Am Fam Physician. 2022;105(2):137-143

Patient information: Please refer to the provided handout regarding fever of unknown origin in adults, authored by the writers of this piece.

Author disclosure: No pertinent financial connections.

Fevers of unknown origin are characterized by multiple instances of a temperature of 101°F or higher, alongside inconclusive diagnostic assessments. The potential causes are diverse but typically fall under infection, malignancy, noninfectious inflammatory diseases, or other miscellaneous reasons. In adults, most cases stem from uncommon manifestations of common illnesses, with around 75% resolving spontaneously without a definitive explanation. In the absence of specific localizing symptoms, the investigation should start with a detailed history and physical examination to help narrow down potential causes. The initial tests should focus on infectious origins, cancers, inflammatory conditions, and miscellaneous factors such as venous thromboembolism and thyroid issues. If inflammatory markers like the erythrocyte sedimentation rate or C-reactive protein are elevated and a diagnosis is still elusive after initial assessments, an 18 F fluorodeoxyglucose positron emission tomography scan with computed tomography could be beneficial in reaching a conclusion. If non-invasive tests yield no results, the recommended invasive procedure is a tissue biopsy due to its relatively high diagnostic success rate. Depending on the clinical context, this may involve biopsies from the liver, lymph nodes, temporal artery, skin, muscle, or bone marrow. Empirical antimicrobial treatment is not proven to be effective for fever of unknown origin and should be avoided except in specific patient populations like those who are neutropenic, immunocompromised, or critically ill.

Fevers of unknown origin in adults present a significant diagnostic puzzle in medicine. For many patients in affluent nations who experience such fevers, the root cause remains unidentified, often attributed to atypical variations of common illnesses rather than rare conditions. The absence of a standardized diagnostic approach leads to frustration for both medical professionals and patients, with numerous tests and procedures often failing to provide a definitive answer. Currently, the prevailing definition of fevers of unknown origin only necessitates a documented temperature of 101°F or higher on multiple occasions and inconclusive diagnostic investigations. Prior definitions had suggested specific timeframes for assessments, but these were acknowledged as arbitrary and are not encompassed in the current consensus.

Differential Diagnosis

Typical causes of fevers of unknown origin encompass infections, malignancies, noninfectious inflammatory disorders (such as vasculitides, granulomatous diseases, and connective tissue diseases), miscellaneous factors, and cases that remain undiagnosed. Lower-income nations often see higher rates of infection and malignancy as primary causes of fevers of unknown origin. In contrast, higher-income nations tend to witness a higher prevalence of noninfectious inflammatory disorders and undiagnosed cases, likely due to access to advanced imaging techniques facilitating tumor detection.

SECONDARY EVALUATION CONTINUED

Specialized Tests. In cases where a specific diagnosis is still elusive, specialized tests may be necessary. These can include serologic tests for autoimmune disorders, PCR assays for viral infections, or immunohistochemistry for malignancies.

Consultation with Specialists. If the initial evaluations and tests do not provide a clear diagnosis, consulting with specialists in infectious diseases, rheumatology, hematology, or oncology may be beneficial. Their expertise and specialized knowledge can help in further narrowing down potential causes and guiding treatment plans.

Long-term Monitoring. For cases where the cause of fever remains unidentified despite extensive evaluations, long-term monitoring and follow-up appointments are essential. Regular check-ups and monitoring of symptoms can help in detecting any changes or new developments that may lead to a conclusive diagnosis.

Consideration of Rare Disorders. In some instances, fevers of unknown origin may be attributed to rare or uncommon disorders that require specific diagnostic approaches. Genetic testing, molecular studies, or consults with rare disease specialists may be necessary in such cases.

CONCLUSION

Overall, the evaluation of fevers of unknown origin requires a systematic and comprehensive approach that involves a range of diagnostic tests, imaging procedures, specialist consultations, and long-term monitoring. By following a structured evaluation pathway and considering a wide array of potential causes, healthcare providers can effectively identify the underlying etiology of FUO and provide appropriate treatment and management strategies to improve patient outcomes.

Empiric Treatment and Referral

Empirical antimicrobial therapy should be used judiciously, as it may delay the identification of underlying causes. Consult specialists from infectious disease, rheumatology, or hematology/oncology if a diagnosis remains elusive after initial evaluations.

This article expands on previous studies by Hersch, Oh, Roth, and Basello.

Data Sources: Research included PubMed searches on fever of unknown origin, prolonged fever in adults, and Essential Evidence Plus for relevant POEMs, Cochrane reviews, and clinical decision rules. Searches were conducted from March 29 to April 28, 2021, and September 22, 2021.

Fever occurs when the body temperature rises due to infection, with the hypothalamus adjusting its thermostat. While normal body temperature is 98.6°F (37°C), fever patterns can vary, indicating different conditions.

High fever poses risks, particularly in individuals with heart or lung conditions. Extreme temperatures can lead to organ dysfunction or failure, usually due to severe infections, heatstroke, or substance abuse.

Consequences of fever

Internal and external pyrogens can trigger fever, commonly from infections or inflammatory conditions. The severity and duration of fever can provide clues to the underlying cause.

Some potential consequences of fever include:

• Dehydration
• Electrolyte imbalances
• Increased heart rate
• Decreased appetite
• Muscle aches and weakness
• Confusion or delirium

Causes of Fever in Adults

Fever may result from cancers, inflammatory disorders, or allergic reactions. Medications and drugs, including antibiotics and illicit substances, can also induce fever.

Risk factors

Factors like health status, age, occupation, medications, and exposure help doctors determine the cause of fever. Risk factors can provide insights into potential underlying conditions.

Suspected Causes of Fever Based on Risk Factors:

• Respiratory or gastrointestinal infections
• Bloodstream infections from IV catheters
• Urinary tract infections, especially with catheters
• Pneumonia, particularly in ventilated patients
• Lung collapse due to airway blockage
• Infections or hematomas post-surgery
• Travel to endemic areas
• Conditions causing diarrhea
• Exposure to disease vectors
• Immune system compromise
• Medications affecting body temperature
• Underlying health conditions such as diabetes, cancer, or autoimmune diseases can also increase the risk of fever.
• Pregnancy and postpartum period can lead to hormonal changes that may cause fever.
• Chronic conditions like HIV/AIDS or chronic kidney disease can weaken the immune system and make individuals more prone to fever.
• Exposure to environmental factors such as extreme temperatures or pollution can trigger a fever response in the body.
• Recent travel to areas with known infectious diseases or outbreaks can increase the risk of fever due to exposure to pathogens.

Further evaluation

If initial assessments do not reveal the cause of fever, further evaluation may be necessary. This can involve more in-depth diagnostic tests such as imaging studies (like chest X-rays or CT scans), blood cultures, urine tests, or even spinal taps.

Treatment

Treatment for fever depends on the underlying cause. If the fever is due to a bacterial infection, antibiotics may be prescribed. For viral infections, supportive care such as rest, fluids, and over-the-counter medications may be recommended. In some cases, hospitalization may be necessary for more intensive treatment.

Prevention

Preventing fever often involves good hygiene practices like regular handwashing, staying up to date on vaccinations, and avoiding close contact with sick individuals. Maintaining a healthy lifestyle with a balanced diet and regular exercise can also help boost the immune system and reduce the likelihood of getting sick.