A 5-month-old Hispanic boy, previously healthy, presents to the emergency department (ED) for 5 days of fever, 3 days of diarrhea and rash, and 2 days of vomiting. He had been diagnosed with acute otitis media by his primary care physician 3 days prior to his presentation and started on amoxicillin. The parents brought their son to the ED because of his persistent fever up to 104°F and decreased oral intake. He has no recent travel and no known sick contacts. His immunizations are up to date and he has never been hospitalized. He was born in the United States, full term with an uncomplicated birth history.
On presentation to the ED, the patient is febrile to 103.5°F and tachycardic to 205 beats/minute, with blood pressure of 110/73 mm Hg while crying. Respiratory rate is 39 breaths/minute and his oxygen saturation is 99% on room air. He weighs 6.8 kilograms (13th percentile).
Physical examination reveals a fussy but easily consolable infant with soft and flat anterior fontanelle and II/VI systolic ejection murmur at the left upper sternal border. Lungs are clear with normal work of breathing. He has periorbital erythema with clear sclera, and moist lips and tongue. A blanchable, macular, erythematous rash on his trunk and groin is noted. The patient is uncircumcised with foreskin easily retracted. The rest of physical examination findings are unremarkable including bilateral ear examination.
Urinalysis, obtained by catheter, shows pyuria (10-20 white blood cells [WBC]), small leukocyte esterase, negative nitrite, and small ketones. Stool panel by polymerase chain reaction (PCR) is obtained and is positive for enterotoxigenic Escherichia coli (ETEC). Complete blood cell count (CBC) reveals mild leukocytosis with WBC of 11.9 x 103/mm3 (4-12 x 103/mm3), with 55% segmented neutrophils and 37% lymphocytes; platelets at 484,000 x 103/mm3 (140-440 x 103/mm3); hemoglobin, 8.5 g/dL (10.5-14 g/dL); hematocrit, 26.2% (32%-42 %) with mean corpuscular volume (MCV) at 59 fL (72-88 fL) and red cell distribution width (RDW) of 17.6% (11.5%-14.5 %). Electrolytes are: sodium (Na), 133 mmol/L (132-140 mmol/l); bicarbonate, 17 mmol/L (20-28 mmol/L); blood urea nitrogen (BUN), 8 mg/dL (10-18 mg/dL); creatinine, 0.3 mg/dL (0.2-0.5 mg/dL); and low albumin, 2.9 g/dL (4-5 g/dL). Blood and urine were sent for cultures and patient received a dose of 50 mg/kg intravenous (IV) ceftriaxone.
The patient was admitted to the general pediatric unit with presumed diagnosis of febrile urinary tract infection (UTI), acute bacterial gastroenteritis (ETEC), iron deficiency anemia, and viral exanthem (vs allergic reaction to amoxicillin). Ceftriaxone was continued for the presumed UTI. A renal ultrasound was obtained and revealed normal kidney size and echogenicity.
Eight hours into admission, the patient had decreased responsiveness and concern for altered mental status with a temperature of 105.3°F. lumbar puncture (LP) was completed and cerebrospinal fluid (CSF) showed mild pleocytosis with WBC of 14/mm3 (58% monocytes, 39% lymphocytes); red blood cell (RBC) of 25/mm3; glucose, 68 mg/dL; and protein, 15.4 mg/dL. Gram stain was negative. Empiric ceftriaxone dose was increased to cover for bacterial meningitis (100 mg/kg/d).
Metabolic acidosis resolved with fluids. An iron panel supported the diagnosis of iron deficiency anemia, for which iron was prescribed. The patient’s emesis and diarrhea resolved, and his skin rash faded. Because all cultures were negative at 48 hours, ceftriaxone was discontinued, and the patient was thought to have aseptic meningitis as the source of his persistence fever. Cerebrospinal fluid enterovirus by polymerase chain reaction (PCR) assay was negative. Respiratory viral panel by PCR was obtained to test for other viral etiologies that could help explain the prolonged fever, but ultimately it was negative.
As the patient continued to have fevers without a source for more than 7 days, he met the definition of fever of unknown origin (FUO). The differential diagnosis of FUO is broad and includes infectious and noninfectious causes. See Table 1 for the most common causes of FUO.
Given the patient’s lack of clinical improvement, persistent unexplained fever greater than 102.2°F (mean maximal temperature [Tmax], 105.3°F), sterile pyuria, low albumin, mild thrombocytosis, neutrophil-predominant leukocytosis, CSF pleocytosis with negative culture, and significant sequelae of untreated Kawasaki disease (KD), inflammatory laboratories were drawn and resulted with elevated erythrocyte sedimentation rate (ESR) of 62 mm/h (0-13 mm/h) and C-reactive protein (CRP) of 8 g/dL (<0.3 g/dL). A repeat CBC revealed WBC of 16 x103/mm3 with 76% neutrophils, hemoglobin of 6.9 g/dL, and platelets of 486 x103/mm3. Repeat albumin was 2.4 g/dL.