The nonlinear dynamics of Schistosoma
transmission and the complexity of age- and time-related factors influencing infection-related disease formation have made it difficult for experts to gauge the potential lifetime benefits of repeated anti-schistosomal treatments in endemic communities.50
Risk of infection-associated morbidity increases with both the duration and the intensity of infection, reflecting an aggregate effect of local tissue injury from granulomatous inflammation to parasite eggs deposited in host tissues, and the systemic effects of chronic inflammation.15,21,51
In particular, chronic anemia and growth stunting during childhood are believed to be the result of chronic anti-parasite inflammation that persists throughout childhood and adolescence.16
Although school-based treatment has long been recommended as a means to suppress the heaviest burden of Schistosoma
infection that occurs during childhood,52
field studies indicate that such programs may fail to suppress transmission in high- and medium-risk communities, such that reinfection remains highly likely despite repeated treatments given during school age.6
Although inflammation may subside after successful elimination of infection (with substantial benefits in terms of improved hemoglobin levels and rebound growth)8,13,27,45,53
early reinfection appears to reactivate these inflammation-associated morbidities, resulting in only limited benefits from any single round of therapy.34,54
It is only recently that growth and nutrition-related morbidities have become more widely recognized as significant components of the schistosomiasis-associated disease burden.17
Notably, only two studies have examined the long-term effects of repeated anti-schistosomal treatments (given during childhood) on later adult health.55,56
For now, because the data on the late benefits of treatment are limited, and considering the need for informed policy formulation in this area, it is appropriate at this point to use established modeling techniques (calibrated on available data) to estimate the benefits of repeated treatment campaigns on Schistosoma
-associated growth deficits that may occur during childhood. Our modeling analysis, benchmarked to available individual-level field data, was based on the well-recognized potential of children for “catch-up growth” following recovery from chronic diseases.44
Individuals can acutely increase their post-insult growth velocity up to 4-fold after the growth restriction ceases. This is known as type A catch-up growth. In another form of catch-up growth, known as type B, puberty can be delayed by several years, allowing linear bone growth to continue for an extended compensatory period.44
However, for schistosomiasis, the net impact of any type B recovery is likely to be complex, in that pubertal hormonal changes per se have been shown to down-modulate anti-parasite inflammation and reduce nutritional deficits associated with Schistosoma japonicum
We recognize that one of the limitations of our simulation model is that we are not able to distinguish the relative contributions of these two types of growth recovery. Future longitudinal studies, using careful Tanner staging for sexual maturity57
will be needed to clarify the relative effects of type A and type B recovery following treatment. Other factors, such as diet quality and co-infection with other parasitic worms, including soil-transmitted helminths, may serve to limit actual catch-up growth in treatment campaigns. Our study is limited in that it focused primarily on schistosomiasis and data on the impact of S. haematobium
infection. Outcomes of mass-treatment may prove different for Schistosoma mansoni
- or S. japonicum
particularly if the risk for reinfection is highly episodic or changes significantly during the treatment campaign.
Like other studies of the growth impact of schistosomiasis,27,29,45,49
we have used CDC/NCHS growth standards58
as our norms for affected children. Even though their formulae were developed on the basis of sampling children within the United States population, these 2000 CDC/WHO standards are widely accepted as reference parameters for childhood growth among most other populations.30,59
New reference standards based on sampling in six countries are being developed by the WHO,60
but, at the time of this study, they had not been implemented for children > 5 years of age. Undoubtedly, for future research, the use of these newer international standards should be considered.
We should stress that, as constructed, our model gives a lower bound estimate of growth remediation, and the real benefits could be higher. Indeed, mass drug administration (MDA) may have a double effect in some communities—it can lower human infection levels and may also reduce transmission in some locales, particularly if high-risk adults are included in the treatment campaign. Our present simulation does not account for the coupled process of “human-to-snail transmission” (only its “snail-to-human” part), so that part (1) of the model system could underestimate the effect of drug treatments on the process of contamination and snail infection. However, human-to-snail transmission remains a patchy, nonlinear phenomenon in which a single infected individual (alone) can continue to contaminate one or more snail contact sites and maintain transmission for several months within any given community. This is the likely reason that MDA programs have not reliably reduced transmission in many high-prevalence areas.8,61
Nevertheless, our projections do suggest an increasing benefit from repeated treatments during childhood, even in the face of continuing reinfection.
