This study provides strong evidence of association between helminth infections and learning ability, memory, and verbal fluency in children after controlling for effects of important confounders including SES, nutritional status, age, sex, and presence of other intestinal parasites. To our knowledge, this is the first study to demonstrate a relationship between helminth infection and learning. We provide evidence that all intensities of S. japonicum
infection, not just infections of moderate or high intensity, are associated with poorer performance on tests of learning. This is important because many children in endemic areas harbor only light infections, which may confer a learning disadvantage relative to uninfected children. Furthermore, in most areas of the developing world, educational opportunities are limited and effects on ability to learn in this age group may severely curtail attainment of educational potential. Our finding in the learning domain is congruent with what has been demonstrated in animal models for other kinds of helminth infections. In two such studies, infection with the helminths Strongyloides ratti
and Toxocara canis
were associated with poor performance on spatial learning tasks in mice.29,30
We are aware of only two human studies16,17
in Tanzania and China that reported associations between schistosomiasis infection and any domain of cognitive performance. Unlike our study, both groups found associations between tests of memory and schistosomiasis infection. Specifically, Jukes and others16
found that high-intensity infection with S. haematobium
was associated with cognitive impairment in verbal and short-term memory domains among school age children in Tanzania. In a subset of younger children in China, Nokes and others17
found associations between treatment of S. japonicum
and improvements in tests of memory (free recall, fluency, and picture search tests). We did not find this even when analyses were limited to younger children. The difference in domains of cognitive ability affected could be a reflection of the inherent challenges in quantifying constructs as complex as cognitive ability or the study design differences (cross-sectional versus randomized controlled trial).
infection of moderate or high intensity was found to be associated with poor performance in tests relative to Ascaris
-uninfected children in the memory domain. This finding is consistent with that of Nokes and others16
in China, Sakti and others31
in Indonesia, and Jukes and others17
in Tanzania. Watkins and others,32
in a randomized clinical trial among children in Guatemala, in which albendazole was administered at baseline and at three months for the treatment group, failed to find evidence of improvement in cognitive ability at six-months post-treatment of Ascaris
infection. This finding is certainly possible in the context of their study, given that follow-up period was short and may not have been sufficient to detect any improvements that might have occurred. It is also possible that children require remedial assistance in addition to anti-helminthic therapy to observe improvements in cognitive performance.
This study provides additional support for a relationship between T. trichiura
infection and poor performance in tests of verbal fluency. Specifically, we found that children infected with Trichuris
had almost 4.5 times greater odds of performing poorly in tests of verbal fluency regardless of infection intensity. This finding is congruent with those of other investigators in Jamaican children,33-37
in which improvements in tests of verbal fluency were noted among children treated for moderate or high intensities of Trichuris
Several investigators have demonstrated that helminth infections are associated with poor nutritional status and lower hemoglobin levels or anemia.38-44
Positive associations between higher cognitive performance and better nutritional and hemoglobin status have also been reported.18,20,45-49
Our finding that hemoglobin and nutritional status were inversely related to cognitive performance in the memory and PNIT domains, respectively, is consistent with these previous research findings. Furthermore, this study underscores the importance of rigorous control for confounding variables in the examination of the relationship between helminth infection and cognitive performance. We found SES to be strongest and most consistent correlate of cognitive impairment. This finding is not surprising since higher SES may reflect among other things, access to superior educational and health care opportunities that may be beneficial to children's performance in cognitive tests. Failure to robustly control for SES could result in spurious associations or over-estimation of the true relationship between helminth infection and cognitive performance. In addition, sex was a confounder of these relationships since boys were more intensely infected and performed worse on tests of cognition, especially the WRAML. We explored the potential for effect modification of the effect of helminth on cognitive ability by sex to see if there is a stronger relationship between cognitive impairment and helminth infection among boys. We failed to find evidence for this from our analyses and therefore conclude that helminth infection affects cognitive performance similarly among boys and girls.
Because the relationship between hemoglobin levels and cognitive performance has been well described in the literature and investigators have postulated that cognitive impairment in the context of helminth infection may be mediated through anemia, we built models with and without hemoglobin to see if the effects of parasitic infection on cognitive ability was mediated through hemoglobin. With inclusion of hemoglobin, we expected changes in point estimates to include the null value in the 95% CI if most of the effects on cognitive ability is mediated through this covariate (). We found an increase, rather then a decrease, in the strength of association between cognitive ability (learning and memory) and infection with S. japonicum
and A. lumbricoides
upon adjustment for hemoglobin status. The observation of an 8–10% increase in the strength of association suggests that hemoglobin, although independently associated with cognitive ability, is unlikely to be the dominant mediator of cognitive impairment in the context of S. japonicum
and A. lubmricoides
. In addition, inclusion of nutritional status in multivariable models did not change observed associations, suggesting under-nutrition is not the primary mediator of the observed relationships. Other potential mediating factors may include pro-inflammatory cytokines made in response to infection,50,51
which are known to have a detrimental effect on cognitive function.52,53
In particular, serum tumor necrosis factor-α levels are higher in individuals with schistosomiasis infection,54,55
and this cytokine has been related to decreased performance on cognitive tests in human subjects.53
In addition, abdominal discomfort related to A. lumbricoides
, S. japonicum
, and T. trichiura
infection could affect cognitive performance if significant enough to distract children from cognitive tasks. For the Trichuris
-verbal fluency relationship on the other hand, we observed 22.4% diminution in the strength of association upon adjustment for hemoglobin. This observation suggests that hemoglobin may be playing a more significant mechanistic role in the T. trichiura
The findings presented must be interpreted in light of limitations inherent in cross-sectional study design. First, the cross-sectional design does not allow causal inferences to be made. Although it is possible that cognitive impairment predisposes children to helminth infections, we believe reverse causality is unlikely to explain these findings since SES, not cognitive ability, is more likely to increase children's helminth exposure. We have adjusted for SES, which is directly correlated with cognitive function, and is one of the most important factors related to helminth exposure. Analysis of longitudinal data from this population, to be presented elsewhere, will increase our causal inference in addition to decoupling the temporal relationship between exposure to helminth infection and cognitive performance.
In addition, although we have adjusted for SES and other important confounders, it is possible that there are residual confounding or unmeasured confounding variables that could explain these relationships. Furthermore, it is possible that after the adaptation process of the WRAML, it may not capture constructs such as learning in the same way as when it used in populations in the United States, which may be more similar to the population in which the test was validated. We believe this is unlikely since only minor adaptations were made, and this was done only to replace unfamiliar customs or items with those of a similar level of difficulty. Finally, simultaneous exposure to multiple parasite species is common in our study population, as is the case in most helminth-endemic regions. It is possible that biologic interactions occur among co-infecting species, potentially modifying the association between any helminth species and cognitive performance. It remains an empirical challenge to quantify the effect of poly-parasite helminth exposures on helminth-associated morbidities without simultaneously sacrificing statistical and inferential efficiency given the co-linear distribution of helminths under investigation and the potential for interaction.
We have provided evidence that helminth infection is associated with cognitive impairment in school age children. We found impairments in learning, memory, and verbal fluency for different helminths. It is not surprising that different parasites were associated with deficits in different domains, since these infections cause vastly different host responses based on their location and parasite-specific immunologic and hematologic effects. Given the resource-poor nature of helminth-endemic regions, prioritization of public health interventions that are most cost effective is crucial. Defining the global burden of helminth infections entails assessing more subtle morbidities.56
These morbidities, particularly when clinically apparent at low intensities of infection that are highly prevalent, likely contribute significantly to disability-adjusted life years.7