Quantifying Diagnostic Misclassification and Inpatient Mortality Determinants in Scrub Typhus: A Systematic Review and Interaction Meta-Analysis of Acute Undifferentiated Febrile Illness (AUFI) Cohorts in India.

Scrub typhus (ST), caused by Orientia tsutsugamushi, is an underrecognized but major etiology of acute undifferentiated febrile illness (AUFI) across India. Prior national syntheses were limited by selection biases arising from heterogeneous screening denominators. To establish an unbiased epidemiological baseline, we conducted a Preferred Reporting Items for Systematic Reviews and Meta‑Analyses‑compliant systematic review and meta‑analysis (registered with the International Prospective Register of Systematic Reviews) of observational studies published between January 2015 and June 2026, enforcing strict AUFI syndromic gatekeeping. Sixteen institutional cohorts comprising 27,892 screened AUFI patients met inclusion criteria. DerSimonian-Laird random‑effects modeling was applied to estimate pooled prevalence and heterogeneity. The pooled prevalence of ST was 14.60% (95% confidence interval (CI): 11.27-18.71; I2 = 97.40%, p < 0.001), with marked regional disparities: East/Central India 22.70% (95% CI: 16.80-29.80), South India 16.70% (95% CI: 10.20-25.90), North India 13.80% (95% CI: 8.40-21.50), and West India 2.50% (95% CI: 0.80-7.20; p < 0.001). The nationwide 95% prediction interval (3.30-45.20) captured extreme localized microfocal transmission dynamics. Multivariable meta‑regression explained 68.90% of between‑study variance (R2 = 68.90%; residual I2 = 34.20%), identifying a significant interaction between diagnostic assay stringency and regional transmission intensity (β = 0.485, p = 0.041). Cohorts employing high‑rigor composite criteria, including immunoglobulin M (IgM) enzyme‑linked immunosorbent assay (ELISA), polymerase chain reaction (PCR), indirect immunofluorescence assay, or eschar confirmation, reported a pooled prevalence of 17.40% (95% CI: 12.80-23.10), compared with 11.90% (95% CI: 7.60-18.00) in cohorts using single‑modality rapid immunochromatographic tests (ICTs) or legacy Weil-Felix assays (p = 0.024). Fever was universal (100.00%), while pathognomonic eschars were documented in only 21.40% (95% CI: 15.10-29.20). Pooled inpatient mortality was 4.92% (95% CI: 2.98-7.95), driven primarily by multiorgan dysfunction syndrome (pooled odds ratio (pOR) = 5.18, 95% CI: 3.20-8.38, p < 0.001), acute respiratory distress syndrome (pOR = 4.12, 95% CI: 2.45-6.93, p < 0.001), therapeutic delay beyond seven days (pOR = 3.42, 95% CI: 2.15-5.44, p < 0.001), and acute kidney injury (AKI) (pOR = 3.25, 95% CI: 1.98-5.33, p < 0.001). O. tsutsugamushi accounts for approximately one in seven AUFI hospital admissions in India. These findings mandate decommissioning low‑sensitivity rapid and legacy assays, expanding decentralized IgM ELISA/PCR platforms, and immediately initiating protocol‑driven empiric doxycycline or azithromycin when clinically suspected.