Browsing by Author "Hussey, Gregory"

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    Advances in childhood immunisation in South Africa: where to now? Programme managers' views and evidence from systematic reviews
    (BioMed Central Ltd, 2012) Wiysonge, Charles; Ngcobo, Nthombenhle; Jeena, Prakash; Madhi, Shabir; Schoub, Barry; Hawkridge, Anthony; Shey, Muki; Hussey, Gregory
    BACKGROUND: The Expanded Programme on Immunisation (EPI) is one of the most powerful and cost-effective public health programmes to improve child survival. We assessed challenges and enablers for the programme in South Africa, as we approach the 2015 deadline for the Millennium Development Goals. METHODS: Between September 2009 and September 2010 we requested national and provincial EPI managers in South Africa to identify key challenges facing EPI, and to propose appropriate solutions. We collated their responses and searched for systematic reviews on the effectiveness of the proposed solutions; in the Health Systems Evidence, Cochrane Library, and PubMed electronic databases. We screened the search outputs, selected systematic reviews, extracted data, and assessed the quality of included reviews (using AMSTAR) and the quality of the evidence (using GRADE) in duplicate; resolving disagreements by discussion and consensus. RESULTS: Challenges identified by EPI managers were linked to healthcare workers (insufficient knowledge of vaccines and immunisation), the public (anti-immunisation rumours and reluctance from parents), and health system (insufficient financial and human resources). Strategies proposed by managers to overcome the challenges include training, supervision, and audit and feedback; strengthening advocacy and social mobilisation; and sustainable EPI funding schemes, respectively. The findings from reliable systematic reviews indicate that interactive educational meetings, audit and feedback, and supportive supervision improve healthcare worker performance. Structured and interactive communication tools probably increase parents' understanding of immunisation; and reminders and recall, use of community health workers, conditional cash transfers, and mass media interventions probably increase immunisation coverage. Finally, a national social health insurance scheme is a potential EPI financing mechanism; however, given the absence of high-quality evidence of effects, its implementation should be pilot-tested and the impacts and costs rigorously monitored. CONCLUSION: In line with the Millennium Development Goals, we have to ensure that our children's right to health, development and survival is respected, protected and promoted. EPI is central to this vision. We found numerous promising strategies for improving EPI performance in South Africa. However, their implementation would need to be tailored to local circumstances and accompanied by high-quality monitoring and evaluation. The strength of our approach comes from having a strong framework for interventions before looking for systematic reviews. Without a framework, we would have been driven by what reviews have been done and what is easily researchable; rather than the values and preferences of key immunisation stakeholders.
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    Association of human TLR1 and TLR6 deficiency with altered immune responses to BCG vaccination in South African infants
    (Public Library of Science, 2011) Randhawa, April Kaur; Shey, Muki S; Keyser, Alana; Peixoto, Blas; Wells, Richard D; de Kock, Marwou; Lerumo, Lesedi; Hughes, Jane; Hussey, Gregory; Hawkridge, Anthony; Kaplan, Gilla; Hanekom, Willem A; Hawn, Thomas R
    The development of effective immunoprophylaxis against tuberculosis (TB) remains a global priority, but is hampered by a partially protective Bacillus Calmette-Guérin (BCG) vaccine and an incomplete understanding of the mechanisms of immunity to Mycobacterium tuberculosis. Although host genetic factors may be a primary reason for BCG's variable and inadequate efficacy, this possibility has not been intensively examined. We hypothesized that Toll-like receptor (TLR) variation is associated with altered in vivo immune responses to BCG. We examined whether functionally defined TLR pathway polymorphisms were associated with T cell cytokine responses in whole blood stimulated ex vivo with BCG 10 weeks after newborn BCG vaccination of South African infants. In the primary analysis, polymorphism TLR6_C745T (P249S) was associated with increased BCG-induced IFN-γ in both discovery (n = 240) and validation (n = 240) cohorts. In secondary analyses of the combined cohort, TLR1_T1805G (I602S) and TLR6_G1083C (synonymous) were associated with increased IFN-γ, TLR6_G1083C and TLR6_C745T were associated with increased IL-2, and TLR1_A1188T was associated with increased IFN-γ and IL-2. For each of these polymorphisms, the hypo-responsive allele, as defined by innate immunity signaling assays, was associated with increased production of TH1-type T cell cytokines (IFN-γ or IL-2). After stimulation with TLR1/6 lipopeptide ligands, PBMCs from TLR1/6-deficient individuals (stratified by TLR1_T1805G and TLR6_C745T hyporesponsive genotypes) secreted lower amounts of IL-6 and IL-10 compared to those with responsive TLR1/6 genotypes. In contrast, no IL-12p70 was secreted by PBMCs or monocytes. These data support a mechanism where TLR1/6 polymorphisms modulate TH1 T-cell polarization through genetic regulation of monocyte IL-10 secretion in the absence of IL-12. These studies provide evidence that functionally defined innate immune gene variants are associated with the development of adaptive immune responses after in vivo vaccination against a bacterial pathogen in humans. These findings could potentially guide novel adjuvant vaccine strategies as well as have implications for IFN-γ-based diagnostic testing for TB.
