**4.1 Dexamethasone**

One such drug which has been recommended for use in critically ill COVID-19 subjects is the corticosteroid dexamethasone. A number of trials, most notably the RECOVERY trial have investigated the use of dexamethasone in individuals receiving advanced care for COVID-19, and have shown that the drug may of therapeutic *Targeting Mononuclear Phagocytes to Treat COVID-19 DOI: http://dx.doi.org/10.5772/intechopen.98967*

utility for severe cases [81]. This trial showed that in ventilated patients and patients receiving supplemental oxygen, that administration of IV dexamethasone resulted in a significant increase in 28-day mortality. Interestingly, however, the same results were not observed for individuals not receiving supplemental oxygen.

Among other mechanisms, one way by which corticosteroids decrease inflammation is by modulating cytokine release from monocytes and macrophages [82]. This can include, among other cytokines, IL-8, GM-CSF, and TNF-α [82, 83]. By modulating cytokine production in monocytes and macrophages, dexamethasone may lessen the strong cytokine storm that occurs in many people infected with SARS-CoV-2 [84].

#### **4.2 Baricitinib**

Baricitinib is a JAK 1 and 2 inhibitor which has currently received an emergency use authorization to be used in combination with remdesivir for the treatment of COVID-19. Previously, it had been approved for the treatment of rheumatoid arthritis [85]. In patients with COVID-19, in combination with remdesivir it has been shown to be superior to remdesivir alone in improving clinical status, especially in ventilated individuals [86]. Baricitinib likely functions in COVID-19 by decreasing the release of inflammatory cytokines from immune cells, including macrophages.

Non-human primate studies of baricitinib has shown that it can decrease the production of pro-inflammatory cytokines in lung macrophages, including TNF-α, IL-6, and IL-1β [72]. These modulations in cytokine expression from macrophages also blunted neutrophil influx into the lungs of these animals, which likely represents the mechanism by which the drug improves COVID-19 outcomes.

#### **4.3 Tocilizumab**

Tocilizumab is a monoclonal antibody therapeutic which has been approved for the treatment of rheumatoid arthritis [87]. Its mechanism of action is to act as an antagonist for the interleukin-6 receptor. By blocking this receptor, it is able to decrease signal transduction of this pathway and decrease the host inflammatory response. During the COVID-19 pandemic, it has gained considerable interest as a therapeutic for COVID-19. Its use is recommended as a single IV dose in combination with dexamethasone in patients who are critically ill in the ICU and receiving mechanical ventilation [88] . The evidence supporting the use of tocilizumab in COVID-19 is somewhat mixed, with some studies showing no benefit in the disease [89].

Macrophages are key producers of IL-6, and the IL-6 receptor is expressed on the surface of macrophages [90]. In COVID-19, some patients experience an overly strong cytokine response, commonly referred to as a cytokine storm, or hyperinflammation. Treatment with tocilizumab may be able to decrease this strong inflammatory response through blunting IL-6 signaling [91].

#### **4.4 Non-steroidal anti-inflammatory drugs (NSAIDs)**

To date, there has been considerable controversy to the potential benefit of NSAIDs for the treatment of COVID-19. These drugs inhibit the activity of the cyclooxygenase isoforms 1 and 2 [92]. In March of 2020, the French Minister of Health raised concerns based on case reports in the country showing individuals with worsened symptoms after the administration of NSAIDs [93]. This was further supported by previous studies in lower respiratory infections suggesting that NSAID usage could worsen disease outcomes. These studies, however, were relatively weak, and additional research is likely necessary to determine the effect of these drugs on respiratory infections [94]. There is some evidence that suggests that NSAIDs may be able to decrease the production of pro-inflammatory cytokines including TNF-α from macrophages, which may represent a potential mechanism of action of any potential benefits for the treatment of COVID-19 [95].
