title: Cytokine profile in PFAPA syndrome suggests continuous inflammation and reduced anti-inflammatory response.
abstract: PFAPA syndrome is characterized by periodic episodes of high fever, aphthous stomatitis, pharyngitis, and/or cervical adenitis. It is of unknown etiology and manifests usually before 5 years of age. We determined serum and intracellular cytokine levels in six PFAPA patients (4 males, 2 females, mean age 8 years (+/- 1.2 SEM), range 4-13) during the symptom-free period as well as 6-12 hours and 18-24 hours after fever onset. Values were compared to age-matched, healthy controls. Febrile PFAPA attacks led to a significant increase in IL-6 and IFN-gamma serum concentrations compared to symptom-free periods and to controls, with IL-1beta, TNF-alpha and IL-12p70 levels being significantly higher than in controls. Lymphocytic IFN-gamma and CD8+ IL-2 production was consistently significantly elevated compared to healthy children. During the asymptomatic period, serum concentrations of IL-1beta, IL-6, TNF-alpha and IL-12p70 were significantly increased compared to controls. Intracellular TNF-alpha synthesis was not elevated at any time point. Soluble TNFRp55 levels were even lower in between febrile episodes, reaching values comparable to controls during attacks, whereas soluble TNFRp75 levels increased during attacks compared to healthy children. Anti-inflammatory IL-4 in serum was at all times lower in PFAPA patients compared to controls with no difference in levels of intracellular IL-4 and IL-10 or serum IL-10. The observed increase of pro-inflammatory mediators, even between febrile attacks, suggests a dysregulation of the immune response in PFAPA syndrome, with continuous pro-inflammatory cytokine activation and a reduced anti-inflammatory response.
authors.affiliation: Department of Infectious Diseases and Immunology, Children's Hospital, University of Munich, Germany. stojanos@mail.nih.gov
authors.forename: Silvia
authors.initials: S
authors.lastname: Stojanov
authors.forename: Florian
authors.initials: F
authors.lastname: Hoffmann
authors.forename: Anja
authors.initials: A
authors.lastname: Kéry
authors.forename: Ellen D
authors.initials: ED
authors.lastname: Renner
authors.forename: Dominik
authors.initials: D
authors.lastname: Hartl
authors.forename: Peter
authors.initials: P
authors.lastname: Lohse
authors.forename: Kristina
authors.initials: K
authors.lastname: Huss
authors.forename: Peter
authors.initials: P
authors.lastname: Fraunberger
authors.forename: James D
authors.initials: JD
authors.lastname: Malley
authors.forename: Stephanie
authors.initials: S
authors.lastname: Zellerer
authors.forename: Michael H
authors.initials: MH
authors.lastname: Albert
authors.forename: Bernd H
authors.initials: BH
authors.lastname: Belohradsky
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000096:biosynthesis* / Q000097:blood; D005260:Female; D005334:Fever / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis / Q000097:blood; D015847:Interleukin-4 / Q000096:biosynthesis / Q000097:blood; D008199:Lymphadenitis / Q000378:metabolism*; D008297:Male; D010612:Pharyngitis / Q000378:metabolism*; D013281:Stomatitis, Aphthous / Q000378:metabolism*; D013577:Syndrome
chemical_list: D016207:Cytokines; D016753:Interleukin-10; D015847:Interleukin-4