Robert S Heyderman

University of Malawi, Zomba, Southern Region, Malawi

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Publications (104)665.49 Total impact

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    ABSTRACT: Background. HIV-infected persons on antiretroviral therapy (ART) remain at higher risk of pulmonary tuberculosis (TB) than HIV-uninfected individuals. This increased susceptibility may be due to impairment of alveolar macrophage (AM) function and/or mycobacteria-specific alveolar CD4+ T cell responses observed in HIV-infected ART-naive adults. Methods. Peripheral blood was drawn and bronchoalveolar lavage (BAL) performed on healthy, 35 HIV-uninfected, 25 HIV-infected ART-naive and 50 HIV-infected ART-treated asymptomatic adults. Phagosomal proteolysis of AM was assessed with fluorogenic beads. Mycobacteria-specific CD4+ T cell responses were measured by intracellular cytokine staining. Results. HIV-infected adults on ART exhibited lower plasma HIV viral load and higher blood CD4+ T cell count than ART-naïve adults. AM proteolysis and total mycobacteria-specific Th1 CD4+ T cell responses in individuals on ART for ≥4 years were similar to HIV-uninfected controls but those on ART for <4 years had impaired responses. Total Influenza-specific alveolar Th1 CD4+ T cell responses were intact in all individuals receiving ART. In contrast, BAL and blood mycobacteria-specific polyfunctional CD4+ T cell responses were impaired in adults on ART irrespective of duration. Conclusion. AM and mycobacteria-specific alveolar CD4+ T cell responses in HIV-infected adults on ART for <4 years are impaired and may partly explain the high risk of TB in HIV-infected individuals on ART. Strategies to augment ART to improve lung immune cell function and reduce the high incidence of TB in HIV-infected adults who initiate ART should be investigated.
    American Journal of Respiratory and Critical Care Medicine 09/2014; · 11.04 Impact Factor
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    ABSTRACT: Background Improved diagnostic tests for tuberculosis in children are needed. We hypothesized that transcriptional signatures of host blood could be used to distinguish tuberculosis from other diseases in African children who either were or were not infected with the human immunodeficiency virus (HIV). Methods The study population comprised prospective cohorts of children who were undergoing evaluation for suspected tuberculosis in South Africa (655 children), Malawi (701 children), and Kenya (1599 children). Patients were assigned to groups according to whether the diagnosis was culture-confirmed tuberculosis, culture-negative tuberculosis, diseases other than tuberculosis, or latent tuberculosis infection. Diagnostic signatures distinguishing tuberculosis from other diseases and from latent tuberculosis infection were identified from genomewide analysis of RNA expression in host blood. Results We identified a 51-transcript signature distinguishing tuberculosis from other diseases in the South African and Malawian children (the discovery cohort). In the Kenyan children (the validation cohort), a risk score based on the signature for tuberculosis and for diseases other than tuberculosis showed a sensitivity of 82.9% (95% confidence interval [CI], 68.6 to 94.3) and a specificity of 83.6% (95% CI, 74.6 to 92.7) for the diagnosis of culture-confirmed tuberculosis. Among patients with cultures negative for Mycobacterium tuberculosis who were treated for tuberculosis (those with highly probable, probable, or possible cases of tuberculosis), the estimated sensitivity was 62.5 to 82.3%, 42.1 to 80.8%, and 35.3 to 79.6%, respectively, for different estimates of actual tuberculosis in the groups. In comparison, the sensitivity of the Xpert MTB/RIF assay for molecular detection of M. tuberculosis DNA in cases of culture-confirmed tuberculosis was 54.3% (95% CI, 37.1 to 68.6), and the sensitivity in highly probable, probable, or possible cases was an estimated 25.0 to 35.7%, 5.3 to 13.3%, and 0%, respectively; the specificity of the assay was 100%. Conclusions RNA expression signatures provided data that helped distinguish tuberculosis from other diseases in African children with and those without HIV infection. (Funded by the European Union Action for Diseases of Poverty Program and others).
