Adult-Onset Still' s Disease Presenting as Fever of Unknown Origin in a Patient with HIV Infection

There are several published diagnostic strategies to aid in the diagnosis of fever of unknown origin (FUO). Choosing the appropriate strategy for the individual patient is dependent not only on the presenting signs and symptoms but also on the medical history, exposures, and risk factors that are unique to the patient. Historically, if the patient was known to have HIV infection, the cause of fever was often secondary to infections due to opportunistic organisms. However, in patients without HIV infection, the causes of FUO have been classically organized into 4 categories: infection related, malignancy related, inflammatory response, and other [1]. Infections account for ∼ 28% of FUO and include etiologies such as tuberculosis, infective endocarditis, or intra-abdominal abscess. Malignancies, including either Hodgkin or non-Hodgkin lymphoma, renal cell carcinoma, or hepatic metastases, account for ∼ 17% of FUO. Inflammatory etiologies, often autoimmune disorders or vasculitis, account for ∼ 21% of FUO. FUO attributable to deep venous thrombosis or as an adverse effect of therapy occurs with a frequency of ∼ 15%, and these cases are categorized as FUO due to “other” causes. Even with thorough investigation, 19% of patients never receive a final definitive diagnosis.

Several studies have investigated causes of infection in HIV-infected patients [2– 4]. These studies have involved patients with CD4 cell counts < 200 cells/mm³ and, often, < 50 cells/mm³. They demonstrate that febrile illnesses are most commonly caused by infection due to opportunistic organisms. For example, the distribution of infections in a study by Armstrong et al. [4] included disseminated Mycobacterium avium (31% of infections), Pneumocystis carinii pneumonia (13%), cytomegalovirus (11%), disseminated histoplasmosis (7%), and lymphoma (7%).

Case report. A 43-year-old man with a history of HIV infection, hypertension, hypercholesterolemia, and splenectomy presented to a local community hospital in July 2006 with a 2-month history of joint pain; a 3-week history of waxing and waning skin rash, drenching night sweats, and nightly fevers (maximum temperature, 39.4° C); a 2-week history of pharyngitis; and a 1-week history of myalgias. The rash was observed to be a light-colored erythematous, nonpruritic, flat macular rash without any pustules. Lymphadenopathy had been noted by his primary physician 3 months earlier. He denied any headache, chest pain, shortness of breath, vomiting, abdominal pain, constipation, dysuria, or frequent urination.

The patient had only traveled in the southeastern United States and denied any unusual food exposures, arthropod bites, or contact with sick adults or children. He was in a monogamous relationship with his wife and wore a condom during all sexual encounters. The patient was up to date on all of his immunizations. His only recent medication change was the addition of tenofovir-emtricitabine therapy, which was initiated 10 weeks prior to presentation to the hospital. The patient was highly compliant with his antiretroviral therapy and had achieved CD4 cell counts >1000 cells/mm³ and an undetectable HIV RNA load.

Therapy with tenofovir-emtricitabine and efavirenz was stopped at hospital admission to rule out a potential drug-induced fever. A complete blood count revealed a WBC count of 23,100 cells/µ L. An infectious etiology was not identified by multiple blood cultures and serological examination for parvovirus B19; Rickettsia, Ehrlichia, Mycoplasma, Streptoccocus, Leptospira, and Toxoplasma species; cytomegalovirus; hepatitis A, B, and C; and Q fever or by acid-fast bacilli testing or influenza assays. These pathogens are either common causes of opportunistic infection in the HIV-infected population or are commonly found during the summer season in the southeastern United States. In addition, a chest radiograph, bone marrow biopsy, skin biopsy, CT, and minimal rheumatological examination were performed. Chest radiograph findings were normal. Examination of the bone marrow biopsy specimen revealed that all cell lines were present; no granulomas or organisms were identified, and results of multiple stains were negative. Examination of the skin biopsy specimen revealed perivascular inflammation and dermal edema. The CT did not detect any abscesses or lymphadenopathy. The patient's erythrocyte sedimentation rate was 40 mm/h, he had test results that were positive for antinuclear antibodies (antibody titer, 1:640) and negative for rheumatoid factor, and he had a C-reactive protein level of 11 mg/dL. At that time, oral prednisone therapy (20 mg twice daily) was started to treat suspected systemic lupus erythematosus or connective tissue disease. His rash, myalgias, and arthralgias resolved; however, his fevers and elevated WBC count (24,900 cells/µ L) persisted.

