Elevated procalcitonin levels in febrile children with exanthema subitum undergoing clinically indicated PCT testing: a retrospective cohort study

BACKGROUND: Human herpesvirus 6 (HHV-6), the causative agent of exanthema subitum (ES), is a major viral cause of acute encephalopathy in Japan. Serum procalcitonin (PCT) is widely used as a biomarker of severe bacterial infections and has also been proposed as an early predictor of encephalopathy. However, elevated PCT levels are occasionally observed in ES without bacterial co-infection or encephalopathy, potentially complicating interpretation of PCT levels in febrile children. The association between primary HHV-6 infection and PCT elevation remains unclear. We therefore investigated clinical and laboratory factors associated with serum PCT levels in young children with primary HHV-6 infection. METHODS: We conducted a retrospective cohort study of 188 febrile children aged < 60 months who underwent serum PCT measurement between April 2021 and May 2024. Thirty children with clinically diagnosed ES and laboratory-confirmed primary HHV-6 infection were compared with 53 children with other virologically confirmed febrile illnesses. In exploratory analyses, multivariable logistic regression identified factors associated with ES, and multivariable linear regression explored factors associated with serum PCT levels in the ES group. RESULTS: Median serum PCT levels were significantly higher in the ES group than in controls (0.28 [interquartile range (IQR) 0.10-0.61] vs. 0.10 [IQR 0.10-0.31] ng/mL; P = 0.018). The PCT/C-reactive protein ratio was also higher in ES (P = 0.018). ES patients had lower white blood cell, neutrophil, and platelet counts, and higher aspartate aminotransferase and lactate dehydrogenase levels. In exploratory multivariable analysis, younger age (odds ratio [OR] 0.92; 95% confidence interval [CI] 0.87-0.98; P = 0.006), lower platelet count (OR 0.88; 95% CI 0.82-0.94; P < 0.001), and higher PCT level (OR 1.74; 95% CI 1.02-2.95; P = 0.042) were associated with ES. Among patients with ES, lower lymphocyte count and absence of febrile seizures were associated with higher PCT levels. All ES patients had a self-limited clinical course without encephalopathy. CONCLUSIONS: Among febrile children undergoing clinically indicated PCT testing, primary HHV-6 infection was associated with modest PCT elevation. These elevations may reflect HHV-6-associated hematologic alterations rather than bacterial co-infection or disease severity, highlighting the need for cautious interpretation of PCT in ES.