Publications by authors named "Malcolm E Molyneux"

177 Publications

How Does Blood-Retinal Barrier Breakdown Relate to Death and Disability in Pediatric Cerebral Malaria?

J Infect Dis 2020 Aug 26. Epub 2020 Aug 26.

Department of Eye and Vision Science, Institute of Life Course and Medical Sciences, University of Liverpool, a member of Liverpool Health Partners, Liverpool, UK.

Background: In cerebral malaria, the retina can be used to understand disease pathogenesis. The mechanisms linking sequestration, brain swelling and death remain poorly understood. We hypothesized that retinal vascular leakage would be associated with brain swelling.

Methods: We used retinal angiography to study blood-retinal barrier integrity. We analyzed retinal leakage, histopathology, brain MRI, and associations with death and neurological disability in prospective cohorts of Malawian children with cerebral malaria.

Results: Three types of retinal leakage were seen: Large focal leak (LFL), punctate leak (PL) and vessel leak. LFL and PL were associated with death (OR 13.20, 95%CI 5.21-33.78 and 8.58, 2.56-29.08 respectively), and brain swelling (p<0.05). Vessel leak and macular non-perfusion were associated with neurological disability (3.71, 1.26-11.02 and 9.06, 1.79-45.90). LFL was observed as an evolving retinal hemorrhage. A core of fibrinogen and monocytes was found in 39 (93%) white-centered hemorrhages.

Conclusions: Blood-retina barrier breakdown occurs in three patterns in cerebral malaria. Associations between LFL, brain swelling, and death suggest that the rapid accumulation of cerebral hemorrhages, with accompanying fluid egress, may cause fatal brain swelling. Vessel leak from barrier dysfunction, and non-perfusion were not associated with severe brain swelling, but with neurological deficits, suggesting hypoxic injury in survivors.
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http://dx.doi.org/10.1093/infdis/jiaa541DOI Listing
August 2020

HIV infection compounds the lymphopenia associated with cerebral malaria in Malawian children.

J Blood Med 2019 19;10:9-18. Epub 2018 Dec 19.

Malawi Liverpool Wellcome Trust Clinical Research Programme, College of Medicine, Blantyre, Malawi,

Aim: Cerebral malaria (CM), unlike severe malarial anemia (SMA), has previously been characterized by pan-lymphopenia that normalizes in convalescence, while HIV infection is associated with depletion of CD4 T cells. In this study, we investigate whether HIV infection in Malawian children exacerbates the pan-lymphopenia associated with CM.

Methods: We investigated the absolute and percentage lymphocyte-subset counts and their activation and memory status in Malawian children presenting with either CM who were HIV-uninfected (n=29), HIV-infected (n=9), or SMA who were HIV-uninfected (n=30) and HIV-infected (n=5) in comparison with HIV-uninfected children without malaria (n=42) and HIV-infected children without malaria (n=4).

Results: HIV-infected CM cases had significantly lower absolute counts of T cells (=0.006), CD4 T cells (=0.0008), and B cells (=0.0014) than HIV-uninfected CM cases, and significantly lower percentages of CD4 T cells than HIV-uninfected CM cases (=0.005). HIV-infected SMA cases had significantly lower percentages of CD4 T cells (=0.001) and higher CD8 T cells (=0.003) in comparison with HIV-uninfected SMA cases. HIV-infected SMA cases had higher proportions of activated T cells (=0.003) expressing CD69 than HIV-uninfected SMA cases.

Conclusion: HIV infection compounds the perturbation of acute CM and SMA on lymphocytes, exacerbating subset-specific lymphopenia in CM and increasing activation status in SMA, potentially exacerbating host immunocompromise.
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http://dx.doi.org/10.2147/JBM.S187081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305159PMC
December 2018

Peripheral blood RNA gene expression in children with pneumococcal meningitis: a prospective case-control study.

BMJ Paediatr Open 2017 31;1(1):e000092. Epub 2017 Aug 31.

Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, Blantyre, Malawi.

Introduction: Invasive pneumococcal disease (IPD), caused by is a leading cause of pneumonia, meningitis and septicaemia worldwide, with increased morbidity and mortality in HIV-infected children.

Objectives: We aimed to compare peripheral blood expression profiles between HIV-infected and uninfected children with pneumococcal meningitis and controls, and between survivors and non-survivors, in order to provide insight into the host inflammatory response leading to poorer outcomes.

Design And Setting: Prospective case-control observational study in a tertiary hospital in Malawi.

Participants: Children aged 2 months to 16 years with pneumococcal meningitis or pneumonia.

Methods: We used the human genome HGU133A Affymetrix array to explore differences in gene expression between cases with pneumococcal meningitis (n=12) and controls, and between HIV-infected and uninfected cases, and validated gene expression profiles for 34 genes using real-time quantitative PCR (RT-qPCR) in an independent set of cases with IPD (n=229) and controls (n=13). Pathway analysis was used to explore genes differentially expressed.

Results: Irrespective of underlying HIV infection, cases showed significant upregulation compared with controls of the following: S100 calcium-binding protein A12 (S100A12); vanin-1 (VNN1); arginase, liver (ARG1); matrix metallopeptidase 9 (MMP9); annexin A3 (ANXA3); interleukin 1 receptor, type II (IL1R2); CD177 molecule (CD177); endocytic adaptor protein (NUMB) and S100 calcium-binding protein A9 (S100A9), cytoskeleton-associated protein 4 (CKAP4); and glycogenin 1 (GYG1). RT-qPCR confirmed differential expression in keeping with microarray results. There was no differential gene expression in HIV-infected compared with HIV-uninfected cases, but there was significant upregulation of folate receptor 3 (FOLR3), S100A12 in survivors compared with non-survivors.

