Robert S Heyderman

Liverpool School of Tropical Medicine, Liverpool, England, United Kingdom

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Publications (212)1396.95 Total impact

  • Infection and Immunity 12/2015; 83(12):4896-4896. DOI:10.1128/IAI.01156-15 · 3.73 Impact Factor
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    ABSTRACT: Pneumonia is the 2nd leading cause of years of life lost worldwide and is a common cause of adult admissions to hospital in sub-Saharan Africa. Risk factors for adult pneumonia are well characterised in developed countries, but are less well described in sub-Saharan Africa where HIV is a major contributing factor. Exposure to indoor and outdoor air pollution is high, and tobacco smoking prevalence is increasing in sub-Saharan Africa, yet the contribution of these factors to the burden of chronic respiratory diseases in sub-Saharan Africa remains poorly understood. Furthermore, the extent to which the presence of chronic respiratory diseases and exposure to air pollution contribute to the burden of pneumonia is not known. The Acute Infection of the Respiratory Tract Study (The AIR Study) is a case-control study to identify preventable risk factors for adult pneumonia in the city of Blantyre, Malawi. Cases will be adults admitted with pneumonia, recruited from Queen Elizabeth Central Hospital, the largest teaching hospital in Malawi. Controls will be adults without pneumonia, recruited from the community. The AIR Study will recruit subjects and analyse data within strata defined by positive and negative HIV infection status. All participants will undergo thorough assessment for a range of potential preventable risk factors, with an emphasis on exposure to air pollution and the presence of chronic respiratory diseases. This will include collection of questionnaire data, clinical samples (blood, urine, sputum and breath samples), lung function data and air pollution monitoring in their home. Multivariate analysis will be used to identify the important risk factors contributing to the pneumonia burden in this setting. Identification of preventable risk factors will justify research into the effectiveness of targeted interventions to address this burden in the future. The AIR Study is the first study of radiologically confirmed pneumonia in which air pollution exposure measurements have been undertaken in this setting, and will contribute important new information about exposure to air pollution in urban SSA. Through identification of preventable risk factors, the AIR Study aims to facilitate future research and implementation of targeted interventions to reduce the high burden of pneumonia in SSA.
    BMC Pulmonary Medicine 12/2015; 15(1):96. DOI:10.1186/s12890-015-0090-3 · 2.40 Impact Factor
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    ABSTRACT: Background. The Malawi Liverpool Wellcome Trust Clinical Research Programme (MLW) has routinely collected specimens for blood culture from febrile patients, and cerebrospinal fluid from patients with suspected meningitis, presenting to Queen Elizabeth Central Hospital (QECH), Blantyre, Malawi, since 1998. Methods. We present bloodstream infection (BSI) and meningitis surveillance data from 1998 to 2014. Automated blood culture, manual speciation, serotyping, and antimicrobial susceptibility testing were performed at MLW. Population data for minimum-incidence estimates in urban Blantyre were drawn from published estimates. Results. Between 1998 and 2014, 167 028 blood cultures were taken from adult and pediatric medical patients presenting to QECH; Salmonella Typhi was isolated on 2054 occasions (1.2%) and nontyphoidal Salmonella (NTS) serovars were isolated 10 139 times (6.1%), of which 8017 (79.1%) were Salmonella Typhimurium and 1608 (15.8%) were Salmonella Enteritidis. There were 392 cases of NTS meningitis and 9 cases of Salmonella Typhi meningitis. There have been 3 epidemics of Salmonella BSI in Blantyre; Salmonella Enteritidis from 1999 to 2002, Salmonella Typhimurium from 2002 to 2008, and Salmonella Typhi, which began in 2011 and was ongoing in 2014. Multidrug resistance has emerged in all 3 serovars and is seen in the overwhelming majority of isolates, while resistance to third-generation cephalosporins and fluoroquinolones is currently uncommon but has been identified. Conclusions. Invasive Salmonella disease in Malawi is dynamic and not clearly attributable to a single risk factor, although all 3 epidemics were associated with multidrug resistance. To inform nonvaccine and vaccine interventions, reservoirs of disease and modes of transmission require further investigation. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.
