Browsing by Author "Hatherill, Mark"

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    The candidate TB vaccine, MVA85A, induces highly durable Th1 responses
    (Public Library of Science, 2014) Tameris, Michele; Geldenhuys, Hennie; Luabeya, Angelique KanyKany; Smit, Erica; Hughes, Jane E; Vermaak, Samantha; Hanekom, Willem A; Hatherill, Mark; Mahomed, Hassan; McShane, Helen; Scriba,Thomas J
    BACKGROUND: Vaccination against tuberculosis (TB) should provide long-term protective immunity against Mycobacterium tuberculosis ( M.tb ). The current TB vaccine, Bacille Calmette-Guerin (BCG), protects against disseminated childhood TB, but protection against lung TB in adolescents and adults is variable and mostly poor. One potential reason for the limited durability of protection may be waning of immunity through gradual attrition of BCG-induced T cells. We determined if a MVA85A viral-vector boost could enhance the durability of mycobacteria-specific T cell responses above those induced by BCG alone. METHODS: We describe a long-term follow-up study of persons previously vaccinated with MVA85A. We performed a medical history and clinical examination, a tuberculin skin test and measured vaccine-specific T cell responses in persons previously enrolled as adults, adolescents, children or infants into three different Phase II trials, between 2005 and 2011. RESULTS: Of 252 potential participants, 183 (72.6%) consented and completed the study visit. Vaccine-induced Ag85A-specific CD4+ T cell responses were remarkably persistent in healthy, HIV-uninfected adults, adolescents, children and infants, up to 6 years after MVA85A vaccination. Specific CD4+ T cells expressed surface markers consistent with either CD45RA−CCR7+ central memory or CD45RA−CCR7− effector memory T cells. Similarly durable Ag85A-specific CD4+ T cell responses were detected in HIV-infected persons who were on successful antiretroviral therapy when MVA85A was administered. By contrast, Ag85A-specific CD4+ T cell frequencies in untreated MVA85A-vaccinated HIV-infected persons were mostly undetectable 3-5 years after vaccination. CONCLUSION: MVA85A induces remarkably durable T cell responses in immunocompetent persons. However, results from a recent phase IIb trial of MVA85A, conducted in infants from the same geographic area and study population, showed no vaccine efficacy, suggesting that these durable T cell responses do not enhance BCG-induced protection against TB in infants.
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    Comparison of mantoux and tine tuberculin skin tests in BCG-vaccinated children investigated for tuberculosis
    (Public Library of Science, 2009) Pan, Wenli; Matizirofa, Lyness; Workman, Lesley; Hawkridge, Tony; Hanekom, Willem; Mahomed, Hassan; Hussey, Gregory; Hatherill, Mark
    Background: Tuberculin skin tests (TSTs) are long-established screening methods for tuberculosis (TB). We aimed to compare agreement between the intradermal Mantoux and multipuncture percutaneous Tine methods and to quantify risk factors for a positive test result. Methodology/Principal Findings: 1512 South African children younger than 5 years of age who were investigated for tuberculosis (TB) during a Bacille Calmette Guerin (BCG) trial were included in this analysis. Children underwent both Mantoux and Tine tests. A positive test was defined as Mantoux ≥15 mm or Tine ≥ Grade 3 for the binary comparison. Agreement was evaluated using kappa (binary) and weighted kappa (hierarchical). Multivariate regression models identified independent risk factors for TST positivity. The Mantoux test was positive in 430 children (28.4%) and the Tine test in 496 children (32.8%, p<0.0001), with observed binary agreement 87.3% (kappa 0.70) and hierarchical agreement 85.0% (weighted kappa 0.66). Among 173 children culture-positive for Mycobacterium tuberculosis, Mantoux was positive in 49.1% and Tine in 54.9%, p<0.0001 (kappa 0.70). Evidence of digit preference was noted for Mantoux readings at 5 mm threshold intervals. After adjustment for confounders, a positive culture, suggestive chest radiograph, and proximity of TB contact were risk factors for a positive test using both TST methods. There were no independent associations between ethnicity, gender, age, or over-crowding, and TST result. Conclusions/Significance: The Tine test demonstrated a higher positive test rate than the Mantoux, with substantial agreement between TST methods among young BCG-vaccinated children. TB disease and exposure factors, but not demographic variables, were independent risk factors for a positive result using either test method. These findings suggest that the Tine might be a useful screening tool for childhood TB in resource-limited countries.
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    Diagnosis and management of potentially infectious patients with suspected pulmonary tuberculosis in a developing country setting
    (2011) González-Angulo, Licé Yulieth; Hatherill, Mark
    This thesis comprises two projects, which focus on simple TB control strategies that can help reduce the risk of M. tuberculosis transmission ... New effective and field-adapted interventions are needed to improve TB programme outcomes. Two projects, which focus on breaking the cycle of TB transmission in developing country settings, are reported.
