Since its emergence in Wuhan in December 2019, and its transition from an epidemic in China to a global pandemic, the novel SARS-CoV-2 virus has crippled healthcare systems worldwide (1). Its rapid spread has proven to be a global threat, with over 600 million cases and 6 million deaths reported internationally (2). The virus belongs to the Coronaviridae family, Betacoronavirus genus and is related to the previously observed middle east respiratory syndrome-related coronavirus (MERS-CoV), as well as severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) (3). Coronavirus, a zoonotic virus which primarily resides in bats, has mutated extensively over the past decade in order to be able to infect a human host (4, 5). Following its species boundary extension, and after successfully establishing an animal-to-human transmission, coronavirus presented with a wide symptomatology which ranges from completely asymptomatic (6), to a mild-moderate disease not requiring hospitalization (7). Nonetheless, some patients might experience a severe lower respiratory tract infection that may contribute to greater morbidity and mortality especially when it progresses into acute respiratory distress syndrome (ARDS), or acute lung injury among others (8). The severe symptomatology and mortality of COVID-19 patients has been greatly linked to the existence of various preceding comorbid conditions such as: hypertension, diabetes, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), cerebrovascular disease, cardiovascular disease, etc. (8). Other risk factors include but are not limited to age, socioeconomic status, ethnicity, male gender, diet, lifestyle, and the quality of healthcare provided (9). Consequently, the severity of the disease dictates the treatment options, and given the pandemic-related crises, effective treatment has become an urgent need.

While massive efforts have been channeled into the prevention of the disease, including multiple global vaccination campaigns and government-enforced social restrictions, treatment options have been limited. Currently, the standard of care includes maintaining adequate oxygen level, fluid resuscitation, and ventilation when necessary (10). In patients requiring oxygen supplementation, corticosteroids have been shown, in multiple trials, to improve outcomes such as mortality (11–13). On a pharmacological level, the mainstay of treatment for COVID-19 involves the use of already discovered agents such as the nonsteroidal anti-inflammatory drug aspirin (14). Additionally, antiretroviral protease inhibitors used to treat human immunodeficiency virus (HIV), ritonavir/lopinavir, were also examined in the setting of COVID-19 as combination agents with or without other drug families such as nirmatrelvir-ritonavir (15). Other options include anti-interleukin monoclonal antibodies such as tocilizumab and sarilumab (15), various antiviral agents such as ribavirin and favipiravir (15), and anti-inflammatory agents like corticosteroids, and interferons have also been repurposed in an attempt to combat the global burden of COVID-19 (10). Additionally, remdesivir was also explored in the context of COVID-19 (16). And other agents such as the antimalarial drug hydroxychloroquine displayed mixed results (17).

Due to time constraints imposed by the abrupt emergence of the disease, the utilization of existing treatments has been the most efficient strategy in combating the burden of the disease. This is owed greatly to the results of several randomized control trials (RCTs) demonstrating a benefit from the use of these agents, with a couple of notable mentions such as the randomized evaluation of COVID-19 therapy (RECOVERY) trial (4, 5, 18–20). It is a large multicenter trial involving 176 centers across the United Kingdom. It was conducted with the aim of identifying treatments that may improve outcomes for COVID-19 patients. They randomized 6,425 patients (2,401 dexamethasone arm versus 4,321 usual care arm) to receive dexamethasone versus usual care. Additionally, smaller studies have found mixed result, which will be discussed later on. In this review, we are going to focus on corticosteroids, synthetic derivates of the natural steroid cortisol. With the rapid irresistible spread of the pandemic, these astonishing agents were used to treat patients with COVID-19 and have demonstrated a marked decrease in mortality in severe cases (13). The working theory is that steroids counter the inflammatory response, hence they might prevent the progression to a late, immune-mediated stage of COVID-19 disease (20). Consequently, the aim of this paper is to portray the therapeutic benefit of several corticosteroids in treating COVID-19, as well as to touch upon some of their failures and adverse outcomes.

Two databases including Pubmed and Ovid Medline were searched until May 23, 2023 using both the keywords and MeSH terms including: “COVID-19” OR “Coronavirus” OR “SARS-COV-2” and “Dexamethasone” OR “Methylprednisolone” OR “Steroids” OR “Corticosteroids.” Articles included were randomized control trials (RCTs) and retrospective observational studies discussing the use of glucocorticoid among other commonly studied agents (hydroxychloroquine, ritonavir, ribavirin, lopinavir, remdesivir, aspirin, tocilizumab) in patients with throat-swab or PCR confirmed COVID-19 in adults aged more than 18 years. Exclusion criteria were articles discussing the use of agents outside the scope of the review (vitamin D, sex steroids, convalescent plasma), and articles discussing the treatment specific complications of COVID-19 [anosmia, multisystem inflammatory syndrome in children (MIS-C)]. Ongoing and prospective trials were excluded from this review. There was no exclusion on the basis of language.

