Table 2:

Differential diagnosis for patients with periodic fevers and elevated inflammatory markers

ConditionUnique features
Familial Mediterranean fever

  • Polyserositis, recurrent fevers, brief flares lasting 1–4 d, variable interval between flares

Periodic fever, aphthous stomatitis, pharyngitis, adenitis

  • Onset in childhood (age < 5 yr)

  • Recurrent fevers lasting 3–7 d

  • Aphthous stomatitis, tonsillitis (occasionally with white exudates), pharyngitis with diffuse hyperemia of the entire palate, cervical and mesenteric lymphadenopathy, abdominal pain, chills, headache, vomiting, diarrhea, hepatosplenomegaly and joint pain

  • Flares every 3–5 wk. Patients are well between episodes

Cryopyrin-associated periodic syndromes

  • Chronic infantile neurologic cutaneous and articular syndrome: neonatal onset of urticarial skin rash and arthropathy, chronic aseptic meningitis, brain atrophy and sensorineural hearing loss

  • Familial cold autoinflammatory syndrome: recurrent episodes of urticaria-like skin rash that is triggered by exposure to cold associated with low-grade fever, general malaise, conjunctivitis, and arthralgia or myalgia

  • Muckle–Wells syndrome: recurrent fever, recurrent urticaria-like skin rash, sensorineural deafness, generalized symptoms of inflammation (conjunctivitis, headaches, arthralgia or myalgia) and secondary amyloidosis

Tumour necrosis factor receptor–associated periodic syndrome

  • Onset is usually in infancy or childhood but occasionally in adolescence or adulthood

  • Episodes start with myalgia, joined by fever for 1–3 wk, accompanied by skin, joint, abdominal and ocular symptoms. Skin lesions may include centrifugal, migratory or erysipelas-like erythema, edematous plaques and urticarial lesions. Ocular symptoms can manifest as conjunctivitis, periorbital edema (pathognomonic) or uveitis. Serositis and secondary amyloidosis are common

Cyclic neutropenia

  • Recurrent decrease in blood neutrophil counts (ranging from subnormal levels to severe neutropenia), usually with a cycle length of about 21 d

  • Symptoms during the neutropenic phase include fever, mouth ulcers, pneumonia and peritonitis

Recurrent viral infections

  • Common in preschool- and school-aged children, sick contacts

  • Associated symptoms of coryza, cough

Infective endocarditis

  • Janeway lesions, Osler nodes, splinter hemorrhages

  • History of congenital heart disease with surgical repair

Immunodeficiency

  • Recurrent deep-seated infections, poor response to antibiotics, failure to thrive

  • Family history of immunodeficiency

Parasitic infection, such as malaria

  • Associated travel history

Systemic lupus erythematosus

  • Skin findings, positive immunologic criteria (antinuclear antibody or anti–double-stranded-DNA, anti-Smith, antiphospholipid, low complement, direct Coombs test)

Inflammatory bowel disease

  • Can present with low-grade fever and abdominal pain. Predominantly gastrointestinal symptoms

Malignancy (leukemia, lymphoma)

  • Weight loss, night sweats, bone pain, bruises, lymphadenopathy, hepatosplenomegaly