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    Does helminth treatment reduce the risk of active tuberculosis in a cohort of children from high tuberculosis risk population who have been vaccinated with BCG at birth?
    (2009) Workman, Lesley; Ehrlich, Rodney; Little, Francesca; Hatherill, Mark
    [Background] Research in adults and older children has shown an association between Mycobacterium tuberculosis and helminth infection, with those infected with helminths at greater risk of tuberculosis. This association is believed to be on the basis that chronic helminth infection can result in a functional impairment of the immune response that is necessary to clear or control infection by Mycobacterium tuberculosis (Elias et al. 2001; Rook et al. 2006; Fincham 2001). It is thus possible that the introduction of regular deworming programmes in a vulnerable population of children under the age of five years could assist their immune systems to ward off tuberculosis infection and reduce the risk of tuberculosis disease in such a population. A randomised controlled trial to compare two methods of administering bacille Camlette-Guerin (BCG) vaccination to newborns from a high tuberculosis risk population provided an opportunity to test this hypothesis in a sub-study. [Objective] The objective of this study is to determine if young children in a high-risk tuberculosis population who have been vaccinated with BCG at birth and have been treated for helminth infection are at lower risk of tuberculosis disease than children who have been vaccinated with BCG at birth but not treated for helminth infection. [Method] A case control study nested within a cohort recruited for a separate randomised control trial to compare two methods of administering BCG vaccination was carried out. Children who presented to their local clinic or hospital with symptoms of tuberculosis or a history of exposure to tuberculosis were admitted to a case verification (CV) ward for investigation of tuberculosis. Investigation of tuberculosis included a detailed history, including past helminth treatment, physical examination, tuberculin skin test, chest radiograph, gastric washing and induced sputum for culture of tuberculosis and clinical examination. A diagnostic algorithm was developed by specialist physicians and biostatisticians to classify the children into one of five tuberculosis categories. A total of 510 children (median age 18.13 months) were included in the primary analysis of this case control study. Those defined as cases were the 328 classified as "definite or probable TB" and 182, classified as "not TB", comprised the control group. Those classified as "possible TB" or "unlikely TB" were excluded. A secondary analysis was performed that included the 337 children who had been classified as "unlikely TB" with the controls resulting in a total of 847 children (median age 18.37 months). The 328 children classified as "definite or probable TB" were defined as cases and the 519 classified as "unlikely or not TB" comprised the control group. Univariate analysis was used to explore a possible relationship between tuberculosis and helminth treatment using all the variables in the sub-study (n=510 primary analysis; n=847 secondary analysis). For both the primary and secondary analysis a multivariate logistic regression model was built using a reduced sample that had a complete set of data for all the variables: primary analysis (n=435); secondary analysis (n=724). This final model was then fitted on a more complete sample as the final variables selected had fewer missing data for the observations: primary analysis (n=493); secondary analysis (n=822). [Result] A total of 35.69% of the study sample in the primary analysis had been treated for helminth infection. The proportion of children who had been treated for helminth infection was similar in the cases and controls (35.98% and 35.16% respectively). Univariate logistic regression showed no association between tuberculosis and treatment for helminth infection: [odds ratio (OR) 1.04; 95% confidence interval (CI) 0.71 - 1.51]. Multivariate analysis adjusted for the effect of nutritional status, recorded as height for age z score (haz), number of occupants sharing the same dwelling as the child, gender and birth site showed a similar result: (OR 1.03; 95% CI 0.69 " 1.53). The OR is very close to 1 with a 95% CI that includes 1, which indicates that there is not a statistically significant association between tuberculosis and helminth treatment. In the secondary analysis, a total of 38.61% of the study sample had been treated for helminth infection. In this analysis the proportion of children who had been treated for helminth infection showed a difference between the cases and controls (35.98% and 40.27% respectively). Univariate logistic regression showed a 17% relative reduction in tuberculosis odds but this was not a statistically significant result: (OR 0.83; 95% CI 0.63 " 1.11). Multivariate analysis adjusted for the effect of haz, number of children sharing the same dwelling as the child and gender, showed a similar result: (OR 0.85; 95% CI 0.63 " 1.15). [Conclusion] The primary analysis of this observational study does not support the hypothesis that helminth treatment reduces the risk of tuberculosis disease in young children in a high-risk tuberculosis population. Although the secondary analysis showed a 15% relative reduction in tuberculosis odds after adjusting for the effect of haz, number of occupants sharing the same dwelling as the child and gender, this was not a statistically significant result. [Final Conclusion] This study does not support the hypothesis that helminth treatment reduces the risk of tuberculosis disease in young children in a high-risk tuberculosis population.