Two authors (AB and YF) screened the abstracts and titles of relevant articles identified through the search. Articles were selected based on their relevance and the inclusion/exclusion criteria mentioned above. Duplicates were removed, and disagreements were resolved by discussion or by consulting a third author (RZ). The authors screened the reference lists of relevant articles to further identify potential articles that could be included in the study.

The medicinal history of corticosteroids goes back to 1930 when studies showed that adrenocortical samples extracted from animals have the potential to combat failure of the adrenal glands when administered to humans (21). Following that, in 1940, corticosteroids were split into two groups, one displaying the ability to retain bodily fluid and sodium, while the other showing an anti-inflammatory potential (21). Later, in 1948, and for the first time, cortisone was administered to a patient suffering from rheumatoid arthritis (21). The latter marked the beginning of the long and successful journey of corticosteroids in the field of medicine. In the years that followed, multiple synthetic steroids were marketed (21). And by 1960, their entire side effect profile was meticulously explained (21).

Since the initial description of their effects on immunity, metabolism, and cognition in 1949, glucocorticoids have been put into clinical use for a variety of conditions (22). Their clinical use has been enhanced through the chemical modification of naturally occurring steroids, such as cortisol, into a variety of synthetic glucocorticoids with most exerting a more potent effect than their original molecules (23–25). It took about 20 years from discovering the formation of cholesterol, to establishing an effective formulation of a topical steroid in 1952 (26).

The nonendocrine uses of corticosteroids, achieved at supraphysiologic doses, are numerous and span over almost every area in medicine through almost all routes (27). They are mostly used as agents to treat a variety of conditions that involve dysfunction of the immune system, which can be allergic, autoimmune, or inflammatory in nature. They are also used for their ability to amplify the catecholamine response in the body which is helpful in increasing vascular tone in the setting of hypotensive shock (28).

The endocrine benefits of corticosteroids can be therapeutic or diagnostic for the treatment of dysfunctional adrenal glands (29). Since excess production of corticosteroids can cause Cushing’s syndrome, whereas their deficiency can lead to Addison’s disease, they are equally useful in the diagnosis and treatment of the aforementioned phenomena, with various doses being used to rule out the different etiologies of Cushing’s syndrome (29). Additionally, a physiologic dose of glucocorticoids is essential for patients with primary adrenal insufficiency whereby the primary failure is in the adrenal glands, or secondary adrenal insufficiency which is a result of pituitary dysfunction, to maintain the physiologic effect of cortisol (30). This is particularly important to consider in the peri-operative period, whereby supraphysiologic doses are required to withstand intervention (29).

Corticosteroids can be delivered via multiple routes (31). For example, systemic steroids can be widely used to treat multiple inflammatory, allergic and immune mediated disorders, yet dosing is extremely important to prevent one of their notorious side effects: the suppression of the hypothalamic-pituitary-adrenal axis (31). Alternatively, topical or inhaled corticosteroids can be used in instances where a local effect is desired, such as in the case of treating chronic obstructive pulmonary disorder (COPD), or asthma where the target organ is the lung (31). Furthermore, intranasal corticosteroids can be used in mediating allergic rhinitis of a moderate-to-severe form (31).

It is important to mention that despite the local concentration of inhaled and topical corticosteroids, the difference and uniqueness of their systemic bioavailability largely dictates their resultant systemic side effects (31). In terms of some pharmacokinetic properties of certain corticosteroids, it has been shown that the oral bioavailability is the smallest, whereas the pulmonary residence is the greatest for fluticasone propionate (32). Alternatively, flunisolide and budesonide showed the smallest pulmonary residence (32). Also, in terms of half-life, short-to-medium intervening corticosteroids such as prednisone and methyl-prednisone exhibit a half-life ranging from 8 to 36 h, while the long-acting ones such as dexamethasone and betamethasone display a 36 to 54 h long half-life (33). When it comes to potency of their anti-inflammatory activity, prednisolone showed a 5 times greater anti-inflammatory potency, while dexamethasone and betamethasone showed a 25 to 30 times increase as compared to the synthetic cortisol, hydrocortisone (33). This is attributed to their longer plasma half-life, which is a consequence of their synthetic alteration from the original molecule cortisol, which leads to different receptor binding and hence slower degradation of the steroid molecule by the liver (34).

