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← Paediatrics and child health indexChapter sections
OverviewAetiologyPathophysiologyClinical features and red flagsInvestigationsDifferential diagnosisManagementComplicationsMonitoring and follow-upSpecial situationsCommon pitfallsQuestionsSources
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Educational draft · awaiting clinical reviewThe full textbook explains uncertainty but does not replace live national or local guidance, specialist advice, or current prescribing information.

Periodic fever syndromes awareness

Paediatrics and child health · UK scope · Sources checked 27 Aug 2026 · Clinical review pending

RapidFull
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Fever with physiological instability

Shock, meningism, respiratory failure, severe abdominal guarding, cytopenia, coagulopathy, encephalopathy or an immunocompromised state requires emergency infection, malignancy and macrophage-activation assessment before a periodic-fever label.

Action: Use ABCDE, obtain cultures and time-critical tests, give sepsis treatment when indicated and involve paediatrics; the existence of recurrent similar attacks never justifies withholding emergency care from a different or severe episode.

Overview

Recognise stereotyped sterile inflammatory attacks, distinguish PFAPA from monogenic autoinflammatory disease and recurrent infection, capture objective evidence during flares and refer early enough to prevent amyloidosis and organ damage.

Construct a calendar before naming a syndrome. Record age at first episode, exact duration and spacing, season, measured temperature, symptoms in the same order, treatment and whether the child returns completely to normal. Ask ancestry, consanguinity and family renal failure, fever, deafness or amyloidosis. Obtain previous cultures, blood counts and antibiotic responses.

PFAPA is common and usually self-limiting. Fevers recur predictably with aphthous ulcers, pharyngitis and cervical adenitis, while children grow and remain well between attacks. Absence of one component does not exclude it. Marked abdominal serositis, long attacks, cold trigger, hearing change, persistent inflammation or family pattern redirects toward monogenic disease.

Investigate during fever and health. During an attack, FBC, CRP or ESR, ferritin and chemistry confirm inflammation and exclude cytopenia or organ failure; cultures follow clinical infection probability. When well, persistent CRP or serum amyloid A suggests ongoing subclinical disease. Urinalysis and protein quantification screen AA amyloidosis.

Aetiology

01

PFAPA immune cycling

Preschool children develop recurrent sterile innate immune activation with aphthae, pharyngitis and cervical adenitis despite no defined single-gene defect.

02

Familial Mediterranean fever

Biallelic or sometimes phenotype-producing MEFV variants activate pyrin inflammasomes, causing brief fever and serositis with ancestry-dependent prevalence.

03

Mevalonate kinase deficiency

Biallelic MVK variants disrupt isoprenoid metabolism and trigger childhood inflammatory attacks after vaccination, infection or stress.

04

TRAPS and CAPS

Dominant TNFRSF1A or NLRP3 pathway variants cause longer migratory inflammatory attacks or cold-triggered urticaria-like disease with neurological and hearing risk.

Pathophysiology

  1. 1
    Inflammasome activation

    Innate danger-sensing complexes overproduce interleukin-1 without infection or autoantibody, creating fever, serositis, rash and acute-phase response.

  2. 2
    Attack and interval biology

    Pathway activation rises abruptly during stereotyped flares and may fully settle or remain subclinical between episodes depending on syndrome.

  3. 3
    Serum amyloid A persistence

    Repeated or continuous hepatic acute-phase production deposits AA fibrils in kidneys and other organs when inflammation is inadequately controlled.

  4. 4
    Syndrome-specific tissue injury

    CAPS can injure cochlea and central nervous system, while FMF serositis and TRAPS fasciitis create characteristic organ pain.

Clinical features and red flags

PFAPA pattern

Predictable preschool fever with aphthous ulcers, pharyngitis or cervical adenitis occurs with normal growth and complete interval wellness.

Familial Mediterranean fever

Brief one- to three-day fever with severe abdominal or pleuritic pain, arthritis or erysipelas-like leg rash suggests pyrin disease.

Mevalonate kinase deficiency

Longer fever with nodes, aphthae, vomiting, diarrhoea and rash after vaccination or infection suggests MVK pathway disease.

TRAPS pattern

Attacks lasting over a week with migratory muscle pain, overlying rash, abdominal pain and periorbital oedema suggest TNF-receptor disease.

CAPS pattern

Cold-triggered urticaria-like rash, conjunctival inflammation, headache or meningism, bony overgrowth and hearing loss suggests cryopyrin activation.

