Robert S Heyderman

University of Malawi, Zomba, Southern Region, Malawi

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Publications (114)706.39 Total impact

  • Katherine M Gaskell, Nicholas A Feasey, Robert S Heyderman
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    ABSTRACT: Despite widespread antiretroviral therapy use, severe bacterial infections (SBI) in HIV-infected adults continue to cause significant morbidity and mortality globally. Four main pathogens account for the majority of documented SBI: Streptococcus pneumoniae, non-typhoidal strains of Salmonella enterica, Escherichia coli and Staphylococcus aureus. The epidemiology of SBI is dynamic, both in developing countries where, despite dramatic successes in antiretroviral therapy, coverage is far from complete, and in settings in both resource-poor and resource-rich countries where antiretroviral therapy failure is becoming increasingly common. Throughout the world, this complexity is further compounded by rapidly emerging antimicrobial resistance, making management of SBI very challenging in these vulnerable patients. We review the causes and treatment of SBI in HIV-infected people and discuss future developments in this field.
    Expert Review of Anti-infective Therapy 02/2015; 13(2):183-95. · 3.06 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 11/2014; · 5.44 Impact Factor
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    ABSTRACT: We have previously reported high ten-week mortality from cryptococcal meningitis in Malawian adults following treatment-induction with 800mg oral fluconazole (57% [33/58]). National guidelines in Malawi and other African countries now advocate an increased induction dose of 1200mg. We assessed whether this has improved outcomes.
    PLoS ONE 11/2014; 9(11):e110285. · 3.53 Impact Factor
  • John A Crump, Robert S Heyderman
    Transactions of the Royal Society of Tropical Medicine and Hygiene 11/2014; 108(11):673-5. · 1.93 Impact Factor
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    Emerging infectious diseases 11/2014; 20(11):1957-9. · 7.33 Impact Factor
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    ABSTRACT: HIV-infected children on ART have delayed recovery of pneumococcal B-cell memory•Pneumococcal carriage remained high during ART•Mature naïve and resting memory B cells increased after 3 months of ART•Apoptosis prone B cell proportions reduced during ART to levels seen in controls
    Journal of Infection 11/2014; · 4.02 Impact Factor
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    ABSTRACT: As control interventions are rolled out, the burden of malaria may shift from young children to older children and adults as acquisition of immunity is slowed and persistence of immunity is short-lived. Data for malaria disease in adults are difficult to obtain because of co-morbid conditions and because parasitaemia may be asymptomatic. Regular surveys of adult admissions to a hospital in Malawi were conducted to characterize the clinical spectrum of malaria and to establish a baseline to monitor changes that occur in future. Methods: In 2011-2012, at Queen Elizabeth Hospital, Blantyre, four separated one-week surveys in the peak malaria transmission period (wet season) and three one-week surveys in the low transmission period (dry season) were conducted using rapid diagnostic tests (RDT) with confirmation of parasitaemia by microscopy. All adults (aged >=15) being admitted to the adult medical wards regardless of the suspected diagnosis, were enrolled. Participants with a positive malaria test underwent a standardized physical examination and laboratory tests. Malaria syndromes were characterized by reviewing charts and laboratory results on discharge. Results: 765 adult admissions were screened. 63 (8.2%) were RDT-positive with 61 (8.0%) positive by microscopy. Over the course of the seven study weeks, two patients were judged to have incidental parasitaemia, 31 (4.1%) had uncomplicated malaria and 28 (3.7%) had severe malaria. Both uncomplicated and severe malaria cases were more common in the rainy season than the dry season. Prostration (22/28 cases) and hyperparasitaemia (>250,000 parasites/mul) (9/28) were the most common features of severe malaria. Jaundice (4/28), severe anaemia (2/28), hyperlactataemia (2/28), shock (1/28) and haemoglobinuria (1/28) were less commonly seen, and no patient had severe metabolic derangement or organ failure. There were no deaths attributable to malaria. Conclusion: In this study of adults admitted to hospital in southern Malawi, an area with year-round transmission of Plasmodium falciparum, classical metabolic and organ complications of malaria were not encountered. Prostration and hyperparasitaemia were more common indicators of severity in patients admitted with malaria, none of whom died. These data will provide a baseline for monitoring trends in the frequency and clinical patterns of severe malaria in adults.
    Malaria Journal 10/2014; 13(1):391. · 3.49 Impact Factor
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    ABSTRACT: Background Three billion people are exposed to household air pollution from biomass fuel use. Exposure is associated with higher incidence of pneumonia, and possibly tuberculosis. Understanding mechanisms underlying these defects would improve preventive strategies. Methods We used human alveolar macrophages obtained from healthy Malawian adults exposed naturally to household air pollution, and compared with human monocyte-derived macrophages exposed in vitro to respirable-sized particulates. Cellular inflammatory response was assessed by: IL-6 and IL-8 production in response to particulate challenge; phagocytosis of fluorescent-labelled beads and intraphagosomal oxidative burst capacity; ingestion and killing of Streptococcus pneumoniae and Mycobacterium tuberculosis measured by microscopy and quantitative culture. Particulate ingestion was quantified by digital image analysis. Results We were able to reproduce the carbon loading of naturally exposed alveolar macrophages by in vitro exposure of monocyte derived macrophages. Fine carbon black induced IL-8 release from monocyte derived and alveolar macrophages (p<0.05), with similar magnitude responses (log10 increases of 0.93 [SEM 0.2] vs 0.74 [SEM 0.19] respectively). Phagocytosis of pneumococci and mycobacteria was impaired with higher particulate loading. High particulate loading corresponded with a lower oxidative burst capacity (p=0.0015). There was no overall effect on killing of M. tuberculosis. Conclusion Alveolar macrophage function is altered by particulate loading. Our macrophage model is comparable morphologically to the in vivo uptake of particulates. Wood smoke exposed cells demonstrate reduced phagocytosis but unaffected mycobacterial killing, suggesting defects related to chronic wood smoke inhalation limited to specific innate immune functions.
    American Journal of Respiratory Cell and Molecular Biology 09/2014; · 4.11 Impact Factor
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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: 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 07/2014; · 4.02 Impact Factor
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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 06/2014; 9(6):e100640. · 3.53 Impact Factor
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    ABSTRACT: Background / Purpose: The synergistic interaction between influenza and pneumococcal disease is well-studied. However, the exact nature and relationship between influenza infection and pneumococcal carriage is unknown. We postulate that influenza infection increases susceptibility of pneumococcal carriage in a high HIV prevalence setting. Main conclusion: Contrary to our hypothesis, we found a trend towards lower pneumococcal carriage in individuals with influenza infection. This was most likely confounded by age and seasonality.
    16th International Congress on Infectious Diseases 2014; 05/2014
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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. · 54.42 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 03/2014; 9(3):e92226. · 3.53 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; · 9.42 Impact Factor
  • Christopher Moxon, Samuel Wassmer, Danny Milner, Ngawina Chisala, Terrie Taylor, Karl Seydel, Malcolm Molyneux, Charles Esmon, Colin Downey, Cheng-Hock Toh, Alister Craig, Robert Heyderman
    The Lancet 02/2014; 383:S75. · 39.21 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: 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; · 3.14 Impact Factor

