Select causes of fever of unknown origin in children

Condition	Associated clinical findings (which may not be present)
Condition	History	Examination	Laboratory, imaging, or other initial tests
Generalized infections
Brucellosis	Sustained fever pattern Lethargy Osteoarticular pain Exposures: Animals or animal products (eg, unpasteurized milk/cheese, insufficiently cooked/raw meat)	Uveitis Hepatomegaly Splenomegaly Testicular tenderness	Mild elevation of hepatic aminotransferases Lymphocytopenia Positive blood culture
Cat scratch disease	Gastrointestinal complaints Exposures: Cats/kittens	Localized lymphadenopathy Hepatomegaly Splenomegaly Liver tenderness Papular lesion at entry site	Lymphocytosis
Leptospirosis	Rigors Myalgia Headache Cough Gastrointestinal complaints Exposures: Animal urine, contaminated soil or water, infected animal tissue	Relative bradycardia* Bulbar conjunctivitis Pharyngeal hyperemia	Thrombocytopenia Hyponatremia Proteinuria Pyuria Granular casts Small nodular densities on CXR
Malaria	Relapsing fever pattern Exposures: Travel to malaria-endemic area	Splenomegaly	Anemia Lymphocytopenia
Mycobacteria tuberculosis	Intermittent fever pattern Exposures: Travel to endemic area or contact with traveler to endemic area	Phlyctenular conjunctivitis Funduscopy: Choroid tubercles Chronic nontender lymphadenopathy	Positive TST or IGRA Anemia Lymphocytopenia Hilar lymphadenopathy (pulmonary TB) Sterile pyuria (in genitourinary TB)
Salmonellosis	Gastrointestinal symptoms Fatigue Malaise Headaches Urinary symptoms Respiratory symptoms Exposures: Poultry, eggs, reptiles	Weight loss Hepatomegaly Splenomegaly
Toxoplasmosis	Exposures: Feline feces, pica (dirt), consumption of game meat	Lymphadenopathy (cervical or supraclavicular) Funduscopy: Chorioretinitis in nonvascular distribution Pharyngeal hyperemia	Lymphocytosis
Tularemia	Fever Chills Anorexia Malaise Headache Fatigue Muscle soreness Gastrointestinal complaints Exposures: Dead animal carcasses (eg, rabbits), ingestion of rabbit or squirrel meat; ticks, mosquitoes, lice, fleas, flies	Vary depending upon the portal of entry; may include: Pharyngeal hyperemia Eschar at entry site Tender regional lymphadenopathy Bulbar and palpebral conjunctivitis	Thrombocytopenia Elevated hepatic aminotransferases Pyuria
Typhoid fever	Abdominal pain Chills Diarrhea or constipation Headache Exposures: Travel to endemic area	Relative bradycardia* Rose spots	Anemia Leukopenia or leukocytosis (especially in children <5 years of age) Elevation of hepatic aminotransferases Positive blood culture
Localized infections
Osteomyelitis and septic arthritis	Bone pain Limp	Bone tenderness or joint tenderness	Elevated ESR/CRP
Infective endocarditis	Pre-existing cardiac lesion	New-onset cardiac murmur Conjunctival hemorrhage Hepatomegaly Splenomegaly Petechiae	Anemia Leukocytosis Elevated ESR/CRP Positive blood culture Hematuria Proteinuria
Intra-abdominal abscess (subphrenic, perinephric, pelvic)	Previous intra-abdominal disease or surgery Vague abdominal pain	Abdominal tenderness (may be absent)	Sterile pyuria
Liver abscess/hepatic infection	Possible jaundice (jaundice is not common with a single pyogenic liver abscess) Most often in immunocompromised patients	Hepatomegaly Right upper quadrant pain	Abnormal hepatic aminotransferases (not always present; more likely with multiple abscesses or hepatic infection)
Urinary tract infection	Dysuria Urgency Frequency Incontinence Abdominal pain	Suprapubic tenderness Costovertebral angle tenderness	Pyuria Bacteriuria Hematuria Positive urine culture
Rheumatologic diseases
Juvenile idiopathic arthritis	Intermittent fever pattern (≥1 fever spike per day with return to normal temperature between fevers) Arthralgias Ill-appearing with fever	Salmon-pink rash with fever Erythema nodosum Lymphadenopathy Hepatomegaly Splenomegaly Arthritis	Leukocytosis Thrombocytosis Anemia Elevated ESR Mild elevation of aminotransferases
Systemic lupus erythematosus	Malaise Headache Anterior chest pain Dyspnea Neuropsychiatric complaints (eg, depression, decreased academic performance)	Tachycardia Tachypnea Weight loss Oral ulcers Malar rash Erythema nodosum Pericardial rub Small joint arthritis	Anemia Neutropenia Thrombocytopenia Hematuria Proteinuria
