Respiratory and Meningeal Pathogens Research Unit

Johannesburg, South Africa

Respiratory and Meningeal Pathogens Research Unit

Johannesburg, South Africa
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Weinberger D.M.,Harvard University | Harboe Z.B.,Statens Serum Institute | Sanders E.A.M.,University Utrecht | Ndiritu M.,Center for Geographic Medicine Research Coast | And 9 more authors.
Clinical Infectious Diseases | Year: 2010

Background. The 92 capsular serotypes of Streptococcus pneumoniae differ greatly in nasopharyngeal carriage prevalence, invasiveness, and disease incidence. There has been some debate, though, regarding whether serotype independently affects the outcome of invasive pneumococcal disease (IPD). Published studies have shown variable results with regard to case-fatality ratios for specific serotypes and the role of host factors in affecting these relationships. We evaluated whether risk of death due to IPD is a stable serotype-associated property across studies and then compared the pooled effect estimates with epidemiologic and biological correlates. Methods. We performed a systematic review and meta-analysis of serotype-specific disease outcomes for patients with pneumonia and meningitis. Study-specific estimates of risk of death (risk ratio [RR]) were pooled from 9 studies that provided serotype-specific data on pneumonia and meningitis using a random-effects method with serotype 14 as the reference. Pooled RRs were compared with RRs from adults with low comorbidity scores to evaluate potential confounding by host factors. Results. Significant differences were found in the RR estimates among serotypes in patients with bacteremic pneumonia. Overall, serotypes 1, 7F, and 8 were associated with decreased RRs, and serotypes 3, 6A, 6B, 9N, and 19F were associated with increased RRs. Outcomes among meningitis patients did not differ significantly among serotypes. Serotypes with increased RRs had a high carriage prevalence, had low invasiveness, and were more heavily encapsulated in vitro. Conclusions. These results suggest that IPD outcome, like other epidemiologic measures, is a stable serotypeassociated property. © 2010 by the Infectious Diseases Society of America. All rights reserved.

Aaron L.,Harvard University | Kim S.,Rutgers University | Jean-Philippe P.,Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc | Madhi S.,Respiratory and Meningeal Pathogens Research Unit | And 4 more authors.
International Journal of Tuberculosis and Lung Disease | Year: 2016

Setting: Standardized clinical case definitions represent the best option for pediatric tuberculosis (TB) disease diagnosis and classification. OBJECTIVE: To apply published guidelines for intrathoracic TB classification for use in reporting diagnostic studies with passive case finding to presumed TB patients from International Maternal Pediatric Adolescent AIDS Clinical Trials P1041, a trial of isoniazid prophylaxis in healthy human immunodeficiency virus exposed, bacille Calmette-Gúerin vaccinated infants which employed active surveillance to assess a novel application of these guidelines in this setting. METHODS: P1041 presumed TB patients were retrospectively cross-classified by protocol-defined and National Institutes of Health (NIH) classifications, and agreement was assessed. RESULT S: Of 219 TB suspects, 166 had signs/symptoms, with 158 considered TB (21 confirmed, 92 probable, 45 possible) and 8 not TB (6 TB unlikely, 2 alternative diagnoses). Weight loss and failure to thrive represented the majority of the observed signs/symptoms. Among those with signs/symptoms, agreement between definitions was poor. Furthermore, 53 TB presumptives were without signs/symptoms, including 33 classified by the P1041 protocol as TB. CONCLUS ION: Poor agreement between P1041 and NIH classifications reflects cases identified through active vs. passive surveillance, the latter reflecting the intended use of NIH definitions. Given the interest in standardized definitions for broader application, future efforts could focus on expanding TB disease classification to presumed TB patients identified through active surveillance. © 2016 The Union.

Madhi S.A.,National Science Foundation | Madhi S.A.,Respiratory and Meningeal Pathogens Research Unit | Adrian P.,National Science Foundation | Adrian P.,Respiratory and Meningeal Pathogens Research Unit | And 10 more authors.
Journal of Infectious Diseases | Year: 2010

Serotype-specific antibody concentration and opsonophagocytic activity (OPA) were evaluated after 3 doses of pneumococcal conjugate vaccine. Groups included human immunodeficiency virus (HIV)-positive infants with CD4+ cell percentages ≥25% who initiated immediate antiretroviral treatment (the HIV+/ART+ group) or whose antiretroviral treatment was deferred until clinically or immunologically indicated (the HIV+/ART+ group). Immune responses were also evaluated in HIV-noninfected infants born to HIV-seronegative (M+/I+) or HIV-positive mothers (M+/I+). Antibody concentrations were similar between HIV+/ART+ and HIV+/ART+ infants. However, antibody concentrations were lowerin M+/I+ infants than in M+/I+ infants. Nevertheless, M+/I+ infants had superior OPA responses, compared with those in HIV+/ART+ infants, who in turn had better OPA responses, compared with those in HIV+/ART+ infants. © 2010 by the Infectious Diseases Society of America.

