Lifting the Burden of Schistosomiasis—Defining Elements of Infection‐Associated Disease and the Benefits of Antiparasite Treatment

Over the past 50 years, the challenge of schistosomiasis control has persisted as a complex dilemma for health policymakers-there has even been a debate about whether schistosomiasis has any “significance” to public health and whether it has priority for control [1]. The major schistosome parasites of humans, Schistosoma haematobium, S. mansoni, and S. japonicum, are prevalent in many parts of Africa, the Middle East, South America, China, Southeast Asia, and the Philippines, and there are >200 million people who are infected worldwide [2]. The article by Koukounari et al. [3] in this issue of the Journal is part of a modern, multigroup research effort that aims to better define the impact of schistosomiasis on children's health and to refine the understanding of the specific benefits of mass treatment in schistosomiasis-endemic settings. One of the particular strengths of the study is its large size and the broad distribution of its study subjects across the country of Burkina Faso. The study children were treated there as part of the ongoing Schistosomiasis Control Initiative (SCI). The SCI, which has now been implemented in 7 countries in sub-Saharan Africa, is a collaborative program focused on schistosomiasis morbidity control that is supported by national health and education ministries and the Bill and Melinda Gates Foundation through the Imperial College London. In the article, Koukounari et al. report on the impact of the first year of praziquantel therapy on anemia and nutritional health outcomes among Burkinabé school-aged children (6–14 years old) who were tested at 16 sentinel schools. The study subjects were sampled from among the >3 million children from S. haematobium-endemic areas who were treated during the first year of therapy in the country. The pretreatment results show that, even after adjustment for age, sex, nutritional status, and environmental factors, there is a significant association between heavy S. haematobium infection and individual risk of heavy hematuria. Of interest, then, is that in examining the subjects' adjusted risk for anemia in this pretreatment setting, independent effects were apparent for high-intensity infection and for hematuria in reducing hemoglobin levels. These findings mirror those of recent studies of S. japonicum, which suggested that both anemia of chronic inflammation and chronic iron loss contribute separately to the causation of anemia in schistosomiasis japonica [4]. Fortunately, with treatment, infection intensity and hematuria scores were markedly improved throughout the study population, and hemoglobin levels were significantly increased among those who had been the most anemic at the start as well as among those who had had the highest level of pretreatment hematuria. Why is there continuing controversy about the disease burden of schistosomiasis and the benefits of its populationbased chemotherapy? The answer derives from our lingering uncertainty about the true disability caused by Schistosoma infection [5]. In areas of endemicity, chronic schistosomiasis represents a significant but poorly gauged cause of disease. Schistosomiasis is a complex, chronic condition that persists for decades, and the experience of infection is strongly embedded in the pattern of rural poverty. Because it is transmitted only by select species of intermediate host snails, the distribution of schistosomiasis can be patchy, but it is always strongly tied to poor sanitation and the local environment [6]. Although many studies have attempted to measure different “objective” clinical outcomes of infection, such as hepatosplenomegaly and tissue fibrosis (detected on ultrasound), most of these studies have failed to capture the impact of infection on patient-centered disease—that is, the performance status of the infected individual. The most obvious, life-threateningforms of advanced disease caused by schistosomiasis are relatively rare (∼1% of infected subjects) [7]. Meanwhile, the majority of schistosomiasis-infected subjects are variably sick but do not come to medical attention, perhaps because the chronicity of their condition embeds the disease as “normal” in their experience and does not provoke a demand for immediate attention, particularly where local health resources are scarce. Certain schistosomiasis-related health outcomes can be subtle and are thus not well recognized. Nevertheless, in metaanalysis of combined data from multiple clinical studies, we can detect significant associations between schistosomiasis and important performance-related healthdeficits, such as malnutrition, anemia, and loss of work productivity. In the context of the rural poverty trap [8], performancerelated outcomes are highly significant to household survival, yet because the clinical manifestations are seen in the context of multiple comorbidities, they are much more difficult to quantify and to attribute specifically to schistosome infection. In effect, our limited epidemiological methods have to date prevented us from clearly identifying the impact of schistosome infection on very important