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What Are the Recent Findings on COVID-19 Induced Inflammation?

  • Authors: WebMD Health News Author: Ralph Ellis; CME Author: Charles P. Vega, MD
  • CME / ABIM MOC / CE Released: 5/13/2022
  • Valid for credit through: 5/13/2023
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Target Audience and Goal Statement

This activity is intended for primary care physicians, infectious disease specialists, nurses, pharmacists, physician assistants, and other members of the healthcare team who care for patients at risk of COVID-19.

The goal of this activity is for learners to be better able to assess the role of monocytes in the pathogenesis of SARS-CoV-2.

Upon completion of this activity, participants will:

  • Distinguish important elements of the molecular response to infection
  • Analyze the role of monocytes in infection with SARS-CoV-2
  • Outline implications for the healthcare team


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WebMD Health News Author

  • Ralph Ellis

    Freelance writer, Medscape


    Disclosure: Ralph Ellis has disclosed no relevant financial relationships.

CME Author

  • Charles P. Vega, MD

    Health Sciences Clinical Professor of Family Medicine
    University of California, Irvine School of Medicine


    Disclosure: Charles P. Vega, MD, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: GlaxoSmithKline; Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

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  • Leigh A. Schmidt, MSN, RN, CMSRN, CNE, CHCP

    Associate Director, Accreditation and Compliance
    Medscape, LLC


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  • Esther Nyarko, PharmD

    Director, Accreditation and Compliance
    Medscape, LLC


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  • Yaisanet Oyola, MD

    Associate Director, Accreditation and Compliance
    Medscape, LLC


    Disclosure: Yaisanet Oyola, MD, has no relevant financial relationships.

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What Are the Recent Findings on COVID-19 Induced Inflammation?

Authors: WebMD Health News Author: Ralph Ellis; CME Author: Charles P. Vega, MDFaculty and Disclosures

CME / ABIM MOC / CE Released: 5/13/2022

Valid for credit through: 5/13/2023


Note: The information on the coronavirus outbreak is continually evolving. The content within this activity serves as a historical reference to the information that was available at the time of this publication. We continue to add to the collection of activities on this subject as new information becomes available. It is the policy of Medscape Education to avoid the mention of brand names or specific manufacturers in accredited educational activities. However, manufacturer names related to COVID-19 vaccines may be provided in this activity to promote clarity. The use of manufacturer names should not be viewed as an endorsement by Medscape of any specific product or manufacturer.

Clinical Context

The pathology associated with the SARS-CoV-2 virus is not only associated with a readily transmissible viral infection, but it also depends on a significant inflammatory response associated with infection. The authors of the current study provide a brief review of the inflammatory processes of infection. Inflammasomes are activated when myeloid cells detect invasive infection. This, in turn, leads to the release of interleukin (IL)-1, a potent mediator of inflammation.

Inflammasomes can also promote the generation of large complexes within cells, which ultimately disrupt the cell membrane, resulting in cell death and the release of cytokines that recruit other immune cells to the site of infection. Lactate dehydrogenase is a marker of this process of pyroptosis and serves as one of the best indicators of the severity of COVID-19.

The current study by Junquiera and colleagues focuses on the potential infection of monocytes with SARS-CoV-2 and the roles of these cells in pyroptosis in cases of COVID-19.

Study Synopsis and Perspective

Since the start of the COVID-19 pandemic, members of the healthcare team have been trying to understand why some people with coronavirus develop severe inflammation, which can lead to respiratory distress and damage organs.

A study that was published in Nature[1] and conducted by researchers at Boston Children's Hospital and Massachusetts General Hospital in Boston, Massachusetts, provides a possible answer.

Researchers determined the coronavirus infects immune cells called "monocytes" in the blood and "macrophages" in the lungs. That infection causes the immune cells to "die a fiery death called pyroptosis" and release inflammatory alarm signals, Boston Children's Hospital said in a news release.[2]

"When cells die by pyroptosis, they release all kinds of inflammatory proteins that cause fever and summon more immune cells to the site," Judith Lieberman, a pediatric immunologist at Boston Children's Hospital who led the research, told CNN.[3]

"We don't have any way of treating that once it gets started. It's just sort of it's like a little fire. It spreads and explodes and no fire extinguisher is capable of putting it out."

While it is already established that the SARS-CoV-2 virus is the cause of severe COVID-19 related multi-system failure and death, Lieberman told CNN the study helps explain why older people and people with underlying health conditions, such as diabetes and obesity, are more likely to become severely ill with COVID-19, as those conditions already have some inflammation.