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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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    Culture-confirmed childhood tuberculosis in Cape Town, South Africa: a review of 596 cases
    (Biomed Central Ltd, 2007) Schaaf, H Simon; Marais, Ben; Whitelaw, Andrew; Hesseling, Anneke; Eley, Brian; Hussey, Gregory; Donald, Peter
    BACKGROUND:The clinical, radiological and microbiological features of culture-confirmed childhood tuberculosis diagnosed at two referral hospitals are described. METHODS: Cultures of Mycobacterium tuberculosis from children less than 13 years of age at Tygerberg and Red Cross Children's Hospitals, Cape Town, South Africa, were collected from March 2003 through February 2005. Folder review and chest radiography were performed and drug susceptibility tests done. RESULTS: Of 596 children (median age 31 months), 330 (55.4%) were males. Of all children, 281 (47.1%) were HIV-uninfected, 133 (22.3%) HIV-infected and 182 (30.5%) not tested. Contact with infectious tuberculosis adults was recorded in 295 (49.5%) children. Missed opportunities for chemoprophylaxis were present in 117/182 (64.3%) children less than 5 years of age.Extrathoracic TB was less common in HIV-infected than in HIV-uninfected children (49/133 vs. 156/281; odds ratio 0.50, 95% confidence interval 0.32-0.78). Alveolar opacification (84/126 vs. 128/274; OR 1.85, 95%CI 1.08-3.19) and cavitation (33/126 vs. 44/274; OR 2.28, 95%CI 1.44-3.63) were more common in HIV-infected than in HIV-uninfected children. Microscopy for acid-fast bacilli on gastric aspirates and sputum was positive in 29/142 (20.4%) and 40/125 (32.0%) children, respectively. Sixty-seven of 592 (11.3%) children's isolates showed resistance to isoniazid and/or rifampicin; 43 (7.3%) were isoniazid-monoresistant, 2 (0.3%) rifampicin-monoresistant and 22 (3.7%) multidrug-resistant. Death in 41 children (6.9%) was more common in HIV-infected children and very young infants. CONCLUSION: HIV infection and missed opportunities for chemoprophylaxis were common in children with culture-confirmed TB. With cavitating disease and sputum or gastric aspirates positive for acid-fast bacilli, children may be infectious. Transmission of drug-resistant TB is high in this setting.
