What is the best course of action for a patient presenting with a viral infection of unknown source, testing negative for influenza (flu) and coronavirus disease 2019 (COVID-19), with no clear diagnosis?

Management of Viral Infection with Unknown Source (Negative Flu and COVID-19 Testing)

For a patient presenting with viral symptoms but testing negative for both influenza and COVID-19, provide supportive care with symptomatic management while monitoring for clinical deterioration, and consider repeat testing or alternative diagnoses if symptoms worsen or persist beyond expected timeframes.

Initial Diagnostic Approach

Recognize Testing Limitations

• RT-PCR testing for COVID-19 can produce false-negative results due to incorrect sample collection, insufficient viral load at the sampling site, or missing the time-window of viral replication 1
• Nasopharyngeal samples are superior to oropharyngeal samples in early disease stages for detecting SARS-CoV-2 1
• A single negative test does not definitively exclude COVID-19 infection, particularly in patients with high clinical suspicion 1

Consider Repeat Testing When Indicated

• For patients with high clinical suspicion despite negative initial testing, repeat nasopharyngeal RT-PCR swab tests combined with chest imaging may help confirm or exclude COVID-19 1
• The constellation of fever, chills, neck pain, headache, sore throat with white plaque, and congestion suggests upper respiratory tract infection that may have bacterial component despite negative rapid tests 2

Symptomatic Management Strategy

Fever Control

• For fever >38.5°C: Administer ibuprofen 200mg orally every 4-6 hours (maximum 4 times in 24 hours) 2
• Ensure adequate hydration and nutrition with protein-rich foods to support immune function 2

Respiratory Symptom Management

• Provide reassurance that post-viral cough commonly persists for 2-8 weeks after resolution of other cold symptoms 3
• Advise avoidance of irritants that may trigger cough 3
• Adequate rest during recovery is essential 3

Adjunctive Treatments

• Povidone-iodine mouth or nasal spray can be considered as adjunctive treatment to reduce viral load in the pharynx 2

When to Consider Bacterial Superinfection

Clinical Indicators

• White plaque on tonsils is particularly concerning for bacterial infection, even with negative strep test (which can have false negatives) 2
• Persistent high fever, worsening symptoms, or development of new symptoms may indicate bacterial superinfection 2

Antibiotic Consideration

• If bacterial pharyngitis/tonsillitis is suspected based on clinical presentation (fever, white plaque, neck pain), azithromycin is recommended as first-line therapy when strep test is negative but clinical suspicion remains high 2
• Alternative options include amoxicillin or fluoroquinolones if azithromycin is contraindicated 2

Monitoring and Follow-Up

Red Flag Symptoms Requiring Immediate Re-evaluation

• Dyspnea at rest 3
• Respiratory rate ≥30/min 3
• Oxygen saturation ≤93% 3
• Persistent high fever 3
• Chest pain 3
• Hemoptysis 3

Scheduled Reassessment

• Schedule reassessment in 2 weeks to evaluate symptom resolution 3
• If symptoms do not improve within 48-72 hours of antibiotic therapy (if prescribed), re-evaluation is necessary to consider alternative diagnoses 2
• If cough persists beyond 3-4 weeks total duration, proceed with chest radiography and spirometry as initial investigations 3

Imaging Considerations

When Imaging is NOT Indicated

• Imaging is not indicated for patients with mild clinical features who are COVID-19 negative without risk factors for disease progression 1
• Chest radiography is not mandatory for acute post-viral cough when clinical examination is reassuring 3
• Avoid premature use of chest radiography, which exposes patients to unnecessary radiation 3

When Imaging IS Indicated

• Chest CT scan is the most accurate radiological tool to confirm COVID-19 diagnosis in uncertain cases with high clinical suspicion but negative RT-PCR 1
• Chest X-ray can be helpful when CT scan is unavailable 1
• Lung ultrasound may be used as first-line screening tool to discriminate low-risk from higher-risk patients when skills are available 1
• Obtain chest radiography immediately if constitutional symptoms develop 3

Important Clinical Pitfalls to Avoid

Over-Investigation

• Avoid over-investigation of acute post-viral cough in patients with reassuring clinical examination 3
• Do not routinely image patients with mild symptoms and negative testing unless risk factors for progression are present 1

Misdiagnosis

• Do not misdiagnose asthma when nocturnal symptoms and wheezing are absent 3
• Avoid unnecessary antibiotic prescription when patient has no fever, normal vital signs, and clear lungs 3
• Remember that both influenza and COVID-19 have similar presentations (fever, cough, headache, muscle aches, fatigue), making clinical diagnosis without testing unreliable 4

Co-infection Possibility

• Consider the possibility of co-infection with multiple viral pathogens, though this is rare (0.54% in one series) 5
• Co-infections may remain undiagnosed unless screening is performed 5

Alternative Diagnoses to Consider

If Symptoms Persist or Worsen

• Consider pertussis testing if cough becomes paroxysmal with inspiratory whoop 3
• Consider asthma and proceed with spirometry and bronchial provocation testing if cough becomes nocturnal or associated with wheezing 3
• Evaluate for other respiratory pathogens or non-infectious causes based on clinical presentation 1