COVID-19 & SARS-CoV-2
From spike-ACE2 entry to when steroids actually help
Virology and cell entry
Classification. SARS-CoV-2 is an enveloped, positive-sense single-stranded RNA virus in genus Betacoronavirus (family Coronaviridae). Its ~30-kb genome is among the largest of any RNA virus. It has four structural proteins: spike (S), envelope (E), membrane (M) and nucleocapsid (N). The club-shaped spike projections form the crown (corona) seen on electron microscopy.
Replication. A positive-sense genome acts directly as mRNA. Host ribosomes translate it into a replicase polyprotein, which viral proteases, including the main protease, cut into working enzymes such as the RNA-dependent RNA polymerase (RdRp, nsp12). Both the main protease and RdRp are drug targets.
Entry. The receptor-binding domain of the spike S1 subunit attaches to host ACE2 on respiratory epithelium and type II alveolar cells. The host serine protease TMPRSS2 then cleaves spike to expose S2, which drives membrane fusion. Endosomal cathepsin L is an alternative priming route.
- Spike S1 + ACE2Receptor binding
- TMPRSS2 primingCleaves spike and exposes S2
- Membrane fusionViral entry
- +ssRNA translatedRdRp replicates the genome
- Virion assemblyRelease and spread
ACE2 is also the receptor for SARS-CoV-1 and the common-cold coronavirus NL63; MERS-CoV uses DPP4 (CD26) instead.
Transmission, presentation and risk
Transmission. Spread is chiefly by respiratory droplets and fine aerosols; fomites play a minor role. Median incubation is ~5 days (range 2–14). Infectivity peaks near symptom onset, and presymptomatic and asymptomatic people account for substantial spread.
Presentation. Typical symptoms are fever, dry cough, fatigue, dyspnea, myalgia, headache and sore throat, along with the relatively characteristic anosmia and ageusia (loss of smell and taste). GI symptoms such as diarrhea occur. The course ranges from asymptomatic to critical illness. Some patients feel well despite low oxygen saturation, then deteriorate in the second week as the inflammatory phase begins.
Risk factors. Older age is the strongest predictor of severe disease. Others include obesity, diabetes, hypertension and cardiovascular disease, chronic lung or kidney disease, immunocompromise, pregnancy and male sex.
Severe disease
ARDS. Diffuse alveolar damage with hyaline membranes causes non-cardiogenic pulmonary edema, a PaO2/FiO2 ratio of 300 or less, and bilateral ground-glass opacities on chest CT that are typically peripheral and lower-lobe predominant. Patients may need high-flow oxygen or mechanical ventilation.
Cytokine storm. A hyperinflammatory phase raises IL-6, ferritin, CRP and LDH, and lymphopenia is characteristic. High IL-6 and ferritin predict severe disease and death and are the rationale for immunomodulator therapy. Lymphopenia at admission is a simple bedside marker of worse prognosis.
Hypercoagulability. COVID-19 is prothrombotic: D-dimer is markedly elevated, and DVT, PE, arterial thrombosis and pulmonary microthrombi all increase. Hospitalized patients receive prophylactic anticoagulation (heparin or LMWH), and a rising D-dimer tracks worse outcomes.
Diagnosis and treatment
Testing. Nasopharyngeal RT-PCR, which detects viral RNA, is the gold standard and the most sensitive test. Rapid antigen tests detect the N protein; they are fast and cheap but less sensitive and work best when viral load is high. Serology reflects prior infection or vaccination, not acute disease. Because mRNA, vector and subunit vaccines deliver only spike, anti-N antibodies point to past natural infection.
| Feature | RT-PCR | Rapid antigen |
|---|---|---|
| Detects | Viral RNA | N protein |
| Sensitivity | Highest; gold standard | Lower; best at high viral load |
| Setting | Laboratory, hours | Point of care, minutes |
Match the drug to the phase. Early disease is driven by viral replication, so antivirals work best then. Later damage is inflammatory, so immunosuppression helps only once the patient is hypoxemic.
- ExposureIncubation ~2–14 days (median 5)
- Symptom onsetViral replication peaks
- Days 0–5Antivirals most effective
- Day ~7–10Inflammatory phase; give steroids if hypoxemic
- ARDS or recoveryCytokine storm and VTE risk
Antivirals. Nirmatrelvir inhibits the viral main protease (Mpro/3CLpro). Ritonavir, an HIV protease inhibitor, is added only as a CYP3A4 inhibitor to raise nirmatrelvir levels. The combination (Paxlovid) is oral and is given to high-risk outpatients within 5 days of onset; review the full medication list first, because ritonavir causes many drug interactions. Remdesivir (IV) is a nucleotide analog that inhibits RdRp, and molnupiravir is an alternative.
Anti-inflammatory therapy. Dexamethasone (6 mg daily for up to 10 days; RECOVERY trial) reduces mortality in patients who need supplemental oxygen or ventilation. It gives NO benefit, and may harm, in mild non-hypoxemic disease. For rapidly progressing inflammation, add tocilizumab (anti-IL-6 receptor antibody) or baricitinib (JAK1/2 inhibitor).
| Drug | Target | Who gets it |
|---|---|---|
| Nirmatrelvir-ritonavir | Main protease; ritonavir boosts via CYP3A4 | High-risk outpatients within 5 days |
| Remdesivir | RNA-dependent RNA polymerase | IV antiviral, early disease |
| Dexamethasone | Broad anti-inflammatory | Hypoxemic patients on oxygen or ventilation |
| Tocilizumab, baricitinib | IL-6 receptor; JAK1/2 | Rapidly progressing inflammation |
| Heparin or LMWH | Coagulation cascade | Thromboprophylaxis in hospitalized patients |
MIS-C, vaccines and other coronaviruses
MIS-C. Multisystem inflammatory syndrome in children appears ~2–6 weeks after SARS-CoV-2 infection, which is often mild. It is Kawasaki-like: persistent fever, rash, conjunctivitis, mucocutaneous and GI symptoms, and cardiac involvement (myocarditis, coronary aneurysms, shock) with high inflammatory markers. Treat with IVIG and steroids.
Vaccines. mRNA vaccines (Pfizer-BioNTech, Moderna) deliver spike-encoding mRNA in lipid nanoparticles; it is translated in the cytoplasm and never enters the nucleus, and the resulting spike protein triggers anti-spike immunity. Adenovirus-vector and protein-subunit (Novavax) vaccines also target spike. Rare myocarditis occurs, mainly in young males.
Other coronaviruses. SARS-CoV-1 (2002–2003) and SARS-CoV-2 (the 2019 pandemic virus) both use ACE2. MERS-CoV, first identified in 2012 with a camel reservoir, uses DPP4 (CD26) and has a much higher case-fatality rate (~35%) than SARS-CoV-2.