A fever is a biological response, signaling that the body’s immune system is actively fighting an intruder or dealing with inflammation. Most fevers are short-lived, resolving on their own or with common medications once the underlying cause becomes clear. When a fever persists for an extended period without an obvious source, this prolonged elevation in body temperature prompts a comprehensive medical investigation to identify the hidden process driving the persistent warmth.
Defining an Unexplained Fever
A fever is medically defined as a body temperature of 100.4°F (38°C) or higher. For a fever to be officially considered “unexplained,” or a Fever of Unknown Origin (FUO), it must meet specific criteria regarding both height and duration. The medical standard requires the temperature to be 101°F (38.3°C) or higher on several occasions and continue for a minimum of three weeks. The cause must remain unknown even after a thorough initial medical evaluation, typically involving three days of hospital investigation or three comprehensive outpatient visits.
Categories of Potential Causes
The conditions responsible for an unexplained fever are typically grouped into three broad categories: infectious, inflammatory/autoimmune, and malignant. These causes are often common diseases presenting in an atypical or occult manner, meaning they lack the usual localizing symptoms.
Infectious Causes
While common infections rarely lead to an unexplained fever, the infectious causes that do are often hidden or subacute. These include localized collections of pus, known as abscesses, which can form deep within the abdomen, pelvis, or liver without causing surface pain. Chronic bacterial infections like miliary tuberculosis or subacute bacterial endocarditis, an infection of the heart valve lining, can also present solely with a persistent fever. Certain chronic viral infections, such as Cytomegalovirus (CMV) or Epstein-Barr Virus (EBV), and infections linked to travel, like Q fever or brucellosis, must also be considered.
Inflammatory/Autoimmune Causes
This major category involves conditions where the immune system mistakenly targets the body’s own tissues, leading to chronic inflammation. These systemic rheumatic diseases can cause fever before more specific symptoms like joint pain or rash appear. Conditions such as Adult-onset Still’s disease, a type of inflammatory arthritis, and vasculitis, including Giant cell arteritis in older adults, are significant causes. Systemic Lupus Erythematosus (SLE) can also manifest with an unexplained fever as one of its earliest and most prominent symptoms.
Malignancy (Cancer)
A persistent, unexplained fever can also be a symptom of certain cancers, referred to as a paraneoplastic syndrome. The fever is caused by the tumor itself releasing fever-inducing substances, rather than infection. Lymphoma, renal cell carcinoma (kidney cancer), and hepatocellular carcinoma (liver cancer) are frequently cited malignancies, especially when combined with other nonspecific symptoms like unexplained weight loss or night sweats.
The Medical Investigation Process
The investigation of a prolonged fever is a methodical process that begins with a comprehensive review of the patient’s background.
Initial History and Examination
The initial history focuses intensely on details, including recent travel, dietary habits, exposure to animals, and a complete accounting of all current and recent medications, as some drugs can induce a fever. The physical examination must be meticulous, with special attention paid to the skin, lymph nodes, joints, and any new heart murmurs that could suggest a hidden source of infection or inflammation.
Laboratory Screening
Initial laboratory work involves broad screening tests designed to detect generalized disease processes. This includes a complete blood count (CBC) to look for abnormalities in white blood cells or anemia, and a comprehensive metabolic panel to assess liver and kidney function. Inflammatory markers, such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), are measured to confirm the presence of a significant inflammatory state.
Advanced Testing and Imaging
If the initial evaluation provides no clear diagnosis, the investigation moves to targeted testing and imaging. Blood cultures are repeated, and specific antibody tests are performed to look for evidence of chronic or atypical infections. Imaging studies begin with a chest X-ray and often progress to computed tomography (CT) scans of the abdomen and pelvis to visualize deep-seated abscesses or tumors. When standard tests are inconclusive, advanced imaging like a Positron Emission Tomography-Computed Tomography (PET-CT) scan is used because it highlights areas of increased metabolic activity, pinpointing hidden sites of disease. If non-invasive tests fail, a tissue biopsy from an area of concern may be necessary to secure a definitive diagnosis. The complexity of the workup often necessitates consultation with subspecialists, including infectious disease experts, rheumatologists, or oncologists.
Monitoring and When to Seek Emergency Care
While the medical investigation is underway, patients must closely monitor their condition and manage symptoms at home. It is helpful to keep a detailed log of the temperature, noting the time the fever peaks and any accompanying symptoms like chills, sweating, or pain. Maintaining adequate hydration is important, as fever increases the body’s fluid requirements. Specific warning signs indicate a potentially life-threatening complication and necessitate an immediate emergency room visit:
- A severe headache or a stiff neck, which can be signs of meningitis.
- Significant difficulty breathing or chest pain.
- The sudden onset of confusion, altered mental status, or extreme lethargy.
- A rash that does not fade when pressed (a non-blanching rash), which can signal a severe blood infection.
- Any temperature exceeding 104°F (40°C).