    New England Journal of Medicine 05/2014; 370(18):1712-1723. · 51.66 Impact Factor
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    ABSTRACT: Background. To document bacterial meningitis trends amongst adults and children presenting to a large teaching hospital in Malawi during introduction of Hib vaccination and the roll-out of antiretroviral therapy (ART). Methods. We analysed data from 51,000 consecutive cerebrospinal fluid (CSF) samples obtained from adults, adolescents and children with suspected meningitis admitted to the Queen Elizabeth Central Hospital, Blantyre, Malawi, between 2000 and 2012. Results. There has been a significant decline in the total number of CSF isolates over 12 years (incident rate ratio 0.93 [95% CI 0.92-0.94], p<0.001). This decline has been entirely in children under 5 years (IRR =0.87, 95%CI 0.85-0.88, p<0.001) and coincides with the introduction of Hib vaccination. The number of adult isolates has remained unchanged (IRR=0.99, 95%CI 0.97-1.0, p=0.135) despite rapid scale-up of ART provision. In children<5 years, S. pneumoniae, Non typhoidal Salmonellae and Hib were the most frequently isolated pathogens and have all declined over this time period. S. pneumoniae was the most frequently isolated pathogen in older children and adults. Estimated incidence of bacterial meningitis in 2012 is 20/100 000 cases in children<14 years, 6/100 000 adolescents and 10/100 000 adults. Conclusion. Rates of bacterial meningitis have declined in children not adults, coinciding with the introduction of Hib vaccination. The highly successful roll-out of ART has not yet resulted in a reduction in the incidence in adults where the burden remains high. Long term surveillance of bacterial meningitis outside of the epidemic meningitis belt in Africa is essential.
    Clinical Infectious Diseases 02/2014; · 9.37 Impact Factor
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    ABSTRACT: HIV-1-infected persons are at higher risk of lower respiratory tract infections than HIV-1-uninfected individuals. This suggests strongly that HIV-infected persons have specific impairment of pulmonary immune responses, but current understanding of how HIV alters pulmonary immunity is incomplete. Alveolar macrophages (AMs), comprising small and large macrophages, are major effectors of innate immunity in the lung. We postulated that HIV-1 impairs pulmonary innate immunity through impairment of AM physiological functions. AMs were obtained by bronchoalveolar lavage from healthy, asymptomatic, antiretroviral therapy-naive HIV-1-infected and HIV-1-uninfected adults. We used novel assays to detect in vivo HIV-infected AMs and to assess AM functions based on the HIV infection status of individual cells. We show that HIV has differential effects on key AM physiological functions, whereby small AMs are infected preferentially by the virus, resulting in selective impairment of phagocytic function. In contrast, HIV has a more generalized effect on AM proteolysis, which does not require direct viral infection. These findings provide new insights into how HIV alters pulmonary innate immunity and the phenotype of AMs that harbors the virus. They underscore the need to clear this HIV reservoir to improve pulmonary immunity and reduce the high incidence of lower respiratory tract infections in HIV-1-infected individuals.Mucosal Immunology advance online publication, 29 January 2014; doi:10.1038/mi.2013.127.
    Mucosal Immunology 01/2014; · 7.54 Impact Factor
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    ABSTRACT: Background. S. Typhimurium (STm) remain a prominent cause of bacteremia in sub-Saharan Africa. Complement-fixing antibodies to STm develop by 2 years of age. We hypothesized that STm-specific CD4+ T cells develop alongside this process.Methods. Eighty healthy Malawian children aged 0-60 months were recruited. STm-specific CD4+ T cells producing IFNγ, TNFα and IL2 were quantified using intra-cellular cytokine staining. Antibodies to STm were measured by serum bactericidal activity assay (SBA), and anti-STm IgG antibodies by ELISA.Results. Between 2006 and 2011, 449 STm bacteremias were detected in children <5 years. STm-specific CD4+ T cells were acquired in infancy peaked at 14 months and then declined. STm-specific SBA was detectable in newborns, declined in the first 8 months, and then increased to peak at 35 months. Acquisition of SBA correlated with acquisition of anti-STm-LPS IgG (r=0.329, 95% CI [0.552, 0.062] p=0.01) but not anti-STm-OMP or anti-STm-FliC.Conclusion. Acquisition of STm-specific CD4+ T cells in early childhood is consistent with early exposure to STm or cross-reactive protein antigens priming this T cell development. STm-specific CD4+ T cells appear insufficient to protect against invasive NTS disease, but sequential acquisition of SBA to STm LPS is associated with decline in incidence of iNTS.