Conclusion: Children with IPD demonstrated increased expression in genes regulating immune activation, oxidative stress, leucocyte adhesion and migration, arginine metabolism, and glucocorticoid receptor signalling.
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http://dx.doi.org/10.1136/bmjpo-2017-000092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862186PMC
August 2017

Risk of nontyphoidal Salmonella bacteraemia in African children is modified by STAT4.

Nat Commun 2018 03 9;9(1):1014. Epub 2018 Mar 9.

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.

Nontyphoidal Salmonella (NTS) is a major cause of bacteraemia in Africa. The disease typically affects HIV-infected individuals and young children, causing substantial morbidity and mortality. Here we present a genome-wide association study (180 cases, 2677 controls) and replication analysis of NTS bacteraemia in Kenyan and Malawian children. We identify a locus in STAT4, rs13390936, associated with NTS bacteraemia. rs13390936 is a context-specific expression quantitative trait locus for STAT4 RNA expression, and individuals carrying the NTS-risk genotype demonstrate decreased interferon-γ (IFNγ) production in stimulated natural killer cells, and decreased circulating IFNγ concentrations during acute NTS bacteraemia. The NTS-risk allele at rs13390936 is associated with protection against a range of autoimmune diseases. These data implicate interleukin-12-dependent IFNγ-mediated immunity as a determinant of invasive NTS disease in African children, and highlight the shared genetic architecture of infectious and autoimmune disease.
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http://dx.doi.org/10.1038/s41467-017-02398-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844948PMC
March 2018

Pathology-Based Research in Africa.

Clin Lab Med 2018 03;38(1):67-90

Pacific Northwest University of Health Sciences, 200 University Parkway, Room BHH 423, Yakima, WA 98901, USA. Electronic address:

The process of conducting pathology research in Africa can be challenging. But the rewards in terms of knowledge gained, quality of collaborations, and impact on communities affected by infectious disease and cancer are great. This report reviews 3 different research efforts: fatal malaria in Malawi, mucosal immunity to HIV in South Africa, and cancer research in Uganda. What unifies them is the use of pathology-based approaches to answer vital questions, such as physiology, pathogenesis, predictors of clinical course, and diagnostic testing schemes.
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http://dx.doi.org/10.1016/j.cll.2017.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5894888PMC
March 2018

Presentation of life-threatening invasive nontyphoidal Salmonella disease in Malawian children: A prospective observational study.

PLoS Negl Trop Dis 2017 12 7;11(12):e0006027. Epub 2017 Dec 7.

Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Malawi.

Nontyphoidal Salmonellae commonly cause invasive disease in African children that is often fatal. The clinical diagnosis of these infections is hampered by the absence of a clear clinical syndrome. Drug resistance means that empirical antibiotic therapy is often ineffective and currently no vaccine is available. The study objective was to identify risk factors for mortality among children presenting to hospital with invasive Salmonella disease in Africa. We conducted a prospective study enrolling consecutive children with microbiologically-confirmed invasive Salmonella disease admitted to Queen Elizabeth Central Hospital, Blantyre, in 2006. Data on clinical presentation, co-morbidities and outcome were used to identify children at risk of inpatient mortality through logistic-regression modeling. Over one calendar year, 263 consecutive children presented with invasive Salmonella disease. Median age was 16 months (range 0-15 years) and 52/256 children (20%; 95%CI 15-25%) died. Nontyphoidal serovars caused 248/263 (94%) of cases. 211/259 (81%) of isolates were multi-drug resistant. 251/263 children presented with bacteremia, 6 with meningitis and 6 with both. Respiratory symptoms were present in 184/240 (77%; 95%CI 71-82%), 123/240 (51%; 95%CI 45-58%) had gastrointestinal symptoms and 101/240 (42%; 95%CI 36-49%) had an overlapping clinical syndrome. Presentation at <7 months (OR 10.0; 95%CI 2.8-35.1), dyspnea (OR 4.2; 95%CI 1.5-12.0) and HIV infection (OR 3.3; 95%CI 1.1-10.2) were independent risk factors for inpatient mortality. Invasive Salmonella disease in Malawi is characterized by high mortality and prevalence of multi-drug resistant isolates, along with non-specific presentation. Young infants, children with dyspnea and HIV-infected children bear a disproportionate burden of the Salmonella-associated mortality in Malawi. Strategies to improve prevention, diagnosis and management of invasive Salmonella disease should be targeted at these children.
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http://dx.doi.org/10.1371/journal.pntd.0006027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745124PMC
December 2017

Age- and sex-related changes in hematological parameters in healthy Malawians.

J Blood Med 2017 28;8:123-130. Epub 2017 Aug 28.

The Malaria Immunology Group, Malawi-Liverpool Wellcome Trust Clinical Research Programme, College of Medicine, Blantyre, Malawi.

Aim: The aim of the study was to determine how values for white blood cell (WBC) counts, hemoglobin (Hb), hematocrit (Hct), mean corpuscular volume (mcv), and platelet counts vary with age and sex in healthy Malawians.

Methods: We recruited 660 (316 male and 344 female) participants in 12 different age groups. An ethylenediaminetetraacetic acid-anticoagulated blood sample collected from each participant was analyzed using a hematological analyzer.

Results: WBC counts decreased with age with the lowest counts observed in the 20 to <60 years old group. Median WBC counts for 20 to <60 year old females (5.9×10/L) were significantly higher than those for men (4.7×10/L; =0.015) of the same age. Hb and Hct increased between 5 and 10 years in males and 10 and 15 years in females to adult levels. Males aged 5 to <10 years had significantly higher Hb (13.05 g/dL) and Hct (42.50%) compared to females of the same age (10.40 g/dL and 32.55%, respectively; <0.0001 for both parameters). Platelet counts in males, which were highest between 3 and 5 years (376×10/L), decreased to lowest counts among 5 to <10 year olds (238×10/L), while in females these decreased from 402×10/L in 6 to <10 years olds to 226×10/L in 10 to <15 year olds. mcv median values were high in neonates reaching a nadir at 13-18 months and then increased throughout life. Females aged 0 to <6 months had significantly higher mcv values (81.85 fL) than males of the same age (69.3 fL; <0.0001).

