The advent of a global pandemic.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has infected over 18 million people globally, as of August 2020. Of those infected, more than 700,000 people have been killed by coronavirus disease 2019 (COVID-19). Our current understanding is that the crisis began with several cases of pneumonia in Wuhan, China in early December 2019 (1). The World Health Organization (WHO) declared COVID-19 a public health emergency of international concern on January 30, 2020. COVID-19 was subsequently declared a pandemic by the WHO Director General on March 11. By August 2020, the WHO-documented distribution of COVID-19 infections is as follows: 9.9+ million cases in the Americas, 3+ million cases in Europe, 2+ million in South-East Asia, 1.5+ million cases in the Eastern Mediterranean, 800,000+ cases in Africa, and 300,000+ cases in the Western Pacific.
Efforts to contain SARS-CoV2 are stymied by the fact that many of the infected are asymptomatic. One study estimates that up to 45% of those infected are asymptomatic (2). Symptomatic individuals have an onset between 2 and 14 days after exposure to the virus (3). Relatively mild symptoms described by the Centers for Disease Control (CDC) include: fever, chills, shortness of breath or difficulty breathing, fatigue, muscle or body aches, headaches, loss of the sense of smell, sore throat, congestion or runny nose, nausea or vomiting and diarrhea. More severe responses to infection can progress from cytokine release syndrome (CRS), also known as the “cytokine storm”, to acute respiratory distress syndrome (ARDS), multiorgan failure, and death. CRS is thought to be an important step in the progression to ARDS in SARS-CoV2, SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) infections (1,4). The clinical presentation of CRS ranges from mild fever, arthralgia, myalgia to high fever, uncontrolled systemic inflammatory responses, vascular leakage to disseminated intravascular coagulation and organ failure among other symptoms (5). ARDS is formally defined as a respiratory failure within a week of a known insult that is characterized by bilateral opacities that are not fully explained by cardiac function or volume overload, effusion (fluid buildup), lung collapse, nodules and oxygenation below a specific threshold (6). The death rate associated with ARDs is 40%.
Biology of SARS-CoV2 and COVID-19
SARS-CoV2 is a member of the Coronaviridae family, specifically the Coronavirinae subfamily that includes 4 genera: α-coronavirus, β-coronavirus, γ-coronavirus and δ-coronavirus (7). SARS-CoV2, SARS-COV and MERS-CoV are all RNA β coronaviruses. SARS-CoV2 shares 80% sequence identity with SARS-COV and 50% sequence identity with MERS-CoV (1,8). SARS-COV emerged from China in 2002 and spread globally, infecting over 8,000 and killing more than 700 people (8,9). MERS-CoV emerged from Saudi Arabia in 2012 and was responsible for over 2,000 infections and over 800 deaths globally (9). All three coronaviruses cause severe respiratory disease in humans. Although the SARS-CoV2 symptoms are milder and the mortality rate is thought to be lower (~3%-6.7%) than SARS-CoV (9.6%) and MERS-CoV (35%), it has a faster transmission rate in humans (7,8,10).
