This study suggests that underlying infection with S. haematobium offers a modest degree of clinical protection against P. falciparum malaria in an age-specific fashion to children exposed to both parasitic infections. Through a matched cohort study we have followed children over a malaria transmission season and demonstrated that children infected with schistosomiasis have less malaria, longer disease-free intervals until the first clinical episode, and reduced parasitemias during that episode. This difference is manifest between the ages of four and eight years. Differences disappear after nine years of age. Similarly, differences are less pronounced after the first clinical malaria episode. Little difference in hematologic parameters was noted at any time point between groups.
Although the study was not powered to detect difference according to schistosoma ova production, there appears to be decreased malaria protection with increased egg secretion. We hypothesized that increased egg production might result in enhanced protection from clinical malaria (possibly by increased immune reactivity to egg production) but our results contradict this prediction. An age-specific correlation between malaria and schistosomiasis egg production was found in children 4–8 years of age excreting low quantities of eggs. These children had an increased time to first malaria infection. An association between low egg excretion and reduced malaria parasitemias has been described.19
It is possible that children who produce fewer eggs are better able to control the schistosoma infection through an enhanced immune response, which might also help to protect from falciparum malaria. Conversely, participants secreting large amounts of eggs may experience immune tolerance to high antigenic stimulation, which results in blunting the immune protective responses and eliminates the interactive effect noted with secretion of low amounts of eggs.
The mechanisms behind helminth-associated protection from malaria are likely multifactorial. We hypothesize that it is immunologically mediated. Clinical malaria is characterized by a bimodal immune response requiring Th1 cytokine production for control of the initial parasitemia that converts to Th2-mediated cytokine production for parasite clearance.20,21
Helminth infections, which are known to be potent inducers of host Th2 cytokine production,22–24
can down-regulate the effects of a secondary Th1-dependent parasitic challenge. This is illustrated in mice with ova-producing S. mansoni
infections in which impaired Th1-dependent lesional healing is noted in Leishmania major
while increased anemia and death is noted in P. chabaudi
infection (normally non-lethal to these mice) along with measurably suppressed Th2 responses.4
Recently, mice co-infected with filariasis and P. chabaudi
were noted to have more severe malaria along with increased interferon-γ responsiveness, which suggests an imbalance in malaria-induced immunopathology.26
In humans, blunted peripheral blood mononuclear cell (PBMC)–derived Th1 cytokine production has been demonstrated in subjects with underlying intestinal helminth infections after stimulation with tetanus toxoid,27
oral cholera toxin B vaccine,28
and schistosomal antigens.22,29,30
Helminth infections have also been associated with cellular anergy17,31
and decreased proliferative response to hepatitis C virus antigen.32
We are evaluating the immunologic response to malaria and schistosoma using sera and PBMCs collected from these volunteers at the time of clinical infection to validate our theory.
An immunologic explanation for schistosomiasis-mediated resistance to malaria might explain the age-associated differences noted in this study. Studies at this site with seasonal malaria transmission have found that children up to 10 years of age remain highly susceptible to clinical malaria, with disease burden decreasing significantly in children more than 10 years of age.11,14
Previous prevalence studies at our site have found in children 1–4 years of age an incidence of S. haematobium
of 5.6% (5 of 89) (K. Lyke, O. Doumbo, unpublished data). Younger children are unlikely to acquire schistosomiasis in part because of limited independence and water exposure, whereas acquisition increases after the age of six, peaks near the age of nine, and diminishes after the age of 14 with the development of immunity.33
It is possible that enhanced parasitic interaction occurs between the ages of four and eight years when disease susceptibility overlaps. Given the difficulties of collecting urine in children 1–3 years of age and the low prevalence rate of schistosomiasis, we elected to enroll only children 4–14 years of age. We cannot rule out the fact that schistosomiasis may be exerting an even greater protective effect against malaria acquisition in children younger than four years of age.
An intriguing alternate possibility is that iron-scavenging parasites provide protection against malaria. Iron deficiency and subsequent anemia has been shown to be protective against the acquisition of malaria.34
Conversely, iron supplementation has been shown to increase susceptibility to P. vivax.35
We did not find reduced hemoglobin levels in children infected with S. haematobium
despite monthly surveillance, but we cannot rule out the possibility of sub-clinical iron deficiency as a causative mechanism for protection against malaria.
Seventeen percent of the SN children acquired S. haematobium upon examination after the study period. Schistosomiasis transmission peaks in early dry season when cercariae are concentrated in standing water pools. Therefore, most of the transmission likely occurred after study monitoring ceased and not during the rainy season when water sources were rapidly flowing. When analysis was repeated after eliminating individuals who had subsequently acquired schistosomiasis, power was lost as the sample size decreased below that calculated as necessary for statistical significance (300 matched pairs). Nevertheless, the robust differences noted in the 6–8-year-old age group remained, as did trends in children 4–8 years of age.
Efforts were made to reduce confounding variables. The effect of other concomitant infections is unknown. Previous studies performed in 120 children from Bandiagara showed no detectable filarial infections (i.e., Loa loa, Onchocerca vol-vulus, or Wuchereria bancrofti). The prevalence of HIV is less than 2% among adults in Mali. Study children were not tested individually for these infections, but children with clinically apparent diseases were excluded from the study. No difference was reported in the use of bed nets or other malaria-preventative techniques. Close attention was paid to matching individuals by residence sector (and by extension, water sources), although local environmental differences in exposure to mosquitoes could not be controlled. In the interest of safety, we treated all children for schistosomiasis after one season, negating the ability to determine ongoing clinical interaction of dual infection.
This study reports a modest protective effect of S. haematobium against P. falciparum malaria. We found reduced clinical malaria, reduced parasitemias, and increased time to first clinical infection in those with S. haematobium. We hypothesize that an imbalance of Th1/Th2-mediated cytokines might account for this finding. Immunologic studies to evaluate this possibility are ongoing. The protective effects disappear after the first infection of the malaria season although the course of these infections over multiple transmission seasons is unclear. The implications of these findings could be far-reaching in that they may extend to other helminth co-infections and could affect vaccine trial outcomes, parasite treatment programs, and preventive health care maintenance policy worldwide.