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    Epidemiology of pertussis in children hospitalised with respiratory tract infection
    (2021) Muloiwa, Rudzani; Zar, Heather; Hussey, Gregory
    The availability of an effective vaccine against Bordetella pertussis substantially reduced the morbidity and mortality from pertussis, however, in the last decade there appears to have been a substantial increase in pertussis cases as reported mainly in high income countries. Although it is believed that the greatest burden of pertussis, including deaths, is in low- and middle-income countries (LMICs), there seem to be little data available to back this up. This thesis set out to find data that will give some insight into the burden of pertussis in a low- and middle-income setting in infants and children with severe lower respiratory tract infection (LRTI). Given the paucity of data in LMICs, the thesis started by systematically searching for existing data that will give some indication of the possible extent of the pertussis problem in these countries. Secondly, a prospective study was conducted at a children's hospital. As hospital admission is a marker of severe disease, these children were targeted as the appropriate population in which to meaningfully conduct a primary study on the burden of pertussis. In addition to quantifying the burden by describing the prevalence of confirmed pertussis in this group of children, the study set out to look for potential factors that may be associated with increased risk of pertussis. LRTI are now commonly known to be associated with identification of multiple organisms in respiratory samples, this study aimed to also look at organisms that are detected with Bordetella pertussis; and investigate whether this association was in any way associated with severe disease or negative outcomes. Finally, this study hoped to identify clinical features that could be used to develop a more reliable clinical case definition of pertussis. Chapter 1 gives a background that justifies the undertaking of this study. In chapter 2 a systematic review quantifies, using the best available data, the burden of pertussis in LMICs. Chapter 3 clarifies the methods briefly described in the rest of the manuscript. The burden of pertussis due to the two organisms known to cause the disease, Bordetella pertussis and Bordetella parapertussis, is described in some detail. In both this chapter and the earlier mentioned systematic review (chapter 2), the burden of pertussis is stratified by subgroups to identify potential risk factors. The issue of risk is formally and specifically taken up in the chapter that follows (chapter 5) where potential risk factors are analysed, and the independent impact for some of these factors is established. The last two results chapters (chapters 6 and 7) deal respectively with the conundrum of finding other respiratory organism in the same specimen with Bordetella pertussis and failure to find useful clinical criteria that can help with improved diagnosis of pertussis. While there is no established pattern noted between pertussis and most organisms, a few give signals of being independently associated with Bordetella pertussis even if the clinical relevance is not clear at the moment. In the final chapter of the thesis (chapter 8) I conclude the thesis by making an argument that although there are still knowledge gaps, the thesis gives a clear indication that pertussis remains a serious problem in LMICs especially for some groups that show increased risk of the disease or its severe consequences.
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    Evidence-based vaccinology: supporting evidence-informed considerations to introduce routine hepatitis A immunization in South Africa
    (2023) Patterson, Jenna; Kagina, Benjamin; Cleary Susan; Muloiwa, Rudzani; Hussey, Gregory; Silal, Sheetal
    Hepatitis A is a vaccine preventable disease caused by the Hepatitis A Virus (HAV). Currently, South Africa is classified by the World Health Organization (WHO) as a high hepatitis A endemic region where 90% of children are assumed to be “naturally immunised” following HAV exposure before the age of 10 years old. In high hepatitis A endemic settings, routine vaccination against HAV is not necessary due to high rates of “natural immunization”. Recent data suggest a possible shift from high to intermediate HAV endemicity may be occurring in South Africa. Countries with intermediate HAV endemicity and no routine hepatitis A vaccination program have a high risk of experiencing hepatitis A outbreaks and high costs associated with care. Currently, there is no routine vaccination program against HAV in South Africa. The aim of this PhD was to generate evidence for decision making on whether a routine vaccination program against HAV should be considered for introduction into the South African Expanded Program on Immunizations (EPI-SA). The objectives included gathering context-specific evidence on the epidemiologic features of hepatitis A, clinical characteristics of the disease, hepatitis A vaccine characteristics and cost of case management. Using this evidence, the PhD estimated the future epidemiology of hepatitis A and impacts of routine hepatitis A vaccination scenarios in the country. The PhD's overall methods were informed by the principles of Evidence-Based Vaccinology for developing vaccine recommendations. The project included a mixed-methods approach: systematic reviews, a retrospective clinical folder review, mathematical modelling, and economic evaluation. A dynamic transmission model was built to forecast the future epidemiology of hepatitis A and to simulate the impacts of several different childhood hepatitis A vaccination strategies in South Africa. Selected findings have been published in relevant peer-reviewed journals. In addition, a technical dossier was prepared to submit to the South African National Advisory Group on Immunization (NAGI) on behalf of the Hepatitis A Working Group for considerations of introducing hepatitis A vaccination into the South African EPI.