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    Early-life immunity and susceptibility to Mycobacteria
    (2018) Logan, Erin; Horsnell, William; Hatherill, Mark; Cunningham, Adam F
    The naïve and not-yet developed infant immune system exhibits heightened susceptibility to external factors (e.g pathogens), and is shaped by these and others, such as maternal immunity. However, we do not yet fully understand their impact on development of infant immunity. A better understanding of these effects would benefit children world-wide, but especially those in low-middle income countries (LMIC), where increased exposure to pathogens due to poorer living conditions highlights the necessity of robust early-life immunity. Mycobacterium tuberculosis (Mtb) and helminths are pathogens co-endemic in many LMIC and cause significant morbidity and mortality in children. Infant immune responses to these pathogens, whether during standalone infection, co-infection or resulting from maternal infection are not fully understood. To contribute to this knowledge gap, we investigated early-life immune responses, how they relate to childhood Mtb/helminth infection and how they are affected by maternal infectious history and immunity. Analysis of clinical humoral responses revealed total IgG that increased significantly between baseline and tuberculosis (TB) investigation in infants who did not acquire Mtb infection; these infants also exhibited raised levels of measles-specific IgG and BCG-specific IgG2. No active helminth infections were detected, but the presence of Ascaris lumbricoides- and Trichuris trichiura-specific class-switched antibodies indicated prior exposure. No association was found between helminth-specific humoral responses and risk of Mtb infection, nor with maternal helminth-specific humoral responses. Conversely, data from murine experiments revealed a protective effect of maternal helminth infection (Nippostrongylus brasiliensis) on BCG infection in offspring, with reduced lung bacterial burden and increased numbers of activated CD4+ T cells and B cells. Maternal Nb infection may have a synergistic effect on BCG vaccination, as BCGvaccinated/infected pups from Nb-infected mothers had reduced lung bacterial burdens, increased CD4+ T cell and B cell responses and increased IFNγ-producing CD4+ T cells. Findings from this study suggest that childhood vaccines could provide heterologous protection against unrelated pathogens such as Mtb. The murine data suggest a protective effect of maternal helminth infection against BCG infection in offspring, but no similar finding was observed with the clinical data. The clear protective effect of maternal Nb infection during offspring BCG infection warrants a more in-depth clinical study addressing the functional effects of maternal helminth infection on Mtb infection outcome in infants.
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    Evaluation of the utility of specific CXR features for diagnosis of pulmonary tuberculosis in young children using multiple readers
    (2015) Ho-Yee, Ruschka; Andronikou, Savvas; Beningfield, Stephen J; Hatherill, Mark
    INTRODUCTION: The diagnosis of childhood pulmonary tuberculosis (TB) can be notoriously difficult. The chest X-ray (CXR) is a significant diagnostic resource in the detection of PTB in children. However, non-specific radiological features combined with variable inter-observer assessment s contribute to diagnostic uncertainty. The CXR would be of most value when used specifically to evaluate those features of childhood TB that it shows best and where expert observers agree, namely those signs indicating lymphadenopathy. AIM: To identify simple and reliable CXR features of primary TB in children by determining signs and anatomical sites of best observer agreement. METHOD: This is a retrospective descriptive study within a clinical trial performed by the South African TB Vaccine Initiative (SATVI). Healthy BCG-vaccinated newborn infants in a high TB prevalence rural area in Worcester, near Cape Town, South Africa, were followed for a minimum of two years for possible incident al pulmonary TB. Three independent, blinded, expert paediatric radiologists reported the resultant CXR images using a standardised data collection tick sheet, on which the specific anatomical sites and signs of pathology consistent with pulmonary TB were recorded. The first 200 original data collection tick sheets were sampled and recorded in a pre-compiled data spreadsheet for our study. The sampled data were t hen analysed using kappa statistics. RESULTS: The overall combined agreement for airway compression (by presumed lymphadenopathy) was 0.5%. Five % of the CXR's had soft tissue densities reflecting lymphadenopathy on the frontal view and 5% on the lateral view. The most common site reflecting lymphadenopathy through airway narrowing or displacement was the left main bronchus. The hilar region (kappa 0.27) on the frontal CXR and behind bronchus intermedius (kappa 0.18) on the lateral were the most common sites of soft tissue densities reflecting lymphadenopathy. There were no positive findings for cavitation or pleural effusion. The overall decisions reflecting PTB (lymphadenopathy or miliary) by each individual reader were 27.6% by Reader 1, 8.5% by Reader 2 and 24.6 % by Reader 3. Abnormal findings not specific for PTB were found in 3.5 % by Reader 1, 10.5% by Reader 2 and 3.5% by Reader 3.68. 3 % of the radiographs were reported as normal by Reader 1, 81.9% by Reader 2 and 66.8 % by Reader 3. Only 5% of the radiographs were found to be unreadable by one reader. The overall agreement of all three readers on PTB was 14.6 % and for normal CXR 49.2%. CONCLUSIONS: The fair degree of agreement amongst expert readers suggests that the CXR alone is not a reliable tool for detecting pulmonary TB and should be utilised in conjunction with the clinical features and/or skin tests and blood results. Soft tissue masses rather than airway compression are a more reliable sign for lymphadenopathy, with the most agreed upon sites on the frontal projection for soft tissue mass detection being the right hilar region, followed by the left hilum. Unfortunately, this study could not confirm the usefulness of the CXR in subcategorising PTB into severe and non-severe groups due to the absence of any positive features for severe PTB in the selected sample. The use of prescribed tick-sheets with specified features for detecting lymphadenopathy did not have the expected impact of promoting interobserver consensus of CXR findings in children in terms of detection of TB. The absence of a credible reference standard for lymphadenopathy remains a significant limitation.