    The Journal of Infectious Diseases 01/2014; · 5.85 Impact Factor
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    ABSTRACT: Objective To assess mortality risk among adults presenting to an African teaching hospital with sepsis and severe sepsis in a setting of high HIV prevalence and widespread ART uptake. Methods Prospective cohort study of adults (age ≥16 years) admitted with clinical suspicion of severe infection between November 2008 and January 2009 to Queen Elizabeth Central Hospital, a 1250-bed government-funded hospital in Blantyre, Malawi. Demographic, clinical and laboratory information, including blood and cerebrospinal fluid cultures were obtained on admission. Results Data from 213 patients (181 with sepsis and 32 with severe sepsis; M:F = 2:3) were analysed. 161 (75.6%) patients were HIV-positive. Overall mortality was 22%, rising to 50% amongst patients with severe sepsis. The mortality of all sepsis patients commenced on antiretroviral therapy (ART) within 90 days was 11/28(39.3%) compared with 7/42 (16.7%) among all sepsis patients on ART for greater than 90 days (p=0.050). Independent associations with death were hypoxia (OR=2.4; 95% CI, 1.1-5.1) and systolic hypotension (OR 7.0; 95% CI: 2.4-20.4). Conclusions Sepsis and severe sepsis carry high mortality among hospitalised adults in Malawi. Measures to reduce this, including early identification and targeted intervention in high-risk patients, especially HIV-positive individuals recently commenced on ART, are urgently required.
    Journal of Infection. 01/2014;
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    ABSTRACT: HIV-infected African adults are at a considerably increased risk of life-threatening invasive pneumococcal disease (IPD) which persists despite antiretroviral therapy (ART). Defects in naturally acquired pneumococcal-specific T-cell immunity have been identified in HIV-infected adults. We have therefore determined the extent and nature of pneumococcal antigen-specific immune recovery following ART. HIV-infected adults were followed up at 3, 6 and 12 months after initiating ART. Nasopharyngeal swabs were cultured to determine carriage rates. Pneumococcal-specific CD4 T-cell immunity was assessed by IFN-γ ELISpot, proliferation assay, CD154 expression and intracellular cytokine assay. S. pneumoniae colonization was detected in 27% (13/48) of HIV-infected patients prior to ART. The rates remained elevated after 12 months ART, 41% (16/39) (p = 0.17) and significantly higher than in HIV-uninfected individuals (HIVneg 14%(4/29); p = 0.0147). CD4+ T-cell proliferative responses to pneumococcal antigens increased significantly to levels comparable with HIV-negative individuals at 12 months ART (p = 0.0799). However, recovery of the pneumococcal-specific CD154 expression was incomplete (p = 0.0015) as were IFN-γ ELISpot responses (p = 0.0040) and polyfunctional CD4+ T-cell responses (TNF-α, IL-2 and IFN-γ expression) (p = 0.0040) to a pneumolysin-deficient mutant strain. Impaired control of pneumococcal colonisation and incomplete restoration of pneumococcal-specific immunity may explain the persistently higher risk of IPD amongst HIV-infected adults on ART. Whether vaccination and prolonged ART can overcome this immunological defect and reduce the high levels of pneumococcal colonisation requires further evaluation.
