The global distribution map of schistosomiasis shows a large overlap of Schistosoma haematobium- and S. mansoni-endemic areas in Africa. Yet, little is known about the consequences of mixed Schistosoma infections for the human host. A recent study in two neighboring co-endemic communities in Senegal indicated that infection intensities of both species were higher in mixed than in single infections. Here, we investigated the relationship between mixed Schistosoma infections and morbidity in the same population. So far, this has only been studied in children. Schistosoma infection was assessed by microscopy. Schistosoma-specific morbidity was assessed by ultrasound according to WHO guidelines. Multivariable logistic regression models were used to identify independent risk factors for morbidity. Complete parasitological and morbidity data were obtained from 403 individuals. Schistosoma haematobium-specific bladder morbidity was observed in 83% and S. mansoni-specific hepatic fibrosis in 27% of the participants. Bladder morbidity was positively associated with S. haematobium infection intensity (OR = 1. 9 (95% CI 1. 3–2. 9) for a 10-fold increase in intensity). Moreover, people with mixed infections tended to have less bladder morbidity than those with single S. haematobium infections (OR = 0. 3 (95% CI 0. 1–1. 1) ). This effect appeared to be related to ectopic S. mansoni egg elimination in urine. Hepatic fibrosis on the other hand was not related to S. mansoni infection intensity (OR = 0. 9 (95% CI 0. 6–1. 3) ), nor to mixed infections (OR = 1. 0 (95% CI 0. 7–1. 7) ). This is the first population-wide study on the relationship between mixed Schistosoma infections and morbidity. Mixed infections did not increase the risk of S. mansoni-associated morbidity. They even tended to reduce the risk of S. haematobium-associated morbidity, suggesting a protective effect of S. mansoni infection on bladder morbidity. These unexpected results may have important consequences for schistosomiasis control in co-endemic areas and warrant further investigation.
Worldwide more than 207 million people are infected with Schistosoma, 85% of whom live in Africa [1]. Due to the large overlap in Schistosoma haematobium- and S. mansoni-endemic areas [2]–[4] many people are at risk of co-infection. Yet, little is known about mixed Schistosoma infections and their impact on host morbidity. Clinical manifestations of schistosomiasis are associated with the species-specific oviposition sites [2]. Both S. haematobium and S. mansoni mature in the portal vein of the human host and form male-female pairs. Subsequently, the S. mansoni male carries the female to the mesenteric plexus whereas the S. haematobium couple continues its way to the veins of the pelvis. In these respective sites, they lay eggs, which are eventually eliminated from the body via the urine (S. haematobium) or feces (S. mansoni). About half of the eggs, however, are carried away with the blood stream and/or trapped in the tissues. These retained eggs provoke inflammatory and granulomatous immune responses [2]. For S. haematobium, this can lead to inflammation, ulceration and pseudopolyposis of bladder and ureteral walls, and in children this is often accompanied by hematuria. Chronic lesions may evolve to fibrotic and sandy patches with severe sequelae such as hydroureter, hydronephrosis, and squamous bladder cancer [2], [5], [6]. For S. mansoni, egg deposition can lead to inflammatory hepatic schistosomiasis and hepatosplenomegaly in children and adolescents [7]. Trapped schistosomal eggs are gradually replaced by fibrotic deposits, and give rise to chronic hepatic schistosomiasis [2]. In mixed S. mansoni and S. haematobium infections, the above-described processes act in parallel, which may result in more severe or other abnormalities than in single infections. So far, only two studies have investigated the relationship between mixed infections and host morbidity. In Zimbabwe, a positive association between S. mansoni egg output and liver size was found in the presence but not in the absence of S. haematobium. Yet, this effect was very little [8]. In a study in Mali, mixed infection was associated with reduced hepatic morbidity on one hand and increased bladder morbidity on the other [9]. Both studies were performed in schoolchildren, in whom severe hepatic schistosomiasis is unlikely to have developed already [2], [7], [10]. Community-wide studies would therefore be more appropriate to investigate mixed infections and morbidity. In northern Senegal, many communities have in the past decades become co-endemic for S. mansoni and S. haematobium [11]–[16]. Schistosoma mansoni was introduced in Richard-Toll in 1988 upon construction of the Diama dam and rapidly spread throughout the region [17], [18]. By 1994, virtually the entire Guiers Lake (‘Lac de Guiers’) area had become exposed to this species [19]. Today, both S. mansoni and S. haematobium are widely spread, resulting in a large number of people with mixed infections in the communities around the lake. Recently, we reported on the distribution of and risk factors for mixed Schistosoma infections in two communities on the banks of Lake Guiers. Individuals with mixed infections were found to have higher infection intensities than those with single infections [20]. In the present study, we set out to investigate the relationship between mixed Schistosoma infections and morbidity in the same communities. We studied the patterns of S. haematobium-specific bladder morbidity and S. mansoni-specific hepatic morbidity in this co-endemic focus, and compared morbidity in people with mixed Schistosoma infections to those with single infections.