Albrich W.C.,Respiratory and Meningeal Pathogens Research Unit | Madhi S.A.,Respiratory and Meningeal Pathogens Research Unit | Madhi S.A.,National Science Foundation | Adrian P.V.,Respiratory and Meningeal Pathogens Research Unit | And 14 more authors.
Clinical Infectious Diseases | Year: 2012

Background. There is major need for a more sensitive assay for the diagnosis of pneumococcal community-acquired pneumonia (CAP). We hypothesized that pneumococcal nasopharyngeal (NP) proliferation may lead to microaspiration followed by pneumonia. We therefore tested a quantitative lytA real-time polymerase chain reaction (rtPCR) on NP swab samples from patients with pneumonia and controls. Methods. In the absence of a sensitive reference standard, a composite diagnostic standard for pneumococcal pneumonia was considered positive in South African human immunodeficiency virus (HIV)-infected adults hospitalized with radiographically confirmed CAP, if blood culture, induced good-quality sputum culture, Gram stain, or urinary Binax demonstrated pneumococci. Results of quantitative lytA rtPCR in NP swab samples were compared with quantitative colony counts in patients with CAP and 300 HIV-infected asymptomatic controls. Results. Pneumococci were the leading pathogen identified in 76 of 280 patients with CAP (27.1%) using the composite diagnostic standard. NP colonization density measured by lytA rtPCR correlated with quantitative cultures (r = 0.67; P <. 001). The mean lytA rtPCR copy number in patients with pneumococcal pneumonia was 6.0 log10 copies/mL, compared with patients with CAP outside the composite standard (2.7 log10 copies/mL; P <. 001) and asymptomatic controls (0.8 log10 copies/mL; P <. 001). A lytA rtPCR density ≥8000 copies/mL had a sensitivity of 82.2% and a specificity of 92.0% for distinguishing pneumococcal CAP from asymptomatic colonization. The proportion of CAP cases attributable to pneumococcus increased from 27.1% to 52.5% using that cutoff.Conclusions.A rapid molecular assay of NP pneumococcal density performed on an easily available specimen may significantly increase pneumococcal pneumonia diagnoses in adults. © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved.

Groome M.J.,University of Witwatersrand | Groome M.J.,Respiratory and Meningeal Pathogens Research Unit | Albrich W.C.,Respiratory and Meningeal Pathogens Research Unit | Wadula J.,University of Witwatersrand | And 3 more authors.
Paediatrics and International Child Health | Year: 2012

Background: Invasive bacterial disease causes significant morbidity and mortality in children in developing countries. The burden of invasive disease caused by Staphylococcus aureus and S. aureus antimicrobial resistance patterns in African children in settings with a high prevalence of HIV infection remain ill-defined. Aims and Objectives: To describe the burden of community-onset bacteraemic S. aureus infections in children in an area with a high prevalence of paediatric HIV infection, and to describe the antimicrobial resistance patterns. Methods: A retrospective record review of children hospitalised at Chris Hani Baragwanath Hospital, Soweto, with S. aureus bacteraemia between January 2005 and December 2006 was conducted. Community-onset S. aureus bloodstream infections were defined as S. aureus cultured from blood obtained within 48 hours of admission. Results: Community-onset S. aureus bacteraemia was identified in 161 children, representing an incidence of 26/100,000, with 63 (39%) isolates identified as methicillin-resistant (10/100,000). The incidence of community-onset S. aureus bacteraemia, both methicillin-susceptible and methicillin-resistant, was inversely related to age and greater in HIV-infected than uninfected children. High rates of antibiotic resistance were observed in MRSA isolates and only resistance to amikacin, fusidic acid and ciprofloxacin was,40%. MRSA isolates were frequently multidrug-resistant. Among HIV-infected children, resistance to trimethoprim-sulfamethoxazole was 100% and to rifampicin was 78%. Conclusions: This study highlights the burden of S. aureus bacteraemia in a setting with a high prevalence of paediatric HIV infection. The high incidence of S. aureus bacteraemia coupled with a high prevalence of methicillin resistance, particularly in HIV-infected children, needs to be considered in the empirical management of paediatric sepsis in settings such as ours. © W. S. Maney & Son Ltd 2012.

