The most severe presentation of COVID-19 is characterized by a hyperinflammatory state attributed to the massive pro-inflammatory cytokine release, called “cytokine storm”. Several specific anti-inflammatory/immunosuppressive agents are being evaluated by ongoing clinical trials; however, there is currently insufficient evidence for their efficacy and safety in COVID-19 treatment. Given the role of phosphodiesterase 4 (PDE) 4 and cyclic adenosine monophosphate in the inflammatory response, we hypothesize that selective PDE4 inhibition may attenuate the cytokine storm in COVID-19, through the upstream inhibition of pro-inflammatory molecules, particularly TNF-α, and the regulation of the pro-inflammatory/anti-inflammatory balance. Conversely, other anti-cytokine agents lead to the downstream inhibition of specific targets, such as IL-1, IL-6 or TNF-α, and may not be efficient in blocking the cytokine storm, once it has been triggered. Due to their mechanism of action targeting an early stage of the inflammatory response and ameliorating lung inflammation, we believe that selective PDE4 inhibitors may represent a promising treatment option for the early phase of COVID-19 pneumonia before the cytokine storm and severe multiorgan dysfunction take place. Furthermore, PDE4 inhibitors present several advantages including an excellent safety profile; the oral route of administration; the convenient dosing; and beneficial metabolic properties. Interestingly, obesity and diabetes mellitus type 2 have been reported to be risk factors for the severity of COVID-19. Therefore, randomized clinical trials of PDE4 inhibitors are necessary to explore their potential therapeutic effect as an adjunct to supportive measures and other therapeutic regiments.

COVID-19 最严重的表现是由于大量促炎细胞因子释放而导致的高炎症状态，称为“细胞因子风暴”。正在进行的临床试验正在评估几种特定的抗炎/免疫抑制剂；然而，目前没有足够的证据证明它们在治疗 COVID-19 中的有效性和安全性。鉴于磷酸二酯酶 4 (PDE) 4 和环磷酸腺苷在炎症反应中的作用，我们假设选择性 PDE4 抑制可能通过上游促炎分子（特别是 TNF-α）的抑制来减弱 COVID-19 中的细胞因子风暴，以及促炎/抗炎平衡的调节。相反，其他抗细胞因子药物会导致特定靶标（例如 IL-1、IL-6 或 TNF-α）的下游抑制，一旦触发，可能无法有效阻止细胞因子风暴。由于其作用机制针对炎症反应的早期阶段并改善肺部炎症，我们相信选择性 PDE4 抑制剂可能是细胞因子风暴和严重多器官功能障碍发生之前的 COVID-19 肺炎早期阶段的一种有前景的治疗选择。此外，PDE4 抑制剂具有多种优势，包括出色的安全性；口服给药途径；方便的剂量；和有益的代谢特性。有趣的是，据报道，肥胖和 2 型糖尿病是导致 COVID-19 严重程度的危险因素。因此，有必要对 PDE4 抑制剂进行随机临床试验，以探索其作为支持措施和其他治疗方案的辅助手段的潜在治疗效果。