What are the causes of prolonged fever?

Causes of Prolonged Fever

Prolonged fever (>10 days) has three major categories of causes: infectious diseases (most common), malignancies, and rheumatologic/autoimmune conditions, with the specific etiology varying significantly by age, immune status, and underlying medical conditions.

Infectious Causes

Acute and Subacute Infections

• Respiratory infections are the predominant cause of acute fever, with viral pathogens being most common, followed by bacterial pneumonia and exacerbations of underlying lung disease 1
• Q fever should be strongly considered when prolonged fever (>10 days) presents with normal leukocyte count, thrombocytopenia, and elevated liver enzymes 2
• Endocarditis is a critical diagnosis not to miss, comprising 60-78% of chronic Q fever cases and being invariably fatal if untreated 2
• Blood culture-negative infections are common when patients have received prior antibiotics, which is a major pitfall in diagnosis 3

Chronic Infections

• Chronic Q fever occurs in <5% of acute infections but can manifest months to decades later as endocarditis, vascular infections, osteomyelitis, or chronic hepatitis 2
• Tuberculosis, histoplasmosis, brucellosis, and other granulomatous infections should be considered based on exposure history 4
• Parasitic infections including intestinal helminths, schistosomiasis, strongyloidiasis, and filariasis can cause chronic fever, particularly in travelers 1

High-Risk Populations for Chronic Infection

• Patients with valvular heart disease, vascular grafts, or arterial aneurysms have approximately 40% risk of developing infective endocarditis after acute Q fever 2
• Immunosuppressed patients and pregnant women are at increased risk for progression to chronic infection 2
• Patients with indwelling devices (pacemakers, defibrillators, catheters) have high likelihood of device-related infection, with 30-40% of S. aureus bacteremia cases involving cardiac devices 2, 3

Rheumatologic and Autoimmune Causes

• Rheumatologic diseases account for approximately 30% of fever of unknown origin cases 5
• Juvenile rheumatoid arthritis (JRA) and adult Still's disease can present with prolonged fever, hepatosplenomegaly, and characteristic double quotidian fever pattern without initial joint manifestations 4
• Late-onset rheumatoid arthritis (LORA) presents acutely in elderly patients with fever and highly elevated rheumatoid factor, often without typical musculoskeletal findings 6
• Autoinflammatory diseases frequently manifest as recurrent fever attacks with variable presentations 7
• Polymyalgia rheumatica, temporal arteritis, systemic lupus erythematosus, and vasculitides should be considered in the differential 6, 5

Malignancies

• Neoplastic causes are increasingly common with age, representing a major category of prolonged fever particularly in elderly patients 1, 6
• Lymphomas and leukemias must be ruled out in patients with fever, hepatosplenomegaly, and constitutional symptoms 4

Key Diagnostic Patterns

Laboratory Findings Suggesting Specific Diagnoses

• Normal WBC with thrombocytopenia and elevated liver enzymes: highly suggestive of acute Q fever 2
• Highly elevated ESR (≥100 mm/h), elevated CRP, relative lymphocytopenia, and chronic thrombocytosis: compatible with inflammatory and infectious disorders 6
• Elevated ferritin with elevated transaminases: seen in JRA and adult Still's disease 4
• Up to 75% of patients with prolonged fever have normal white blood cell counts, so normal WBC does not exclude serious infection 3, 8

Critical Clinical Patterns

• Prolonged fever with hepatosplenomegaly, aseptic meningitis, and pericarditis: consider JRA 4
• Fever with new heart murmur or signs of heart failure: endocarditis until proven otherwise 3
• Persistent bacteremia or fever >5-7 days despite appropriate antibiotics: suggests abscess formation, resistant organisms, or need for surgical intervention 2

Essential Diagnostic Approach

History and Exposure Assessment

• Obtain detailed travel history, animal exposures, unpasteurized dairy consumption, and occupational exposures for Q fever and other zoonotic infections 3
• Document all medications, especially recent antibiotics, as prior antibiotic use obscures diagnosis and causes culture-negative infections 3
• Assess for underlying valvular disease, vascular grafts, aneurysms, and immunosuppression as these dramatically increase risk for chronic infections 2, 3
• Inquire about recent dental procedures as periodontal disease is strongly associated with endocarditis 3

Initial Laboratory Workup

• Complete blood count with differential, inflammatory markers (ESR, CRP), liver function tests, urinalysis, and blood cultures should be obtained as first-line investigations 3, 8
• Blood cultures must be obtained BEFORE initiating empirical antibiotics to avoid culture-negative infections 3, 8
• Serologic testing for Q fever should be performed when clinical presentation suggests this diagnosis 8

Advanced Imaging

• Transesophageal echocardiography (TEE) is more sensitive than transthoracic echo for detecting valvular vegetations and should be performed when endocarditis is suspected 2
• FDG-PET/CT has high sensitivity and specificity for low-grade vascular infections and can visualize infectious foci not seen by other methods 2, 1

Critical Pitfalls to Avoid

• Never initiate empirical antibiotics without obtaining blood cultures first, as this is the major cause of culture-negative infections and obscures diagnosis 3, 8
• Do not assume normal WBC excludes infection, as leukocyte count is normal in up to 75% of prolonged fever cases 3, 8
• Fever may be absent in elderly and immunocompromised patients despite serious infection, so normal temperatures do not exclude infection 3
• Do not miss endocarditis in patients with valvular disease, as it has 10-year mortality of 19% even with treatment and is invariably fatal if untreated 2
• Recognize that TEE has reduced sensitivity for abscess detection in prosthetic valves, and CT imaging may be needed 2