Abstract

Author summary

Citation: Lim RM, Lahoti R, Clark J, Arinaitwe M, Anguajibi V, Alonso S, et al. (2025) The relationship between expelled eggs, morbidity and age in a Schistosoma mansoni endemic setting in Uganda: Implications for current elimination policies. PLoS Negl Trop Dis 19(9): e0012750. https://doi.org/10.1371/journal.pntd.0012750

Editor: Jennifer A. Downs, Weill Cornell Medical College, UNITED STATES OF AMERICA

Received: December 3, 2024; Accepted: August 18, 2025; Published: September 3, 2025

Copyright: © 2025 Lim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All data underlying the results presented in this manuscript are contained within the manuscript and its supporting information files. The full de-identified dataset, along with the code and models used to generate the analyses and figures is openly available at: https://github.com/Rivka1234/morbidity.

Funding: R.M.L. was supported by the Wellcome Trust PhD program (218492/Z/19/Z; under the supervision of A.B.P., J.P.W., and P.H.L.L.), the European Research Council (ERC) Starting Grant Schisto Persist 680088 was granted to P.H.L.L., the Engineering and Physical Sciences Research Council, EPSRC reference: EP/T003618/1 was also granted to P.H.L.L., and the European and Developing Countries Clinical Trials Partnership (EDCTP) RIA2017NIM-1842 was granted to J.P.W. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Schistosomiasis is a parasitic disease caused by trematodes of the Schistosoma genus. It is a substantial cause of global morbidity, with the highest disease burden found within sub-Saharan Africa [1]. Schistosoma mansoni is one of the key species responsible for the hepato-splenic and intestinal forms of the disease in humans, and infection is acquired by contact with freshwater infested with cercariae larvae that are shed from intermediate Biomphalaria spp snail hosts. Cercariae penetrate human skin, enter the bloodstream and migrate through the heart and lungs to the liver where they mate and mature [2,3]. Afterwards, most adult S. mansoni worms travel to the portal vein and mesenteric venules, where adult worm pairs are estimated to produce up to 300 eggs per day [4]. These laterally spined eggs are either shed from the body in the faeces, which drives onward transmission, or become trapped in host tissues. This can cause inflammation, granulomas, damage, and scarring, which can obstruct the veins surrounding the liver and cause hepatomegaly, portal hypertension, liver dysfunction and periportal fibrosis [5,6]. Infection can also cause non-specific symptoms such as abdominal pain, diarrhoea, blood in the stool, malnutrition, anaemia, stunting, and cognitive dysfunction [6,7].

The Niamey Protocol was developed to standardise the ultrasound-based evaluation of morbidity, focusing on detecting organ dysfunction, periportal fibrosis, portal hypertension, hepatosplenomegaly and ascites [8]. Other less specific diagnostic methods for morbidity include faecal occult blood point-of-care tests, visual identification of blood in stool, diarrhoea, self-reported abdominal pain and blood tests for anaemia [9]. Periportal fibrosis as diagnosed by the Niamey Protocol is aimed to be specific to S. mansoni-associated fibrosis. In contrast, less specific tests including liver and spleen enlargement may complicate the accurate attribution of morbidity causes. This limitation is particularly relevant in regions co-endemic for other infectious diseases such as malaria and soil-transmitted helminths (STHs) which can present with similar morbidity outcomes [10]. Additionally, these morbidity data are not typically collected during routine surveillance, monitoring and evaluation activities. Instead, faecal egg counts indicating current infection intensity are used as a proxy for morbidity with those shedding a high number of eggs assumed to be most at risk for morbidity [11–13].