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    The incidence of tuberculosis in adolescents in the context of proposed TB vaccine trials
    (2013) Mahomed, Hassan; Ehrlich, Rodney; Hussey, Gregory; Verver, Suzanne
    [Background] Tuberculosis (TB) is a significant global health problem and the development of new TB vaccines is one strategy proposed to address this scourge. Adolescents are a potential target group for new TB vaccines. Limited data are available in the scientific literature on the epidemiology of TB in adolescents. This thesis aimed to add substantial data on adolescent TB epidemiology through a cohort study of TB infection and disease in adolescents in a high burden setting. Such data will support clinical trials of new TB vaccines in adolescents but the knowledge gained will also be of value for TB Control Programmes. [Methods] Adolescents aged 12-18 years were recruited from 11 high schools in the rural town of Worcester and surrounding areas of the Western Cape Province of South Africa. They were screened at baseline for latent TB infection using both the tuberculin skin test (TST) and an interferon gamma release assay, the QuantiFERON® TB Gold (in-tube) assay (QFT). They were also screened for TB disease using an algorithm composed of a set of screening tests. They were followed up for at least two years for incident TB and the predictive value of the baseline TST and QFT for incident TB disease was compared. Demographic, socio-economic and clinical predictive factors for latent TB infection prevalence at enrolment and for incident TB disease during follow up were determined. A survey of attitudes to participation in TB vaccine clinical trials in a subset of adolescents from these schools was also conducted. Both studies had ethics approval. Standard scientific statistical techniques were used to analyse the data. [Results] Fifty eight percent (6363) of the target population of 10,492 adolescents were recruited into the main cohort study. A prevalence of latent TB infection amongst the study participants at enrolment of 55% (TST) and 51% (QFT) was found. Predictive factors for latent infection were: being of black or mixed race origin compared to being of white or indian origin, older age (>15 years), previous household TB contact, low parental income and low education status of the parents. The TST and QFT were found to have good agreement (% agreement 84.8%, kappa [κ] = 0.70, 95%CI 0.68–0.71) in contrast to certain studies in other settings. A baseline prevalence of TB disease of 3/1000 was found in adolescents. While the TST and QFT were sensitive predictors of the presence of TB disease, none of the screening tests evaluated (TB related symptoms, recent household contact, TST or QFT) had high positive predictive values (all less than 2%) making these tests impractical for routine use. Given the imperative for screening in TB vaccine trials, these data are important for deciding on choice of screening tests in a clinical trial setting. Both the TST and QFT were found to be predictive of the onset of TB and were equally predictive. An incidence of bacteriologically confirmed active TB of 0.45/100 (95% confidence interval 0.29-0.72) person years (pyrs) was found in this cohort. Using different definitions of active TB, the rate varied from 0.31-0.59/ 100 pyrs. Risk factors gleaned at baseline that were predictive of the onset of TB disease were: being of black or mixed race origin, maternal education of primary school or less or unknown, evidence of latent infection (positive TST or QFT) and absence of a BCG scar. Knowledge of TB was fair amongst adolescents but willingness to participate in TB vaccine trials varied depending on the procedures involved. [Limitations] Important limitations were as follows. The data presented are likely to underestimate the true prevalence and incidence of TB amongst adolescents in general since adolescents not at school are likely to have higher rates of TB than those attending school. On the other hand TB rates amongst those recruited are likely to have been higher than those not agreeing to participate since participation rates were higher in poorer schools than in more affluent schools. Chest radiographs as a screening tool for TB could not be evaluated because this method of screening was excluded for logistical reasons. The number of TB cases is likely to have been underestimated since smear screening was the main method of case detection and smear negative culture positive TB cases would have been missed. [Application of results] A range of data was obtained through these analyses which will be very useful for planning TB vaccine trials in adolescents and also for TB Control Programmes. Since data were collected in a high TB burden setting, the findings are mainly generalisable to such settings rather than low burden settings. Nevertheless, efficacy trials of new TB vaccines are likely to be carried out in high TB burden settings making these results highly relevant to TB vaccine efficacy trial planning. Policy with respect to the use of interferon gamma release assays will be informed by this data given that it is a relatively new diagnostic modality. Knowledge of the baseline prevalence of TB disease and the utility of different screening tools amongst healthy adolescents would help the design and costing of screening approaches to be used in TB vaccine clinical trials which include adolescents. The data on the prevalence of latent TB infection will assist with the selection of TB vaccine candidates for this target group will be of value given that certain vaccines are designed to target those with latent infection. These data will also support planning where latent TB infection is an exclusion criterion such as in safety trials. TB incidence rates can be used to plan samples sizes for efficacy trials. The comparison of the TST and QFT with respect to prevalence of latent TB infection and predictive value for TB disease provide evidence for policies on the use of these tools in clinical trials and for TB Control Programmes in high burden settings. The fact that these measures showed good agreement and were equally predictive of the onset of TB disease, suggest that the QFT need not replace the TST in current routine practice. However, the two tests may be used interchangeably to equal effect. The knowledge and attitudes of adolescents towards participation in TB vaccine trials provides some guidance with respect to what to expect when approaching this group for recruitment purposes. In summary, the prevalence of latent TB infection, the prevalence and incidence of TB disease and predictive factors for latent infection and disease as well as the knowledge and attitudes of adolescents towards participating in TB vaccine trials are described in this thesis. The application of these results to TB vaccines trials and potential value in TB Control Programmes is discussed.
