Differential Diagnosis for Fever
Systematic Categorization Framework
The differential diagnosis for fever is best organized into four major categories: infections, malignancies, autoimmune/inflammatory conditions, and miscellaneous causes, with infections representing the most common etiology in most clinical settings. 1, 2
Primary Diagnostic Categories
Infectious Etiologies (Most Common)
Bacterial Infections
- Enteric fever/typhoid - particularly in patients with travel to South/Southeast Asia or Middle East/North Africa 3, 4
- Bacterial cervical lymphadenitis 5
- Meningococcemia - requires immediate empirical treatment without waiting for culture results 3
- Staphylococcal scalded skin syndrome 5
- Toxic shock syndrome 5
- Scarlet fever 5
- Rocky Mountain spotted fever 5
- Leptospirosis 5
- Brucellosis - consider in patients from Middle East/North Africa 6
Parasitic Infections
- Malaria (Plasmodium falciparum, P. vivax, P. ovale, P. malariae) - highest priority in patients with tropical travel, especially Sub-Saharan Africa 3, 4, 6
- Most P. falciparum presents within 1 month but can occur up to 6 months; other species can present up to a year or longer 3, 6
Viral Infections
- Measles, adenovirus, enterovirus, Epstein-Barr virus 5
- Dengue fever - common in South/Southeast Asia and tropical regions 5, 3
- Viral hemorrhagic fevers - consider in Sub-Saharan Africa travelers 3, 4
- Cytomegalovirus - particularly post-transfusion mononucleosis syndrome occurring ~1 month after transfusion 5
Rickettsial Infections
- Scrub typhus - common in South/Southeast Asia 3
- Rickettsial infections - consider in Sub-Saharan Africa 3, 4
Malignancies
- Hematological malignancies - lymphomas, leukemias 5, 1
- Solid tumors - particularly those with metastatic disease 1, 2
- Must be carefully excluded before initiating immunosuppressive therapy, as glucocorticoids or immunomodulating agents are potentially deleterious if malignancy is misdiagnosed 5
Autoimmune/Inflammatory Conditions
Rheumatologic Diseases
- Still's disease (systemic juvenile idiopathic arthritis and adult-onset Still's disease) - characterized by high spiking fevers (typically ≥39°C), often with quotidian pattern 5
- Juvenile rheumatoid arthritis 5
- Kawasaki disease - in young children with unexplained fever ≥5 days plus principal clinical features (extremity changes, polymorphous exanthem, conjunctival injection, oral/lip changes, cervical lymphadenopathy) 5
Vasculitis
- Various forms must be considered in the differential 5
Miscellaneous Causes
- Drug hypersensitivity reactions 5
- Stevens-Johnson syndrome 5
- Mercury hypersensitivity reaction (acrodynia) 5
- Venous thromboembolism 1
- Thyroiditis 1
- Decubitus ulcers, perineal/perianal abscesses, retained foreign bodies 5
- Otitis media - often silent in critically ill patients 5
Critical Diagnostic Approach by Clinical Context
For Returned Travelers (Within Past Year)
Malaria testing must be performed immediately in all patients - this is the single most important potentially fatal cause requiring urgent exclusion. 3, 4, 6
Geographic-Specific Priorities:
- Sub-Saharan Africa: P. falciparum malaria (highest priority), typhoid, rickettsial infections, viral hemorrhagic fevers 3, 4, 6
- South/Southeast Asia: Typhoid/enteric fever (highest incidence), dengue, scrub typhus, malaria 3, 6
- Middle East/North Africa: Enteric fever, brucellosis 6
For Critically Ill/ICU Patients
Infection-Related
- Nosocomial infections - catheter-related bloodstream infections, ventilator-associated pneumonia, surgical site infections 5, 2
- CNS infections - particularly in patients with intracranial devices (ventriculostomy catheters, ventriculoperitoneal shunts) requiring CSF analysis 5
- Post-transfusion CMV mononucleosis syndrome - suspect when spiking fevers (up to 40°C) fail to respond to antimicrobials with negative bacterial cultures, typically occurring ~1 month post-transfusion 5
Non-Infectious
For Pediatric Patients
- Kawasaki disease - requires fever ≥5 days plus ≥4 of 5 principal clinical features; can diagnose on day 4 if coronary artery disease detected 5
- Viral infections - more common than in adults 5
- Mortality in febrile children is significantly higher than non-febrile children 4
Monogenic/Autoinflammatory Disorders
- VEXAS syndrome - consider in adult patients 5
- CHIP (clonal hematopoiesis of indeterminate potential) - consider in adult patients 5
- Inherited autoinflammatory disorders - germline or somatic, inherited or acquired 5
Special Population Considerations
Immunocompromised Patients
- Lower threshold for hospitalization and empiric antimicrobial therapy required 3, 4, 6
- May present with atypical or more severe manifestations 3, 6
- Higher risk for disseminated CMV disease or diffuse interstitial pneumonia 5
Elderly Patients (≥50 Years)
- Heightened suspicion for occult bacterial infection with fever and chills 4
- May not mount typical fever response despite true infection 7
Critical Pitfalls to Avoid
- Never assume any geographic location is "low-risk" - even Mediterranean and Middle Eastern countries harbor serious infections 6
- Do not delay malaria testing - if initial tests negative but suspicion remains, three thick films/RDTs over 72 hours required to confidently exclude 3, 6
- Fever may be absent in true infection - especially in elderly and immunocompromised patients 7
- Oral temperatures have poor sensitivity - use core temperature measurements when accurate diagnosis is critical 4, 7
- Consider non-infectious causes based on clinical context - drug reactions, malignancies, autoimmune conditions 5, 1, 7