Publications by authors named "Terrie E Taylor"

156 Publications

School-based screening and treatment may reduce P. falciparum transmission.

Sci Rep 2021 Mar 25;11(1):6905. Epub 2021 Mar 25.

Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.

In areas where malaria remains entrenched, novel transmission-reducing interventions are essential for malaria elimination. We report the impact screening-and-treatment of asymptomatic Malawian schoolchildren (n = 364 in the rainy season and 341 in the dry season) had on gametocyte-the parasite stage responsible for human-to-mosquito transmission-carriage. We used concomitant household-based surveys to predict the potential reduction in transmission in the surrounding community. Among 253 students with P. falciparum infections at screening, 179 (71%) had infections containing gametocytes detected by Pfs25 qRT-PCR. 84% of gametocyte-containing infections were detected by malaria rapid diagnostic test. While the gametocyte prevalence remained constant in untreated children, treatment with artemether-lumefantrine reduced the gametocyte prevalence (p < 0.0001) from 51.8 to 9.7% and geometric mean gametocyte density (p = 0.008) from 0.52 to 0.05 gametocytes/microliter. In community surveys, 46% of all gametocyte-containing infections were in school-age children, who comprised only 35% of the population. Based on these estimates six weeks after the intervention, the gametocyte burden in the community could be reduced by 25-55% depending on the season and the measure used to characterize gametocyte carriage. Thus, school-based interventions to treat asymptomatic infections may be a high-yield approach to not only improve the health of schoolchildren, but also decrease malaria transmission.
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http://dx.doi.org/10.1038/s41598-021-86450-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994823PMC
March 2021

Adipose tissue parasite sequestration drives leptin production in mice and correlates with human cerebral malaria.

Sci Adv 2021 Mar 24;7(13). Epub 2021 Mar 24.

Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA.

Circulating levels of the adipokine leptin are linked to neuropathology in experimental cerebral malaria (ECM), but its source and regulation mechanism remain unknown. Here, we show that sequestration of infected red blood cells (iRBCs) in white adipose tissue (WAT) microvasculature increased local vascular permeability and leptin production. Mice infected with parasite strains that fail to sequester in WAT displayed reduced leptin production and protection from ECM. WAT sequestration and leptin induction were lost in CD36KO mice; however, ECM susceptibility revealed sexual dimorphism. Adipocyte leptin was regulated by the mechanistic target of rapamycin complex 1 (mTORC1) and blocked by rapamycin. In humans, although infection did not increase circulating leptin levels, iRBC sequestration, tissue leptin production, and mTORC1 activity were positively correlated with CM in pediatric postmortem WAT. These data identify WAT sequestration as a trigger for leptin production with potential implications for pathogenesis of malaria infection, prognosis, and treatment.
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http://dx.doi.org/10.1126/sciadv.abe2484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990332PMC
March 2021

Revisiting Co-Trimoxazole Prophylaxis for African Adults in The Era of Antiretroviral Therapy: A Randomized Controlled Clinical Trial.

Clin Infect Dis 2021 Mar 21. Epub 2021 Mar 21.

Malaria Research Program, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, United States.

Background: Daily co-trimoxazole is recommended for African adults living with HIV irrespective of antiretroviral treatment, immune status, or disease stage. Benefits of continued prophylaxis and whether co-trimoxazole can be stopped following immune reconstitution are unknown.

Methods: We conducted a randomized, controlled trial at two sites in Malawi that enrolled HIV-infected adults with undetectable viral load and CD4 count of >250/mm 3 and randomized them to continue daily co-trimoxazole, discontinue daily co-trimoxazole and begin weekly chloroquine, or discontinue daily co-trimoxazole. The primary endpoint was the preventive effect of co-trimoxazole prophylaxis against death or World Health Organization (WHO) HIV/AIDS Stage 3-4 events, using Cox proportional hazards modelling, intention to treat population.

Results: 1499 adults were enrolled. The preventive effect of co-trimoxazole on the primary endpoint was 22% (95%CI -14-47%, p=0.20) versus no prophylaxis and 25% (95%CI -10-48%, p=0.14) versus chloroquine. When WHO HIV/AIDS Stage 2 events were added to the primary endpoint, preventive effect increased to 31% (95%CI 3-51%, p=0.032) and 32% (95%CI 4-51%, p=0.026), respectively. Co-trimoxazole and chloroquine prophylaxis effectively prevented clinical malaria episodes (3.8 and 3.0, respectively, versus 28/100 person-years, p<0.001).

Conclusions: Malawian adults living with HIV who immune reconstituted on ART and continued co-trimoxazole prophylaxis experienced fewer deaths and WHO HIV/AIDS Stage 3-4 events compared to prophylaxis discontinuation, though statistical significance was not achieved. Cotrimoxazole prevented a composite of death plus WHO HIV/AIDS Stage 2-4 events. Given poor healthcare access and lack of routine viral load monitoring, co-trimoxazole prophylaxis should continue in adults on ART after immune reconstitution in sub-Saharan Africa.
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http://dx.doi.org/10.1093/cid/ciab252DOI Listing
March 2021

Population Attributable Fraction of Anemia Associated with Infection in Children in Southern Malawi.

Am J Trop Med Hyg 2021 Jan 4. Epub 2021 Jan 4.

Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland.

Anemia is a leading cause of morbidity in sub-Saharan Africa. The etiologies of anemia are multifactorial, and it is unclear what proportion of anemia is attributable to malaria in children of different ages in Malawi. We evaluated the population attributable fraction (PAF) of anemia due to malaria using multiple cross-sectional surveys in southern Malawi. We found a high prevalence of anemia, with the greatest proportion attributable to malaria among school-age children (5-15 years) in the rainy season (PAF = 18.8% [95% CI: 16.3, 21.0], compared with PAF = 5.2% [95% CI: 4.0, 6.2] among young children pooled across season [< 5 years] and PAF = 9.7% [95% CI: 6.5, 12.4] among school-age children in the dry season). Malaria control interventions will likely lead to decreases in anemia, especially among school-age children.
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http://dx.doi.org/10.4269/ajtmh.20-1120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941802PMC
January 2021

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

Submicroscopic malaria infection is not associated with fever in cross-sectional studies in Malawi.