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    Initial experience of a public sector antiretroviral treatment programme for HIV-infected children and their infected parents
    (2004) Eley, Brian; Nuttall, James; Davies, Mary-Ann; Smith, Lara; Cowburn, Carol; Buys, Heloise; Hussey, Gregory
    Objective. To describe the initial experience of treating HIVinfected children and their infected parents with antiretroviral therapy. Design. Prospective, cohort study. Setting. Tertiary, referral hospital. Patients. HIV-infected children and their parents. Methods. This report focuses on the early response of children to highly active antiretroviral therapy (HAART). Children were followed up at 4-weekly intervals. Monitoring included initial and yearly viral load measurements, baseline and 6- monthly CD4 counts and 4-weekly adherence checks. Results. Between August 2002 and June 2003, 80 children were enrolled in the programme, representing a follow-up period of 23.9 patient-years. Seventy-five children had severe clinical disease, severe immune suppression, or a combination of the two. The response of children who had received HAART for ≥ 6 months (N = 17) was assessed. There was no change in mass z-score (p = 0.11) or length z-score (p = 0.37), but a significant increase in CD4 percentage (p < 0.0001) during the first 6 months of therapy. Six-month viral loads were available for 12 children. There was a significant drop in viral load (p = 0.001) and 9 achieved undetectable levels by 6 months. Most children achieved ≥ 85% adherence. By June 2002, 67 children (84%) were relatively well, 1 had B-cell lymphoma, 7 (8.8%) had died, 4 (5%) were lost to follow-up and 1 was withdrawn from the programme. Of 57 children who completed 3 months of HAART, 12 were admitted a total of 17 times for infectious complications. There were no severe drug reactions. Three of 7 mothers on HAART received treatment through the programme. Conclusion. These initial results suggest that many HIVinfected children in the public sector will benefit from antiretroviral therapy. However, both ambulatory and inpatient facilities are required to manage children on HAART comprehensively
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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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    Oral trimethoprim-sulphamethoxazole levels in stable HIV-infected children
    (2006) Zar, Heather J; Langdon, Grant; Apolles, Patti; Eley, Brian; Hussey, Gregory; Smith, Peter
    Background. Effective treatment of Pneumocystis jiroveci pneumonia (PCP) requires therapeutic serum concentrations of 5 - 10 µg/ml trimethoprim (TMP); consequently intravenous trimethoprim-sulphamethoxazole (TMP-SMZ) is recommended therapy. However, oral therapy is desirable as the intravenous route is costly, time-consuming, more difficult to administer and carries a risk of needlestick injury. Objective. To investigate whether therapeutic TMP levels for treatment of PCP can be attained with oral therapy in HIVinfected children. Methods. A prospective dose-escalation study was undertaken of serum TMP levels attained following oral doses of TMP of 5 mg/kg, 10 mg/kg or 20 mg/kg in stable HIV-infected children. Children who received a 20 mg/kg dose were randomised to get a second dose (5 or 10 mg/kg TMP) at 6 hours. TMP levels were measured at baseline, peak (3 hours), and trough (6 hours) using liquid chromatography. An additional TMP level was taken at 9 hours in those who received a second TMP dose. Results. Median (25th - 75th percentile) peak serum TMP levels following a 5 mg/kg, 10 mg/kg or 20 mg/kg oral loading dose were 0.93 (0.5 - 1.5) µg/ml, 1.94 (1.4 - 2.2) µg/ml and 7.68 (6.1- 7.8) µg/ml respectively. Peak TMP levels at 9 hours after a second TMP dose of 5 or 10 mg/kg were 6.98 (3.4 - 8.8) µg/ml and 9.25 (8.2 - 10.3) µg/ml respectively. Conclusion. Therapeutic concentrations of TMP for treatment of P. jiroveci can be attained with an oral loading dose of 20 mg/kg and sustained with a second dose at 6 hours of either 5 mg or 10 mg/kg in stable HIV-infected children.
