degranulation (77), and enhanced production of highly inflammatory neutrophil extracellular traps (NET) (78). Colchicine, which targets neutrophils, has shown some preliminary efficacy restricted to early outpatient therapy (79), as in-depth immunological profiling shows that neutrophils far exceed any other immune cell type in the blood (61, 80) and lung (81) of COVID-19 patients. Similarly, monocytes, although an order-of-magnitude lower in number than neutrophils, also display abnormalities in the blood, with evidence of proliferation and reduced levels of cyclooxygenase 2 (59). The massive influx of activated neutrophils and monocytes in COVID-19 can also generate highly damaging reactive oxygen species in the lung. These species are unaffected by anticytokine therapy, but catalytic antioxidants, such as compounds of the Tris-malonic fullerene family, which are effective in multiple animal models, could be beneficial (82).Timing of administration of anti-inflammatory therapy may impact efficacy. It is likely that early administration will result in the greatest benefit as it provides the best chance of preventing the cytokine storm and subsequent clinical deterioration. Current clinical trials and practice inadequately address this.Anticoagulation.A striking difference between COVID-19 and other severe respiratory infections is the significantly higher incidence of pulmonary and extrapulmonary thromboses (83–86). It was initially thought that these thromboses were secondary to sepsis-associated disseminated intravascular coagulation. However, it is likely that excessive or dysregulated immuno-thrombosis is driving the mechanism for the hypercoagulable state, with myeloid cells cooperating with coagulation pathways (predominantly, platelets) to restrict pathogen spread (87–89).The interaction between the immune system and coagulation pathways that leads to increased thrombosis is complicated. SARS-CoV-2 infects both the alveolar epithelium and endothelium via ACE2, facilitating extensive spread of infection, inflammation, and injury in alveolar-capillary beds (90). This inflammation and damage, coupled with increased platelet-vessel wall interaction, platelet activation, and reduced von Willebrand factor cleavage by reduced metalloprotease, are likely key contributors to thrombotic microangiopathy (91–93). Increased neutrophils, tissue macrophages, and abnormal monocytes and platelets (59) also contribute to abnormal immunothrombosis. NETosis in blood and tissue directly enhances thrombosis by triggering platelet activation and endothelial inflammation. Complement also contributes via C1q, C3, C3a, and C5a and the MAC complex to activate platelets and platelet-bound complement, which in turn increases the activity of neutrophils and NETosis (94).In most countries, patients admitted to hospital are immediately started on anticoagulation therapy with low molecular weight or unfractionated heparin as thromboprophylaxis. The benefit of therapeutic levels of anticoagulation as thromboprophylaxis is less clear but is supported by early results from REMAP-CAP and ATTACC trials (95). Other nonheparin-based anticoagulants like rivaroxaban (factor Xa inhibitors) have been tested in the context of comparing therapeutic vs. prophylactic anticoagulation and do not improve clinical outcomes (96). Given the immune system-coagulation pathways interplay, the most effective therapy for prevention of thrombosis might be a combination of anticoagulants and anti-inflammatory drugs.Affordable treatments that are effective early in the disease course, easy to deliver, and have minimal side effects would greatly improve our response to the pandemic. Inhaled therapies could address this need, and many novel therapeutics could be delivered this way, including corticosteroids, IFN, aptamers, and fullerene-based antioxidants.Inhaled corticosteroid (ICS) treatment may be effective in COVID-19 given that oral dexamethasone has shown benefit. ICS provides rapid delivery of corticosteroid directly to the lung, where it might down-regulate ACE2 expression and therefore SARS-CoV-2 entry (97). Early data have suggested the benefit of inhaled budesonide in early COVID-19 (98, 99). Well-established doses of inhaled corticosteroids have minimal systemic effects (100). Regulatory bodies in the United Kingdom have now endorsed ICS in nonhospitalized patients with the aim of preventing hospital admission.Another inhaled option is IFN, a family of proteins that display profound antiviral activity. Studies of genetic susceptibility to severe infection and natural autoantibodies against IFN-α have revealed that the severity of COVID-19 is highly dependent on the endogenous level of type 1 IFN (101, 102). Inhaled delivery of IFN-β, which is not susceptible to antibody inhibition, has shown value in early-phase studies and is being assessed at a larger scale (103). The combination of ICS and IFN-β could target both the excessive host response and the virus early in the disease, reducing viral burden and hospitalization as well as transmission.Aptamers.Aptamers are binding reagents made from modified nucleic acids, which have the same high affinity and specificity for pathogens as antibodies (104–106). A collection of modified DNA aptamers that target a broad range of epitopes on the SARS-CoV-