Malar J 2020 Jun 29;19(1):233. Epub 2020 Jun 29.

Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA.

Background: Submicroscopic Plasmodium falciparum infections are widespread in many areas. However, the contribution of these infections to symptomatic malaria is not well understood. This study evaluated whether participants with submicroscopic P. falciparum infections have higher prevalence of fever than uninfected participants in southern Malawi.

Methods: A total of 16,650 children and adults were enrolled in the course of six cross-sectional surveys during the dry season (October-November) and after the rainy season (April-May) between 2012 and 2014 in three districts in southern Malawi. Demographic and socioeconomic data were collected in conjunction with data on clinical histories, use of malaria preventive measures, and anti-malarial medication taken within 2 weeks of the survey. Axillary temperatures were measured, and blood samples were collected for P. falciparum detection by microscopy and PCR. Participants without malaria parasites detected on microscopy but with a positive PCR for P. falciparum were defined as having submicroscopic infection. Fever was defined as having any one of: reported fever in the past 2 weeks, reported fever in the past 48 h, or a temperature of ≥ 37.5 °C measured at the time of interview.

Results: Submicroscopic P. falciparum infections and fever were both detected in 9% of the study population. In the final analysis adjusted for clustering within household and enumeration area, having submicroscopic P. falciparum infection was associated with reduced odds of fever in the dry season (odds ratio = 0.52; 95% CI 0.33-0.82); the association in the rainy season did not achieve statistical significance (odds ratio = 1.20; 95% CI 0.91-1.59). The association between submicroscopic infection and fever was consistent across all age groups. When the definition of fever was limited to temperature of ≥ 37.5 °C measured at the time of interview, the association was not statistically significant in either the rainy or dry season.

Conclusions: In this series of cross-sectional studies in southern Malawi, submicroscopic P. falciparum infection was not associated with increased risk of fever. Submicroscopic detection of the malaria parasite is important in efforts to decrease transmission but is not essential for the clinical recognition of malaria disease.
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http://dx.doi.org/10.1186/s12936-020-03296-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322713PMC
June 2020

Prevalence and Clinical Management of Non-malarial Febrile Illnesses among Outpatients in the Era of Universal Malaria Testing in Malawi.

Am J Trop Med Hyg 2020 08 18;103(2):887-893. Epub 2020 Jun 18.

Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland.

Increasing access to rapid diagnostic tests for malaria (mRDTs) has raised awareness of the challenges healthcare workers face in managing non-malarial febrile illnesses (NMFIs). We examined NMFI prevalence, clinical diagnoses, and prescribing practices in outpatient clinics across different malaria transmission settings in Malawi. Standardized facility-based malaria surveillance was conducted at three facilities one of every 4 weeks over 2 years. Information on demographics, presenting symptoms, temperature, clinical diagnosis, and treatment were collected from outpatients presenting with malaria-like symptoms. Of the 25,486 patients with fever, 69% had NMFI. Non-malarial febrile illness prevalence was lower in 5- to 15-year-old patients (55%) than in children < 5 years (72%) and adults > 15 years of age (77%). The most common clinical diagnoses among febrile patients with negative mRDTs in all age-groups and settings were respiratory infections (46%), sepsis (29%), gastroenteritis (13%), musculoskeletal pain (9%), and malaria (5%). Antibiotic prescribing was high in all age-groups and settings. Trimethoprim-sulfamethoxazole (40%) and amoxicillin (29%) were the most commonly prescribed antibiotics and were used for nearly all clinical diagnoses. In these settings with minimal access to diagnostic tools, patients with fever and a negative mRDT received a limited number of clinical diagnoses. Many were likely to be inaccurate and were associated with the inappropriate use of the limited range of available antibiotics. Prescription and diagnostic practices for NMFIs in the facilities require research and policy input. Resource-limited malaria-endemic countries urgently need more point-of-care diagnostic tools and evidence-based diagnosis and treatment algorithms to provide effective and cost-efficient care.
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http://dx.doi.org/10.4269/ajtmh.18-0800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410417PMC
August 2020

Parasite histones are toxic to brain endothelium and link blood barrier breakdown and thrombosis in cerebral malaria.

Blood Adv 2020 07;4(13):2851-2864

Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom.

Microvascular thrombosis and blood-brain barrier (BBB) breakdown are key components of cerebral malaria (CM) pathogenesis in African children and are implicated in fatal brain swelling. How Plasmodium falciparum infection causes this endothelial disruption and why this occurs, particularly in the brain, is not fully understood. In this study, we have demonstrated that circulating extracellular histones, equally of host and parasite origin, are significantly elevated in CM patients. Higher histone levels are associated with brain swelling on magnetic resonance imaging. On postmortem brain sections of CM patients, we found that histones are colocalized with P falciparum-infected erythrocytes sequestered inside small blood vessels, suggesting that histones might be expelled locally during parasite schizont rupture. Histone staining on the luminal vascular surface colocalized with thrombosis and leakage, indicating a possible link between endothelial surface accumulation of histones and coagulation activation and BBB breakdown. Supporting this, patient sera or purified P falciparum histones caused disruption of barrier function and were toxic to cultured human brain endothelial cells, which were abrogated with antihistone antibody and nonanticoagulant heparin. Overall, our data support a role for histones of parasite and host origin in thrombosis, BBB breakdown, and brain swelling in CM, processes implicated in the causal pathway to death. Neutralizing histones with agents such as nonanticoagulant heparin warrant exploration to prevent brain swelling in the development or progression of CM and thereby to improve outcomes.
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http://dx.doi.org/10.1182/bloodadvances.2019001258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362376PMC
July 2020

Plasma cell-free DNA predicts pediatric cerebral malaria severity.

JCI Insight 2020 06 18;5(12). Epub 2020 Jun 18.

Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.

