Reply
Authors: Michael Charlton
Journal: Hepatology (2015)

We read with interest the letters by Kuniholm et al. and by Engle et al., both with Dr. Purcell from the National Institute of Allergy and Infectious Diseases at the National Institutes of Health as corresponding author. We would like to respond to both letters in turn. The title of the first letter finishes with the alluring statement, "Facts trump opinion." We could not agree more. The first objection seems to be to questions regarding the specificity and sensitivity attributes of the in-house (helper T lymphocyte; HTL) assay that was used in the National Health and Nutrition Examination Survey (NHANES) and the literature we cite to support the possibility that assay attributes may have contributed to the variation in observed hepatitis E virus (HEV) seroprevalence between NHANES studies. The references we cited were intended to demonstrate marked variation in estimates of prevalence of HEV with assays used. We did not intend to imply that each of the references pertained to the HTL assay. We regret the misunderstanding. The authors of the letter cite their own work (reference 38) demonstrating the high specificity and reproducibility of their HTL assay. We note that this work finishes with the statement that, "Highly discrepant results among U.S. blood donor sera indicate that anti-HEV seroprevalence data in non-HEV-endemic countries may be unreliable and should be interpreted with caution." Once again, we could not agree more. One of the issues is that the "facts" about HEV vary with assays. In our discussion, we present several possible explanations for the dramatic decline in the estimated seroprevalence of HEV immunoglobulin G (IgG) in the NHANES study populations. We include an actual decline in seroprevalence and variation in assay performance characteristics among possible explanations. We stand by these elements of our discussion. The title of the second letter finishes with a similarly alluring statement, "No easy answers." With regard to the possibility of a cohort effect explaining the differences in the seroprevalence between the NHANES studies, we agree again. Our discussion refers to this possibility in the first paragraph, among others. We do not purport to have answers, easy or otherwise, regarding the true seroprevalence of HEV infection in the United States. However, we believe that a dispassionate consideration of all plausible scientific explanations for the differences in HEV seroprevalence between NHANES studies is necessary. The NHANES data sets are made publically accessible, in part, to facilitate the generation of independent perspectives. The authors in their letter also point out that the NHANES did not examine all "meat consumption." We italicized "meat consumption" in our article to reflect this. We did not suggest or state that all meats were considered. We agree that the type of meats considered is important. Finally, the authors in their letter ask why the higher absolute seroprevalence of HEV IgG in age strata of persons of non-U.S. birth did not translate to multivariate significance. It is the fate of many parameters to lose statistical significance in multivariate analyses. In this instance, adjusting for differences in race, antibodies to hepatitis A virus status, marital status, and meat consumption among persons born outside of the United States reduced the statistical significance of place of birth. We thank the authors for their concerns and insights. Michael Charlton, M.B.B.S., F.R.C.P. Division of Hepatology Department of Medicine Intermountain Medical Center Salt Lake City, UT