What are the non‑infectious causes of fever and the recommended work‑up?

Non-Infectious Causes of Fever

Drug-Induced Fever

Beta-lactam antibiotics are the most common medication cause of fever, typically emerging 7–21 days after initiation (median 8 days) and resolving within 1–7 days after discontinuation. 1

• Drug fever can be caused by any medication through hypersensitivity mechanisms, with no characteristic fever pattern distinguishing it from infectious causes 2
• The diagnosis is established by temporal relationship between drug administration and fever onset, followed by defervescence after drug withdrawal 2, 1
• Rash and eosinophilia occur in only a small fraction of drug fever cases and should not be relied upon for diagnosis 2, 3
• Patients who experienced anaphylaxis or toxic epidermal necrolysis must never be rechallenged with the offending drug 2, 1

Life-Threatening Hyperthermic Syndromes

Malignant Hyperthermia

• Triggered by succinylcholine or halogenated anesthetics (halothane most common), with onset potentially delayed up to 24 hours after exposure, especially in patients on steroids 2, 1
• Results from genetically determined dysregulation of cytoplasmic calcium control in skeletal muscle, causing intense muscle contraction and fever 2
• Immediate management requires discontinuation of the trigger agent, administration of dantrolene, and aggressive cooling 1

Neuroleptic Malignant Syndrome

• Strongly associated with antipsychotics (phenothiazines, haloperidol) 1
• Presents with muscle rigidity, fever, and elevated creatine kinase 1
• Treatment requires immediate drug discontinuation, benzodiazepines, external cooling, and intravenous fluids 1

Serotonin Syndrome

• Results from excessive 5-HT₁A receptor stimulation from SSRIs, linezolid, or other serotonergic agents 1
• Manifests with autonomic instability and neuromuscular hyperactivity 1

Withdrawal Syndromes

• Withdrawal from alcohol, opioids, barbiturates, or benzodiazepines produces fever accompanied by tachycardia, diaphoresis, and hyperreflexia 1
• May appear days after ICU admission when drug history is unavailable 1

Cardiovascular & Thromboembolic Causes

• Acute myocardial infarction and post-infarction pericardial injury (Dressler syndrome) 1
• Venous thrombosis and pulmonary infarction 1, 4
• Fat embolism 1

Neurological Causes

• Intracranial hemorrhage and ischemic stroke 1
• Non-convulsive status epilepticus 1
• Central fever from hypothalamic dysfunction 1

Endocrine & Metabolic Disorders

• Adrenal insufficiency 1
• Thyroid storm (hypermetabolic state with high fever) 1
• Acute gout attacks 1

Gastrointestinal & Hepatobiliary Causes

• Acalculous cholecystitis in critically ill patients 1
• Acute pancreatitis 1

Iatrogenic & Procedural Causes

• Febrile reactions to blood product transfusion 1
• Cytokine release syndrome following certain immunotherapies 1
• Immune reconstitution inflammatory syndrome after initiation of antiretroviral or immunosuppressive therapy 1
• Transplant rejection episodes 1
• Tumor lysis syndrome 1
• Jarisch-Herxheimer reaction after antimicrobial treatment of spirochetal infections 1

Pulmonary Causes

• Atelectasis in postoperative or ventilated patients 1
• Fibroproliferative phase of acute respiratory distress syndrome 1
• Non-infectious pneumonitis (drug-induced, radiation-induced) 1

Musculoskeletal Causes

• Heterotopic ossification in the early post-injury period 1

Malignancy-Related Fever

• Neoplastic fever (paraneoplastic syndrome) caused by tumor-produced cytokines 4, 5
• Tumor necrosis 4

Recommended Diagnostic Work-Up

Initial Assessment

• Perform focused physical examination for silent infectious sources: otitis media, pressure ulcers (sacrum, back, head), perineal/perianal abscesses, and retained tampons 2, 6
• Review all medications initiated within the preceding 21 days 1, 3
• Assess for recent procedures, transfusions, or immunotherapy 1

Laboratory Testing

• Serum procalcitonin: levels ≥0.5 ng/mL favor bacterial infection (SIRS: 0.6–2.0 ng/mL, severe sepsis: 2–10 ng/mL, septic shock: >10 ng/mL), while persistently low levels support non-infectious etiology 2, 1, 3
• Endotoxin activity assay has 98.6% negative predictive value for Gram-negative infection 2
• Complete blood count with differential, comprehensive metabolic panel, and liver function tests 6
• Blood cultures (≥2 sets) before antibiotics 6

Imaging

• Chest radiography when respiratory symptoms present 6
• Echocardiography if endocarditis suspected 6
• Consider 18F-FDG PET/CT in HIV patients, recognizing that lymphadenopathy may be malignant, from opportunistic infections, or HIV-related 2

Temperature Monitoring

• Core temperature monitoring using pulmonary artery thermistor, bladder catheter, or esophageal balloon is preferred when precise measurement is critical 1

Critical Management Principles

When to Treat Empirically for Infection

• Delayed initiation of effective antimicrobial therapy increases mortality in sepsis; antibiotics must be administered within 1 hour when infection is suspected 1, 3
• In hemodynamically unstable patients or those with clinical deterioration, treat as infectious fever with empirical antimicrobials immediately, regardless of procalcitonin level 3
• Neutropenic patients (ANC <500/µL) require immediate hospitalization and empiric vancomycin plus antipseudomonal β-lactam 6

When to Withhold Antibiotics

• In stable patients with procalcitonin <0.5 ng/mL and temporal relationship to new medication, consider drug fever and discontinue suspected agent 3
• Observation without empiric antibiotics is appropriate in stable individuals lacking a focal source, as persistent fever alone rarely warrants antimicrobial therapy 6

Management of Specific Non-Infectious Causes

• Drug fever: immediate discontinuation of suspected medication; fever resolves within 1–7 days 2, 1
• Malignant hyperthermia: dantrolene and aggressive cooling 1
• Neuroleptic malignant syndrome: benzodiazepines, external cooling, IV fluids 1
• Neoplastic fever: nonsteroidal anti-inflammatory drugs (naproxen test can differentiate from infectious fever) 5

Common Pitfalls to Avoid

• Never delay empirical antimicrobial therapy in unstable patients while pursuing non-infectious diagnoses, as delay increases sepsis mortality 1, 3
• Do not rely on rash or eosinophilia to diagnose drug fever, as these occur infrequently 2, 3
• Do not rechallenge with suspected drug unless absolutely essential, as more severe reactions may occur 2, 3
• In critically ill patients, assume infectious etiology until proven otherwise, particularly when procalcitonin is elevated or patient shows clinical deterioration 3
• Recognize that opportunistic infections (Pneumocystis jiroveci, CMV) are more likely in HIV patients receiving chemotherapy and require high index of suspicion 2