Conclusion: This study provides hematological values according to age and sex that are suitable for reference use in studies among Malawian subjects.
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http://dx.doi.org/10.2147/JBM.S142189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587168PMC
August 2017

Leukocyte counts and lymphocyte subsets in relation to pregnancy and HIV infection in Malawian women.

Am J Reprod Immunol 2017 Sep 6;78(3). Epub 2017 Apr 6.

Malawi-Liverpool Wellcome Trust Clinical Research Programme, College of Medicine, Blantyre, Malawi.

Problem: We investigated leukocyte and lymphocyte subsets in HIV-infected or HIV-uninfected, pregnant or non-pregnant Malawian women to explore whether HIV infection and pregnancy may act synergistically to impair cellular immunity.

Method Of Study: We recruited 54 pregnant and 48 non-pregnant HIV-uninfected women and 24 pregnant and 20 non-pregnant HIV-infected Malawian women. We compared peripheral blood leukocyte and lymphocyte subsets between women in the four groups.

Results: Parturient HIV-infected and HIV-uninfected women had more neutrophils (each P<.0001), but fewer lymphocytes (P<.0001; P=.0014) than non-pregnant women. Both groups had fewer total T cells (P<.0001; P=.002) and CD8 T cells (P<.0001; P=.014) than non-pregnant women. HIV-uninfected parturient women had fewer CD4 and γδ T cells, B and NK cells (each P<.0001) than non-pregnant women. Lymphocyte subset percentages were not affected by pregnancy.

Conclusion: Malawian women at parturition have an increased total white cell count due to neutrophilia and an HIV-unrelated pan-lymphopenia.
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http://dx.doi.org/10.1111/aji.12678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5573949PMC
September 2017

Cytokine Profiles in Malawian Children Presenting with Uncomplicated Malaria, Severe Malarial Anemia, and Cerebral Malaria.

Clin Vaccine Immunol 2017 Apr 5;24(4). Epub 2017 Apr 5.

Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi.

Proinflammatory cytokines are involved in clearance of , and very high levels of these cytokines have been implicated in the pathogenesis of severe malaria. In order to determine how cytokines vary with disease severity and syndrome, we enrolled Malawian children presenting with cerebral malaria (CM), severe malarial anemia (SMA), and uncomplicated malaria (UCM) and healthy controls. We analyzed serum cytokine concentrations in acute infection and in convalescence. With the exception of interleukin 5 (IL-5), cytokine concentrations were highest in acute CM, followed by SMA, and were only mildly elevated in UCM. Cytokine concentrations had fallen to control levels when remeasured at 1 month of convalescence in all three clinical malaria groups. Ratios of IL-10 to tumor necrosis factor alpha (TNF-α) and of IL-10 to IL-6 followed a similar pattern. Children presenting with acute CM had significantly higher concentrations of TNF-α ( < 0.001), interferon gamma (IFN-γ) ( = 0.0019), IL-2 ( = 0.0004), IL-6 ( < 0.001), IL-8 ( < 0.001), and IL-10 ( < 0.001) in sera than healthy controls. Patients with acute CM had significantly higher concentrations of IL-6 ( < 0.001) and IL-10 ( = 0.0003) than those presenting with acute SMA. Our findings are consistent with the concept that high levels of proinflammatory cytokines, despite high levels of the anti-inflammatory cytokine IL-10, could contribute to the pathogenesis of CM.
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http://dx.doi.org/10.1128/CVI.00533-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5382826PMC
April 2017

A trial of a 7-valent pneumococcal conjugate vaccine in HIV-infected adults.

Malawi Med J 2016 09;28(3):115-122

Imperial College London, London, United Kingdom.

Background: is a leading and serious coinfection in adults with human immunodeficiency virus (HIV) infection, particularly in Africa. Prevention of this disease by vaccination with the current 23-valent polysaccharide vaccine is suboptimal. Protein conjugate vaccines offer a further option for protection, but data on their clinical efficacy in adults are needed.

Methods: In this double-blind, randomized, placebo-controlled clinical efficacy trial, we studied the efficacy of a 7-valent conjugate pneumococcal vaccine in predominantly HIV-infected Malawian adolescents and adults who had recovered from documented invasive pneumococcal disease. Two doses of vaccine were given 4 weeks apart. The primary end point was a further episode of pneumococcal infection caused by vaccine serotypes or serotype 6A.

Results: From February 2003 through October 2007, we followed 496 patients (of whom 44% were male and 88% were HIV-seropositive) for 798 person-years of observation. There were 67 episodes of pneumococcal disease in 52 patients, all in the HIV-infected subgroup. In 24 patients, there were 19 episodes that were caused by vaccine serotypes and 5 episodes that were caused by the 6A serotype. Of these episodes, 5 occurred in the vaccine group and 19 in the placebo group, for a vaccine efficacy of 74% (95% confidence interval [CI], 30 to 90). There were 73 deaths from any cause in the vaccine group and 63 in the placebo group (hazard ratio in the vaccine group, 1.18; 95% CI, 0.84 to 1.66). The number of serious adverse events within 14 days after vaccination was significantly lower in the vaccine group than in the placebo group (3 vs. 17, P = 0.002), and the number of minor adverse events was significantly higher in the vaccine group (41 vs. 13, P = 0.003).

