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Introduction   

Fever of Unknown origin (FUO) is a common diagnosis seen in emergency departments (EDs) across the United States. This diagnosis was first described by Dr. Beeson and Petersdorf in 1961. In their studies, these pioneers were some of the first to break down the workup and management of FUO based on potential presenting diagnoses and developed the classic FUO definition (6).  

Understanding the assessment, causes, pathophysiology, diagnostic workup management, and treatment of FUO is important for ED nurses to understand to improve patient outcomes.  

Definition 

Providers generally refer to a febrile illness without an obvious initial diagnosis as FUO (8). Most febrile illnesses will resolve spontaneously before a diagnosis is made, or a diagnosis is made due to the onset of distinguishing signs and symptoms that are present in the patient (8). 

Before defining fever, it is important to discuss temperature fluctuations based on the time of day. The average body temperature is 36.7°C (97.9°F) and can reach as high as 38°C (100.4°F) in the late afternoon or early evening and can reach as low as 35.3°C (95.5°F) due to differing factors such as demographics, certain diseases, body mass, and physiologic factors (5)(7). 

The definition of FUO consists of the following 3 components: 

• Fever Parameters 
• Most studies of FUO define fever as a temperature above 38.3°C (100.9°F), however, definitions can range from 38.0°C (100.4°F) to 38.5°C (101.3°F) (8).  
• Duration Minimum  
• A minimum of 3 weeks of unexplained febrile occurrences is mandatory to meet the definition of FUO (8).  
• Diagnostic Testing Minimum 
• Many definitions of FUO require certain diagnostic tests to be performed before a febrile illness can be labeled as having an “unknown origin.” These tests vary but can include certain radiographic imaging and basic lab tests (i.e., CBC, urinalysis) (8).  

Categories of FUO 

FUOs are divided into 4 categories.  

Table 1. Category-based definitions of FUO 

Adapted from (8)  

Epidemiology 

FUO epidemiology can vary based on a multitude of factors such as age group, geography, cause of fever, immune HIV status, and environmental exposures. An infectious etiology is most common in developing countries, while in developed countries, FUO is likely due to non-infectious inflammatory diseases (2)(4).  

Pathophysiology 

It is difficult to determine the pathophysiology of FUO since there are so many potential differential diagnoses that could be causing the fever in the first place. Understanding the pathophysiology of fever itself, however, is important in understanding FUO.  

A fever occurs with either exogenous or endogenous pyrogens (chemically different substances that can cause fever) causing an increase in the body’s thermoregulatory set point. In the instance of hyperthermia, the set point is unchanged, and the temperature of the body increases in an uncontrolled manner due to endogenous heat production or exogenous heat exposure (1).  

Etiology 

There are more than 200 conditions that can cause FUO. While infections remain a significant cause, as mentioned previously, most cases of FUO in the developed world are caused by noninfectious inflammatory disorders (2)(4).  

The most common causes are lumped into 4 subgroups including infection, malignancy, noninfectious inflammatory disease, and miscellaneous causes (3).  

Infection accounts for 20%-40% of cases and is divided up into bacterial or viral causes. Examples are listed below (3, 4)  

• Bacterial 
• Urinary tract infections (UTI) 
• Pelvic or abdominal abscesses 
• Endocarditis 
• Dental abscesses 
• Tuberculosis 
• Endocarditis 
• Viral 
• Epstein-Barr virus (EBV)  
• Cytomegalovirus (CMV) 

Malignancy accounts for 20-30% of cases and may include the following: 

• Lymphoma (Hodgkin and non-Hodgkin) 
• Colorectal/breast/pancreatic cancer 
• Metastases to liver/brain 
• Renal cell carcinoma  
• Leukemia 

(3, 4) 

Noninfectious inflammatory disease accounts for 10-30% of cases and can include the following:  

• Connective Tissue Diseases 
• Rheumatoid arthritis (RA) 
• Systemic lupus erythematosus (SLE) 
• Juvenile rheumatoid arthritis 
• Granulomatous Diseases  
• Sarcoidosis  
• Vasculitis Syndromes 
• Giant cell/temporal arteritis 
• Polymyalgia rheumatica (3)(4). 

Miscellaneous: Accounts for 10-20% and can include the following: 

• Thyroiditis 
• Pulmonary emboli (PE) 
• Cirrhosis 
• Thromboembolic disease 
• Drug-induced fever 
• Crohn’s disease 
• Fictitious fever  

(3)(4) 

Initial Evaluation 

Since patients with classic FUO have had a prolonged fever, most of these patients can go through initial or successive evaluations in an outpatient setting instead of being hospitalized However, patients who are severely sick or thought to be at risk for life-threatening conditions should be hospitalized to receive empiric treatment and to speed up diagnostic testing.  

There is no evidence to support an algorithmic or structured protocol-based approach to testing vs. avoiding a battery of tests. However, clinicians typically use a protocol-based approach and supplement additional tests based on the patient’s assessment and history (8).  

Patient History 

Obtaining a detailed patient history is one of the most important factors in the evaluation of FUO. The patient history can ultimately lead the clinician down the correct path to determining the diagnosis causing the fevers in the patient. Additionally, obtaining a collateral history from the patient’s family or partner can help fill in missing gaps in the patient’s history (8).  