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    Factors affecting diagnostic and prognostic performance of a transcriptomic signature of risk of tuberculosis in HIV-uninfected South African adults
    (2022) Mulenga, Humphrey; Hatherill, Mark; Scriba, Thomas J
    Background Host blood transcriptomic signatures, such as RISK11, have potential as tests for diagnosing and predicting tuberculosis. This thesis aimed to review the literature, evaluate host and non-host factors associated with variability of the RISK11 signature and impact on discriminatory performance and evaluate RISK11 performance in combination with tests of Mycobacterium tuberculosis sensitization. Methods A systematic review of discriminatory performance of transcriptomic signatures for tuberculosis was conducted. RISK11, QuantiFERON-TB Gold-Plus and host factors were analysed in a prospective cohort, in which a cross-sectional study of upper respiratory organisms was nested. Effects on RISK11 were quantified using multivariable generalised regression. Discriminatory performance of RISK11, and RISK11/QuantiFERON combinations, were quantified by area under the curve and/or sensitivity and specificity. Results In the literature, one signature (90% sensitivity; 74% specificity) met the minimal criteria for a triage test; one signature (86% sensitivity; 84% specificity) met the minimal criteria for a predictive test. In the prospective cohort, RISK11 scores were higher among individuals with prevalent tuberculosis (+18.90%), night sweats (+14.65%) and incident tuberculosis (+7.29%). Cough was associated with 72.55% higher RISK11 score in prevalent tuberculosis cases. Stratification by cough improved diagnostic performance from area under curve of 0.74 overall, to 0.97 in cough-positive participants. Adjustment for host factors affecting controls did not change RISK11 discriminatory performance. In the cross-sectional study, RISK11 scores were higher by +16.7%, +67.8% and +13.5% in participants with coronavirus, influenza and rhinovirus, respectively, such that RISK11 could not differentiate prevalent tuberculosis from upper respiratory viruses. Compared to RISK11, the Either-Positive test combination decreased diagnostic negative likelihood ratio from 0.7 to 0.3, and prognostic negative likelihood ratio from 0.9 to 0.3, but did not improve upon QuantiFERON alone. Compared to QuantiFERON, the Both-Positive test combination increased diagnostic positive likelihood ratio from 1.3 to 4.7, and prognostic positive likelihood ratio from 1.4 to 2.8, but did not improve upon RISK11 alone. Conclusion RISK11 holds promise as a triage test for tuberculosis. Further optimisation, or development of new signatures is needed to improve discrimination of subclinical tuberculosis, without cough, and to mitigate the impact of viral co-infection. RISK11/QuantiFERON combination testing is not recommended.
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    Inflammatory and myeloid-associated gene expression before and one day after infant vaccination with MVA85A correlates with induction of a T cell response
    (2014-06-09) Matsumiya, Magali; Harris, Stephanie A; Satti, Iman; Stockdale, Lisa; Tanner, Rachel; O’Shea, Matthew K; Tameris, Michelle; Mahomed, Hassan; Hatherill, Mark; Scriba, Thomas J; Hanekom, Willem A; McShane, Helen; Fletcher, Helen A
    Abstract Background Tuberculosis (TB) remains a global health problem, with vaccination likely to be a necessary part of a successful control strategy. Results of the first Phase 2b efficacy trial of a candidate vaccine, MVA85A, evaluated in BCG-vaccinated infants were published last year. Although no improvement in efficacy above BCG alone was seen, cryopreserved samples from this trial provide an opportunity to study the immune response to vaccination in this population. Methods We investigated blood samples taken before vaccination (baseline) and one and 28 days post-vaccination with MVA85A or placebo (Candin). The IFN-γ ELISpot assay was performed at baseline and on day 28 to quantify the adaptive response to Ag85A peptides. Gene expression analysis was performed at all three timepoints to identify early gene signatures predictive of the magnitude of the subsequent adaptive T cell response using the significance analysis of microarrays (SAM) statistical package and gene set enrichment analysis. Results One day post-MVA85A, there is an induction of inflammatory pathways compared to placebo samples. Modules associated with myeloid cells and inflammation pre- and one day post-MVA85A correlate with a higher IFN-γ ELISpot response post-vaccination. By contrast, previous work done in UK adults shows early inflammation in this population is not associated with a strong T cell response but that induction of regulatory pathways inversely correlates with the magnitude of the T cell response. This may be indicative of important mechanistic differences in how T cell responses develop in these two populations following vaccination with MVA85A. Conclusion The results suggest the capacity of MVA85A to induce a strong innate response is key to the initiation of an adaptive immune response in South African infants but induction of regulatory pathways may be more important in UK adults. Understanding differences in immune response to vaccination between populations is likely to be an important aspect of developing successful vaccines and vaccination strategies. Trial registration ClinicalTrials.gov number NCT00953927