BACKGROUNDPrediction of adverse outcomes in cerebral malaria (CM) is difficult. We hypothesized that cell-free DNA (cfDNA) levels would facilitate identification of severe and potentially fatal CM cases.METHODSIn this retrospective study, plasma from Malawian children with CM (n = 134), uncomplicated malaria (UM, n = 77), and healthy controls (HC, n = 60) was assayed for cfDNA using a fluorescence assay. Host and parasite cfDNA was measured by quantitative PCR. Immune markers were determined by ELISA, Luminex, or cytometric bead array.RESULTSTotal cfDNA increased with malaria severity (HC versus UM, P < 0.001; HC versus CM, P < 0.0001; UM versus CM, P < 0.0001), was elevated in retinopathy-positive (Ret+) CM relative to Ret- CM (7.66 versus 5.47 ng/μL, P = 0.027), and differentiated Ret+ fatal cases from survivors (AUC 0.779; P < 0.001). cfDNA levels in patients with non-malarial febrile illness (NMF, P = 0.25) and non-malarial coma (NMC, P = 0.99) were comparable with UM. Host DNA, rather than parasite DNA, was the major cfDNA contributor (UM, 268 versus 67 pg/μL; CM, 2824 versus 463 pg/μL). Host and parasite cfDNA distinguished CM by retinopathy (host, AUC 0.715, P = 0.0001; parasite, AUC 0.745, P = 0.0001), but only host cfDNA distinguished fatal cases (AUC 0.715, P = 0.0001). Total cfDNA correlated with neutrophil markers IL-8 (rs = 0.433, P < 0.0001) and myeloperoxidase (rs = 0.683, P < 0.0001).CONCLUSIONQuantifying plasma cfDNA is a simple assay useful in identifying children at risk for fatal outcome and has promise as a point-of-care assay. Elevated cfDNA suggests a link with host inflammatory pathways in fatal CM.FUNDINGNIH NCATS (AK), Burroughs-Wellcome (AK), and National Health and Medical Research Council of Australia (SJR).
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http://dx.doi.org/10.1172/jci.insight.136279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406267PMC
June 2020

Central Nervous System Virus Infection in African Children with Cerebral Malaria.

Am J Trop Med Hyg 2020 07 23;103(1):200-205. Epub 2020 Apr 23.

Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, California.

We aimed to identify the contribution of central nervous system (CNS) viral coinfection to illness in African children with retinopathy-negative or retinopathy-positive cerebral malaria (CM). We collected cerebrospinal fluid (CSF) from 272 children with retinopathy-negative or retinopathy-positive CM and selected CSF from 111 of these children (38 retinopathy positive, 71 retinopathy negative, 2 retinopathy unknown) for analysis by metagenomic next-generation sequencing. We found CSF viral coinfections in 7/38 (18.4%) retinopathy-positive children and in 18/71 (25.4%) retinopathy-negative children. Excluding HIV-1, human herpesviruses (HHV) represented 61% of viruses identified. Excluding HIV-1, CNS viral coinfection was equally likely in children who were retinopathy positive and retinopathy negative ( = 0.1431). Neither mortality nor neurological morbidity was associated with the presence of virus (odds ratio [OR] = 0.276, 95% CI: 0.056-1.363). Retinopathy-negative children with a higher temperature, lower white blood cell count, or being dehydrated were more likely to have viral coinfection. Level of consciousness at admission was not associated with CNS viral coinfection in retinopathy-negative children. Viral CNS coinfection is unlikely to contribute to coma in children with CM. The herpesviruses other than herpes simplex virus may represent incidental bystanders in CM, reactivating during acute malaria infection.
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http://dx.doi.org/10.4269/ajtmh.19-0962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356427PMC
July 2020

Amount of Brain Edema Correlates With Neurologic Recovery in Pediatric Cerebral Malaria.

Pediatr Infect Dis J 2020 04;39(4):277-282

Department of Imaging Sciences, Division of Diagnostic and Interventional Neuroradiology, University of Rochester Medical Center, Rochester, New York.

Background: Cerebral malaria (CM) remains a leading cause of mortality and morbidity in children in sub-Saharan Africa. Recent studies using brain magnetic resonance imaging have revealed increased brain volume as a major predictor of death. Similar morphometric predictors of morbidity at discharge are lacking. The aim of this study was to investigate the utility of serial cranial cisternal cerebrospinal fluid (CSF) volume measurements in predicting morbidity at discharge in pediatric CM survivors.

Methods: In this case-control study, 54 Malawian pediatric CM survivors with neurologic sequelae evident at discharge who underwent serial magnetic resonance imaging scans while comatose were matched to concurrently admitted children with serial imaging who made full recoveries. Serial cranial cisternal CSF volume quantified by radiologists blinded to outcome was evaluated as a predictor of neurologic deficits at discharge. The probability of neurologic sequelae was determined using a model that included coma duration and changes in cisternal CSF volume over time.

Results: Coma duration before admission was similar between cases and controls (16.1 vs. 15.3; P = 0.81), but overall coma was longer among children with sequelae (60 vs. 38 hours; P < 0.01). Lower initial CSF volumes and decreased volumes over time were both associated with a higher probability of neurologic sequelae at discharge.

Conclusions: Among pediatric CM survivors with prolonged coma, lower initial CSF volume and decreasing volume during coma is associated with neurologic sequelae at discharge. These findings suggest that cerebral edema is an underlying contributor to both morbidity and mortality in pediatric CM.
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http://dx.doi.org/10.1097/INF.0000000000002573DOI Listing
April 2020

CD8+ T cells target cerebrovasculature in children with cerebral malaria.

J Clin Invest 2020 03;130(3):1128-1138

Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Rockville, Maryland, USA.

BACKGROUNDCerebral malaria (CM) accounts for nearly 400,000 deaths annually in African children. Current dogma suggests that CM results from infected RBC (iRBC) sequestration in the brain microvasculature and resulting sequelae. Therapies targeting these events have been unsuccessful; findings in experimental models suggest that CD8+ T cells drive disease pathogenesis. However, these data have largely been ignored because corroborating evidence in humans is lacking. This work fills a critical gap in our understanding of CM pathogenesis that is impeding development of therapeutics.METHODSUsing multiplex immunohistochemistry, we characterized cerebrovascular immune cells in brain sections from 34 children who died from CM or other causes. Children were grouped by clinical diagnosis (CM+ or CM-), iRBC sequestration (Seqhi, Seqlo, Seq0) and HIV status (HIV+ or HIV-).RESULTSWe identified effector CD3+CD8+ T cells engaged on the cerebrovasculature in 69% of CM+ HIV- children. The number of intravascular CD3+CD8+ T cells was influenced by CM status (CM+ > CM-, P = 0.004) and sequestration level (Seqhi > Seqlo, P = 0.010). HIV coinfection significantly increased T cell numbers (P = 0.017) and shifted cells from an intravascular (P = 0.004) to perivascular (P < 0.0001) distribution.CONCLUSIONWithin the studied cohort, CM is associated with cerebrovascular engagement of CD3+CD8+ T cells, which is exacerbated by HIV coinfection. Thus, CD3+CD8+ T cells are highly promising targets for CM adjunctive therapy, opening new avenues for the treatment of this deadly disease.FUNDINGThis research was supported by the Intramural Research Program of the National Institutes of Health.
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http://dx.doi.org/10.1172/JCI133474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269583PMC
March 2020

A clinical trial of enteral Levetiracetam for acute seizures in pediatric cerebral malaria.

