Causes of Undiagnosed Fever

Fever is one of the most common clinical symptoms that often indicates an underlying issue, typically an infection or inflammation. In most cases, a physical examination, medical history, and diagnostic tests help physicians determine the cause of the fever. However, there are instances when a patient presents with a persistent fever, and despite comprehensive investigations, no clear diagnosis is made. This perplexing condition is known as an undiagnosed fever or fever of unknown origin (FUO).

Undiagnosed fever can pose significant challenges for both patients and healthcare providers. It requires a methodical and patient-specific approach to pinpoint the underlying cause.

What is an Undiagnosed Fever?

Undiagnosed fever, commonly referred to in clinical terms as Fever of Unknown Origin (FUO), is defined as:

• A body temperature above 38.3°C (101°F),
  
• Persists for more than three weeks,
  
• Remains undiagnosed even after three outpatient visits or three days of hospital evaluation.
  

This clinical definition helps differentiate routine fevers from more concerning and elusive ones.

Major Categories of Causes of Undiagnosed Fever

The underlying causes of undiagnosed fever can be grouped into four major categories:

1. Infections
   
2. Neoplastic (Cancer-related) Causes
   
3. Autoimmune or Inflammatory Disorders
   
4. Miscellaneous and Drug-related Causes
   

Let’s explore each category in detail.

1. • Tuberculosis (TB)
     TB remains a global cause of undiagnosed fever. Extrapulmonary tuberculosis, such as abdominal or spinal TB, may not show respiratory symptoms, making diagnosis difficult. 
   • Abscesses
     Deep-seated abscesses in organs like the liver, brain, or abdomen may not produce noticeable external signs and are often missed in routine examinations. 
   • Endocarditis
     Infections of the heart lining, especially in patients with prosthetic valves or underlying heart disease, can cause long-standing fevers with minimal symptoms. 
   • HIV and Opportunistic Infections
     HIV can cause fever directly or indirectly through secondary infections like cytomegalovirus or Pneumocystis jirovecii pneumonia. 
   • Infectious Causes :- Infections are the most frequent cause of FUO, especially in developing countries. However, some infections remain difficult to detect due to atypical presentations, slow progression, or hidden anatomical locations.
   • Parasitic and Fungal Infections :- Diseases like malaria, leishmaniasis, histoplasmosis, or brucellosis may not be common in some regions and thus are overlooked during standard testing.
2. Neoplastic Causes :- Cancer-related fevers, especially when the cancer is undetected, can account for a significant proportion of FUO cases. Malignancy-induced fever often arises from substances released by cancer cells or as a result of tissue necrosis.
   • Lymphomas
     Hodgkin’s and non-Hodgkin’s lymphomas can cause recurrent or constant fever, sometimes accompanied by night sweats and weight loss, but without obvious lymph node enlargement. 
   • Leukemia
     Especially acute leukemias may present solely with fever, fatigue, and mild anemia, while standard imaging may not reveal much. 
   • Renal Cell Carcinoma (Kidney Cancer)
     Known for its “silent” nature, it often manifests with fever as one of the first signs in some cases. 
   • Occult Solid Tumors
     Hidden tumors such as pancreatic or colorectal cancers
3. Miscellaneous and Drug-Induced Causes :- Some causes of undiagnosed fever do not fall into traditional categories and may require a high index of suspicion to identify.
   • Drug Fever
     Certain medications, including antibiotics (e.g., penicillin), anticonvulsants, and cardiac drugs, can trigger fever as a hypersensitivity reaction. The fever often resolves upon stopping the medication.
   • Thyroiditis
     Subacute thyroiditis (inflammation of the thyroid) can cause low-grade fever, neck discomfort, and fatigue, and is sometimes mistaken for a viral illness.
   • Sarcoidosis
     A multisystem inflammatory disease that can mimic infections or cancer. Fever may be one of its early signs.
   • Factitious Fever
     In rare cases, especially in healthcare professionals, individuals may intentionally manipulate thermometer readings or induce symptoms. This psychological condition is known as Munchausen syndrome.
4. Autoimmune and Inflammatory Disorders :- In autoimmune disorders, the body’s immune system mistakenly attacks its own tissues, resulting in inflammation and fever.
   • Systemic Lupus Erythematosus (SLE)
     Particularly common in young women, lupus may cause fevers due to systemic inflammation affecting the joints, skin, and internal organs.
   • Rheumatoid Arthritis (RA)
     In its early or atypical stages, RA can cause fever before joint symptoms become prominent.
   • Adult-Onset Still’s Disease
     A rare inflammatory disorder, it presents with spiking fevers, joint pain, and a salmon-colored rash, often confused with infections or malignancy.
   • Vasculitis
     Diseases like temporal arteritis or polyarteritis nodosa involve inflammation of blood vessels and can lead to prolonged fever with no immediate clues.

Challenges in Diagnosing Undiagnosed Fever

Diagnosing FUO is inherently challenging due to:

• Atypical Presentations :- Diseases may not present in classical ways.
  
• Lack of Localized Symptoms :- Many conditions cause fever without clear signs.
  
• Overreliance on Tests :- Some conditions require clinical acumen rather than extensive testing.
  
• Comorbidities :- Existing health conditions can cloud the diagnostic process.
  

Often, time itself becomes a diagnostic tool. As the disease progresses, new signs or symptoms emerge that help guide the final diagnosis.

When to Seek Specialized Evaluation

If a fever persists beyond 2–3 weeks and no diagnosis is established despite standard evaluations, it is crucial to seek care from an infectious disease specialist or internist with expertise in FUO. Hospitals with access to advanced imaging like PET-CT scans and facilities for tissue biopsy may expedite diagnosis.

Conclusion

Undiagnosed fever is a medical puzzle that requires a careful blend of clinical insight, patience, and investigative expertise. While it can be caused by elusive infections, hidden cancers, or autoimmune disorders, many cases are ultimately diagnosed with methodical follow-up and reevaluation. In some instances, the fever may resolve on its own without a definitive diagnosis.

Understanding the possible causes of undiagnosed fever not only helps healthcare professionals remain vigilant but also empowers patients to pursue persistent symptoms without delay. Early identification and appropriate intervention are key to managing such complex medical scenarios effectively.