Publication Stats

1k Citations
706.39 Total Impact Points

Institutions

  • 2012–2014
    • University of Malawi
      • College of Medicine
      Zomba, Southern Region, Malawi
    • The Queen Elizabeth Central Hospital in Blantyre
      Kapeni, Southern Region, Malawi
  • 2011–2014
    • Liverpool School of Tropical Medicine
      • Respiratory Infection Laboratory
      Liverpool, England, United Kingdom
  • 2010–2014
    • Malawi-Liverpool-Wellcome Trust Clinical Research Programme
      Kapeni, Southern Region, Malawi
  • 2003–2014
    • University of Bristol
      • School of Cellular and Molecular Medicine
      Bristol, England, United Kingdom
    • University of Dundee
      • Undergraduate Tayside Centre for General Practice
      Dundee, Scotland, United Kingdom
  • 2008–2011
    • University of Liverpool
      Liverpool, England, United Kingdom
    • The Australian Society of Otolaryngology Head & Neck Surgery
      Evans Head, New South Wales, Australia
  • 2009
    • Medical Research Council Unit, The Gambia Unit
      Bakau, Banjul, Gambia
    • The Queen Elizabeth Hospital
      Tarndarnya, South Australia, Australia
    • Cornell University
      • College of Veterinary Medicine
      Ithaca, NY, United States