Severe COVID-19 Has Two Phases, Suggesting Futility of Seeking Single Therapy
Key findings
- In this study, Massachusetts General Hospital researchers examined lung samples from 23 patients who died of COVID-19
- Viral RNA was high in 11 patients and low or undetectable in the others
- High virus was associated with a shorter disease duration, diffuse alveolar damage, high interferon response and initiation of wound healing and fibrosis; viral clearance was associated with waning interferon response and lung tissue damage
- Viral load varied not only between patients but sometimes between different lung lobes from the same patient
- Determining the peak and nadir of SARS-CoV-2 lung infection may help guide therapy for severe COVID-19
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Interferons are a primary early defense against viruses, and research using human cells suggests SARS-CoV-2, the virus that can cause COVID-19, elicits a robust interferon response that can control viral replication.
Researcher Niyati Desai, MD, former research fellow Azfar Neyaz, MD, and researcher AnnaMaria Szabolcs, MD, PhD, all from the Massachusetts General Hospital Cancer Center; and Angela Shih, MD, of the Department of Pathology at Mass General; and colleagues recently presented a more nuanced view, tying the expression of interferon-stimulating genes to the duration of SARS-CoV-2 infection. Their report, published in Nature Communications, provides insights that could help improve treatment strategies for patients with COVID-19.
Two Phases of COVID-19
The researchers analyzed lung autopsy specimens from 23 patients who died of COVID-19. Viral RNA was high in 11 patients and low or undetectable in the others. Other finding included:
- The high-virus cases were associated with a shorter disease duration, diffuse alveolar damage, high interferon response and initiation of wound healing and fibrosis
- Low-virus cases were more heterogeneous, probably reflecting inherent patient differences in the evolution of host response, but viral clearance was associated with waning interferon response and lung tissue damage
Viral load varied not only between patients but sometimes also between different lung lobes from the same patient.
Cytokine Pathways
The team evaluated several cytokine pathways proposed to be involved in COVID-19 lung damage:
- JAK2, STAT1 and STAT2 were significantly upregulated in high- vs. low-virus cases
- Expression of IL-6 and IL-6 receptor genes was variable and not correlated with viral levels
- IL-22 was undetectable in most samples
Implications for Therapy
Determining the peak and nadir of SARS-CoV-2 lung infection may help guide therapy for severe COVID-19. For example, remdesivir and other antivirals are likely to be of greater benefit in the early phase of the disease when viral levels are high.
Baricitinib, an oral JAK inhibitor, has received emergency use authorization for use in combination with remdesivir in certain hospitalized adults with COVID-19. Given the findings here about the JAK2 pathway, it too may be more effective in the early phase.
Corticosteroid therapy is now standard care for certain hospitalized patients with COVID-19. This recommendation is based on a report in The New England Journal of Medicine in which dexamethasone was associated with reduced 28-day mortality, but only among patients with symptoms for more than seven days. Steroids may not be effective in the early phase of COVID-19.
Tocilizumab, an IL-6 inhibitor, did not prevent intubation or death in a randomized, controlled trial of moderately ill hospitalized patients with COVID-19, also published in The New England Journal of Medicine. However, tocilizumab might have utility in a subset of patients identified by biomarkers rather than by viral load or stage of infection.
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