Faecal egg counts (quantified as eggs-per-gram (EPG) of stool) and therefore diagnosis of S. mansoni is most commonly conducted using light microscopy and the Kato-Katz thick smear method [14]. For operational purposes, The World Health Organization (WHO) classifies infections as light, moderate and heavy (1–99, 100–399 and ≥400 EPG, respectively) [15]. However, the Kato-Katz method lacks sensitivity, particularly in low prevalence regions and when numbers of expelled eggs are low [16]. There can also be significant variation in day-to-day egg shedding rates from the same individual [17]. In 2017 the WHO endorsed the use of point-of-care circulating cathodic antigen (POC-CCA) tests for S. mansoni diagnosis [18]. These tests detect antigens regurgitated by feeding adult worms which are excreted in an infected person’s urine [18] and have higher sensitivity than Kato-Katz when detecting low-intensity infections [16], but concerns about the specificity of POC-CCA have emerged. A study by Clark et al. (2022) used Bayesian latent class analysis to assess the relationship between EPG, POC-CCA, and true infection status, and determined that using a POC-CCA score of G3 [19] offered a false positive rate of ~10–18% and high sensitivity (~90%) [20]. However, whilst statistical correlations between egg counts and POC-CCA exist [16,21,22] the two diagnostics measure different aspects of infection: egg output versus worm presence, and therefore may not align in their relationship to morbidity.

The main method of schistosomiasis control recommended by the WHO is mass drug administration (MDA), where at-risk communities are treated with the anthelminthic drug praziquantel, regardless of individual current infection status [23,24]. Due to the observed relationship between infection intensity and morbidity prevalence at the start of MDA, the initial objective of these programmes was reduce infection intensities as measured by Kato-Katz as a proxy indication for the reduction in morbidity prevalence [23,25]. School-aged-children (SAC) were therefore targeted for treatment as they typically harbour the highest infection intensities, to lower risk of morbidities later in life and because this age group is easier to access through schools [23]. However, whilst praziquantel treatment is effective at killing adult worms [22], it is not effective on juvenile worms and does not prevent reinfection [22]. As a result, heavy infections can rapidly develop/return post-treatment with the potential to cause further morbidity. Additionally, disease symptoms and associated morbidity may not be reversible with treatment especially if the infection is chronic or severe [26–28]. Furthermore, recent evidence challenges the use of current S. mansoni infection intensity as predictive of morbidity. A multi-country cohort study of SAC using ultrasound, clinical findings, and self-reported symptoms found no consistent association between WHO-defined infection intensity categories and morbidity markers [29]. An earlier comparative study from Egypt and Kenya also found no clear epidemiological association between infection intensities and morbidity markers such as periportal fibrosis or portal hypertension, despite substantial differences in infection intensity and prevalence of these conditions between the two regions [30]. Moreover, a recent systematic review and meta-analysis found an association between liver morbidity and current Schistosoma infection caused by intestinal species prior to the implementation of nationwide MDA programmes in 2003, however this association diminished in the post-MDA era [31].

Despite this lack of contemporary evidence to support the relationship between infection intensity and morbidity, the 2021–2030 Neglected Tropical Disease Roadmap which has targeted schistosomiasis for Elimination as a Public Health Problem (EPHP), has set the threshold for achieving this as <1% of heavy infections (>400EPG) in SAC in a community. This approach therefore continues to use infection intensity as a proxy metric for morbidity control [32]. Key to achieving EPHP is the inclusion of all children over two years of age (supported by the development and deployment of a paediatric formulation of praziquantel [33]), and an increase to biannual treatment in areas of high endemicity or persistent hotspots [34]. However, as control efforts advance there is growing concern that current morbidity definitions may not adequately take into consideration the differences between heavy and moderate infection intensities [35,36], or account for the impact of decades of MDAs, that may have mitigated disease progression leaving individuals with underlying morbidity or undetectable infections which could be missed by current guidelines. One solution posed by many is the redefining of targets based on overall infection prevalence, rather than heavy-intensity infections alone [35–37], though it is also unclear whether this would be any more suitable.

