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

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Figure 1. Study participants and risk analysis flow chart.

Figure 2. Spatial distribution of S. haematobium and P. falciparum infections in Kalifabougou, Mali at enrollment (May 2011).

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, P<0.0001, Bernoulli model); red circles = clusters of P. falciparum infections in May 2011 (cluster 1: 35 cases, n = 41, RR = 1.90, P<0.001; cluster 2: 12 cases, n = 12, RR = 2.15, P = 0.04, Bernoulli model). Map data: Landsat image obtained from glovis.usgs.gov (latitude: 12.952, longitude: −8.173, imagery date: March 2011).

Figure 3. Kaplan-Meier plots of risk of P. falciparum infection or febrile malaria.

A) Time to first PCR-confirmed P. falciparum blood-stage infection by S. haematobium (Sh) infection status at enrollment. Data shown is only for individuals who were PCR-negative for P. falciparum 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 P. falciparum (Pf) and S. haematobium (Sh) infection status at enrollment. C) Time to first febrile malaria episode by S. haematobium (Sh) infection status and anemia status at enrollment. (−) negative status; (+) positive status. P 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 S. haematobium at enrollment.