Introduction
The coronavirus disease 2019 (COVID-19) pandemic made an excruciating
situation over the past year as no practical therapeutic approach has
been identified yet (1). Similar to those infected with severe acute
respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory
syndrome coronavirus (MERS-CoV), and influenza virus, patients infected
with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are
believed to experience these phases: virus invasion, immune activation,
exaggerated inflammatory response, acute respiratory distress syndrome
(ARDS), and ultimately, recovery or death (2).
The severity of COVID-19 varies from mild or asymptomatic cases to
severe and life-threatening ones. Only 5% of COVID-19 patients reach
the critical phase of ARDS (3). Patients with the severe form of the
disease have particular clinical or paraclinical characteristics,
including decreased PaO2/FiO2 (P/F)
ratio and the number of peripheral lymphocytes, high C-reactive protein
(CRP), lactate dehydrogenase (LDH), D-dimer, or IL-6 (4). This condition
typically occurs in the second week of illness or later, following a
catastrophic, self-destructive immune response and cytokine storm. The
cytokine storm eventually may result in multi-organ failure, shock, or
death. Consequently, any strategy to prevent or modulate this crisis can
contribute to a reduction in mortality and morbidity rates (5). Although
different antivirals, hydroxychloroquine, azithromycin, intravenous
immunoglobulin (IVIG), and immunomodulatory agents, such as tocilizumab,
have been explored in the treatment of COVID-19, no significant positive
outcomes have been achieved yet (6). Under these conditions, the only
life-saving strategy could be to suppress inflammation, which is best
achieved by corticosteroids (7).
The mechanism by which corticosteroids act to prevent or treat ARDS
might be the down-regulation of the systemic and pulmonary inflammatory
responses and preventing exudative fluid accumulation in the lung
tissue, resulting in better respiratory indices and pulmonary repair,
and decreases of respiratory failure (8). As soon as the patient
develops any symptoms or signs of disease progression, corticosteroid
therapy must be switched on (9). Low to moderate doses of
corticosteroids are generally used to prevent their potential adverse
effects. Nevertheless, high doses are recommended for specific
situations (10). As well as controlling or preventing ARDS in the
context of COVID-19, corticosteroids offer many other benefits (11).
Management of sepsis and the potential adrenal insufficiency induced by
septic shock is another reason to administer corticosteroids (12).
Patients with COVID-19 who began corticosteroid treatment would promptly
experience shorter-term symptoms and more clinical improvement during
the first seven days (13).
Different studies conducted on patients admitted to the intensive care
unit (ICU) due to COVID-19 have shown the association between
corticosteroid therapy and reduced hospitalization in the ICU,
mechanical ventilation, and mortality if received early. Besides, more
rapid defervescence, improved oxygenation, and reduced need for
intubation and mechanical ventilation are other benefits of
corticosteroid therapy in patients with COVID-19 (14). However,
corticosteroids have been associated with a more extended
hospitalization, which may advise against their use since
corticosteroids are generally administered for more ill patients, and
these patients are reasonably more likely to have longer hospitalization
duration (15). Not only are corticosteroids used for ARDS, multi-organ
failure, and shock in the setting of COVID-19, but also they have been
applied for other purposes, such as SARS-CoV-2-related severe cutaneous
manifestations. For instance, erythema multiforme (EM)-like exanthem and
other dermatoses, which have been extensively reported in patients with
COVID-19, respond well to corticosteroid treatment (16). Furthermore,
oral corticosteroids, such as prednisolone, have also been used to
relieve post-COVID-19 anosmia (17). There have also been cases of
exacerbated immune thrombocytopenia (ITP) controlled by corticosteroids
(18).
At the onset of the pandemic, hydrocortisone was applied for severe
COVID-19, possibly due to its proven benefits in septic shock (19).
Today, nearly all studies have emphasized dexamethasone as a drug of
choice for COVID-19 treatment, while in the previous SARS-CoV, MERS-CoV,
and influenza A (H1N1) epidemics, methylprednisolone was more tended to
be applied (20,21). Methylprednisolone and dexamethasone have increased
pulmonary bioavailability compared to other corticosteroids.
Methylprednisolone has higher mineral-corticoid activity, whereas
dexamethasone has higher glucocorticoid activity. Long-term adverse
effects, such as volume overload, electrolyte imbalance, dysglycemia,
and hypercortisolism, are less common with methylprednisolone due to its
faster onset and shorter duration of action (22). The results of the
RECOVERY trial illuminated the maximum benefit of low-dose dexamethasone
(23). The mechanism by which dexamethasone exerts its immunosuppressive
effects is reducing antibody synthesis by plasma cells, inhibition of T
cells, and blockage of macrophages and NK cells (figure 1) (24). Some
centers have tried nebulized triamcinolone preceded by a pulse of
intravenous dexamethasone to maximize corticosteroids’ concentration in
the lungs (25). Interestingly, an inhaled corticosteroid named
ciclesonide would have effectively inhibited the replication of
SARS-CoV-2 (26).
In contrast to some therapeutic options for which we can consider a
specific change in laboratory biomarkers to define their necessity,
there is currently no such definition for corticosteroids in COVID-19
patients (27). For example, tocilizumab is typically indicated in
situations where IL-6 levels are increased, or antimicrobials can be
considered for patients with higher procalcitonin levels (28, 29).