Our results suggest that repeated treatment during childhood has the potential to reverse most, but not all, growth impairment associated with schistosomiasis. In particular, early treatment of S. haematobium
with PZQ beginning at or before 6 years of age, with repeated treatments into the adolescent years, appears likely to be most effective in facilitating catch-up growth among repeatedly infected children. The gender-specific differences in growth observed among our benchmark Kenyan population () were consistent with those found in treatment studies of S. mansoni
infection in Brazil.29,49
In those studies, infected males were found to suffer more undernutrition, but they also had more dramatic improvements after anti-schistosome therapy.49
Among our calibration sample of children, boys had higher average egg burdens than girls (geometric mean = 96 eggs/10 mL urine versus 36 eggs/10 mL urine), which might explain a higher risk of inflammation with corresponding worsening of growth-related morbidity outcomes. Another possible factor contributing to gender difference may be a difference in daily activity patterns, with higher rates of caloric consumption and/or higher rates of reinfection among boys.62
More research on the question of the relative gender-specific, growth-related disease risk is needed.
Historically, policy-makers have tended to underestimate the health impact of non-lethal morbidities associated with schistosomiasis (compare, e.g., the conclusions stated in References 63–66
to the meta-analysis in Reference 15
). However, multiple cross-sectional studies have documented growth retardation in children infected with all species of Schistosoma
In terms of policy implications, there are likely to be important economic effects of childhood growth retardation that results in permanent stunting of adults. Short stature is associated with a decrease in productivity in many settings: previous studies estimate that a 1% decrease in adult stature is associated with a 1.4% decrease in productivity in less-developed economies.69–71
Unmeasured confounders, such as differences in food availability, undoubtedly exist,13
but the reproducibility of the benefits of specific anti-schistosomal therapy suggest a significant growth effect of chronic schistosomiasis wherever it occurs.27,28,45,49
Although the durable long-term impact of anti-schistosomal treatment in reversing wasting or stunting has not been as well studied, treatment outcomes studies, including randomized-placebo controlled trials, indicate the potential for growth improvement with specific anti-schistosomal therapy. In the Philippines, in villages endemic for S. japonicum
, children who were most wasted or stunted at baseline had the best relative outcomes after treatment.45
In Kenya, marked improvement in growth was observed after a single dose of an anti-schistosomal drug (metrifonate or PZQ) for the treatment of S. haematobium
at follow-up after 8 months.27
Of note, an inflammatory response related to growth impairment has been shown when reinfection occurs after successful primary treatment of S. japonicum
This association, however, has not been examined in areas endemic for S. haematobium
or S. mansoni,
and the potential importance of this link to later growth impairments remains an important area for future study.
Other aspects of schistosomiasis-related morbidity and impairment were not included in our model. However, the age dynamics and reversibility of outcomes such as anemia and learning-related disabilities could easily be incorporated into future modeling efforts to identify the optimal timing and frequency for their prevention. Other modifications may need to be considered as new data emerge. Children's growth patterns exhibit different rates according to levels of bone maturity and sexual development.44,57,72,73
Retardation in growth will continue if inflammation persists or quickly recurs,74
but there is a potential for regaining a normal growth velocity.75
Changes in environment and nutrient availability are not necessarily sufficient to reverse early growth impairment.72
However, the effect of a delayed puberty, sometimes seen in low resource settings, can be beneficial for catch-up growth if the causative insult has ceased.75
Our results suggest that in the typical setting of endemic schistosomiasis, where reinfection can rapidly occur after treatment, mass administration campaigns that include periodic retreatment through adolescence may be needed to obtain a healthy rate of growth.
Data are scarce on the true prevalence of schistosomiasis among preschool-age children.76
Our analysis was calibrated on detailed information from school-age children (5–20 yr) in one affected village. In the future, to assess the potential benefit of anti-schistosomal treatment during preschool years, it will be important to include these younger subjects in community-based studies, including more sensitive diagnostics for Schistosoma
infection than the standard, relatively insensitive assays based on egg-detection in stool and urine.77–81
Quantifying pro-inflammatory markers such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) among preschool-age children with serologic evidence of early infection could provide evidence of early effects of infection before egg numbers reach their threshold to be reliably detected in the excreta.47,80,81
Our simulations indicate that if growth deficits are associated with infection in preschool years, then starting treatment at earlier ages (preschool years) might yield the best results for achieving near-normal growth in high-risk areas. As structured, our model did not indicate a benefit for early age therapy. However, it was based only on data for children 5 years of age and older, and in areas where earlier growth deficits can be tied to schistosomiasis, then initiation of treatment in preschool years will likely prove beneficial. For now, and for the particular type of village setting studied here, our model clearly suggests that every other year treatments during school age (6–20 yrs) and high community adherence to treatment (> 50%) will provide the best aggregate growth outcomes among at-risk individuals.