Pediatric Annals

Feature Article 

Periodic Fever Syndromes

Victoria M. Wurster, BS; James G. Carlucci, MD; Kathryn M. Edwards, MD

Abstract

Reimann and deBarardini first described periodic fevers in the 1940s, calling the fevers “periodic” because of their regularly recurring nature.1,2 Their patients were young at onset and had cycles of fever that often persisted for years, if not decades. Since then, syndromes of periodic fever have been more broadly characterized by recurrent and unprovoked fever episodes lasting from a few days to a few weeks, separated by symptom-free intervals of various durations.

Abstract

Reimann and deBarardini first described periodic fevers in the 1940s, calling the fevers “periodic” because of their regularly recurring nature.1,2 Their patients were young at onset and had cycles of fever that often persisted for years, if not decades. Since then, syndromes of periodic fever have been more broadly characterized by recurrent and unprovoked fever episodes lasting from a few days to a few weeks, separated by symptom-free intervals of various durations.

Victoria M. Wurster, BS; James G. Carlucci, MD; and Kathryn M. Edwards, MD, are with Vanderbilt University School of Medicine, Department of Pediatrics, Division of Pediatric Infectious Diseases.

Ms. Wurster and Dr. Carlucci have disclosed no relevant financial relationships. Dr. Edwards has disclosed the following relevant financial relationships: Centers for Disease Cotnrol and Prevention, National Institutes of Health, and Novartis: Contracted research recipient.

Address correspondence to: Kathryn M. Edwards, MD; fax: 615-343-9723; or e-mail: kath-ryn.edwards@vanderbilt.edu.

Reimann and deBarardini first described periodic fevers in the 1940s, calling the fevers “periodic” because of their regularly recurring nature.1,2 Their patients were young at onset and had cycles of fever that often persisted for years, if not decades. Since then, syndromes of periodic fever have been more broadly characterized by recurrent and unprovoked fever episodes lasting from a few days to a few weeks, separated by symptom-free intervals of various durations.

Typically, fever is the dominant symptom, has an abrupt onset and termination, and is identical in its presentation with each recurrence. The patient generally has a completely normal developmental course between episodes. There is a spectrum of manifestations among periodic fever syndromes, although common associated symptoms include rash, arthralgia, myalgia, and gastrointestinal complaints.

A differential diagnosis of recurrent fevers should include recurrent infection, neoplasm, and noninfectious inflammatory disorders being ruled out by clinical characteristics and laboratory studies. Some of these conditions are considered to be somewhat rare, but the practitioner should know how to identify them.

Hereditary Periodic Fever Syndromes

Autosomal Recessive

Familial Mediterranean Fever

Familial Mediterranean fever (FMF) is caused by MEFV gene mutations, resulting in altered pyrin (also known as pyrinmarenostrin) protein. Because pyrin regulates interleukin (IL)-1 beta secretion, nuclear factor-kappa B (NFKB) activation, and apoptosis, mutated pyrin protein promotes increased IL-1 beta processing and apoptosis. Most mutations occur on exons 10 and 2 of chromosome 16p, and the most common FMF-associated mutation is M694V. In fact, it is postulated that carriers of this mutation descended from a single ancestor. Especially high carrier frequency rates, from 1:3 to 1:5, have been described in those of Middle Eastern descent.3 Because of these high rates, FMF is considered the most common hereditary fever syndrome.

Clinical Features of FMF

Most patients (90%) experience their first attack within the first 2 decades of life, most at younger than age 10 years (80%). Symptoms include abdominal pain with peritonitis, arthritis, pleuritis, myalgia, erysipelas-like erythema, and changes in bowel habits.4 Arthritis of FMF is typically a monoarthritis with or without effusion.

Less common findings of FMF include pericarditis and acute scrotal swelling and tenderness. Type AA amyloidosis has been reported as a severe complication of FMF, mainly affecting the kidneys. A high FMF prevalence is present in non-Ashkenazi Jewish people, Turks, Armenians, and Arabs, although this should not rule out FMF in patients of other ethnicities.

Laboratory Findings

Neutrophilia and markers of inflammation are evident during attacks. C-reactive protein (CRP), serum amyloid A (SAA), and erythrocyte sedimentation rate (ESR), are all significantly higher in patients with newly diagnosed FMF than in those in other stages of the disease.

