What is the diagnostic approach and management for a fever lasting more than two weeks?

Causes of Fever Lasting More Than 2 Weeks

Fever persisting beyond 2 weeks requires systematic evaluation across four major diagnostic categories: infectious diseases (most common at ~50%), inflammatory/rheumatologic conditions, malignancies, and miscellaneous causes including drug reactions. 1, 2, 3

Primary Diagnostic Categories

Infectious Causes (~50% of cases)

Infections remain the leading cause of prolonged fever, with specific pathogens varying by age, exposure history, and immune status. 1, 2, 4

• Tuberculosis is the most common infectious etiology worldwide in adults with fever of unknown origin 3
• Urinary tract infections occur in 3-7% of febrile children without localizing signs, with higher rates in girls (8.1% ages 1-2 years) and uncircumcised male infants (8-12.4%) 1
• Q fever (Coxiella burnetii) can present as chronic infection with phase I IgG titers ≥1:1024, particularly in patients with valvular heart disease or vascular abnormalities 5
• Katayama syndrome (acute schistosomiasis) presents 4-6 weeks after freshwater exposure with fever, eosinophilia, and urticarial rash 5
• Bacterial endocarditis must be excluded in patients with cardiac risk factors 5
• Occult abscesses (intra-abdominal, hepatic, splenic) require imaging evaluation 3

Inflammatory/Rheumatologic Diseases (5-10% of cases)

Kawasaki disease is the critical diagnosis not to miss in children with fever ≥5 days, as delayed treatment beyond 10 days significantly increases coronary artery aneurysm risk. 5, 1

• Kawasaki disease requires fever for ≥5 days plus 4 of 5 criteria: bilateral conjunctival injection, oral mucosal changes, polymorphous rash, extremity changes, cervical lymphadenopathy ≥1.5 cm 5
• Adult-onset Still's disease is a leading rheumatologic cause in adults 3
• Multisystem Inflammatory Syndrome in Children (MIS-C) occurs 2-6 weeks post-SARS-CoV-2 exposure with significantly higher and longer fever duration 1
• Familial Mediterranean fever and other autoinflammatory syndromes present with recurrent fever episodes 6, 4

Malignancies (5-10% of cases)

Lymphoma is the most common malignant cause of prolonged fever in both adults and children. 3, 4, 7

• Lymphoma (Hodgkin's and non-Hodgkin's) frequently presents with fever, night sweats, and weight loss 3, 7
• Leukemia should be suspected with cytopenias, thrombocytopenia, or abnormal cells on blood smear 1, 4
• Mediastinal or abdominal lymphadenopathy may not be apparent on initial imaging and requires serial evaluation 7

Miscellaneous Causes (10-20% of cases)

Drug-induced fever occurs with a mean lag time of 21 days (median 8 days) after drug initiation and can take 1-7 days to resolve after discontinuation. 5

• Drug fever can be caused by any medication through hypersensitivity; rash and eosinophilia are uncommon 5
• Central fever from hypothalamic dysfunction 4
• Neuroleptic malignant syndrome from antipsychotics (especially haloperidol in ICU settings) presents with muscle rigidity and elevated creatinine phosphokinase 5
• Malignant hyperthermia from anesthetics can have delayed onset up to 24 hours 5

Age-Specific Risk Stratification

Neonates (0-28 days) have 13% incidence of serious bacterial infection and require comprehensive evaluation including lumbar puncture. 1

• Young infants (29-90 days) have 9% SBI incidence and may be risk-stratified using Rochester or Philadelphia criteria 1
• Infants are at highest risk for incomplete Kawasaki disease with prolonged fever as the primary finding 1
• Children aged 1 month to 2 years account for 55% of prolonged fever cases 4

Essential Diagnostic Workup

Initial laboratory evaluation must include urinalysis with catheterized urine culture (never bag specimen), complete blood count with differential, blood cultures before antibiotics, inflammatory markers (CRP, ESR, procalcitonin), and comprehensive metabolic panel with liver function tests. 1

First-Line Investigations

• Urinalysis and urine culture (catheterized specimen) to exclude UTI 1
• Complete blood count with differential to assess for cytopenias, leukocytosis, or abnormal cells 1, 4
• Blood cultures (obtained before antibiotics) for bacteremia/endocarditis 1
• Inflammatory markers: CRP, ESR, procalcitonin help distinguish infectious from non-infectious causes 5, 1
• Comprehensive metabolic panel including liver enzymes 1

Second-Line Investigations Based on Clinical Suspicion

• Echocardiography is urgent for suspected Kawasaki disease 1
• Chest imaging for tuberculosis, lymphoma, or pulmonary infections 3
• Abdominal/pelvic imaging for occult abscesses or lymphadenopathy 3, 7
• FDG-PET scan is a promising modality for localizing occult inflammation or malignancy 3
• Q fever serologies (phase I and II IgG/IgM) if epidemiologic risk factors present 5
• Tuberculin skin test or interferon-gamma release assay for TB screening 3

Special Populations

• Travel history mandates evaluation for dengue (4-8 day incubation), chikungunya (2-3 days), malaria, and schistosomiasis 5
• Immunocompromised patients require broader infectious workup including opportunistic pathogens 5
• Cardiac risk factors (valvular disease, prosthetic valves, vascular grafts) necessitate endocarditis evaluation and Q fever serologies 5

Critical Pitfalls to Avoid

The presence of one viral infection does not exclude coexisting bacterial infection—maintain vigilance for dual pathology. 1

• Do not rely on bag urine specimens; they have unacceptably high contamination rates 1
• Kawasaki disease can be diagnosed on day 4 of fever if 4 principal criteria are present—do not wait unnecessarily 5
• Drug fever diagnosis requires temporal correlation with medication initiation/discontinuation; rechallenge is rarely indicated 5
• Serial examinations and repeat imaging may be necessary as lymphadenopathy or other findings can emerge over time 7
• Approximately 25-50% of cases remain undiagnosed despite thorough evaluation; most have self-limited illness 1, 2, 3

Prognosis

Approximately 50% of children with true fever of unknown origin will have self-limited illness without specific diagnosis, while the other 50% will ultimately be diagnosed with infectious, inflammatory, or neoplastic conditions. 1

• Delayed Kawasaki disease diagnosis beyond 10 days significantly increases coronary artery aneurysm risk 1
• UTI with pyelonephritis carries 27-64% risk of renal scarring with potential for hypertension (10-20%) and end-stage renal disease (10%) 1
• Q fever patients with valvular defects remain at lifelong risk for chronic infection recrudescence 5