Disentangling the drivers of morbidity across different age groups remains a challenge for how best to optimise resource allocation and treatment strategies. Whilst previous studies have largely focused on SAC, there is a notable gap in research that examines morbidity and the influence of co-endemic infections on morbidity across the full spectrum of age groups in the same community, especially for PSAC. Additionally, although both the Kato-Katz method and the more sensitive POC-CCA diagnostic have been employed in past studies, there is a lack of research that systematically applies both diagnostics, detecting worm antigens and eggs simultaneously alongside multiple morbidity predictors, both specific and nonspecific, across all age groups.

Therefore, the objective of this study was primarily to understand whether infection intensity is associated with morbidity at a given time point, and whether egg- and antigen-based diagnostics have differing relationships with morbidity. We further examined the age-related distributions of morbidities, potentially reflecting the impacts of long-term chronic exposure. Finally, we sought to examine the relationship between Schistosoma-associated morbidity and the presence of current infections, including S. mansoni, Plasmodium, or STH.

Methods

Results

Discussion

Here we observed extremely high S. mansoni prevalence levels in Bugoto, Uganda, with 100% of 11–14-year-olds and 73% of the overall population infected with S. mansoni (based on Kato-Katz and/or POC-CCA diagnostics). We found relatively low to moderate infection intensities on average (arithmetic mean = 139 EPG, geometric mean = 81 EPG) and low prevalence of image pattern scores which could indicate liver fibrosis (IP(B-F) = 9%; IP(C-F) = 4%). However, counter to our expectations, we observed a moderate prevalence of other morbidity markers including PVD (34%), PSL (33%) and anaemia (13%) in this community.

Contrary to our initial hypothesis that morbidity would be highest in adults due to cumulative infections, PSAC showed the highest burdens: 50% had PVD dilation, 48% had enlarged PSL, and 24% were anaemic. This could be explained by immunological differences in developing immune systems. PSAC may produce a less effective Th-2-mediated granulomatous response, leading to reduced egg excretion and increased tissue egg retention, exacerbating morbidity even in low-intensity infections [51,52]. Supporting this, 43 individuals were egg-negative by Kato-Katz but positive by POC-CCA, with younger children overrepresented suggesting either undetected low-intensity infections or increased tissue egg deposition. Moreover, a limitation of our study was the absence of individual-level data on treatment history or duration of residence, making it uncertain whether adults have had continuous exposure. In contrast, PSAC are more likely to have lived their entire lives by the lake and to be treatment naive. Therefore, these factors may explain the unexpectedly high morbidity observed in PSAC and highlight the importance of using sensitive diagnostics such as POC-CCA, particularly in younger children, where low-intensity or tissue-localised infections may go undetected.

A recent study of PSAC in another highly schistosomiasis-endemic region of Uganda observed similar results: where 8% of the PSAC living in communities near Lake Albert had periportal fibrosis (IP (B-F score); [53]), comparable to the 5% we observed in Bugoto PSAC. However, we found much higher levels of other morbidity markers (PVD and PSL) in contrast to Lake Albert community PSAC who had no apparent signs of PVD and only 0.6% had enlarged PSL. These differences may be explained by methodological and epidemiological factors. While Pach et al. used a stricter ≥4 SD threshold to define morbidity, we applied a more sensitive ≥2 SD cut-off. Applying their threshold to our data reduces PVD prevalence to 0%, but PSL remains at 7%. Higher malaria prevalence (32% vs. 16%) may contribute to this difference as malaria was positively associated with PSL in our cohort, and higher previous exposure would likely be higher in our study location. The similar IP scores observed in both our study and Pach et al. (2024) suggest that early-life exposure to S. mansoni is sufficiently intense to initiate liver pathology regardless of region and, despite differences, both studies indicate the presence of incipient morbidity resulting from early infections and add further evidence to the need for exploration of the patterns of morbidity and morbidity risk factors among PSAC in diverse geographical regions.