Neutrophil-derived S100A12, a damage-associated molecular pattern (DAMP) protein involved in mediating inflammatory responses, was a relatively sensitive biomarker in monitoring inflammation, disease activity, and response to treatment in patients with FMF and other autoinflammatory disorders.5 Other elevated results in FMF patients include bilirubin (during attacks), IL-12 (during and between attacks), and IL-10 (during attacks). In patients with significant arthritis, anticyclic citrullinated peptide (anti-CCP) may also be elevated.

Treatment

Oral colchicine reduces the severity and frequency of FMF episodes, although the mechanism is unknown. As many as 75% of patients have experienced complete remission with colchicine therapy. Colchicine use can be limited, however, by its gastrointestinal and other side effects, or by interactions with other CYP-450-3A4-metabolized drugs.

In colchicine non-responders, the following have been shown to be of some benefit: anakinra, an IL-1 receptor antagonist; interferon-alpha (IFN-alpha); antitumor necrosis factor (anti-TNF) agents, such as etanercept, thalidomide, and infliximab; and selective serotonin reuptake inhibitors (SSRIs).6,7,8

Hyperimmunoglobulinemia D Syndrome

The mevalonate kinase gene (MVK) on chromosome 12 has been linked to hyperimmunoglobulinemia D syndrome (HIDS). This gene facilitates the cholesterol biosynthetic pathway, as well as pathways producing non-sterol isoprenoids involved in protein translation, glycosylation, and electron transport. More than 60 mutations in MVK have been described, resulting in one of two phenotypes of mevalonate kinase deficiency: HIDS, the milder form, or mevalonic aciduria, the more severe form. The carrier frequency rate for an MVK mutation has been found to be as high as 1:65 in the Dutch population.9

Clinical Features of HIDS

HIDS typically presents in the first year of life (median 6 months). A prototypical febrile attack includes a prodrome of malaise followed shortly by fever lasting for 3 to 6 days and subsequent lymphadenopathy with or without splenomegaly; gastrointestinal symptoms, such as abdominal pain, vomiting, and diarrhea; joint pain; rash; sterile arthritis; and Behçet’s-like oral or genital ulcers.10

Less common are headache, hepatomegaly, and conjunctivitis. Attacks can be provoked by illness, vaccination, or stress and recurrence varies with each person, with episodes occurring from once every 2 weeks to less than one episode per year. Patients are asymptomatic between episodes.

Type AA amyloidosis is a serious, long-term complication occurring in 3% of patients. Recent results showed that patients with HIDS experience diminished quality of life, including perception of general health, vitality, and social functioning. The international HIDS database ( www.hids.net) allows further investigation into clinical features.11

Laboratory Findings

During attacks, markers of inflammation — including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and neutrophilia — are present. Serum amyloid A (SAA) is also elevated.11 The hallmark finding is elevated polyclonal IgD to a median concentration of 400 U/mL, although IgD is not always elevated. IgA is also elevated in 75% to 80% of patients. Elevated mevalonic acid in the urine or reduced MVK activity is diagnostic.

Treatment

Randomized clinical trials have been performed testing thalidomide and simvastatin, with only simvastatin having a moderate effect on reducing episode length in HIDS.12,13 Anakinra, etanercept (a TNF-alpha inhibitor), or high-dose corticosteroids at onset of attack also have been effective in some patients.14,15

Autosomal Dominant

Tumor Necrosis Factor Receptor 1-Associated Periodic Syndrome

Tumor necrosis factor receptor 1-associated periodic syndrome (TRAPS, also known as benign autosomal dominant periodic fever, familial Hibernian fever, or autosomal dominant periodic fever with amyloidosis) is characterized by multiorgan involvement resulting from missense mutations in the gene encoding TNF receptor 1 (TNFR1) on chromosome 12p13. TNFR1 is in the proinflammatory TNF receptor superfamily, involved in T-cell, B-cell, and osteoclast regulation. Misfolding and mislocation of this receptor is characteristic of TRAPS, resulting in TNF’s inability to bind to the mutant receptor. Recent findings suggest a possible gain-of-function mutation in TNFR1 that may result in accumulation of mutant TNFR1 in the endoplasmic reticulum, in turn resulting in a stress response and subsequent inflammatory dysregulation. Two TNFR1 mutations (R92Q, P46L) have been found in at least 1% of chromosomes per one analysis, though the diagnosis of TRAPS remains rare in comparison to FMF.16

