DHM COVID-19 Clinical Dispatch

Bite-sized, weekly clinical updates
 

Issue #4: SARS-CoV2 and the Inflammatory Response

This week we bring you all the way back to our immunology days as we take a look at the cellular mechanisms of SARS-CoV2 infection and its impact on the host immune response. 

We start with the basic mechanisms of viral entry and replication in the respiratory epithelium, including a new term to us - pyroptosis! - A severely inflammatory cell death.

We then introduce the hypothesized, hyper-inflammatory state of COVID-19 and discuss the mechanisms by which the host response to SARS-CoV2 causes severe disease. 

Our Big Take-away for the week?
SARS-CoV2 appears to be similar to SARS-CoV and MERS in its mechanism for viral entry, replication and induction of cell death. For reasons not entirely clear, some patients experience a disordered inflammatory response with high levels of inflammatory markers.  And though corticosteroids have not been effective in COVID-19, some (very early) promising data are emerging to support IL-6 blockade. 

Also, be sure to check out "What We're Reading," our weekly literature round-up at the end. Happy Thursday!

- The COVID Clinical Working Group

Getting Basic - Cellular Mechanisms of COVID

Figure 1. SARS-CoV-2 infects cells of the respiratory tract that express the ACE2 receptor. Viral replication triggers cell death through pyroptosis, leading to activation of inflammatory pathways. Figure adapted from: Tay, et al. Nature Reviews Immunology

Unlike common coronaviruses that only infect the upper respiratory tract, SARS-CoV-2 (as well as SARS-CoV and MERS) is capable of infecting the lower respiratory tract. SARS-CoV-2 enters cells via the ACE2 receptor, which is expressed on multiple cells throughout the body, and multiple types of cells found in airway. Specifically, this viral entry into target cells is mediated by the Spike (S) protein. Two ongoing areas of therapeutic investigation are focused on targeting the ACE2 receptor or the viral S protein.

Some hypothesize that cell death of SARS-CoV2 infected cells is mediated by a specific pathway called pyroptosis. In contrast to apoptosis, which is generally non-inflammatory, pyroptosis is pro-inflammatory and was first described in Salmonella-infected cells in 2001. Among cytokines induced in this pathway is interleukin-1ẞ, high levels of which have been found in patients with COVID infection.

It’s 2AM: Do You Know Where Your T-Cells Are?

In a recent Nature Reviews Immunology article, Tay et al describe what is hypothesized about the host immune response to SARS-CoV-2. 

The figure below illustrates what is understood about functional and dysfunctional immune response to viral infection. Cell death releases attracts monocytes, macrophages and T cells, promoting further inflammation and establishing a pro-inflammatory feedback loop. 

In a defective immune response (left side) this may lead to further accumulation of immune cells in the lungs, causing overproduction of pro-inflammatory cytokines (IFN-y, IL6, IL2, IP10), which eventually damages the lung infrastructure. The resulting cytokine storm circulates to other organs, leading to multi-organ damage. In addition, non-neutralizing antibodies produced by B cells may enhance SARS-CoV-2 infection through antibody-dependent enhancement (ADE), further exacerbating organ damage. 

Alternatively, in a healthy immune response (right side), the initial inflammation attracts virus-specific T cells to the site of infection, where they can eliminate the infected cells before the virus spreads. Neutralizing antibodies in these individuals can block viral infection, and alveolar macrophages recognize neutralized viruses and apoptotic cells and clear them by phagocytosis. Altogether, these processes lead to clearance of the virus and minimal lung damage, resulting in recovery.

Fight that Aggression with Immunosuppression

Can we target this inflammatory response to improve outcomes for severe COVID-19?

Maybe! Blunting this dysfunctional immune response is an attractive therapeutic target to reduce the severe lung injury in COVID. The broad approach, corticosteroids, have been trialed in SARS and MERS without clear benefit and are associated with higher risk for mortality in influenza, according to a recent meta-analysis. Recent approaches focus on targeting key inflammatory mediators, such as IL-6 (seen below). Its activity can be inhibited with the monoclonal antibody tocilizumab, which binds the IL-6 receptor. An early single-center study on tocilizumab in COVID-19 is our Paper of the Week!

