Alyssa Courtney. Recurrent or Periodic Fevers – investigate or reassure?, Don't Forget the Bubbles, 2018. Available at:
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.
- 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
The 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.
|Infectious Causes||Non-Infectious Causes|
|Viral diseases: Repeated independent respiratory viral infections; Parvovirus B19 infection; Epstein-Barr (EBV) virus infection; Recurrent herpes virus infection||Immune-mediated and granulomatous diseases: Crohn disease; Behçet disease; Systemic lupus erythematosus (SLE); Juvenile dermatomyositis (JDM); Acute rheumatic fever; Leukoclastic angiitis syndromes; Sarcoidosis; Granulomatous hepatitis.|
|Bacterial diseases: Relapsing fever (Borrelia recurrentis and other borreliae); Brucellosis; trench fever (Bartonella quintana); syphilis (Treponema pallidum); rat bite fever (Spirillum minus); Melioidosis (Burkholderia pseudomallei); Whipple disease; chronic meningococcemia; infective endocarditis; subacute cholangitis; abscesses, especially occult dental abscesses; osteomyelitis; tuberculosis.||Periodic fever syndromes and autoinflammatory disorders: Cyclic neutropenia; Periodic fever; aphthous stomatitis; pharyngitis; adenopathy (PFAPA) syndrome; familial Mediterranean fever (FMF); hyperimmunoglobulinemia D with periodic fever syndrome (HIDS); cryopyrin-associated periodic syndromes (CAPS): familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), neonatal onset multisystem inflammatory disease (NOMID); TNF receptor-associated periodic syndrome (TRAPS); systemic juvenile idiopathic arthritis (sJIA)|
|Fungal diseases: Histoplasmosis; coccidioidomycosis||Neoplasms|
|Parasitic diseases: Malaria; Vvsceral leishmaniasis||Hypersensitivity diseases: Hypersensitivity pneumonitis; drug fever; Weber-Christian disease (panniculitis)|
|Other conditions: Sweet syndrome; Fabry disease; congenital insensitivity to pain with anhidrosis; anhidrotic ectodermal dysplasia; sickle cell crisis; Castleman disease; Erdheim-Chester disease; Kikuchi-Fujimoto disease; diabetes insipidus; central nervous system abnormalities; factitious fever|
- 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 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 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
|Signs and Symptoms||Possible Diagnosis|
|Relative bradycardia||Brucellosis, drug fever|
|Bradycardia due to a conduction defect||Acute rheumatic fever, infective endocarditis|
|Oral ulcers||Crohn disease, Behçet disease, cyclic neutropenia, PFAPA, HIDS, HSV, drug fever|
|Lymphadenopathy||Cyclic neutropenia, PFAPA, sJIA, HIDS, EBV|
|Arthritis/arthralgia||sJIA, FMF, HIDS, TRAPS, MWS, FCAS, Behçet disease, parvovirus B19, relapsing fever, trench fever, chronic meningococcemia, rat bite fever, Brucellosis|
|Splenomegaly||sJIA, HIDS, FMF, TRAPS, EBV, relapsing fever, chronic meningococcemia, Brucellosis, malaria, visceral leishmaniasis|
|Uveitis||Crohn disease, Behçet disease|
|Weight loss||Crohn disease, malignancy|
|Fatigue||Endocarditis, sJIA, malignancy|
|Abdominal pain||Crohn disease, FMF, HIDS, TRAPS, parvovirus B19, relapsing fever|
|Serositis||FMF, sJIA, systemic lupus erythematosus|
|Conjuctivitis||TRAPS (painful conjunctivitis), FCAS, trench fever|
|Genital ulcers||Behçet disease|
|Transient rash during fevers||sJIA|
|Erythema nodosum||Crohn disease, Behçet disease, parvovirus B19|
|Sensorineural deafness||MWS, NOMID|
|Morning fever||Diabetes 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 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.
- 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
|Test||Diagnosis||Reason for suspicion|
|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|
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. 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 <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.
|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.
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|
|Synonyms||FCUS||–||CINCA||–||MKD Etiocholanolone fever||Hibernian fever|
|Inheritance pattern||Autosomal dominant||Autosomal dominant||Sporadic||Autosomal recessive||Autosomal recessive||Autosomal dominant|
|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|
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.
- Verbsky JW. When to Suspect Autoinflammatory/Recurrent Fever Syndromes. Pediatric Clinics of North America, Feb 2017, Volume 64, Issue 1, Pages 111-125.
- Marshall GS. Prolonged and recurrent fevers in children. Journal of Infection, Jan 2014, Volume 68, Pages S83-S93.
- Torregiani S, Filocamo G, and Esposito S. Recurrent Fever in Children. Int J Mol Sci. Apr 2016, Volume 17, Issue 4, Page 448.
- 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.
- 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.