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    Isolation of Non-Tuberculous Mycobacteria in Children Investigated for Pulmonary Tuberculosis
    (Public Library of Science, 2006) Hatherill, Mark; Hawkridge, Tony; Whitelaw, Andrew; Tameris, Michele; Mahomed, Hassan; Moyo, Sizulu; Hanekom, Willem; Hussey, Gregory
    Objective To evaluate the frequency and clinical significance of non-tuberculous mycobacteria (NTM) isolates among children investigated for pulmonary tuberculosis in a rural South African community. METHODS: Children were investigated for pulmonary tuberculosis as part of a tuberculosis vaccine surveillance program (2001-2005). The clinical features of children in whom NTM were isolated, from induced sputum or gastric lavage, were compared to those with culture-proven M. tuberculosis . RESULTS: Mycobacterial culture demonstrated 114 NTM isolates from 109 of the 1,732 children investigated, a crude yield of 6% (95% CI 5-7). The comparative yield of positive NTM cultures from gastric lavage was 40% (95% CI 31-50), compared to 67% (95% CI 58-76) from induced sputum. 95% of children with NTM isolates were symptomatic. Two children were HIV-infected. By contrast, M. tuberculosis was isolated in 187 children, a crude yield of 11% (95% CI 9-12). Compared to those with culture-proven M. tuberculosis , children with NTM isolates were less likely to demonstrate acid-fast bacilli on direct smear microscopy (OR 0.19; 95% 0.0-0.76). Children with NTM were older (p<0.0001), and more likely to demonstrate constitutional symptoms (p = 0.001), including fever (p = 0.003) and loss of weight or failure to gain weight (p = 0.04), but less likely to demonstrate a strongly positive tuberculin skin test (p<0.0001) or radiological features consistent with pulmonary tuberculosis (p = 0.04). DISCUSSION: NTM were isolated in 6% of all children investigated for pulmonary tuberculosis and in more than one third of those with a positive mycobacterial culture. NTM may complicate the diagnosis of PTB in regions that lack capacity for mycobacterial species identification. The association of NTM isolates with constitutional symptoms suggestive of host recognition requires further investigation.
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    Optimal tuberculosis case-finding methodologies for field trials of new tuberculosis vaccines in young children
    (2013) Moyo, Sizulu; Hussey, Gregory; Hatherill, Mark; Verver, Suzanne
    There is paucity of evidence to guide case-finding strategies in field trials of new tuberculosis vaccines conducted in young children. To investigate case-finding and case detection methods for tuberculosis in tuberculosis field trials conducted in young children.
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    A quantitative analysis of complexity of human pathogen-specific CD4 T cell responses in healthy M. tuberculosis infected South Africans
    (Public Library of Science, 2016) Arlehamn, Cecilia S Lindestam; McKinney, Denise M; Carpenter, Chelsea; Paul, Sinu; Rozot, Virginie; Makgotlho, Edward; Gregg, Yolande; Van Rooyen, Michele; Ernst, Joel D; Hatherill, Mark; Hanekom, Willem A; Peters, Bjoern; Scriba, Thomas J; Sette, Alessandro
    Author Summary: Human pathogen-specific immune responses are tremendously complex and the techniques to study them ever expanding. There is an urgent need for a quantitative analysis and better understanding of pathogen-specific immune responses. Mycobacterium tuberculosis (Mtb) is one of the leading causes of mortality due to an infectious agent worldwide. Here, we were able to quantify the Mtb-specific response in healthy individuals with Mtb infection from South Africa. The response is highly diverse and 66 epitopes are required to capture 80% of the total reactivity. Our study also show that the majority of the identified epitopes are restricted by multiple HLA alleles. Thus, technical advances are required to capture and characterize the complete pathogen-specific response. This study demonstrates further that the approach combining identified epitopes into "megapools" allows capturing a large fraction of the total reactivity. This suggests that this technique is generally applicable to the characterization of immunity to other complex pathogens. Together, our data provide for the first time a quantitative analysis of the complex pathogen-specific T cell response and provide a new understanding of human infections in a natural infection setting.