Signal transduction events downstream of the IL-6 receptor promote a hyperinflammatory state. Tocilizumab blocks that signaling by binding to the IL-6 receptor and preventing IL-6 from activating it, thereby inhibiting the downstream signal transduction. Figure from: Fu, et al. J Trans Med.

Quick Lit - One-Page Literature Review

What We're Reading

Here are the articles that our team is reading this week, which are particularly relevant to this issue. To see more in-depth summaries please head over to our Literature Database!

• “COVID-19 infection: the perspectives on immune responses” (Shi et al, Nature, March 23): This perspective piece highlights the proposed two-phase immune response during COVID-19 infection and suggests potential therapies tailored towards each of these phases. 

• “COVID-19: consider cytokine storm syndromes and immunosuppression” (Mehta et al, Lancet, March 28):  This correspondence letter recommends identifying and treating hyperinflammation, such as secondary HLH, in severe COVID-19.

• “Dysregulation of immune response in patients with COVID-19 in Wuhan, China” (Qin et al, Clin Infect Dis, March 12): This single-center retrospective study from China stratifies the inflammatory markers of 452 COVID patients by disease severity. Severe cases were found to have relatively higher levels of inflammatory cytokines (IL-2, IL-6, IL-8, IL-10, TNFa) and lower lymphocyte counts, suggesting immune dysregulation in severe COVID-19.

• “SARS-CoV-2 and viral sepsis” (Li et al, Lancet, April 2020): This review article provides an overview of what is understood and still unknown about the cellular mechanisms of SARS-CoV-2 infection. When dysregulated, the adaptive immune response is not effectively initiated in organ systems throughout the body. Whether this is due to “direct virus-induced tissue damage, systemic cytokine storm, or the synergistic effects of both,” remains an open question. 

• “Clinical and immunological features of severe and moderate coronavirus disease 2019” (Chen et al, JCI March 2020): This retrospective study demonstrates that in SARS-CoV-2 infection, dysregulated number of immune cells, especially CD4 and CD8 T cells, and their associated pro-inflammatory cytokines, may serve as important and potentially therapeutically relevant biomarkers of systemic inflammation and severe disease.

• “Effective Treatments of Severe COVID-19 Patients with Tocilizumab” (Xu, et al, PNAS April 2020): Toclizumab is a recombinant humanized antihuman IL-6 receptor that is typically used in treatment for rheumatoid arthritis. In this prospective, nonrandomized, noncontrolled experimental study, it was administered to 20 patients with severe or critical COVID19 diagnosed over a 9-10 day period. These patients were all discharged an average of 15.1 days after drug administration with improvements in oxygen requirement, fever, lymphocyte%, and CRP. 

• “Pharmacologic Treatments for Severe Coronavirus Disease 2019” (Sanders et al, JAMA April 2020):  This review article on pharmacologic treatments for COVID-19 covers the rationale and evidence of potential drug targets based on the virus life cycle, including hydroxychloroquine/chloroquine, lopinavir/ritonavir, remdesivir, corticosteroids and IL-6 inhibitors. Given lack of evidence around therapies to date, this review serves mainly to describe the proposed mechanism and early evidence. 

Test Yourself!

Can you answer this question from last issue’s article of the week?

In the Tang et al retrospective analysis reviewed last week, anticoagulant therapy was associated with lower mortality for which group of patients?

1. All patients with COVID-19

2. All patients with severe COVID-19

3. All patients with COVID-19 and malignancy

4. All patients with COVID-19 and moderate coagulopathy (D-dimer >2-fold upper limit of normal)

5. All patients with severe COVID-19 and severe coagulopathy (D-dimer >6-fold ULN or SIC score ≥4)

See the answer here!

Links

Questions, thoughts, insights? Share them here! Clinical Knowledge Portal

Prior Dispatches:

Issue 1:  GI symptoms in COVID

Issue 2: Predictors of Severe COVID Disease

Issue 3: Hypercoagulability in COVID-19