Vasculitis (eg, polyarteritis nodosa)	Malaise Abdominal pain Myalgia Muscle weakness	Weight loss Hypertension Palpable purpura Subcutaneous nodules Asymmetric neuropathy Testicular tenderness Funduscopic examination: Perivascular sheathing	Positive stool guaiac
Neoplasms
Leukemia	Limb or bone pain	Gingival hypertrophy Hepatosplenomegaly Lymphadenopathy Testicular enlargement	Cytopenia in ≥1 cell line Bizarre/immature WBCs Neutropenia Mediastinal mass
Lymphoma	Intermittent, remittent, or relapsing fever pattern Fatigue Night sweats	Weight loss Lymphadenopathy Hepatosplenomegaly	Mediastinal mass or lymphadenopathy
Other causes
Altered thermoregulation	History of brain damage or CNS dysfunction		Normal ESR/CRP
Diabetes insipidus (central or nephrogenic)	Polyuria Polydipsia More common in Ulster Scots (nephrogenic)	Weight loss Lack of sweat with fever Decreased peripheral perfusion	Hypernatremia Normal ESR/CRP
Drug fever	Resolution with discontinuation of offending drug Exposures: Virtually any drug or complementary and alternative agent	Rash	Leukocytosis Eosinophilia Elevated ESR
Factitious fever	Absence of nonspecific symptoms (malaise, discomfort) during fever Discrepancy between temperatures recorded or reported by the patient or caregiver and those obtained rectally under direct observation	Rapid defervescence without diaphoresis	Normal ESR/CRP
Familial dysautonomia	Lack of sweat during fever More common in patients of Ashkenazi Jewish descent	Labile blood pressure Decreased/absent tears Absent corneal reflex Hypodontia, adontia, or conical teeth Smooth tongue Erythematous or blotchy skin Decreased DTR	Normal ESR/CRP
Hemophagocytic lymphohistiocytosis	May have positive family history Exposures: Infection, immunologic disorder, malignancy, drugs	Lymphadenopathy Hepatosplenomegaly Skin lesions (generalized rash, erythroderma, edema, petechiae, purpura) Neurologic symptoms	Cytopenias in ≥1 cell line (especially anemia and thrombocytopenia) Coagulopathy Liver dysfunction
Infantile cortical hyperostosis	Limb or bone pain	Bony tenderness Swelling of overlying tissues	Leukocytosis Elevated ESR
Inflammatory bowel disease	Gastrointestinal complaints Delayed sexual maturation More common in adolescents	Weight loss Short stature or decreased height velocity Oral ulcers Perianal fistulae, skin tags, or fissures Erythema nodosum	Anemia Positive stool guaiac Elevated ESR/CRP
Kawasaki disease		Bulbar conjunctivitis Strawberry tongue, cracked lips Rash Edema and periungual desquamation of hands and feet Cervical lymphadenopathy	Thrombocytosis Sterile pyuria
Kikuchi-Fujimoto disease	Fatigue Gastrointestinal complaints Joint pain More common in females and patients <40 years of age	Cervical lymphadenopathy Hepatosplenomegaly Arthritis Rash	Leukopenia Atypical lymphocytes Thrombocytopenia Pancytopenia Elevated ESR Mildly elevated hepatic transferases
Multisystem inflammatory syndrome in children	Persistent fever Gastrointestinal symptoms (abdominal pain, vomiting, diarrhea) Rash Mucous membrane involvement Neurocognitive symptoms (headache, lethargy, confusion) Respiratory symptoms	Shock Myocardial dysfunction Arrhythmia Acute respiratory failure Hepatomegaly Rash Neurologic findings: Encephalopathy, seizures, coma, meningoencephalitis	Abnormal blood counts Elevated inflammatory markers Elevated cardiac markers (eg, troponin) Hypoalbuminemia Echocardiogram: Depressed LV function, coronary artery dilation/aneurysm Chest imaging: small pleural effusion, patchy or focal consolidation, atelectasis
Periodic fever disorders: Cyclic neutropenia Hyperimmunoglobulin D syndrome PFAPA syndrome Deficiency of IL-1 or IL-36 receptor antagonist	Recurrent fever pattern	Refer to UpToDate content on periodic fever syndromes	Elevated ESR/CRP during episodes

FUO: fever of unknown origin; CXR: chest radiography; TST: tuberculin skin test; IGRA: interferon gamma release assay; TB: tuberculosis; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; WBC: white blood cell; CNS: central nervous system; DTR: deep tendon reflexes; LV: left ventricle; PFAPA: periodic fever with aphthous stomatitis, pharyngitis, and adenitis; IL: interleukin.

* Relative bradycardia: For patients ≥13 years with temperature ≥38.9°C (102°F), failure of the pulse to increase as expected with fever (approximately 10 beats per minute for each 0.6°C [1°F]).

Graphic 111282 Version 4.0

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Select causes of fever of unknown origin in children