Clinical Features of TRAPS

TRAPS is typically diagnosed at about 3 years. The most prevalent manifestations are abdominal pain, arthralgia, and severe myalgia caused by a monocytic fasciitis. Other symptoms include vomiting, constipation, conjunctivitis, painful periorbital edema, development of inguinal hernias, and erythematous rashes. Renal type AA amyloidosis is a long-term complication seen in 14% to 25% of patients.17 Febrile attacks are varied, lasting from a few days to several months — the average duration of each episode is 21 days. Possible triggers of attacks include injury, infection, hormonal changes, and exercise.

Laboratory Findings

During attacks, one finds elevated inflammatory markers, polyclonal elevation of immunoglobulin (mainly IgA), leukocytosis, and anemia. In the asymptomatic intervals, there may still be elevated acute phase reactants, as well as serum amyloid A (SAA).17

Treatment

For most patients, nonsteroidal anti-inflammatory drugs (NSAIDs) or oral steroids can control symptoms. Monotherapy with etanercept reduces the requirement for steroids but does not completely abolish attacks.17 Recently, anakinra was found to be efficacious for several patients, resulting in the prompt alleviation of symptoms and the prevention of relapses.18,19

Cyclic Neutropenia

Cyclic neutropenia (CN) is an inherited or sporadic disorder that occurs secondary to heterozygous mutations in the ELANE (ELAstase-Neutrophil Expressed) gene. ELANE encodes neutrophil elastase; the mutated form of this protein is proposed to mislocalize, resulting in the unfolded protein response and apoptosis of differentiating myeloid cells.

Mutated neutrophil elastase is also the causative factor in severe congenital neutropenia (SCN), a phenotypically more severe disease than CN.20 In fact, CN and SCN may be two phenotypes of the same clinical entity.

Clinical Features of CN

CN typically presents in early childhood, with recurrent week-long episodes of fever, along with pharyngitis, mouth ulcers, lymphadenopathy, cellulitis, sinusitis, otitis, and bronchitis. Acute peritonitis can also occur and present with abdominal pain, ileus, or septic shock, which can be fatal. Although adult/acquired cases have been described, most patients present before 1 year of age. Episodes correlate with neutropenia, with cycles lasting from 14 to 40 days; more than 90% of patients have a cycle length of about 21 days.

Clinically, CN can appear similar to PFAPA (periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis). However, PFAPA episodes are not associated with neutropenia during attacks, but instead are often associated with neutrophilia.

Laboratory Features

Neutropenia is an absolute neutrophil count (ANC) less than 1,500/mcL. In CN, neutrophil counts fall to less than 200/μL for 3 to 5 days, then climb to 2,000/mcL for the remainder of the cycle.21 Oscillations of monocytes, reticulocytes, platelets, eosinophils, and lymphocytes have been identified. Cyclic neutropenia is diagnosed after documenting an ANC less than 500/mcL persisting for 3 to 5 days per cycle, for at least three separate periodic cycles.

Treatment

Supportive therapy includes prophylactic antibiotics and appropriate dental care to limit gingivitis and oral infection. Administration of granulocyte colony stimulating factor (G-CSF) has been used effectively for more than 20 years in reducing the duration of neutropenia to 2 days within each cycle, as well as reducing cycle length to 14 days.22 In patients with recurrent severe infections, G-CSF has been shown to increase neutrophil counts 10- to 20-fold. Most patients respond to 2 to 3 mcg/kg of G-CSF daily or every other day.

Cryopyrin-Associated Periodic Syndromes (CAPS)

Three disorders — familial cold autoinflamatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal onset multisystem inflammatory disease (NOMID) — are associated with missense mutations in the CIAS1 (human cold-induced autoinflammatory syndrome 1) gene on chromosome 1q, encoding the cryopyrin protein. Similar in structure to pyrin, cryopyrin activates cytokine production (IL-1 and IL-18), as well as apoptosis and NFKB, a regulator of apoptosis and inflammatory response. All the CAPS are extremely rare in clinical practice.

Clinical Features of CAPS

The two common findings in all CAPS are urticaria-like rash characterized by lymphocytic infiltration (as opposed to mast cells) on histology, and arthralgias/arthritis.

