Skip to content

Recurrent or Periodic Fevers – investigate or reassure?


A 3 year old girl presents to your clinic with her mother. Their GP has referred her due to monthly fevers. Otherwise appears well, growing normally and developing well.

Bottom line

Are they fevers?

Recurrent fevers are common and are most often due to recurrent viral or bacterial infections

FIRST exclude an infectious process or a malignancy (rare)

NEXT, consider immune-mediated and autoinflammatory diseases (genetic testing is available)

Unclear diagnosis – basic investigations and watchful follow-up are recommended

Infections linked to a single target organ (urinary tract, skin, lung), look for local predisposing conditions and consider specialist referral

The definition remains unclear.

Recurrent or periodic fevers: >12 episodes over 12 months with a minimal interval of seven days between episodes

Previously: at least three episodes of unexplained fever in a six-month period, with a minimum interval of seven days between episodes

Fever-of-Unknown-Origin (FUO): daily fever for ≥14 days that defies explanation after a careful history, physical examination, and basic laboratory tests

What is normal?

The average child under 2 years has 6 or 7 respiratory illnesses per year (most of which are viral) unless they attend daycare or have school-aged siblings, in which case they may have as many as 10.

Beware! Elevated temperatures are seen after meals, exercise, chewing gum and with ovulation. Moreover, there is a normal diurnal variation in temperature, with lows in the morning and highs in the afternoon.


  • Check for red flags
  • Keep a meticulous fever diary
  • Serial clinical and laboratory evaluations
  • Vigilance for the appearance of new signs and symptoms
  • Targeted investigations
  • The pace of the work-up is determined by the severity of the illness.


Red flags for malignancy

  • Poor growth
  • Weight loss
  • Lethargy
  • Night sweats.

Lymphoma, juvenile myelomonocytic leukaemia and atrial myxoma have been reported to cause recurrent fever in children.

Red Flags for primary immunodeficiency

  • Four or more episodes of otitis within 1 year
  • Two or more serious episodes of sinusitis within 1 year
  • Two or more cases of pneumonia within 1 year
  • Failure to gain weight or grow normally
  • Recurrent, deep skin or organ abscesses
  • Two or more deep-seated infections including septicaemia
  • Persistent thrush in the mouth or fungal infection on skin
  • Two or more months on antibiotics with little effect
  • Need for intravenous antibiotics to clear infections
  • A family history of primary immunodeficiency

Ask: Age at onset, family history, duration of febrile episodes, length of the interval between episodes, associated symptoms, travel history, exposure to animals, response to treatment, infectious diseases…the usual extensive run through…..including the rarities!

New symptoms may prompt a new line of investigation

  • Periorbital oedema – primary EBV infection
  • Palpitations – hyperthyroidism
  • Increasing lymphadenopathy – lymph node biopsy
  • Loose stools – inflammatory bowel disease
  • Rash, anaemia and thrombocytopenia – ANA screen

Signs and Symptoms suggestive of a specific diagnosis

Signs and SymptomsPossible Diagnosis
Relative bradycardiaBrucellosis, drug fever
Bradycardia due to a conduction defectAcute rheumatic fever, infective endocarditis
Oral ulcersCrohn disease, Behçet disease, cyclic neutropenia, PFAPA, HIDS, HSV, drug fever
LymphadenopathyCyclic neutropenia, PFAPA, sJIA, HIDS, EBV
Arthritis/arthralgiasJIA, FMF, HIDS, TRAPS, MWS, FCAS, Behçet disease, parvovirus B19, relapsing fever, trench fever, chronic meningococcemia, rat bite fever, Brucellosis
SplenomegalysJIA, HIDS, FMF, TRAPS, EBV, relapsing fever, chronic meningococcemia, Brucellosis, malaria, visceral leishmaniasis
UveitisCrohn disease, Behçet disease
Weight lossCrohn disease, malignancy
FatigueEndocarditis, sJIA, malignancy
Abdominal painCrohn disease, FMF, HIDS, TRAPS, parvovirus B19, relapsing fever
SerositisFMF, sJIA, systemic lupus erythematosus
ConjuctivitisTRAPS (painful conjunctivitis), FCAS, trench fever
Genital ulcersBehçet disease
Transient rash during feverssJIA
PetechiaeChronic meningococcemia
Erythema nodosumCrohn disease, Behçet disease, parvovirus B19
Erysipelas-like erythemaFMF
Sensorineural deafnessMWS, NOMID
Morning feverDiabetes insipidus

PFAPA: Periodic fever, aphthous stomatitis, pharyngitis, adenopathy syndrome; FMF: Familial Mediterranean fever; HIDS: Hyperimmunoglobulinemia D with periodic fever syndrome; FCAS: familial cold autoinflammatory syndrome; MWS: Muckle-Wells syndrome; NOMID: Neonatal onset multisystem inflammatory disease; TRAPS: TNF receptor–associated periodic syndrome; sJIA: systemic juvenile idiopathic arthritis; HSV: Herpes simplex virus. EBV: Epstein-Barr virus.