Conclusions: The 7-valent pneumococcal conjugate vaccine protected HIV-infected adults from recurrent pneumococcal infection caused by vaccine serotypes or serotype 6A. (Current Controlled Trials number, ISRCTN54494731.).
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5117001PMC
September 2016

Severe anemia in Malawian children.

Malawi Med J 2016 09;28(3):99-107

Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi; College of Medicine, University of Malawi, Blantyre, Malawi; Emma Children's Hospital, the Global Child Health Group, Academic Medical Center, Amsterdam, The Netherlands; Child and Reproductive Health Group, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.

Background: Severe anemia is a major cause of sickness and death in African children, yet the causes of anemia in this population have been inadequately studied.

Methods: We conducted a case-control study of 381 preschool children with severe anemia (hemoglobin concentration, <5.0 g per deciliter) and 757 preschool children without severe anemia in urban and rural settings in Malawi. Causal factors previously associated with severe anemia were studied. The data were examined by multivariate analysis and structural equation modeling.

Results: Bacteremia (adjusted odds ratio, 5.3; 95% confidence interval [CI], 2.6 to 10.9), malaria (adjusted odds ratio, 2.3; 95% CI, 1.6 to 3.3), hookworm (adjusted odds ratio, 4.8; 95% CI, 2.0 to 11.8), human immunodeficiency virus infection (adjusted odds ratio, 2.0; 95% CI, 1.0 to 3.8), the genetic disorder (adjusted odds ratio, 2.4; 95% CI, 1.3 to 4.4), vitamin A deficiency (adjusted odds ratio, 2.8; 95% CI, 1.3 to 5.8), and vitamin B deficiency (adjusted odds ratio, 2.2; 95% CI, 1.4 to 3.6) were associated with severe anemia. Folate deficiency, sickle cell disease, and laboratory signs of an abnormal inflammatory response were uncommon. Iron deficiency was not prevalent in case patients (adjusted odds ratio, 0.37; 95% CI, 0.22 to 0.60) and was negatively associated with bacteremia. Malaria was associated with severe anemia in the urban site (with seasonal transmission) but not in the rural site (where malaria was holoendemic). Seventy-six percent of hookworm infections were found in children under 2 years of age.

Conclusions: There are multiple causes of severe anemia in Malawian preschool children, but folate and iron deficiencies are not prominent among them. Even in the presence of malaria parasites, additional or alternative causes of severe anemia should be considered.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5116999PMC
September 2016

Bednets and malaria in Africa.

Malawi Med J 2016 09;28(3):92-93

Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5116997PMC
September 2016

A medical career in Malawi - personal reflections.

Malawi Med J 2016 09;28(3):82-83

University of Liverpool.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5116994PMC
http://dx.doi.org/10.4314/mmj.v28i3.5DOI Listing
September 2016

Cytokine Profiles during Invasive Nontyphoidal Salmonella Disease Predict Outcome in African Children.

Clin Vaccine Immunol 2016 07 5;23(7):601-9. Epub 2016 Jul 5.

School of Immunity and Infection, College of Medicine and Dental Sciences, University of Birmingham, Birmingham, United Kingdom Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom

Nontyphoidal Salmonella is a leading cause of sepsis in African children. Cytokine responses are central to the pathophysiology of sepsis and predict sepsis outcome in other settings. In this study, we investigated cytokine responses to invasive nontyphoidal Salmonella (iNTS) disease in Malawian children. We determined serum concentrations of 48 cytokines with multiplexed immunoassays in Malawian children during acute iNTS disease (n = 111) and in convalescence (n = 77). Principal component analysis and logistic regression were used to identify cytokine signatures of acute iNTS disease. We further investigated whether these responses are altered by HIV coinfection or severe malnutrition and whether cytokine responses predict inpatient mortality. Cytokine changes in acute iNTS disease were associated with two distinct cytokine signatures. The first is characterized by increased concentrations of mediators known to be associated with macrophage function, and the second is characterized by raised pro- and anti-inflammatory cytokines typical of responses reported in sepsis secondary to diverse pathogens. These cytokine responses were largely unaltered by either severe malnutrition or HIV coinfection. Children with fatal disease had a distinctive cytokine profile, characterized by raised mediators known to be associated with neutrophil function. In conclusion, cytokine responses to acute iNTS infection in Malawian children are reflective of both the cytokine storm typical of sepsis secondary to diverse pathogens and the intramacrophage replicative niche of NTS. The cytokine profile predictive of fatal disease supports a key role of neutrophils in the pathogenesis of NTS sepsis.
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http://dx.doi.org/10.1128/CVI.00128-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4933780PMC
July 2016

Evidence for spleen dysfunction in malaria-HIV co-infection in a subset of pediatric patients.

Mod Pathol 2016 Apr 26;29(4):381-90. Epub 2016 Feb 26.

Department of Immunology and Infectious Disease, The Harvard School of Public Health, Boston, MA, USA.

The spleen has an important role in the clearance of malaria parasites, and the role of HIV co-infection on this process is yet to be described. Using a combination of histological and molecular methods, we systematically evaluated parasite load across multiple organs from HIV-positive and HIV-negative cases of an autopsy study of pediatric comatose children with malaria infection (n=103) in Blantyre, Malawi. Quantification of parasite load across organs was done using histology. A subset of cases was further characterized for parasite localization and stage of development using immunohistochemistry-based labeling of parasite and host cells (5 HIV-positive, 10 HIV-negative), and quantitative RT-PCR (qRT-PCR) of asexual and sexual-specific genes (4 HIV-positive, 5 HIV-negative). The results were compared with clinical information including HIV status. The HIV-positive rate was 21% for the group studied (20 of 95) and HIV-positive patients had a significantly shorter duration of time between onset of illness and death, and were significantly older than HIV-negative patients. We found that spleens of HIV-positive cases had significantly higher parasite loads compared with those of HIV-negative cases in each of the three methods we used: (i) standard histology, (ii) immunohistochemistry-based labeling of Plasmodium lactate dehydrogenase (pLDH), and (iii) molecular detection of asexual parasite transcript apical membrane antigen 1 (AMA1). Immunohistochemistry-based labeling of macrophage marker CD163 in a subset of spleens revealed fewer activated macrophages containing engulfed parasites and a greater number of free unphagocytosed parasites in the HIV-positive cases. The mechanism by which HIV infection is associated with more rapid progression to severe cerebral malaria disease is possibly impairment of parasite destruction by splenic macrophages, supported by published in vitro studies showing inefficient phagocytosis of malaria parasites by HIV-infected macrophages.
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http://dx.doi.org/10.1038/modpathol.2016.27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4811692PMC
April 2016