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    The relationship between metabolic acidosis, lactate, the lactate:pyruvate ratio, and outcome, in children with post-operative cardiogenic and septic shock
    (2007) Hatherill, Mark; Swingler, George H
    Measures of the severity of metabolic acidosis (base excess) and of the severity of the underlying acid-base derangements (levels of lactate, chloride, albumin, and strong ion gap) have been used to differentiate survivors from nonsurvivors in various types of adult critical illness, including states of severe hamodynamic compromise following cardiac surgery on cardiopulmonary bypass (CPB) and in septic shock. prognostic studies of acid-base data for critically ill children in the settings of post-operative cardiogenci shock and septic shock are relatively scarce. It has been suggested that hyperchloraemia migh be a benign phenomenon that should not prompt escalation of therapy. Although it is recognised that hypoalbuminaemia is associated with adverse outcome, and obscrues the extent of underlying metabolic acidosis, the significance of 'unmeasured' anions estimated from the strong ion gap remains controversial. It has been suggested that the admission lactate level is strongly predictive of paediatric intensive care unit (PICU) outcome in both shock states, but it is not known whether calculation of the lactate: pyruvate ratio would add prognostic value in children with either post-operative cardiogenic, or septic shock.
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    TB incidence in an adolescent cohort in South Africa
    (Public Library of Science, 2013) Mahomed, Hassan; Ehrlich, Rodney; Hawkridge, Tony; Hatherill, Mark; Geiter, Lawrence; Kafaar, Fazlin; Abrahams, Deborah Ann; Mulenga, Humphrey; Tameris, Michele; Geldenhuys, Hennie
    BACKGROUND: Tuberculosis (TB) is a major public health problem globally. Little is known about TB incidence in adolescents who are a proposed target group for new TB vaccines. We conducted a study to determine the TB incidence rates and risk factors for TB disease in a cohort of school-going adolescents in a high TB burden area in South Africa. METHODS: We recruited adolescents aged 12 to 18 years from high schools in Worcester, South Africa. Demographic and clinical information was collected, a tuberculin skin test (TST) performed and blood drawn for a QuantiFERON TB Gold assay at baseline. Screening for TB cases occurred at follow up visits and by surveillance of registers at public sector TB clinics over a period of up to 3.8 years after enrolment. RESULTS: A total of 6,363 adolescents were enrolled (58% of the school population targeted). During follow up, 67 cases of bacteriologically confirmed TB were detected giving an overall incidence rate of 0.45 per 100 person years (95% confidence interval 0.29-0.72). Black or mixed race, maternal education of primary school or less or unknown, a positive baseline QuantiFERON assay and a positive baseline TST were significant predictors of TB disease on adjusted analysis. CONCLUSION: The adolescent TB incidence found in a high burden setting will help TB vaccine developers plan clinical trials in this population. Latent TB infection and low socio-economic status were predictors of TB disease.
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    The burden of Perinatal Tuberculosis in HIV-infected mothers and their infants
    (2018) Downing, Katrina Jo; Hatherill, Mark; Davies, Mary-Ann
    South Africa is one of six countries worldwide that has the highest national burden of tuberculosis (TB) and the largest number of HIV-infected people in the world. HIV infection, Mycobacterium tuberculosis (M.tb) infection and TB disease is most common during a woman’s reproductive age, particularly in South African women. HIV co-infection increases the risk of TB disease either by facilitating reactivation of a latent TB infection or by favouring the progression of a recently acquired TB infection towards active disease in HIV-infected patients. Globally, HIV-TB co-infected adults are 19 times more likely to develop TB disease than HIV-uninfected adults, in the absence of preventive therapy. In South Africa 61% of TB cases are reported to be HIV-infected. HIV-infected pregnant women with latent TB infection are more likely to progress to active TB disease and women in the early postpartum period are twice as likely to develop TB as non-pregnant women, usually at 3 months post-delivery. More pregnant women die from TB disease than from any other pregnancy or childbirth related causes, particularly in South Africa. This risk is greater in HIV-infected, pregnant women, who account for 29.7% of pregnant women attending public antenatal clinic services in South Africa. Infants of pregnant women with TB have increased risks of mortality and morbidity compared to infants of women without TB, and these risks are even higher in pregnant women co-infected with HIV and TB. The risk of M.tb exposure, infection and TB disease in HIV-exposed, uninfected infants is high. An analysis is presented on the relationships between sociodemographic and clinical risk factors and M.tb infection and TB disease in HIVinfected mothers and HIV-exposed infants examined in the setting of an infant TB vaccine clinical trial. Prevalence of maternal M.tb infection and the incidence rate of maternal TB disease and infant M.tb infection and TB disease in this cohort is also investigated. The protocol (Part A) outlines the study design and the methodology of the research for this sub-analysis. The literature review (Part B) provides an overview of recent and current literature on the prevalence and incidence rate of M.tb infection and TB disease in HIV-infected pregnant and post-partum women and their HIV-exposed infants in resource-limited settings, particularly in sub-Saharan Africa and specifically in South Africa. Literature on the risk factors associated with the exposure and progression to M.tb infection and TB disease in these susceptible populations is described. The results of the sub- analysis are presented as a manuscript (Part C). The main findings are the incidence rate of maternal TB was 1.36/100 person-years and incidence rate of infant M.tb infection and TB was 2.47 and 3.62/100 personyears respectively. Maternal CD4 count >350 cells/mm³ was strongly associated with QFT positivity that may have affected the estimate of maternal M.tb infection. Infant M.tb infection was driven by new household TB contact(s) as was infant TB disease in addition to higher QFT values (IU/ml) and maternal smoking. Determining which pregnant or postpartum HIV-infected women and their infants are at the highest risk of becoming M.tb infected and developing TB disease, by improving active TB screening of mother-infant pairs, could be an important public health means to reducing the burden of disease and death caused by TB, particularly in HIV endemic areas of South Africa where Prevention of Mother to Child Transmission coverage is greater than 95%.
