Differential Diagnosis of Fever in Adults
The differential diagnosis of fever in adults must systematically consider both infectious and noninfectious etiologies, with infectious causes taking priority in initial evaluation due to their impact on mortality if treatment is delayed. 1
Primary Categories
The differential diagnosis falls into four major categories:
1. Infectious Causes (Most Common)
These should be evaluated first as early treatment improves outcomes:
- Respiratory infections: Pneumonia, viral upper respiratory infections (including SARS-CoV-2)
- Bloodstream infections: Bacteremia, endocarditis, catheter-related infections
- Urinary tract infections: Particularly catheter-associated UTI
- Intra-abdominal infections: Cholecystitis (including acalculous), abscess, peritonitis
- Endemic infections (geography-dependent): Tuberculosis, malaria, leishmaniasis 2
- Viral infections: CMV, EBV, adenovirus (particularly in immunocompromised)
2. Noninfectious Inflammatory/Rheumatologic Diseases
These are increasingly recognized, especially in women and elderly patients 3:
- Adult-onset Still's disease (quotidian fever, evanescent rash, marked hyperferritinemia >1000 ng/mL) 4, 5
- Polymyalgia rheumatica with or without temporal arteritis 4, 3
- Behçet's disease 4
- Familial Mediterranean fever (periodic fever <3 weeks) 4
- Subacute thyroiditis 3
- Gout
3. Malignancies
All neoplasms presenting as fever typically meet classical fever of unknown origin criteria 4:
- Lymphomas
- Leukemias
- Solid tumors with metastases
4. Noninfectious Causes Specific to Critical Care 1
Cardiovascular/Thrombotic:
- Acute myocardial infarction
- Pulmonary infarction
- Venous thrombosis
- Dressler syndrome
Neurologic:
- Stroke
- Intracranial hemorrhage
- Nonconvulsive status epilepticus
- Neuroleptic malignant syndrome
- Serotonin syndrome
- Malignant hyperthermia
Drug-Related:
- Drug fever
- Cytokine release syndrome
- Jarisch-Herxheimer reaction
Metabolic/Endocrine:
- Thyroid storm
- Adrenal insufficiency
Other:
- Pancreatitis
- Blood product transfusion
- Atelectasis
- Fat emboli
- Pneumonitis without infection
- ARDS (fibroproliferative phase)
- Heterotopic ossification
- Transplant rejection
- Tumor lysis syndrome
- Substance withdrawal (alcohol, opiates, barbiturates, benzodiazepines)
Key Clinical Patterns to Recognize
Periodic fever lasting <3 weeks suggests autoinflammatory syndromes (Behçet's, FMF) rather than classical FUO 4
Quotidian fever + evanescent rash + polyarthralgia + ferritin >1000 strongly suggests Adult-onset Still's disease 5
Fever in elderly patients or immunocompromised may present without typical fever patterns—maintain high suspicion even with normal temperatures 6
Critical Pitfalls to Avoid
Don't reflexively culture everything—target diagnostic studies based on clinical suspicion rather than sending cultures for all possible sources 1
Don't assume all fever is infectious—noninfectious causes account for a substantial proportion, particularly in ICU patients where obvious noninfectious etiologies (immediate postoperative fever) should not trigger extensive workup 1
Don't rely on oral temperatures alone—they have poor sensitivity; use core temperature measurements when fever is suspected 6
Don't forget drug fever—review all medications as a reversible cause
In women and elderly patients, maintain higher suspicion for rheumatologic diseases, which are increasing in frequency 3
Context-Specific Considerations
Up to 75% of fever of unknown origin cases resolve spontaneously without definitive diagnosis 7, emphasizing that not all fevers require exhaustive investigation when patients are clinically stable.
Most adult FUO cases result from uncommon presentations of common diseases rather than rare diagnoses 7—keep common things common in your differential.