Approach to recurrent fever in childhood

Case 1.

Nicole is a 3-year-old girl with a history of febrile episodes since 5 months of age. The episodes recur every 2 to 4 weeks but last no more than 3 days. During the episodes, she is miserable and her parents describe persistent fever with a temperature up to 39°C, abdominal pain, and bloating. She has no rash, ocular changes, oral ulcers, pharyngitis, lymphadenopathy, coryza, respiratory symptoms, or musculoskeletal complaints. Antipyretics have minimal effect, and antibiotic therapy has had no effect on the duration of her episodes. Nicole has been to the emergency department on several occasions for abdominal pain associated with fever and was admitted on one occasion for overnight monitoring and intravenous fluids. During one of her typical febrile episodes, bloodwork results revealed the following: white blood cell count of 15.2 × 10⁹/L, hemoglobin level of 118 g/L, platelet count of 389 × 10⁹/L, erythrocyte sedimentation rate (ESR) of 18 mm/h, and C-reactive protein (CRP) level of 446.7 nmol/L (46.9 mg/L). Test results were negative for antinuclear antibodies and rheumatoid factor. Nicole is an otherwise healthy child, with normal growth and development. Her family is of Turkish descent. On examination between febrile episodes she appears very well, with no focus of infection.

Case 2.

Robert is a 4-year-old boy with recurrent febrile episodes over the past 18 months, with temperatures spiking to 39.5°C to 40°C within a few hours of onset. His episodes recur every 3 to 4 weeks, last 3 to 5 days, and are associated with sore throat, tender cervical lymphadenopathy, and occasionally oral ulcers. He has no rash, ocular changes, respiratory symptoms, or musculoskeletal complaints. He is absent from day care with each episode, and his parents regularly have to take time off from work. During one of his typical febrile episodes, his bloodwork results revealed the following: white blood cell count of 11.6 × 10⁹/L, hemoglobin level of 112 g/L, platelet count of 364 × 10⁹/L, ESR of 26 mm/h, and a CRP level of 321.0 nmol/L (33.7 mg/L). Test results were negative for antinuclear antibodies and rheumatoid factor. His inflammatory markers normalized following the febrile episode. Robert is an otherwise healthy child and entirely well between episodes. His family is of Japanese and Scottish descent.

Approach to recurrent fevers in childhood.

Although repeated febrile episodes are common in young children and often caused by acute viral infections, family members frequently worry about other potential causes such as chronic infections, immune system defects, malignancy, and inflammatory conditions. As a primary care provider, it can be challenging to identify the children who warrant further workup and potential therapy. The pattern of fever might provide clues to the underlying process (Table 2)³; however, because periodic fever syndromes tend to reveal their pattern of fever and associated features only over time, they can be difficult to identify early in the course of their presentation.

Table 3 identifies key components of the clinical history and physical examination of children who present with prolonged, recurrent, or periodic fevers.^3,4 In an otherwise healthy child, a complete blood count with differential, ESR, and CRP level might be all the testing that is required. However, if the history and physical examination findings raise suspicion of a particular underlying cause, further workup is necessary. For example, if a child has a history of exposure to potential infections or other triggers (eg, had contact with a sick person, recent travel, use of prescription medications and herbal products), recurrent infections caused by unusual or opportunistic pathogens, or constitutional symptoms (eg, weight loss, night sweats, malaise), additional investigations are warranted (Table 3) and a referral to a specialist might be indicated (Figure 1).³ Once infections, immunodeficiency, malignancy, inflammatory bowel disease, and adverse drug reactions have been ruled out, autoinflammatory diseases—including periodic fever syndromes—should be considered.

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Figure 1.

Approach to recurrent fever patterns in childhood

EBV—Epstein-Barr virus.

Adapted from Long.³

Periodic fever syndromes and other inherited auto-inflammatory diseases.

The term autoinflammation describes a state of seemingly unprovoked inflammation. Whereas the more classically recognized autoimmune diseases such as systemic lupus erythematosus are characterized by dysregulation of the adaptive immune system (with high-titre autoantibodies and proliferation of antigen-specific T cells), the autoinflammatory diseases relate to inborn errors of the innate immune system.^2,5 Hereditary periodic fever syndromes were the first group of monogenic disorders to be classified as auto-inflammatory, but many more continue to be described (Table 4).^6,7

The spectrum of autoinflammatory diseases is now thought to include several other conditions such as gout, systemic juvenile idiopathic arthritis, adult-onset Still disease, and Behçet syndrome. Whether these latter conditions prove to be polygenic in origin, with contributions from both innate and adaptive immunity, is an area of ongoing research.^2,5,7

Familial Mediterranean fever (FMF).

First described in 1945,⁸ FMF (also known as familial paroxysmal polyserositis) is the most common and well known monogenic autoinflammatory syndrome. Characterized by seemingly unprovoked recurrent attacks of fever and inflammatory serositis, arthritis, and rash, FMF results from autosomal recessive mutations in the MEFV (MEditerranean FeVer) gene on chromosome 16p.^9,10 Familial Mediterranean fever is most prevalent among Sephardi- and Ashkenazi-Jewish, Armenian, Arab, Italian, and Turkish populations, with carrier rates as high as 1:3 to 1:5.¹¹

Clinical signs and symptoms of FMF develop in 20% of patients by age 2, in 50% by age 10, and in 90% by age 20.¹¹ A typical attack lasts between 12 and 72 hours, with fever peaking soon after onset. Abdominal pain (often mimicking appendicitis) accompanies fever in more than 90% of patients,¹² whereas arthritis (50% to 75%),¹³ pleuritis (30% to 45%),^11,14 erysipelas-like rash (7% to 40%),¹⁵ and pericarditis (<1%)¹⁶ occur less commonly. Because fever can be the only manifestation of an attack, especially in younger children, FMF should be considered in the differential diagnosis of all children with recurrent fevers, particularly in the aforementioned ethnic groups.⁷