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    Transmission of tuberculosis in high school students in Worcester, South Africa
    (2020) Bunyasi, Erick; Hatherill, Mark; Wood, Robin
    Introduction Although adolescents have the highest force of Mycobacterium tuberculosis infection1 and rapidly increasing burden of tuberculosis (TB) disease through 10–19 years of age,2 there are few studies on adolescent Mycobacterium tuberculosis infection, transmission, and TB disease in the WHO African region. Adolescents in the high TB burden countries of Africa are therefore an important, but neglected risk group for global TB control efforts. Adolescents spend a considerable amount of their time in school classrooms, but there is paucity of data on classroom risk of Mycobacterium tuberculosis transmission. To the best of our knowledge, no published study has conducted measurement of air quality and air sampling for Mycobacterium tuberculosis DNA in school classrooms, a novel approach that may support targeted TB disease case–finding strategies which may be more efficient than symptom–based TB screening in the congregate school setting. The overall aims of this PhD project were: 1) To conduct a systematic review of adolescent latent TB infection (LTBI) and TB disease prevalence, and to examine the relationship between adolescent Mycobacterium tuberculosis infection and TB disease rates, in high TB burden African countries. 2) To describe temporal changes in prevalence of LTBI among adolescents living in a single TB endemic South African community, across two time periods spanning the decade 2005–2015. 3) To describe temporal changes in adolescent TB disease notification rates in the same community for the decade 2005–2015. 4) To determine classroom ventilation risk for Mycobacterium tuberculosis transmission in tandem with a pilot study of air sampling for Mycobacterium tuberculosis DNA; and to investigate the operational feasibility and yield of a pragmatic, symptom–based approach to TB disease surveillance in high schools. Methods To achieve Aim 1, we performed a bibliographic database search for studies conducted and published between 1990 and 2018 on prevalence of adolescent (10–19 years) LTBI and TB disease in high TB burden African countries. We calculated the ratio between the number of Mycobacterium tuberculosis infections based on Annual Risk of TB Infection (ARTI) estimates and the number of microbiologically–confirmed TB disease cases per year, and compared the observed ratio to the expected ratio of 8–12 published by Styblo et al.3 To achieve Aim 2, we collected adolescent LTBI (defined by positive QuantiFERON® –TB Gold In–Tube test) prevalence data from eight South African high schools, spanning the decade 2005–2015, from databases of an adolescent cohort study (2005–2007) and an adolescent vaccine trial (2014–2015). We used the two–sample test of equality of proportions to compare changes in LTBI prevalence over the two periods. To achieve Aim 3, we collected adolescent TB disease notification data from the same community (using an electronic tuberculosis disease register) for the decade 2005–2015 and we used the Mann–Kendall test to explore temporal changes in notification rates. To achieve Aim 4, we conducted a cross sectional study of 72 classrooms occupied by 1,836 high school learners, in addition to 7 comparator clinic spaces selected for high a priori risk of Mycobacterium tuberculosis transmission, and performed ventilation (carbon dioxide concentration) measurement to define spaces with high ventilation risk (>1,000 ppm) and ddPCR air sampling for Mycobacterium tuberculosis DNA, with active TB symptom screening among learners. Results 1) There is paucity of data on adolescent LTBI and TB disease prevalence in high TB burden African countries (1990–2018). Based on the limited available data, both LTBI (16%–55%)4–8 and TB disease prevalence rates are high (180–679 cases per 100,000),6–10 but corresponding infection–to–disease ratios are inconsistently low compared to that expected from Styblo's Rule.3 2) Overall adolescent LTBI prevalence remained high and relatively unchanged (44–49%) between 2005– 2015. 11 However, although average LTBI prevalence was unchanged in lower socio–economic quintile schools, prevalence increased in highest socio–economic quintile schools (from 20% to 38%).11 3) Adolescent TB disease notification rates fell 45% (662 to 361 per 100,000) in the same community over the same period. Despite this decrease, recent TB disease prevalence remains high and is three– fold higher in older (15–19 years) than younger (10–14 years) adolescents (566 vs. 151 per 100,000 in 2015). 