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Background: Scrub typhus (ST) is a life-threatening infectious disease if appropriate treatment is unavailable. Large discrepancy of clinical severity of ST patients was reported among age groups, and the underlying risk factors for severe disease are unclear. Methods: Clinical and epidemiological data of ST patients were collected in 55 surveillance hospitals located in Guangzhou City, China, from 2012 to 2018. Severe prognosis and related factors were determined and compared between pediatric and elderly patients. Results: A total of 2,074 ST patients including 209 pediatric patients and 1,865 elderly patients were included, with a comparable disease severity rate of 11.0% (95% CI 7.1%–16.1%) and 10.3% (95% CI 9.0%–11.8%). Different frequencies of clinical characteristics including lymphadenopathy, skin rash, enlarged tonsils, etc. were observed between pediatric and elderly patients. Presence of peripheral edema and decreased hemoglobin were the most important predictors of severe illness in pediatric patients with adjusted ORs by 38.99 (9.96–152.67, p<0.001) and 13.22 (1.54–113.50, p = 0.019), respectively, while presence of dyspnea and increased total bilirubin were the potential determinants of severe disease in elderly patients with adjusted ORs by 11.69 (7.33–18.64, p<0.001) and 3.17 (1.97–5.11, p<0.001), respectively. Compared with pediatric patients, elderly patients were more likely to receive doxycycline (64.8% v.s 9.9%, p<0.001), while less likely to receive azithromycin therapy (5.0% v.s 41.1%, p<0.001). Conclusion: The disease severity rate is comparable between pediatric and elderly ST patients, while different clinical features and laboratory indicators were associated with development of severe complications for pediatric and elderly patients, which is helpful for diagnosis and progress assessment of disease for ST patients. Author summary: The study investigated different clinical features and risk factors for severe disease between pediatric and elderly patients with scrub typhus. We found that significantly higher frequencies of lymphadenopathy, skin rash, enlarged tonsils, etc. were observed in pediatric patients than elderly patients. Other non-specific signs, subjective complaints, and chest radiographic abnormality were overpresented in elderly patients. Risk factors for severe disease between pediatric and elderly patients with scrub typhus were different. Presence of peripheral edema and decreased hemoglobin were the most important factors for pediatric patients, while presence of dyspnea and increased total bilirubin for elderly patients. These findings reminded medical workers to acknowledge this important difference and to adopt an age specific method in the differential diagnosis and risk assessment for scrub typhus. [ABSTRACT FROM AUTHOR]