The mildest of the CAPS, FCAS is characterized by urticaria-like rash plus polyarthralgia. Attacks develop 30 minutes to 6 hours after cold exposure and last approximately 12 to 24 hours. There is often sweating, thirst, nausea, and headache. Other symptoms can include conjunctivitis or joint swelling. Onset occurs within 6 months of age, but attacks continue into adulthood.

MWS is considered of intermediate severity, with attacks lasting 1 to 2 days and occurring frequently (and almost continuously in a number of patients). Temperature typically does not rise above 100.4°F. Episodes occur with a rash identical to that of FCAS, lancinating limb pain, and malaise, and can also present with arthralgia, abdominal pain, and conjunctivitis. Long-term effects of the disease include sensorineural hearing loss, which becomes evident in adolescence, and severe type AA amyloidosis.

Neonatal onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic cutaneous articular syndrome (CINCA) presents in the neonatal period and is the most severe phenotype of the three disorders. Disease activity is fairly continuous and can involve a deforming arthropathy with early ossification and cartilaginous overgrowth.

The hallmark of NOMID/CINCA among the cryopyrinopathies is severe central nervous system involvement, characterized by intellectual disability, chronic aseptic meningitis, sensorineural hearing loss, uveitis, and vision loss caused by optic nerve atrophy. There are also characteristic facial abnormalities, including saddle-back nose, frontal bossing, and mid-face hypoplasia. Severe, systemic type AA amyloidosis can also occur.

Laboratory Findings

FCAS is characterized by leukocytosis during attacks. Inflammatory markers are elevated during fever episodes in MWS and can persist in the intervals between episodes. Coagulopathy and eosinophilia can occur in NOMID/CINCA.

Treatment

Anakinra, rilonacept (an IL-1 inhibitor), and canakinumab (an IL-1 beta receptor antagonist) have shown promise in all three disorders, with prevention of symptoms found in FCAS, complete remission in MWS, and a resolution of uveitis, rash, and fever in patients with NOMID/CINCA.23–26

Sporadic Periodic Fever Syndromes

Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) Syndrome

Although PFAPA is considered a periodic fever syndrome of unknown etiology, there appears to be a dysregulation of anti-inflammatory and pro-inflammatory cytokines. Mutations in MEFV (implicated in FMF), MVK (implicated in HIDS), CARD15 (implicated in Crohn’s disease), and TNFr1A (implicated in TRAPS) have been found in those diagnosed with PFA-PA, but the significance of this is unclear.27 Of those PFAPA patients with mutations, there is a higher occurrence of abdominal pain, diarrhea, vomiting, rash, and joint pain.28 There have also been reports of familial cases of PFAPA that may suggest heritability.29,30,31 Of all the periodic fever syndromes diagnosed in childhood, PFA-PA is thought to be the most common.

Clinical Features

PFAPA presents with regularly recurring fevers accompanied by mouth ulcers, pharyngitis, and lymphadenopathy. Symptomatic episodes recur at 4- to 6-week intervals, last for approximately 4 to 5 days, and resolve spontaneously.

Specific diagnostic criteria proposed in 1989 remain in use and include:

  1. Regularly recurring fevers with an early age of onset (typically younger than 5 years);

  2. Constitutional symptoms in the absence of upper respiratory infection with at least one of the following: aphthous stomatitis, lymphadenopathy (typically cervical), or pharyngitis;

  3. Exclusion of cyclic neutropenia, as well as other intermittent fever syndromes; and

  4. Asymptomatic intervals between episodes; and

  5. Normal growth and development.32

Although researchers are in the process of compiling long-term follow-up outcomes for a large cohort of PFAPA patients, initial 1999 follow-up of 83 children highlighted a resolution of fever and lack of long-term sequelae in many patients.33

Laboratory Findings

During febrile episodes, neutrophilia along with elevation of the ESR and CRP occur. These markers of inflammation suggest a defect in innate immunity, with additional evidence of elevated levels of IFN-gamma, TNF-alpha, and IL-6 concentrations.33 Recently, an examination of PFAPA cytokine levels showed an increase in plasma IFN-gamma, as well as IL-6 concentrations occurring 6 to 12 hours after fever onset, with elevated IL-1 beta, IL-6, TNF-alpha, and IL12p70 (all pro-inflammatory cytokines) during symptom-free intervals when compared with controls.34 These results suggest a state of chronic pro-inflammatory cytokine activation.

