Background: Epstein-Barr virus-associated Infectious Mononucleosis (EBV-IM) is a common disease following primary EBV infection in children and adolescents. While EBV-IM is mostly self-limiting, symptoms like fatigue may persist over several months or even result in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This large clinical observational study aimed at identifying risk factors for protracted courses of EBV-IM in young people. Methods: A cohort of N=200 children, adolescents, and young adults with acute primary EBV infection was recruited from hospitals and private practices. Data on the patients' medical history as well as clinical and laboratory parameters were collected at a baseline visit (V1) within four weeks after symptom onset (Tonset) and at two follow-up visits (V2 and V3) one and six months after Tonset. Risk factors for protracted symptoms at V3 were modeled using multivariable logistic regressions. Results: Protracted symptoms were observed in 55/183 (30.1%) and protracted fatigue in 34/181 (18.8%) patients at V3. A medical history indicating an increased susceptibility to infectious diseases as well as distinct severe IM symptoms, e.g. severe gastrointestinal symptoms, were significantly associated with protracted disease [OR: 2.31; P=0.011 and OR: 3.42; P=0.027] and with chronic fatigue [OR: 2.98; P=0.006 and OR: 3.54; P=0.034], respectively. Occurrence of twelve or more clinical and laboratory parameters until and including V1 discriminated between fatigue and no fatigue at V3 [OR 2.43, P=0.033]. Conclusion: A clinical history of immune dysregulation as well as distinct severe IM symptoms might predict protracted post-viral disease and thus help in the identification of young patients at risk.

A.B. received lecture fees from Siemens. U.B. received research grants for ME/CFS or EBV studies from the Federal Ministry of Education and Research, the Federal Ministry of Health, the Bavarian State Ministry of Health and Care, the Bavarian State Ministry of Science and the Arts, the German Center for Infection Research, the People for Children (Menschen fuer Kinder) foundation, the Weidenhammer-Zoebele Foundation, the Lost Voices Foundation, and the ME/CFS research foundation. All other authors have no conflict of interest to declare.

The German Center for Infection Research (DZIF) (grant numbers 07_905 and 07_909). Funding was acquired by U.B. and received by P.L., S.E-S., A.H., D.H., F.H., J.M., T.B., H-J.D., C.F., and T.S..

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