    Clinical Infectious Diseases 11/2015; 61(suppl 4):S363-S371. DOI:10.1093/cid/civ691 · 8.89 Impact Factor
  • John A. Crump · Robert S. Heyderman ·
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    ABSTRACT: Salmonella enterica is a leading cause of community-acquired bloodstream infection in Africa. The contribution of typhoidal and nontyphoidal Salmonella serovars to invasive disease varies considerably in place and time, even within the same country. Nonetheless, many African countries are now thought to experience typhoid fever incidence >100 per 100 000 per year with approximately 1% of patients dying. Invasive nontyphoidal Salmonella (iNTS) disease was estimated to cause 3.4 million illnesses and 681 316 deaths in 2010, with the most disease in Africa. Antimicrobial drug resistance is a growing problem in S. Enterica that threatens to further compromise patient outcomes. Reservoirs for nontyphoidal Salmonella and the predominant routes of transmission for typhoidal and nontyphoidal Salmonella are not well understood in Africa, hampering the design of evidence-based, non-vaccine- and vaccine-based prevention measures. It is difficult to distinguish clinically invasive Salmonella disease from febrile illnesses caused by other pathogens. Blood cultures are the mainstay of laboratory diagnosis, but lack sensitivity due to the low magnitude of bacteremia, do not produce results at point of care, and are not widely available in Africa. Serologic approaches to diagnosis remain inaccurate, and nucleic acid amplification tests are also compromised by low concentrations of bacteria. High-throughput whole-genome sequencing, together with a range of novel analytic pipelines, has provided new insights into the complex pattern of epidemiology, pathogenesis, and host adaptation. Concerted efforts are therefore needed to apply these new tools in the context of high-quality field surveillance to improve diagnosis, patient management, control, and prevention of invasive Salmonella infections in Africa. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.
    Clinical Infectious Diseases 11/2015; 61(suppl 4):S235-S240. DOI:10.1093/cid/civ709 · 8.89 Impact Factor
  • Robert S. Heyderman · John A. Crump ·

    Emerging infectious diseases 11/2015; 21(11). DOI:10.3201/eid2111.150624 · 6.75 Impact Factor
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    ABSTRACT: Background. Multiyear epidemics of Salmonella enterica serovar Typhi have been reported from countries across eastern and southern Africa in recent years. In Blantyre, Malawi, a dramatic increase in typhoid fever cases has recently occurred, and may be linked to the emergence of the H58 haplotype. Strains belonging to the H58 haplotype often exhibit multidrug resistance and may have a fitness advantage relative to other Salmonella Typhi strains. Methods. To explore hypotheses for the increased number of typhoid fever cases in Blantyre, we fit a mathematical model to culture-confirmed cases of Salmonella enterica infections at Queen Elizabeth Central Hospital, Blantyre. We explored 4 hypotheses: (1) an increase in the basic reproductive number (R0) in response to increasing population density; (2) a decrease in the incidence of cross-immunizing infection with Salmonella Enteritidis; (3) an increase in the duration of infectiousness due to failure to respond to first-line antibiotics; and (4) an increase in the transmission rate following the emergence of the H58 haplotype. Results. Increasing population density or decreasing cross-immunity could not fully explain the observed pattern of typhoid emergence in Blantyre, whereas models allowing for an increase in the duration of infectiousness and/or the transmission rate of typhoid following the emergence of the H58 haplotype provided a good fit to the data. Conclusions. Our results suggest that an increase in the transmissibility of typhoid due to the emergence of drug resistance associated with the H58 haplotype may help to explain recent outbreaks of typhoid in Malawi and similar settings in Africa. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.