BMC Pediatr 2019 11 1;19(1):399. Epub 2019 Nov 1.

Blantyre Malaria Project, Blantyre, Malawi.

Background: Acute seizures are common in pediatric cerebral malaria (CM), but usual care with phenobarbital risks respiratory suppression. We undertook studies of enteral levetiracetam (eLVT) to evaluate pharmacokinetics (PK), safety and efficacy including an open-label, randomized controlled trial (RCT) comparing eLVT to phenobarbital.

Methods: Children 24-83 months old with CM were enrolled in an eLVT dose-finding study starting with standard dose (40 mg/kg load, then 30 mg/kg Q12 hours) titrated upward until seizure freedom was attained in 75% of subjects. The RCT that followed randomized children to eLVT vs. phenobarbital for acute seizures and compared the groups on minutes with seizures based upon continuous electroencephalogram. Due to safety concerns, midway through the study children allocated to phenobarbital received the drug only if they continued to have seizures (either clinically or electrographically) after benzodiazepine treatment. Secondary outcomes were treatment failure requiring cross over, coma duration and neurologic sequelae at discharge. PK and safety assessments were also undertaken.

Results: Among 30 comatose CM children, eLVT was rapidly absorbed and well-tolerated. eLVT clearance was lower in patients with higher admission serum creatinine (SCr), but overall PK parameters were similar to prior pediatric PK studies. Within 4 h of the first dose, 90% reached therapeutic levels (> 20 μg/mL) and all were above 6 μg/mL. 7/7 children achieved seizure freedom on the initial eLVT dose. Comparing 23 eLVT to 21 phenobarbital patients among whom 15/21 received phenobarbital, no differences were seen for minutes with seizure, seizure freedom, coma duration, neurologic sequelae or death, but eLVT was safer (p = 0.019). Phenobarbital was discontinued in 3/15 due to respiratory side effects.

Conclusion: Enteral LVT offers an affordable option for seizure control in pediatric CM and is safer than phenobarbital.

Trial Registration: NCT01660672 . NCT01982812 .
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http://dx.doi.org/10.1186/s12887-019-1766-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824014PMC
November 2019

Net age, but not integrity, may be associated with decreased protection against Plasmodium falciparum infection in southern Malawi.

Malar J 2019 Sep 24;18(1):329. Epub 2019 Sep 24.

Center for Vaccine Development and Global Health, University of Maryland School of Medicine, 685 W, Baltimore Street, Baltimore, MD, 21201, USA.

Background: Distribution campaigns for insecticide-treated nets (ITN) have increased the use of ITNs in Malawi, but malaria prevalence remains high even among those using the nets. Previous studies have addressed ITN ownership, insecticide resistance, and frequency of ITN use as possible contributing factors to the high prevalence of malaria infection despite high ITN coverage, but have rarely considered whether the condition of the ITN, or how many people use it, impacts efficacy. This study assessed how ITN integrity, ITN age, and the number of persons sharing a net might mitigate or reduce protective efficacy among self-identified ITN users in Malawi.

Methods: From 2012 to 2014, six cross-sectional surveys were conducted in both the rainy and dry seasons in southern Malawi. Data were collected on ITN use, integrity (number and size of holes), and age. Blood samples for detecting Plasmodium falciparum infection were obtained from reported ITN users over 6 months of age. Generalized linear mixed models were used to account for clustering at the household and community level. The final model controlled for gender, household eaves, and community-level infection prevalence during the rainy season.

Results: There were 9646 ITN users with blood samples across six surveys, 15% of whom tested positive for P. falciparum infection. Among children under 5 years old, there was a 50% increased odds of P. falciparum infection among those sleeping under an ITN older than two years, compared to those using an ITN less than 2 years old (OR = 1.50; 95% CI 1.07-2.08). ITN integrity and number of individuals sharing an ITN were not associated with P. falciparum infection.

Conclusions: Older ITNs were associated with higher rates of P. falciparum in young children, which may indicate that insecticide concentrations play a larger role in infection prevention than the physical barrier of an ITN. ITN use was self-reported and the integrity measures lacked the precision of newer methods, suggesting a need for objective measures of ITN use and more precise assessment of ITN integrity.
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http://dx.doi.org/10.1186/s12936-019-2930-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760057PMC
September 2019

Comparison of CD8 T Cell Accumulation in the Brain During Human and Murine Cerebral Malaria.

Front Immunol 2019 24;10:1747. Epub 2019 Jul 24.

Faculty of Biology, Medicine and Health, The Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, United Kingdom.

CD8 T cells have been shown to play a critical role in the pathogenesis of experimental cerebral malaria (ECM) in mice, but their role in development of human cerebral malaria (HCM) remains unclear. Thus, in this study we have provided the first direct contrast of the accumulation of CD8 T cells in the brain during HCM and ECM. HCM cases were from children who died of cerebral malaria at Queen Elizabeth Central Hospital (Malawi) between 2003 and 2010. ECM was induced by infecting C57BL/6J mice with ANKA. We demonstrate similarities in the intracerebral CD8 T cell responses in ECM and HCM, in particular an apparent shared choroid plexus-meningeal route of CD8 T cell accumulation in the brain. Nevertheless, we also reveal some potentially important differences in compartmentalization of CD8 T cells within the cerebrovascular bed in HCM and ECM.
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http://dx.doi.org/10.3389/fimmu.2019.01747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668485PMC
October 2020

Impact of Multiplicity of Infection on Clinical Disease in Malawi.