Tempia S.,South African National Institute for Communicable Diseases | Tempia S.,Centers for Disease Control and Prevention | Walaza S.,South African National Institute for Communicable Diseases | Viboud C.,U.S. National Institutes of Health | And 10 more authors.
Clinical Infectious Diseases | Year: 2014

Background. There are few published data describing the mortality burden associated with influenza and respiratory syncytial virus (RSV) infection in children in low- and middle-income countries and particularly from Africa and settings with high prevalence of human immunodeficiency virus (HIV).Methods. We modeled the excess mortality attributable to influenza (seasonal and pandemic) and RSV infection by applying Poisson regression models to monthly all-respiratory and pneumonia and influenza deaths, using national influenza and RSV laboratory surveillance data as covariates. In addition, we estimated the seasonal influenza- and RSV-associated deaths among HIV-infected and -uninfected children using Poisson regression models that incorporated HIV prevalence and highly active antiretroviral therapy coverage as covariates.Results. In children <5 years of age, the mean annual numbers of seasonal influenza- and RSV-associated all-respiratory deaths were 452 (8 per 100 000 person-years [PY]) and 546 (10 per 100 000 PY), respectively. Infants <1 year of age experienced higher mortality rates compared with children 1-4 years of age for both influenza (22 vs 5 per 100 000 PY) and RSV (35 vs 4 per 100 000 PY). HIV-infected compared with HIV-uninfected children <5 years of age were at increased risk of death associated with influenza (age-adjusted relative risk [aRR], 11.5; 95% confidence interval [CI], 9.6-12.6) and RSV (aRR, 8.1; 95% CI, 6.9-9.3) infection. In 2009, we estimated 549 (11 per 100 000 PY) all-respiratory influenza A(H1N1)pdm09-associated deaths among children aged <5 years.Conclusions. Our findings support increased research efforts to guide and prioritize interventions such as influenza vaccination and HIV prevention in low- and middle-income countries with high HIV prevalence such as South Africa. © The Author 2014.

Murray J.,Johns Hopkins International Vaccine Access Center | Cohen A.,Centers for Disease Control and Prevention | Walaza S.,South African National Institute for Communicable Diseases | Groome M.,Respiratory and Meningeal Pathogens Research Unit | And 19 more authors.
PLoS ONE | Year: 2015

Local disease burden data are necessary to set national influenza vaccination policy. In 2010 the population of South Africa was 50 million and the HIV prevalence was 11%. We used a previously developed methodology to determine severe influenza burden in South Africa. Hospitalized severe acute respiratory illness (SARI) incidence was calculated, stratified by HIV status, for four age groups using data from population-based surveillance in one site situated in Gauteng Province for 2009-2011. These rates were adjusted for each of the remaining 8 provinces based on their prevalence of risk factors for pneumonia and healthcare- seeking behavior. We estimated non-hospitalized influenza-associated SARI from healthcare utilization surveys at two sites and used the percent of SARI cases positive for influenza from sentinel surveillance to derive the influenza-associated SARI rate. We applied rates of hospitalized and non-hospitalized influenza-associated SARI to census data to calculate the national number of cases. The percent of SARI cases that tested positive for influenza ranged from 7-17% depending on age group, year, province and HIV status. In 2010, there were an estimated 21,555 total severe influenza cases in HIV-uninfected individuals and 13,876 in HIV-infected individuals. In 2011, there were an estimated 29,892 total severe influenza cases in HIV-uninfected individuals and 17,289 in HIV-infected individuals. The incidence of influenza-associated SARI was highest in children <5 years and was higher in HIV-infected than HIV-uninfected persons in all age groups. Influenza virus was associated with a substantial amount of severe disease, especially in young children and HIV-infected populations in South Africa.

