Co-infection of long-term carriers of Plasmodium falciparum with Schistosoma haematobium enhances protection from febrile malaria: a prospective cohort study in Mali.

Malaria and schistosomiasis often overlap in tropical and subtropical countries and impose tremendous disease burdens; however, the extent to which schistosomiasis modifies the risk of febrile malaria remains unclear.We evaluated the effect of baseline S. haematobium mono-infection, baseline P. falciparum mono-infection, and co-infection with both parasites on the risk of febrile malaria in a prospective cohort study of 616 children and adults living in Kalifabougou, Mali. Individuals with S. haematobium were treated with praziquantel within 6 weeks of enrollment. Malaria episodes were detected by weekly physical examination and self-referral for 7 months. The primary outcome was time to first or only malaria episode defined as fever (≥ 37.5 °C) and parasitemia (≥ 2500 asexual parasites/µl). Secondary definitions of malaria using different parasite densities were also explored.After adjusting for age, anemia status, sickle cell trait, distance from home to river, residence within a cluster of high S. haematobium transmission, and housing type, baseline P. falciparum mono-infection (n = 254) and co-infection (n = 39) were significantly associated with protection from febrile malaria by Cox regression (hazard ratios 0.71 and 0.44; P = 0.01 and 0.02; reference group: uninfected at baseline). Baseline S. haematobium mono-infection (n = 23) did not associate with malaria protection in the adjusted analysis, but this may be due to lack of statistical power. Anemia significantly interacted with co-infection (P = 0.009), and the malaria-protective effect of co-infection was strongest in non-anemic individuals. Co-infection was an independent negative predictor of lower parasite density at the first febrile malaria episode.Co-infection with S. haematobium and P. falciparum is significantly associated with reduced risk of febrile malaria in long-term asymptomatic carriers of P. falciparum. Future studies are needed to determine whether co-infection induces immunomodulatory mechanisms that protect against febrile malaria or whether genetic, behavioral, or environmental factors not accounted for here explain these findings

Identification and Characterization of CRF02_AG, CRF06_cpx, and CRF09_cpx Recombinant Subtypes in Mali, West Africa

Multiple HIV-1 subtypes and circulating recombinant forms (CRFs) are known to cocirculate in Africa. In West Africa, the high prevalence of CRF02_AG, and cocirculation of subtype A, CRF01_AE, CRF06_cpx, and other complex intersubtype recombinants has been well documented. Mali, situated in the heart of West Africa, is likely to be affected by the spread of recombinant subtypes. However, the dynamics of the spread of HIV-1 recombinant subtypes as well as nonrecombinant HIV-1 group M subtypes in this area have not been systematically assessed. Herein, we undertook genetic analyses on full-length env sequences derived from HIV-1-infected individuals living in the capital city of Mali, Bamako. Of 23 samples we examined, 16 were classified as CRF02_AG and three had a subsubtype A3. Among the remaining HIV-1 strains, CRF06_cpx and CRF09_cpx were each found in two patients. Comparison of phylogenies for six matched pol and full-length env sequences revealed that two strains had discordant subtype/CRF designations between the pol and env regions: one had A3polCRF02_AGenv and the other had CRF02_AGpolA3env. Taken together, our study demonstrated the high prevalence of CRF02_AG and complexity of circulating HIV-1 strains in Mali. It also provided evidence of ongoing virus evolution of CRF02_AG, as illustrated by the emergence of more complex CRF02_AG/A3 intersubtype recombinants in this area

Multiple linear regression model of parasite density at the first febrile malaria episode by different parasite density thresholds^a.

<p>Abbreviations: CL, confidence limit; HbAS, sickle cell trait; NA = not assessed due to lack of individuals with heavy <i>S. haematobium</i> mono-infection in analysis.</p>a<p>Effect of infection status at enrollment on parasite density in log(parasites/µl) using a general linear model with adjustments for age, distance from home to clinic, sickle cell trait, baseline anemia status, and residence in the cluster of high <i>S. haematobium</i> transmission.</p>b<p>1–9 eggs/10 mL urine.</p>c<p>≥10 eggs/10 ml urine.</p><p>Multiple linear regression model of parasite density at the first febrile malaria episode by different parasite density thresholds^{<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0003154#nt111" target="_blank">a</a>}.</p

Kaplan-Meier plots of risk of <i>P. falciparum</i> infection or febrile malaria.

