The Longitudinal Immune Response to Coronavirus Disease 2019: Chasing the Cytokine Storm

Abstract

The clinical progression of the severe acute respiratory syndrome coronavirus 2 infection, coronavirus 2019 (COVID-19), to critical illness is associated with an exaggerated immune response, leading to magnified inflammation termed the "cytokine storm." This response is thought to contribute to the pathogenicity of severe COVID-19. There is an initial weak interferon response and macrophage activation that results in delayed neutrophil recruitment leading to impeded viral clearance. This causes prolonged immune stimulation and the release of proinflammatory cytokines. Elevated levels of inflammatory markers in COVID-19 (e.g., d-dimer, C-reactive protein, lactate dehydrogenase, ferritin, and interleukin-6) are reminiscent of the cytokine storm seen in severe hyperinflammatory macrophage disorders. The dysfunctional immune response in COVID-19 also includes lymphopenia, reduced T cells, reduced natural killer cell maturation, and unmitigated plasmablast proliferation causing aberrant IgG levels. The progression to severe disease is accompanied by endotheliopathy, immunothrombosis, and hypercoagulability. Thus, both parts of the immune system-innate and adaptive-play a significant role in the cytokine storm, multiorgan dysfunction, and coagulopathy. This review highlights the importance of understanding the immunologic mechanisms of COVID-19 as they inform the clinical presentation and suggest potential therapeutic targets.

Analysis of respiratory and systemic immune responses in COVID-19 reveals mechanisms of disease pathogenesis

“…Reduced HLA-DR expression indicative of immature monocytes has been identified in blood myeloid cells in severe COVID-19 (Schulte-Schrepping et al, 2020;Silvin et al, 2020) and may derive from inflammation-induced mobilization of immature monocytes from the bone marrow, termed emergency myelopoiesis (Schultze et al, 2019;Shi et al, 2011;Venet et al, 2020). While a cytokine storm marked by elevated levels of serum cytokines is implicated in pathogenesis of severe COVID-19 and emergency myelopoiesis (Chau et al, 2020;Copaescu et al, 2020;Lucas et al, 2020;Schulte-Schrepping et al, 2020), our results show that inflammatory cytokines detected in the blood lacked CCL2 and other chemokines, which direct recruitment of multiple immune cell types. Our findings rather suggest that pro-inflammatory cytokines emanating from the respiratory tract recruit circulating inflammatory monocytes to the lungs and perpetuate lung damage.…”

Saddle pulmonary embolism and clot in transit in COVID-19 infection: a case report of catastrophic venous thromboembolism

“… 5 Usually these complications were seen in the second phase of the illness (7–10 days after symptom onset), triggered by a hyper-immune response associated with a markedly elevated D-dimer. 6 Along with this was a newly described ‘COVID associated coagulopathy’ which led to increasingly observed thrombosis due to inflammation-induced coagulopathy and was associated with a poor prognosis. 1 , 2 Anticoagulation with heparin (mostly prophylactic dosing) appeared to confer a lower mortality in a subset of patients with very severe COVID-19 who had extreme elevations of D-dimer.…”

Extracorporeal Blood Purification in moderate and severe COVID-19 patients: a prospective cohort study

“…Possibly a case of semantics; the immunological disturbances in COVID-19 encompass both innate and adaptive arms [46, 4, 49] and clinically possess many hallmarks of cytokine storm syndrome [50, 51].…”