Type III IFNs can be a valid alternative to type I IFNs, because they maintain antiviral functions yet are less toxic and less prone to mediate immunopathology (182). The type III IFN, IFN-λ, activates NK cells indirectly (compared to type I IFNs which directly act on NK cells), resulting in a less potent and slower immune response (183, 184). IFN-λ activates NK cells by stimulating macrophages to produce IL-12 which in turn induce NK cells to produce IFN-γ (185). Pegylated IFN-λ is being tested in COVID-19 positive patients with mild symptoms in the absence of respiratory distress (NCT04331899). While IFN-λ can lead to the eventual activation of NK cells, its primary utility is in preventing the tissue damaging potential of neutrophils at mucosal surfaces, such as the lungs. However, IFN-λ also has been shown to reduce the rate of tissue repair, which in the context of COVID-19 which has a long disease course, could mean greater risk of secondary infections. Since exogenous administration of any IFN therapy poses the risk of tipping the balance toward severe COVID-19 immunopathology, Broggi et al. assessed the levels of IFNs in upper and lower respiratory samples from healthy and COVID-19 patients. In this preprint, they report that while the upper airway swabs showed similar mRNA expression levels of type I and III IFN compared to healthy controls, the BALF samples of severe COVID-19 patients had significantly elevated type I and III IFN levels (186). Therefore, as with all of the therapies discussed in this review, careful consideration about safe and effective timing should guide our design of clinical trials.