Biology of Dexamethasone: The First Lifesaving Drug for Covid-19

How does it work; how does it fare against other drugs and diseases; its side effects, immunosuppression concerns, and clinical benefits.

The First Lifesaving Drug

It’s in the headlines. A cheap and widely available drug saves lives from severe Covid-19. The RECOVERY Trial by Oxford University in the UK included 2104 patients on dexamethasone and 4321 who were not. This is one of the largest clinical trials to date.

Preliminary results showed that the drug lowered the death risk from 40% to 28% for patients on ventilators, and from 25% to 20% for those requiring supplemental oxygen over 28 days. There were no substantial side effects. And it did not help mild Covid-19 cases without any breathing issues.

Putting it into context, dexamethasone could save one life when applied to eight patients on ventilators and 25 patients needing oxygen therapy. So, the NNT (Number Needed to Treat) value of dexamethasone in rescuing ventilator-related death is eight, which is impressive by clinical standards. For comparison, the NNT of statins in preventing heart diseases is 104.

This is the only drug so far that has been shown to reduce mortality — and it reduces it significantly. It’s a major breakthrough,” Peter Horby, Professor of Emerging Infectious Diseases and Global Health and Chair of the UK New and Emerging Respiratory Virus Threats Advisory Group, who led the study said. The WHO general director, Dr Tedros Adhanom Ghebreyesus, congratulates the Oxford study for their “lifesaving scientific breakthrough.” And Russia has already started using dexamethasone to treat Covid-19, the health ministry official Sergei Avdeev announced.

The NNT value of dexamethasone in rescuing Covid-19 ventilator-related death is 8, which is impressive by clinical standards.

Despite that peer-review is not conducted yet, raw data of a properly done randomized, placebo-controlled trial with population-based sample size is hard to refute.

How Does Dexamethasone Fare Against Other Drugs?

The Oxford RECOVERY Trial (full protocol here) tested dexamethasone, lopinavir-ritonavir, hydroxychloroquine, and azithromycin in a randomized placebo-controlled manner. Only dexamethasone emerged triumphant in preventing Covid-19 death.

The antiviral remdesivir only shorten hospital stay and has no significant effects on the Covid-19 death rate. It is also expensive and in shortage. In contrast, dexamethasone is cheap and widely available. “For less than £50, you can treat 8 patients and save one life,” Martin Landray, Professor of Medicine and Epidemiologist and one of the chief researchers of the Oxford study, said.

Notably, a New York preprint study of about 1000 patients showed that hydroxychloroquine + zinc reduced mortality in Covid-19 patients that did not require ICU level of care. Hydroxychloroquine acts as a zinc transporter and zinc inside the cell could inhibit the activity of SARS-CoV-2.

How Does Dexamethasone Work?

Dexamethasone is a synthetic glucocorticoid (i.e., a class of corticosteroid) given orally or intravenously to treat diseases such as arthritis, allergies, asthma, and some forms of cancers. It mimics the action of cortisol that the body naturally produces to quell inflammation.

Dexamethasone stops two phases of inflammation and exerts both anti-inflammatory and immunosuppressive effects.

As dexamethasone is long-acting and has systemic effects, it is about 25-times more potent than other synthetic corticosteroids. Glucocorticoids (a class of corticosteroids) are also stronger than nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen or aspirin. Glucocorticoids stop two phases — i.e., vasodilation and immune cells migration — of inflammation. In contrast, NSAIDs only inhibit the vascular stage. Hence, dexamethasone is both anti-inflammatory and immunosuppressive.

Dexamethasone’s biological pathways overlap with that of Covid-19 pathology.

On the biochemical level, glucocorticoids easily diffuse through the host cell membranes and bind to the glucocorticoid receptor in the cell cytoplasm. This receptor binding triggers a cascade of reactions that end up suppressing pro-inflammatory cytokines IL-1, IL-2, IL-6, IL-8, TNF, and IFN-gamma. Importantly, five of these are linked to Covid-19 severity.

Moreover, one of the primary culprits of Covid-19 cytokine storm is the overactivation of macrophages, which is also inhibited by glucocorticoids. A 2019 cell culture study has also shown that dexamethasone rescued human alveolar (air sacs) cells from destruction by pro-inflammation cytokines.

Potential Side Effects

High and long-term doses would cause side effects. “Chronic use is associated with a sobering list of adverse effects, but a few days, or even a week, of steroid therapy [including dexamethasone] is generally free of significant side effects,” a 2013 review stated. The Oxford study used a low-to-moderate dose for ten days, which is justified considering that uncontrolled and excessive inflammation fuels the critical stage of Covid-19.

In any case that dexamethasone causes side effects, the common ones are increased appetite, aggression, agitation, mood changes, blurred vision, dizziness, headache, tingling in arms and legs, irregular heartbeats, etc. As corticosteroids have systems-wide effects, its potential side effects are broad-spectrum too. People with chronic diseases, such as diabetes, dyslipidemia, heart diseases, hypertension, peptic ulcer disease and osteoporosis, are more prone to develop side effects from corticosteroids.

Immunosuppression Concerns vs Clinical Benefits

Dexamethasone is anti-inflammatory and immunosuppressive at the same time, as mentioned. There are concerns of the latter weakening immune responses to the Covid-19 virus. “Corticosteroids have been avoided in most cases of pneumonia due to concerns that their immunosuppressive effects may actually worsen the underlying infection,” a 2017 book chapter stated. According to a 2020 review in Lancet, glucocorticoids (a class of corticosteroids) did not work well against previous coronaviruses.

But sometimes clinical practice suggests otherwise. Corticosteroids are useful in specific types of pneumonia, especially the Pneumocystis jiroveci fungal pneumonia. A 2018 meta-analysis of six clinical trials calculated that low-dosing of corticosteroids (including glucocorticoids like dexamethasone) shortened hospitalization period for community-acquired pneumonia compared to placebo. There is also evidence supporting low-dose glucocorticoids (including dexamethasone) in lowering the severity of acute respiratory distress syndrome (ARDS; a typical outcome of severe Covid-19), a 2014 review of meta-analyses and clinical trials concluded.

In severe pneumonia or ARDS, benefits of glucocorticoids outweigh their immunosuppression concerns, which are seen only in high doses.

Note that a low dose was used to treat severe pneumonia and ARDS, which is backed by science. “The anti-inflammatory and immunosuppressive effects of glucocorticoids are dose-dependent, with immunosuppressive effects seen mostly at higher doses,” a 2020 book chapter affirmed. High glucocorticoids could stop T-cells from functioning properly, but not B-cells — both of which are responsible for orchestrating immune reactions catered to a specific pathogen.

The Oxford RECOVERY Trial is the best example: Low-to-moderate dose of dexamethasone cut the risk of death of Covid-19 patients on ventilators by one-third (from 40% to 28%), saving one life for every eight patients treated without any prominent side effects. And, lastly, it is not helpful to those that can breathe properly so there’s no need to stockpile it.