Timely administration of corticosteroids is vital for preventing and
treating ARDS, disseminated intravascular coagulation, hypotension,
shock, and death, all of which occur more prevalently in the first 5 to
7 days of disease. This matter corresponds to when a patient with
COVID-19 develops shortness of breath. Patients whose oxygenation or
radiological outcomes are progressively deteriorating are the best
candidates for receiving glucocorticoids (30). The timing of a
corticosteroid regimen for a COVID-19 patient should be decided
cautiously since it should be administered neither too early to suppress
the body’s immune defense nor too late to be unable to overcome the
advanced stages of ARDS (2). The reason why many critically ill,
ICU-admitted COVID-19 patients do not respond to delayed corticosteroid
therapy may be the excessive inflammatory responses that have caused
irreversible damage to the lungs (31).
Almost all studies agree on the most beneficial effect of low-dose
corticosteroids on severe forms of COVID-19, which are ventilated and
have developed ARDS (32). Many centers have reached the point where a
low-to-moderate dose of methylprednisolone (0.5 to 1 mg/kg/day) appears
reasonable for approximately one week (33). However, at the beginning of
the pandemic, when anti-retroviral drugs, such as ritonavir, were
studied for COVID-19 treatment, a lower dose of methylprednisolone or
prednisolone was chosen because of ritonavir’s interactions with those
drugs, resulting in increased levels of the corticosteroids in serum
(34). Furthermore, the RECOVERY trial revealed a lower mortality rate
with 6 mg/day of dexamethasone than the control group (23). In
critically decompensated patients, recovery therapy with a 3-day
glucocorticoid pulse therapy (intravenous methylprednisolone: 200–400
mg/day) followed by low-to-moderate dose corticosteroids for 21 days is
also indicated (35).
Any medical treatment may be otherwise harmful in certain respects if
misused, used longer than necessary, or in inappropriate doses.
Corticosteroids are a double-edged sword used to treat viral pneumonia
(36). Despite their beneficial effects on controlling critically ill
COVID-19 patients, corticosteroids should be administrated with caution
due to their immunosuppressive effect. Their arbitrary administration
can even trigger more viral replication, which is potentially harmful to
the patient. Nonetheless, despite the controversy in their use in viral
pneumonia, they had been abundantly used in influenza virus, SARS-CoV,
and MERS-CoV epidemics (33,37). Studies have shown that patients taking
chronic low-dose corticosteroid therapy for any disorder, such as
neurologic or rheumatologic diseases, are not prone to severe forms of
COVID-19 infection than those not on such regimen (38). Adrenal
insufficiency due to removal of the hypothalamic-pituitary-adrenal (HPA)
axis is another formidable consequence of the long-term use of
corticosteroid (39). Other unwanted events include dysglycemia and
unmasking of diabetes, avascular necrosis or osteonecrosis of the
femoral head (ONFH), hypertension, bacterial super-infections and
subsequent antibiotic overuse, opportunistic infections, such as
pulmonary aspergillosis or rhino-orbital or rhino-cerebral mucormycosis,
and electrolytes imbalances, such as hypernatremia and hypokalemia
(10,32,40-45). Additionally, some patients with COVID-19 are prone to
pneumothorax, the improvement of which may be delayed by corticosteroid
therapy (46). Another critical issue that should be considered is the
co-administration of corticosteroids and anticoagulants, such as
heparin, in the context of COVID-19 is a predisposition to
gastrointestinal (GI) bleeding (47).
Corticosteroid therapy has also been reported to prolong viral shedding.
However, some studies suggest combining immunoglobulin and
corticosteroids to enhance the immune response to overcome prolonged
viral shedding, besides its synergistic effects in improving oxygen
saturations (9,35).
Corticosteroids should be administered cautiously under certain
conditions. For example, during pregnancy, the corticosteroid
administration’s benefits to the mother to manage her COVID-19 should be
weighed carefully against the potential fetal harm (48). Measures must
be taken to differentiate between chorioamnionitis and COVID-19 in
pregnant patients with fever (48).
It is well-described that COVID-19 is less common or less severe in
patients with chronic obstructive pulmonary disease (COPD) than in the
general population. One reason may be the vital role of corticosteroids,
whether inhaled or systemic, in the maintenance treatment of these
patients, intended to protect them from severe COVID-19 infection (49).
It is unknown whether patients afflicted with disorders like COPD who
should take corticosteroids routinely for their condition must continue
their corticosteroid regimen if they are infected with SARS-CoV-2 or
not, since corticosteroids may be harmful in the early stages of
COVID-19 infection (50).
Therefore, strategies should be undertaken to avoid corticosteroids
associated adverse events, such as the most short-acting ones like
methylprednisolone, should be used because as soon as it is tapered or
discontinued, its adverse events are more likely to disappear (51). A
further protective measure can be administering bisphosphonates and
vitamin E to prevent osteoporosis or osteonecrosis (52). Close
monitoring of blood sugar is required after the discharge of the patient
(53). Choosing and administering the appropriate class of
glucose-lowering agents, such as metformin or various types of short or
long-acting insulin, depending on blood sugar levels, the exact
corticosteroid type being utilized, and the hyperglycemic peak time is
also warranted (54).
Various institutions or guidelines have provided advice on how to
administer corticosteroids in the context of COVID-19. Both the world
health organization (WHO) and the center for disease control and
prevention (CDC) had prohibited corticosteroid use for this application
at the beginning of the outbreak. Nonetheless, currently, a low dose of
dexamethasone is the drug of choice in many COVID-19 patients (10, 55).
Also, the national health commission of the People’s Republic of China
recommended hydrocortisone as the appropriate corticosteroid in COVID-19
(56). Moreover, the surviving sepsis guideline of the COVID-19 has
always recommended steroids for severe forms of COVID-19, particularly
ARDS, to suppress the exaggerated inflammatory response (57).