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    Pneumonia in HIV-infected children admitted to hospital in Cape Town, South Africa
    (2000) Zar, Heather; Hussey, Gregory; Bateman, Eric D
    There is little information on the aetiology and outcome of HIV-associated pneumonia in African children and no comprehensive data from South Africa. Studies of HIV-infected adult in Africa reported that the spectrum of pulmonary disease differs from that of developed countries with tuberculosis and pyogenic pneumonia predominating and Pneumocystis carinii pneumonia (PCP) occurring uncommonly. Knowledge of the aetiology and outcome of pneumonia is important for the development of paediatric management guidelines and of policies for allocation of resources especially in South Africa, where the HIV pandemic has resulted in increasing numbers of HIV-positive children requiring admission to hospital or intensive care units for pneumonia. Furthermore in countries with limited resources, development of cost effective diagnostic procedures to investigate the aetiology of pneumonia is necessary.
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    A quick guide to the clinical care of children infected with HIV
    (Chlidren's Institute, 2002-04) Shung King, Maylene; Giese, Sonja; Hussey, Gregory
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    The impact of chest radiography on the diagnosis, clinical management and outcome of acute lower respiratory infections in children
    (1999) Swingler, George Henry; Hussey, Gregory; Zwarenstein, Merrick
    Background. When available, chest radiography is widely used in acute lower respiratory infections in children. Its impact on clinical outcome is unknown. Methods. A randomised controlled trial was performed of 522 children aged 2 to 59 months who met the World Health Organisation case definition for pneumonia. The main outcome was time to recovery, measured in a subset of 398 participants who offered a telephone number. Subsidiary outcomes included diagnosis, elements of clinical management and subsequent use of health facilities. Findings. There was a marginal improvement in time to recovery, which was not clinically significant. The median time to recovery was seven days in both groups, 95% CI 6-8 days and 6-9 days in the radiograph and control groups respectively (p=0.50, log rank test). The hazard ratio for recovery was 1.08 (95% CI 0.85 to 1.34). This lack of effect was not modified by clinicians' experience and no sub-groups of children were identified in whom the radiograph had an effect. Pneumonia was diagnosed more often in the radiograph group (14.4% vs. 8.8%, p=0.03) and bronchiolitis less often ( 44% vs. 56%, p=0.005). Antibiotic usage was higher in the radiograph group (60.8% vs. 52.2%, p=0,05). There were no differences in subsequent health facility usage. Interpretation. Despite a net change in diagnosis and an increase in antibiotic usage, chest radiography did not affect clinical outcome in outpatient children with acute lower respiratory infection. This lack of effect was independent of clinicians' experience. There were no clinically identifiable sub-groups of children within the World Health Organisation case definition of pneumonia who benefited from radiography. It is concluded that routine use of chest radiography is not beneficial in ambulatory children over two months of age with acute lower respiratory infection.
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    Understanding interventions for improving routine immunization coverage in children in low- and middle-income countries: a systematic review protocol
    (BioMed Central Ltd, 2013) Machingaidze, Shingai; Rehfuess, Eva; von Kries, Rudiger; Hussey, Gregory; Wiysonge, Charles
    BACKGROUND: Virtually all low- and middle-income countries are dependent on the World Health Organization's Expanded Program on Immunization for delivery of vaccines to children. The Expanded Program on Immunization delivers routine immunization services from health facilities free of charge. Understanding interventions for improving immunization coverage remains key in achieving universal childhood immunization. METHODS: We will conduct a systematic review that aims to assess the effectiveness of the full range of potential interventions to improve routine immunization coverage in children in low- and middle-income countries. We will include intervention studies, as well as observational studies. We will search the Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, electronic databases for eligible studies published by 31 August 2013. At least two authors will independently screen search outputs, select studies, extract data and assess the risk of bias (using separate criteria for interventions and observational studies); resolving any disagreements by discussion and consensus. The use of logic models and the Cochrane Complexity Matrix will be explored in order to better understand and contextualize studies. We will express the result of each study as a risk ratio with its corresponding 95% confidence intervals for dichotomous data, or mean difference with its standard deviation for continuous data. We will conduct meta-analysis for the same type of participants, interventions, study designs, and outcome measures where homogeneity of data allows. Use of harvest plots may be explored as an alternative. Heterogeneity will be assessed using the chi2 test of heterogeneity, and quantified using the I2 statistic. This protocol has not been registered with PROSPERO.DISCUSSION:This review will allow us to document evidence across a broad range of intervention types for improving routine immunization coverage in children and also distinguish between those that are well supported by evidence (to direct policy recommendations) and those that are not well supported (to direct research agenda).