Timing is vital!

Irregular, intermittent, recurrent fevers in the well-appearing child less than 6 years are likely to be sequential viral illnesses. (also consider autoinflammatory disease)

Relentless daily fevers suggest an underlying infectious, rheumatologic, or malignant condition, although in many children such fevers are ultimately self-limited and no definitive diagnosis is made.

Autoimmune diseases in early childhood are rarer than in late childhood and adolescence. Fever episodes generally have a long duration, and during afebrile intervals, symptoms tend to persist, often worsening over time.

High fevers of abrupt onset that occur with clockwork periodicity are classic for periodic fever, aphthous stomatitis, pharyngitis, and adenopathy (PFAPA) syndrome; cyclic neutropenia should be considered if the periodicity is approximately 21 days. In other instances, the temporal pattern may be less regular and the child can appear in bad condition between the episodes without adequate growth, as in auto-inflammatory disorders or EBV.

Consider daily variation in temperature: patients with JIA may be subnormal in the mornings and high in the afternoons. In sJIA, fever can be the initial isolated sign for up to months.

Paroxysmal fever cycles occur every 2–3 days in malaria, and the diagnosis is suspected based on travel history and associated findings such as haemolysis, jaundice, and hepatosplenomegaly.

Think outside the box…

Uncommon presentation of a common illness, such as:

  • Bacterial sinusitis without much in the way of nasal drainage (bifrontal headache)
  • Pneumonia without cough or chest pain (dullness to percussion)
  • Consider occult abdominal abscess or osteomyelitis—that is partially treated by empiric courses of antibiotics

Common presentation of an uncommon disease, such as:

  • Kawasaki Disease – (rash, conjunctivitis, changes in the oral mucosa or peripheral extremities, or cervical lymphadenopathy)
  • Tuberculosis or Histoplasmosis (cough and infiltrate on chest X-ray, especially if hilar or mediastinal lymphadenopathy)
  • Leukaemia/lymphoma (bruising, bleeding, splenomegaly, and/or lymphadenopathy)
  • Tick-borne rickettsiosis (summer, leukopenia, thrombocytopenia and elevated hepatic transaminases)
  • Subacute bacterial endocarditis (abnormal heart value, changing murmur, and embolic phenomena)

Other rare causes of recurrent fever include factitious fever, drug fever, diabetes insipidus, histiocytic disorders and central nervous system abnormalities, such as agenesis of the corpus callosum or hypothalamic dysfunction.


Basic bloods

  • FBC, Chem20
  • Immunoglobulin levels
  • Vaccine titres (diphtheria, tetanus, pneumococcus)
  • Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) (when afebrile) Assess the trend!
  • Uric acid and lactate dehydrogenase (LDH)
  • Consider TFTs and blood culture

Relevant infectious workup – urine culture, blood culture, throat culture

Relevant rheumatology workup

Consider stool culture and calprotectin/urine cultures

Imaging or other investigations as indicated (eg, masses on examination, endoscopy to rule out inflammatory bowel disease, bone scan to rule out osteomyelitis)

Genetic testing is available for a number of autoinflammatory syndromes but it is not 100% sensitive so your patient can still clinically have an autoinflammatory syndrome

TestDiagnosisReason for suspicion
Infectious diseases
Tuberculin skin test, IGRATuberculosisExposure to active case, homeless shelter, travel, immigration
Histoplasma serologyHistoplasmosisResidence in Ohio Valley, bird exposures
EBV serologyEBV infectionFatigue, lymphadenopathy, cytopenias, elevated transaminases
Bartonella serologyCat scratch diseaseExposure to kittens, chronic granulomatous papule
Brucella serologyBrucellosisConsumption of unpasteurized milk products
Toxoplasma serologyToxoplasmosisExposure to cats, consumption of poorly cooked meat
Francesella serologyTularemiaTick bite with eschar, rabbit hunting
HIV Ab/Ag or PCRHIV infectionSexually active, mononucleosis-like illness, cytopenias
Stool culture for SalmonellaTyphoid feverTravel to developing country, hepatosplenomegaly, rose spots
Antinuclear Ab, RF, C3, C4, slit lamp examVarious rheumatologic diseasesRash, arthritis, cytopenias, renal dysfunction, acute phase reaction
ASO, anti-DNAse-B AbRheumatic feverMigratory polyarthritis, erythema marginatum, heart murmur
Flow cytometry, LDH, UA, bone marrow aspirateLeukemia/lymphoma, various malignanciesFatigue, bruising, bleeding, lymphadenopathy, weight loss, cytopenias
Catecholamine screen, mIBG scanNeuroblastomaOpsoclonus–myoclonus, diarrhea
CT, PETSolid tumors/lymphomaLocalizing symptoms
Thyroid function profileHyperthyroidismNervousness, irritability, tachycardia, tremors
Sinus CTSinusitisHeadache, congestion
EchocardiogramEndocarditisFatigue, murmur, splenomegaly, hematuria, thrombocytopenia
EndoscopyIBDLoose stools, weight loss, acute phase reaction, anemia
Abdominal U/S or CTAbdominal abscessAbdominal discomfort
Bone scanOsteomyelitisMusculoskeletal complaints