Am J Trop Med Hyg 2019 08;101(2):412-415

Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland.

Multiplicity of infection (MOI), the number of unique parasite genotypes found in one infected individual, may contribute to the development of clinical malaria disease. However, the independent contribution of MOI and parasite density to clinical disease has not been well characterized. We conducted a two-year longitudinal cohort study of adults and children in a high-transmission setting in Malawi to test the hypothesis that increased MOI was independently associated with clinical disease, after accounting for parasite density. Of 1,062 episodes of infection, 477 (44.9%) were associated with symptoms. After controlling for repeated measures within an individual, key demographic factors, and parasite density, there was no association between MOI and clinical disease (OR = 1.02, 95% CI: 0.70-1.51). Although the limited ability to discern MOI in low-density asymptomatic infections may have impacted our results, we conclude that MOI is not an independent risk factor for clinical disease.
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http://dx.doi.org/10.4269/ajtmh.19-0093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685583PMC
August 2019

Binding Heterogeneity of Plasmodium falciparum to Engineered 3D Brain Microvessels Is Mediated by EPCR and ICAM-1.

mBio 2019 05 28;10(3). Epub 2019 May 28.

Seattle Children's Research Institute, Seattle, Washington, USA

Cerebral malaria is a severe neurological complication associated with sequestration of -infected erythrocytes (IE) in the brain microvasculature, but the specific binding interactions remain under debate. Here, we have generated an engineered three-dimensional (3D) human brain endothelial microvessel model and studied binding under the large range of physiological flow velocities that occur in both health and disease. Perfusion assays on 3D microvessels reveal previously unappreciated phenotypic heterogeneity in parasite binding to tumor necrosis factor alpha (TNF-α)-activated brain endothelial cells. While clonal parasite lines expressing a group B erythrocyte membrane protein 1 (PfEMP1) present an increase in binding to activated 3D microvessels, IE expressing DC8-PfEMP1 present a decrease in binding. The differential response to endothelium activation is mediated by surface expression changes of endothelial protein C receptor (EPCR) and intercellular adhesion molecule 1 (ICAM-1). These findings demonstrate heterogeneity in parasite binding and provide evidence for a parasite strategy to adapt to a changing microvascular environment during infection. The engineered 3D human brain microvessel model provides new mechanistic insight into parasite binding and opens opportunities for further studies on malaria pathogenesis and parasite-vessel interactions. Cerebral malaria research has been hindered by the inaccessibility of the brain. Here, we have developed an engineered 3D human brain microvessel model that mimics the blood flow rates and architecture of small blood vessels to study how infected human erythrocytes attach to brain endothelial cells. By studying parasite lines with different adhesive properties, we show that the malaria parasite binding rate is heterogeneous and strongly influenced by physiological differences in flow and whether the endothelium has been previously activated by TNF-α, a proinflammatory cytokine that is linked to malaria disease severity. We also show the importance of human EPCR and ICAM-1 in parasite binding. Our model sheds new light on how binds within brain microvessels and provides a powerful method for future investigations of recruitment of human brain pathogens to the blood vessel lining of the brain.
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http://dx.doi.org/10.1128/mBio.00420-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538777PMC
May 2019

Meta-analysis of Plasmodium falciparum Signatures Contributing to Severe Malaria in African Children and Indian Adults.

mBio 2019 04 30;10(2). Epub 2019 Apr 30.

Seattle Children's Research Institute, Seattle, Washington, USA

The clinical presentation of severe malaria differs between children and adults, but the mechanistic basis for this remains unclear. Contributing factors to disease severity include total parasite biomass and the diverse cytoadhesive properties mediated by the polymorphic gene parasite ligand family displayed on infected erythrocytes. To explore these factors, we performed a multicohort analysis of the contribution of expression and parasite biomass to severe malaria in two previously published pediatric cohorts in Tanzania and Malawi and an adult cohort in India. Machine learning analysis revealed independent and complementary roles for adhesion types and parasite biomass in adult and pediatric severe malaria and showed that similar profiles, including upregulation of group A and DC8 , predict severe malaria in adults and children. Among adults, patients with multiorgan complications presented infections with significantly higher parasite biomass without significant differences in adhesion types. Conversely, pediatric patients with specific complications showed distinct signatures. Cerebral malaria patients showed broadly increased expression of genes, in particular group A and DC8 , while children with severe malaria anemia were classified based on high transcription of DC8 only. This study represents the first large multisite meta-analysis of expression, and it demonstrates the presence of common profiles in severe malaria patients of different ages across distant geographical sites, as well as syndrome-specific disease signatures. The complex associations between parasite biomass, adhesion type, and clinical presentation revealed here represent the most comprehensive picture so far of the relationship between cytoadhesion, parasite load, and clinical syndrome. malaria can cause multiple disease complications that differ by patient age. Previous studies have attempted to address the roles of parasite adhesion and biomass in disease severity; however, these studies have been limited to single geographical sites, and there is limited understanding of how parasite adhesion and biomass interact to influence disease manifestations. In this meta-analysis, we compared parasite disease determinants in African children and Indian adults. This study demonstrates that parasite biomass and specific subsets of genes are independently associated with detrimental outcomes in both childhood and adult malaria. We also explored how parasite adhesion types and biomass play different roles in the development of specific severe malaria pathologies, including childhood cerebral malaria and multiorgan complications in adults. This work represents the largest study to date of the role of both adhesion types and biomass in severe malaria.
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http://dx.doi.org/10.1128/mBio.00217-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6495371PMC
April 2019

Barriers and Facilitators to Obtaining Informed Consent in a Critical Care Pediatric Research Ward in Southern Malawi.

