What are the non‑infectious causes of acute febrile illness in adults and what initial work‑up should be performed?

Non-Infectious Causes of Acute Febrile Illness

Non-infectious etiologies must be actively considered in every febrile adult, particularly when fever persists despite appropriate antimicrobial therapy or when the clinical presentation lacks a clear infectious source. 1, 2

Major Categories of Non-Infectious Fever

Drug-Related Fever

• Beta-lactam antibiotics are the most common medication cause, typically appearing 7–21 days after initiation (median 8 days) and resolving within 1–7 days after discontinuation 1, 2, 3
• Antimicrobial-induced fever persists as long as the drug is continued; immediate discontinuation is the primary management 3
• Malignant hyperthermia can develop up to 24 hours after exposure to succinylcholine or halogenated anesthetics (especially halothane), causing intense muscle contraction, fever, and elevated creatine phosphokinase 1, 2
• Neuroleptic malignant syndrome is strongly associated with antipsychotics (phenothiazines, haloperidol), presenting with muscle rigidity, fever, and elevated creatine phosphokinase; requires immediate drug discontinuation, benzodiazepines, external cooling, and IV fluids 1, 2, 3
• Serotonin syndrome results from excessive 5-HT1A receptor stimulation (SSRIs, linezolid), manifesting with autonomic instability and neuromuscular hyperactivity 1, 2
• Withdrawal syndromes from alcohol, opioids, barbiturates, or benzodiazepines produce fever with tachycardia, diaphoresis, and hyperreflexia; may occur days after ICU admission when drug history is unavailable 1, 2

Cardiovascular & Thromboembolic Causes

• Acute myocardial infarction and Dressler syndrome (pericardial injury syndrome) 1, 3
• Venous thrombosis and pulmonary infarction 1, 3
• Fat emboli 1, 3

Neurological Causes

• Intracranial hemorrhage and stroke 1, 3
• Nonconvulsive status epilepticus 1, 3
• Central fever from hypothalamic dysfunction 3

Endocrine & Metabolic Disorders

• Adrenal insufficiency 1, 3
• Thyroid storm 1, 3
• Gout 1, 3

Gastrointestinal & Hepatobiliary

• Acalculous cholecystitis 1
• Pancreatitis 1, 3

Iatrogenic & Procedural

• Blood product transfusion reactions 1, 3
• Cytokine release syndrome 1, 3
• Immune reconstitution inflammatory syndrome 1, 3
• Transplant rejection 1, 3
• Tumor lysis syndrome 1
• Jarisch-Herxheimer reaction 1

Pulmonary Causes

• Atelectasis 1, 3
• Fibroproliferative phase of acute respiratory distress syndrome 1, 3
• Pneumonitis without infection 1, 3

Musculoskeletal

• Heterotopic ossification 1

Initial Diagnostic Work-Up

Clinical Assessment

• Systematically document all indwelling devices (central lines, urinary catheters, endotracheal tubes, surgical drains) and insertion dates to detect device-related infections versus non-infectious complications 2
• Review all medications started within the past 21 days; drug fever is a diagnosis of exclusion 2, 3
• Examine for muscle rigidity (neuroleptic malignant syndrome, malignant hyperthermia), autonomic instability (serotonin syndrome), or withdrawal signs (tachycardia, diaphoresis, hyperreflexia) 1, 2
• Assess for hepatosplenomegaly, new cardiac murmurs, joint swelling, or neurological deficits to identify specific syndromes 4

Laboratory Testing

• Complete blood count with differential: pancytopenia suggests bone marrow infiltration; eosinophilia suggests drug reaction 4, 3
• Comprehensive metabolic panel: elevated transaminases may indicate drug-induced hepatitis or non-infectious inflammation 4
• Procalcitonin or C-reactive protein when pre-test probability of bacterial infection is low-to-intermediate; these biomarkers guide discontinuation of antimicrobials rather than initial diagnosis 1, 2, 3
• Elevated band neutrophil count >1,500 cells/µL (likelihood ratio 14.5) or neutrophil proportion >90% (likelihood ratio 7.5) favor bacterial infection 2

Imaging

• Chest radiograph for suspected pulmonary source 2, 4
• Diagnostic abdominal ultrasound for abdominal pain, abnormal liver tests, or recent abdominal surgery 2
• CT chest/abdomen/pelvis with IV contrast when initial imaging is nondiagnostic; CT chest identifies pulmonary source in ≈72% of surgical ICU patients, and CT abdomen/pelvis has positive predictive value of 81.8% for septic foci 2
• Avoid routine abdominal or sinus imaging in patients lacking localizing signs, symptoms, or laboratory abnormalities 2
• 18F-FDG PET/CT provides sensitivity of 84–86% and diagnostic yield of ≈56% when initial work-up is inconclusive; perform within 3 days of starting glucocorticoids if steroids are required 2

Temperature Measurement

• Use rectal or oral thermometry (≥38°C) rather than axillary, tympanic, or temporal-artery methods 2
• Core temperature monitoring (pulmonary artery thermistor, bladder catheter, esophageal balloon) is preferred when accurate measurements are critical 1, 2

Critical Management Principles

When to Withhold Empiric Antibiotics

• In clinically stable adults, empirical antibiotics should be avoided because they can obscure the underlying diagnosis and cause harm; therapeutic decisions must be driven by targeted clinical assessment 2, 4, 3
• Observation without empiric antibiotics is appropriate in stable individuals lacking a focal source; persistent fever alone rarely warrants antimicrobial therapy 4

When Empiric Antibiotics Are Mandatory

• Neutropenia (ANC <500/µL or <100/µL expected >7 days) 2, 4
• Hemodynamic instability or septic shock 2, 4
• Altered mental status or respiratory distress 2
• Suspected cholangitis or tick-borne rickettsial disease 2
• Delay of effective antimicrobial therapy increases mortality in sepsis; initiate within 1 hour when infection is suspected 1, 3

Specific Management of Non-Infectious Syndromes

• Drug fever: immediate discontinuation of the suspected medication; fever resolves within 1–7 days 1, 2, 3
• Neuroleptic malignant syndrome: immediate discontinuation of antipsychotic, intensive supportive care, benzodiazepines, external cooling, IV fluids 1, 3
• Malignant hyperthermia: discontinue triggering agent, dantrolene, aggressive cooling 1
• Patients who experienced anaphylaxis or toxic epidermal necrolysis should never be rechallenged with the offending drug 1, 3

Common Pitfalls to Avoid

• Automatic "fever workup" panels lead to unnecessary testing, blood loss, radiation exposure, and patient transport risks 2
• Empiric antibiotics in stable patients can mask the underlying diagnosis and may be harmful 2, 4
• Unreliable temperature methods (oral, tympanic, temporal artery, chemical dot) should be avoided 2
• Routine removal of central venous catheters is not indicated; removal is reserved for clinically unstable patients or microbiologic evidence of catheter-related infection 2
• Delaying antibiotics in septic patients increases mortality; when uncertain, treat empirically for infection first 3
• Non-infectious causes account for up to 35.5% of fever of unknown origin cases in general hospital populations, so maintain a high index of suspicion 3