    Clinical Infectious Diseases 11/2015; 61(suppl 4):S251-S258. DOI:10.1093/cid/civ710 · 8.89 Impact Factor
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    ABSTRACT: Streptococcus pneumoniae is a nasopharyngeal commensal that occasionally invades normally sterile sites to cause blood stream infection and meningitis. Although pneumococcal population structure and evolutionary genetics are well defined, it is not clear whether pneumococci that cause meningitis are genetically distinct from those that do not. Here, we used whole genome sequencing of 140 isolates of S. pneumoniae recovered from blood stream infection (n = 70) and meningitis (n = 70) to compare their genetic content. By fitting a double-exponential decaying function model we show that these isolates share a common core of 1427 (95% CI 1425-1430) genes and that there is no difference in the core genome or accessory gene content from these disease manifestations. Gene presence/absence alone does therefore not explain the virulence behavior of pneumococci that reach the meninges. Our analysis however supports the requirement of a range of previously described virulence factors and vaccine candidates for both meningitis and bacteremia causing pneumococci. This high-resolution view suggests that despite considerable competency for genetic exchange, all pneumococci are under considerable pressure to retain key components advantageous for colonization and transmission, and that they are essential for access to and survival in sterile sites.
    Infection and immunity 10/2015; 83(10). DOI:10.1128/IAI.00814-15 · 3.73 Impact Factor
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    ABSTRACT: Background: Household air pollution in low income countries is an important cause of mortality from respiratory infection. We hypothesised that chronic smoke exposure is detrimental to alveolar macrophage function, causing failure of innate immunity. We report the relationship between macrophage function and prior smoke exposure in healthy Malawians. Methods: Healthy subjects exposed daily to cooking smoke at home volunteered for bronchoalveolar lavage. Alveolar macrophage particulate content was measured as a known correlate of smoke exposure. Phagocytosis and intraphagosomal function (oxidative burst and proteolysis) were measured by a flow cytometric assay. Cytokine responses in macrophages were compared following re-exposure in vitro to wood smoke, before and after glutathione depletion. Results: Volunteers had a range of alveolar macrophage particulate loading. The macrophage capacity for phagosomal oxidative burst was negatively associated with alveolar macrophage particulate content (n = 29, r2 = 0.16, p = 0.033), but phagocytosis per se and proteolytic function were unaffected. High particulate content was associated with lower baseline CXCL8 release (ratio 0.51, CI 0.29-0.89) and lower final concentrations on re-exposure to smoke in vitro (ratio 0.58, CI 0.34-0.97). Glutathione depletion augmented CXCL8 responses by 1.49x (CI 1.02-2.17) compared with wood smoke alone. This response was specific to smoke as macrophages response to LPS were not modulated by glutathione. Conclusion: Chronic smoke exposure is associated with reduced human macrophage oxidative burst, and dampened inflammatory cytokine responses. These are critical processes in lung defence against infection and likely to underpin the relationship between air pollution and pneumonia.
    PLoS ONE 09/2015; 10(9):e0138762. DOI:10.1371/journal.pone.0138762 · 3.23 Impact Factor
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    ABSTRACT: Importance: HIV-1 typically replicates in CD4+ T cells. However, HIV-1 can evolve to infect macrophages, especially within the brain. Understanding how CCR5-using macrophage-tropic viruses evolve and differ from CCR5-using T cell-tropic viruses may provide insights into viral evolution and pathogenesis within the central nervous system. We characterized the HIV-1 env viral entry gene from subject-matched macrophage-tropic and T cell-tropic viruses to identify entry features of macrophage-tropic viruses. We observed several differences between T cell-tropic and macrophage-tropic Env proteins, including functional differences with host CD4 receptor engagement and possible changes in the CD4 binding site and V1/V2 region. We also identified viruses with phenotypes between that of "true" macrophage-tropic and T cell-tropic viruses, which may represent evolutionary intermediates in a multi-step process to macrophage tropism.