In brief, the routes of administration and dosing are extremely important in preventing more serious side effects such as steroid-induced osteonecrosis, whereby most cases were observed when patients with preexisting comorbidities were given high dosages of systemic corticosteroids (35). On another note, the dosing and type of corticosteroid used are important to consider in the case of pregnancy (33). Some corticosteroids such as prednisone and prednisolone are preferred for treating maternal disorders since they do not cross the placenta readily (33). Whereas others such as betamethasone and dexamethasone show extensive transplacental crossing and are therefore indicated for the treatment of fetal diseases, especially when the risk of preterm birth is particularly high (33).

The two main routes studied for the treatment of COVID-19 have been inhalation and systemic administration. For patients suffering from COVID-19 and requiring oxygen supplementation, based on mixed results from large trials such as the RECOVERY and COVID STEROID 2 trial, the most commonly used systemic steroid has been dexamethasone (18, 36, 37). In resource-limited settings dexamethasone might not be available, hence it has been deemed reasonable to administer an equivalent corticosteroid. Such alternatives could be hydrocortisone, methylprednisolone, or prednisone (38). On the other hand, inhaled corticosteroids have not been studied as extensively, and further trials are required to establish their role in the management of early, mild-moderate COVID-19 disease.

The most common side effects are usually associated with oral and systemic corticosteroids, and these include immunosuppression as patients face an increased risk for dangerous and uncommon infections (39). Additionally, since cortisol and corticosteroids bear an astonishing functional and structural similarity, the chronic intake of corticosteroids can potentially suppress the adrenal gland, leading to severe and potentially fatal adverse events such as hypotension (39). Also, iatrogenic corticosteroids are the primary cause for Cushing syndrome and the display of cushingoid characteristics (40). Although rare, some psychiatric side effects were also noted in a minority of patients, including psychosis (41, 42). The short use of corticosteroids is linked to less severe adverse events such as hyperglycemia, hypertension, electrolyte imbalance, and pancreatitis among others (41). Whereas the chronic use is related to more dangerous side effects like bone abnormalities and osteoporosis, hyperlipidemia, as well as negative outcomes on various organ systems such as the liver, eye, intestine and stomach (41), displayed in Figure 1. Unique to inhaled corticosteroids, patients can present with a fungal mouth infection (oral thrush/oral candidiasis) (43). On another note, antenatal corticosteroids have been linked to the dysfunction of the hypothalamic-pituitary-adrenocortical axis (44). In short, despite the wide range of adverse effects of corticosteroids on multiple organ systems, they can effectively be minimized when the course of treatment is short, and the dosages are progressively tapered down.

Corticosteroids, being structurally related to cortisol, are naturally lipophilic and are well renowned for their immunosuppressive effects (45). Given this lipophilicity, they passively diffuse across the cell membrane, bind to an intracellular glucocorticoid receptor, and migrate into the nucleus where they influence the transcription of multiple downstream genes. This is done by altering the affinity of transcription factors to promoter sites of said genes. The mechanism of action is depicted in Figure 2. First, they aim to selectively enhance the transcription of anti-inflammatory cytokines by the aforementioned mechanism (46). Second, they simultaneously block the promoter sites of genes that code for pro-inflammatory cytokines, as well as adhesion molecules that assist in inflammation (46). These include, but are not limited to, interleukins and eicosanoids such as interleukin(s) 1, 2, 6, tumor necrosis factor-alpha (TNF-a), granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-gamma (IFN-y) among others (47). Another major mediator of their immunosuppressive process is the downregulation of nuclear factor kB (Nf-kb), which plays a major role in mediating cellular signaling pathways that are involved in amplifying the immune response (46, 48).

Leukotrienes, prostaglandins, prostacyclins, and thromboxanes are among important pro-inflammatory cellular signaling molecules that are derived from membrane phospholipids of cells. Phospholipase A2 is an enzyme that works to initially catalyze the breakdown of membrane phospholipids into the aforementioned molecules. Not only have glucocorticoids been shown to inhibit phospholipase A2, but they furthermore inactivate the enzymatic conversion of downstream products by inhibiting enzymes such as cyclooxygenases 1 and 2 (COX-1, COX-2), lipoxygenases, and various synthases, similar to how non-steroidal anti-inflammatory drugs (NSAIDs) work, albeit in a more potent fashion (49). The result is a decrease in vascular changes and cardinal inflammatory signaling. Additionally, these agents also alter the physiology of cells that mediate inflammation in the body. This is done by changing basic immune cellular functions such as margination, migration, phagocytosis, and survival (50, 51). The effect on humoral immunity seems to be less profound than on cell-mediated immunity (38). Indeed, several lab studies corroborate these findings, which include the reduction of eosinophils, B, and more so T lymphocytes. There is a similar effect on macrophages, however, the effect is seen at much higher doses (52, 53). Neutrophils generally show an increase in number due to a decreased ability to adhere to endothelial walls (54). This is a consequence of the downregulation of leukocyte adhesion protein, resulting in an increase of neutrophils in the bloodstream from sites such as the bone marrow and vascular endothelia (54).