J Empir Res Hum Res Ethics 2019 04;14(2):152-168

3 Northern Arizona University, Flagstaff, AZ, USA.

Informed consent is an ethical requirement in clinical research. Obtaining informed consent is challenging in resource-constrained settings. We report results of a formative qualitative study that examined factors that facilitate and hinder informed consent for clinical research among critically ill children in Malawi. We argue that truly informed consent in a pediatric intensive care unit (PICU) is challenged by parental distress, time constraints when balancing care for critically ill patients with research-related tasks, and social hierarchies and community mistrust toward certain research procedures. We interviewed health care providers and parents of children attending a critical care unit to identify potential challenges and solicit strategies for addressing them. Providers and caregivers suggested practical solutions to enhance research participant understanding of clinical trial research, including the use of visual materials, community engagement strategies, and using patients as advocates in promoting understanding of research procedures.
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http://dx.doi.org/10.1177/1556264619830859DOI Listing
April 2019

Neurodevelopmental Impairments 1 Year After Cerebral Malaria.

Pediatrics 2019 02 29;143(2). Epub 2019 Jan 29.

Department of Osteopathic Medical Specialties, College of Osteopathic Medicine, Michigan State University, East Lansing, Michigan.

: media-1vid110.1542/5972295739001PEDS-VA_2018-1026 BACKGROUND AND OBJECTIVES: Cerebral malaria (CM) causes significant mortality and morbidity in sub-Saharan African children. Reliable morbidity estimates are scarce because of methodological variability across studies. We describe the incidence, course, and severity of neurodevelopmental impairments in survivors of CM and the associated patient characteristics to inform epidemiologic estimates of malaria morbidity rates and prevention and treatment efforts.

Methods: We conducted an exposure-control study of 85 survivors of CM and 100 age-matched patients in a control group who were enrolled at hospital discharge and assessed after 1, 6, and 12 months using caregiver interviews and standardized developmental, cognitive, and behavioral measures.

Results: Developmental or cognitive impairment (<10th percentile of the control distribution) and/or new onset of caregiver-reported behavior problems occurred in 53% of case patients compared with 20% of the patients in the control group (odds ratio 4.5; 95% CI: 2.4 to 8.6; < .001). In case patients, developmental or cognitive impairment at the 12-month assessment was associated with HIV-positive status and short stature at presentation, more prolonged fever and coma during admission, and severe atrophy or multifocal abnormalities being found on MRI at the 1-month assessment.

Conclusions: One-half of survivors of CM were neurodevelopmentally impaired at the 1-year assessment. With these results, we support prevention trials of acute, neuroprotective interventions and the allocation of resources to evaluation, education, and rehabilitation efforts to reduce the significant long-term burden of CM-associated impairments on families and their communities.
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http://dx.doi.org/10.1542/peds.2018-1026DOI Listing
February 2019

Cerebral malaria is associated with differential cytoadherence to brain endothelial cells.

EMBO Mol Med 2019 02;11(2)

Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool, UK

Sequestration of -infected erythrocytes (IE) within the brain microvasculature is a hallmark of cerebral malaria (CM). Using a microchannel flow adhesion assay with TNF-activated primary human microvascular endothelial cells, we demonstrate that IE isolated from Malawian paediatric CM cases showed increased binding to brain microvascular endothelial cells compared to IE from uncomplicated malaria (UM) cases. Further, UM isolates showed significantly greater adhesion to dermal than to brain microvascular endothelial cells. The major mediator of parasite adhesion is erythrocyte membrane protein 1, encoded by genes. Higher levels of gene transcripts predicted to bind host endothelial protein C receptor (EPCR) and ICAM-1 were detected in CM isolates. These data provide further evidence for differential tissue binding in severe and uncomplicated malaria syndromes, and give additional support to the hypothesis that CM pathology is based on increased cytoadherence of IE in the brain microvasculature.
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http://dx.doi.org/10.15252/emmm.201809164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365927PMC
February 2019

Challenges in Treatment for Fever among School-Age Children and Adults in Malawi.

Am J Trop Med Hyg 2019 02;100(2):287-295

Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland.

Prompt and effective treatment is key to malaria control and prevention, as it reduces disease morbidity and mortality and minimizes the number of transmission reservoirs. Transmission reduction may be particularly important among school-age children (SAC, 5-15 years old), who have the highest prevalence of infection in southern Malawi. We hypothesized that one factor contributing to this difference in prevalence is that SAC are less likely to seek appropriate treatment for fever than children younger than 5 years. In this study, we assessed treatment-seeking behaviors of people of all ages between 2012 and 2014 in Malawi. During each of the five cross-sectional surveys, all members of ∼900 households reported on fever and treatment-seeking in the previous 2 weeks. Multilevel logistic regression was used to analyze predictors of whether febrile people sought treatment and whether they did so at formal (government/private clinics) or informal sources (primarily shops). Twenty-two percent of participants (3,579/16,621) reported fever, and 2,715 of those (75.9%) sought treatment. Seeking treatment exclusively from local shops remains a common practice, although use of recommended diagnostic testing and antimalarial drugs was infrequently reported there. Although SAC were not significantly less likely than children aged < 5 years to seek treatment, SAC and adults (age ≥ 16 years) were significantly less likely to use formal sources. Our results indicate that encouraging treatment at government/private clinics and increasing retail access to appropriate antimalarial testing and treatment, especially among SAC, could help remedy inadequate treatment of symptomatic disease and potentially reduce transmission in Malawi.
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http://dx.doi.org/10.4269/ajtmh.18-0687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367621PMC
February 2019

Association Between Age and Plasmodium falciparum Infection Dynamics.

Am J Epidemiol 2019 01;188(1):169-176

Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland.

Few data exist on the incidence or duration of natural Plasmodium falciparum infections in high-transmission settings. School-aged children (SAC) carry a disproportionate burden of infections, suggesting either increased incidence or increased duration. We estimated the incidence and duration of unique infections according to age groups. The Mfera Cohort Study (2014-2017) in Malawi had 2 years of follow-up, with 120 participants tested monthly and during sick visits. Blood samples were collected to detect P. falciparum by microscopy and polymerase chain reaction. Positive samples underwent genotyping. Simulation was used to account for high rates of nondetection of infection among low-parasitemia infections, which increase in frequency with age. Adults had significantly fewer unique infections per person per year (median, 2.5) compared with SAC and children younger than 5 years of age (6.3 and 6.6, respectively). Over half of all genotypes were persistent. Infections lasted significantly longer in adults (median, 180 days) and SAC (median, 163 days) compared with children younger than 5 years of age (median, 97 days), after accounting for age-dependent nondetection of infection. SAC acquired new infections at the same rate as children younger than 5 years, but they maintained these infections for longer periods of time, similar to adults. This study provides new insights into P. falciparum infection dynamics that should be considered when designing malaria control strategies.
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http://dx.doi.org/10.1093/aje/kwy213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321803PMC
January 2019

Clinical Implications of Asymptomatic Plasmodium falciparum Infections in Malawi.

