The epidemiology of periportal fibrosis and relevance of currentSchistosoma mansoniinfection: a population-based, cross-sectional study

Abstract

ABSTRACTBackgroundIntestinal schistosome infections are known to cause periportal fibrosis (PPF). Yet, the epidemiology of PPF remains poorly understood, especially in settings endemic withSchistosoma mansoni.MethodsWe randomly sampled 1442 households from 38 villages in Mayuge, Buliisa, and Pakwach Districts of Uganda within the SchistoTrack Cohort to examine 2834 individuals aged 5-90 years. PPF was diagnosed using ultrasound and image patterns C-F from the Niamey Protocol.S. mansoniinfection status/intensity was diagnosed by Kato-Katz microscopy and point-of-care circulating cathodic antigens (POC-CCA). Schistosome infection, coinfections, and comorbidities were examined as exposures for PPF. Logistic regressions were run with standard errors clustered by household.FindingsPPF prevalence was 12·10% (343/2834), varying from 5·00-19·46% across districts.S. mansoniprevalence by Kato-Katz, and POC-CCA trace negative and positive was 43·37% (1229/2834), 40·86% (1158/2834), and 65·73% (1863/2834) respectively. Individual schistosome infection status/intensity was not correlated with the likelihood of PPF. Living in a village where adults had <5% prevalence of heavy intensity infections (400+ eggs per gram of stool) was associated with 30.2% decreased odds of PPF. The likelihood of PPF with age linearly increased from 5-25, exponentially changed from 26-45, remain unchanged from 45- 60, and steadily decreased past 60 years. History of liver diseases, human immunodeficiency virus positivity (HIV+), and ultrasound-detected chronic hepatitis/early cirrhosis-like disease were associated with >2-fold increased PPF likelihood.InterpretationCurrent individual schistosome infections alone are uninformative for PPF. History of HIV+ and underlying chronic hepatitis/early cirrhosis-like disease were risk factors and could be investigated for PPF surveillance and management.FundingNuffield Department of Population Health Pump Priming Fund, Wellcome Trust Institutional Strategic Support Fund (204826/Z/16/Z), John Fell Fund, Robertson Foundation Fellowship, and UKRI EPSRC Award (EP/X021793/1).Research in contextEvidence before this studyMorbidity due to parasitic infection is a complex interplay of current and past exposures. World Health Organization (WHO) guidelines for elimination of schistosomiasis as a public health problem assume current infection is a reliable proxy indicator of prevalent morbidity. Community infection thresholds are defined in guidelines and, when met, the assumption is there is no schistosomiasis-related morbidity. There is a lack of evidence for the association of infection with prevalent morbidity in the context of repeated treatment from routine mass drug administration. To evaluate WHO guidelines, there is a need for large-scale population- based, cross-sectional studies in endemic areas where current infection is compared with current morbidity at the same timepoint. A cross-sectional design also enables the investigation of a wide range of risk factors to assess the relative importance of current schistosome infection. Periportal fibrosis is a schistosomiasis-associated severe morbidity with clinical consequences such as portal hypertension, upper gastrointestinal tract bleeding, and ultimately premature death. Yet, little is known about the distribution of this disease; no information is available on its most basic epidemiology including age and gender-specific likelihoods. It is schistosomiasis-specific or attributable to schistosome pathology unlike more subtle conditions with complex aetiologies (e.g. anaemia). Hence, investigating periportal fibrosis serves as a first line, conservative approach to evaluating World Health Organization guidelines for elimination of schistosomiasis-related morbidity as a public health problem. A systematic literature search as part of an ongoing metanalysis was prospectively registered on PROSPERO (CRD42022333919). Databases were searched on 18thMay 2022 and included the Cochrane Central Register of Controlled Trials, Embase, Global Health, Global Index Medicus, and Medline. The following general terms were used: “Schistosoma” AND “fibrosis” AND “intensity” AND “infection” AND “periportal OR liver”. Studies were included that consideredSchistosoma mansoni,S. japonicum,orS. mekongispecies. Only original research articles in English were considered. No restriction on date of publication, age, gender, or region was applied. Infection was required to be diagnosed as opposed to self-reported. Periportal fibrosis was defined by the study authors.Added value of this studyNo population-wide or adjusted analyses were found to characterize the age-specific likelihood of periportal fibrosis. Studies focused on unadjusted associations in nonrandomly sampled populations of narrow age groups. In a single case (Weigand et al 2021) where adjusted analyses were completed (with age and gender considered), national programmatic data was used with sparsely nonrandomly sampled schoolchildren and limited frequency of the outcome of periportal fibrosis. Ultrasound data collection protocols and validation across studies were poorly reported. There was a lack of investigations on coinfections and comorbidities with only eight studies initiated (or published) from 2003 onwards after the start of mass drug administration in sub-Saharan Africa.Implications of all available evidenceTo our knowledge, this study is the first to characterize the epidemiology of periportal fibrosis with respect to the most common intestinal schistosome pathogen (S. mansoni). We conducted a comprehensive, population-based study of all ages (5+ years) eligible for mass drug administration in an area that has received at least 13 rounds of treatment. Here we provide clear evidence for the lack of association of currentS. mansoniinfection status and intensity with periportal fibrosis irrespective of the diagnostic for schistosome infection. No support was found for current WHO elimination guidelines despite using arguably the most biologically specific and severe morbidity associated with schistosomiasis. We also characterized the age-specific likelihood of periportal fibrosis, identifying a transitional age as young as 25 years. We identified future avenues for research into coinfections such as HIV and hepatitis B that appear to influence periportal fibrosis status even after controlling for a wide range of biosocial determinants of schistosome infection, treatment, and unrelated liver fibrosis. Future work is needed to understand if/how coinfections alter the pathogenesis of periportal fibrosis. Importantly, World Health Organization guidelines should be differentiated for schistosomiasis morbidities to discourage the use of infection status/intensity/prevalence as a proxy indicator for monitoring the elimination of periportal fibrosis as a public health problem.