An image pattern of B when measuring periportal fibrosis is often not measured due to its indeterminate nature [8], and although we cannot comment on fibrosis due to not having a corresponding PT score (see limitations below), we observed an image score of B almost exclusively in the 3–14-year-olds. A similar study which took place in Uganda from 2003-2005 also found only cases of periportal fibrosis with an image pattern of B in SAC, which they suggested could indicate early changes which, without treatment, would have progressed to more severe fibrosis [41]. The fact that these changes were no longer detectable after treatment in this study further supports the interpretation that IP score B may represent early liver changes directly attributable to S. mansoni infection. This finding almost 20 years prior to our own study highlights that this is not a new phenomenon but underscores that IP score B is a consistent marker of early morbidity. With the relative success of two decades of MDAs, particularly in SAC, potentially resulting in the lower incidence of severe morbidities traditionally found in older age groups (as were also found in our population, albeit at extremely low levels), the focus of studies are changing and looking at these more subtle clinical manifestations such as IP score B, which could characterise emerging morbidity in younger age groups.

The age associated distribution we observed could be linked to the timing of MDAs and the impact of sustained treatment in the face of rapid reinfection over many years. This study took place in May 2022 prior to any MDA treatments that year. In Bugoto, annual MDA of SAC began in 2003 [25,41], extending to the whole community (excluding PSAC) from 2004 and became biannual in 2019 [38]. Consequently, PSAC within this study cohort would not have been part of MDA. SAC would have experienced between 1 and 12 MDAs based on their age, and adults could have undergone a maximum of 22 MDAs throughout their lifetime if they had lived in this region since the control programme started. However, MDA coverage in Bugoto has been very low, especially in adults [44]. Furthermore, individuals born before the initiation of nationwide praziquantel MDA programmes would have experienced a longer period of untreated exposure during early life. This may contribute to the lower S. mansoni-specific IP scores observed in 15–20-year-olds, who likely benefited from regular MDA during childhood. Our results using PVD and PSL support this interpretation, showing a loss of the protective effect of treatment in adults over 40 years old, a group who were already aged 20 or more when praziquantel MDA began and may have sustained irreversible hepatic damage before treatment was available. Importantly, these findings strengthen the evidence that praziquantel may reduce schistosomiasis-associated morbidity, while also highlighting the need for early intervention. Starting treatment at school age may come too late for some children, as shown by the presence of extensive fibrosis in an 8-year-old and the high prevalence of PVD, PSL, and anaemia in PSAC in our study.

Importantly, we found no clear association between most of our morbidity markers and current S. mansoni infections. Only self-reported blood in stool was associated with current infection when measured with POC-CCA. The observed association between self-reported blood in stool and POC-CCA positivity, but not with Kato-Katz results, could be due to blood in stool not exclusively being a result of high-intensity infections, but rather from factors such as mucosal inflammation or immune-mediated tissue damage, which can occur even in lower-intensity infections. Because POC-CCA detects circulating antigens from live adult worms regardless of egg output, it may identify individuals with ongoing worm activity and associated morbidity that Kato-Katz misses, particularly in those with intermittent or low egg shedding and subtle morbidity.

According to the WHO thresholds, the Ugandan community examined here does not meet the criteria for having achieved either morbidity control (<5% heavy infections) or EPHP (<1% heavy infections) [15], as 11% of the population had heavy infections. Furthermore, morbidity was evident even among those individuals with light or moderate infections. While we did observe a trend of increasing PVD and PSL at very high EPG (>1200 and 1800 respectively), this represented a very small number of individuals and lies well beyond the WHOs threshold for heavy infection (≥400 EPG). This raises questions about the adequacy of these thresholds in reflecting actual morbidity risk and important ethical considerations regarding subtle morbidities and whether these are a health burden to individuals, their families and communities [45].