Clin Infect Dis 2019 01;68(1):106-112

Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore.

Background: Asymptomatic Plasmodium falciparum infections are common in Malawi; however, the implications of these infections for the burden of malaria illness are unknown. Whether asymptomatic infections eventually progress to malaria illness, persist without causing symptoms, or clear spontaneously remains undetermined. We identified asymptomatic infections and evaluated the associations between persistent asymptomatic infections and malaria illness.

Methods: Children and adults (N = 120) who presented at a health facility with uncomplicated malaria were followed monthly for 2 years. During follow-up visits, participants with malaria symptoms were tested and, if positive, treated. Samples from all visits were tested for parasites using both microscopy and polymerase chain reaction, and all malaria infections underwent genotyping. Cox frailty models were used to estimate the temporal association between asymptomatic infections and malaria illness episodes. Mixed models were used to estimate the odds of clinical symptoms associated with new versus persistent infections.

Results: Participants had a median follow-up time of 720 days. Asymptomatic infections were detected during 23% of visits. Persistent asymptomatic infections were associated with decreased risk of malaria illness in all ages (hazard ratio 0.50, P < .001). When asymptomatic infections preceded malaria illness, newly-acquired infections were detected at 92% of subsequent clinical episodes, independent of presence of persistent infections. Malaria illness among children was more likely due to newly-acquired infections (odds ratio, 1.4; 95% confidence interval, 1.3-1.5) than to persistent infections.

Conclusions: Asymptomatic P. falciparum infections are associated with decreased incidence of malaria illness, but do not protect against disease when new infection occurs.
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http://dx.doi.org/10.1093/cid/ciy427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293006PMC
January 2019

Admission EEG findings in diverse paediatric cerebral malaria populations predict outcomes.

Malar J 2018 May 22;17(1):208. Epub 2018 May 22.

Epilepsy Division, Department of Neurology, University of Rochester, 265 Crittenden Blvd, CU 420694, Rochester, NY, 14642, USA.

Background: Electroencephalography at hospital presentation may offer important insights regarding prognosis that can inform understanding of cerebral malaria (CM) pathophysiology and potentially guide patient selection and risk stratification for future clinical trials. Electroencephalogram (EEG) findings in children with CM in Uganda and Malawi were compared and associations between admission EEG findings and outcome across this diverse population were assessed. Demographic, clinical and admission EEG data from Ugandan and Malawian children admitted from 2009 to 2012 with CM were gathered, and survivors assessed for neurological abnormalities at discharge.

Results: 281 children were enrolled (Uganda n = 122, Malawi n = 159). The Malawian population was comprised only of retinopathy positive children (versus 72.5% retinopathy positive in Uganda) and were older (4.2 versus 3.7 years; p = 0.046), had a higher HIV prevalence (9.0 versus 2.8%; p = 0.042), and worse hyperlactataemia (7.4 versus 5.2 mmol/L; p < 0.001) on admission compared to the Ugandan children. EEG findings differed between the two groups in terms of average voltage and frequencies, reactivity, asymmetry, and the presence/absence of sleep architecture. In univariate analyses pooling EEG and outcomes data for both sites, higher average and maximum voltages, faster dominant frequencies, and retained reactivity were associated with survival (all p < 0.05). Focal slowing was associated with death (OR 2.93; 95% CI 1.77-7.30) and a lower average voltage was associated with neurological morbidity in survivors (p = 0.0032).

Conclusions: Despite substantial demographic and clinical heterogeneity between subjects in Malawi and Uganda as well as different EEG readers at each site, EEG findings on admission predicted mortality and morbidity. For CM clinical trials aimed at decreasing mortality or morbidity, EEG may be valuable for risk stratification and/or subject selection.
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http://dx.doi.org/10.1186/s12936-018-2355-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5963073PMC
May 2018

Simulation models predict that school-age children are responsible for most human-to-mosquito Plasmodium falciparum transmission in southern Malawi.

Malar J 2018 Apr 3;17(1):147. Epub 2018 Apr 3.

Department of Epidemiology, School of Public Health, University of Michigan, M5507 SPH II, 1415 Washington Heights, Ann Arbor, MI, 48109, USA.

Background: Malaria persists in some high-transmission areas despite extensive control efforts. Progress toward elimination may require effective targeting of specific human populations that act as key transmission reservoirs.

Methods: Parameterized using molecular-based Plasmodium falciparum infection data from cross-sectional community studies in southern Malawi, a simulation model was developed to predict the proportions of human-to-mosquito transmission arising from (a) children under 5 years old (U5s), (b) school-age children (SAC, 5-15 years), (c) young adults (16-30 years), and (d) adults > 30 years. The model incorporates mosquito biting heterogeneity and differential infectivity (i.e. probability that a blood-fed mosquito develops oocysts) by age and gametocyte density.

Results: The model predicted that SAC were responsible for more than 60% of new mosquito infections in both dry and rainy seasons, even though they comprise only 30% of this southern Malawi population. Young adults were the second largest contributors, while U5s and adults over 30 were each responsible for < 10% of transmission. While the specific predicted values are sensitive to the relative infectiousness of SAC, this group remained the most important contributor to mosquito infections under all realistic estimates.

Conclusions: These results suggest that U5 children play a small role compared to SAC in maintaining P. falciparum transmission in southern Malawi. Models that assume biting homogeneity overestimate the importance of U5s. To reduce transmission, interventions will need to reach more SAC and young adults. This publicly available model can be used by others to estimate age-specific transmission contributions in epidemiologically similar sites with local parameter estimates of P. falciparum prevalence and bed net use.
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http://dx.doi.org/10.1186/s12936-018-2295-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5883608PMC
April 2018

Noninvasive measures of brain edema predict outcome in pediatric cerebral malaria.

Surg Neurol Int 2018 1;9:53. Epub 2018 Mar 1.

