What are the steps to diagnose and treat fever?

Diagnosing Fever in Adult Patients

Begin with a thorough history focusing on recent exposures (animal contact, travel, occupational risks), medication review (especially antibiotics, antipsychotics, recent drug changes), and timeline of symptom onset, followed by physical examination targeting skin lesions, lymphadenopathy, cardiac murmurs, abdominal tenderness, and neurological findings including muscle rigidity. 1, 2, 3

Initial Clinical Assessment

Critical History Elements

• Occupational and environmental exposures: veterinarians, farmers, slaughterhouse workers, or living within 10 miles of livestock farms (particularly for Q fever consideration) 1
• Travel history: destinations visited, timing relative to symptom onset, and region-specific endemic diseases 1, 3
• Medication timeline: all drugs started 7-21 days before fever onset, with beta-lactam antibiotics being the most common culprit for drug fever 2
• Substance use: recent cessation of alcohol, opiates, barbiturates, or benzodiazepines causing withdrawal fever 1, 2
• Immunocompromise status: transplant recipients, neutropenia, or HIV infection 1

Targeted Physical Examination

• Skin and mucous membranes: rashes, petechiae, or lesions suggesting drug reaction, vasculitis, or embolic phenomena 2, 3
• Cardiovascular: new murmurs (endocarditis), peripheral stigmata of endocarditis 1
• Neurological: muscle rigidity (neuroleptic malignant syndrome, malignant hyperthermia), altered mental status, meningismus 1, 2, 3
• Abdominal: right upper quadrant tenderness (acalculous cholecystitis), hepatosplenomegaly 1, 2

Initial Diagnostic Workup

Mandatory First-Line Testing

• Complete blood count with differential 4, 3
• Comprehensive metabolic panel including liver enzymes, alkaline phosphatase, and bilirubin 1, 3
• Urinalysis and urine culture 4, 3
• Blood cultures: minimum of two sets, with at least one obtained peripherally by venipuncture 1
• Chest radiograph (portable acceptable initially for ICU patients) 1, 4
• Inflammatory markers: erythrocyte sedimentation rate and C-reactive protein 5, 6
• Procalcitonin: to distinguish infectious from non-infectious causes 2, 3

Respiratory Source Evaluation

When pneumonia is suspected based on cough, rales, or radiographic infiltrates:

• Respiratory secretions: obtain via endotracheal aspirate (intubated patients) or expectorated sputum (non-intubated patients) before invasive sampling 1
• Avoid saline instillation in endotracheal tubes unless deep suctioning fails, as saline dilutes specimens and may introduce contaminants 1
• CT chest: consider when chest radiograph is negative but clinical suspicion remains high, particularly for posterior-inferior lung pathology or in immunocompromised patients 1
• Thoracic ultrasound: perform when expertise available and chest radiograph shows abnormalities, to identify pleural effusions and parenchymal consolidation 1

Catheter-Related Infection Evaluation

For patients with indwelling catheters and suspected catheter-related sepsis:

• Remove suspect catheter and culture a 5-7 cm intracutaneous segment 1
• Simultaneous blood cultures: one peripheral and one from the suspected catheter 1
• Quantitative cultures or differential time to positivity if both blood cultures grow the same organism 1

Abdominal Source Evaluation

• Diagnostic abdominal ultrasound: perform in post-surgical patients or when abdominal symptoms, abnormal examination, or elevated transaminases/alkaline phosphatase/bilirubin are present 1
• Do not routinely perform abdominal ultrasound in asymptomatic patients without laboratory abnormalities 1
• CT abdomen/pelvis: consider when ultrasound is non-diagnostic and clinical suspicion persists 6

Advanced Diagnostic Testing

When Initial Workup is Unrevealing

• 18F-FDG PET/CT: recommended when erythrocyte sedimentation rate or C-reactive protein are elevated and diagnosis remains elusive after initial evaluation 1, 5, 6
• Region-specific serologic testing: tuberculosis, cytomegalovirus, Epstein-Barr virus, HIV based on exposure history 6
• Q fever testing: PCR of whole blood or serum in first 2 weeks after symptom onset (before antibiotics), or fourfold increase in phase II IgG antibody titer by IFA of paired specimens 1, 4

Invasive Diagnostic Procedures

When non-invasive testing fails to establish diagnosis:

• Tissue biopsy has the highest diagnostic yield and is the invasive test of choice 5
• Bronchoscopy: particularly useful for Pneumocystis jiroveci, Aspergillus, and Cryptococcus neoformans in immunocompromised patients 1
• Biopsy targets: liver, lymph node, temporal artery, skin, bone marrow based on clinical findings 5

Non-Infectious Causes to Consider

Drug-Induced Fever

• Suspect when: fever persists despite appropriate antibiotic therapy without clear infectious source 2
• Timing: typically 7-10 days after drug initiation (mean 21 days, median 8 days) for beta-lactams 2
• Resolution: within 1-3 days after drug discontinuation 2
• Management: immediate discontinuation of suspected medication 2

Life-Threatening Syndromes Requiring Emergency Intervention

• Neuroleptic malignant syndrome: fever with muscle rigidity in patients on antipsychotics—requires immediate drug discontinuation, benzodiazepines, external cooling, and IV fluids 2, 3
• Malignant hyperthermia: high fever with muscle rigidity—requires immediate emergency care 2, 3
• Serotonin syndrome: fever in patients on serotonergic medications 1, 2

Other Non-Infectious Causes

The differential includes acalculous cholecystitis, acute myocardial infarction, Dressler syndrome, adrenal insufficiency, thyroid storm, intracranial bleeding, stroke, nonconvulsive status epilepticus, venous thrombosis, pulmonary infarction, blood transfusion reactions, cytokine release syndrome, transplant rejection, tumor lysis syndrome, gout, and atelectasis 1, 2

Critical Management Principles

Empiric Antimicrobial Therapy

• Initiate immediately when infection is suspected after obtaining cultures, particularly within 1 hour of sepsis diagnosis 3
• Target therapy based on suspected source, risk for multidrug-resistant pathogens, and local susceptibility patterns 3
• Avoid empiric antibiotics in fever of unknown origin unless patient is neutropenic, immunocompromised, or critically ill 4, 5, 6

Special Populations

• Neutropenic patients: require hospitalization and empiric vancomycin plus antipseudomonal antibiotics 3
• Returning travelers: test for malaria in all patients who visited tropical countries within 1 year 3
• Immunocompromised patients: may present without typical fever, cough, or leukocytosis despite severe infection 1

Common Pitfalls

• Delaying antibiotics in suspected sepsis increases mortality—when uncertain between infectious and non-infectious causes, treat empirically for infection first 2, 3
• Portable chest radiographs have low positive predictive value for pneumonia in ICU patients—maintain high clinical suspicion despite negative films 4
• Previous antibiotic administration lowers quantitative culture inocula after 24 hours, hampering interpretation 1
• Not all febrile episodes require investigation—obvious non-infectious causes like immediate postoperative fever do not mandate full workup 1
• Uncommon presentations of common diseases are more likely than rare diseases in fever of unknown origin 5, 7, 6
• Up to 75% of fever of unknown origin cases resolve spontaneously without definitive diagnosis 5