The diagnosis of FMF is made based on clinical findings rather than genetic testing.¹⁷ In children, criteria proposed in 2009 require recurrent (≥3) attacks with at least 2 of the following 5 features: fever lasting between 12 and 72 hours, abdominal pain, chest pain, arthritis, and a positive family history for FMF.¹⁸ During attacks, acute phase reactant levels (including CRP, serum amyloid A, fibrinogen, and complement) increase, and leukocytosis and elevated ESR might also be found.¹¹ The acute phase serum protein levels can remain elevated even between attacks, which predisposes patients to systemic amyloidosis, the life-threatening complication of FMF. Colchicine, the treatment of choice, prevents amyloidosis in nearly all patients and prevents attacks in 60% to 70% of patients; however, 20% to 30% of patients only partially respond, and 5% are nonresponders.¹⁹ In these latter cases, interleukin-1 inhibitors might be effective.²⁰

Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome.

First described in 1987,²¹ PFAPA is the most common periodic fever syndrome. It has yet to be characterized by a known genetic mutation or underlying cause. The onset of PFAPA is almost always before the age of 5. Other than cyclic hematopoiesis (also known as cyclic neutropenia), PFAPA is the only autoinflammatory condition with strict “clocklike” periodicity between attacks of fever (parents can often predict the first day of fever). In any individual child, the interval between episodes is nearly constant, usually every 21 to 28 days, with fever lasting 3 to 5 days and associated features nearly identical.²²

Clinically, aphthae (shallow ulcers in the buccal mucosa and pharynx that heal without scarring) have been reported in 70% of patients.^22,23 Pharyngitis (consisting of erythematous, enlarged tonsils) and cervical adenitis are present in 80% to 100% of patients; generalized lymphadenopathy or hepatosplenomegaly suggests a diagnosis other than PFAPA.^22,24 Abdominal pain, nausea, vomiting, arthralgia, and headaches might also occur but are usually mild. During attacks, mild leukocytosis with neutrophilia and a modest left shift can occur along with elevation of acute phase reactants such as CRP levels and ESR. Throat cultures are negative for microorganisms in 90% of patients,²² with positive findings likely representing benign carriage, as the natural history of each attack is not affected by antibiotic therapy.

The diagnosis of PFAPA is made based on clinical findings once other causes of recurrent fevers in children have been excluded. Children must be completely asymptomatic (with normal levels of acute phase reactants) during interval periods and demonstrate normal growth and development. Diagnostic criteria for PFAPA are summarized in Box 1.²⁴ Although no long-term complications have been reported in patients with PFAPA, there is a considerable effect on quality of life that includes disruptions of family routine. Treatment with antibiotics and colchicine is generally ineffective; however, a single dose of prednisone (0.6 to 2 mg/kg) at the onset of symptoms and, if necessary, the following day can abort the attack in almost all patients. Inexplicably, prednisone might actually shorten the interval between episodes.^21,22 Cimetidine (40 mg/kg daily in 2 divided doses) might prevent recurrences in one-third of patients.²⁵ For children requiring frequent corticosteroids or with marked effect on quality of life, tonsillectomy (with or without adenoidectomy) has been shown to induce remission compared with control groups.²⁶

Prognosis is excellent, and patients do not develop amyloidosis. Although the frequency and severity of attacks tend to resolve in adolescence, up to 15% of patients might continue to experience attacks for at least 18 years.²⁷

Role of genetic testing.

If a clinical pattern consistent with one of the autoinflammatory diseases can be identified, the family and physician often seek confirmation with genetic testing. A genetic diagnosis should be pursued in a logical manner recognizing the cost and limitations of testing. A simple interactive tool is available online (www.printo.it/periodicfever/), and the resultant diagnostic score can be used to stratify the risk of a genetic periodic fever syndrome in a patient with recurrent fever.²⁸ Worth noting is that the diagnosis of a child with a periodic fever syndrome is much more challenging in a multiethnic population than in regions with high prevalence for a particular condition (such as FMF). For this reason, validation of the algorithms and decision tools for the genetic testing of the expanding spectrum of autoinflammatory diseases is ongoing.

Case 1.

Three-year-old Nicole had a classic presentation of, including the ethnic background for, FMF. Her diagnostic score for periodic fever, calculated with the online interactive tool, placed her at high risk of a monogenic periodic fever syndrome. Genetic testing revealed homozygosity for the most common FMF-associated mutation: M694V. She was started on colchicine daily, with near-complete remission of her symptoms. She will require treatment with colchicine all her life; fortunately colchicine is safe to use during pregnancy and has been reported to improve pregnancy outcomes in women with FMF. Thus far, urinalyses and serum amyloid A screening results have remained negative; however, she will be monitored for amyloidosis her entire life and will receive genetic counseling should she consider having children of her own.

Case 2.

Four-year-old Robert demonstrated a clinical pattern consistent with PFAPA syndrome. His diagnostic score for periodic fever placed him at low risk for a monogenic periodic fever syndrome, and no genetic testing was performed. The frequency of his attacks did not improve with regular use of cimetidine. Although treatment with prednisone was successful in aborting an attack when given on the first day of fever, the frequency of his episodes increased, much to the disappointment of his parents. He ultimately underwent adenotonsillectomy, with complete resolution of his symptoms.