It's all about the history: Diagnosing fever of unknown origin

Certain clues can go a long way toward narrowing down the cause.

When encountering an inpatient with fever of unknown origin (FUO), a hospitalist's first step should be the same as with any puzzling patient: Look for clues from the history and other presenting symptoms, said Jennifer Hanrahan, DO, associate professor of medicine at Case Western Reserve University in Cleveland, during a session at Hospital Medicine 2014 in Las Vegas in March.

Fever from an infection often presents with night sweats and weight loss, even if the patient has an appetite. Those symptoms aren't usually seen in a patient whose fever has a rheumatological cause; instead, he or she is more likely to present with arthralgias, myalgias, and fatigue. Feverish cancer patients, meanwhile, may have night sweats and weight loss but are also more likely to have pain and lack of appetite, she said.

“These simple distinctions, and a few other rules of thumb, can take you a long way toward FUO diagnosis,” Dr. Hanrahan said.

Classical FUO

There are 4 types of FUO, Dr. Hanrahan said: classical, health-care associated, HIV-related, and immunodeficient.

Classical FUO involves a temperature higher than 38°C on at least 3 occasions over at least 2 weeks, or for more than 3 days in the hospital. It is usually caused by an infection, neoplasm, connective tissue disease, or a miscellaneous or unknown source, she said.

Of interest, the cause of classical FUO tends to vary by age, with infection being the source about 50% of the time in patients younger than 65 years old. Up to 30% of patients younger than 50 will have fevers whose cause is never discovered, she added.

If a patient is at least 65 years old, the odds that the fever originated from infection drops below 25%, Dr. Hanrahan said. In this age group, temporal arteritis is the cause 30% of the time and neoplasm 12% of the time. About 8% of these patients have fevers that remain undiagnosed.

“In older patients, always consider temporal arteritis,” she said. “This is the most commonly overlooked diagnosis in this age group.”

For all age groups, common infectious causes of classical FUO include subacute endocarditis, intra-abdominal or pelvic abscess, tuberculosis, typhoid fever and Epstein-Barr virus. More uncommon infectious causes are toxoplasmosis, histoplasmosis, brucellosis, trichinosis, and Whipple's disease, she said.

Patients also may have infections related to travel, such as leishmaniasis or Q fever, or could have genetic diseases such as TNF-receptor-associated periodic syndrome (TRAPS), which is more common in Ireland, Dr. Hanrahan noted.

Common inflammatory/autoimmune causes of fever are adult-onset Still's disease, systemic lupus erythematosus, and polyarteritis nodosa. The cancers that present as FUO are usually lymphoma, renal cell cancer, leukemia, colon cancer, hepatoma, or central nervous system tumors located in the anterior hypothalamus, she said.

Other FUO causes

Health care-associated FUOs are distinguished by a fever that isn't present on admission but, once present, persists for at least 3 days above 38°C. Diagnosis is often made via chart review and history, which looks “substantially different than with classical FUO,” Dr. Hanrahan said. Recent procedures, devices, drugs, or venous thromboembolism should be considered as causes.

HIV-related FUO is marked by, obviously, a confirmed HIV infection and a fever of more than 3 weeks' duration in an outpatient setting or more than 3 days' duration in an inpatient setting. The CD4 cell count is most helpful in determining the likely cause, which is often infection, malignancy, drug fever, or immune reconstitution inflammatory syndrome (IRIS), she said.

FUO in an immunocompromised patient is also marked by fever of more than 38°C for 3 days, as well as by negative cultures at 48 hours. The cause is most often infection, although etiology is only established in about half of cases, Dr. Hanrahan said.

“Infections in these patients may be life-threatening, and the tempo of the workup is quicker than with other types of FUO,” Dr. Hanrahan said. “This is the one type of patient with FUO where use of empiric antibiotics may be necessary.”

Post-op and drug-related fever

In the hospital, fevers most often occur in ICU patients; after surgical procedures; and in patients with neurological problems, with prior transfusions, or with underlying malignancy or immunodeficiency, Dr. Hanrahan said.

Postoperative fever can arise from the trauma of surgery, medications, blood clots, transfusions, and, of course, infections, she noted. Other causes may include myocardial infarction, pancreatitis, alcohol withdrawal, or an underlying disease like HIV. “Remember that the [temperature itself] does not predict if it's a viral or bacterial infection,” Dr. Hanrahan said.

Drug fever is very common in hospitalized patients but is difficult to diagnose. “It's a diagnosis of exclusion,” she said. Clues include that the patient looks less sick than you would expect, has a fever of around 38.9°C to 40°C, and has relative bradycardia when the fever is higher than 38.9°C. In 5% to 10% of cases, the patient has a maculopapular rash that, when present, makes drug fever the obvious diagnosis, Dr. Hanrahan said.

Common drugs that can trigger fever are antibiotics, especially beta-lactams and sulfonamides; sleep medications; seizure medications; stool softeners; diuretics; antihypertensives; antidepressants; antiarrhythmics; and NSAIDs. If a rash isn't present, the fever will usually resolve within 72 hours of stopping the medication. If there is a rash, it may prolong the fever beyond 3 days postmedication, she said.

Laboratory findings that indicate a fever originates from medication include an elevated white blood cell count with left shift; mildly elevated liver function test results; very high erythrocyte sedimentation rate (ESR); and low-grade eosinophilia, she added.

Making the diagnosis

Diagnosing fever of unknown origin is, by definition, tricky. “Your best tools are history, history, history, careful chart review, history, physical exam, and history,” Dr. Hanrahan said.

History-taking should include asking about the presenting illness as well as the medical history of the patient and his or her family, including HIV and sexually transmitted infections; asking about travel, medications, and exposure to pets and animals; asking about hobbies and occupation; and asking about past surgeries and invasive procedures, she said.

Initial diagnostic tests might include a complete blood count with differential; liver function tests; basic metabolic panel; urine analysis; ESR/C-reactive protein and ferritin; chest X-ray and/or CT scan; blood cultures; abdomen and pelvic CT; and HIV serology, she said.

“You should perform tests based on physical exam abnormalities or clues in the patient's history,” Dr. Hanrahan said. “If the initial history, exam, and basic workup don't yield a diagnosis, then ask more questions.”

The answers to these questions, along with the initial evaluation and review of laboratory findings, may point to a need for even more testing. Tests at this point often include transthoracic/transesophageal echocardiogram, serological tests for infections, and/or serology for autoimmune disease, she said.

“This amount of testing can go a long way. Many causes of fever will be diagnosed without invasive tests [such as biopsies], through revisiting the history and lab abnormalities,” Dr. Hanrahan said. “Don't just throw everything on the wall right away to see what sticks.”

Remember, too, that if a patient is clinically stable and no cause of the fever has been found after careful review, it's appropriate to discharge him or her for observation in the outpatient setting, she added.

“Generally, the longer the fever goes on without a diagnosis, the less likely a diagnosis will be made,” she said.