Plasmodium vivax infection: a major determinant of severe anaemia in infancy

Despite comparatively low-level endemicity, patent parasitaemia in southern Papua is associated with 17 % of all haemoglobin concentrations under 7 g/dL. In infants and young children, the corresponding proportions rise to 34 and 23 %, respectively. Although P. vivax is less prevalent than P. falciparum overall, this study has shown that in Mimika District it is the commoner species in children under 5 years of age and that it is associated with a higher population-attributable fraction of anaemia in infants. This study also suggests that mixed species infections are associated with a greater reduction in haemoglobin than P. falciparum or P. vivax infections alone.

In this survey, 17 % of individuals were parasitaemic and approximately one-third of these were febrile. Presence of fever did not confer a greater risk of anaemia. Although parasitaemia was strongly associated with anaemia, the population attributable fractions presented are still likely to represent under-estimates of the true total effect of malaria on haemoglobin concentrations in the community. Full haematological recovery takes several weeks following acute malaria [32] suggesting that many aparasitaemic individuals may have been experiencing the haematological after-effects of recent malaria infection. Nearly a half of the survey participants had a history of fever in the preceding month and these individuals had significantly lower haemoglobin concentrations than those without a history of fever. Since 35 % of fevers in the community are estimated to be due to malaria, parasitaemia is likely to have been responsible for a sizeable, but unmeasured, proportion of all reduced haemoglobin concentrations in the aparasitaemic group.

The estimated adjusted population-attributable fractions of moderate or severe anaemia in infants were based on small numbers. Nevertheless, the finding that P. vivax accounts for a greater fraction of anaemia than P. falciparum is in agreement with results from the local hospital [1, 19, 33] as well as a previous cross-sectional survey in Papua New Guinea [34]. At the hospital, P. vivax is the most common cause of malaria-related admission in the first year of life and produces an equal or greater reduction in haemoglobin than P. falciparum [1, 19, 33]. Others have also observed that morbidity from vivax malaria is maximal at a much younger age than falciparum malaria [35–38], a phenomenon that Maitland and colleagues speculate is due to greater ease of transmission and more rapid acquisition of immunity [39]. In keeping with this hypothesis, it is the authors’ view that both the greater prevalence of vivax malaria and the severity of the associated anaemia in infancy observed in this study are not chance findings but are related to multiple relapses causing repetitive insults to the haematological system and inducing early development of immunity. Two sources of evidence from this study support this hypothesis. First, there was a statistically significant reduction in the prevalence of P. vivax parasitaemia with age, whereas there was no such reduction for P. falciparum. Second, infants with P. vivax parasitaemia in this study had had significantly more episodes of fever in the last month than infants with P. falciparum (median 1 vs 0 episodes, p = 0.007). The subsequent decline in the fraction of anaemia attributable to either species of Plasmodium with increasing age is likely to relate to three main factors: the acquisition of some degree of immunity, especially in the case of vivax malaria, the increasing importance of alternative causes of anaemia, such as intestinal helminthiasis and chronic infections, and lastly the increasing likelihood that lack of parasitaemia represents a state of remission or a period between primary infections rather than a state of complete malaria naivety.

This study showed that mixed species infections were associated with a greater drop in haemoglobin and a higher risk of moderate or severe anaemia than infections with P. falciparum or P. vivax alone. This finding is consistent with other work from Papua [1, 19] and Papua New Guinea [40] but in direct contradiction to research carried out in Thailand and elsewhere [39]. Concomitant infection with P. vivax in northern Thailand has been postulated to attenuate the risk of severe anaemia secondary to P. falciparum infection, possibly due to some degree of cross-species immunity [32, 39]. In Papua, where endemicity of both species is higher, mixed infection may reflect a greater likelihood of having had multiple recent malaria infections (likely due to P. vivax), driving deeper levels of anaemia.

This study has several limitations. Due to the cross-sectional design it was not possible to draw solid conclusions about the direction of the observed associations. Although anaemia is an established sequel of both falciparum and vivax malaria, there is evidence that iron deficiency anaemia reduces the risk of falciparum malaria [41] and conversely, that administering iron supplements to iron-replete individuals may slightly increase the risk [42, 43]. The comparative effect of this reverse causation is likely to be small since there were no special community-wide supplementation programmes at the time of the survey.

The population-attributable fractions were estimated using odds ratios as approximations of relative risk. Since moderate or severe anaemia was not a particularly rare outcome, this may have resulted in slight overestimation of the attributable fractions, particularly for 1–5 years olds who had a prevalence of moderate or severe anaemia of 9.4 %.

Selection bias may have affected the population-attributable fractions due to their heavy reliance on the prevalence of parasitaemia in the sample. Those who did not provide a blood sample (mostly due to absence at the time of the survey) tended to be older males. Overall, there was relatively little effect of increasing age or gender on the odds of parasitaemia, however those who did not provide a blood sample could conceivably have been at greater risk of malaria acquisition due to behavioural or lifestyle factors. If this were true, the fraction of anaemia attributable to malaria may have been underestimated.

Several potentially important confounders could not be controlled for in analyses. Infestation with intestinal helminths has been shown to cause an additive reduction in haemoglobin concentrations in malaria co-infected children [44]. Although there is a great deal of geospatial overlap between malaria and intestinal helminths [45], the immunological relationship remains less clear [46, 47]. Two studies by Nacher and Spiegel, respectively, suggest that the presence of intestinal helminths increases the risk of falciparum malaria by a factor of between 1.5 and 2.2 [48, 49]. Even if this is the case, the results of this study for infants and children under 5 years are unlikely to be significantly confounded since intestinal helminth density does not typically peak until early adulthood and a previous study showed minimal impact of intestinal helminthiasis on haemoglobin concentrations before 30 months of age [50].

Haemoglobin and red cell abnormalities as a whole are protective against severe malarial anaemia [51–53] but their effect on the risk of uncomplicated Plasmodium infection is less clear and may differ between species [51, 54, 55]. Since these disorders are themselves risk factors for anaemia, differences in their distribution between participants with and without parasitaemia could potentially have confounded the models.

Incorporating weight for age/gender/ethnicity into the multivariable regression models should have accounted for at least some of the potential confounding caused by iron deficiency anaemia. Since iron deficiency is thought to be protective against Plasmodium infection, any residual confounding is likely to have biased the results towards the null. Finally, the effects of chronic disease and bacteraemia could not be controlled for in this analysis. The former is unlikely to have been important in the younger age groups and bacteraemia would be expected to be rare in the community setting.