[Show abstract][Hide abstract] 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
[Show abstract][Hide abstract] 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
[Show abstract][Hide abstract] 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; DOI:10.1128/JVI.00946-15 · 4.44 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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; 100(Suppl 3):A2-A3. DOI:10.1136/archdischild-2015-308599.5 · 2.90 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: Case fatality rates among African children with cerebral malaria remain in the range of 15 to 25%. The key pathogenetic processes and causes of death are unknown, but a combination of clinical observations and pathological findings suggests that increased brain volume leading to raised intracranial pressure may play a role. Magnetic resonance imaging (MRI) became available in Malawi in 2009, and we used it to investigate the role of brain swelling in the pathogenesis of fatal cerebral malaria in African children.
We enrolled children who met a stringent definition of cerebral malaria (one that included the presence of retinopathy), characterized them in detail clinically, and obtained MRI scans on admission and daily thereafter while coma persisted.
Of 348 children admitted with cerebral malaria (as defined by the World Health Organization), 168 met the inclusion criteria, underwent all investigations, and were included in the analysis. A total of 25 children (15%) died, 21 of whom (84%) had evidence of severe brain swelling on MRI at admission. In contrast, evidence of severe brain swelling was seen on MRI in 39 of 143 survivors (27%). Serial MRI scans showed evidence of decreasing brain volume in the survivors who had had brain swelling initially.
Increased brain volume was seen in children who died from cerebral malaria but was uncommon in those who did not die from the disease, a finding that suggests that raised intracranial pressure may contribute to a fatal outcome. The natural history indicates that increased intracranial pressure is transient in survivors. (Funded by the National Institutes of Health and Wellcome Trust U.K.).
New England Journal of Medicine 03/2015; 372(12):1126-37. DOI:10.1056/NEJMoa1400116 · 55.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Antibiotic-tolerant bacterial persistence prevents treatment shortening in drug-susceptible tuberculosis, and accumulation of intracellular lipid bodies has been proposed to identify a persister phenotype of Mycobacterium tuberculosis cells. In Malawi, we modeled bacillary elimination rates (BERs) from sputum cultures and calculated the percentage of lipid body-positive acid-fast bacilli (%LB + AFB) on sputum smears. We assessed whether these putative measurements of persistence predict unfavorable outcomes (treatment failure/relapse).
Adults with pulmonary tuberculosis received standard 6-month therapy. Sputum samples were collected during the first 8 weeks for serial sputum colony counting (SSCC) on agar and time-to positivity (TTP) measurement in mycobacterial growth indicator tubes. BERs were extracted from nonlinear and linear mixed-effects models, respectively, fitted to these datasets. The %LB + AFB counts were assessed by fluorescence microscopy. Patients were followed until 1 year posttreatment. Individual BERs and %LB + AFB counts were related to final outcomes.
One hundred and thirty-three patients (56% HIV coinfected) participated, and 15 unfavorable outcomes were reported. These were inversely associated with faster sterilization phase bacillary elimination from the SSCC model (odds ratio [OR], 0.39; 95% confidence interval [CI], .22-.70) and a faster BER from the TTP model (OR, 0.71; 95% CI, .55-.94). Higher %LB + AFB counts on day 21-28 were recorded in patients who suffered unfavorable final outcomes compared with those who achieved stable cure (P = .008).
Modeling BERs predicts final outcome, and high %LB + AFB counts 3-4 weeks into therapy may identify a persister bacterial phenotype. These methods deserve further evaluation as surrogate endpoints for clinical trials.
[Show abstract][Hide abstract] ABSTRACT: HIV-infected women seeking early infant HIV diagnosis (EID) services in Malawi were asked about factors potentially associated with returning for EID results. Many (33.3%) infants failed to complete the EID process because of time and costs required for multiple visits. Infants of mothers receiving antiretroviral treatment were less likely to drop out (adjusted risk ratio 0.51), suggesting that EID completion may improve in programs providing antiretroviral treatment to all pregnant women.
[Show abstract][Hide abstract] ABSTRACT: Background:
Data on causes of death due to respiratory illness in Africa are limited.
From January to April 2013, 28 African countries were invited to participate in a review of severe acute respiratory illness (SARI)-associated deaths identified from influenza surveillance during 2009-2012.
Twenty-three countries (82%) responded, 11 (48%) collect mortality data, and 8 provided data. Data were collected from 37 714 SARI cases, and 3091 (8.2%; range by country, 5.1%-25.9%) tested positive for influenza virus. There were 1073 deaths (2.8%; range by country, 0.1%-5.3%) reported, among which influenza virus was detected in 57 (5.3%). Case-fatality proportion (CFP) was higher among countries with systematic death reporting than among those with sporadic reporting. The influenza-associated CFP was 1.8% (57 of 3091), compared with 2.9% (1016 of 34 623) for influenza virus-negative cases (P < .001). Among 834 deaths (77.7%) tested for other respiratory pathogens, rhinovirus (107 [12.8%]), adenovirus (64 [6.0%]), respiratory syncytial virus (60 [5.6%]), and Streptococcus pneumoniae (57 [5.3%]) were most commonly identified. Among 1073 deaths, 402 (37.5%) involved people aged 0-4 years, 462 (43.1%) involved people aged 5-49 years, and 209 (19.5%) involved people aged ≥50 years.
Few African countries systematically collect data on outcomes of people hospitalized with respiratory illness. Stronger surveillance for deaths due to respiratory illness may identify risk groups for targeted vaccine use and other prevention strategies.
The Journal of Infectious Diseases 02/2015; 212(6). DOI:10.1093/infdis/jiv100 · 6.00 Impact Factor
[Show abstract][Hide abstract] 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.