Important aspects of the patient history include but are not limited to the following: 

• Family History 
• Travel history 
• Immunization history  
• Dental history  
• Occupational history  
• Nutrition and weight history 
• Sexual history 
• Recreational habits 
• Surgery, trauma, or procedures 
• Animal contacts 
• Drug history (illicit and prescription)  

(8) 

History of Present Illness (HPI):  

HPI is a critical portion of the assessment. 

• Fever history 

• • It is important to gather information about the fever which includes the date the fever began, recorded maximum daily temperatures, duration, and frequency of febrile episodes (8).  

• Fever patterns 

• • Historically, fever patterns have been used to narrow down the differential diagnoses of FUO. In some studies, it has been proven however that precise fever patterns are not specific enough to narrow down the differentials. However, some clinicians still utilize fever patterns in their workup for FUO.  

• • Some examples include the following: 

• • Tertian fever in extended malaria (occurring every 3rd day) 

• • Undulant fevers seen in brucellosis (fevers in the evening with associated sweating which resolves by morning) 

• • Cyclical Pel-Ebstein fevers in Hodgkin’s disease (high fevers that last one week and have week-long remissions) 

• • Morning fevers are seen in typhoid, tuberculosis, and polyarteritis nodosa (4)(8).  

• Method of obtaining temperature measurement 

• • Additionally, it is important to determine how the patient is obtaining their temperature and to determine if a witness is present who can validate the results (8).  

• • Occasionally, patients can assume they have a fever due to subjective symptoms including sweats or chills and these patients should be educated on the importance of performing an actual temperature measurement, and creating a fever diary before additional workups are performed (8).  

Historical and Physical Examination Clues:  

In addition to the patient history taken from the patient, family, and/or friends, there are historical clues and physical examination findings present during the initial evaluation that can point to a potential diagnosis.  

These are categorized into the 4 subgroups mentioned previously. 

Infectious causes of FUO: If infectious etiology is probable, the HPI should include prior invasive surgeries/procedures, TB exposure, dentition, tick/mosquito bites, pet contacts, rodent exposure, blood transfusion history, and immunosuppressive drug use.  

For example, exposure to cats may suggest cat scratch disease or toxoplasmosis, daycare centers are known to spread acute EBV easily and exposure to birds may suggest a Chlamydia psittaci infection (2).  

Important physical assessment findings may include spinal tenderness which could indicate vertebral osteomyelitis, splenomegaly can indicate EBV, miliary TB, or CMV and epididymal nodules could be indicative of extrapulmonary tuberculosis (2).  

Malignant cause of FUO: When considering if malignancy is the cause of FUO it is important to ask about unintentional weight loss, cancer screenings, smoking, alcohol use, and family history of cancer.  

On physical examination, relative bradycardia (a pulse that is lower than expected in a particular disease state) could suggest CNS/lymphoma malignancy, a new heart murmur can indicate atrial myxoma and isolated liver enlargement could be suggestive of liver metastases or a hepatoma (2).  

Non-infectious causes of FUO: Autoimmune and collagen vascular diseases can manifest as FUO if the fever comes before other, more specific manifestations like arthritis, renal involvement, or pneumonitis (2). When looking into rheumatologic disorders it is best to ask about oral ulcers, family history of autoimmune disorders, and muscle and joint pain/stiffness.  

During the physical assessment, pay close attention to oral ulcers which could indicate SLE, and Bechet disease, lymphadenopathy can indicate sarcoidosis, RA, and SLE and rashes could indicate SLE, juvenile RA, and sarcoidosis (2).  

Miscellaneous causes of FUO: Cirrhosis and Crohn’s are often overlooked when it comes to FUO. It is imperative to ask the patient about past medical history, IV drug use, history of alcohol intake, non-alcoholic hepatosteatosis (NASH) as well as hepatitis (2). On physical assessment, splenomegaly can indicate liver cirrhosis and Crohn’s disease (2).  

Physical Examination 

Another important piece of the workup for FUO is the physical examination. Every organ system should be evaluated and there may even be parts of the examination that are essential in patients with FUO that may not be a part of a provider’s usual practice (8).  

Physical assessment should include the following: 

• Abdomen (including liver/spleen size, prostate, and rectal exam) 
• Genitalia (including a gynecologic pelvic exam in women with pelvic symptoms and testes/epididymis exam in men) 
• Cardiac 
• Joints and spine 
• Lungs 
• Lymph nodes 
• Neurological examination (including cognition and cranial nerves) 
• Oral cavity (including teeth, gums, and palate) 
• Ophthalmologic examination (including fundoscopy and conjunctivae) 
• Skin and nails (including wounds) 
• Temporal arteries 
• Thyroid  

(3)(4)(8) 

Laboratory Studies 

Another important part of the clinical workup is the laboratory studies. These studies can reveal potential diagnoses of FUO and further lead to other needed diagnostic tools.  

