Influence of Anemia on Plasmodium falciparum Gametocyte Sex Ratios in Acutely Symptomatic Children

Abstract

Anemia is common in African children but little is known about how malarial anemia influences Plasmodium falciparum gametocyte sex ratios (PfGSR) and transmission in endemic areas in Africa. We investigated the changes in PfGSR in 1126 consecutive children with acute, symptomatic, uncomplicated falciparum malaria who did (n = 99) or did not (n = 1027) have anemia (defined as a hematocrit < 25%) and who were treated with various antimalarial drugs in an endemic area of southwest Nigeria. On presentation, anemic children were significantly younger and had a significantly higher PfGSR (0.28 + 0.07 (se) v 0.15 + 0.02, P = 0.044). In anemic, but not in non-anemic children, a duration of illness > 3 d was associated with a male-biased sex ratio (defined as PfGSR > 0.5) (P = 0.029). Hematocrit correlated negatively with PfGSR in non-anemic but not in anemic children (r = -0.219, P = 0.027 and r = -0.106, P = 0.697, respectively) suggesting that the critical hematocrit producing 'all or none effect' on PfGSR was a value below 25% in this cohort of children. Temporal changes showed that, in general, in anemic children, PfGSR was significantly higher at enrolment than in non-anemic children treated with chloroquine (CQ), amodiaquine (AQ) and amodiaquine-sulfalene-pyrimethamine (ASP) (P < 0.0007 in all cases), and remained significantly higher by day 7 or 14 in those treated with AQ and pyrimethaminesulfadoxine plus probenecid (PSP) (P < 0.007 in all cases). In children who received the same treatment, the ratio of the sex specific half-life male:female, the 'gametocyte maleness index', was one and a half to two folds higher in anemic than non-anemic children suggesting anemia prolongs the survival of microgametocytes and may encourage transmission. These findings have implications for malaria control efforts in endemic sub-Saharan countries where malarial anemia is common.

Population structure of Plasmodium falciparum gametocyte sex ratios in malarious children in an endemic area

“…However, its increased frequency post-treatment indicates that a sex ratio of 0.5 occurs more frequently due to non-artemisinin drugs, increasing immunity (≥5 years), and anaemia (Table 2). These three factors are more likely to have negative impact on male than female gametocytes [8,9,34], and lead to the production of male gametocytes as a form of fertility insurance [4]. The frequent occurrence of malaria-associated anaemia in children [35], its association with increased gametocyte carriage [36], and the proclivity of drug-related increased frequency of a sex ratio of 0.5 may have implications for transmission in endemic areas.…”

Biology of Plasmodium falciparum gametocyte sex ratio and implications in malaria parasite transmission

“…Several investigations proposed a role of human host factors, such as anaemia and immunity [ 11 , 67 – 70 ] and of parasite factors such as asexual parasite density [ 4 ], parasite diversity [ 71 ] and competition, as well as the duration of malaria infection [ 12 , 72 – 74 ]. Anaemia, a factor associated to malaria, was shown to affect parasite sex allocation not only through increased gametocyte production but also through a more male-biased sex ratio [ 25 , 27 ], with the erythropoietin (Epo) hormone, an erythropoiesis inductor, being shown in rodent and avian malaria parasites to play a role in the male biased shift of sex ratio [ 25 ].…”

Effects of mefloquine and artesunate mefloquine on the emergence, clearance and sex ratio of Plasmodium falciparum gametocytes in malarious children

“…There are potential implications of the findings of the present study: primaquine is gametocytocidal and can shorten gametocyte clearance time [ 29 , 41 ] but its inclusion as part of artemisinin-based combination therapy is fraught with the danger of inducing haemolysis in a population where the child prevalence of glucose phosphate dehydrogenase (G6PD) deficiency may be close to 20% or where anti-malarial (dapsone)-induced haemolysis may be a potential public health problem (Premji et al, unpublished observation) or where malaria-associated anaemia is a public health problem [ 42 ] and is associated with an increased risk of gametocyte carriage and sex ratio changes that may influence transmission [ 43 ]. There is need to find combination drugs that are safe and can rapidly clear gametocytaemia in children (and adults) with falciparum malaria living in areas of intense transmission in Africa.…”