The patient was then transferred to our medical facility (Dwight D. Eisenhower Army Medical Center; Fort Grodon, GA) for further care. A review of his recent laboratory values indicated well-controlled HIV infection (CD4 cell count, 573 cells/mm³; HIV RNA load, < 50 copies/mL). After consultation with an infectious diseases specialist, HIV therapy (tenofovir-emtricitabine and efavirenz) was restarted, prednisone therapy was stopped, and evaluation focusing on the typical inflammatory etiologies and infections in immunocompetent individuals was initiated. The patient's ferritin level was found to be markedly elevated at 4705 ng/mL, and his WBC count was 30,900 cells/µ L, with 90.4% granulocytes. As a result of these findings, aspirin (975 mg orally 4 times daily) was started to treat presumptive adult-onset Still' s disease [5, 6]. Unfortunately, salicylate levels of only 3.8 mg/dL and 4.3 mg/dL were achieved, and fevers (maximum temperature, 39.7° C) 2– 3 times per night with drenching night sweats continued. Subsequently, oral prednisone therapy (40 mg daily; equivalent to 0.5 mg/kg) was restarted [7]. During this time, serum protein electrophoresis results revealed a mildly elevated band in the γ region. A skeletal survey was negative for lytic lesions, previous examination of a bone marrow biopsy specimen showed normal numbers of plasma cells, and the patient had neither hypercalcemia (calcium level, 8.9 mg/dL) nor an erythrocyte sedimentation rate >100 mm/h (erythrocyte sedimentation rate, 40 mm/h). The patient received a final diagnosis of adult-onset Still's disease.

The patient met all 4 of the major criteria and 3 of the minor Yamaguchi criteria for the diagnosis of Still' s disease [8]. The patient was asplenic (secondary to idiopathic thrombocytopenic purpura refractory to steroid therapy several years earlier) and, thus, could not be evaluated for splenomegaly. The positive antinuclear antibody titer in this patient was of unknown significance. In a study by Crispin et al. [9], 3 of 23 patients with Still' s disease had a low antinuclear antibody titer (< 1:160) and still received a diagnosis of Still' s disease (rather than systemic lupus erythematosus) [10]. We were unable to assess a glycosylated ferritin level, as suggested by Fautrel et al. [5], because the test was not available locally or regionally at the time. The ferritin level was >15 times the upper limit of normal. Although it was not as elevated as the levels reported by Meijvis et al. [11] or Evensen et al. [12], it surpassed the levels reported by several sources as suggestive of adult-onset Still's disease [13, 14]. The patient did not have any of the adult-onset Still's disease exclusion criteria (results of tests for parvovirus B19, double-stranded DNA, and rheumatoid factor were negative) or an exposure history; thus, tropical infections or sexually transmitted diseases were unlikely.

The patient was discharged from the hospital with a treatment regimen of aspirin (975 mg orally 4 times daily) and prednisone (0.5 mg/kg), with a significant improvement in his myalgias, arthralgias, fevers, and rash. Two weeks after discharge from the hospital, his ferritin level (1800 ng/mL) and WBC count (18.3 cells/µ L, with 92% neutrophils) were improved. Three weeks after hospitalization, the patient's arthralgias reoccurred; thus, the dosage of aspirin was increased from 3.9 g/day to 4.5 g/day (divided into 4 doses) in an effort to better achieve blood salicylate levels of 15– 25 mg/dL [15]. At a 5-week follow-up visit, the patient was doing well, and tapering of prednisone therapy was started. Unfortunately, this resulted in a reoccurrence of his fevers (maximum temperature, 40° C) and joint swelling. Accordingly, his prednisone dosage was increased back to 45 mg/day. After 5 months of limited response, the patient was offered biological therapy with anakinra, an IL-1 receptor antagonist, to facilitate a successful corticosteroid taper. He has remained asymptomatic for many months, and his abnormal laboratory parameters have resolved since initiating therapy with anakinra.

Discussion. This case illustrates an uncommon cause of FUO in an HIV-infected patient. Adult-onset Still' s disease is an inflammatory disorder characterized by high spiking fevers, arthritis, and a salmon-colored evanescent rash [7]. Adult Still' s disease in an HIV-infected individual has, to our knowledge, only been reported once in the literature [16]. Similar to our patient, the previously reported patient presented with high CD4 cell and WBC counts, indicating an intact immune system. That patient' s fevers failed to respond to nonsteroidal anti-inflammatory drugs (indomethacin) but did respond to corticosteroids.

The overall evaluation of patients with FUO requires a careful and thorough approach. In all cases, it is important to reconsider the patient' s history and reevaluate the differential diagnosis to ensure that it fits their profile. This case illustrates the importance of immune status in individuals with HIV infection. With the advent of HAART, HIV-infected patients' immune systems are remaining intact, and HIV-infected individuals are now experiencing diseases more commonly found in the general population. We advocate the evaluation of disease status (CD4 cell count and viral load) in HIV-infected individuals as a primary starting point in the evaluation of FUO. Assuming that the etiology is an opportunistic infection in patients with a higher CD4 cell count and controlled viremia could lead to a prolonged time to diagnosis and potentially unnecessary empirical antibiotic treatment.

As HIV therapy continues to improve, it will become necessary to apply the FUO differential typical for immunocompetent individuals to HIV-infected patients to discover malignancies, infections, and inflammatory processes that are manifesting as fevers. In addition, more research is needed to better characterize the causes and distribution of febrile illnesses in HIV-infected patients with an intact immune system and low viral load.

• Received August 24, 2007.
• Accepted November 1, 2007.

• © 2008 Infectious Diseases Society of America