Diagnosis and treatment of periodic fevers: A single centre experience

Abstract

Introduction: Diagnosis of periodic fever syndromes is difficult due to atypical presentations and overlap in inflammatory symptoms. Treatment of suspected periodic fevers varies widely due to the lack of established clinical guidelines.The utility of genetic testing in identifying monogenic periodic fever syndromes is also unclear due to high frequency of variants of uncertain significance, somatic mutations and heterozygous mutations in genes associated with autosomal recessive conditions. Objectives: This study aims to evaluate the diagnosis, treatment and use of genetic testing of patients diagnosed with periodic fever syndromes at a single tertiary paediatric hospital. Methods: We retrospectively reviewed the clinical history of patients diagnosed with periodic fever syndromes at Queensland Children's Hospital, Brisbane, Australia between November 2014 and June 2018. Results: 43 patients were diagnosed based on their clinical presentation with periodic fever syndromes.10 patients were diagnosed with PFAPA, 9 with TRAPS, 6 with CAPS, 4 with MKD and 14 unspecified.-Median age of onset of symptoms was 24m (range: birth-96m) and median age of diagnosis was 60m (9m-180m).Median time to diagnosis from onset of symptoms was 24m (0-149m). Multiple medications were used in 15 patients.The medications used varied widely (prednisolone (22), anakinra (9), etanercept (5), tofacitinib (2), tocilizumab (2), cimetidine (2)). Genetic testing of between 1-26 genes was performed in 26 patients (60%).1-3 genes were tested in 13 patients, targeted panels in 10 patients, SNP only in 1 patient.Genetic variants were identified in 9 patients (34% of those tested) however only 2 of these variants were clearly pathogenic (7.7% of those tested). Clinical diagnosis and the Eurofever classification criteria were in agreement for patients diagnosed with CAPS (p=0.046) and TRAPS (p=0.025) but not for patients diagnosed with MKD (p=0.47).10 of the patients where clinical diagnosis and Eurofever classification criteria were in agreement had 2 diagnoses positive on the classification score.Two patients diagnosed with CAPS were exclusively positive for CAPS on the classification score and none of the patients diagnosed with TRAPS were exclusively positive for TRAPS.6 of the 7 TRAPS patients had a positive eurofever score for at least one PFS diagnosis. Conclusion: As reported in previous studies there was a significant delay between onset of symptoms and diagnosis.This reflects an ongoing need to raise awareness of these conditions with primary care providers. The large number of patients treated with multiple medications and the broad range of medications used reflects the lack of established treatment protocols and varied response to treatments in this group of patients. The clinical diagnosis and diagnostic score showed agreement for CAPS and TRAPs however many patients had a diagnostic score positive for more than one diagnosis meaning that a combination of clinical score and clinical judgement is required to make a diagnosis. Consistent with previous studies many patients with heterozygous mutations in genes associated with periodic fevers were identified.The significance of these variants is not clear and the diagnostic yield from genetic testing in this cohort was low. Further improvements in availability of next generation sequencing and molecular understanding of autoinflammatory conditions will hopefully improve this yield and allow more confident diagnoses and targeted therapies.L6279732732019-06-11 <br />