Scrub Typhus IgM Region-specific Cut-off Determination: Is It Really Essential in the Diagnosis?

Introduction: Scrub typhus (ST), a re-emerging vector-borne disease caused by Orientia tsutsugamushi ( O . tsutsugamushi ), is an important cause of acute febrile illness in India. Clinical features are often non-specific, and eschar is infrequently detected, making laboratory confirmation essential. As background seroprevalence and antigenic variability differ regionally, this study aimed to define an appropriate immunoglobulin M (IgM) enzyme-linked immunosorbent assay (ELISA) cut-off for accurate diagnosis. Materials and Methods: This cross-sectional study was conducted at a tertiary care teaching hospital in Southern India between August 2024 and July 2025. A total of 620 participants were enrolled, including 370 clinically suspected ST cases and 250 controls (healthy volunteers, chronic liver disease patients, dengue IgM-positive cases, and other confirmed acute undifferentiated febrile illnesses). Serum samples were tested for anti- O . tsutsugamushi IgM using a commercial ELISA (InBios International, Inc.). Optical density (OD) values were analysed using receiver operating characteristic (ROC) curve analysis to determine the optimal diagnostic cut-off. Results: ROC analysis demonstrated excellent diagnostic performance with an area under the curve (AUC) of 0.954 (95% CI: 0.935–0.969; P < .0001). An OD cut-off value of >0.4854, derived using the Youden index, yielded a sensitivity of 98.65% and a specificity of 93.2%. No false positives were observed among healthy controls, while limited cross-reactivity (6.8%) was noted among controls, particularly dengue and other acute undifferentiated febrile illness groups. Conclusion: A region-specific ST IgM ELISA cut-off OD value of >0.4854 provides excellent diagnostic accuracy in our setting, ensuring maximal case detection with acceptable false-positive rates in this high-prevalence setting. Adoption of this optimised threshold can improve clinical decision-making and early institution of appropriate therapy in endemic areas.