morbidity outcomes. The limitations in the available data led many policymakers in the 1970s and 1980s to conclude that most schistosomiasis per se was “asymptomatic” and, as such, did not need to be treated unless serious complications ensued. This mind-set reflected the high cost of treatment ($4 per person) during that era, and at the time it was considered appropriate in many settings to limit intervention to treating only those persons with intense infections or advanced disease [9]. To a large extent, the conventional wisdom that average schistosomiasis-associated morbidity is only “minimal” persists even today and enters into many of today's discussions about the merits of populationbased therapy [10]. However, as detailed below, there are cogent reasons to believe that schistosome infection causes significant disabling morbidity in most infected subjects and so deserves greater attention with public health implementation of broad-based control to prevent or delay reinfection [11]. Why has schistosomiasis-related morbidity been hard to spot in clinical studies? On the basis of a systematic review of available studies [5], the answers include the following. Misclassification bias. Despite the time-honored use of standardized parasitological examination for egg detection in stool or urine, problems persist in the accurate detection of Schistosoma infection and the quantification of infection intensity [12]. Because of day-to-day variation in egg excretion, many infections of light intensity are missed in standard parasitologic testing, with the result that the many of the local “uninfected” subjects used in comparison groups for field studies are, in fact, truly infected. This phenomenon reduces our power to detect small but significant differences in sensitive variables, such as hemoglobin levels or height and weight deficits. Multiple causative pathways for individual disease outcomes. Anemia in schistosomiasis can be related to inflammatory suppression of erythropoiesis (“anemia of chronic disease”) alone or to excessive iron loss in combination with dietary iron deficiency [13]. Measurable growth stunting and caloric undernutrition can be dependent on context from study to study—for instance, on growth rate, ethnicity, and available food resources. Age- and time-dependent differences in disease formation. We know that untreated schistosomiasis is a chronic inflammatory disease engendered by the human host response to parasite eggs deposited in the wall of the bowel (S. mansoni and S. japonicum) or in the walls of the bladder and ureters (S. haematobium). Local inflammation and ulceration are essential components of egg release (transmission) and so are nearly always present during active infection. Some host tissue damage is acute and reversible, but progressive fibrotic injury accumulates over time, and this latter form of chronic disease is often irreversible. The “subtlety” of acute and chronic disease presentation can depend on the important effect modification of an individual's age, his or her current and past underlying nutritional status, and the presence of comorbidities. Typically, the late forms of schistosomiasis-related disease will not be reversible with antiparasite therapy and therefore may not be thought to be “attributable” to schistosome infection. Potential nonlinearity of the effect of infection intensity. There is a general belief that heavy infection (a high worm burden) places an individual at a higher risk for disease formation. This once seemed plausible on the basis of the premise that a greater rate of egg deposition in host tissues will result in greater cumulative inflammation and tissue damage, as was shown for hematuria outcomes in the study by Koukounari et al. [3]. However, on reexamination of older data [14], the correlation between infection intensity and the prevalence of other forms of disease is actually fairly loose, and subjects with infections of light intensity will also manifest the more severe forms of schistosomiasis-related disease, including bladder granulomata [15] and malnutrition [3]. For these subjects, disease formation is more likely a function of the intensity of their individual antiparasite immune responses and not worm burden. For this subset of patients, it is the presence or absence of schistosome infection that drives their disease risk, not the intensity of infection. In the past, when only a subset of the study population showed advanced infection-associated deficits, the conclusion frequently drawn was that “on average” there was no serious deficit due to infection. Yet the failure to show a statistically significant effect is not the same as the absence of an effect, and the asymmetric impact of moderate anemia and growth stunting in the context of developing economies [16] means that average infection does indeed have a significant health and economic impact. Careful observations of such relevant outcomes in current studies that combine adequate sampling power and appropriate multilevel adjustment for age, sex, baseline morbidity, and infection status will enable a much better definition of the impact of schistosomiasis and the specific benefits of its treatment and cure.