"They're much, much more likely to start these inflammatory fires," she said. "They have sort of a low slow burn going on anyway. And once it gets started it's really hard to put out the fire."

The research team examined blood samples from patients with COVID-19 at Massachusetts General Hospital and compared them with blood samples from healthy people and patients with other respiratory illnesses. They also looked at lung autopsy tissue from COVID-19 fatalities.

All the patients had signs of respiratory distress, but patients with COVID-19 had more dying cells.

About 6% of blood monocytes found in patients infected with SARS-CoV-2 died "an inflammatory death," as did about a quarter of macrophages from the lung tissue, the Boston Children's Hospital news release said.[2]

The research also indicated antibodies produced by people with COVID-19 may actually help infection and inflammation occur.

Researchers noticed that people with COVID-19 had a higher number of monocytes carrying a receptor called "CD16," Boston Children's Hospital said. Antibodies, which are naturally produced by the body to fight off a virus, attach to the CD16 receptors.

"The antibodies coat the virus," Lieberman said in the news release. "Then cells with the CD16 receptor take up the virus."

Fortunately, the researchers found antibodies that healthy people create after taking mRNA vaccines did not help the infection of monocytes to occur.

Junqueira and colleagues found that “opsonizing antibodies in monocyte infection and inflammasone activation suggest that antibodies may contribute to deleterious immune reactions associated with severe disease”[4] According to Junqueira, overwhelming evidence shows that vaccine-generated neutralizing antibodies prevent infection and improve clinical outcome of breakthrough infections.

Characterizing how specific antibody features change the functions of anti-spike antibodies will be important not only for understanding the pathogenesis of SARS-CoV-2, but also for members of the healthcare team to be better able to select the best therapies for treatment and/or prevention of severe COVID-19 disease.

Study Highlights

  • Researchers examined blood and plasma from patients with COVID-19, other infections, and healthy control participants.
  • 6% of monocytes from patients with COVID-19 demonstrated membrane damage consistent with pyroptosis; however, no lymphocytes from patients with COVID-19 demonstrated this phenomenon.
  • There were higher levels of markers of monocyte pyroptosis among patients with severe vs mild COVID-19.
  • Although some reports have suggested that monocytes and macrophages can be infected with SARS-CoV-2, this has not been confirmed. Monocytes do not express ACE2, which is the usual binding site for SARS-CoV-2.
  • In the current sample, ≈ 10% of monocytes from persons with COVID-19 stained positive for SARS-CoV-2; ≈ 95% of these cells had evidence of active viral replication.
  • 8% of lung macrophages were infected with SARS-CoV-2; four times that number had evidence of activated inflammasomes.
  • Alarmins released by damage to the lung tissue could be the impetus which stimulates inflammation; however, additional studies are still needed to determine the exact process.
  • Infection of monocytes was rare in the absence of antispike antibody or COVID-19 pooled plasma, suggesting that antispike antibody opsonized virus is primarily responsible for the infection of monocytes. This finding correlates with recent research that has found higher SARS-CoV-2 antibody levels among patients with severe COVID-19.
  • The CD16 and CD64 monocyte receptors mediated the uptake of SARS-CoV-2 virus.
  • An ACE2 antagonist did not impact uptake of SARS-CoV-2 by monocytes, but either remdesivir or depletion of immunoglobulin did.
  • Elevated pyroptosis plasma biomarkers may be beneficial in prognostic and therapeutic efforts.
  • The virus produced by monocytes was not infectious. It appears that pyroptosis occurs before the cell can produce more mature, infectious virus.

Clinical Implications

  • Inflammasomes are activated when myeloid cells detect invasive infection. Inflammasomes can also promote pyroptosis and the release of highly inflammatory cytokines. Lactate dehydrogenase is a marker of this process of pyroptosis and serves as one of the best indicators of the severity of COVID-19.
  • The current study by Junquiera and colleagues finds that monocytes can be infected with SARS-CoV-2, even without expression of ACE2. The presence of SARS-CoV-2 antibodies can facilitate this process, and the process of pyroptosis prevents monocytes from propagating the production of infectious SARS-CoV-2 virus particles.
  • Implications for the healthcare team: The healthcare team needs to be aware of new inflammatory pathways of COVID-19 as potential treatment targets to potentially improve patient outcomes.


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