# SARS-CoV-2 Treatment: Current Therapeutic Options and the Pursuit of Tailored Therapy
## 9 Corticosteroids  
Corticosteroids modulate immune responses (both innate and adaptive) through pleiotropic mechanisms [71]. They suppress inflammatory responses mainly by inhibiting the activation of nuclear factor (NF)-\(\kappa\)B, genes, encoding pro-inflammatory cytokines IL-4, IL-10, IL-13, and TGF\(\beta\) (Tables 2 and 3) [21; 72; 73]. Preliminary data from the RECOVERY trial showed an improved survival in hospitalized COVID-19 patients receiving either invasive mechanical ventilation or oxygen alone and who were treated with dexamethasone (6 mg once daily, administered orally or intravenously) [22]. Compared with usual care or a placebo, 28-day all-cause mortality resulted lower in patients with severe and critical COVID-19 when treated with systemic corticosteroids (i.e., dexamethasone or equivalent doses of other corticosteroids if not available) [74]. However, theoretical concerns that corticosteroids might slow viral clearance have been raised, thus co-administration with remdesivir is recommended. A phase 4 clinical trial (NCT04663555) is ongoing in order to evaluate the effect of dexamethasone in patients with ARDS and COVID-19 [75]. Pooled data from epidemiological studies showed a low prevalence of asthma and chronic obstructive pulmonary disease (COPD) in hospitalized COVID-19 patients, despite the high burden of these diseases [76]. Therefore, it has been suggested that inhaled corticosteroids (i.e., budesonide) might reduce the infection risk and the development of COVID-19 symptoms, inhibiting coronavirus replication and cytokine production. Indeed, in vitro studies showed a reduction of SARS-CoV-2 replication and a downregulated expression of both ACE2 and transmembrane protease serine 2 (TMPRSS2) genes, involved in viral entry into the host cells [77; 78]. Recently, an open-label, parallel-group, phase 2, randomized controlled trial compared the early administration of inhaled budesonide (total daily dose 1600 ug, until symptom resolution) with symptomatic treatment of cough and fever in 146 patients with mild COVID-19, stratified for age, sex, and number of comorbidities. Budesonide induced a 91% decrease of clinical impairment, reducing both the likelihood of requiring urgent care and time to recovery. Therefore, inhaled budesonide seems to be an effective treatment for early COVID-19 infection, likely unaffected by the emergence of new SARS-CoV-2 variants [79]. Nonetheless, the safety and efficacy of corticosteroids for the treatment of COVID-19 warrant more thorough investigations, particularly in patients with diabetes, obesity, hypertension, and cardiovascular disease. Indeed, many side effects related to a neurophysiological exposure to glucocorticoids (i.e., hyperglycemia, hypertension, weight gain and increased risk of cardiovascular events) are associated with severe outcomes in COVID-19. Bearing in mind that adverse effects related to glucocorticoid administration depend on the dose and duration of therapy, potential risks associated with the relatively short exposure to corticosteroids (~7-10 days) in treating COVID-19 should be further clarified [4; 71]. Additionally, as corticosteroids are substrates and moderate CYP3A4 inducers, potential pharmacokinetic interactions (Tables 4 and 5) should be assessed. \begin{table}
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