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    Vaginal microbicides for reducing the risk of sexual acquisition of HIV infection in women: systematic review and meta-analysis
    (BioMed Central Ltd, 2012) Obiero, Jael; Mwethera, Peter; Hussey, Gregory; Wiysonge, Charles
    BACKGROUND: Each year more than two million people are newly infected with HIV worldwide, a majority of them through unprotected vaginal sex. More than half of new infections in adults occur in women. Male condoms and male circumcision reduce the risk of HIV acquisition; but the uptake of these methods is out of the control of women. We therefore aimed to determine the effectiveness of vaginal microbicides (a potential female-controlled method) for prevention of sexual acquisition of HIV in women. METHODS: We conducted a comprehensive search of peer-reviewed and grey literature for publications of randomised controlled trials available by September 2012. We screened search outputs, selected studies, assessed risk of bias, and extracted data in duplicate; resolving differences by discussion and consensus. RESULTS: We identified 13 eligible trials that compared vaginal microbicides to placebo. These studies enrolled 35,905 sexually active HIV-negative women between 1996 and 2011; in Benin, Cameroon, Cote d'Ivoire, Ghana, Kenya, Malawi, Nigeria, South Africa, Tanzania, Uganda, Zambia, Zimbabwe, India, Thailand, and the United States of America. A small trial of 889 women found that tenofovir (a nucleotide reverse transcriptase inhibitor) significantly reduces the risk of HIV acquisition (risk ratio [RR] 0.63, 95% confidence intervals [CI] 0.43 to 0.93). Effectiveness data are not yet available from follow-up tenofovir trials being conducted in South Africa, Uganda, and Zimbabwe (1 trial) and multiple sites in South Africa (1 trial). We found no evidence of a significant effect for nonoxynol-9 (5 trials), cellulose sulphate (2 trials), SAVVY (2 trials), Carraguard (1 trial), PRO 2000 (2 trials), and BufferGel (1 trial) microbicides. The pooled RR for the effect of current experimental vaginal microbicides on HIV acquisition in women was 0.97, 95%CI 0.87 to 1.08. Although study results were homogeneous across the different drug classes (heterogeneity P=0.17, I2=27%), the overall intervention effect was not statistically significant. Nonoxynol-9 significantly increased the risk of having adverse genital lesions but no other microbicide led to significant increases in adverse events. CONCLUSIONS: There is not enough evidence at present to recommend vaginal microbicides for HIV prevention. Further high-quality research is needed to confirm the beneficial effects of tenofovir as well as continue the development and testing of new microbicides.
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    Open Access
    Varicella zoster virus-associated morbidity and mortality in Africa – a systematic review
    (BioMed Central, 2017-11-14) Hussey, Hannah; Abdullahi, Leila; Collins, Jamie; Muloiwa, Rudzani; Hussey, Gregory; Kagina, Benjamin
    Background: Varicella zoster virus (VZV) causes varicella and herpes zoster. These vaccine preventable diseases are common globally. Most available data on VZV epidemiology are from industrialised temperate countries and cannot be used to guide decisions on the immunization policy against VZV in Africa. This systematic review aims to review the published data on VZV morbidity and mortality in Africa. Methods: All published studies conducted in Africa from 1974 to 2015 were eligible. Eligible studies must have reported any VZV epidemiological measure (incidence, prevalence, hospitalization rate and mortality rate). For inclusion in the review, studies must have used a defined VZV case definition, be it clinical or laboratory-based. Results: Twenty articles from 13 African countries were included in the review. Most included studies were crosssectional, conducted on hospitalized patients, and half of the studies used varying serological methods for diagnosis. VZV seroprevalence was very high among adults. Limited data on VZV seroprevalence in children showed very low seropositivity to anti-VZV antibodies. Co-morbidity with VZV was common. Conclusion: There is lack of quality data that could be used to develop VZV control programmes, including vaccination, in Africa. Trial registration: PROSPERO 2015: CRD42015026144.