Abbreviations : Ab: antibody; Ag: antigen; ASO: anti-streptolysin-O; C3: complement component 3; C4: complement component 4; CT: computed tomography; EBV: Epstein–Barr virus; HIV: human immunodeficiency virus; IBD: inflammatory bowel disease; IGRA: interferon gamma release assay; LDH: lactate dehydrogenase; mIBG: (radio-ionated) meta-iodobenzylguanidine; PCR: polymerase chain reaction; PET: positron emission tomography; RF: rheumatoid factor; U/S: ultrasound; UA: uric acid.

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

If the periodicity is strictly regular, PFAPA syndrome and cyclic neutropenia should be suspected. PFAPA syndrome, first described in 1987, is the most common periodic fever in children. The typical patient has onset of symptoms at around 3 years of age. Episodes occur every 3–6 weeks and last 3–4 days, with maximum temperatures as high as 40.3 °C. Constitutional symptoms and malaise are common. Localizing symptoms such as abdominal pain, diarrhoea, arthralgia, and rash have been reported in case series. CRP (not procalcitonin) is elevated during PFAPA episodes.

In comparison, cyclic neutropenia has an onset of <5 years and episodes last 5-7 days. PFAPA syndrome is much more common than cyclic neutropenia, which should be excluded by laboratory testing in all suspicious cases.

In PFAPA syndrome, blood tests show only mild leukocytosis and a moderate increase in erythrocyte sedimentation rate (ESR) during attacks, while no abnormality is found between episodes. A child affected by PFAPA syndrome has few complaints apart from recurrent fever and does not show an increased risk of infection.

Distinctive features of PFAPA syndrome:

  • Fever episodes are stereotypical, circumspect, unprovoked, and recur with clockwork periodicity
  • Identifiable prodrome is common
  • There is evidence of upper respiratory tract inflammation
  • Rash and arthritis are absent
  • Acute phase reactants are elevated during episodes and normal between episodes
  • The child is failing to fail-to-thrive
  • Episodes are aborted by steroid therapy
  • Episodes resolve after tonsillectomy
  • The syndrome resolves by adolescence
  • There are no long-term sequelae

Prognosis is good, most have complete resolution of fever episodes by 9 years of age.

Steroids are very effective in aborting PFAPA episodes. Caution needs to be exercised that the fever illness being treated is a PFAPA episode and not an intercurrent infection. Tonsillectomy is often curative, but, given the associated morbidity and risks, this option should be reserved for children whose episodes are severely disruptive to the child and family (as well as those children who have other indications for tonsillectomy).

On the contrary, a child with cyclic neutropenia may present repeated bacterial infections due to neutropenia. Cellulitis, especially in the perianal region, is common during the neutropenic period.

In cyclic neutropenia, neutropenia is not necessarily present at the time of fever; diagnosis requires multiple leukocyte counts for a 4–6 week period.

Which children with recurrent fevers should have DNA sequencing?

Findings of: positive family history, thoracic pain, abdominal pain, diarrhoea, vomiting, rash and arthralgia favour monogenic disorders rather than PFAPA syndrome; exudative pharyngitis and aphthous ulcers favour PFAPA syndrome.

In 2008, Gattorno and colleagues derived and validated the Gaslini score: a diagnostic score to predict which children with PFAPA-like symptoms are likely to test positive for one of the heritable periodic syndromes.

Age at onsetMonthsX−0.067=a
Abdominal pain0 = Never1.494b
2 = Sometimes or often
3 = Always
Aphthous ulcers0 = Never−1.504c
1 = Sometimes or often
2 = Always
Thoracic pain0 = Absent1.958d
1 = Present
Diarrhea0 = Never0.901e
1 = Sometimes
2 = Often
3 = Always
Family history0 = Negative1.503f
1 = Positive

For each variable, multiply the code number (e.g., 0, 1, 2, etc.) by the corresponding coefficient to obtain the value. Add the values (a + b + c + d + e + f) to get the total score. In a validation set, a score >1.32 identified children who were positive for heritable periodic fever syndromes with 87% sensitivity and 72% specificity).

