Cytokine storm and the prospects for immunotherapy with COVID-19

THREE STAGES OF DISEASE

To tackle this problem, we must first examine what is known about the interaction between the pathogen and the host immune system. SARS-CoV-2 is spread by droplets that come into contact with mucous membranes. Interestingly, not all individuals who are exposed acquire the infection. Once a person is infected, the disease progresses through 2 or 3 main stages (Figure 1).

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Figure 1

Three stages of COVID-19 disease.

Stage 1 is an asymptomatic or paucisymptomatic incubation period in which there is a high level of viral shedding in the upper respiratory tract. Implicitly, this stage marks engagement of the innate immune system as the initial mode of host defense.

Stage 2 is a period of nonsevere symptomatic illness in which viral loads peak approximately 5 days after symptom onset.¹ At this stage adaptive immunity is engaged, allowing development of specific T- and B-cell responses required to end the infectious process. The disease ends in stage 2 in approximately 80% of infected individuals.

Finally, stage 3 is characterized by severe respiratory illness with progressive pneumo-nitis that may or may not lead to respiratory failure, which, in its final stages causes diffuse alveolar damage. Stage 3 is also frequently attended by progressive fever, multiorgan dysfunction, hypercoagulability, and shock.²

Immunologically, SARS-CoV-2 infects cells that express the angiotensin-converting enzyme 2 receptor, including cells of the respiratory tract, endothelial cells, and likely hematopoietic cells, including macrophages. With full engagement of the integrated immune response, the development of neutralizing anti bodies is believed to be a critical event in recovery as well as the gene ration of virus-specific T-cell responses, ultimately leading to viral clearance.³

Attempts to correlate the stages of clinical disease described above with SARS-CoV-2 viral loads from respiratory secretions, blood, and tissues have yielded conflicting results. Some patients with advanced disease have high viral loads while others do not.⁴

WHY DO SOME PATIENTS GO ON TO STAGE 3?

Why host antiviral defenses fail and why some patients go on to stage 3 is not yet clear, but attempts to reconcile these findings suggest that this progression may be driven by ongoing viral infection. In support of this hypothesis is a recent study documenting that SARS-CoV-2 infection actually induces a low interferon response, an immune pathway critical for antiviral defense, while at the same time inducing a strong inflammatory response, thus creating a perfect storm of continued viral replication and unbridled inflammation.^5,6

The clinical state of patients with stage 3 disease is characterized by hypercytokinemic inflammation. This syndrome has variably been referred to as “cytokine storm.” The cy-tokine storm of COVID-19 bears similarities to other conditions that are also referred to under this umbrella, including primary hemophagocytic lymphohistiocytosis (HLH), as well as secondary forms such as macrophage activation syndrome (MAS) and secondary HLH, which are often encountered in the setting of autoimmunity, cancer, or viral infections.^7,8 In COVID-19, and unlike in MAS or secondary HLH, the primary target organ is the lung, leading to an acute respiratory distress syndrome. While stage 3 COVID-19 is not secondary HLH or MAS, it does share features both clinically and pathologically.⁵

Recently, a variant of this cytokine storm has been described in children with COVID-19 and has been dubbed multisystem inflammatory syndrome in children (MIS-C).⁹

Laboratory features are quite similar among these disorders, with marked elevations of acute-phase reactants (eg, C-reactive protein, ferritin), lymphopenia, coagulation defects, and elevated levels of numerous inflammatory cytokines; prominent among them are interleukin 6 (IL-6), IL-1, IL-2, IL-7, IL-17, granulocyte macrophage-colony stimulating factor (GM-CSF), and tumor necrosis factor (TNF).¹⁰

Why there is an increased incidence of this inflammatory late-stage complication in select young individuals and more frequently in patients who are elderly and in those with comorbidities is poorly understood. Interestingly, though, in a study attempting to further understand why otherwise-healthy individuals can die from viral illness, 30% of patients dying from H1N1 influenza were found to carry single copies of genes commonly encountered in patients with HLH,¹¹ suggesting a link between immune predisposition to HLH and outcome. We can also postulate that the chronic low-grade inflammation and an increase in self-reactivity that characterize the aging immune system also may contribute. Importantly, recent studies have shown that immunologic aging proceeds at different rates in different individuals; thus, mere chronologic age is, not surprisingly, a relatively crude predictor of COVID-19 progression.¹²

IMPLICATIONS FOR THERAPY

From a therapeutic perspective, there is a clear need for an effective antiviral agent that can prevent viral infection in exposed individuals and limit tissue damage in those with established disease (stages 1 and 2).

In stage 3, in the absence of any effective antiviral therapy, we are relegated to supportive care. It is at this stage that the experimental use of agents designed to limit tissue damage driven by uncontrolled inflammation is being investigated. Given the similarities between stage 3 COVID-19 and other hypercytokinemic states, a variety of nonspecific immunosuppressive strategies have been proposed, such as glucocorticoids, hydroxychloroquine, colchicine, and other immunomodulators, as well as Janus kinase inhibitors and a number of targeted therapies directed at pivotal cytokines (Table 1). For now, the experience with such agents largely consists of anecdotal case reports and small clinical trials.¹³

As of this writing, more than 900 clinical trials of various therapeutics for COVID-19 are registered at clinicaltrials.gov. Agents that have been proposed or are in use include anti-IL-1, anti-IL-6, anti-GM-CSF, and anti-TNF drugs, and Janus kinase inhibitors. A conceptual framework of such therapies is displayed in Table 1.