    Journal of Virology 09/2015; 89(22). DOI:10.1128/JVI.00946-15 · 4.44 Impact Factor
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    ABSTRACT: Serotype 1 Streptococcus pneumoniae is a leading cause of invasive pneumococcal disease (IPD) worldwide, with the highest burden in developing countries. We report the whole-genome sequencing analysis of 448 serotype 1 isolates from 27 countries worldwide (including 11 African). The global serotype 1 population shows a strong phylogeographic structure at the continental level, and within Africa there is further region specific structure. Our results demonstrate that region specific diversification within Africa has been driven by limited cross-region transfer events, genetic recombination and antimicrobial selective pressure. Clonal replacement of the dominant serotype 1 clones circulating within regions is uncommon, however here we report the accessory gene content that has contributed to a rare clonal replacement event of ST3081 with ST618 as the dominant cause of IPD in the Gambia.
    08/2015; 1(2). DOI:10.1099/mgen.0.000027
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    ABSTRACT: Post-licensure real world evaluation of vaccine implementation is important for establishing evidence of vaccine effectiveness (VE) and programme impact, including indirect effects. Large cohort studies offer an important epidemiological approach for evaluating VE, but have inherent methodological challenges. Since March 2012, we have conducted an open prospective cohort study in two sites in rural Malawi to evaluate the post-introduction effectiveness of 13-valent pneumococcal conjugate vaccine (PCV13) against all-cause post-neonatal infant mortality and monovalent rotavirus vaccine (RV1) against diarrhoea-related post-neonatal infant mortality. Our study sites cover a population of 500,000, with a baseline post-neonatal infant mortality of 25 per 1000 live births. We conducted a methodological review of cohort studies for vaccine effectiveness in a developing country setting, applied to our study context. Based on published literature, we outline key considerations when defining the denominator (study population), exposure (vaccination status) and outcome ascertainment (mortality and cause of death) of such studies. We assess various definitions in these three domains, in terms of their impact on power, effect size and potential biases and their direction, using our cohort study for illustration. Based on this iterative process, we discuss the pros and cons of our final per-protocol analysis plan. Since no single set of definitions or analytical approach accounts for all possible biases, we propose sensitivity analyses to interrogate our assumptions and methodological decisions. In the poorest regions of the world where routine vital birth and death surveillance are frequently unavailable and the burden of disease and death is greatest We conclude that provided the balance between definitions and their overall assumed impact on estimated VE are acknowledged, such large scale real-world cohort studies can provide crucial information to policymakers by providing robust and compelling evidence of total benefits of newly introduced vaccines on reducing child mortality. Copyright © 2015. Published by Elsevier Ltd.
    Vaccine 07/2015; 33(38). DOI:10.1016/j.vaccine.2015.07.062 · 3.62 Impact Factor
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    ABSTRACT: A procoagulant state is implicated in cerebral malaria (CM) pathogenesis, but whether disseminated intravascular coagulation (DIC) is present or associated with fatal outcome is unclear. To determine the frequency of overt DIC according to International Society on Thrombosis and Haemostasis (ISTH) criteria, in children with fatal and non-fatal CM. Malawian children were recruited into a prospective cohort study in the following diagnostic groups: retinopathy positive CM (n=140), retinopathy negative CM (n=36), non-malarial coma (n=14), uncomplicated malaria (n=91), mild non-malarial febrile illness (n=85) and healthy controls (n=36). Assays in the ISTH DIC criteria were measured together with 3 fibrin-related markers, protein C, antithrombin and soluble thrombomodulin. Data enabling assignment of the presence or absence of 'overt DIC' were available in 98/140 children with retinopathy positive CM. Overt DIC was present in 19 (19%) and was associated with fatal outcome (Odds ratio [OR] 3.068; 95% Confidence Interval [CI] 1.085-8.609; P=0.035). The three fibrin-markers and soluble thrombomodulin levels were higher in CM cases than uncomplicated malaria cases (all P=<0.001). Mean fibrin degradation product level was higher in fatal CM (71.3 [95% CI 49.0-93.6]) than non-fatal CM (48.0 [37.7-58.2]; P=0.032), but on multivariate logistic regression, thrombomodulin was the only coagulation related marker independently associated with fatal outcome (OR 1.084 [1.017 - 1.156]; P=0.014). Despite these laboratory derangements no child in the study had clinically evident bleeding or thrombosis. Overt DIC score and high thrombomodulin levels are associated with fatal outcome in CM, but infrequently indicate a consumptive coagulopathy. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 07/2015; 13(9). DOI:10.1111/jth.13060 · 5.72 Impact Factor
