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Still Febrile After All These Weeks

Fever curve. Temperatures in Celsius during hospitalization.

Fever curve. Temperatures in Celsius during hospitalization.

A previously healthy 28-year-old man was admitted to an outside hospital with fever, pharyngitis, and diarrhea. His symptoms began with generalized fatigue, fever, night sweats, pharyngitis, diffuse myalgias and arthralgias, and 10-pound weight loss. He self-administered a 5-day course of azithromycin. Afterwards, he developed malodorous and watery diarrhea, abdominal cramping, tenesmus, and incomplete evacuation.

On admission, he was afebrile and hemodynamically stable. Initial laboratory studies were notable for elevated inflammatory markers including erythrocyte sedimentation rate of 60 (normal range 0-22 mm/h), C-reactive protein of 213 (normal ≤4.9 mg/L), and white blood cells of 8.6 (normal range, 3.5-10.5 × 109 cells/L). Initial work-up included negative Group A strep culture, negative cytomegalovirus, hepatitis C virus, and human immunodeficiency virus serologies. Epstein-Barr virus immunoglobulin G was positive, with a negative immunoglobulin M, suggesting a prior infection. Computed tomography (CT) of the abdomen showed mesenteric lymphadenopathy and mild splenomegaly. Urinalysis showed pyuria and microscopic hematuria, and ceftriaxone was administered due to concern for pyelonephritis. Additionally, he was found to have asymptomatic chlamydia urethritis and was treated with a second course of azithromycin prior to being discharged from the hospital.


Following discharge, his symptoms worsened, with reported fevers of up to 40.5°C and persistent diarrhea. This prompted him to return to the hospital for further evaluation, where he was admitted for sepsis. Empiric broad-spectrum antibiotic coverage with intravenous vancomycin and intravenous piperacillin-tazobactam was initiated, as well as oral vancomycin for suspected Clostridium difficile colitis. Laboratory studies noted persistent elevated erythrocyte sedimentation rate of 60 (normal range, 0-22 mm/h), C-reactive protein of 289.7 (normal ≤4.9 mg/L), and white blood cells of 20.6 (normal range 3.5-10.5 × 109 cells/L). Further evaluation showed microcytic anemia and elevated liver enzymes. CT of the neck was obtained given his symptoms of pharyngitis and revealed cervical lymphadenopathy. Further review of systems elicited a complaint of dysuria associated with tenderness on prostate examination. Urinalysis showed persistent pyuria and microhematuria. Prostate-specific antigen level, urine cultures, and voided bladder 3 cultures were negative, and a transrectal ultrasound showed no abscess.

Given the vast differential diagnosis and no clear etiology for his fever, diarrhea, and lymphadenopathy, an extensive work-up was initiated. Gastrointestinal evaluation including stool studies for C. difficile, Microsporidia, GiardiaCryptosporidium, vancomycin-resistant Enterococcus, and Shiga toxin, returned negative. Hepatitis and celiac serologies were negative. Findings during esophagogastroduodenoscopy and colonoscopy were not consistent with inflammatory bowel disease. Infectious evaluation for bacterial, viral, fungal, and tick-borne illnesses was negative. Hematologic investigation revealed markedly elevated ferritin of 7097 (normal range 24-336 mg/L), lactate dehydrogenase of 364 (normal range 140-280 U/L), haptoglobin of 330 (normal range 30-200 mg/dL), and fibrinogen of 4.3.

Throughout his hospitalization, he had persistent fevers. Given his constellation of symptoms, strong consideration was given to the diagnosis of hematophagocytic lymphohistiocytosis. A bone marrow biopsy was performed and showed increased macrophages with morphologic features of hemophagocytosis, but was not characteristic of hematophagocytic lymphohistiocytosis. A positron emission tomography (PET) scan revealed increased fluorodeoxyglucose uptake by the bone marrow, spleen, tonsil, and multiple lymph nodes, suggestive of lymphoma. At this point in his work-up, it was noted that his fever curve depicted temperatures in a quotidian pattern with the highest values exceeding 39°C and typically occurring in the evening (Figure). Closer physical examination identified a faint, transient, and salmon-tinted rash that accompanied these febrile episodes. With this new information, our suspicion for adult-onset Still’s disease increased. However, lymphoma had not been ruled out; thus, a lymph node biopsy was performed and showed reactive lymphoid hyperplasia, without malignant cells.

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-Erica Lin, MD, Isabel A. Hujoel, MD, Thomas G. Mason II, MD

This article originally appeared in the March 2017 issue of The American Journal of Medicine.

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