<p>A) Time to first PCR-confirmed <i>P. falciparum</i> blood-stage infection by <i>S. haematobium</i> (Sh) infection status at enrollment. Data shown is only for individuals who were PCR-negative for <i>P. falciparum</i> at enrollment. B) Time to first febrile malaria episode (defined as fever of ≥37.5°C and asexual parasite density ≥2500 parasites/µl on blood smear) by <i>P. falciparum</i> (Pf) and <i>S. haematobium</i> (Sh) infection status at enrollment. C) Time to first febrile malaria episode by <i>S. haematobium</i> (Sh) infection status and anemia status at enrollment. (−) negative status; (+) positive status. <i>P</i> values for log-rank analyses (all groups) are shown. Blue shading indicates time period during which praziquantel was given to all individuals who were determined to be infected with <i>S. haematobium</i> at enrollment.</p

Effect of baseline <i>Schistosoma haematobium</i> mono-infection, <i>Plasmodium falciparum</i> mono-infection, and co-infection on first or only malaria episode (with anemia interaction term)^a.

<p>Abbreviations: CL, confidence limit; HR, hazard ratio; HbAS, sickle cell trait.</p>a<p>Risk of first or only malaria episode was adjusted for age, distance from home to river, sickle cell trait, anemia status at baseline, residence in the cluster of high <i>S. haematobium</i> transmission, and roof type in the classic Cox proportional hazards model with inclusion of interaction terms between anemia status and the two covariates with <i>S. haematobium</i> infection (anemia*co-infection and anemia*<i>S. haematobium</i> mono-infection).</p><p>Effect of baseline <i>Schistosoma haematobium</i> mono-infection, <i>Plasmodium falciparum</i> mono-infection, and co-infection on first or only malaria episode (with anemia interaction term)^{<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0003154#nt109" target="_blank">a</a>}.</p

Study participants and risk analysis flow chart.

<p>Study participants and risk analysis flow chart.</p

Spatial distribution of <i>S. haematobium</i> and <i>P. falciparum</i> infections in Kalifabougou, Mali at enrollment (May 2011).

<p>Shapes indicate infected and uninfected cases as noted. Large colored circles show significant, unadjusted clusters: green circle = cluster of co-infected cases in May 2011 (27 cases, n = 158, relative risk [RR] = 6.51, <i>P</i><0.0001, Bernoulli model); red circles = clusters of <i>P. falciparum</i> infections in May 2011 (cluster 1: 35 cases, n = 41, RR = 1.90, <i>P</i><0.001; cluster 2: 12 cases, n = 12, RR = 2.15, <i>P</i> = 0.04, Bernoulli model). Map data: Landsat image obtained from <a href="http://glovis.usgs.gov" target="_blank">glovis.usgs.gov</a> (latitude: 12.952, longitude: −8.173, imagery date: March 2011).</p

Effect of baseline <i>Schistosoma haematobium</i> mono-infection, <i>Plasmodium falciparum</i> mono-infection, and co-infection on first or only malaria episode^a.

<p>Abbreviations: CL, confidence limit; HR, hazard ratio; HbAS, sickle cell trait.</p>a<p>Risk of first or only malaria episode was adjusted for age, distance from home to river, sickle cell trait, anemia status at baseline, residence in the cluster of high <i>S. haematobium</i> transmission, and roof type in the classic Cox proportional hazards model.</p><p>Effect of baseline <i>Schistosoma haematobium</i> mono-infection, <i>Plasmodium falciparum</i> mono-infection, and co-infection on first or only malaria episode^{<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0003154#nt107" target="_blank">a</a>}.</p