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    ABSTRACT: Carriage of either single or multiple pneumococcal serotypes (multiple carriage) is a prerequisite for developing invasive pneumococcal disease. However, despite the reported high rates of pneumococcal carriage in Malawi, no data on carriage of multiple serotypes has been reported previously. Our study provides the first description of the prevalence of multiple pneumococcal carriage in Malawi. The study was conducted in Blantyre and Karonga districts in Malawi, from 2008 to 2012. We recruited 116 children aged 0-13 years. These children were either HIV-infected (N = 44) or uninfected (N = 72). Nasopharyngeal samples were collected using sterile swabs. Pneumococcal serotypes in the samples were identified by microarray. Strains that could not be typed by microarray were sequenced to characterise possible genetic alterations within the capsular polysaccharide (CPS) locus. The microarray identified 179 pneumococcal strains (from 116 subjects), encompassing 43 distinct serotypes and non-typeable (NT) strains. Forty per cent (46/116) of children carried multiple serotypes. Carriage of vaccine type (VT) strains was higher (p = 0.028) in younger (0-2 years) children (71 %, 40/56) compared to older (3-13 years) children (50 %, 30/60). Genetic variations within the CPS locus of known serotypes were observed in 19 % (34/179) of the strains identified. The variants included 13-valent pneumococcal conjugate vaccine (PCV13) serotypes 6B and 19A, and the polysaccharide vaccine serotype 20. Serotype 6B variants were the most frequently isolated (47 %, 16/34). Unlike the wild type, the CPS locus of the 6B variants contained an insertion of the licD-family phosphotransferase gene. The CPS locus of 19A- and 20-variants contained an inversion in the sugar-biosynthesis (rmlD) gene and a 717 bp deletion within the transferase (whaF) gene, respectively. The high multiple carriage in Malawian children provides opportunities for genetic exchange through horizontal gene transfer. This may potentially lead to CPS locus variants and vaccine escape. Variants reported here occurred naturally, however, PCV13 introduction could exacerbate the CPS genetic variations. Further studies are therefore recommended to assess the invasive potential of these variants and establish whether PCV13 would offer cross-protection. We have shown that younger children (0-2 years) are a reservoir of VT serotypes, which makes them an ideal target for vaccination.
    BMC Infectious Diseases 07/2015; 15(234). DOI:10.1186/s12879-015-0980-2 · 2.61 Impact Factor
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    ABSTRACT: Nontyphoidal Salmonellae (NTS) are responsible for a huge burden of bloodstream infection in Sub-Saharan African children. Recent reports of a decline in invasive NTS (iNTS) disease from Kenya and The Gambia have emphasised an association with malaria control. Following a similar decline in iNTS disease in Malawi, we have used 9 years of continuous longitudinal data to model the interrelationships between iNTS disease, malaria, HIV and malnutrition. Trends in monthly numbers of childhood iNTS disease presenting at Queen's Hospital, Blantyre, Malawi from 2002 to 2010 were reviewed in the context of longitudinal monthly data describing malaria slide-positivity among paediatric febrile admissions, paediatric HIV prevalence, nutritional rehabilitation unit admissions and monthly rainfall over the same 9 years, using structural equation models (SEM). Analysis of 3,105 iNTS episodes identified from 49,093 blood cultures, showed an 11.8% annual decline in iNTS (p < 0.001). SEM analysis produced a stable model with good fit, revealing direct and statistically significant seasonal effects of malaria and malnutrition on the prevalence of iNTS disease. When these data were smoothed to eliminate seasonal cyclic changes, these associations remained strong and there were additional significant effects of HIV prevalence. These data suggest that the overall decline in iNTS disease observed in Malawi is attributable to multiple public health interventions leading to reductions in malaria, HIV and acute malnutrition. Understanding the impacts of public health programmes on iNTS disease is essential to plan and evaluate interventions.