Red flags requiring action

  • Poor growth, persistent symptoms between attacks, organ enlargement, lymphadenopathy, clubbing or fixed rash argues against uncomplicated PFAPA and needs broader investigation.
  • Neutropenia during predictable roughly three-week episodes suggests cyclic neutropenia and requires serial FBC rather than clinical PFAPA diagnosis.
  • Travel, exposure, immunodeficiency, central lines or immunosuppression maintains a high infection probability even when fever has recurred previously.

Investigations

  1. 01
    First-line fever diary and recordsFirst stepFirst line
    Why
    Demonstrate stereotyped duration, interval, associated features, treatment response and complete inter-episode recovery.
    Interpretation and limitations
    Predictable recurrence supports periodic fever, while changing sites and incomplete recovery increases infection or systemic-disease concern.
  2. 02
    Attack and interval inflammatory profile
    Why
    Compare FBC, CRP or ESR, ferritin, renal and liver tests during fever and health.
    Interpretation and limitations
    Normalisation supports PFAPA; persistent inflammation suggests monogenic disease or another chronic inflammatory source.
  3. 03
    Urinalysis protein and serum amyloid A
    Why
    Detect renal AA amyloidosis and quantify subclinical inflammatory control in at-risk syndromes.
    Interpretation and limitations
    Proteinuria or persistently raised serum amyloid A accelerates specialist treatment even when attacks seem tolerable.
  4. 04
    Serial neutrophil counts
    Why
    Capture the approximately 21-day profound neutrophil nadir of cyclic neutropenia.
    Interpretation and limitations
    Obtain repeated counts across several weeks; one normal count outside the nadir cannot exclude the diagnosis.
  5. 05

Differential diagnosis

01

Recurrent infection

Changing symptoms, sick contacts, positive cultures, incomplete wellness and site-specific findings support repeated infection rather than sterile stereotyped attacks.

02

Cyclic neutropenia

Fever, mouth ulcers and infection recur about every 21 days with profound neutropenia captured by serial blood counts.

03

Immunodeficiency

Opportunistic organisms, poor growth, chronic diarrhoea, persistent thrush and incomplete recovery suggest impaired host defence rather than autoinflammation.

04

Malignancy or inflammatory disease

Weight loss, night pain, cytopenia, organ enlargement, fixed inflammation or progressive symptoms require oncological, rheumatological and marrow assessment.

05

Factitious or environmental fever

Discordant measured temperatures, absent inflammatory response or exposure pattern requires careful safeguarding and environmental assessment without accusatory assumptions.

Management

01Acute feverExclude a different emergencyFirst stepA child with recurrent fever presents unwell or with atypical features.+
  1. 1Use ABCDE and assess sepsis, meningism, macrophage activation, abdomen and immune status.
  2. 2Obtain cultures and give antimicrobials when clinical probability warrants them.
  3. 3Compare the episode with the established pattern but never let the label override current physiology.
02DocumentProve periodic inflammationFever episodes recur with a similar symptom sequence.+
  1. 1Use a fever diary and retrieve temperatures, cultures, blood counts and treatment responses.
  2. 2Measure inflammatory tests during an attack and again when fully well.
  3. 3Use serial neutrophil counts, urinalysis and targeted tests for specific competing diagnoses.

Complications

01

AA amyloidosis

Sustained serum amyloid A causes renal protein loss and progressive kidney failure, especially in untreated familial Mediterranean fever.

02

Hearing and neurological damage

Untreated cryopyrin-associated disease can cause sensorineural deafness, chronic aseptic meningitis, raised intracranial pressure and irreversible developmental harm.

03

Adhesions and chronic pain

Repeated serositis in FMF can cause persistent abdominal or chest pain, reproductive effects and unnecessary surgery.

04

Diagnostic and antibiotic burden

Repeated emergency investigation and empirical antibiotics disrupt school and family life and promote adverse effects without controlling sterile inflammation.

Monitoring and follow-up

  • Continue a fever diary with objective temperature, duration, features, missed school and medicine response.
  • Measure CRP or serum amyloid A during health at syndrome-specific intervals to detect silent inflammation.
  • Check urinalysis, protein quantification, blood pressure and renal function for amyloidosis risk.
  • During colchicine review adherence, attacks, FBC, liver, renal function, CK symptoms and interacting medicines.
  • During IL-1 blockade monitor infection, blood counts, liver tests, vaccination and injection reactions.
  • Review hearing, neurological symptoms, eyes, growth and development in CAPS or other high-risk phenotypes.
  • Reassess diagnosis whenever the attack pattern, interval wellness or laboratory signature changes.

