Inhaled corticosteroids: not just for asthma, but for COVID-19?
Inhaled corticosteroids: not just for asthma, but for COVID-19?
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DOI：
10.1016/s2213-2600(22)00053-4
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发表时间：
2022-06
期刊：
影响因子：
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通讯作者：
Openshaw PJM
中科院分区：
文献类型：
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作者：
Liew F;Openshaw PJM
已经开发了一种多管齐下的方法来治疗COVID-19疾病：抗病毒药物和抗体治疗在SARS-CoV-2载量高的早期感染期间有效，而全身性类固醇和细胞因子阻滞剂最适合晚期炎症阶段1 -3（图）。在呼吸道合胞病毒感染的人体攻毒研究中，呼吸道粘膜预先存在的所谓免疫张力对于粘膜对病毒感染的接受性至关重要。4然而，到目前为止，在SARS-CoV-2感染中，很少关注改变呼吸道粘膜的状况。在本期《柳叶刀呼吸医学》中，Jonathan R Baker及其同事5提供了STOIC研究结果的最新进展，6表明在感染的初始阶段存在独特的鼻腔炎症反应，这可能会通过早期吸入布地奈德而改变。这一点很重要，因为皮质类固醇吸入剂被广泛用于哮喘，并且便宜，安全，容易获得。在2009-10年甲型H1N1流感大流行中，哮喘是严重疾病的主要危险因素。[7]在COVID-19的第一波疫情期间，人们认为哮喘将再次成为预后不良的预测因素，但在英国对2400万SARS-CoV-2感染患者进行的OpenSAFELY研究8表明，哮喘只是一个弱风险因素，使用皮质类固醇吸入器的慢性阻塞性肺病或哮喘患者在感染SARS-CoV-2后的预后更差（也许是因为他们倾向于有使人衰弱的既往肺部疾病）。然而，一项多中心英国研究报告称，在入院后2周内使用吸入性皮质类固醇的50岁或以上重度哮喘患者的生存率有所改善。9因此，吸入性皮质类固醇在COVID-19疾病中的作用存在相当大的不确定性。Baker及其同事招募了146名出现新的COVID-19症状的参与者;这些患者被随机分配（1：1）接受吸入干粉布地奈德或标准治疗。6布地奈德治疗后，尽管给药途径是肺部，但鼻和血浆样本中的炎症特征都发生了变化。然而，炎症介质如白细胞介素（IL）-10和IL-33的浓度变化很小，尽管有统计学意义（p<0.05）。作者推测，在症状出现7天内吸入布地奈德，通过调节鼻粘膜炎症改变疾病结局。贝克及其同事的研究结果还显示，11名临床恶化的COVID-19患者的抗病毒反应减弱。这一发现表明，需要一些适当的抗病毒炎症来预防严重疾病，这可能解释了为什么全身性地塞米松尚未显示出对轻度COVID-19疾病患者有益，实际上可能会造成伤害。2全身性类固醇会引起广泛的免疫抑制，这在严重COVID-19的晚期炎症阶段可能有帮助，但在疾病的早期阶段会通过抑制清除病毒所需的粘膜炎症而造成伤害。吸入类固醇可能会改变而不是抑制粘膜炎症，从而预防严重疾病（图）。
A multipronged approach has been developed for the treatment of COVID-19 disease: antivirals and antibody therapy are effective during early infection when the SARS-CoV-2 load is high, whereas systemic steroids and cytokine blockade are best for the late inflammatory phase1–3 (figure). In human challenge studies of respiratory syncytial virus infection, the preexisting so-called immunological tone of the respiratory mucosa is crucial to the receptiveness of the mucosa to viral infection. 4 However, so far, in SARS-CoV-2 infection, there has been little focus on altering the condition of the respiratory mucosa. In this issue of The Lancet Respiratory Medicine, Jonathan R Baker and colleagues5 provide an update on the outcomes of the STOIC study, 6 showing that there is a distinctive nasal inflammatory response during the initial phase of infection, which might be altered by early administration of inhaled budesonide. This is important, since corticosteroid inhalers are widely used for asthma and are cheap, safe, and readily available.In the influenza A H1N1 pandemic of 2009–10, asthma was a major risk factor for severe disease. 7 During the first wave of COVID-19, it was assumed that asthma would again be a predictor of poor outcomes, but the OpenSAFELY study8 of 24 million patients with SARS-CoV-2 infection in the UK showed that asthma is only a weak risk factor and that patients with chronic obstructive pulmonary disease or asthma who use corticosteroid inhalers have worse outcomes after SARS-CoV-2 infection (perhaps because they tend to have debilitating previous lung disease). However, a multicentre UK study reported that patients aged 50 years or older with severe asthma who had used inhaled corticosteroids within 2 weeks of admission show improved survival. 9 Therefore, there is considerable uncertainty about the effect of inhaled corticosteroids in COVID-19 disease. Baker and colleagues recruited 146 participants experiencing new symptoms of COVID-19; these patients were randomly assigned (1: 1) to receive inhaled dry-powder budesonide or standard care. 6 After treatment with budesonide, there were changes in the inflammatory profile in both nasal and plasma samples, although the route of administration was to the lung. However, the changes in the concentration of inflammatory mediators such as interleukin (IL)-10 and IL-33 were small, albeit statistically significant (p< 0· 05). The authors speculate that inhaled budesonide, taken within 7 days of symptom onset, alters disease outcome by modulating inflammation in the nasal mucosa. 5 The findings by Baker and colleagues also show a blunted antiviral response in 11 individuals with COVID-19 who clinically deteriorated. This finding suggests that some appropriate antiviral inflammation is required to prevent severe disease, which might explain why systemic dexamethasone has not been shown to benefit patients with mild COVID-19 disease, and in fact might cause harm. 2 Systemic steroids cause widespread immunosuppression, which might be helpful during the late inflammatory phase of severe COVID-19, but cause harm in the early phase of illness by dampening mucosal inflammation required to clear the virus. It is possible that inhaled steroids redirect rather than suppress mucosal inflammation, thus preventing severe disease (figure).