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 of what I found:

  • Are they fevers?? Check out Andy Tagg’s ‘Feel the Heat’ article on how to accurately check children’s temperature!
  • Initial presentation with fever is covered by Henry Goldstein’s ‘Finding the Fever’ article
  • 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 is recommended
  • Infections linked to a single target organ (urinary tract, skin, lung), look for local predisposing conditions and consider specialist referral

Definition - remains unclear

Recently: >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 illness per year (most of which are viral), unless they attend day care 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 – see history below
  • Meticulous fever diary
  • Serial clinical and laboratory evaluations
  • Vigilance for the appearance of new signs and symptoms
  • Targeted investigations
  • 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 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 interval between episodes, associated symptoms, travel history, exposure to animals, and 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

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.


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 an 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 square……..

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 – see my previous article: ‘Kawasaki Disease – Beware the Incomplete!’ (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


Test Diagnosis Reason for suspicion
Infectious diseases
Tuberculin skin test, IGRA Tuberculosis Exposure to active case, homeless shelter, travel, immigration
Histoplasma serology Histoplasmosis Residence in Ohio Valley, bird exposures
EBV serology EBV infection Fatigue, lymphadenopathy, cytopenias, elevated transaminases
Bartonella serology Cat scratch disease Exposure to kittens, chronic granulomatous papule
Brucella serology Brucellosis Consumption of unpasteurized milk products
Toxoplasma serology Toxoplasmosis Exposure to cats, consumption of poorly cooked meat
Francesella serology Tularemia Tick bite with eschar, rabbit hunting
HIV Ab/Ag or PCR HIV infection Sexually active, mononucleosis-like illness, cytopenias
Stool culture for Salmonella Typhoid fever Travel to developing country, hepatosplenomegaly, rose spots
Antinuclear Ab, RF, C3, C4, slit lamp exam Various rheumatologic diseases Rash, arthritis, cytopenias, renal dysfunction, acute phase reaction
ASO, anti-DNAse-B Ab Rheumatic fever Migratory polyarthritis, erythema marginatum, heart murmur
Flow cytometry, LDH, UA, bone marrow aspirate Leukemia/lymphoma, various malignancies Fatigue, bruising, bleeding, lymphadenopathy, weight loss, cytopenias
Catecholamine screen, mIBG scan Neuroblastoma Opsoclonus–myoclonus, diarrhea
CT, PET Solid tumors/lymphoma Localizing symptoms
Thyroid function profile Hyperthyroidism Nervousness, irritability, tachycardia, tremors
Sinus CT Sinusitis Headache, congestion
Echocardiogram Endocarditis Fatigue, murmur, splenomegaly, hematuria, thrombocytopenia
Endoscopy IBD Loose stools, weight loss, acute phase reaction, anemia
Abdominal U/S or CT Abdominal abscess Abdominal discomfort
Bone scan Osteomyelitis Musculoskeletal 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, and 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. Localising 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 <5 years and episodes last 5-7 days. PFAPA syndrome is much more common than cyclic neutropenia, which should, nonetheless, 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.

Comprehensive DNA sequencing for the monogenic autoinflammatory fever syndromes is available. Which children with recurrent fevers should be tested?


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.

Variable Code Coefficient Value
Age at onset Months X −0.067 = a
Abdominal pain 0 = Never 1.494 b
2 = Sometimes or often
3 = Always
Aphthous ulcers 0 = Never −1.504 c
1 = Sometimes or often
2 = Always
Thoracic pain 0 = Absent 1.958 d
1 = Present
Diarrhea 0 = Never 0.901 e
1 = Sometimes
2 = Often
3 = Always
Family history 0 = Negative 1.503 f
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 obtain 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
Synonyms FCUS CINCA MKD Etiocholanolone fever Hibernian fever
Inheritance pattern Autosomal dominant Autosomal dominant Sporadic Autosomal recessive Autosomal recessive Autosomal dominant
Ethnicity European European Any Mediterranean European European
Age at onset <1 year <20 years <1 year <20 years <1 year <20 years
Frequency of attacks Variable Variable Continuous Variable 2–4 weeks Variable
Duration of attacks 1–2 days 2–3 days Continuous 1–3 days 3–7 days >7 days
Clinical findings Rash
Erysipeloid erythema
Amyloidosis No Yes No Yes No Yes
Treatment modalities Anti-IL-1 Anti-IL-1 Anti-IL-1 Colchicine Anti-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 acute severe 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.


  1. Verbsky JW. When to Suspect Autoinflammatory/Recurrent Fever Syndromes. Pediatric Clinics of North America, Feb 2017, Volume 64, Issue 1, Pages 111-125.
  2. Marshall GS. Prolonged and recurrent fevers in children. Journal of Infection, Jan 2014, Volume 68, Pages S83-S93.
  3. Torregiani S, Filocamo G, and Esposito S. Recurrent Fever in Children. Int J Mol Sci. Apr 2016, Volume 17, Issue 4, Page 448.
  4. 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.
  5. 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.

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