Author Correction for Hochman et al., Fatal Pediatric Cerebral Malaria Is Associated with Intravascular Monocytes and Platelets That Are Increased with HIV Coinfection.

mBio 2016 Feb 2;7(1):e02068-15. Epub 2016 Feb 2.

Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA

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http://dx.doi.org/10.1128/mBio.02068-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742709PMC
February 2016

Lymphocyte Perturbations in Malawian Children with Severe and Uncomplicated Malaria.

Clin Vaccine Immunol 2015 Nov 18;23(2):95-103. Epub 2015 Nov 18.

Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, Blantyre, Malawi School of Immunity and Infection, College of Medicine and Dental Sciences, University of Birmingham, Birmingham, United Kingdom Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom Wellcome Trust Sanger Institute, Cambridge, United Kingdom

Lymphocytes are implicated in immunity and pathogenesis of severe malaria. Since lymphocyte subsets vary with age, assessment of their contribution to different etiologies can be difficult. We immunophenotyped peripheral blood from Malawian children presenting with cerebral malaria, severe malarial anemia, and uncomplicated malaria (n = 113) and healthy aparasitemic children (n = 42) in Blantyre, Malawi, and investigated lymphocyte subset counts, activation, and memory status. Children with cerebral malaria were older than those with severe malarial anemia. We found panlymphopenia in children presenting with cerebral malaria (median lymphocyte count, 2,100/μl) and uncomplicated malaria (3,700/μl), which was corrected in convalescence and was absent in severe malarial anemia (5,950/μl). Median percentages of activated CD69(+) NK (73%) and γδ T (60%) cells were higher in cerebral malaria than in other malaria types. Median ratios of memory to naive CD4(+) lymphocytes were higher in cerebral malaria than in uncomplicated malaria and low in severe malarial anemia. The polarized lymphocyte subset profiles of different forms of severe malaria are independent of age. In conclusion, among Malawian children cerebral malaria is characterized by lymphocyte activation and increased memory cells, consistent with immune priming. In contrast, there are reduced memory cells and less activation in severe malaria anemia. Further studies are required to understand whether these immunological profiles indicate predisposition of some children to one or another form of severe malaria.
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http://dx.doi.org/10.1128/CVI.00564-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4744922PMC
November 2015

Grading fluorescein angiograms in malarial retinopathy.

Malar J 2015 Sep 24;14:367. Epub 2015 Sep 24.

Department of Eye and Vision Science, University of Liverpool, Liverpool, UK.

Background: Malarial retinopathy is an important finding in Plasmodium falciparum cerebral malaria, since it strengthens diagnostic accuracy, predicts clinical outcome and appears to parallel cerebral disease processes. Several angiographic features of malarial retinopathy have been described, but observations in different populations can only be reliably compared if consistent methodology is used to capture and grade retinal images. Currently no grading scheme exists for fluorescein angiographic features of malarial retinopathy.

Methods: A grading scheme for fluorescein angiographic images was devised based on consensus opinion of clinicians and researchers experienced in malarial retinopathy in children and adults. Dual grading were performed with adjudication of admission fluorescein images from a large cohort of children with cerebral malaria.

Results: A grading scheme is described and standard images are provided to facilitate future grading studies. Inter-grader agreement was >70 % for most variables. Intravascular filling defects are difficult to grade and tended to have lower inter-grader agreement (>57 %) compared to other features.

Conclusions: This grading scheme provides a consistent way to describe retinal vascular damage in paediatric cerebral malaria, and can facilitate comparisons of angiographic features of malarial retinopathy between different patient groups, and analysis against clinical outcomes. Inter-grader agreement is reasonable for the majority of angiographic signs. Dual grading with expert adjudication should be used to maximize accuracy.
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http://dx.doi.org/10.1186/s12936-015-0897-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4583163PMC
September 2015

Fatal Pediatric Cerebral Malaria Is Associated with Intravascular Monocytes and Platelets That Are Increased with HIV Coinfection.

mBio 2015 Sep 22;6(5):e01390-15. Epub 2015 Sep 22.

Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA

Cerebral malaria (CM) is a major contributor to malaria deaths, but its pathophysiology is not well understood. While sequestration of parasitized erythrocytes is thought to be critical, the roles of inflammation and coagulation are controversial. In a large series of Malawian children hospitalized with CM, HIV coinfection was more prevalent than in pediatric population estimates (15% versus 2%, P < 0.0001, chi-square test), with higher mortality than that seen in HIV-uninfected children (23% versus 17%, P = 0.0178, chi-square test). HIV-infected (HIV(+)) children with autopsy-confirmed CM were older than HIV-uninfected children (median age, 99 months versus 32 months, P = 0.0007, Mann-Whitney U test) and appeared to lack severe immunosuppression. Because HIV infection is associated with dysregulated inflammation and platelet activation, we performed immunohistochemistry analysis for monocytes, platelets, and neutrophils in brain tissue from HIV(+) and HIV-uninfected children with fatal CM. Children with autopsy-confirmed CM had significantly (>9 times) more accumulations of intravascular monocytes and platelets, but not neutrophils, than did children with nonmalarial causes of coma. The monocyte and platelet accumulations were significantly (>2-fold) greater in HIV(+) children than in HIV-uninfected children with autopsy-confirmed CM. Our findings indicate that HIV is a risk factor for CM and for death from CM, independent of traditional measures of HIV disease severity. Brain histopathology supports the hypotheses that inflammation and coagulation contribute to the pathogenesis of pediatric CM and that immune dysregulation in HIV(+) children exacerbates the pathological features associated with CM. IMPORTANCE : There are nearly 1 million malaria deaths yearly, primarily in sub-Saharan African children. Cerebral malaria (CM), marked by coma and sequestered malaria parasites in brain blood vessels, causes half of these deaths, although the mechanisms causing coma and death are uncertain. Sub-Saharan Africa has a high HIV prevalence, with 3 million HIV-infected (HIV(+)) children, but the effects of HIV on CM pathogenesis and mortality are unknown. In a study of pediatric CM in Malawi, HIV prevalence was high and CM-attributed mortality was higher in HIV(+) than in HIV-uninfected children. Brain pathology in children with fatal CM was notable not only for sequestered malaria parasites but also for intravascular accumulations of monocytes and platelets that were more severe in HIV(+) children. Our findings raise the possibility that HIV(+) children at risk for malaria may benefit from targeted malaria prophylaxis and that adjunctive treatments targeting inflammation and/or coagulation may improve CM outcomes.
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http://dx.doi.org/10.1128/mBio.01390-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4611030PMC
September 2015

T-Regulatory Cells and Inflammatory and Inhibitory Cytokines in Malawian Children Residing in an Area of High and an Area of Low Malaria Transmission During Acute Uncomplicated Malaria and in Convalescence.

J Pediatric Infect Dis Soc 2015 Sep 7;4(3):232-41. Epub 2015 Jan 7.

Malawi-Liverpool Wellcome Trust Clinical Research Programme , College of Medicine , Blantyre ; Basic Medical Sciences Department , College of Medicine , Blantyre, Malawi.

Background: Malaria still infects many Malawian children, and it is a cause of death in some of them. Regulatory T cells (Tregs) help in negating immune-related pathology, it but can also favor multiplication of malaria parasites. The question remains whether children recovering from uncomplicated malaria (UCM) have higher Tregs and interleukin (IL)-10 levels in convalescence.

Methods: We recruited children between the ages of 6 and 60 months presenting with acute UCM in Blantyre (low transmission area) and Chikwawa (high transmission area). We observed the children after 1 month and 3 months and analyzed their blood samples for parasitemia, lymphocyte subsets, and levels of the cytokines interferon (IFN)-γ, IL-10, and transforming growth factor (TGF)-β. Blood samples from age-matched controls were also analyzed for the same parameters.

Results: Compared with controls, acute UCM was associated with mild lymphopenia, splenomegaly, and high levels of IFN-γ, tumor necrosis factor-α, and IL-10, which normalized in convalescence. In Chikwawa, Treg counts were significantly (P < .0001) higher in convalescence compared with acute disease, whereas in Blantyre, these were as low as in healthy controls both during acute disease and in convalescence. Blantyre had a higher percentage of parasiteamic children (15% versus 12%) in convalescence compared with Chikwawa, but none of these developed symptomatic malaria during the study duration. Concentrations of TGF-β were higher at time points for the study participants and in controls from Blantyre compared with those recruited in Chikwawa.

Conclusions: The high transmission area was associated with high Tregs counts and IL-10 concentrations in convalescence, which could have an effect on parasite clearance. We recommend that children recovering from UCM, especially those from high transmission area, should sleep under insecticide-treated nets, be screened for parasitemia, and a provision of antimalarial prophylaxis should be considered.
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http://dx.doi.org/10.1093/jpids/piu140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4554200PMC
September 2015

Correlation of hemorrhage, axonal damage, and blood-tissue barrier disruption in brain and retina of Malawian children with fatal cerebral malaria.

Front Cell Infect Microbiol 2015 16;5:18. Epub 2015 Mar 16.

Department of Pathology and Laboratory Medicine, Vancouver General Hospital and University of British Columbia Vancouver, BC, Canada ; Department of Ophthalmology and Visual Science, Vancouver General Hospital and University of British Columbia Vancouver, BC, Canada.

Background: The retinal and brain histopathological findings in children who died from cerebral malaria (CM) have been recently described. Similar changes occur in both structures, but the findings have not been directly compared in the same patients. In this study, we compared clinical retinal findings and retinal and cerebral histopathological changes in a series of patients in Blantyre, Malawi, who died of CM.

Methods: The features systematically compared in the same patient were: (1) clinical, gross and microscopic retinal hemorrhages with microscopic cerebral hemorrhages, (2) retinal and cerebral hemorrhage-associated and -unassociated axonal damage, and fibrinogen leakage, and (3) differences in the above features between the pathological categories of CM without microvascular pathology (CM1) and CM with microvascular pathology (CM2) in retina and brain.

Results: Forty-seven patients were included: seven CM1, 28 CM2, and 12 controls. In the 35 malaria cases retinal and cerebral pathology correlated in all features except for non-hemorrhage associated fibrinogen leakage. Regarding CM1 and CM2 cases, the only differences were in the proportion of patients with hemorrhage-associated cerebral pathology, and this was expected, based on the definitions of CM1 and CM2. The retina did not show this difference. Non-hemorrhage associated pathology was similar for the two groups.