Blantyre Malaria Project, University of Malawi College of Medicine, Chichiri, Blantyre, Malawi.

Background: Increased brain volume (BV) and subsequent herniation are strongly associated with death in pediatric cerebral malaria (PCM), a leading killer of children in developing countries. Accurate noninvasive measures of BV are needed for optimal clinical trial design. Our objectives were to examine the performance of six different magnetic resonance imaging (MRI) BV quantification measures for predicting mortality in PCM and to review the advantages and disadvantages of each method.

Methods: Receiver operator characteristics were generated from BV measures of MRIs of children admitted to an ongoing research project with PCM between 2009 and 2014. Fatal cases were matched to the next available survivor. A total of 78 MRIs of children aged 5 months to 13 years (mean 4.0 years), of which 45% were males, were included.

Results: Areas under the curve (AUC) with 95% confidence interval on measures from the initial MRIs were: Radiologist-derived score = 0.69 (0.58-0.79; = 0.0037); prepontine cistern anteroposterior (AP) dimension = 0.70 (0.56-0.78; = 0.0133); SamKam ratio [Rt. parietal lobe height/(prepontine AP dimension + fourth ventricle AP dimension)] = 0.74 (0.63-0.83; = 0.0002); and global cerebrospinal fluid (CSF) space ascertained by ClearCanvas = 0.67 (0.55-0.77; = 0.0137). For patients with serial MRIs ( = 37), the day 2 global CSF space AUC was 0.87 (0.71-0.96; < 0.001) and the recovery factor (CSF volume day 2/CSF volume day 1) was 0.91 (0.76-0.98; < 0.0001). Poor prognosis is associated with radiologist score of ≥7; prepontine cistern dimension ≤3 mm; cisternal CSF volume ≤7.5 ml; SamKam ratio ≥6.5; and recovery factor ≤0.75.

Conclusion: All noninvasive measures of BV performed well in predicting death and providing a proxy measure for brain volume. Initial MRI assessment may inform future clinical trials for subject selection, risk adjustment, or stratification. Measures of temporal change may be used to stage PCM.
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http://dx.doi.org/10.4103/sni.sni_297_17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5858047PMC
March 2018

A targeted approach for routine viral load monitoring in Malawian adults on antiretroviral therapy.

Trop Med Int Health 2018 05 30;23(5):526-532. Epub 2018 Mar 30.

Division of Malaria Research, Institute for Global Health, University of Maryland School of Medicine, Baltimore, MD, USA.

Objectives: WHO recommends HIV viral load (VL) testing 6 months after antiretroviral therapy (ART) initiation and every 12 months thereafter, but cost prohibits routine, universal VL testing in many developing countries. We sought to devise a targeted approach to routine VL monitoring that could reduce cost and identify those at low risk for virologic failure (VF).

Methods: We analysed screening data from a clinical trial enrolling adults on ART in Malawi. We identified risk factors associated with VF and employed the Knill-Jones method to assign summary score identifying persons at lower risk for VF.

Results: Among 957 adults, prevalence of VF was 9.4%. Factors independently associated with VF included age <38 years (OR 3.44, 95% CI 2.01-5.89), ART duration >2.5 years (OR 2.98, 95% CI 1.79-4.96), ART adherence <95% (OR 1.76, 95% CI 1.06-2.94), CD4 count <200 cells/μl (OR 5.94, 95% CI 3.27-10.78), haemoglobin <13 g/dl (OR 2.76, 95% CI 1.70-4.50) and CD8 count >885 cells/μl (OR 2.10, 95% CI 1.28-3.44). Our VF prediction summary score included all factors above except CD8 count and was fairly accurate with validated area under receiver operating characteristic curve of 0.76. Implementation could reduce VL testing by 65%.

Conclusion: A simple score incorporating age, ART duration and adherence, and CD4 count can accurately identify adults at low risk for VF in a sub-Saharan African setting. In areas with high ART utilisation and limited VL testing capacity, a targeted approach could optimise routine VL monitoring while identifying adults in need of alternate ART regimens.
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http://dx.doi.org/10.1111/tmi.13047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932246PMC
May 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

1.5 Tesla Magnetic Resonance Imaging to Investigate Potential Etiologies of Brain Swelling in Pediatric Cerebral Malaria.

Am J Trop Med Hyg 2018 02 4;98(2):497-504. Epub 2018 Jan 4.

Epilepsy Care Team, Chikankata Hospital, Mazabuka, Zambia.

The hallmark of pediatric cerebral malaria (CM) is sequestration of parasitized red blood cells in the cerebral microvasculature. Malawi-based research using 0.35 Tesla (T) magnetic resonance imaging (MRI) established that severe brain swelling is associated with fatal CM, but swelling etiology remains unclear. Autopsy and clinical studies suggest several potential etiologies, but limitations of 0.35 T MRI precluded optimal investigations into swelling pathophysiology. A 1.5 T MRI in Zambia allowed for further investigations including susceptibility-weighted imaging (SWI). SWI is an ideal sequence for identifying regions of sequestration and microhemorrhages given the ferromagnetic properties of hemozoin and blood. Using 1.5 T MRI, Zambian children with retinopathy-confirmed CM underwent imaging with SWI, T2, T1 pre- and post-gadolinium, diffusion-weighted imaging (DWI) with apparent diffusion coefficients and T2/fluid attenuated inversion recovery sequences. Sixteen children including two with moderate/severe edema were imaged; all survived. Gadolinium extravasation was not seen. DWI abnormalities spared the gray matter suggesting vasogenic edema with viable tissue rather than cytotoxic edema. SWI findings consistent with microhemorrhages and parasite sequestration co-occurred in white matter regions where DWI changes consistent with vascular congestion were seen. Imaging findings consistent with posterior reversible encephalopathy syndrome were seen in children who subsequently had a rapid clinical recovery. High field MRI indicates that vascular congestion associated with parasite sequestration, local inflammation from microhemorrhages and autoregulatory dysfunction likely contribute to brain swelling in CM. No gross radiological blood brain barrier breakdown or focal cortical DWI abnormalities were evident in these children with nonfatal CM.
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http://dx.doi.org/10.4269/ajtmh.17-0309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929182PMC
February 2018