Clinical Review Approach to recurrent fever in childhood Gordon S. Soon MD FRCPC Ronald M. Laxer MDCM FRCPC Abstract Objective To provide an approach to recurrent fever in childhood, explain when infections, malignancies, and immunodefciencies can be excluded, and describe the features of periodic fever and other autoinfammatory syndromes. Sources of information PubMed was searched for relevant articles regarding the pathogenesis, clinical fndings, diagnosis, prognosis, and treatment of periodic fever and autoinfammatory syndromes. Main message Fever is a common sign of illness in children and is most frequently due to infection. However, when acute and chronic infections have been excluded and when the fever pattern becomes recurrent or periodic, the expanding spectrum of autoinfammatory diseases, including periodic fever syndromes, should be considered. Familial Mediterranean fever is the most common inherited monogenic autoinfammatory syndrome, and early recognition and treatment can prevent its life-threatening complication, systemic amyloidosis. Periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome is the most common periodic fever syndrome in childhood; however, its underlying genetic basis remains unknown. Conclusion Periodic fever syndromes and other autoinfammatory diseases are increasingly recognized in children and adults, especially as causes of recurrent fevers. Individually they are rare, but a thorough history and physical examination can lead to their early recognition, diagnosis, and appropriate treatment. ever is one of the most common presenting com- plaints in childhood and most frequently is due to F infection. Whether febrile episodes are acute (last- EDITOR’S KEY POINTS ing a few days) or more chronic (lasting longer than • Although periodic fever syndromes are rare, they 2 weeks), infection is the most likely cause. However, are important to recognize, as appropriate diagnosis if acute and chronic infections can be excluded, and if and treatment affects short-term morbidity, improves fevers are prolonged, recurrent, or periodic, the remain- patients’ quality of life, and also might prevent long-term ing differential diagnosis includes malignancy, immuno- complications that can lead to mortality. defciency, and infammatory conditions (Table 1). • The differential diagnosis of fever in childhood can Recurrent or periodic fever syndromes are defned by be daunting when recurrent or periodic fever patterns 3 or more episodes of unexplained fever in a 6-month persist despite exclusion of acute and chronic infections, 1 period, occurring at least 7 days apart. These condi- inflammatory bowel disease, and malignancy. The tions are typically associated with a constellation of expanding spectrum of autoinflammatory diseases— symptoms, including ocular, oropharyngeal, gastroin- including the most commonly encountered periodic testinal, dermatologic, musculoskeletal, and neurologic fever syndromes such as familial Mediterranean fever manifestations. The interval between attacks of fever and periodic fever, aphthous stomatitis, pharyngitis, and is irregular in some of the syndromes and fever recurs adenitis syndrome—should be considered in such patients. with strict periodicity in others, but the fevers resolve A thorough history (including family pedigree), targeted spontaneously without antibiotic, anti-infammatory, or physical examination, and thoughtful investigations often immunosuppressive therapy.2 Patients generally feel lead to a diagnosis. well between episodes but often suffer considerably This article is eligible for Mainpro+ certified during the attacks of fever. Although individual periodic Self-Learning credits. To earn credits, go to fever syndromes are rare, they are extremely important www.cfp.ca and click on the Mainpro+ link. to recognize, as appropriate diagnosis and treatment not only affects short-term morbidity and improves This article has been peer reviewed. quality of life for patients and their families but also Can Fam Physician 2017;63:756-62 might prevent long-term complications that can lead La traduction en français de cet article se trouve à to mortality. Family physicians play an important role www.cfp.ca dans la table des matières du numéro in identifying and coordinating the investigation and d’octobre 2017 à la page e408. ongoing management of these patients. 