    PLoS Neglected Tropical Diseases 07/2015; 9(7):e0003979. DOI:10.1371/journal.pntd.0003979 · 4.45 Impact Factor
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    ABSTRACT: In HIV-uninfected adults with pulmonary tuberculosis (TB), anti-TB treatment is associated with changes in Mycobacterium tuberculosis (Mtb)-specific immune responses, which correlate with sputum bacillary load. It is unclear if this occurs in HIV-infected TB patients. We investigated changes in Mtb-specific immune responses and sputum bacillary clearance during anti-TB treatment in HIV-infected and HIV-uninfected adults with pulmonary TB. Sputum bacillary load was assessed by smear microscopy and culture. Mtb-specific IFN-γ secreting peripheral blood mononuclear cells were enumerated using an ELISPOT assay following stimulation with PPD, ESAT-6 and CFP-10. The baseline frequency of Mtb-specific IFN-γ secreting cells was lower in HIV-infected than HIV-uninfected patients (median PPD 32 vs. 104 Spot Forming Units (SFU), p = 0.05; CFP-10 19 vs. 74 SFU, p = 0.01). ESAT-6-specific IFN-γ secreting cells and sputum bacillary load declined progressively during treatment in both HIV-infected and HIV-uninfected patients. HIV infection did not influence the 2-month sputum culture conversion rate (Odds Ratio 0.89, p = 0.95). These findings suggest that changes in ESAT-6-specific immune responses during anti-TB treatment correspond with changes in sputum bacillary load irrespective of host HIV infection status. The utility of Mtb-specific IFN-γ responses as a proxy measure of treatment response in HIV-infected TB patients warrants further evaluation in other settings. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
    Tuberculosis (Edinburgh, Scotland) 05/2015; 190(4). DOI:10.1016/ · 2.71 Impact Factor
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    ABSTRACT: The emergence of multidrug-resistant (MDR) typhoid is a major global health threat affecting many countries where the disease is endemic. Here whole-genome sequence analysis of 1,832 Salmonella enterica serovar Typhi (S. Typhi) identifies a single dominant MDR lineage, H58, that has emerged and spread throughout Asia and Africa over the last 30 years. Our analysis identifies numerous transmissions of H58, including multiple transfers from Asia to Africa and an ongoing, unrecognized MDR epidemic within Africa itself. Notably, our analysis indicates that H58 lineages are displacing antibiotic-sensitive isolates, transforming the global population structure of this pathogen. H58 isolates can harbor a complex MDR element residing either on transmissible IncHI1 plasmids or within multiple chromosomal integration sites. We also identify new mutations that define the H58 lineage. This phylogeographical analysis provides a framework to facilitate global management of MDR typhoid and is applicable to similar MDR lineages emerging in other bacterial species.
