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(Pharmacology) 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.
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