Recurrent Fever of Unknown Origin Responsive to Prednisone

A 59-year-old woman presented with a 10-day history of fever that was intermittent and high-grade with night sweats, chills, and nonspecific chest and back pain. She had returned to the United States from Dominican Republic 7 months before presentation and had no recent hospital admission. Current medications were amlodipine, aspirin, and calcium supplements. There had been no change in medications. Past medical history was remarkable for recurrent high-grade fever approximately 5 years earlier that lasted for 1 month with extensive but unrevealing inpatient workup. Fever resolved following a course of empiric corticosteroids. She had previously received a diagnosos of alpha thalassemia trait, which is asymptomatic except for microcytic anemia, and has not required treatment.

Examination revealed a middle-aged woman who was febrile (temperature, 39.4°C [103°F]), with no significant lymphadenopathy, no palpable masses, no rash, and no synovitis or arthritis. Initial laboratory results revealed mild leukopenia without neutropenia, normal sedimentation rate and lactate level, with elevated hsCRP. Peripheral blood smear was normal.

CT scan of the chest, abdomen, and pelvis revealed mild para-aortic lymphadenopathy. CT-guided biopsy revealed benign lymphoid tissue with stains negative for acid-fast bacilli and fungi. Thoracic spine MRI found no evidence of discitis, osteomyelitis, or metastatic disease. Whole body gallium scan revealed no abnormal localization. She had a benign screening colonoscopy and mammogram the year before.

Autoimmune workup (ANA, rheumatoid factor, c-ANCA, p-ANCA) and serial blood, urine, and stool cultures were also negative. HIV screen and PPD were negative. Transthoracic echocardiogram did not show any evidence of vegetations. Workup for borreliosis, coccidioidomycosis, toxoplasmosis, malaria parasites, dengue fever, leptospirosis, syphilis, cryptococcosis, histoplasmosis, legionellosis, cat scratch disease, anaplasmosis, and ehrlichiosis all were netagative.

The patient continued to have intermittent spikes of high-grade fever (temerature up to 39.4°C [103°F]). Empiric corticosteroids were started on hospital day 6 with resolution of fever by day 7. She was discharged home on day 8 on a regimen of prednisone taper. At follow-up visits 8 days and 2 months after discharge, the patient felt well and reported no further incidence of fever.

Discussion

Fever of unknown origin (FUO) was historically defined as temperature higher than 38.3°C on several occasions, lasting longer than 3 weeks, with a diagnosis that remains uncertain after 1 week of inpatient investigation.¹ An updated classification defines FUO as fever with uncertain diagnosis following 3 outpatient visits or 3 days in the hospital or 1 week of "intelligent and invasive" ambulatory investigation without elucidation of a cause.²

In the absence of neutropenia and HIV infection, this patient met the criteria for classic FUO. No guidelines exist as to the workup for classic FUO,³ however the spectrum of differentials as well as local prevalence of disease guide a reasonable approach to the use of diagnostic modalities.⁴ Recommendations as to further management in patients who still have persistent fever despite nonrevealing diagnostic workup do not exist.

In our patient, autoimmune workup was unrevealing, and there was no evidence of arthritis, arthralgias, or rash during the course of the admission; normal ESR and absence of suggestive symptoms made temporal arteritis unlikely. A review of medication history did not reveal a possible etiology for drug fever. Infectious causes, including tuberculosis considered in view of fairly recent travel to Central America, were ruled out. Pathology for lymphoma was negative despite the finding of mildly enlarged para-aortic lymph nodes. The previous history of fever lasting for 1 month 5 years earlier was another confounding factor in the patient’s history, the interval being uncharacteristically long for the majority of causes of recurrent FUO (eg, Behcet disease, relapsing polychondritis, adult-onset Still disease, and Castleman disease). Gallium scan, also negative, was an attempt to localize a possible inflammatory or infectious focus.

Treatment

The role of empiric therapy with antimicrobials and corticosteroids in FUO remains controversial.⁵ It is believed that such treatment may possibly obscure the diagnosis and may be unnecessary because the overall prognosis of undiagnosed FUO is generally good. In our patient with persistent high-grade fevers and a nondiagnostic workup, a decision was made to start empiric corticosteroids, with dramatic resolution of fever and return of well-being that remained sustained at her follow-up visits.

FUO is a syndrome that has remained a diagnostic dilemma. In the absence of a definitive diagnosis, the treatment of these patients is a clinical challenge.

We suggest that empiric therapy with adequate follow-up and monitoring be considered in patients with undiagnosed FUO.

References:

1. Petersdorf RG, Beeson PB. Fever of unexplained origin: report on 100 cases. Medicine (Baltimore). 1961;40:1-30.

2. Durack DT, Street AC. Fever of unknown origin-reexamined and redefined. Curr Clin Top Infect Dis. 1991;11:35-51.

3. Mourad O, Palda V, Detsky AS. A comprehensive evidence-based approach to fever of unknown origin. Arch Intern Med. 2003;163:545-551.

4. Hayakawa K, Ramasamy B, Chandrasekar PH. Fever of unknown origin: an evidence-based review. Am J Med Sci. 2012;344:307-316.

5. Bleeker-Rovers CP, Vos FJ, de Kleijn EM, et al. A prospective multicenter study on fever of unknown origin: the yield of a structured diagnostic protocol. Medicine(Baltimore). 2007;86:26-38.