Other approaches, especially those therapeutic strategies that can target signaling pathways, either to suppress redundant immune responses or reduce viral replication, will be particularly noteworthy. Acknowledgments We acknowledge research funding from the National Nature Science Foundation of China (Grant Nos. evidence for the immunomodulatory and anti-inflammatory activity of macrolides (e.g., erythromycin, clarithromycin, roxithromycin, and azithromycin).62 Macrolides can interfere with the replication cycle of influenza virus, resulting in the inhibition of viral production from infected cells. Moreover, macrolide treatment of influenza virus-infected mice increased survival, suppressed inflammation, and reduced inflammatory cell counts.62 Arbidol is an antiviral that has complicated mechanisms. Both membrane-fusion-inhibition and immunomodulatory activity may contribute to its effects.63 Our current research confirmed that post-treatment with arbidol-reduced mortality, lung lesion formation, and viral-induced inflammation by modulating the expression of pro-inflammatory cytokines in influenza-infected mice.64 These data suggest that arbidol might also be effective in the treatment of severe influenza infections in humans. Herbs may also be a potential FRAP2 choice for patients hospitalized with severe influenza. Several Chinese herbal prescriptions were recommended and authorized by the Chinese government during the 2009 H1N1 and 2013 H7N9 Nepsilon-Acetyl-L-lysine pandemics.65,66 Systematic reviews for clinical trials of these herbs used in influenza treatment have revealed that few herbal medicines showed a positive effect on viral shedding, but they had a positive Nepsilon-Acetyl-L-lysine effect on resolution or relief of symptoms.67,68 Moreover, many herbs exhibit beneficial immunomodulatory effects for the rapid recovery of viral infections and might be effective treatments for infection with severe influenza.69 We have reported that extracts from Jiawei-Yupingfeng-Tang (a traditional Chinese herbal formula) can alleviate influenza-induced lung lesions with both antiviral and immunomodulatory activity.70 We also have confirmed that epigallocatechin gallate (EGCG), a green tea-derived polyphenol, can inhibit the pathogenesis of influenza-infected cells due to its antioxidant activity.71 Polyphenols, triterpenoids, and flavonoids, all from herbs, may potentially be active components in protecting against cytokine storm during severe influenza (unpublished data). However, confirmation in a larger series of clinical studies is required. 4. Conclusions The persistent outbreaks of avian influenza in Asia and parts of Africa suggest that severe influenza, such as avian influenza, poses a major threat to public health. Many severe-influenza-infected patients died from overwhelming viral pneumonia and serious complications caused by cytokine storm. In this review, we have highlighted the pathology of cytokine storm and, in particular, how an enhanced broad immune response can sometimes worsen the outcome of disease. Although the precise molecular events surrounding cytokine storm have not been clarified, immunomodulatory strategies and novel approaches in targeting the host’s response to severe influenza have been advocated. Considering that these agents work on different intracellular pathways, they might ideally be used in combination to obtain a better outcome. Based on the promising results mentioned above, combination therapies pairing S1PR and PPAR agonists, COX-2 inhibitors, and antioxidants with conventional antiviral agents are promising treatments that deserve further study in randomized clinical trials. Other approaches, especially those therapeutic strategies that can target signaling pathways, Nepsilon-Acetyl-L-lysine either to suppress redundant immune responses or reduce viral replication, will be particularly noteworthy. Acknowledgments We acknowledge research funding from the National Nature Science Foundation of China (Grant Nos. 81403163 and 81402404) and Yi Chang Scientific and Technological Bureau (Grant Nos. A14301-04 and A14301-10)..
Other approaches, especially those therapeutic strategies that can target signaling pathways, either to suppress redundant immune responses or reduce viral replication, will be particularly noteworthy