    PLoS ONE 01/2014; 9(6):e100640. · 3.53 Impact Factor
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    ABSTRACT: Background Nevirapine, an NNRTI used in HIV treatment, can cause hypersensitivity reactions in 6%–10% of patients. In the most serious cases (1.3%) this can manifest as Stevens–Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN).Methods DNA samples were obtained and analysed from a total of 209 adult patients with nevirapine hypersensitivity (57 from a prospective cohort and 152 routine clinic patients) and compared with 463 control patients on nevirapine without any hypersensitivity. The case group included 70 patients with SJS/TEN. All individuals were genotyped for two SNPs in the CYP2B6 gene [c.516G>T (CYP2B6*9) and c.983T>C (CYP2B6*18)] using the TaqMan real-time genotyping platform. The replication cohort comprised 29 controls and 55 nevirapine hypersensitive patients, including 8 SJS/TEN cases.Results An association between the CYP2B6 c.983T>C polymorphism and nevirapine-induced SJS/TEN was observed. In the SJS/TEN group, 30% of individuals possessed at least one c.983T>C versus 16% in the tolerant group [P = 0.006; OR (95% CI) 2.24 (1.27–3.94)]. This association was not significant in the replication cohort [P = 0.075; OR (95% CI) 4.33 (0.80–23.57)]. Combined analysis resulted in an OR of 2.52 (95% CI 1.48–4.20; P = 0.0005) for the association of c.983T>C with SJS/TEN. No association was observed for c.983T>C with other hypersensitivity phenotypes and for CYP2B6 c.516G>T with any hypersensitivity phenotypes.Conclusions Our data show an association between the c.983T>C polymorphism and nevirapine-induced SJS/TEN. CYP2B6 c.983T>C has a frequency of 5%–10% in a variety of African populations, but is not observed in Caucasians, thus representing an ethnic-specific predisposing factor.
    Journal of Antimicrobial Chemotherapy 01/2014; · 5.34 Impact Factor
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    ABSTRACT: Blood-stream infection (BSI) is one of the principle determinants of the morbidity and mortality associated with advanced HIV infection, especially in sub-Saharan Africa. Over the last 10 years, there has been rapid roll-out of anti-retroviral therapy (ART) and cotrimoxazole prophylactic therapy (CPT) in many high HIV prevalence African countries. A prospective cohort of adults with suspected BSI presenting to Queen's Hospital, Malawi was recruited between 2009 and 2010 to describe causes of and outcomes from BSI. Comparison was made with a cohort pre-dating ART roll-out to investigate whether and how ART and CPT have affected BSI. Malawian census and Ministry of Health ART data were used to estimate minimum incidence of BSI in Blantyre district. 2,007 patients were recruited, 90% were HIV infected. Since 1997/8, culture-confirmed BSI has fallen from 16% of suspected cases to 10% (p<0.001) and case fatality rate from confirmed BSI has fallen from 40% to 14% (p<0.001). Minimum incidence of BSI was estimated at 0.03/1000 years in HIV uninfected vs. 2.16/1000 years in HIV infected adults. Compared to HIV seronegative patients, the estimated incidence rate-ratio for BSI was 80 (95% CI:46-139) in HIV-infected/untreated adults, 568 (95% CI:302-1069) during the first 3 months of ART and 30 (95% CI:16-59) after 3 months of ART. Following ART roll-out, the incidence of BSI has fallen and clinical outcomes have improved markedly. Nonetheless, BSI incidence remains high in the first 3 months of ART despite CPT. Further interventions to reduce BSI-associated mortality in the first 3 months of ART require urgent evaluation.
    PLoS ONE 01/2014; 9(3):e92226. · 3.53 Impact Factor
  • Journal of neurology, neurosurgery, and psychiatry 01/2014; 85(10):e4. · 4.87 Impact Factor
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    ABSTRACT: Neonatal meningitis is an important cause of morbidity in sub-Saharan Africa and requires urgent empiric treatment with parenteral administered antibiotics. Here we describe the etiology, antimicrobial susceptibility and suitability of the World Health Organization (WHO) first-line recommended antibiotics (penicillin and gentamicin) for bacterial meningitis in young infants in Malawi. We reviewed all cerebrospinal fluid samples received from infants ≤2 months of age with clinically suspected meningitis between January 1, 2002 and December 31, 2008 at the Queen Elizabeth Central Hospital in Blantyre, Malawi. We identified 259 culture-positive isolates from 259 infants ≤2 months of age. Sixty isolates were from neonates ≤7 days old, in whom the most common pathogens were group B streptococcus (GBS) (27/60; 45.0%), Streptococcus pneumoniae (13/60; 21.7%) and nontyphoidal Salmonella enterica (NTS) (7/60; 11.7%). One hundred and ninety one isolates were from young infants who were >7 days ≤2 months of age. In this group, the most common isolates were S. pneumoniae (80/191; 41.9%), GBS (38/191; 19.9%) and NTS (34/191; 17.8%). In view of these results, the WHO recommendations for empiric penicillin and gentamicin for suspected neonatal meningitis should be re-evaluated.