Comment: As postulated, histopathological features of hemorrhages, axonal damage and non-hemorrhage associated fibrinogen leakage correlated in the retina and brain of individual patients, although the difference in hemorrhages between the CM1 and CM2 groups was not consistently observed in the retina. These results help to underpin the utility of ophthalmoscopic examination and fundus findings to help in diagnosis and assessment of cerebral malaria patients, but may not help in distinguishing between CM1 and CM2 patients during life.
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http://dx.doi.org/10.3389/fcimb.2015.00018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4360761PMC
September 2015

Quantitative Assessment of Multiorgan Sequestration of Parasites in Fatal Pediatric Cerebral Malaria.

J Infect Dis 2015 Oct 7;212(8):1317-21. Epub 2015 Apr 7.

College of Osteopathic Medicine, Michigan State University, East Lansing Blantyre Malaria Project, University of Malawi College of Medicine.

Children in sub-Saharan Africa continue to acquire and die from cerebral malaria, despite efforts to control or eliminate the causative agent, Plasmodium falciparum. We present a quantitative histopathological assessment of the sequestration of parasitized erythrocytes in multiple organs obtained during a prospective series of 103 autopsies performed between 1996 and 2010 in Blantyre, Malawi, on pediatric patients who died from cerebral malaria and controls. After the brain, sequestration of parasites was most intense in the gastrointestinal tract, both in patients with cerebral malaria and those with parasitemia in other organs. Within cases of histologically defined cerebral malaria, which includes phenotypes termed "sequestration only" (CM1) and "sequestration with extravascular pathology" (CM2), CM1 was associated with large parasite numbers in the spleen and CM2 with intense parasite sequestration in the skin. A striking histological finding overall was the marked sequestration of parasitized erythrocytes across most organs in patients with fatal cerebral malaria, supporting the hypothesis that the disease is, in part, a result of a high level of total-body parasite sequestration.
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http://dx.doi.org/10.1093/infdis/jiv205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4577044PMC
October 2015

Brain swelling and death in children with cerebral malaria.

N Engl J Med 2015 Mar;372(12):1126-37

From the Department of Osteopathic Medical Specialties, College of Osteopathic Medicine (K.B.S., L.L.F., T.E.T.), Department of Radiology (M.J.P., C.A.H.), and Department of Neurology and Ophthalmology, International Neurologic and Psychiatric Epidemiology Program (G.L.B.), Michigan State University, East Lansing; the Blantyre Malaria Project (K.B.S., S.D.K., D.A.M., F.W.M., L.L.F., T.E.T.) and Malawi-Liverpool-Wellcome Trust Clinical Research Programme (R.S.H., M.E.M.), Queen Elizabeth Central Hospital (S.D.K., C.A.C.) and the Department of Anatomy (S.J.G.), University of Malawi College of Medicine - both in Blantyre, Malawi; the Department of Immunology and Infectious Diseases, Harvard School of Public Health (C.V., D.A.M.), and the Department of Pathology, Brigham and Women's Hospital (D.A.M.) - both in Boston; the Department of Radiology, University of California San Diego, San Diego (W.G.B.); and the Liverpool School of Tropical Medicine, Liverpool, United Kingdom (M.E.M.).

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.).
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http://dx.doi.org/10.1056/NEJMoa1400116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4450675PMC
March 2015

The pathogenesis of pediatric cerebral malaria: eye exams, autopsies, and neuroimaging.

Ann N Y Acad Sci 2015 Apr 23;1342:44-52. Epub 2015 Feb 23.

Department of Osteopathic Medical Specialties, College of Osteopathic Medicine, Michigan State University, East Lansing, MI; Blantyre Malaria Project, University of Malawi College of Medicine, Blantyre, Malawi.

Several advances in our understanding of pediatric cerebral malaria (CM) have been made over the past 25 years. Accurate clinical diagnosis is enhanced by the identification of a characteristic retinopathy, visible by direct or indirect ophthalmoscopy, the retinal changes (retinal whitening, vessel color changes, white-centered hemorrhages) being consistently associated with intracerebral sequestration of parasites in autopsy studies. Autopsies have yielded information at tissue levels in fatal CM, but new insights into critical pathogenetic processes have emerged from neuroimaging studies, which, unlike autopsy-based studies, permit serial observations over time and allow comparisons between fatal cases and survivors. Brain swelling has emerged as the major risk factor for death, and, among survivors, brain volume diminishes spontaneously over 24-48 hours. Studies of life-threatening and fatal malaria are suggesting new approaches to identifying and caring for those at highest risk; potential adjuvants should be evaluated and implemented where they are most needed.
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http://dx.doi.org/10.1111/nyas.12690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405463PMC
April 2015

Differential PfEMP1 expression is associated with cerebral malaria pathology.

PLoS Pathog 2014 Dec 4;10(12):e1004537. Epub 2014 Dec 4.

Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, Blantyre, Malawi; Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.

Plasmodium falciparum is unique among human malarias in its ability to sequester in post-capillary venules of host organs. The main variant antigens implicated are the P. falciparum erythrocyte membrane protein 1 (PfEMP1), which can be divided into three major groups (A-C). Our study was a unique examination of sequestered populations of parasites for genetic background and expression of PfEMP1 groups. We collected post-mortem tissue from twenty paediatric hosts with pathologically different forms of cerebral malaria (CM1 and CM2) and parasitaemic controls (PC) to directly examine sequestered populations of parasites in the brain, heart and gut. Use of two different techniques to investigate this question produced divergent results. By quantitative PCR, group A var genes were upregulated in all three organs of CM2 and PC cases. In contrast, in CM1 infections displaying high levels of sequestration but negligible vascular pathology, there was high expression of group B var. Cloning and sequencing of var transcript tags from the same samples indicated a uniformly low expression of group A-like var. Generally, within an organ sample, 1-2 sequences were expressed at dominant levels. 23% of var tags were detected in multiple patients despite the P. falciparum infections being genetically distinct, and two tags were observed in up to seven hosts each with high expression in the brains of 3-4 patients. This study is a novel examination of the sequestered parasites responsible for fatal cerebral malaria and describes expression patterns of the major cytoadherence ligand in three organ-derived populations and three pathological states.
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http://dx.doi.org/10.1371/journal.ppat.1004537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4256257PMC
December 2014

The systemic pathology of cerebral malaria in African children.

