Effect of transmission setting and mixed species infections on clinical measures of malaria in Malawi

<p>Background: In malaria endemic regions people are commonly infected with multiple species of malaria parasites but the clinical impact of these Plasmodium co-infections is unclear. Differences in transmission seasonality and transmission intensity between endemic regions have been suggested as important factors in determining the effect of multiple species co-infections.</p> <p>Principal Findings: In order to investigate the impact of multiple-species infections on clinical measures of malaria we carried out a cross-sectional community survey in Malawi, in 2002. We collected clinical and parasitological data from 2918 participants aged >6 months, and applied a questionnaire to measure malaria morbidity. We examined the effect of transmission seasonality and intensity on fever, history of fever, haemoglobin concentration ([Hb]) and parasite density, by comparing three regions: perennial transmission (PT), high intensity seasonal transmission (HIST) and low intensity seasonal transmission (LIST). These regions were defined using multi-level modelling of PCR prevalence data and spatial and geo-climatic measures. The three Plasmodium species (P. falciparum, P. malariae and P. ovale) were randomly distributed amongst all children but not adults in the LIST and PT regions. Mean parasite density in children was lower in the HIST compared with the other two regions. Mixed species infections had lower mean parasite density compared with single species infections in the PT region. Fever rates were similar between transmission regions and were unaffected by mixed species infections. A history of fever was associated with single species infections but only in the HIST region. Reduced mean [Hb] and increased anaemia was associated with perennial transmission compared to seasonal transmission. Children with mixed species infections had higher [Hb] in the HIST region.</p> <p>Conclusions: Our study suggests that the interaction of Plasmodium co-infecting species can have protective effects against some clinical outcomes of malaria but that this is dependent on the seasonality and intensity of malaria transmission.</p&gt

Methods for detecting PER2::LUCIFERASE bioluminescence rhythms in freely moving mice [preprint]

Circadian rhythms are driven by daily oscillations of gene expression. An important tool for studying cellular and tissue rhythms is the use of a gene reporter, such as bioluminescence from the reporter gene luciferase controlled by a rhythmically expressed gene of interest. Here we describe methods that allow measurement of bioluminescence from a freely-moving mouse housed in a standard cage. Using a LumiCycle In Vivo (Actimetrics), we determined conditions that allow detection of circadian rhythms of bioluminescence from the PER2 reporter, PER2::LUC, in freely behaving mice. We tested delivery of D-luciferin via a subcutaneous minipump and in the drinking water. Further, we demonstrate that a synthetic luciferase substrate, CycLuc1, can support circadian rhythms of bioluminescence, even when delivered at a lower concentration than D-luciferin. We share our analysis scripts and suggestions for further improvements in this method. This approach will be straightforward to apply to mice with tissue-specific reporters, allowing insights into responses of specific peripheral clocks to perturbations such as environmental or pharmacological manipulations

Population pharmacokinetics of sulfadoxine and pyrimethamine in Malawian children with malaria.

In addition to parasite resistance, inadequate levels of exposure to antimalarial drugs may contribute to treatment failure. We developed population pharmacokinetic (PK) models to describe the distribution of sulfadoxine (SDX) and pyrimethamine (PYM) in children with uncomplicated malaria in Malawi. The concentration levels of antimalarial drugs in whole blood were determined using high-performance liquid chromatography. We found no evidence of underdosing in children as compared with adults; the children had drug exposure levels similar to those described in adults. Treatment failure was more likely in children with lower PYM concentrations on day 14 (P = 0.024), and there was a trend for lower SDX concentrations on day 14 (P = 0.061). SDX and PYM concentrations at levels predictive of treatment failure have been identified at day 14. Less than one-third of the children displayed drug concentration levels above these thresholds after receiving the recommended SDX-pyrimethamine (SP) dose. Our findings suggest that PK factors contributed to the observed high rate of treatment failure, and we therefore recommend a higher SP dose for children under the age of 5 years

Opsonic phagocytosis of Streptococcus pneumoniae by alveolar macrophages is not impaired in HIV-infected Malawian adults

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Bacterial meningitis in Malawian adults: pneumococcal disease is common, severe, and seasonal

We prospectively collected laboratory details and outcome data on all patients with laboratory-confirmed cases of meningitis that presented to our unit in Blantyre, Malawi, from 1 April 1998 through 31 March 1999. There were 502 patients with cases of meningitis; the most common causative organisms were Cryptococcus neoformans and Streptococcus pneumoniae. This pattern probably reflects the local human immunodeficiency virus (HIV) seroprevalence (31%) and is different from the pattern in 1974, when Neisseria meningitidis was the most common isolate. There has been an 8-fold increase in the number of meningitis cases per year since 1974, and a doubling of the percentage of medical admissions due to meningitis. The inpatient mortality rate among patients with cases of pneumococcal meningitis was 61%, and in the group as a whole was 41%. Despite the HIV-related pattern of infecting pathogens among these cases of meningitis and the increased incidence of the condition, there was evidence that the typical seasonal pattern of pneumococcal meningitis, which peaks in the cold, dry season, was preserved.</p

Erythropoiesis in HIV-infected and uninfected Malawian children with severe anemia

Anemia is common in HIV infection, but the pathophysiology is poorly understood. Bone marrow analysis in 329 severely anemic (hemoglobi

A community-based study of the incidence of trimethoprim-sulfamethoxazole-preventable infections in Malawian adults living with HIV.

Item does not contain fulltextThe benefits of trimethoprim-sulfamethoxazole (TS) prophylaxis reported for persons living with HIV in Cote d'Ivoire are difficult to extrapolate to sub-Saharan African countries where bacterial resistance to TS is higher and cross-resistance between TS and sulfadoxine-pyrimethamine (SP) may impair SP efficacy for malaria treatment. We conducted a community-based cohort study to measure the incidence of potentially TS-preventable illnesses in Blantyre, Malawi. We found a high incidence of malaria, invasive bacterial infections, and probable bacterial pneumonias but low rates of Pneumocystis jiroveci pneumonia, isosporiasis, and Toxoplasma encephalitis. Most bacterial isolates were resistant to TS but sensitive to azithromycin, a possible alternative to TS. Clinical trials are needed to determine the role of TS or alternative regimens for prophylaxis against secondary infections among people living with HIV in sub-Saharan Africa. These should also assess benefit in patients receiving antiretroviral therapy