Special situations

Well intervals discriminate

Complete return to normal growth and behaviour supports PFAPA, while persistent inflammation or symptoms demand a wider diagnosis.

One normal neutrophil count fails

Cyclic neutropenia is missed unless counts are repeated across the expected three-week nadir and recovery cycle.

Colchicine protects kidneys

In FMF, daily treatment is continued between attacks to suppress serum amyloid A and prevent renal amyloidosis.

Steroid response is nonspecific

Rapid PFAPA improvement after prednisolone is useful but cannot replace exclusion of infection and monogenic fever.

Genetics follows phenotype

Large panels generate uncertain variants, so attack duration, rash, serositis, hearing and ancestry should guide testing.

Common pitfalls

  1. 01

    Calling recurrent infection PFAPA without cultures and interval assessment.

  2. 02

    Using one normal neutrophil count to exclude cyclic neutropenia.

  3. 03

    Ignoring persistent inflammation between attacks.

  4. 04

    Stopping colchicine when an FMF attack ends.

  5. 05

    Diagnosing a syndrome from a variant of uncertain significance.

  6. 06

    Using antibiotics for every typical sterile PFAPA episode.

  7. 07

    Letting a known periodic fever label delay sepsis treatment.

Practice

Two practice questions

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Paediatrics and child healthOriginal SBA

FMF damage prevention

A child with genetically and clinically confirmed familial Mediterranean fever feels well between brief serositis attacks. Which treatment best prevents AA amyloidosis?

Choose one answer, then submit
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Sources and review status5 sources · checked 27 Aug 2026 · clinical review pending+
Sources

Sources and review status

National guidance is shown before implementation-dependent detail. Typical adult dose examples remain subject to patient factors, contraindications and the live BNF or specialist protocol. Source check completed 27 Aug 2026; clinical approval remains outstanding.

  • NHSGGC Recurrent Fever Referral GuidanceChildhood recurrent-fever assessment, important mimics and referral thresholds.
  • NHS Genomics Familial Periodic Fever SyndromesPhenotype-led genomics, colchicine, cytokine-directed care and amyloidosis prevention.
  • NICE TA777 CanakinumabIL-1 treatment commissioning for selected periodic fever syndromes.
  • NHS England Periodic Fever TreatmentUK periodic-fever burden and commissioned cytokine-directed treatment.
  • European Chronic Neutropenia ConsensusSerial blood-count strategy for excluding cyclic neutropenia in children.

Editorial contact: Doctor’s Passport editorial team. Source-check date is separate from clinical approval. Report a content problem · Content changes

Authoring stateComplete draft
Serial FBC two or three times weekly across six weeks may be needed when cyclic neutropenia is plausible because a single normal neutrophil count between attacks is uninformative. Immunoglobulins, vaccine responses, imaging, marrow or autoimmune tests are added from growth, infection and systemic clues rather than routinely.

One dose of prednisolone at PFAPA onset can abort fever, but may shorten the interval to the next attack and repeated exposure requires a clear plan. Colchicine can reduce episodes in selected frequent PFAPA, and tonsillectomy is considered after shared ENT and paediatric discussion when burden is high. Antibiotics do not treat sterile PFAPA.

FMF requires daily colchicine even between attacks because preventing amyloidosis is as important as symptom control. Monitor adherence, blood counts, liver, kidney and creatine kinase risks. Colchicine-resistant or intolerant disease and other monogenic syndromes may respond to anakinra or canakinumab through a national autoinflammatory service.

Genetic results need expert interpretation. A variant of uncertain significance cannot create a syndrome, while a convincing phenotype can exist with no identifiable variant. Treatment response supports mechanism but should not be used as the sole diagnostic test. Provide a fever emergency plan defining when a usual attack still needs sepsis assessment.