    Nature Genetics 05/2015; 47(6). DOI:10.1038/ng.3281 · 29.35 Impact Factor
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    N. Lelijveld · A. Seal · J. Wells · R. Heyderman · M. Nyirenda · M. Kerac ·
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    ABSTRACT: Aims Severe Acute malnutrition (SAM) is an important cause of child mortality worldwide and most treatment to date has focused on reducing those deaths. However, with emerging evidence that early nutritional adversity affects adult health, it is vital that treatment strategies also start looking beyond short term outcomes at programme discharge. To do this, improved evidence on the long term implications is needed; in this study, we examined growth and body composition 7 years after an episode of SAM. Methods We present latest data from a follow-up of 462 ex-malnourished Malawian children, comparing their growth and body composition to both siblings and age/sex matched community controls. These are the known survivors of an original cohort of 1024 children admitted to a large Malawian nutrition ward, from 2006 to 2007, for treatment of SAM. The current round of follow-up is 7 years after the original episode of malnutrition. Linear regression is used to analyse interim anthropometric data. Results To date, 321/412 (78%) of searches have been successful. Median age of the ex-malnourished ‘case’ children was 9 yrs 2 months (range: 7–20 years). 79/321 (25%) are HIV positive; 35/321 (11%) died in the last six years. Cases are significantly more stunted and underweight than community controls. Waist-hip ratio was significantly higher for cases suggestive of adverse body composition, however skinfold thickness ratio (subscapular+waist/tricep) was not significantly different between the groups. Sitting height ratio was also significantly higher for case children suggesting that torso length has been preserved and limb growth compromised. In addition, ex-malnourished case children had evidence of functional impairment with their hand-grip strength significantly weaker than that of community controls. Table 1 presents further details. Conclusions These results indicate that SAM may be associated with a number of adverse long-term effects, including stunting, abnormal body composition and functional impairment. It will be crucial to identify effective strategies, not only to prevent SAM in the first place, but to improve long-term outcomes in SAM survivors. Interventions might include more proactive case finding to encourage earlier detection and continued follow-up after the initial treatment to support high risk children and families.
    Archives of Disease in Childhood; 04/2015
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    ABSTRACT: Pneumonia and gastroenteritis are leading causes of vaccine-preventable childhood morbidity and mortality. Malawi introduced pneumococcal conjugate and rotavirus vaccines to the immunisation programme in 2011 and 2012, respectively. Evaluating their effectiveness is vital to ensure optimal implementation and justify sustained investment. A national evaluation platform was established to determine vaccine effectiveness and impact in Malawi. Impact and effectiveness against vaccine-type invasive pneumococcal disease, radiological pneumonia and rotavirus gastroenteritis are investigated using before-after incidence comparisons and case-control designs, respectively. Mortality is assessed using a prospective population cohort. Cost-effectiveness evaluation is nested within the case-control studies. We describe platform characteristics including strengths and weaknesses for conducting vaccine evaluations. Integrating data from individual level and ecological methods across multiple sites provides comprehensive information for policymakers on programme impact and vaccine effectiveness including changes in serotype/genotype distribution over time. Challenges to robust vaccine evaluation in real-world conditions include: vaccination ascertainment; pre-existing rapid decline in mortality and pneumococcal disease in the context of non-vaccine interventions; and the maintenance of completeness and quality of reporting at scale and over time. In observational non-randomised designs ascertainment of vaccine status may be biased particularly in infants with fatal outcomes. In the context of multiple population level interventions targeting study endpoints attribution of reduced incidence to vaccine impact may be flawed. Providing evidence from several independent but complementary studies will provide the greatest confidence in assigning impact. Welcome declines in disease incidence and in child mortality make accrual of required sample sizes difficult, necessitating large studies to detect the relatively small but potentially significant contribution of vaccines to mortality prevention. Careful evaluation of vaccine effectiveness and impact in such settings is critical to sustaining support for vaccine programmes. Our evaluation platform covers a large population with a high prevalence of HIV and malnutrition and its findings will be relevant to other settings in sub-Saharan Africa. Copyright © 2015. Published by Elsevier Ltd.
