Published online Feb 8, 2018. doi: 10.5409/wjcp.v7.i1.49
Peer-review started: September 24, 2017
First decision: November 27, 2017
Revised: December 3, 2017
Accepted: December 14, 2017
Article in press: December 14, 2017
Published online: February 8, 2018
To describe the frequency and clinical characteristics of patients with undifferentiated periodic fever (UPF) and to investigate whether a clinical classification of UPF based on the PRINTO-Eurofever score can help predicting the response to treatment and the outcome at follow-up.
Clinical and therapeutic information of patients with recurrent fever who presented at a single pediatric rheumatology center from January 2006 through April 2016 were retrospectively collected. Patients with a clinical suspicion of hereditary periodic fever (HPF) syndrome and patients with clinical picture of periodic fever, aphthae, pharingitis, adenitis (PFAPA) who were refractory to tonsillectomy underwent molecular analysis of five HPF-related genes: MEFV (NM_000243.2), MVK (NM_000431.3), TNFRSF1A (NM_001065.3), NLRP3 (NM_001079821.2), NLRP12 (NM_001277126.1). All patients who had a negative genetic result were defined as UPF and further investigated. PRINTO-Eurofever score for clinical diagnosis of HPF was calculated in all cases.
Of the 221 patients evaluated for periodic fever, twelve subjects with a clinical picture of PFAPA who were refractory to tonsillectomy and 22 subjects with a clinical suspicion of HPF underwent genetic analysis. Twenty-three patients (10.4%) resulted negative and were classified as UPF. The median age at presentation of patients with UPF was 9.5 mo (IQR 4-24). Patients with UPF had a higher frequency of aphthae (52.2% vs 0%, P = 0.0026) and musculoskeletal pain (65.2% vs 18.2%, P = 0.0255) than patients with genetic confirmed HPF. Also, patients with UPF had a higher frequency of aphthous stomatitis (52.2% vs 10.7%, P < 0.0001), musculoskeletal pain (65.2% vs 8,0%, P < 0.0001), and abdominal pain (52.2% vs 4.8%, P < 0.0001) and a lower frequency of pharyngitis (56.6% vs 81.3%, P = 0.0127) compared with typical PFAPA in the same cohort. Twenty-one of 23 patients with UPF (91.3%) received steroids, being effective in 16; 13 (56.2%) were given colchicine, which was effective in 6. Symptoms resolution occurred in 2 patients with UPF at last follow-up. Classification according to the PRINTO-Eurofever score did not correlate with treatment response and prognosis.
UPF is not a rare diagnosis among patients with periodic fever. Clinical presentation place UPF half way on a clinical spectrum between PFAPA and HPF. The PRINTO-Eurofever score is not useful to predict clinical outcome and treatment response in these patients.
Core tip: Children with non-infectious recurrent fever more often fall into two diagnostic categories. The first and most common is periodic fever, aphthae, pharingitis, adenitis (PFAPA), the second, far more rare, are hereditary periodic fevers. Very recently a third category has been increasingly recognized, and is that of undifferentiated periodic fevers or undifferentiated periodic fever (UPF). UPF include patients who do not meet the diagnostic criteria for PFAFA or for a monogenic disease. The clinical presentation and management of patients with UPF are poorly defined. In this study, the authors describe a cohort of patients with UPF showing that: (1) The clinical manifestations are on a half way of clinical spectrum between PFAPA and hereditary periodic fever; (2) PRINTO-Eurofever score is not useful to guide treatment choices and does not predict disease course; and (3) Both steroids and colchicine are useful to control symptoms in most cases. The authors conclude that further studies are needed to better define UPF and guide their management in clinical practice.