This study was part of a larger investigation on the epidemiology of schistosomiasis and innate immune responses (SCHISTOINIR: www. york. ac. uk/res/schistoinir) for which approval was obtained from the review board of the Institute of Tropical Medicine, the ethical committee of the Antwerp University Hospital and ‘Le Comité National d' Ethique de la Recherche en Santé’ in Dakar. Informed and written consent was obtained from all participants prior to inclusion into the study. This study was conducted from July until November 2009 in Ndieumeul (also known as Thiekène) and Diokhor Tack, two neighboring communities on the Nouk Pomo peninsula in Lake Guiers. Details on the study area have been described elsewhere [20]. Two urine and two feces samples were collected from each participant on consecutive days for microscopic analysis [21], [22]. Per feces sample, two Kato-Katz slides of 25 mg fecal material each were prepared and microscopically examined for Schistosoma species [22]. Schistosoma mansoni infection intensity was expressed as the number of eggs detected per gram of feces (epg). Urine filtration was performed using a filter of 12 µm pore-size (Isopore) according to standard procedures [21]. Schistosoma haematobium infection intensity was expressed as the number of eggs detected per 10 ml of urine (ep10ml). Ectopic eggs were measured qualitatively (positive/negative). Ectopic egg elimination refers to elimination of schistosomal eggs via the unusual route – i. e. S. mansoni eggs in urine or S. haematobium eggs in feces. Single infection was defined as passing eggs of only one species, and mixed infection as passing eggs of both S. mansoni and S. haematobium, regardless of the route of egg elimination [20]. Microhematuria was determined in a subsample using Combur 7 dipsticks (Roche) on the first urine sample. All community members were offered praziquantel (one dose of 40 mg/kg body weight) and mebendazole (one dose of 500 mg) treatment after the study according to WHO guidelines [23]. Participants were examined using a portable ultrasonography device with convex transducer. Pathologic lesions associated with S. haematobium or S. mansoni infection were recorded according to the Niamey guidelines [10]. All examinations were performed by the same clinician who was blind to the participant' s infection status. Participants with severe pathology that needed further treatment were referred to the appropriate health authority. For S. haematobium-specific morbidity, the urinary bladder score was determined [10]. A score of ≥1 was considered as S. haematobium-specific urinary bladder morbidity in accordance with previous studies [9], [24]–[30]. Individuals with a score of 0 were categorized as controls. For S. mansoni-specific morbidity, the liver image pattern was determined [10]. Additional measurement of periportal thickening was not included as this approach has been shown to be not reproducible [31]. Liver image patterns of C to F were categorized as S. mansoni-specific hepatic morbidity [31]–[35]. Individuals with liver image pattern A or B are not likely to have periportal fibrosis [10] and were therefore categorized as controls. Individuals with signs of hepatic morbidity that were not specific for S. mansoni (e. g. hepatitis, cirrhosis or fatty liver) were excluded [10]. IBM SPSS 19. 0 (SPSS, Inc.) was used for statistical analysis. Results were considered significant when the p-value was <0. 05. As egg outputs showed skewed distributions, data were normalized by log (base 10) -transformation after adding half of the detection limit to allow for zeros. Differences between groups were determined by the Pearson Chi-square test for community and gender, and by the Mann-Whitney U test for age. Furthermore, the Pearson Chi-square test was used to determine the association between bladder morbidity and microhematuria, as well as between bladder and liver morbidity. Because of the non-linear trend of morbidity over age, the population was divided into four age groups (0–9,10–19,20–39 and ≥40 years) for multivariable regression analysis. Multivariable logistic regression models were used to identify independent risk factors for S. haematobium-specific bladder morbidity and S. mansoni-specific hepatic fibrosis, respectively. Age, gender, community of residence, S. haematobium infection intensity and S. mansoni infection intensity were included as potential risk factors. Moreover, significant interaction terms with age (p<0. 05) were added. Similar models were used to assess the independent effect of mixed infection (as compared to single infection) on S. haematobium-specific bladder morbidity and S. mansoni-specific hepatic fibrosis, respectively. Among S. haematobium-positive subjects, the association between bladder morbidity and mixed infection was investigated using a dummy variable for mixed infection (1 = mixed, 0 = single), and age, gender, community of residence and S. haematobium infection intensity as other determinants. Likewise, the association between hepatic fibrosis and mixed infection was investigated in S. mansoni-positive subjects with a dummy variable for mixed infection and upon correction for age, gender, community of residence and S. mansoni infection intensity.