    Vaccine 04/2015; 33(23). DOI:10.1016/j.vaccine.2015.04.053 · 3.62 Impact Factor
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    ABSTRACT: We evaluated quantitative real-time PCR to establish the diagnosis of rotavirus gastroenteritis in a high disease burden population in Malawi using enzyme immunoassay as the gold standard diagnostic test. In 146 children with acute gastroenteritis and 65 asymptomatic children, we defined a cut-off point in cycle threshold value (26.7) that predicts rotavirus-attributable gastroenteritis in this population. These data will inform the evaluation of direct and indirect rotavirus vaccine effects in Africa. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Journal of clinical microbiology 04/2015; 53(6). DOI:10.1128/JCM.00875-15 · 3.99 Impact Factor
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    ABSTRACT: Between 1998 and 2010, S. Typhi was an uncommon cause of bloodstream infection (BSI) in Blantyre, Malawi and it was usually susceptible to first-line antimicrobial therapy. In 2011 an increase in a multidrug resistant (MDR) strain was detected through routine bacteriological surveillance conducted at Queen Elizabeth Central Hospital (QECH). Longitudinal trends in culture-confirmed Typhoid admissions at QECH were described between 1998-2014. A retrospective review of patient cases notes was conducted, focusing on clinical presentation, prevalence of HIV and case-fatality. Isolates of S. Typhi were sequenced and the phylogeny of Typhoid in Blantyre was reconstructed and placed in a global context. Between 1998-2010, there were a mean of 14 microbiological diagnoses of Typhoid/year at QECH, of which 6.8% were MDR. This increased to 67 in 2011 and 782 in 2014 at which time 97% were MDR. The disease predominantly affected children and young adults (median age 11 [IQR 6-21] in 2014). The prevalence of HIV in adult patients was 16.7% [8/48], similar to that of the general population (17.8%). Overall, the case fatality rate was 2.5% (3/94). Complications included anaemia, myocarditis, pneumonia and intestinal perforation. 112 isolates were sequenced and the phylogeny demonstrated the introduction and clonal expansion of the H58 lineage of S. Typhi. Since 2011, there has been a rapid increase in the incidence of multidrug resistant, H58-lineage Typhoid in Blantyre. This is one of a number of reports of the re-emergence of Typhoid in Southern and Eastern Africa. There is an urgent need to understand the reservoirs and transmission of disease and how to arrest this regional increase.
    PLoS Neglected Tropical Diseases 04/2015; 9(4):e0003748. DOI:10.1371/journal.pntd.0003748 · 4.45 Impact Factor

Publication Stats

4k Citations
1,396.95 Total Impact Points


  • 2011-2015
    • Liverpool School of Tropical Medicine
      • Department of Clinical Sciences
      Liverpool, England, United Kingdom
  • 2008-2015
    • University of Liverpool
      • Liverpool School of Tropical Medicine (LSTM)
      Liverpool, England, United Kingdom
    • Malawi-Liverpool-Wellcome Trust Clinical Research Programme
      Kapeni, Southern Region, Malawi
  • 2014
    • Oxford University Clinical Research Unit
      Thành phố Hồ Chí Minh, Ho Chi Minh City, Vietnam
  • 2010-2014
    • University of Malawi
      Zomba, Southern Region, Malawi
  • 1999-2014
    • University of Bristol
      • School of Cellular and Molecular Medicine
      Bristol, England, United Kingdom
  • 2012
    • The Queen Elizabeth Central Hospital in Blantyre
      Kapeni, Southern Region, Malawi
  • 2009
    • The Queen Elizabeth Hospital
      Tarndarnya, South Australia, Australia
  • 2003
    • Institute of Child Health Calcutta
      Kolkata, West Bengal, India
    • University of Dundee
      • Undergraduate Tayside Centre for General Practice
      Dundee, Scotland, United Kingdom
  • 1995-2000
    • University of Zimbabwe
      • Department of Medicine
      Harare, Harare Province, Zimbabwe
  • 1998-1999
    • Imperial College London
      • Section of Paediatrics
      Londinium, England, United Kingdom
  • 1997
    • Utrecht University
      • Division of Internal Medicine
      Utrecht, Utrecht, Netherlands
  • 1992-1995
    • Imperial College Healthcare NHS Trust
      Londinium, England, United Kingdom
    • SickKids
      • Division of Infectious Diseases
      Toronto, Ontario, Canada