Key points

  • Periodic fever means recurrent stereotyped inflammatory attacks with objective wellness or a stable baseline between them after infection, malignancy, immune deficiency and autoimmune disease are considered.
  • Ask families to record measured temperature, duration, interval, rash, mouth, throat, nodes, serositis, joints, eyes, hearing, triggers and complete recovery in a fever diary.
  • PFAPA usually begins before age five with three- to seven-day fevers every few weeks, aphthous ulcers, pharyngitis or cervical adenitis and normal growth between attacks.
  • PFAPA is clinical: throat cultures are negative during typical attacks and corticosteroid response supports but does not prove the diagnosis; inherited periodic fever must be reconsidered when atypical.
  • FMF attacks usually last one to three days with peritonitis-like abdominal pain, pleurisy, arthritis or erysipelas-like leg rash; colchicine prevents attacks and AA amyloidosis.
  • Mevalonate kinase deficiency causes three- to seven-day attacks with cervical nodes, abdominal symptoms, rash and aphthae, often triggered by vaccination or infection.
  • TRAPS often produces attacks longer than a week with migratory myalgia or rash and periorbital oedema; CAPS can cause cold-triggered urticaria-like rash, red eyes, meningitic symptoms and hearing loss.
  • Obtain FBC, CRP or ESR, ferritin, renal and liver profile, urinalysis and serum amyloid A when available both during an attack and when well to document the inflammatory pattern.
  • Genetic testing is phenotype-led through an autoinflammatory service; broad unsupervised panels create uncertain variants and do not replace clinical assessment.
  • Refer suspected monogenic disease, persistent interval inflammation, proteinuria, hearing or neurological features, or colchicine-resistant FMF for specialist IL-1-directed treatment.
Proteinuria, oedema or persistently raised serum amyloid A between attacks raises AA amyloidosis from uncontrolled monogenic autoinflammation.
  • Prolonged attacks, serositis, migratory myalgia, periorbital oedema, cold-triggered urticaria-like rash, hearing loss or family history suggests monogenic periodic fever.
  • Very high ferritin with cytopenia, hepatitis, coagulopathy or neurological deterioration suggests macrophage activation rather than a routine periodic attack.
    • Phenotype-led genetic testing
    Why
    Confirm MEFV, MVK, TNFRSF1A, NLRP3 or another monogenic autoinflammatory pathway.
    Interpretation and limitations
    Specialist interpretation separates pathogenic variants, low-penetrance alleles and uncertain findings and guides family testing.
    03ClassifySeparate PFAPA from monogenic diseaseInfection and malignancy are excluded and sterile recurrence remains likely.+
    1. 1Assess age, duration, interval wellness, aphthae, serositis, rash, eyes, hearing and family ancestry.
    2. 2Diagnose typical PFAPA clinically and refer atypical or persistent inflammation to an autoinflammatory service.
    3. 3Order genetic testing only from the specialist-supported phenotype and counsel about uncertain results.
    04Prevent damageUse syndrome-specific suppressionAttack burden, persistent inflammation or organ-risk syndrome is confirmed.+
    1. 1Use single-dose corticosteroid or selected tonsil or colchicine strategies for burdensome PFAPA.
    2. 2Give continuous colchicine for FMF and monitor adherence and amyloid risk.
    3. 3Use specialist IL-1 blockade for resistant FMF, CAPS, TRAPS or MKD when indicated.
    Key medicines and prescribing safety3 treatments · regimens, roles and cautions+
    Continuous treatment prevents FMF attacks and, critically, suppresses inflammation enough to prevent AA amyloidosis and renal failure.

    Colchicine for familial Mediterranean fever

    A common age-based start is 0.5 mg once daily below 5 years, 0.5–1 mg daily from 5–10 years and 1–1.5 mg daily above 10 years, divided if needed and titrated by the specialist to attacks and serum amyloid A.

    Adjust for renal or hepatic impairment, monitor FBC, liver, CK and gastrointestinal toxicity, review CYP3A4 and P-glycoprotein interactions and treat overdose as a medical emergency.

    Can terminate a typical PFAPA episode quickly and support family function while longer-term strategy is considered.

    Prednisolone for selected PFAPA attacks

    A specialist plan may use a single oral dose of 1–2 mg/kg, maximum 60 mg, at attack onset; avoid automatic repeated daily courses and record whether fever aborts and the next interval shortens.

    Response is not diagnostic, attacks may recur sooner, frequent dosing creates cumulative steroid toxicity and infection must be excluded when an episode differs from the usual pattern.

    Interleukin-1 blockade treats CAPS and selected colchicine-resistant FMF, TRAPS, MKD or severe undifferentiated autoinflammation.

    Anakinra for monogenic autoinflammation

    Specialist regimens often begin around 1–2 mg/kg subcutaneously once daily, maximum 100 mg at routine starting exposure, with syndrome and severity-specific escalation through the national autoinflammatory service.

    Screen and monitor infection, neutrophils, liver tests and injection reactions, adjust for severe renal impairment and do not use response alone to prove a genetic diagnosis.

    Clinical stateAwaiting review
    JurisdictionUnited Kingdom