Front Cell Infect Microbiol 2014 21;4:104. Epub 2014 Aug 21.

The Blantyre Malaria Project, College of Medicine, University of Malawi Blantyre, Malawi ; Department of Osteopathic Medical Specialties, College of Osteopathic Medicine, Michigan State University East Lansing, MI, USA.

Pediatric cerebral malaria carries a high mortality rate in sub-Saharan Africa. We present our systematic analysis of the descriptive and quantitative histopathology of all organs sampled from a series of 103 autopsies performed between 1996 and 2010 in Blantyre, Malawi on pediatric cerebral malaria patients and control patients (without coma, or without malaria infection) who were clinically well characterized prior to death. We found brain swelling in all cerebral malaria patients and the majority of controls. The histopathology in patients with sequestration of parasites in the brain demonstrated two patterns: (a) the "classic" appearance (i.e., ring hemorrhages, dense sequestration, and extra-erythrocytic pigment) which was associated with evidence of systemic activation of coagulation and (b) the "sequestration only" appearance associated with shorter duration of illness and higher total burden of parasites in all organs including the spleen. Sequestration of parasites was most intense in the gastrointestinal tract in all parasitemic patients (those with cerebral malarial and those without).
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http://dx.doi.org/10.3389/fcimb.2014.00104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4139913PMC
March 2015

Reply: Retinopathy, histidine-rich protein-2 and perfusion pressure in cerebral malaria.

Brain 2014 Sep 11;137(Pt 9):e299. Epub 2014 Jun 11.

2 Department of Eye and Vision Science, University of Liverpool, UK3 St. Paul's Eye Unit, Royal Liverpool University Hospital, Liverpool, UK.

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http://dx.doi.org/10.1093/brain/awu146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4132643PMC
September 2014

Decreasing malaria prevalence and its potential consequences for immunity in pregnant women.

J Infect Dis 2014 Nov 5;210(9):1444-55. Epub 2014 May 5.

Department of Medicine Victorian Infectious Diseases Service Doherty Institute.

Background: As malaria control is intensified, pregnant women may be less exposed to malaria, thus affecting the acquisition of protective antibody.

Methods: Plasma samples were collected from Malawian and Papua New Guinean (PNG) pregnant women enrolled over 7-year periods, during which malaria prevalence fell by over two thirds. Immunoglobulin G (IgG) levels to schizont extract, merozoite antigens, and VAR2CSA-DBL5ε were measured by enzyme-linked immunosorbent assay (ELISA). Levels of IgG to variant surface antigens of infected erythrocytes (IEs) and merozoites and levels of opsonizing IgG to IEs were measured by flow cytometry.

Results: In both settings, levels of antibodies in pregnant women to recombinant antigens and to intact IEs but not of opsonizing antibodies decreased over time. After adjustment for coverage with insecticide-treated bed nets (ITNs), these differences disappeared in the Malawian cohort, whereas in the PNG cohort, time was independently associated with a decrease in several antibody responses measured by ELISA.

Conclusions: The impact of falling parasite prevalence on anti-Plasmodium falciparum serological indicators in pregnant women varies by setting. Increased ITN coverage may affect development of antibodies to recombinant antigens, but levels of opsonizing IgG remained stable over time. Opsonizing IgG against placental-binding IEs may persist, thus offering longer-lasting protection against malaria during pregnancy.
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http://dx.doi.org/10.1093/infdis/jiu264DOI Listing
November 2014

HIV-1 infection and antibodies to Plasmodium falciparum in adults.

J Infect Dis 2014 Nov 3;210(9):1407-14. Epub 2014 May 3.

Department of Medicine, Royal Melbourne Hospital, University of Melbourne Victorian Infectious Diseases Service, Royal Melbourne Hospital, Parkville, Victoria, Australia.

Background: Coinfection with human immunodeficiency virus (HIV) may increase susceptibility to malaria by compromising naturally acquired immunity.

Methods: In 339 adults (64% HIV infected), we measured antibodies to Plasmodium falciparum variant surface antigens (VSA) and antibodies that opsonise infected erythrocytes using parasite lines FCR3, E8B, and R29, and antibodies to merozoite antigens AMA-1 and MSP2. We determined the relationship between malaria antibodies, HIV infection, markers of immune compromise, and risk of incident parasitemia.

Results: HIV-infected adults had significantly lower mean levels of opsonizing antibody to all parasite lines (P < .0001), and lower levels of antibody to AMA-1 (P = .01) and MSP2 (P < .0001). Levels of immunoglobulin G (IgG) to VSA were not affected by HIV status. Opsonising antibody titres against some isolates were positively correlated with CD4 count. There were negative associations between human immunodeficiency virus type 1 (HIV-1) viral load and opsonizing antibodies to FCR3 (P = .04), and levels of IgG to AMA-1 (P ≤ .03) and MSP2-3D7 (P = .05). Lower opsonizing antibody levels on enrollment were seen in those who became parasitemic during follow-up, independent of HIV infection (P ≤ .04 for each line).

Conclusions: HIV-1 infection decreases opsonizing antibodies to VSA, and antibody to merozoite antigens. Opsonizing antibodies were associated with lack of parasitemia during follow up, suggesting a role in protection.
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http://dx.doi.org/10.1093/infdis/jiu262DOI Listing
November 2014