What are the non-infectious causes of fever?

Non-Infectious Causes of Fever

Non-infectious causes account for a small but important proportion of fever cases, representing approximately 0.5% of febrile illnesses in returning travelers but up to 35.5% of fever of unknown origin cases in general hospital populations. 1, 2

Major Categories of Non-Infectious Fever

Drug-Induced Fever

• Beta-lactam antibiotics (penicillins and cephalosporins) are the most common medication causes of drug fever, typically occurring after 7-10 days of administration (mean 21 days, median 8 days) 3
• Antimicrobial-induced fever persists as long as the drug is continued and resolves within 1-3 days after discontinuation 3
• Antipsychotic medications (phenothiazines, thioxanthenes, butyrophenones, amisulpride) can cause fever through neuroleptic malignant syndrome or hypersensitivity reactions 3
• Drug withdrawal from alcohol, opiates, barbiturates, or benzodiazepines causes fever with associated tachycardia, diaphoresis, and hyperreflexia 1, 3
• Drug fever is a diagnosis of exclusion and should be considered when fever persists despite appropriate antibiotic therapy 3

Rheumatologic and Inflammatory Disorders

• Non-infectious inflammatory diseases (connective tissue diseases, vasculitis, granulomatous diseases) emerged as the most frequent cause of fever of unknown origin in Western countries, representing 35.5% of cases 4, 2
• Giant cell arteritis and polymyalgia rheumatica are the most frequent specific diagnoses in elderly patients 4, 2
• Adult-onset Still's disease is the most frequent cause in younger patients 4, 5
• Other inflammatory causes include systemic lupus erythematosus, rheumatoid arthritis, polyarteritis nodosa, ankylosing spondylitis, and polychondritis 5, 2

Malignancy-Related Fever

• Malignancies account for 13.5% of fever of unknown origin cases, with lymphoma and colorectal adenocarcinoma being particularly common 2, 6
• Tumor lysis syndrome can cause fever in cancer patients 1
• In cancer patients, fever can be associated with both infectious and non-infectious causes, making diagnosis challenging 6

Cardiovascular and Thromboembolic Causes

• Acute myocardial infarction and Dressler syndrome (pericardial injury syndrome) 1
• Venous thrombosis and pulmonary infarction 1, 5
• Fat emboli 1

Gastrointestinal and Hepatobiliary Causes

• Acalculous cholecystitis 1
• Pancreatitis 1, 5
• Crohn's disease (occasionally presents with intermittent fever) 5

Neurological Causes

• Intracranial bleeding and stroke 1
• Nonconvulsive status epilepticus 1
• Central fever from hypothalamic dysfunction 7

Endocrine and Metabolic Causes

• Adrenal insufficiency 1
• Thyroid storm 1
• Gout 1

Iatrogenic and Procedural Causes

• Blood product transfusion reactions 1, 7
• Cytokine release syndrome 1
• Immune reconstitution inflammatory syndrome 1
• Transplant rejection 1

Pulmonary Causes

• Atelectasis 1
• Fibroproliferative phase of acute respiratory distress syndrome 1
• Pneumonitis without infection 1

Toxic and Hyperthermic Syndromes

• Malignant hyperthermia 1, 8
• Neuroleptic malignant syndrome (requires immediate discontinuation of antipsychotic, intensive supportive care, benzodiazepines, external cooling, and IV fluids) 3, 8
• Serotonin syndrome 1

Miscellaneous Causes

• Heterotopic ossification 1
• Jarisch-Herxheimer reaction 1
• Factitious fever 5, 2
• Habitual hyperthermia (particularly frequent in younger patients) 2
• Sarcoidosis 5

Clinical Approach to Non-Infectious Fever

When to Suspect Non-Infectious Causes

• Consider non-infectious causes when fever persists despite appropriate antibiotic therapy, when there is no clear infectious source, or when the clinical presentation suggests a specific syndrome 3, 7
• Non-infectious causes should be in the differential diagnosis for all ICU patients with new fever 1, 7
• In neutropenic cancer patients, drug fever should be considered when fever persists despite appropriate antibiotics 3

Diagnostic Strategy

• A comprehensive physical examination focusing on skin, mucous membranes, lymphadenopathy, hepatosplenomegaly, muscle rigidity, and neurological status is essential 8
• Initial laboratory investigations should include complete blood count, liver function tests, and consideration of biomarkers such as procalcitonin to distinguish infectious from non-infectious causes 8
• Biomarkers can assist in guiding discontinuation of antimicrobial therapy when non-infectious causes are identified 1

Critical Management Principles

• The primary management of drug fever is immediate discontinuation of the suspected medication 3
• Supportive care with antipyretics (paracetamol or NSAIDs) and hydration while awaiting resolution 3
• For life-threatening syndromes like neuroleptic malignant syndrome or malignant hyperthermia, immediate emergency care with drug discontinuation and intensive supportive measures is required 3, 8
• When clinical distinction between infectious and non-infectious fever is unclear, empiric antimicrobial therapy should be initiated to avoid delaying treatment in potentially septic patients 7

Important Pitfalls

• Delaying antibiotics in septic patients increases mortality; when uncertain, treat empirically for infection first 7
• Patients who experienced anaphylaxis or toxic epidermal necrolysis should never be rechallenged with the offending drug 3
• Atypical presentations without fever can occur in elderly and immunocompromised patients with severe infections 7