Data from Gattorno et al. Named for the Giannina Gaslini Institute in Genoa, Italy, the principal investigators’ home institution.Codes apply during each episode of fever and not during interval periods.

Autoinflammatory Disorders

These are for the most part monogenic disorders, with well-defined inheritance patterns and ethnic predilections. Many have onset early in life. Attacks occur with variable frequency and duration. Associated signs and symptoms such as rash, serositis, splenomegaly, and arthritis are common. Some of these diseases result in long-term sequelae such as amyloidosis.

Feature Inflammasomopathies Protein folding disorder
Intrinsic (Cryopyrin-associated) Extrinsic
SynonymsFCUSCINCAMKD Etiocholanolone feverHibernian fever
Inheritance patternAutosomal dominantAutosomal dominantSporadicAutosomal recessiveAutosomal recessiveAutosomal dominant
Age at onset<1 year<20 years<1 year<20 years<1 year<20 years
Frequency of attacksVariableVariableContinuousVariable2–4 weeksVariable
Duration of attacks1–2 days2–3 daysContinuous1–3 days3–7 days>7 days
Clinical findingsRash
Erysipeloid erythema
Treatment modalitiesAnti-IL-1Anti-IL-1Anti-IL-1ColchicineAnti-IL-1

Abbreviations. CINCA: chronic infantile neurological, cutaneous and articular syndrome; FCAS: familial cold autoinflammatory syndrome; FUCS: familial cold urticaria syndrome; FMF: familial Mediterranean fever; HIGDS: hyper-IgD syndrome; IL-1: interleukin-1; MKD: mevalonate kinase deficiency; MWS: Muckle-Wells syndrome; NOMID: neonatal onset multi-system inflammatory disease; TNF: tumor necrosis factor; TRAPS: tumor necrosis factor receptor-associated periodic syndrome.

Further rare considerations

  • Deficiency of Interleukin-1 Receptor Antagonist
  • Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature (CANDLE)
  • Stimulator of IFN genes (STING)-associated vasculopathy with onset in infancy (SAVI)
  • Chronic Recurrent Multifocal Osteomyelitis (CRMO)
  • Majeed Syndrome (Chronic Recurrent Multifocal Osteomyelitis, Congenital Dyserythropoietic Anemia, and Dermatosis)
  • Deficiency of Adenosine Deaminase 2 (DADA2)

Long-Term Outcomes and Amyloidosis

Mostly favourable.

Some are associated with amyloidosis. Repeated episodes of severe acute inflammation result in elevated levels of circulating acute phase proteins, including serum amyloid (SAA). Irreversible deposition of SAA in organs may occur as a complication of poorly controlled PFS. Renal amyloidosis causes the greatest morbidity and is the most likely predictor of disease course. Management of this severe complication requires early diagnosis and treatment of PFS.


Most children have self-limited, common illnesses due to the physiological susceptibility to infections typical of the paediatric age group and will have a favourable prognosis.

Think infectious, inflammatory, and neoplastic!

When investigating, consider the age at onset, family history, duration of febrile episodes, length of the interval between episodes, associated symptoms, and response to treatment. 

Knowledge of travel history and exposure to animals is helpful.

Rule out the possibility of an infectious process or a malignancy, especially if steroid therapy is being considered.

Immune-mediated and autoinflammatory diseases with genetic testing should be taken into consideration to guide specific therapy and prevent long-term complications.

Despite thorough evaluation, an increasing proportion of recurrent fevers remain unexplained. A watchful follow-up is thus mandatory because new signs and symptoms may appear over time.


Kara SS, Ozsurekci Y, and Ceyhan, M. Evaluation of Children with Recurrent Fever. J Clin Anal Med, 2016; Volume 7, Issue 5, Pages 681-685.

Marshall GS. Prolonged and recurrent fevers in children. Journal of Infection, Jan 2014, Volume 68, Pages S83-S93.

Ostring GT and Singh-Grewal D. Periodic fevers and autoinflammatory syndromes in childhood. Journal of Paediatrics and Child Health. Sep 2016, Volume 52, Issue 9, Pages 865-871.

Torregiani S, Filocamo G, and Esposito S. Recurrent Fever in Children. Int J Mol Sci. Apr 2016, Volume 17, Issue 4, Page 448.

Verbsky JW. When to Suspect Autoinflammatory/Recurrent Fever Syndromes. Pediatric Clinics of North America, Feb 2017, Volume 64, Issue 1, Pages 111-125.


  • Alyssa Courtney is a general paediatric trainee in Queensland who enjoys clinical teaching, positive teamwork, research, and medication safety. Alyssa also loves travelling, scuba diving and camping with her family. A true child at heart, she loves playing games with her patients.


No data was found

Leave a Reply

Your email address will not be published. Required fields are marked *