1. Clinical Evaluation & Initial Diagnosis

Early recognition of emerging viral infections hinges on a triad of identifying key symptoms, estimating pretest probability based on clinical and epidemiological context, and applying structured triage criteria to prioritize care.

A. Signs & Symptoms

• Fever: A common presenting sign, but its absence does not rule out significant disease. “Silent hypoxia” can occur in afebrile patients.
• Cough & Dyspnea: A dry cough is typical. The onset or worsening of dyspnea, often 5–8 days after initial symptoms, is a red flag for clinical progression.
• Extrapulmonary Manifestations: Systemic effects are common and include myalgias, gastrointestinal complaints (diarrhea, nausea), thrombotic events (pulmonary embolism, deep vein thrombosis), myocarditis, and specific syndromes like Multisystem Inflammatory Syndrome in Children (MIS-C).

B. Differential Diagnosis & Pretest Probability

• Differential Diagnoses: Must consider community-acquired bacterial pneumonia, heart failure exacerbation, COPD or asthma flares, and noninfectious causes of Acute Respiratory Distress Syndrome (ARDS).
• High Pretest Probability: Factors increasing suspicion include known contact with a confirmed case, presence during a local surge, and patient risk factors such as age >60, obesity, diabetes, or immunosuppression.
• Low Pretest Probability: Suggested by a lack of known exposure, atypical clinical features, and low community prevalence.

C. Triage Criteria

• Severe Acute Respiratory Infection (SARI): A key syndromic definition, often defined as fever and cough plus either a respiratory rate >30 breaths/minute or an oxygen saturation (SpO₂) ≤90% on room air.
• Early Warning Scores: Tools like the National Early Warning Score 2 (NEWS2) are invaluable for standardized in-hospital monitoring and triggering rapid response for deteriorating patients.

2. Molecular Diagnostics

Reverse transcription-polymerase chain reaction (RT-PCR) is the gold standard for acute diagnosis, while rapid antigen and serology tests serve important adjunctive roles in specific clinical and public health settings.

A. RT-PCR

• Performance: High analytic sensitivity (95–99%), but clinical sensitivity can be lower. False-negative rates can be up to 29% if samples are collected too early or late in the disease course or from an inadequate site.
• Cycle Threshold (Ct) Value: Inversely correlates with viral load. A lower Ct value implies a higher viral burden. A Ct >30 often suggests low or non-viable virus and reduced infectivity.
• Specimen Yield: The choice of specimen is critical. Bronchoalveolar lavage (BAL) has the highest yield (~95%) in patients with pneumonia, followed by nasopharyngeal (NP) swabs (63–73%). Oropharyngeal (OP) swabs generally have a lower yield.
• Repeat Testing: If the initial RT-PCR is negative but clinical suspicion remains high, repeat testing in 24–48 hours is recommended.

B. Rapid Antigen Tests

• Performance: Lower sensitivity (50–80%) compared to RT-PCR, especially at lower viral loads (Ct >25), but very high specificity (>97%).
• Clinical Use: Best suited for triage in high-prevalence settings or for serial screening programs. A negative result in a symptomatic, high-risk patient should be confirmed with RT-PCR.

C. Serology

• Timing: IgM and IgG antibodies typically appear 7–14 days after symptom onset.
• Clinical Use: Not useful for diagnosing acute illness. Key roles include seroprevalence studies, retrospective confirmation of infection, and screening convalescent plasma donors.

3. Imaging Modalities

Chest imaging is crucial for quantifying the extent of pneumonitis, identifying complications, and helping to predict the clinical trajectory.

A. Chest X-Ray (CXR)

• Typical Findings: Bilateral, peripheral, and lower-zone predominant opacities are characteristic.
• Sensitivity: Moderate, around 69% in hospitalized patients, and may be normal early in the disease course.
• Utility: Portable CXR units are essential for minimizing patient transport and cross-contamination risks in hospital settings.

B. Chest CT

• Typical Findings: The classic pattern includes bilateral, multilobar, and peripherally distributed ground-glass opacities (GGOs), often with subsequent consolidation.
• Prognostic Value: CT severity scores, which quantify the percentage of lung involvement, strongly correlate with the need for ICU admission. Involvement of >50% of the lung parenchyma is a marker of poor prognosis.

C. Artificial Intelligence (AI) & Scoring

Emerging AI-driven software can provide automated quantification of lung involvement and other severity indices, potentially standardizing interpretation and improving workflow.

4. Biomarkers & Laboratory Parameters

Inflammatory and coagulation markers are essential for refining prognosis, detecting complications like bacterial coinfection, and guiding therapeutic decisions.

5. Severity Classification & Risk Stratification

Standardized scores and criteria are vital for effective communication, guiding resource allocation, and determining the appropriate level of care.

A. WHO Clinical Progression Scale

This 11-point ordinal scale (0-10) is widely used in clinical trials and for monitoring. It is based on the level of oxygen and organ support required, providing a simple yet powerful way to track patient status.

B. Algorithmic Triage Pathway

An integrated approach combines clinical signs, diagnostics, and severity scores to direct patients to the most appropriate care setting. This ensures that resources are used efficiently and high-risk patients are identified early.

6. Clinical Decision Points

Timely and appropriate actions based on key clinical triggers are essential for improving outcomes. This involves knowing when to escalate care, when to reassess, and when to initiate specific therapies.

A. Escalation Triggers

• Worsening Hypoxemia: A SpO₂/FiO₂ ratio <300, or any increase in supplemental oxygen requirements.
• Rising Inflammatory Markers: A rapidly rising D-dimer (e.g., >2 µg/mL) or CRP.
• Clinical Deterioration: Development of hypotension, altered mental status, or oliguria.

B. Therapy Timing

• Antivirals (e.g., Remdesivir): Most effective when initiated early. For hospitalized patients requiring low-flow oxygen, initiate within 10 days of symptom onset.
• Oral Antivirals (e.g., Nirmatrelvir/ritonavir): For high-risk ambulatory patients, must be initiated within 5 days of symptom onset to be effective.

C. Isolation Discontinuation

• Mild-to-Moderate Illness: Generally, ≥10 days after symptom onset plus at least 24 hours fever-free without the use of fever-reducing medications.
• Severe/Immunocompromised: May require longer periods, up to 20 days, or a test-based strategy (e.g., negative antigen tests) to confirm clearance of infectious virus.