The emergence of novel, as well as re-emergence of serious respiratory viral diseases in the current decade is of particular concern Fatal acute respiratory distress syndrome (ARDS) with rapid deterioration of vital organ functions has been observed in some patients infected with the highly pathogenic influenza virus strains, severe acute respiratory syndrome coronavirus (SARS-CoV), and middle east respiratory syndrome corona virus (MERS-CoV) The common manifestations of virus-induced fatal ARDS are cytokine storm and activation of monocytes/macrophages, characterized as secondary hemophagocytic syndrome (HPS)/hemophagocytic lymphohistiocytosis (HLH) However, infection-induced HPS/HLH is likely to be under-recognized, which could contribute to the serious progression and high mortality Since there are no established criteria for the diagnosis of infection-induced HPS/HLH, early recognition is crucial for any reasonable attempt at curative treatment Etoposide (ET), a cytotoxic agent, and corticosteroids (CS), with their strong anti-inflammatory activities, have been used to treat other diseases with similar pathophysiology, namely, cytokine-activated macrophages and hemophagocytic activity, but it remains unknown whether these agents can also influence the clinical outcomes in patients with fatal ARDS and secondary HPS/HLH We established an animal model of fatal ARDS, with severe lung injury, hypercytokinemia, and hemophagocytosis Using this animal model, we demonstrated that combined therapy with ET plus CS, targeting monocytes/macrophages, but not inflammatory cytokines, had the potential to attenuate the severity of fatal ARDS Specific treatment against HPS/HLH, including combined ET plus CS therapy, could be considered in patients with fatal ARDS complicated by secondary HPS/HLH To improve the outcomes in patients with infection-induced fatal ARDS, clinical and basic science studies are needed in the future to elucidate the mechanisms underlying the pathogenesis of ARDS and identify new treatment targets