Treatment

For most patients, a single 0.6 to 2 mg/kg/day dose of prednisone administered at fever onset effectively terminates that episode. About 30% of patients experience complete remission of PFAPA while using cimetidine (20 to 40 mg/kg/day divided every 12 hours), although some report further episodes once cimetidine is stopped.

Although most patients report no response to cimetidine, the side-effect profile compared with steroid may warrant an initial trial of cimetidine. Several case reports and two randomized, controlled trials support the efficacy of adenotonsillectomy in PFAPA remission, or at least reduced severity of episodes, with complete recovery in 64% to 100% of patients.33,35,36

A recent Cochrane Collaboration review emphasized the significant benefit of adenotonsillectomy in PFAPA patients.37 However, without a clear understanding of the pathogenesis of PFAPA, surgical intervention, and the risks thereof, must be carefully considered, especially with reported cases of limited or no response to surgery. The frequency of spontaneous resolution of PFAPA episodes before puberty and the lack of long-term sequelae are important factors to weigh before recommending surgery.

Discussion

Although relatively rare in the clinical practice of a pediatrician, periodic fever syndromes should always be considered in cases of regularly recurring fevers of unclear etiology. Shared characteristics of these syndromes include childhood onset, acute onset of inflammatory symptoms, and asymptomatic intervals between episodes. Aside from fever, symptoms common to most of these syndromes include inflammation affecting joints, muscles, skin/mucous membranes, and the abdomen.

Although there have been cases of adult-onset periodic fevers, these syndromes typically present in childhood. Puberty appears to be a significant point in these diseases, with some patients experiencing a reduction in frequency or even complete resolution of symptoms at this time.

A thorough history and exam should differentiate these syndromes, with hallmark associated signs and symptoms remaining the key to clinical diagnosis.

Syndromes may be classified by regular or irregular periodicity, or by nearly continuous fevers (see Figure, page 51). In the case of hereditary periodic fever syndromes, family history, along with early genetic testing, will ultimately lead to accurate diagnosis and appropriate treatment.

Stratification of Periodic Fever Syndromes Based on Fever Frequency. Source: Edwards KM.

Figure. Stratification of Periodic Fever Syndromes Based on Fever Frequency. Source: Edwards KM.

In 2008, Gattorno et al. developed the Gaslini diagnostic criteria to determine when genetic testing for a monogenic periodic fever syndrome is appropriate.38 Certain criteria, including younger age of onset, abdominal pain, aphthous stomatitis, thoracic pain, diarrhea, and positive family history, separate patients into a “high-risk” category for genetic mutation. For high-risk patients, genetic testing is recommended. The Gaslini criteria are available online at www.printo.it/periodicfever, and have been shown to be clinically useful, with a sensitivity of 91% and specificity of 59%.28,38

Treatment options for the periodic fever syndromes often overlap, with successful therapies, including NSAIDs, corticosteroids, anti-TNF agents, and anti-IL-1 agents. Because of the commonality of pyrin gene family (including cryopyrin) involvement in most of these disorders,39 similar treatments antagonizing inflammation, cytokine processing, and apoptotic pathways have proven effective across syndromes.

Summary

Periodic fever syndromes are a subset of autoinflammatory syndromes, with a spectrum of associated manifestations. Fever patterns are varied and can be classified as regular, variable, or nearly continuous. Genetic testing may be warranted in cases at high risk for monogenic mutation by the recently developed Gaslini diagnostic score. Management is typically medical with drugs that modulate inflammatory processes.

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Authors

Victoria M. Wurster, BS; James G. Carlucci, MD; and Kathryn M. Edwards, MD, are with Vanderbilt University School of Medicine, Department of Pediatrics, Division of Pediatric Infectious Diseases.

Ms. Wurster and Dr. Carlucci have disclosed no relevant financial relationships. Dr. Edwards has disclosed the following relevant financial relationships: Centers for Disease Cotnrol and Prevention, National Institutes of Health, and Novartis: Contracted research recipient.

Address correspondence to: Kathryn M. Edwards, MD; fax: 615-343-9723; or e-mail: .kath-ryn.edwards@vanderbilt.edu

10.3928/00904481-20101214-10

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