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Proceedings of the National Academy of Sciences of the United States of America •
The syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is the most common periodic fever disease in children. However, the pathogenesis is unknown. Using a systems biology approach we analyzed blood samples from PFAPA patients whose genetic testing excluded hereditary periodic fevers (HPFs), and from healthy children and pediatric HPF patients. Gene expression profiling could clearly distinguish PFAPA flares from asymptomatic intervals, HPF flares, and healthy controls. During PFAPA attacks, complement (C1QB, C2, SERPING1), IL-1-related (IL-1B, IL-1RN, CASP1, IL18RAP), and IFN-induced (AIM2, IP-10/CXCL10) genes were significantly overexpressed, but T cell-associated transcripts (CD3, CD8B) were down-regulated. On the protein level, PFAPA flares were accompanied by significantly increased serum levels of chemokines for activated T lymphocytes (IP-10/CXCL10, MIG/CXCL9), G-CSF, and proinflammatory cytokines (IL-18, IL-6). PFAPA flares also manifested a relative lymphopenia. Activated CD4(+)/CD25(+) T-lymphocyte counts correlated negatively with serum concentrations of IP-10/CXCL10, whereas CD4(+)/HLA-DR(+) T lymphocyte counts correlated positively with serum concentrations of the counterregulatory IL-1 receptor antagonist. Based on the evidence for IL-1β activation in PFAPA flares, we treated five PFAPA patients with a recombinant IL-1 receptor antagonist. All patients showed a prompt clinical and IP-10/CXCL10 response. Our data suggest an environmentally triggered activation of complement and IL-1β/-18 during PFAPA flares, with induction of Th1-chemokines and subsequent retention of activated T cells in peripheral tissues. IL-1 inhibition may thus be beneficial for treatment of PFAPA attacks, with IP-10/CXCL10 serving as a potential biomarker.
We describe the presentations and clinical outcomes of pediatric patients diagnosed with PFAPA (Periodic Fever, Aphthous lesions, Pharyngitis, and cervical Adenitis). The medical records of children with recurrent fever and referred between 1998 and 2007 to a tertiary pediatric care hospital were reviewed. Children who met clinical criteria for PFAPA were then asked to participate in a follow-up study. One hundred and five children met study criteria for PFAPA which included at least six episodes of periodic fever. Most (62%) were males, the mean age at onset of PFAPA was 39.6 months (80% were <5 years at onset), the mean duration of individual fever episodes was 4.1 days, and the mean interval between episodes was 29.8 days. Accompanying signs and symptoms included aphthous stomatitis (38%), pharyngitis (85%), cervical adenitis (62%), headache (44%), vomiting with fever spikes (27%) and mild abdominal pain (41%). A prodrome (usually fatigue) preceded the fever in 62% of patients. Parents noted that when their child with PFAPA had fever, other family members remained well. Laboratory tests in patients with PFAPA were nonspecific. Individual episodes of fever usually resolved with a single oral dose ( approximately 1 mg/kg) of prednisilone. The interval between fever episodes shortened in 50% of patients who used prednisilone. PFAPA resolved spontaneously (mean length 33.2 months) in 211105 (20%) patients. PFAF'A episodes continued (mean length 23 months) at the end of this study in 661105 (63%) patients. Cimetidine therapy was associated with the resolution of the fevers in 7/26 (27%) patients; tonsillectomy was associated with the resolution of the fevers in 11/11 (100%) patients. PFAPA can usually be defined by its clinical characteristics. Individual febrile episodes usually resolve dramatically with oral prednisilone. The cause of PFAPA is unknown and research is needed to define its etiology. The overall prognosis for children with PFAPA is excellent.