 infections were not reported to national surveillance.
Additional approaches are needed to identify and provide targeted interventions to populations at continued risk for HIV-associated mortality. We sought to describe care utilization and mortality ...following an index hospitalization for people with HIV in South Africa.
We conducted a prospective cohort study among hospitalized patients admitted to medicine wards at a single hospital serving a large catchment area. Participants were followed to 6 months post-discharge. Hospital records were used to describe overall admission numbers and inpatient mortality. Poisson regression was used to assess for associations between readmission or death and independent variables.
Of 124 enrolled participants, 121 lived to hospital discharge. At the time of discharge the median length of stay of sampled patients was 5.5 days and 105 (87%) participants were referred for follow-up, most within 2 weeks of discharge. By 6 months post-discharge, only 18% of participants had attended the clinic to which they were referred and within the referred timeframe; 64 (53%) had been readmitted at least once and 31 (26%) had died. Self-reported skipping care due to difficulty in access (relative risk 1.3, p = 0.02) and not attending follow-up care on time or at the scheduled clinic or not attending clinic at all (relative risk 1.8 and 2.4, respectively, p = 0.001) were associated with readmission or mortality.
The post-hospital period is a period of medical vulnerability and high mortality. Improving post-hospital retention in care may reduce post-hospital mortality.
The World Health Organization (WHO) aims to reduce tuberculosis (TB) deaths by 95% by 2035; tracking progress requires accurate measurement of TB mortality. International Classification of Diseases ...(ICD) codes do not differentiate between HIV-associated TB and HIV more generally. Verbal autopsy (VA) is used to estimate cause of death (CoD) patterns but has mostly been validated against a suboptimal gold standard for HIV and TB. This study, conducted among HIV-positive adults, aimed to estimate the accuracy of VA in ascertaining TB and HIV CoD when compared to a reference standard derived from a variety of clinical sources including, in some, minimally-invasive autopsy (MIA).
Decedents were enrolled into a trial of empirical TB treatment or a cohort exploring diagnostic algorithms for TB in South Africa. The WHO 2012 instrument was used; VA CoD were assigned using physician-certified VA (PCVA), InterVA-4, and SmartVA-Analyze. Reference CoD were assigned using MIA, research, and health facility data, as available. 259 VAs were completed: 147 (57%) decedents were female; median age was 39 (interquartile range IQR 33-47) years and CD4 count 51 (IQR 22-102) cells/μL. Compared to reference CoD that included MIA (n = 34), VA underestimated mortality due to HIV/AIDS (94% reference, 74% PCVA, 47% InterVA-4, and 41% SmartVA-Analyze; chance-corrected concordance CCC 0.71, 0.42, and 0.31, respectively) and HIV-associated TB (41% reference, 32% PCVA; CCC 0.23). For individual decedents, all VA methods agreed poorly with reference CoD that did not include MIA (n = 259; overall CCC 0.14, 0.06, and 0.15 for PCVA, InterVA-4, and SmartVA-Analyze); agreement was better at population level (cause-specific mortality fraction accuracy 0.78, 0.61, and 0.57, for the three methods, respectively).
Current VA methods underestimate mortality due to HIV-associated TB. ICD and VA methods need modifications that allow for more specific evaluation of HIV-related deaths and direct estimation of mortality due to HIV-associated TB.
Household contacts of patients with active pulmonary tuberculosis (TB) often have latent TB infection, and are at risk of progression to disease. We set out to investigate whether index TB case HIV ...status was linked to a higher probability of latent TB infection among household contacts.
Data were collected prospectively from participants in the intervention arm of a household cluster-randomised trial in two South Africa provinces (Mangaung, Free State, and Capricorn, Limpopo). In intervention group households, TB contacts underwent HIV testing and tuberculin skin testing (TST). TST induration was estimated at two cut-offs (≥5mm, ≥10mm). Multilevel Bayesian regression models estimated posterior distributions of the percentage of household contacts with TST induration ≥5mm and ≥10mm by age group, and compared the odds of latent TB infection by key risk factors including HIV status index case age and study province.
A total of 2,985 household contacts of 924 index cases were assessed, with most 2,725 (91.3%) undergoing TST. HIV prevalence in household contacts was 14% and 10% in Mangaung and Capricorn respectively. Overall, 16.8% (458/2,725) had TST induration of ≥5mm and 13.1% (359/2,725) ≥10mm. In Mangaung, children aged 0-4 years had a high TST positivity prevalence compared to their peers in Capricorn (22.0% vs. 7.6%, and 20.5% vs. 2.3%, using TST thresholds of ≥5mm and ≥10mm respectively). Compared to contacts from Capricorn, household contacts living in Mangaung were more likely to have TST induration ≥5mm (odds ratio OR: 3.08, 95% credibility interval CI: 2.13-4.58) and ≥10mm (OR: 4.52, 95% CI: 3.03-6.97). There was a 90% and 92% posterior probability that the odds of TST induration ≥5mm (OR: 0.79, 95% CI: 0.56-1.14) and ≥10mm (OR: 0.77, 95% CI: 0.53-1.10) respectively were lower in household contacts of HIV-positive compared to HIV-negative index cases.
High TST induration positivity, especially among young children and people living in Mangaung indicates considerable TB transmission despite high antiretroviral therapy coverage. Household contact of HIV-positive index TB cases were less likely to have evidence of latent TB infection than contacts of HIV-negative index cases.
The purpose of this prospective cohort study is to characterize the event of acute hospitalization for people living with and without HIV and describe its impact on the care continuum. This study ...describes care-seeking behavior prior to an index hospitalization, inpatient HIV testing and diagnosis, discharge instructions, and follow-up care for patients for patients being discharged from a single hospital in South Africa.
A convenience sample of adult patients was recruited from the medical wards of a tertiary care facility. Baseline information at the time of hospital admission, subsequent diagnoses, and discharge instructions were recorded. Participants were prospectively followed with phone calls for six months after hospital discharge. Descriptive analyses were performed.
A total of 293 participants were enrolled in the study. Just under half (46%) of the participants were known to be living with HIV at the time of hospital admission. Most participants (97%) were given a referral for follow-up care; often that appointment was scheduled within two weeks of discharge (64%). Only 36% of participants returned to care within the first month, 50% returned after at least one month had elapsed, and 14% of participants did not return for any follow up.
Large discrepancies were found between the type of post-discharge follow-up care recommended by providers and what patients were able to achieve. The period of time following hospital discharge represents a key transition in care. Additional research is needed to characterize patients' risk following hospitalization and to develop patient-centered interventions.
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