A Decade of Chronic Norovirus Infection Surveillance at the NIH Clinical Research Center: Clinical Characteristics, Molecular Epidemiology, and Replication

Background Noroviruses are an important viral cause of chronic diarrhea in immunocompromised individuals. Method We collected norovirus-positive stool samples (n=448) from immunocompromised patients (n=88) at the National Institutes of Health Clinical Research Center, U.S. from 2010-2022. We assessed clinical characteristics of the cohort, norovirus molecular epidemiology, and infectivity of norovirus specimens in human intestinal enteroids (HIEs) monolayers. Results Thirty-nine of the 88 patients had sequential stool samples that allowed documentation of chronic norovirus infection with shedding levels ranging from 104 to 1011 genome copies/g of stool. The majority with confirmed chronic norovirus infection in this cohort (32/39, 82%) had clinical evidence of an inborn error of immunity (13 identified monogenic diseases), most with combined immunodeficiency (15 of 32) or common variable immunodeficiency (11 of 32). Noroviruses detected in the cohort were genetically diverse: both Genogroup I (GI.2, GI.3, GI.5, and GI.6) and Genogroup II (GII.1-GII.4, GII.6, GII.7, GII.12, GII.14, and GII.17) genotypes were detected, with GII.4 variants (Osaka, Apeldoorn, Den Haag, New Orleans, and Sydney) predominant (51 of 88, 57.9%). Viruses belonging to the GII.4 Sydney variant group that replicated in HIEs (n=9) showed a higher fold-increase in RNA genome copies during infection compared to others that replicated. Conclusions Genetically and biologically diverse noroviruses established chronic infection in individuals with both inborn and acquired immunologic defects enrolled in an NIH surveillance study spanning 12 years, demonstrating the unique nature of each virus and host interaction.