The following laboratory studies are most typically recommended for discovering the cause of FUO:  

• Complete blood cell (CBC) count with white blood cell (WBC) differential 
• Peripheral blood smear 
• Complete metabolic panel  
• C-reactive protein (CRP) 
• Erythrocyte sedimentation rate (ESR) 
• Ferritin 
• Lactate dehydrogenase 
• Procalcitonin 
• Purified protein derivative (PPD)/interferon-gamma release assay (IGRA) 
• Urinalysis 
• Blood cultures, preferably 3 draws from separate sites at different times  
• Hepatitis A, B, and E serology 
• Heterophile antibody test (e.g., Monospot test) or EBV antibody tests 
• Antinuclear antibody titers 
• Rheumatoid factor  
• Thick and thin blood smears for malaria 
• Thyroid-stimulating hormone (TSH) 
• Thyroxine level 
• HIV antigen-antibody assay  

(3, 4, 8) 

Imaging Studies 

Imaging studies should be directed based on physical, historical, and basic laboratory clues (4). Imaging studies included in the evaluation of FUO can include but are not limited to.  

• Abdominal or pelvic ultrasound or CT 
• Venous duplex Doppler of lower extremities 
• Echocardiography 
• Posteroanterior and lateral chest radiography (XRAY) 
• Thoracic CT angiography 
• FDG-PET/CT whole-body scanning 
• Radionucleotide studies  
• Technetium bone scanning  

Additional Diagnostics Tests 

If the information presented from the above laboratory or imaging tests does not provide all the information needed to reach a diagnosis, additional diagnostic tests could be run as well. These include the naproxen test which can screen out infection vs. neoplasm. Naproxen sodium 250 mg is given every 8 hours for 3 days. A resolution or sharp decline in the fever within 24 hours directs the workup away from infections and can suggest a neoplastic diagnosis. Additional procedures include endoscopy, biopsies, and tissue sampling (4).  

Initial Management 

Treatment should be directed towards the underlying source, as needed, once a diagnosis is finally reached.  

Discontinue Nonessential Medications 

Nonessential medications should be discontinued on the patient. Especially medications that are new to the patient and ones that are known to cause fevers. If a patient is on multiple medications that can cause fevers, serial discontinuation may assist in identifying the offending drug. If the fever resolves within two half-lives of the drug (typically 3-4 days) the diagnosis of drug fever is supported (8).  

Use of Antipyretics 

The use of antipyretics (fever-reducing medications) during the diagnosis of FUO can be tricky. It is not recommended to use antipyretics such as acetaminophen or NSAIDs when the patient is afebrile as these medications can mask other differentiating signs and symptoms of their illness and it can be difficult to monitor fever patterns. Patients are only advised to use antipyretics if they are at high risk for complications from fevers such as cardiac disease or seizures (8).  

Role of Empiric Antibiotics and Glucocorticoids 

Generally, empirical (directed against a likely cause of disease) antibiotics are not recommended when working with FUO patients. Giving antibiotics can hide or delay a diagnosis of potentially serious infections like meningitis or endocarditis. Additionally, they can interfere with isolating an organism from blood cultures (3)(4)(8). If a patient is suspected of having high-risk, life-threatening infections, and is neutropenic, or immunocompromised, empiric antibiotics should be administered that target the probable pathogen while results are pending (3)(8).  

Empiric glucocorticoids are used if a patient is suspected of having giant-cell arteritis to prevent complications such as stroke or vision loss. In addition, glucocorticoids can be used if the patient is very ill, and these medications are thought to improve the patient’s condition. It should be noted, however, that these medications can mask malignancies and worsen infections as well as change biopsy results in diagnosing a malignancy (8). 

Prognosis 

Around 75% of those with FUO will have spontaneous resolution of fever. For continued persistent fevers, additional evaluation outside of the ED can take place. Most of this evaluation has been described in the above sections. It depends on the ED facility, as to which tests will be performed in-house. Other approaches can be utilized in the event of unresolved FUO including continued observation, whole-body imaging, and broad-range molecular testing (8).  

If the initial workup is done and the patient still has fevers, referrals can be made at that time. Based on information found in the workup, common consultations include but are not limited to, infectious disease, hematology/oncology, rheumatology, pulmonology, endocrinology, gastroenterology, interventional radiology, and surgery (3)(4).  

Nursing Implications 

Nurses play such an important role in the management and treatment of a patient with FUO presenting to the ED. Nurses play a critical role in the assessment, monitoring, and care of these patients. Nurses conduct thorough assessments of the patient’s signs and symptoms and medical history. Additionally, nurses pay close attention to changes in the patient’s condition, vital signs, and overall status.  

Moreover, nurses play an important role in collaborating with the healthcare team including but not limited to providers, laboratory and diagnostic testing staff, and other specialties. Overall, nurses in the ED setting can provide patient advocacy and support to further assist in the treatment and management of a patient with FUO.  

Conclusion

Managing FUO patients in the ED setting can prove to be difficult and time-consuming. Nurses working in this area play a vital role in the overall management and treatment of these patients. Nurses need to understand the meaning of FUO, pathophysiology, etiology, and the importance of obtaining a thorough patient history and physical examination to assist in developing an appropriate treatment and management plan for the patient.  

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