The rapid development of the COVID-19 pandemic necessitated the development of an efficient and effective response strategy. Treatment regimens that improve outcomes in severe infection were of particular interest. It seemed that the quickest way to achieve this was through utilizing medications that were already available for other diseases. Particular medications such as aspirin, specific immune modulators (e.g., anti-interleukin therapy), and corticosteroids were being studied (55, 56). Aspirin has been shown to be effective in the context of COVID-19 (14). As for anti-interleukin therapy, tocilizumab has been shown to be beneficial in hospitalized patients, especially when combined with corticosteroids, and sarilumab should only be used instead of tocilizumab when the latter is not available or there are contraindications against its usage (57–59). As for ritonavir and lopinavir, they were proven to be ineffective in the setting of COVID-19 (15, 17). Similarly, ribavirin demonstrated no benefit against COVID-19 (60). The use of favipiravir was likewise ineffective (15). A combination of nirmatrelvir-ritonavir (paxlovid) showed improved outcomes such as mortality (61). Remdesivir was the first antiviral agent approved for COVID-19 and has continued to be recommended as it has remained effective in improving outcomes in patients with mild to moderate COVID-19 (62, 63). Other antiviral agents approved for COVID-19 include molnupiravir and nirmatrelvir, and these agents have been showed to be continuously effective despite the emerging strains such as the Omicron variant (64). Also, evidence for agents such as the antimalarial drugs encompassing hydroxychloroquine and chloroquine have been shown to be ineffective in improving outcomes and potentially harmful (65).

Corticosteroids have been shown in vivo to reduce inflammation that is associated with a dysregulated immune response, hence potentially reducing mortality if given early in the severe stage of the illness (66). In the context of a severe COVID-19 case, where the infection has not been cleared by the initial immune response and has entered the pulmonary phase, the proposed benefit of introducing corticosteroids is thought to be due to the downregulation of immune-mediated lung injury and cytokine storm (67). The hyperinflammatory state of COVID-19 disease is depicted in Figure 3. This would prevent the progression to acute respiratory distress syndrome (ARDS), respiratory failure, or death. Indeed, it has been suggested that SARS-CoV-2 induces the elevation of cytokines such as IL-6, potentially leading to a cytokine storm, an important contributor to mortality (67). This is supported by the finding of elevated levels of cytokines in critical COVID-19 patients, and these levels are directly correlated with higher mortality and a poorer prognosis (67).

An extremely significant disadvantage to the use of steroids in general is their important adverse effect profile. Systemic steroids can affect multiple organ-systems and lead to various side effects, and is generally related to the average dose and duration of treatment. These include: immunosuppression with predisposition to opportunistic infections, osteoporosis, osteonecrosis, fractures, hyperglycemia, promote insulin resistance, Cushing syndrome or cushingoid features, psychiatric disturbances, hypertension, adrenal suppression, glaucoma and cataracts. However, as these issues are dependent on the average dose of corticosteroids and the cumulative duration of treatment, the issue of adverse effects is minor in the short-term treatment of COVID-19 (27, 71–77).

Despite the outstanding universal effort put in favor of minimizing the morbidity and mortality caused by COVID-19 through global vaccination campaigns, yet the search for an effective therapeutic agent remains on the rise. Although many trials have demonstrated a statistically significant result for their primary outcome (decrease in mortality or ventilatory-free days), the benefit of such studies remains questionable due to low number of participants, the open-label study design and early termination following the RECOVERY trial results, or due to a decline in COVID-19 cases. Furthermore, myriad studies showed mixed results, with some reaching secondary, not primary outcomes, and vice versa. Plus, the beneficial dosages remain under suspicion with some trials showing greater risk for higher dosages of corticosteroids. Hence, our review of the literature has concluded that there might be a potential benefit for the use of systemic corticosteroids in the context of a severe COVID-19 pneumonia. However, it is important to push for high quality multi-center placebo-controlled randomized clinical trials to better understand the effectiveness of corticosteroids in the setting of COVID-19.

MA developed the idea and reviewed the framework. AB and YF wrote the first draft of the manuscript. RZ created and edited the figures. RZ, FB, and MA did the final editing. AB, YF, RZ, FB, and MA contributed to corrections and adjustment of subsequent iterations of the manuscript. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.