A current malaria infection was common amongst the participants (31%), being most prevalent in the younger age groups. It was associated with PVD, PSL and anaemia, mirroring the age-related patterns of morbidity, therefore indicating that either undetectable S. mansoni infection or a malaria infection, or a combination could be driving our results. Researchers observed a significant relationship between PSL and both S. mansoni infection and malaria infection in PSAC in Rusinga island, Kenya (also in the north eastern area of Lake Victoria) [10]. As the prevalence of PSL did not decrease after praziquantel treatment they associated this with an increase in malaria prevalence during the study. However, treatment with praziquantel does not always reduce Schistosoma-associated morbidity [26,28,54], therefore the observed hepatomegaly may not have been exclusively caused by malaria infection in Rusinga island. When examining the role of a hookworm infection and morbidity in our study, there was no association between a detected hookworm infection and any of the morbidity markers in our study group. This contrasts with previous findings in the same district in 2013 which found a significant association between anaemia and having a heavy hookworm infection. These differences are likely due to the much higher prevalence of hookworm and anaemia at that earlier time-point, which were 41% and 44% respectively, rather than 14% and 13% observed in our study, and perhaps an indication of successful STH treatment programs which have run alongside Schistosoma MDAs since 2003. These studies along with our own findings highlight the difficulty in disentangling the aetiology of morbidities in regions with co-endemicity and the importance of integrated control programs which have overall benefits in reducing parasite burden and shared associated morbidity.

As we contemplate the new guideline of biannual treatment in all regions with over 50% prevalence [32], we anticipate a decline in severe morbidities [36]. However, this shift will bring new challenges in detecting and managing subtle morbidities, therefore underscoring the need for comprehensive approaches that safeguard the health and well-being of affected communities and individuals of all ages.

Limitations

A measurement of the second order branches used to establish a PT score according to the Niamey protocol were not measured during this study due to constraints with the equipment available. As periportal fibrosis is estimated using a combination of both IP and PT score, we could not accurately report on fibrosis in this study, therefore we gave a description of the IP scores without indicating fibrosis.

Generalisability of our findings is limited by the fact that results are based on a single cross-sectional study in one community in Mayuge District, so our results should be used to complement longitudinal, population-level analyses by capturing under-documented morbidity patterns across all age groups. Additionally, our sample included a higher proportion of female participants (63%), higher than the district average of 51%. This sex imbalance may have influenced the morbidity patterns we observed. For instance, adult males, who exhibited a higher intensity of infection than females, were underrepresented, potentially leading to an underestimation of chronic morbidity in the adult population.

Although the Niamey protocol provides organometric measurements for comparison of height matched individuals with PVD and PSL scores, the recommendation was always to use values from healthy people of the same ethnic group and region [8]. However, in practice this is rarely undertaken, and the Senegalese controls provided in the protocol are usually used, for example [10,27,40,53,55–57] often due to difficulties in finding truly uninfected and unexposed controls from these highly endemic regions. We explored whether those with undetectable S. mansoni infection in our study community had higher morbidity than those in the Sudanese population and found consistently higher measurements for PSL and PVD in the participants from Bugoto (S1 Fig). This could indicate that previous infections leave lasting damage or that subclinical and sub-diagnostic infections, or parasite exposures are indeed causing harm. However, these differences could also be due to inter-site variation [30] or due to the lack of malaria in this Senegal region. This reliance on external comparator data could have introduced misclassification in our designation of morbidity, potentially overestimating the prevalence of enlarged PSL or dilated PVD if the Senegalese reference values underestimate normal liver dimensions for our Ugandan population. Conversely, if underlying morbidity exists even in individuals who test negative for S. mansoni, then our approach may have helped reveal true but subtle disease that would otherwise go unrecognised.

Supporting information

Acknowledgments

We would like to thank the communities of, and individuals in, Bugoto for participating in this study. We would also like to thank Dr Elias Kabbas-Piñango, Raheema Chunara and Thomas Arme for their invaluable work in the field, and Prof. Jonathan Fallowfield and Dr Timothy Kendall for their advice and opinions on liver morbidities.

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