    The Pediatric Infectious Disease Journal 12/2013; · 3.57 Impact Factor
  • Claire M Hallissey, Robert S Heyderman, Neil A Williams
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    ABSTRACT: The mucosal immune system must initiate and regulate protective immunity, while balancing this immunity with tolerance to harmless antigens and bacterial commensals. We have explored the hypothesis that mucosal dendritic cells (DC) control the balance between regulation and immunity, by studying the responses of human tonsil-derived DC to Neisseria meningitidis as a model organism. We show that tonsil DC are able to sample their antigenic environment, internalizing Nm and expressing high levels of HLA-DR and CD86. However, in comparison to monocyte-derived DC (moDC), they respond to pathogen encounter with only low level cytokine production, largely dominated by TGFβ. Functionally, tonsil DC also only stimulated low levels of antigen-specific T cell proliferation and cytokine production when compared to moDC. We therefore propose that the default role for DC in the nasopharynx is to maintain tolerance/ignorance of the large volume of harmless antigens and bacterial commensals encountered at the nasopharyngeal mucosa.
    The Journal of Infectious Diseases 12/2013; · 5.85 Impact Factor
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    ABSTRACT: Through the successful implementation of policies to prevent mother-to-child-transmission (PMTCT) of HIV-1 infection, children born to HIV-1-infected mothers are now much less likely to acquire HIV-1 infection than previously. Nevertheless, HIV-1-exposed uninfected (HEU) children have a substantially increased morbidity and mortality compared with children born to uninfected mothers (unexposed uninfected, UU), predominantly from infectious causes. Moreover, a range of phenotypic and functional immunological differences between HEU and UU children has been reported. As the number of HEU children continues to increase worldwide, two questions with clear public health importance need to be addressed: firstly does exposure to HIV-1 and/or ART in utero or during infancy have direct immunological consequences, or are these poor outcomes simply attributable to the obvious disadvantages of being born into an HIV-affected household? Secondly, can we expect improved maternal care and ART regimens during and after pregnancy, together with optimised infant immunization schedules, to reduce the excess morbidity and mortality of HEU children?
    Clinical & Experimental Immunology 12/2013; · 3.41 Impact Factor
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    ABSTRACT: The polysaccharides (PS) surrounding encapsulated bacteria are generally unable to activate T cells and hence do not induce B cell memory (BMEM). PS conjugate vaccines recruit CD4(+) T cells via a carrier protein, such as tetanus toxoid (TT), resulting in the induction of PS-specific BMEM. However, the requirement for T cells in the subsequent activation of the BMEM at the time of bacterial encounter is poorly understood, despite having critical implications for protection. We demonstrate that the PS-specific BMEM induced in humans by a meningococcal serogroup C PS (Men C)-TT conjugate vaccine conform to the isotype-switched (IgG(+)CD27(+)) rather than the IgM memory (IgM(+)CD27(+)) phenotype. Both Men C and TT-specific BMEM require CD4(+) T cells to differentiate into plasma cells. However, noncognate bystander T cells provide such signals to PS-specific BMEM with comparable effect to the cognate T cells available to TT-specific BMEM. The interaction between the two populations is contact-dependent and is mediated in part through CD40. Meningococci drive the differentiation of the Men C-specific BMEM through the activation of bystander T cells by bacterial proteins, although these signals are enhanced by T cell-independent innate signals. An effect of the TT-specific T cells activated by the vaccine on unrelated BMEM in vivo is also demonstrated. These data highlight that any protection conferred by PS-specific BMEM at the time of bacterial encounter will depend on the effectiveness with which bacterial proteins are able to activate bystander T cells. Priming for T cell memory against bacterial proteins through their inclusion in vaccine preparations must continue to be pursued.
