Nonnegligible Seroprevalence and Predictors of Murine Typhus, Japan (Response)

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In Response: We thank Dr. Iwata (1) for his remarks regarding our study of seroprevalence and predictors of murine typhus in Japan (2). In reference to long-term seropositivity, high seroprevalence of Rickettsia typhi might reflect distant past murine typhus (MT) infections rather than recent infections (2). We acknowledge the significance of this limitation in interpreting our results, which we first addressed in a preprint of the article (T. Aita et al., unpub. data, https://doi.org/10.1101/2023.01.12.23284497). Nonetheless, we posit that R. typhi seroprevalence would include some persons who have recently experienced MT. First, participants with remarkably high R. typhi IgG titers probably had recent MT infections, because R. typhi IgG titers generally undergo a continuous postinfection decline in diagnostic serologic assays. The percentage of persons with antibody titers of >1:3,200 in an indirect immunofluorescence assay was ≈85% at 4 weeks postinfection but decreased to ≈25% within 1 year (3). In addition, antibody titers continued to decrease over 3 years postinfection in an enzyme-linked immunosorbent assay (4). In our study, using an indirect immunoperoxidase-based assay, 20 participants exhibited notably high antibody titers (1:1,280 to >1:40,960). Second, despite raising the diagnostic cutoff from 1:40 to 1:160, the preeminence of R. typhi seroprevalence persisted over that of Orientia tsutsugamushi (2), the causative agent of scrub typhus, which is the most frequent endemic rickettsiosis in Japan. Thus, excluding many persons with distant past infections did not influence the study’s conclusion that R. typhi seroprevalence was significantly higher than that of O. tsutsugamushi. Therefore, the higher R. typhi seroprevalence indicates not only prolonged seropositivity but also recent R. typhi infections.

In conclusion, although Dr. Iwata’s commentary is pivotal for a more precise interpretation of our results, our study indicates the occurrence of recent MT cases in Japan. We aim to elucidate this potential MT reemergence by conducting a case-based prospective study.