What Is a Fever of Unknown Cause?
Fever is part of the human body’s sickness response, mediated by inflammatory cytokines and other pyrogens. It is part of the innate immune system. When it continues unabated without a treatable cause, however, it is no longer a warning signal but an actual disease in itself.
Fever of Unknown Origin (FUO)
Fever of unknown origin (FUO) refers to a prolonged febrile illness whose cause is unknown even after an extensive workup of evaluation and testing. The key to this designation is that it be prolonged, for most fevers spontaneously resolve quickly before any cause is identified.
The criteria for FUO was derived in 1961 and remains the standard criteria list:
- Fever > than 38.3ºC (100.9ºF) at numerous times.
- Duration of fever ≥ 3 weeks.
- Uncertain diagnosis even after 1 week of hospitalized diagnostics.
The majority of FUO cases fall into one of 3 categories:
- Infection: Most commonly tuberculosis, occult abscesses, osteomyelitis, and bacterial endocarditis.
- Malignancy: Most commonly lymphoma, leukemia, and kidney or liver carcinoma.
- Non-infectious inflammatory/autoimmune diseases: E.g., rheumatoid arthritis and other rheumatic diseases, vasculitis, etc.
Age and FUO
- Children, in 1/3 of cases, have an undefined self-limited viral infection
- Older patients have multisystem diseases, such as the rheumatic illnesses, infections, or malignancies
Gender and FUO
- Men can have FUO from prostatitis.
- Women can have FUO from an occult abscess in the reproductive tract, i.e., ovary/fallopian tube.
Initial pursuit of a cause is based on an in-depth history and thorough physical exam with a focus on the most common causes. The list of uncommon causes is extensive, making them expensive and labor intensive to pursue along with the most common causes. Once the commonest etiologies are dismissed, however, the exploration of the less common or exotic causes is justified.
What Are Diagnosis Tests?
The list of all of the causes of fever of unknown origin (FUO) is exhaustive. True FUOs that meet the criteria of 1) repeated episodes of fever > 38.3ºC (100.9ºF) and 2) a duration of fever ≥ 3 weeks usually call for hospitalization, which after one week meets the third criterium of 3) no firm diagnosis even after 1 week of hospitalized diagnostics.
The crucial first step involves a through history and physical exam to garner clues from subtle findings such as a dental history to elicit any tooth or gum sensitivities that may point to a dental abscess; changes in cognition that suggest meningitis; sexual history to consider sexually transmitted infections (STIs); travel history to identify illness endemic elsewhere but rare in the U.S., e.g., malaria; immunosuppression and drug history; animal exposure or occupational toxin exposure; urinary habits, especially at night, that suggest prostatitis or urinary tract infections.
- Blood test for the acute phase reactants, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), to identify and quantify inflammation.
- Normal levels speaks against inflammatory processes.
- Serum lactate dehydrogenase (LDH) that identifies tissue and cellular damage.
- Creatine phosphokinase (CPK) as a biomarker to identify muscle damage, heart tissue necrosis, and neuromuscular disease.
- TB skin test.
- Blood tests for HIV, rheumatoid factor (RF), and antinuclear antibodies (ANA) to identify illness associated with vasculitis, immunosuppression, or autoimmunity.
- Heterophile antibody test for children and young adults to identify Epstein-Barr infection/mononucleosis.
- Serum protein electrophoresis to separate subsets of proteins that predict inflammation, malignancy, tissue injuries, or cell death.
- CT of the chest and abdomen.
- Blood cultures.
- Serologic tests for syphilis, cytomegalovirus (CMV) and Lyme disease.
- Lumbar puncture (LP, or “spinal tap”) for CNS etiologies.
Most of the patients in whom no definitive diagnosis is ever made do well. Rarely, FUO can persist for months or even years without a diagnosis, treated empirically with steroids or other anti-inflammatories.
Management and Treatment for FUO depends on the diagnosis or the absence of a diagnosis.
Management and Treatment of FUO in Which a Diagnosis Is Made
An identified cause of the fever is treated according to the protocols for the particular illness responsible. Treatment for infections, inflammatory conditions, and malignancy are according to specified protocols. When a definitive diagnosis is absent and all screening, diagnostic, and imaging tests are negative, the final tactic is to treat the fever as its own disease.
Management and Treatment of FUO in which a Diagnosis Remains Unknown: Risk Stratification
How patients are approached therapeutically is delineated based on a risk stratification protocol determined by a multinational scoring system that uses weighted measures such as symptoms and white blood cell count (neutropenia), and the presence or absence of hypotension, dehydration, and age:
● For low risk patients: In the absence of any imminent danger, expectant therapy vs. empiric trials of antibiotics and other drugs is based on physician preference, patient dissatisfaction (loss of employment, etc.), and duration of illness.
● For high risk patients: Liberal consultation with infectious disease, rheumatic disease, and immunology specialists should occur before resorting to empiric therapy.
- Initial empirical antibiotic therapy: Should be followed by antifungal therapy if results are negative. After treatment/prophylaxis of infectious agents, empiric anti-inflammatories can be tried. Antipyretics (drugs to lower fever) should be used with caution as they can mask the actual presentation, misleading a physician into a misdiagnosis.
Many drugs have fever as a side effect. A drug fever becomes more likely the more drugs a person is taking, making the elderly and those with chronic disease most at risk. Failure to identify a drug fever leads to unnecessary hospitalization, testing, and therapies that pose risks in any risk-vs-benefit rationale.
A drug fever must initially be a diagnosis of exclusion. If a drug fever is suspected, therapy calls for cessation of the drug and possibly re-introducing it to confirm its effect. If so, alternative drugs are used.
How Can I Prevent a Fever of an Unknown Origin?
Prevention of a fever of unknown origin (FUO) is impossible due to the nature of its unidentified etiology. Avoidance of risks of exposure to exotic, rare illnesses can help prevent those which present as FUO.
- International travel to countries in which diseases are endemic but rare in the US is a preventive measure; vaccination/immunizations against these diseases, if available, should be done prior to travel.
- High-risk behaviors such as unprotected sex, consuming raw/uncooked foods, and hygienic neglect should adhere to the common sense approach of avoidance.
- Patients, as their own best experts, should be suspicious of warning signals such as weight loss, mysterious rashes and skin manifestations, bites, exposure to animals to which they are unaccustomed, toxins in the workplace, digestive, respiratory, and cognitive changes, dental problems, or pain in a specific abdominal quadrant.
- Those on multiple drug regimens should maintain periodic drug-interaction appraisals with their prescribing physicians and should present each one with a full prescription profile from their pharmacy so that each will know what their other doctors are prescribing.
- The best way to prevent a fever of unknown origin is to not ignore it, so that its cause won’t remain unknown. Any fever lasting more than a few days should be reported to a primary care professional, especially if it is in association with other signs and symptoms.