    The Journal of Immunology 11/2013; · 5.52 Impact Factor
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    ABSTRACT: We modelled nevirapine (NVP) pharmacokinetics in HIV-infected Malawian patients to assess the relationship between drug exposure and patient characteristics, genetic polymorphisms and development of hypersensitivity reaction (HSR). 1117 patients were prospectively recruited and followed for 26 weeks with multiple or single serum samples obtained in a subset of patients for NVP quantification. Single nucleotide polymorphisms (SNP) within CYP2B6 and CYP3A4 genes were typed. Non-linear mixed effects modelling was utilised to assess the influence of patient characteristics and host genetics on NVP apparent oral clearance (CL/F), and explore the relationship between NVP CL/F and HSR. Published haplotype distributions were used to simulate NVP concentrations in Caucasians vs. Africans. 180 patients (101 female) were included in the model; twenty-five experienced HSR. No associations between patient demographics or HSR and NVP CL/F were evident. A significant relationship between CYP2B6 c.983T>C and CYP2B6 c.516G>T and NVP CL/F was observed (p<0.01). NVP CL/F was reduced by 23% and 36% in patients with CYP2B6 983TT/516TT and 983TC/516GG or GT, respectively compared to reference genotype. Simulated exposures suggested similar proportions (13-17%) of patients with subtherapeutic NVP amongst Caucasians and an African population. Influence of CYP2B6 polymorphisms on NVP CL/F in this population is in agreement with other reports. Our data indicate a lack of association between NVP exposure and HSR. Based on these data, dose optimisation based solely on ethnicity (without individual gene testing) is unlikely to impact on risk of treatment failure or toxicity even in an African population with high carriage of poor metaboliser mutations.
    Antimicrobial Agents and Chemotherapy 11/2013; · 4.57 Impact Factor
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    ABSTRACT: A major impediment to tuberculosis control in Africa is the difficulty in diagnosing active tuberculosis (TB), particularly in the context of HIV infection. We hypothesized that a unique host blood RNA transcriptional signature would distinguish TB from other diseases (OD) in HIV-infected and -uninfected patients, and that this could be the basis of a simple diagnostic test. Adult case-control cohorts were established in South Africa and Malawi of HIV-infected or -uninfected individuals consisting of 584 patients with either TB (confirmed by culture of Mycobacterium tuberculosis [M.TB] from sputum or tissue sample in a patient under investigation for TB), OD (i.e., TB was considered in the differential diagnosis but then excluded), or healthy individuals with latent TB infection (LTBI). Individuals were randomized into training (80%) and test (20%) cohorts. Blood transcriptional profiles were assessed and minimal sets of significantly differentially expressed transcripts distinguishing TB from LTBI and OD were identified in the training cohort. A 27 transcript signature distinguished TB from LTBI and a 44 transcript signature distinguished TB from OD. To evaluate our signatures, we used a novel computational method to calculate a disease risk score (DRS) for each patient. The classification based on this score was first evaluated in the test cohort, and then validated in an independent publically available dataset (GSE19491). In our test cohort, the DRS classified TB from LTBI (sensitivity 95%, 95% CI [87-100]; specificity 90%, 95% CI [80-97]) and TB from OD (sensitivity 93%, 95% CI [83-100]; specificity 88%, 95% CI [74-97]). In the independent validation cohort, TB patients were distinguished both from LTBI individuals (sensitivity 95%, 95% CI [85-100]; specificity 94%, 95% CI [84-100]) and OD patients (sensitivity 100%, 95% CI [100-100]; specificity 96%, 95% CI [93-100]). Limitations of our study include the use of only culture confirmed TB patients, and the potential that TB may have been misdiagnosed in a small proportion of OD patients despite the extensive clinical investigation used to assign each patient to their diagnostic group. In our study, blood transcriptional signatures distinguished TB from other conditions prevalent in HIV-infected and -uninfected African adults. Our DRS, based on these signatures, could be developed as a test for TB suitable for use in HIV endemic countries. Further evaluation of the performance of the signatures and DRS in prospective populations of patients with symptoms consistent with TB will be needed to define their clinical value under operational conditions. Please see later in the article for the Editors' Summary.
