SARS-CoV-2: a storm is raging (original) (raw)
The two coronaviruses that have been known to cause fatal pneumonia, SARS-CoV and MERS-CoV, are associated with rapid virus replication, an elevation of proinflammatory cytokines, and inflammatory cell infiltration (16). In SARS-CoV infection, it was immune dysregulation, rather than the level of peak viremia, that induced an insufficient type I interferon (IFN) response (too little and too late), aberrant proinflammatory cytokine secretion by alveolar macrophages, and subsequent CD4+ and CD8+ T cell dysfunction (17). Little is known about the determinants of disease severity and immune dysregulation in SARS-CoV-2 infection in humans. The study by Chen et al. (15) provides a window for us to examine the immune dysregulation at 7–10 days of onset, when the cytokine storm rages and the respiratory distress peaks.
Cytokines and chemokines have long been understood to have an important role in immunity and immunopathology, but dysregulated and exuberant immune responses have been shown to potentially cause lung damage and diminished survival. In SARS-CoV-2–infected individuals, interleukin 6 (IL-6), IL-10, and tumor necrosis factor α (TNF-α) surge during illness and decline during recovery. Patients requiring ICU admission have significantly higher levels of IL-6, IL-10, and TNF-α and fewer CD4+ and CD8+ T cells (18). Further, the level of IL-6, IL-10, and TNF-α inversely correlates with CD4+ and CD8+ T cell count (18), confirming previous animal studies showing that it is the cytokine storm that dampens adaptive immunity against SARS-CoV infection (17). In this issue of the JCI, Chen and colleagues (15) present one of the first studies comparing the immunological characteristics between severe and moderate COVID-19. Despite an increase in white blood cell count, CD4+ and CD8+ T cell counts were significantly decreased (P = 0.018 and 0.035, respectively) in severe COVID-19 patients. Serum cytokine levels and analysis of lymphocyte composition on admission suggest that SARS-CoV-2 infection is associated with lymphopenia (particularly in CD4+ T cells and CD8+ T cells but not in B cells), overproduction of cytokines (IL-6, soluble IL-2 receptor [IL-2R], IL-10, and TNF-α), and decreased IFN-γ expression in CD4+ T cells in severe COVID-19, which correlated with disease severity of COVID-19 (Figure 1). Levels of IL-6, IL-2R, IL-10, and TNF-α were mildly elevated or within the normal range in moderate cases, but markedly elevated in most of the severe cases. These cytokines are likely produced by highly inflammatory macrophages that have been implicated in cytokine storm (19). The total lymphocyte counts, and specifically CD4+ T cells and CD8+ T cells, were slightly lower in moderate cases and significantly decreased in severe COVID-19 (15). Most importantly, the authors found that IFN-γ expression in CD4+ T cells was lower (although not statistically significant, P = 0.063) in patients with severe versus moderate COVID-19. This study demonstrates that cytokine storm is associated with COVID-19 disease severity, likely through increased pulmonary pathology, T cell depletion, and CD4+ T cell dysfunction. These findings are in line with those of Diao and colleagues, which suggested that in addition to reduction in T cell counts, surviving T cells appear functionally exhausted (18).
Cytokine storm and T cell lymphopenia is associated with COVID-19 severity. SARS-CoV-2 infection causes COVID-19. Compared with uninfected individuals (left panel), moderate COVID-19 cases exhibit an increase in IL-6 and a decrease in total T lymphocyte counts, particularly CD4+ T cells and CD8+ T cells (middle panel). Severe COVID-19 cases have further increased production of IL-6, IL-2R, IL-10, and TNF-α, while total T lymphocytes, particularly CD4+ T cells and CD8+ T cells, and IFN-γ–expressing CD4+ T cells markedly decrease (right panel). The level of cytokine storm and T cell lymphopenia is associated with pulmonary damage, respiratory distress, and unfavorable outcome. ARDS, acute respiratory distress syndrome; CRP, C-reactive protein; LDH, lactate dehydrogenase.