CoV-2 seronegative patients treated with mAbs had a reduced 28-d mortality, while seropositive patients had no benefit. Early antibody levels in COVID-19 may predict outcome in hospitalized patients (48). The intravenous route of administration presents a barrier to access for many patients. While the casirivimab-imdevimab emergency use authorization was recently modified to allow for four subcutaneous injections when intravenous administration is not feasible, this approach is currently unproven. Casirivimab-imdevimab has now also been shown to be effective at reducing symptomatic infection when used as postexposure prophylaxis (1.5% vs. 7.8%). There is also discussion about the use of mAbs as preexposure prophylaxis. Comprehensive data on this approach is still awaited, however, the combined therapeutic tixagevimab-cilgavimab has been given emergency use authorization for preexposure prophylaxis (49, 50). High cost, limited availability, and logistical challenges have limited the public health impact of mAbs.Anti-inflammatory Therapies.In common with other respiratory viruses, SARS-CoV-2 induces a “cytokine storm” or “cytokine release syndrome” in the most severely affected patients. Medicines directed at suppressing inflammation play an important role in therapy. Experience from SARS-CoV-1 and Middle East respiratory syndrome suggested that glucocorticoids did not confer benefit in inflammatory lung disease (51). However, the RECOVERY trial (3) and subsequently other randomized trials demonstrated reduced mortality with corticosteroids in COVID-19 (52–54). The benefit in the RECOVERY trial (n = 6,425) was seen in those who were mechanically ventilated or receiving supplemental oxygen. Overall, 22.9% patients in the dexamethasone group and 25.7% in the usual care group died within 28 d of randomization (age-adjusted rate ratio, 0.83; 95%CI 0.75 to 0.93). Subanalyses showed this difference was most marked among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%) and those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%). Current recommendations both in the United Kingdom and from the NIH in the United States are for all patients requiring hospitalization for supplemental oxygen treatment to receive 6 mg of dexamethasone per day for 10 d. Corticosteroids can be given orally or intravenously and are not expensive or cumbersome to distribute, making them a relatively accessible therapy.Many inflammatory mediators are induced in COVID-19, including interleukin (IL)-1, IL-2, IL-6, IL-7, GM-CSF, IFN-α–inducible protein 10 (IP-10), monocyte chemoattractant protein 1a (MCP1), and TNF (55–58). The excessive cytokine production drives abnormalities in many different cell types, including neutrophilia (59, 60), monocyte dysfunction (59, 61), and ultimately profound lymphopenia through immune exhaustion (Fig. 2). IL-6 concentrations correlate with viral load and levels are highest prior to the need for mechanical ventilation (62). Early studies with tocilizumab, which binds soluble and membrane-bound IL-6 receptors, showed mixed results (63, 64). Subsequently the large REMAP-CAP and RECOVERY trials have shown a modest mortality benefit in a broad hospitalized population on concurrent glucocorticoid therapy (65, 66). Janus kinase inhibitors target key proinflammatory cytokines induced by COVID-19 (67). Baricitinib with remdesivir, but no glucocorticoid, has shown some efficacy at reducing recovery time, and tofacitinib with glucocorticoid reduced the composite outcome of death or respiratory failure (68, 69). Baricitinib may be an alternative to dexamethasone in some cases and is now being directly compared in ACTT-4 (70).Major immunologic and coagulatory factors implicated in COVID-19 pathology. Viral infection leads to type I IFN, inflammatory mediator, and alarmin release from the respiratory epithelium/endothelium and resident immune cells setting-up a chemotactic gradient pulling cells from circulation into the lung. An emergency myelopoietic state occurs and neutrophils and monocytes display abnormalities in the blood in this state of high inflammation. Lymphocytes concurrently become depleted in circulation. Activated monocytes and macrophages can be an important source of cytokines, including IL-6. Enhanced by complement, clusters of neutrophils and activated platelets occur and neutrophil NETosis in blood and tissue directly augments thrombosis by supporting platelet activation. Size for each cell indicates its relative abundance in each compartment.Trials targeting other inflammatory mediators are underway, although, surprisingly, the most abundantly used anti-inflammatory monoclonal antibodies, which target TNF and have been used in over 10 million autoimmune disease patients to date, have not yet been definitively evaluated for COVID-19 (71–74). IP-10 and MCP-1 may also be good candidate targets since their levels track with COVID-19 disease severity (75) and are associated with respiratory failure (76).It is also surprising that methods to attenuate neutrophilia have not been investigated more thoroughly. Neutrophils in patients with COVID-19 display a range of abnormal features, including low density (59, 60), immaturity, a reduction in genes associated with