756 Canadian Family Physician • Le Médecin de famille canadien | VOL 63: OCTOBER • OCTOBRE 2017 Clinical Review Table 1. Differential diagnoses for recurrent or periodic of 446.7 nmol/L (46.9 mg/L). Test results were nega- fevers in children tive for antinuclear antibodies and rheumatoid fac- tor. Nicole is an otherwise healthy child, with normal CAUSE DIFFERENTIAL DIAGNOSES growth and development. Her family is of Turkish Infectious descent. On examination between febrile episodes she • Bacterial or • Brucellosis, dental abscess, endocarditis, appears very well, with no focus of infection. mycobacterial nontuberculous mycobacteria (eg, Mycobacterium chelonae), occult Case 2. Robert is a 4-year-old boy with recurrent bacterial infection, recurrent bacterial febrile episodes over the past 18 months, with tem- infections, relapsing fever (Borrelia spp peratures spiking to 39.5°C to 40°C within a few other than Borrelia burgdorferi), Yersinia enterocolitica hours of onset. His episodes recur every 3 to 4 weeks, last 3 to 5 days, and are associated with sore throat, • Parasitic • Malaria (eg, Plasmodium vivax, tender cervical lymphadenopathy, and occasionally Plasmodium ovale) oral ulcers. He has no rash, ocular changes, respira- • Viral • Epstein-Barr virus (infectious tory symptoms, or musculoskeletal complaints. He is mononucleosis), hepatitis viruses, absent from day care with each episode, and his par- recurrent viral infections ents regularly have to take time off from work. During Inflammatory or Behçet syndrome, inflammatory bowel one of his typical febrile episodes, his bloodwork immunologic disease (eg, Crohn disease), hereditary results revealed the following: white blood cell count fever syndromes (eg, FMF), juvenile of 11.6 × 109/L, hemoglobin level of 112 g/L, platelet dermatomyositis, PFAPA syndrome, 9 sarcoidosis, systemic lupus count of 364 × 10 /L, ESR of 26 mm/h, and a CRP erythematosus, systemic juvenile level of 321.0 nmol/L (33.7 mg/L). Test results were idiopathic arthritis (Still disease), negative for antinuclear antibodies and rheumatoid vasculitis (eg, polyarteritis nodosa) factor. His infammatory markers normalized follow- Malignant Leukemia, lymphoma ing the febrile episode. Robert is an otherwise healthy child and entirely well between episodes. His family is Other Benign giant lymph node hyperplasia (Castleman disease), CNS abnormalities of Japanese and Scottish descent. (eg, hypothalamic dysfunction), drug fever, factitious fever, IgG4-related Sources of information disease, immunodeficiency syndromes with The PubMed database was searched up to April 2016 recurrent infections for relevant articles regarding the pathogenesis, clinical CNS—central nervous system; FMF—familial Mediterranean fever; fndings, diagnosis, prognosis, and treatment of periodic IgG4—immunoglobulin G4; PFAPA—periodic fever, aphthous stomatitis, fever and autoinfammatory syndromes. All of the identi- pharyngitis, and adenitis. fed manuscripts were full-text English-language papers. Case descriptions Main message Case 1. Nicole is a 3-year-old girl with a history of Approach to recurrent fevers in childhood. Although febrile episodes since 5 months of age. The episodes repeated febrile episodes are common in young children recur every 2 to 4 weeks but last no more than 3 days. and often caused by acute viral infections, family mem- During the episodes, she is miserable and her parents bers frequently worry about other potential causes such describe persistent fever with a temperature up to as chronic infections, immune system defects, malig- 39°C, abdominal pain, and bloating. She has no rash, nancy, and infammatory conditions. As a primary care ocular changes, oral ulcers, pharyngitis, lymphade- provider, it can be challenging to identify the children nopathy, coryza, respiratory symptoms, or musculo- who warrant further workup and potential therapy. The skeletal complaints. Antipyretics have minimal effect, pattern of fever might provide clues to the underlying and antibiotic therapy has had no effect on the dura- process (Table 2)3; however, because periodic fever syn- tion of her episodes. Nicole has been to the emergency dromes tend to reveal their pattern of fever and asso- department on several occasions for abdominal pain ciated features only over time, they can be diffcult to associated with fever and was admitted on one occa- identify early in the course of their presentation. sion for overnight monitoring and intravenous fuids. Table 3 identifes key components of the clinical his- During one of her typical febrile episodes, bloodwork tory and physical examination of children who present results revealed the following: white blood cell count with prolonged, recurrent, or periodic fevers.3,4 In an of 15.2×10 9/L, hemoglobin level of 118 g/L, platelet otherwise healthy child, a complete blood count with count of 389 × 109/L, erythrocyte sedimentation rate differential, ESR, and CRP level might be all the test- (ESR) of 18 mm/h, and C-reactive protein (CRP) level ing that is required. However, if the history and physical VOL 63: OCTOBER • OCTOBRE 2017 | Canadian Family Physician • Le Médecin de