Causes of Low-Grade Fever
Low-grade fever (defined as body temperature between 37.5°C and 38.3°C) has the same broad etiological spectrum as classic fever of unknown origin, with infectious diseases being the most common organic cause (59%), followed by inflammatory non-infectious diseases, drug reactions, malignancies, and miscellaneous conditions including habitual hyperthermia. 1
Primary Etiological Categories
Infectious Causes (Most Common in Organic Fever)
- Bacterial infections account for the majority of organic low-grade fevers, including occult bacteremia, urinary tract infections, and infective endocarditis (particularly important in patients with congenital heart disease) 1, 2
- Viral infections commonly cause low-grade fever with neutrophilic inflammation of airways, though these are typically self-limited 3
- Atypical organisms including Chlamydia and Mycoplasma may contribute to persistent low-grade fever 3
- C. difficile infection should be suspected in any patient with low-grade fever and diarrhea who received antibiotics within 60 days 3
Drug-Induced Fever
- Drug hypersensitivity fever develops after a mean lag time of 21 days (median 8 days) from drug initiation and resolves within 1-3 days (up to 7 days) after discontinuation 4
- Serotonergic medications (like venlafaxine combined with bupropion) can cause fever as part of serotonin syndrome, which may develop within 24-48 hours of combining agents 5
- Anticholinergic agents (such as trihexyphenidyl) can cause hyperthermia as part of anticholinergic syndrome 4
- Drug-induced fever is a diagnosis of exclusion after ruling out infectious causes 4
Inflammatory Non-Infectious Diseases
- Acute rheumatic fever presents with low-grade fever (>37.5°C captures 90% of cases in high-risk populations, though most low-risk populations have fever >38.5°C) along with major criteria including carditis, arthritis, or chorea 3
- Autoimmune conditions represent a significant category in the differential diagnosis of persistent low-grade fever 1, 6
- Inflammatory conditions account for approximately 6.2% of organic low-grade fever cases 1
Malignancies
- Neoplasms account for approximately 3.1% of organic low-grade fever cases 1
- Fever may be the presenting sign of occult malignancy, particularly in older patients 1
Miscellaneous Causes
- Vascular disorders including thromboembolic disease 7
- Tissue necrosis from any cause 7
- Miscellaneous conditions account for 18.7% of organic low-grade fever cases 1
Non-Organic Causes
Habitual Hyperthermia
- Habitual hyperthermia represents a significant proportion (56% in one series) of patients presenting with low-grade fever 1
- These patients typically lack pathological signs on physical examination (significantly more frequent than in organic fever, p<0.0001) 1
- Associated symptoms include dizziness and general malaise rather than objective findings 1
Key Clinical Discriminators
Features Suggesting Organic Fever
- Age: Mean age is significantly higher in organic fever compared to habitual hyperthermia (p<0.02) 1
- Physical findings: Splenomegaly and weight loss are significantly associated with organic fever (p<0.05) 1
- Laboratory markers: Elevated white blood cell count and C-reactive protein are more frequently abnormal in organic fever (p<0.05) 1
- Inflammatory markers: In acute rheumatic fever, C-reactive protein should always be higher than the upper limit of normal (commonly >7.0 mg/dL) and erythrocyte sedimentation rate typically >60 mm/h 3
Critical Pitfall
Do not assume that low body temperature values correlate with less severe underlying disease—there is no relationship between fever magnitude and disease severity, and the etiological spectrum of low-grade fever mirrors that of classic fever of unknown origin. 1 Approximately 12.5% of organic low-grade fever cases remain undiagnosed despite thorough evaluation 1.