    PLoS Medicine 10/2013; 10(10):e1001538. · 15.25 Impact Factor
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    ABSTRACT: This study aimed to define the molecular basis of co-trimoxazole resistance in Malawian pneumococci under the dual selective pressure of widespread co-trimoxazole and sulfadoxine/pyrimethamine use. We measured the trimethoprim and sulfamethoxazole MICs and analysed folA and folP nucleotide and translated amino acid sequences for 143 pneumococci isolated from carriage and invasive disease in Malawi (2002-08). Pneumococci were highly resistant to both trimethoprim and sulfamethoxazole (96%, 137/143). Sulfamethoxazole-resistant isolates showed a 3 or 6 bp insertion in the sulphonamide-binding site of folP. The trimethoprim-resistant isolates fell into three genotypic groups based on dihydrofolate reductase (encoded by folA) mutations: Ile-100-Leu (10%), the Ile-100-Leu substitution together with a residue 92 substitution (56%) and those with a novel uncharacterized resistance genotype (34%). The nucleotide sequence divergence and dN/dS of folA and folP remained stable from 2004 onwards. S. pneumoniae exhibit almost universal co-trimoxazole resistance in vitro and in silico that we believe is driven by extensive co-trimoxazole and sulfadoxine/pyrimethamine use. More than one-third of pneumococci employ a novel mechanism of co-trimoxazole resistance. Resistance has now reached a point of stabilizing evolution. The use of co-trimoxazole to prevent pneumococcal infection in HIV/AIDS patients in sub-Saharan Africa should be re-evaluated.
    Journal of Antimicrobial Chemotherapy 09/2013; · 5.34 Impact Factor
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    ABSTRACT: Endothelial dysregulation is central to the pathogenesis of acute Plasmodium falciparum infection. It has been assumed that this dysregulation resolves rapidly after treatment, but this return to normality has been neither demonstrated nor quantified. We therefore measured a panel of plasma endothelial markers acutely and in convalescence in Malawian children with uncomplicated or cerebral malaria. Evidence of persistent endothelial activation and inflammation, indicated by increased plasma levels of soluble intracellular adhesion molecule 1, angiopoetin 2, and C-reactive protein, were observed at 1 month follow-up visits. These vascular changes may represent a previously unrecognized contributor to ongoing malaria-associated morbidity and mortality.
    The Journal of Infectious Diseases 09/2013; · 5.85 Impact Factor
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    ABSTRACT: The pneumococcal pilus has been shown to be an important determinant of adhesion and virulence in mice models of colonization, pneumonia and bacteremia. Pilus is capable of inducing protective immunity, supporting its inclusion in next-generation pneumococcal protein vaccine formulations. Whether this vaccine target is common amongst pneumococci in sub-Saharan Africa is uncertain. To define the prevalence and genetic diversity of type I and II pili amongst invasive pneumococci in Malawi prior to the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) into routine childhood immunization, we examined 188 S. pneumoniae isolates collected between 2002 - 2008 (17% serotype 1). We found a low frequency of invasive piliated pneumococci (14%) in this high disease burden region and pilus gene sequence diversity similar to that seen previously in multiple global pneumococcal lineages. All common serotypes with pilus were covered by PCV13 and so we predict that pilus prevalence will be reduced in the Malawian pneumococcal population after PCV13 introduction.
    Clinical and vaccine Immunology: CVI 09/2013; · 2.60 Impact Factor

Publication Stats

1k Citations
665.49 Total Impact Points

Institutions

  • 2012–2014
    • University of Malawi
      • College of Medicine
      Zomba, Southern Region, Malawi
    • Liverpool School of Tropical Medicine
      Liverpool, England, United Kingdom
    • The Queen Elizabeth Central Hospital in Blantyre
      Kapeni, Southern Region, Malawi
  • 2011–2014
    • Malawi-Liverpool-Wellcome Trust Clinical Research Programme
      Kapeni, Southern Region, Malawi
  • 2008–2011
    • University of Liverpool
      Liverpool, England, United Kingdom
    • The Australian Society of Otolaryngology Head & Neck Surgery
      Evans Head, New South Wales, Australia
  • 2003–2011
    • University of Bristol
      • School of Cellular and Molecular Medicine
      Bristol, ENG, United Kingdom
    • University of Dundee
      • Undergraduate Tayside Centre for General Practice
      Dundee, Scotland, United Kingdom
  • 2009
    • The Queen Elizabeth Hospital
      Tarndarnya, South Australia, Australia
    • Cornell University
      • College of Veterinary Medicine
      Ithaca, NY, United States
    • Medical Research Council Unit, The Gambia Unit
      Bakau, Banjul, Gambia