4) More than one–third of 72 high school classrooms were inadequately ventilated and one–fifth of classrooms had evidence of airborne Mycobacterium tuberculosis DNA detected by ddPCR air sampling. The average risk of inhaling 1 Mycobacterium tuberculosis DNA copy was similar between clinics and classrooms. Across all classrooms the average risk of a classroom occupant inhaling 1 Mycobacterium tuberculosis DNA copy over 1 lesson (35 minutes) was 0.71%; and the estimated risk over 1 academic year was 100%. However, yield from symptom–based TB screening was low, consistent with the presence of undiagnosed subclinical TB cases and risk of ongoing transmission in the school setting. Conclusion Despite the encouraging decline in adolescent TB disease notification rates observed between 2005–2015 in the study area, adolescent LTBI prevalence remains high, consistent with ongoing medium–term transmission. The relatively high proportion of inadequately ventilated classrooms would place learners at high risk of Mycobacterium tuberculosis transmission if exposed to an infectious occupant. This risk appears material, given the proportion of classrooms with a positive ddPCR air filtrate sample and the estimated cumulative risk of inhaling of at least one copy of Mycobacterium tuberculosis DNA. The presence of previously undiagnosed TB cases among learners is inferred from our classroom ddPCR air sampling data, which further suggest that pragmatic school–based TB symptom screening is an inefficient surveillance strategy that likely missed learners with subclinical TB. Improved ventilation in school classrooms is a low–cost intervention that may reduce the risk of TB transmission in schools. New and more efficient targeted TB disease case–finding strategies are needed for congregate settings, including schools, in high TB burden countries. Based on our preliminary data, classroom ddPCR air sampling for Mycobacterium tuberculosis DNA appears feasible for this purpose, but requires further research to optimise diagnostic accuracy and demonstrate cost–effectiveness and public health value in high TB burden countries.
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    Open Access
    Transport of critically ill children in a resource-limited setting
    (2001) Hatherill, Mark
    Transportation of critically ill children by inexperienced personnel may be associated with increased risk of transfer-related adverse events and mortality. To audit paediatric intensive care unit (PICU) transfer activity and transfer-related adverse events in a resource-limited setting. Twenty-two bed regional PICU of a university children's hospital in Cape Town, South Africa. Prospective one-year audit of all children transferred directly to PICU from other hospitals. Data were collected for patient demographics and diagnostic category, referring hospital, transferring personnel, mode of transport, and the incidence of technical, clinical, and critical adverse events. Data are median (interquartile range, IQR). The transfers of 202 children, median age 2.8 months (1.1-14), median weight 3.5 kg (2.5-8.1) were analysed.
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    The tuberculin skin test versus QuantiFERON TB Gold® in predicting tuberculosis disease in an adolescent cohort study in South Africa
    (Public Library of Science, 2011) Mahomed, Hassan; Hawkridge, Tony; Verver, Suzanne; Abrahams, Deborah; Geiter, Lawrence; Hatherill, Mark; Ehrlich, Rodney; Hanekom, Willem A; Hussey, Gregory D
    Setting This study was conducted in a high tuberculosis (TB) burden area in Worcester, South Africa, with a notified all TB incidence rate of 1,400/100,000. Main Objective To compare the predictive value of a baseline tuberculin skin test (TST) with that of the QuantiFERON TB Gold (In-tube) assay (QFT) for subsequent microbiologically confirmed TB disease among adolescents. METHODS: Adolescents aged 12-18 years were recruited from high schools in the study area. At baseline, blood was drawn for QFT and a TST administered. Participants were followed up for up to 3.8 years for incident TB disease (median 2.4 years). RESULTS: After exclusions, 5244 (82.4%) of 6,363 adolescents enrolled, were analysed. The TB incidence rate was 0.60 cases per 100 person years (pyrs) (95% CI 0.43-0.82) for baseline TST positive (≥5 mm) participants and 0.64 cases per 100 pyrs (95% CI 0.45-0.87) for baseline QFT positive participants. TB incidence rates were 0.22 per 100 pyrs (0.11-0.39) and 0.22 per 100 pyrs (0.12-0.38) among those with a negative baseline TST and QFT respectively. Sensitivity for incident TB disease was 76.9% for TST and 75.0% for QFT (p = 0.81). Positive predictive value was 1.4% for TST and 1.5% for QFT. CONCLUSION: Positive TST and QFT tests were moderately sensitive predictors of progression to microbiologically confirmed TB disease. There was no significant difference in the predictive ability of these tests for TB disease amongst adolescents in this high burden setting. Therefore, these findings do not support use of QFT in preference to TST to predict the risk of TB disease in this study population.