Theodoratou E.,University of Edinburgh | McAllister D.A.,University of Edinburgh | Reed C.,University of Edinburgh | Adeloye D.O.,University of Edinburgh | And 10 more authors.
The Lancet Infectious Diseases | Year: 2014

Background: Globally, pneumonia is a leading cause of mortality and morbidity in children younger than 5 years. Underlying HIV infection is an important risk factor for pneumonia morbidity and mortality in children. There are, however, no global or country level estimates of pneumonia burden in HIV-infected children. We assessed the role of HIV in pneumonia incidence and mortality and estimated the number of pneumonia cases and deaths in HIV-infected children younger than 5 years in 133 high pneumonia-burden countries in 2010. Methods: We estimated the risk of hospital admission and case fatality rate caused by pneumonia in HIV-infected children compared with HIV-uninfected children from a systematic review of studies published in Medline, Embase, and Global Health between Jan 1, 1980, and Aug 31, 2013. We estimated nationwide pneumonia incidence and mortality with two different models that incorporated several risk factors for paediatric pneumonia hospital admission and mortality (including HIV infection). We then estimated the number of pneumonia episodes and deaths that occurred in HIV-infected children in 2010. Findings: The odds ratio (OR) for hospital admission for all-cause pneumonia in HIV-infected children compared with HIV-uninfected children was 6.5 (95% CI 5.9-7.2). The risk of death was higher in children with pneumonia and HIV compared with those with pneumonia only (OR 5.9, 95% CI 2.7-12.7). In 2010, 1.4 million pneumonia episodes (uncertainty range [UR] 0.6 million to 3.3 million) and 88 000 pneumonia deaths (UR 47 400-153 000) occurred in HIV-infected children in low-income countries. Of these, 1.2 million pneumonia episodes (UR 0.5 million-2.7 million) and 85 400 deaths (UR 46 000-147 300) were directly attributable to HIV. 1.3 million (90%) pneumonia episodes and 82 400 (93%) pneumonia deaths in HIV-infected children aged younger than 5 years occurred in the WHO African region. Interpretation: Globally, a small proportion of pneumonia episodes and pneumonia deaths occur in HIV-infected children. However, in the highest HIV-burden countries in sub-Saharan Africa (ie, Swaziland, Lesotho, and Zimbabwe) up to a fifth of all pneumonia cases and 60% of pneumonia deaths occur in HIV-infected children. In these countries, major reductions in child pneumonia mortality can be achieved only if the systemic challenges plaguing the health system (poor coverage of early infant testing for HIV, of antiretroviral drugs in pregnant women and young children, of co-trimoxazole prophylaxis, and of pneumococcal vaccination) can be overcome. Funding: WHO. © 2014 World Health Organization. Published by Elsevier Ltd/Inc/BV. All rights reserved.

Madhi S.A.,South African National Institute for Communicable Diseases | Madhi S.A.,University of Witwatersrand | Madhi S.A.,Medical Research Council Respiratory and Meningeal Pathogens Research Unit | Madhi S.A.,Respiratory and Meningeal Pathogens Research Unit | And 51 more authors.
Vaccine | Year: 2015

Background: Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus are all potentially pathogenic, which frequently colonize the nasopharynx (NP) prior to causing disease.We studied bacterial NP-colonization in 321 HIV-infected and 243 HIV-uninfected children vaccinated with 7-valent pneumococcal conjugate vaccine (PCV7) at 6, 10 and 14 weeks of age. Methods: HIV-uninfected infants included those born to HIV-uninfected (HUU) and HIV-infected women (HEU); HIV-infected children with CD4+ lymphocyte ≥25% were randomized to initiate antiretroviral therapy immediately (ART-Immed) or when clinically indicated (ART-Def). Nasopharyngeal swabs for bacterial culture were taken prior to each PCV7 dose (Visits 1-3) and at 20, 39, 47 and 67 weeks of age (Visits 4-7). Swabs were cultured by standard methods and pneumococcal serotyping done by the Quellung method. Results: Colonization patterns for pneumococcus, H. influenzae and S. aureus did not differ between HUU and HEU children; and were also generally similar between ART-Def and ART-Immed children. Prevalence of PCV7-serotype colonization was similar between HIV-infected and HIV-uninfected children, however, overall pneumococcal and specifically non-vaccine serotype colonization tended to be lower in HIV-infected children. HIV-infected children also had a 44% lower prevalence of S. aureus colonization at Visit-1 (p = 0.010); and H. influenzae colonization was also lower among HIV-infected than HIV-uninfected children at Visit-2, Visit-3, Visit-6 and Visit-7. Conclusion: Vaccine-serotype colonization is similar in PCV-immunized HIV-infected and HIV-uninfected children. We, however, identified a lower prevalence of overall-pneumococcal and H. influenzae colonization in HIV-infected children post-PCV vaccination, the clinical-relevance of which warrants further study. © 2015 Elsevier Ltd.

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