SARS-CoV2 and SARS-CoV enter cells via the angiotensin-converting enzyme-related carboxypeptidase (ACE2) receptor, which is expressed on cardiopulmonary and hematopoietic tissues. (1,11-13). SARS-CoV2 has been reported to have a 10-20 times higher binding affinity for ACE2 than SARS-CoV (7). Receptor-mediated viral entry requires priming of the S1 region of the viral spike (S) by the transmembrane serine protease 2 (TMPRSS2) (8,11,12). The S1 region of the viral spike binds to ACE2 followed by S2 subunit-mediated fusion of the viral and cellular membrane. After membrane fusion, ACE2 and SARS-CoV2 are endocytosed into the cell. SARS-CoV2 internalization has been correlated with increased production of proinflammatory cytokines such as nuclear factor kappa B (NF-κB) and interleukin 6 (IL-6) (8). IL-6 signals through a cis signaling pathway and a trans signaling pathway (13). The cis signaling pathway involves the binding of IL-6 to a complex containing IL-6 receptor (IL-6R) and glycoprotein 130 (gp130). This stimulates the downstream activation of the Janus Kinase/Signal Transducer and Activator of Transcription 3 (JAK/STAT3) pathway. Activation of this pathway can promote CRS via activation of innate and acquired immune mechanisms, including T cell differentiation and B cell activation and differentiation. In the trans signaling pathway, IL-6 forms a complex with soluble IL-6R and gp130 on many cell membranes due to the gp130’s ubiquitous expression. This propagates the CRS-stimulating signal to cells that do not express membrane IL-6R. Other cytokines and growth factors that are altered in response to the trans signaling pathway include increased vascular endothelial growth factor (VEGF), monocyte chemoattractant protein 1 (MCP-1), IL-8, and decreased E-Cadherin in endothelial cells (13). As alluded to previously, CRS is characterized by the release of excessive amount of proinflammatory cytokines such as interferons, interleukins, chemokines, Colony stimulating factors, and tumor necrosis factor alpha, that are harmful to the host (8). Quantitative real time PCR studies of intensive care unit COVID-19 patients have documented elevated transcripts of a variety of cytokines including: IL-2, IL-7, IL-10, G-CSF, IP-10, MIP-1A, TNF and CXCL-8 (14).
Methods for assessing the cytokine storm
A National Cancer Institute scale is commonly used to grade the severity of CRS in patients (5). Other scales include: the Penn Grading Scale, Common Terminology Criteria for Adverse Events (CTCAE) v4.0, Lee et.al, 2014 and the MD Anderson Cancer Center (MDACC) scale (15). Grade 1 is characterized by fever. Symptoms are mild and not life threatening. Symptoms may or may not require treatment depending on the scale used. Grade 2 is characterized by hypotension that is responsive to fluids or low dose vasopressors. Symptoms are more moderate at this stage and may require hospitalization. All scales suggest an intervention. Organ toxicities may also be observed at this stage. Grade 3 is characterized by hypotension that requires high dose vasopressors, hypoxia and organ toxicities. Symptoms are more severe at this stage and require more aggressive interventions. Finally, grade 4 CRS is severe enough to require ventilation. CRS complications at this grade are life threatening.
Efficacy of COVID-19 therapeutic candidates
Circulating IL-6 has been correlated with COVID-19 severity in patients (16). Given the prominent role of IL-6, it is no surprise that tocilizumab, a human monoclonal anti-IL-6R antibody has been administered to patients with severe COVID-19 (17). Tocilizumab is approved for the treatment of CRS triggered by CAR T cell therapy by the Food and Drug Administration (13). Early data indicated that tocilizumab is associated with a shorter duration of vasomotor support and ventilation, shorter median time to recovery, improvement in CRS grade and computerized tomography imaging results in COVID-19 patients (17, 18). However, more recent data from Phase 3 clinical trials indicate that the human IL-6R antibodies tocilizumab and sarilumab are not associated with an overall benefit in COVID-19 patients. The Phase 3 sarilumab trial was recently halted because it failed to reach primary and secondary endpoints (19). A Phase 3 (global randomized, double blind, placebo controlled) tocilizumab trial was also halted because it failed to meet its primary endpoint of improved clinical status in patients hospitalized with severe COVID-19 pneumonia (20).
The corticosteroid dexamethasone, which is known for its anti-inflammatory and immunosuppressive effects, has recently been shown to reduce the mortality of COVID-19 patients on ventilators by one-third according to preliminary data presented to the WHO (21). Dexamethasone is now recommended standard of care for “patients with COVID-19 who are mechanically ventilated and in patients with COVID-19 who require supplemental oxygen but who are not mechanically ventilated” (22,23). However, like tocilizumab, the anti-malarial drug hydroxychloroquine has fallen out of favor and clinical trials have been halted due to lack of efficacy (24). As of mid-August 2020, there are over 3,000 COVID-19-related studies listed on the clinicaltrials.gov website, suggesting many other interventions are still being evaluated. Taken together, the rapid global transmission and high mortality rate of those infected underscores the urgent need to understand COVID’s mechanism of action and quickly pivot when a vaccine or therapeutic candidate is not efficacious.
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