Schistosoma haematobium-specific bladder morbidity was observed in 83% of the study population (334/403; Table 1). Most common lesions concerned multifocal or diffuse bladder wall thickening (n = 189), irregularities (n = 94) or a single mass (n = 19). Microhematuria was twice as prevalent among those with bladder morbidity as compared to those without (44% versus 21%, p = 0. 002). S. mansoni-specific fibrosis was present in 27% (109/403) of the population (Table 2). Liver image patterns up to F were observed, but the large majority had pattern C (89/109). Morbidity of both liver and bladder was observed in 24% (93/391) of the study participants (Table 3). Those who had bladder morbidity tended to be more at risk for hepatic fibrosis and vice versa (odds ratio (OR) = 1. 3 (95% confidence interval (CI) 0. 7–2. 4) ). Figure 1 shows that bladder morbidity was mainly observed in children (<20 years), with a peak in 10-to-19-year-olds. The age-related distribution of bladder morbidity coincided with that of S. haematobium infection intensity and microhematuria, although the peak was slightly later in adolescence, and the subsequent decline in adults less pronounced. The prevalence of hepatic fibrosis increased from 6% in 0-to-9-year-olds to 44% in those ≥20 years old. The more severe forms of hepatic fibrosis (liver image patterns D, E and F) only became apparent in adults (≥20 years old). The peak in the age-related distribution of hepatic fibrosis occurred more than 10 years later in life than the S. mansoni infection intensity peak (Figure 1). Multivariable analysis showed age to be a significant risk factor for bladder morbidity as well as hepatic fibrosis (Table 4). However, age-related patterns of hepatic fibrosis differed between the two communities (p = 0. 033): while the ORs for hepatic fibrosis increased with age in Diokhor Tack (p<0. 001), they did not vary with age in Ndieumeul (data not shown). Individuals from Diokhor Tack were significantly more at risk for hepatic fibrosis but tended to be less at risk for bladder morbidity than their counterparts from Ndieumeul (Table 4). Furthermore, females were less at risk for both forms of morbidity than males. Neither S. mansoni intensity nor S. haematobium intensity was identified as an independent risk factor for hepatic fibrosis. On the other hand, S. haematobium (but not S. mansoni) infection intensity was a strong risk factor for bladder morbidity. After including mixed infection into the multivariable model, the above-described trends remained the same (Table 5). The risk of hepatic fibrosis did not differ between subjects with single S. mansoni and those with mixed infections. Interestingly however, mixed infection tended to be negatively associated with S. haematobium-specific bladder morbidity, suggesting a protective effect of current S. mansoni infection (p = 0. 068). Ectopic S. haematobium eggs were found in one (0. 6%) and ectopic S. mansoni eggs in 23 (13%) out of 176 individuals with mixed infections. Table 6 illustrates the importance of the route of S. mansoni egg elimination in the development of bladder morbidity. Those who eliminated S. mansoni via both urine and feces (n = 17) had highest S. haematobium infection intensities and prevalences of bladder morbidity. Lowest prevalences of morbidity were observed in those who exclusively eliminated S. mansoni eggs via the urine (and not via the feces; n = 6), despite relatively high S. haematobium infection intensities.
Up to now, the relationship between mixed Schistosoma infection and morbidity has only been studied in schoolchildren. This population-wide study is the first to include adults. Mixed infections were not associated with an increased risk of S. mansoni-associated morbidity and even tended to reduce the risk of bladder morbidity. These unexpected results warrant further investigation of a possible protective effect of S. mansoni on bladder morbidity. Especially the role of interspecies interactions and ectopic S. mansoni egg elimination should be studied in more detail, as these phenomena may have important consequences for schistosomiasis morbidity and control in co-endemic areas.
In the developing world, over 207 million people are infected with parasitic Schistosoma worms. Schistosoma haematobium and S. mansoni are the most abundant species in Africa and many people carry both. Yet, little is known about the consequences of such mixed infections. In general, S. haematobium affects the urinary tract of the host and S. mansoni the liver. Here, we investigated the effect of mixed Schistosoma infection on these health problems. We examined 403 people from northern Senegal for Schistosoma infections as well as for abnormalities of the urinary bladder and liver. Recently, we observed that people with mixed Schistosoma infections had generally higher infection intensities than those with single infections. The present study showed that abnormalities of the urinary bladder were more common in heavy than in light S. haematobium infections. Also, they were more common in single S. haematobium than in mixed infections. So far, only two studies have looked into the relationship between mixed Schistosoma infection and abnormalities of the bladder and liver, but only investigated children. Our findings suggest a possible protective effect of S. mansoni on bladder disease, in children as well as in adults. This may have important consequences for schistosomiasis control in co-endemic areas.
medicine
urology
public health and epidemiology
bladder and ureteric disorders
infectious disease epidemiology
microbiology
host-pathogen interaction
parasitic diseases
liver diseases
gastroenterology and hepatology
neglected tropical diseases
portal hypertension
infectious diseases
medical microbiology
epidemiology
biology
pathogenesis
schistosomiasis
Bladder Morbidity and Hepatic Fibrosis in Mixed Schistosoma haematobium and S. mansoni Infections: A Population-Wide Study in Northern Senegal