Association of current Schistosoma mansoni, Schistosoma japonicum, and Schistosoma mekongi infection status and intensity with periportal fibrosis: a systematic review and meta-analysis

Background: Periportal fibrosis is a severe morbidity caused by both current and past exposure to intestinal schistosomes. We aimed to assess the association between current infection status and intensity of Schistosoma mansoni, Schistosoma japonicum, or Schistosoma mekongi with periportal fibrosis.

Methods: In this systematic review and meta-analysis, we searched the Cochrane Central Register of Controlled Trials, Embase, Global Health, Global Index Medicus, and MEDLINE from database inception to June 18, 2024. We applied methodological filters to limit our search to randomised controlled trials or observational studies, including before-and-after study designs. Animal studies were excluded, and no date or language limits were applied. We excluded reviews, editorials, personal opinions, and case reports. Self-reported infection status was an ineligible exposure. Two reviewers independently screened abstracts and full-text reports for eligibility. A third reviewer was consulted in cases of disagreement. The outcome of periportal fibrosis was recorded as reported by study authors to investigate variation in liver fibrosis definitions. For the key exposure of current infection, data were extracted for Schistosoma species, diagnostics, and author-provided infection status and intensity definitions. A meta-analysis was conducted for current schistosome infection status and intensity against author-defined current periportal fibrosis. Pooled effect sizes were derived using inverse-variance weighted random effects. Subgroup analyses included study characteristics and quality. The modified National Institute of Health risk of bias tool was used for assessing study quality. The protocol adhered to PRISMA reporting standards and was prospectively registered on PROSPERO, CRD42022333919.

Findings: Our electronic search retrieved 2853 records, of which 1036 were duplicates. Nine records were identified in bibliographies of eligible full-text reports. We screened 1826 titles and abstracts to find 282 articles that met our inclusion criteria for full-text review. 41 studies were eligible for systematic review, 33 studies were eligible for infection status meta-analysis, and seven studies were eligible for infection intensity meta-analysis. Periportal fibrosis was heterogeneously defined with the Niamey ultrasound protocol most used. When findings were pooled, current schistosome infection status was associated with a higher likelihood of periportal fibrosis compared with no current infection (odds ratio [OR] 2·65, 95% CI 1·79-3·92; p<0·0001). Heterogeneity was high (I²=95·81%). In sub-Saharan Africa, before the widespread introduction of mass drug administration in 2003 there was a significant association between current infection status and periportal fibrosis (OR 5·38, 95% CI 2·03-14·25) but this association was no longer present after 2003 (1·19, 0·82-1·74). No association of current infection status was observed with periportal fibrosis in studies that used the Niamey protocol (1·57, 95% CI 0·95-2·59). Associations depended on moderate to high risk of bias studies. No significant differences in pooled effect sizes were observed between infection intensity categories and periportal fibrosis.

Interpretation: WHO guidelines use current schistosome infection intensity as a proxy for schistosomiasis-related morbidity. Our findings support that current infection status is only tenuously associated with periportal fibrosis. Guidelines are needed to better monitor schistosomiasis-related morbidities.

Funding: Nuffield Department of Population Health Pump Priming Fund, Wellcome Trust Institutional Strategic Support Fund, John Fell Fund, Robertson Foundation, and UK Research and Innovation Engineering and Physical Sciences Research Council.