How does dexamethasone therapy work in severe COVID-19?

Dexamethasone has been highlighted as an effective medicine against severe coronavirus disease 2019 (COVID-19) since the early stages of the pandemic, being more potent with a longer plasma half-life than endogenous glucocorticoid cortisol. The mortality of patients that receive mechanical respiratory assistance is around one third lower when the patient receives dexamethasone, and one fifth lower in patients that receive O2 supplementation without mechanical support, indicative of moderate SARS-CoV-2 infection, while mild cases of COVID-19 gain no benefit from dexamethasone.

Interestingly, for other diseases with otherwise similar respiratory symptoms such as influenza, pneumonia or bacterial sepsis, dexamethasone is contraindicated, with the potent anti-inflammatory and immunosuppressive effects of the glucocorticoid aggravating the infections.

The possible mechanisms that result in dexamethasone being an effective drug against severe SARS-CoV-2 infection are investigated in a new study recently published in the International Journal of Molecular Sciences. The paper’s authors advance the hypothesis that SARS-CoV-2 infection induces cell-specific insensitivity to glucocorticoids, possibly as an unintentional result of the viral replication cycle.

Glucocorticoids

Glucocorticoids generate diverse and strong suppressive effects on the overall immune system, generally exerting an anti-inflammatory effect by downregulating the production of proinflammatory molecules such as interleukin. They can also enhance the clearance of foreign antigens and dead cells from areas of inflammation by stimulating phagocytosis of macrophages and reportedly suppress cellular immunity while stimulating humoral immunity by modulation of the production of cytokines.

While the suppression of a damaging immune response by glucocorticoids can be beneficial, it does nothing to prevent viral replication, and in fact, impedes the ability of the host to fight infection. However, the viral load of SARS-CoV-2 does lower under dexamethasone administration in severe cases. The leading theory, then, is that the drugs appear effective at treating COVID-19 not only because of the lessened organ inflammation experienced by those receiving dexamethasone, but also due to some additional therapeutic properties brought about uniquely during SARS-CoV-2 infection.

Glucocorticoid insensitivity

Glucocorticoid insensitivity has been noted specifically in SARS-CoV-2 infected cells, and a similar state has been reported in some other viral infections. The group state that SARS-CoV-2 likely induces coincidental glucocorticoid resistance during the process of shifting host cellular functions towards its own replication, and while undertaking the process of modulating the innate immune system.

This is supported by observations that SARS-CoV-2 infection activates transcription factors NFκB and AP-1 in host cells, which are known to suppress glucocorticoid receptor activity. Additionally, downstream interferon factors are activated by SARS-CoV-2 that share a coactivator with glucocorticoid receptors, meaning that they could be exhausted by the processes caused by the virus before they can be utilized.

A number of other theories have been proposed to account for the apparent beneficial effect of dexamethasone against COVID-19, contrary to other similar diseases. Cortisol is secreted as part of the hypothalamic-pituitary-adrenal axis, and it has been suggested that insufficient activation of this system could result in severe COVID-19, and that therefore supplementation of the immune-suppressing function of endogenous cortisol is the reason for the observed benefit. Improved lung regeneration has also been suggested, as glucocorticoids are known to have a positive effect on lung surfactants and lung maturation. Additionally, the particular lung cells that SARS-CoV-2 favors are particularly resistant to glucocorticoids, which may go some way to explain the difference observed between COVID-19 and influenza in glucocorticoid response.

Conclusion

Glucocorticoids are effective at suppressing inflammation in other infectious diseases, though poorly suppress pathogen invasion and replication. In the case of SARS-CoV-2, however, intracellular glucocorticoid signaling systems are highly interconnected with the life cycle of the virus. Advanced SARS-CoV-2 infection suppresses innate cellular immunity and induces cell cycle arrest to facilitate better viral replication, and in doing so, modulates the intracellular actions of glucocorticoid receptors.

By making the host cells less susceptible to dexamethasone, SARS-CoV-2 may prevent the glucocorticoid from suppressing host cell immunity as greatly, while allowing it to suppress inflammation in non-infected regions. Administration with interferon has been shown to present synergistic effects with dexamethasone against SARS-CoV-2, and careful studies will be needed to reveal the optimal timing and dosage combination considering the antagonistic effects of each drug.

Journal reference:
Michael Greenwood

Written by

Michael Greenwood

Michael graduated from the University of Salford with a Ph.D. in Biochemistry in 2023, and has keen research interests towards nanotechnology and its application to biological systems. Michael has written on a wide range of science communication and news topics within the life sciences and related fields since 2019, and engages extensively with current developments in journal publications.  

Citations

Please use one of the following formats to cite this article in your essay, paper or report:

  • APA

    Greenwood, Michael. (2021, June 29). How does dexamethasone therapy work in severe COVID-19?. News-Medical. Retrieved on October 08, 2024 from https://www.news-medical.net/news/20210629/How-does-dexamethasone-therapy-in-COVID-19.aspx.

  • MLA

    Greenwood, Michael. "How does dexamethasone therapy work in severe COVID-19?". News-Medical. 08 October 2024. <https://www.news-medical.net/news/20210629/How-does-dexamethasone-therapy-in-COVID-19.aspx>.

  • Chicago

    Greenwood, Michael. "How does dexamethasone therapy work in severe COVID-19?". News-Medical. https://www.news-medical.net/news/20210629/How-does-dexamethasone-therapy-in-COVID-19.aspx. (accessed October 08, 2024).

  • Harvard

    Greenwood, Michael. 2021. How does dexamethasone therapy work in severe COVID-19?. News-Medical, viewed 08 October 2024, https://www.news-medical.net/news/20210629/How-does-dexamethasone-therapy-in-COVID-19.aspx.

Comments

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
Post a new comment
Post

While we only use edited and approved content for Azthena answers, it may on occasions provide incorrect responses. Please confirm any data provided with the related suppliers or authors. We do not provide medical advice, if you search for medical information you must always consult a medical professional before acting on any information provided.

Your questions, but not your email details will be shared with OpenAI and retained for 30 days in accordance with their privacy principles.

Please do not ask questions that use sensitive or confidential information.

Read the full Terms & Conditions.

You might also like...
COVID-19 vaccine uptake higher in people with mental illness but drops for those not on medication