What are the recommended diagnostic tests and treatment options for influenza?

Diagnosis of Influenza and Differential Diagnosis

Diagnostic Testing Recommendations

Use RT-PCR or other molecular assays as the primary diagnostic test for influenza in hospitalized patients, and use rapid molecular assays over rapid antigen tests in outpatients when available. 1

Specimen Collection Priority

The optimal specimen collection strategy follows this hierarchy:

• Nasopharyngeal specimens are superior to all other upper respiratory tract specimens for detecting influenza viruses 1
• If nasopharyngeal specimens unavailable, collect combined nasal and throat swabs rather than single-site specimens 1
• Mid-turbinate nasal swabs are preferred over throat swabs alone 1
• Use flocked swabs over non-flocked swabs to improve viral detection 1
• Collect specimens as soon as possible after illness onset, preferably within 4 days of symptom onset 1

For mechanically ventilated patients with respiratory failure, collect endotracheal aspirate or bronchoalveolar lavage specimens, even if upper respiratory specimens tested negative 1

Test Selection by Clinical Setting

Hospitalized Patients:

• Must use RT-PCR or molecular assays over all other influenza tests to improve detection 1
• Use multiplex RT-PCR panels targeting respiratory pathogens in immunocompromised patients 1
• Consider multiplex RT-PCR in non-immunocompromised hospitalized patients if results influence cohorting, reduce unnecessary testing, or decrease antibiotic use 1
• Do not use RIDTs in hospitalized patients except when molecular assays are unavailable 1
• If RIDTs used due to resource constraints, follow-up testing with RT-PCR is mandatory to confirm negative results 1

Outpatients:

• Use rapid molecular assays (nucleic acid amplification tests) as first-line testing when available 1
• RIDTs are acceptable in outpatients to improve detection, but recognize their limitations 1
• Rapid molecular assays have 86-100% sensitivity compared to RIDTs with only 10-70% sensitivity 1, 2, 3

Critical Limitations of Rapid Antigen Tests

RIDTs have critically poor sensitivity (20-70%, as low as 11-42% in some studies) despite high specificity (>90%) 1, 4, 5

Key pitfalls to avoid:

• Never use negative RIDT results to exclude influenza during periods of high community influenza activity 1, 4
• Never use negative RIDTs for treatment decisions when influenza is circulating in the community 1, 4
• Positive RIDT results are reliable and useful for initiating treatment due to high specificity 1, 6
• The positive predictive value of RIDTs decreases during low influenza activity periods 1
• RIDTs perform better in young children than adults, likely due to higher viral loads 1

Tests to Avoid

Do not use the following for clinical diagnosis:

• Immunofluorescence assays in hospitalized patients unless molecular assays unavailable, and confirm negative results with RT-PCR 1
• Viral culture for initial diagnosis because results take 3-10 days and won't inform timely clinical management 1
• Serologic testing for acute diagnosis—requires paired sera 2-3 weeks apart and cannot guide immediate management 1
• Non-respiratory site specimens (blood, plasma, serum, CSF, urine, stool) for routine influenza testing 1

Clinical Diagnosis and Differential

Clinical Presentation

Clinical diagnosis alone has limited accuracy because symptoms overlap substantially with other respiratory pathogens 1, 7, 8

Typical influenza presents with:

• Abrupt onset of fever, cough, myalgias, headache, malaise, and nonproductive cough 7, 8
• Incubation period of 1-4 days (average 2 days) 7

Performance of Clinical Criteria

The positive predictive value of clinical diagnosis varies significantly by population:

• Healthy adults with fever and cough: 71-83% PPV during influenza season 7, 8
• Adults ≥60 years with fever, cough, and acute onset: only 30% PPV 1, 7, 8
• Hospitalized adults ≥65 years with chronic cardiopulmonary disease: 53% PPV for fever, cough, and illness <7 days 1, 7
• Only 44-51% of hospitalized adults with laboratory-confirmed influenza had typical influenza-like illness symptoms 7, 8

Critical Clinical Pitfall

Do not rely on "sudden onset" alone to diagnose or exclude influenza—the positive predictive value is too low, particularly in older adults and those with chronic conditions 7, 8

Consider influenza in any patient with respiratory symptoms or fever during influenza season, regardless of whether onset appears sudden or gradual 7, 8

Differential Diagnosis Considerations

Other respiratory pathogens produce overlapping symptoms with influenza 1, 7, 8:

• Respiratory syncytial virus (RSV)
• Parainfluenza viruses
• Adenovirus
• Human metapneumovirus
• Coronaviruses (including SARS-CoV-2)
• Mycoplasma pneumoniae
• Streptococcus pneumoniae
• Other bacterial pathogens

Always consider bacterial coinfection or secondary bacterial pneumonia in patients with severe disease, extensive pneumonia, respiratory failure, or clinical deterioration after initial improvement 1

Treatment Recommendations

Who to Treat

Start antiviral treatment as soon as possible for the following patients with documented or suspected influenza, without waiting for laboratory confirmation 1:

• All hospitalized patients regardless of illness duration prior to hospitalization 1
• Outpatients with severe or progressive illness regardless of illness duration 1
• Outpatients at high risk including those with chronic medical conditions, immunocompromised patients, children <2 years, adults ≥65 years 1
• Pregnant women and those within 2 weeks postpartum 1

Antiviral Agents

Use a single neuraminidase inhibitor (NAI)—oral oseltamivir, inhaled zanamivir, or IV peramivir—not combination therapy 1

Standard treatment duration:

• 5 days for uncomplicated influenza in otherwise healthy ambulatory patients 1
• Consider longer duration for immunocompromised patients or those with severe lower respiratory tract disease due to protracted viral replication 1

Treatment efficacy:

• Greatest benefit when started within 24 hours of symptom onset 1
• Oseltamivir reduces median time to improvement by 1.3 days in adults 9
• Treatment within 48 hours still provides benefit 1, 10

Common Treatment Pitfalls

• Do not delay antiviral treatment while waiting for laboratory confirmation in high-risk or hospitalized patients 1, 8
• Do not use higher than FDA-approved doses of neuraminidase inhibitors for routine seasonal influenza treatment 1
• Empirically treat bacterial coinfection in patients presenting with severe disease, extensive pneumonia, or respiratory failure 1