Understanding Fever of Unknown Origin (FUO) in Older Adults
Fever of unknown origin (FUO) is a persistent, unexplained fever lasting for an extended period despite a thorough diagnostic workup. In adults, the traditional definition involves a fever of at least 38.3°C (100.9°F) on several occasions, lasting over three weeks, with an uncertain diagnosis after standard initial investigations. For older adults, this diagnostic puzzle is further complicated by several factors. The aging immune system can present with a blunted febrile response, meaning serious infections might not produce a high fever, and symptoms are often atypical and subtle. This necessitates a different diagnostic approach and a heightened awareness of the specific conditions more prevalent in this population.
The Shifting Causes of FUO with Age
Unlike younger adults, where infections are often the leading cause of FUO, the epidemiology shifts significantly in the elderly. A meta-analysis of FUO cases in older patients confirms that non-infectious inflammatory diseases are the dominant cause in developed countries. Conversely, in regions with higher prevalence, infections such as tuberculosis still hold significant weight. The underlying conditions that contribute to FUO in older individuals fall primarily into three categories: non-infectious inflammatory diseases, infections, and malignancies.
Non-Infectious Inflammatory Diseases
This group, also known as connective tissue diseases or rheumatologic disorders, is the most common cause of FUO in the elderly, with one specific condition standing out.
- Temporal Arteritis (Giant Cell Arteritis): This is the single most frequent specific cause of FUO in older adults. It is a vasculitis (inflammation of blood vessels) that most often affects the arteries of the head. Symptoms can be vague and may include new-onset headaches, jaw pain with chewing (claudication), visual changes, and fatigue, but fever can be the only presenting sign. A high index of suspicion, especially in a patient over 50 with an elevated erythrocyte sedimentation rate (ESR), should prompt an investigation that often includes a temporal artery biopsy.
- Polymyalgia Rheumatica (PMR): Often linked with temporal arteritis, PMR causes pain and stiffness in the shoulders, neck, and hips. It can manifest with fever and elevated inflammatory markers and is diagnosed through a combination of clinical presentation, blood tests, and a response to corticosteroids.
- Other Rheumatologic Conditions: Rarer causes include adult-onset Still's disease, systemic lupus erythematosus (SLE), and sarcoidosis. The presentation of these diseases in older adults can be non-characteristic, making them difficult to diagnose without specific clues.
Infections
While less common than inflammatory diseases in developed nations, infections remain a critical consideration, especially given the increased susceptibility of the aging immune system.
- Tuberculosis (TB): Extrapulmonary and miliary TB are significant causes of FUO in the elderly. The diagnosis can be challenging as classic symptoms like cough or night sweats may be absent. A tuberculin skin test or interferon-gamma release assay is often necessary.
- Abscesses: Intra-abdominal, pelvic, or dental abscesses can be a source of persistent fever. Imaging techniques like CT scans and ultrasounds are crucial for detecting these hidden pockets of infection.
- Infective Endocarditis: Inflammation of the heart's inner lining is more prevalent in older adults, often occurring on pre-existing degenerative or prosthetic valves. Symptoms can be non-specific, and blood cultures or transesophageal echocardiography may be required.
Malignancies
Neoplasms are another major category contributing to FUO in older adults. Their presentation can be insidious, with fever being one of the first or only signs.
- Hematological Malignancies: Lymphoma and leukemia are frequently associated with FUO. Lymphoma can present with painless lymphadenopathy, night sweats, and weight loss, but can also be occult.
- Solid Tumors: Renal cell carcinoma is a common cause, along with liver and metastatic cancers.
Comparison of FUO Causes in Older vs. Younger Adults
| Feature | Older Adults (>65) | Younger Adults (<65) |
|---|---|---|
| Most Common Cause | Non-infectious inflammatory disease (e.g., Temporal Arteritis) | Infections (e.g., endocarditis, abscesses) |
| Symptom Presentation | Atypical and subtle; fever may be blunted | Often more robust febrile response and clearer symptoms |
| Key Infection | Tuberculosis (especially extrapulmonary) | A wider range of viral and bacterial infections |
| Common Malignancies | Lymphoma, Renal Cell Carcinoma | Lymphoma, Leukemia |
| Diagnostic Challenges | Multiple comorbidities, lower tolerance for invasive tests | Less complex medical history, generally better tolerance |
| Undiagnosed Rate | Lower (8-12%) | Higher (up to 30%) |
The Diagnostic Approach
Given the complexity, diagnosing FUO in older adults requires a careful and systematic approach. It starts with a comprehensive history and physical exam, followed by a battery of laboratory and imaging studies. Crucially, the diagnostic plan must consider the patient's overall health, comorbidities, and tolerance for various tests. If initial, less-invasive tests don't yield a diagnosis, more targeted or invasive procedures may be necessary, such as advanced imaging or tissue biopsies.
- Initial Evaluation: Includes complete blood count (CBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), blood and urine cultures, and a chest x-ray.
- Imaging: Abdominal and chest CT scans are often standard, as are transthoracic or transesophageal echocardiograms if endocarditis is suspected. Newer imaging modalities like FDG-PET/CT are increasingly used to locate areas of inflammation or malignancy.
- Invasive Procedures: Biopsies of temporal artery, liver, or bone marrow are considered based on specific clinical clues or elevated inflammatory markers.
- Trial Therapy: While empirical antibiotics should be avoided to prevent masking the true cause, a therapeutic trial of corticosteroids may sometimes be initiated, particularly if temporal arteritis is strongly suspected due to the risk of irreversible vision loss.
Conclusion
While infections and malignancies are still potential culprits, the most common specific cause of fever of unknown origin in older adults is temporal arteritis, an inflammatory multisystem disease. The atypical presentation of many conditions in the elderly, coupled with comorbidities, makes diagnosing FUO a unique and complex challenge. However, due to advances in diagnostic tools and targeted investigative protocols, a definitive diagnosis is often reached, leading to appropriate, life-saving treatment. An accelerated and focused evaluation is critical due to the older adult's lack of physiological reserve.
For a deeper look into a specific disease mentioned here, see the article on Temporal Arteritis (Giant Cell Arteritis).
