What is the differential diagnosis (ddx) and treatment for a patient presenting with symptoms suggestive of influenza?

Differential Diagnosis of Influenza

For patients presenting with influenza-like symptoms, the key differential diagnoses include community-acquired pneumonia, other viral respiratory infections (RSV, adenovirus, enterovirus), acute bronchitis, meningococcal disease (especially in children), and bacterial superinfections—with clinical assessment focusing on specific distinguishing features and severity markers to guide appropriate testing and treatment. 1

Clinical Presentation Distinguishing Features

Typical Influenza Presentation

• Abrupt onset of fever (≥38°C), cough, chills/sweats, myalgias, and malaise provides 70-77% positive predictive value during influenza season 2, 3
• Fever plus cough yields 71-83% positive predictive value in children, though significantly lower (30%) in adults ≥60 years 2
• Critical caveat: Only 44-51% of hospitalized adults with laboratory-confirmed influenza present with typical influenza-like illness 2

Red Flags Suggesting Alternative Diagnoses

Pneumonia indicators (requiring chest radiography): 1

• Dyspnea and tachypnea (respiratory rate >30/min)
• Pleuritic chest pain
• New focal chest examination findings (crackles, diminished breath sounds, dullness to percussion)
• Tachycardia
• Temperature ≥38°C with localized signs

Non-influenza viral infections: 4

• Presence of rash strongly suggests alternative diagnosis (enterovirus with vesicular rash, adenovirus, non-specific viral exanthems)
• Lymphadenopathy
• Central nervous system symptoms beyond typical influenza

Bacterial superinfection/co-infection: 1, 5

• Worsening after initial improvement
• Productive cough with purulent sputum
• Focal consolidation on examination
• Staphylococcus aureus is the most common bacterial isolate in influenza pneumonia (29% of cases) 5
• Streptococcus pneumoniae also common

Meningococcal disease: 1

• Increased risk following influenza infection in children
• Altered consciousness or severe irritability
• Petechial or purpuric rash
• Neck stiffness

Diagnostic Approach Algorithm

Step 1: Clinical Assessment

Assess illness severity immediately: 1

• Vital signs: fever, respiratory rate, blood pressure, heart rate
• Oxygen saturation
• Mental status
• Respiratory examination for focal findings

Step 2: Risk Stratification

Identify high-risk patients requiring closer monitoring: 1

• Age <1 year or ≥65 years
• Chronic cardiac or respiratory disease (especially COPD)
• Immunocompromised status
• Diabetes mellitus
• Pregnancy

Step 3: Laboratory Testing Decision

Testing is NOT routinely needed for: 2, 3

• Low-risk outpatients with typical influenza symptoms during influenza season
• Patients where results won't change management

Testing IS indicated for: 2, 3

• Hospitalized patients with suspected influenza
• When confirmation would influence antiviral or antibiotic decisions
• High-risk patients where confirmation affects management
• Atypical presentations

Preferred diagnostic tests: 2

• RT-PCR or nucleic acid amplification tests (NAAT): Most sensitive and specific (2-6 hours)
• Digital immunoassay (DIA) for non-severe cases
• Rapid molecular assays at point-of-care when available
• Avoid relying on rapid antigen tests alone due to lower sensitivity; confirm negative results with RT-PCR 2

Step 4: Pneumonia Evaluation

Order chest radiography if: 1

• Abnormal vital signs (tachypnea, hypoxia, fever ≥38°C)
• Dyspnea or shortness of breath
• Focal chest examination findings
• High clinical suspicion despite normal examination

Consider C-reactive protein (CRP): 1

• CRP ≥30 mg/L plus suggestive symptoms increases pneumonia likelihood
• CRP <10 mg/L makes pneumonia less likely (especially without dyspnea and daily fever)
• Do NOT routinely measure procalcitonin in outpatient setting 1

Blood tests for hospitalized patients: 1

• Complete blood count (leucocytosis with left shift suggests bacterial infection)
• Urea, creatinine, electrolytes
• Liver function tests
• Creatine kinase if myositis suspected
• CRP if bacterial superinfection suspected

Microbiological testing: 1

• NOT routinely needed in outpatients
• Consider only if results would change therapy
• Blood and respiratory cultures for hospitalized patients with pneumonia

Treatment Approach

Antiviral Therapy

Initiate antivirals within 48 hours (ideally 24 hours) for: 1, 6, 3

• High-risk patients with suspected influenza (regardless of test results if testing delayed)
• Hospitalized patients with suspected or confirmed influenza
• Patients with severe illness or complications

Antiviral options: 7, 6

• Oseltamivir 75 mg twice daily for 5 days (first-line for severe influenza) 6
• Baloxavir conditionally recommended for non-severe influenza in high-risk patients 6
• Benefits: Reduces illness duration by ~24 hours, may decrease complications, hospitalization, and antibiotic use 1, 3

Do NOT delay antiviral treatment waiting for test confirmation in high-risk or severely ill patients 2, 3

Antibiotic Therapy

Strong recommendation AGAINST antibiotics when: 1, 6

• No clinical or radiographic evidence of pneumonia
• Normal vital signs and lung examination
• Bacterial co-infection unlikely

Use empiric antibiotics when: 1, 5

• Pneumonia suspected but imaging cannot be obtained
• Radiographic evidence of pneumonia
• Clinical deterioration or bacterial superinfection suspected
• Must include staphylococcal coverage (S. aureus most common in influenza pneumonia) 5

Symptomatic Management

Recommend for all patients: 1

• Paracetamol or ibuprofen for fever, myalgias, headache
• Rest and adequate fluid intake
• Avoid smoking
• Consider: topical decongestants (short course), throat lozenges, saline nasal drops

Aspirin is contraindicated in children <16 years (Reye's syndrome risk) 1

Severity Assessment for Hospitalized Patients

Use CURB-65 score for pneumonia severity: 1

• Confusion (Mental Test Score <8)
• Urea >7 mmol/L
• Respiratory rate ≥30/min
• Blood pressure (SBP <90 or DBP <60 mmHg)
• Age ≥65 years

Score interpretation: 1

• 0-1: Consider home treatment
• 2: Short inpatient stay or hospital-supervised outpatient treatment
• ≥3: Manage as severe pneumonia
• Bilateral lung shadowing on chest x-ray = severe pneumonia regardless of score 1

Common Pitfalls to Avoid

• Do not rely solely on typical symptoms in older adults (≥60 years)—only 30% positive predictive value 2
• Do not miss meningococcal disease in children with influenza-like illness plus altered consciousness 1
• Do not use antibiotics empirically for uncomplicated influenza without bacterial co-infection evidence 1, 6
• Do not wait for laboratory confirmation before starting antivirals in high-risk or severely ill patients 2, 3
• Do not dismiss influenza outside peak season—sporadic cases occur year-round 2
• Do not forget staphylococcal coverage when treating influenza pneumonia empirically 5

When to Re-consult or Escalate Care

Patients should return if: 1

• No improvement or worsening 48 hours after starting antivirals
• Development of dyspnea or chest pain
• Persistent high fever beyond 3-4 days
• Altered mental status or severe irritability (especially children)
• Signs of dehydration
• Inability to tolerate oral intake