Inhaled Corticosteroid-Induced Adrenal Suppression in Patients With Asthma Detected by Metabolomic Profiling.
Inhaled Corticosteroid-Induced Adrenal Suppression in Patients With Asthma Detected by Metabolomic Profiling.
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DOI：
10.1016/j.jaip.2022.08.004
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发表时间：
2022-10
影响因子：
9.4
通讯作者：
Ortega, Victor E.
中科院分区：
文献类型：
--
作者：
Chiarella, Sergio E.;Bancos, Irina;Ortega, Victor E.
背景：吸入皮质类固醇（ICS）是哮喘管理的基石，最近更新的全球哮喘倡议（GINA）指南也推荐在青少年和成人中使用必要的吸入皮质类固醇-福莫特罗作为缓解选择(2)。重要的是，我们需要考虑使用ICS治疗的背景下，长期担心它可能会抑制下丘脑-垂体-肾上腺（HPA）轴（3-7）。例如，2013年，一个加拿大研究小组报告说，使用大剂量ICS是肾上腺功能不全的独立风险因素。不幸的是，大多数解决这些问题的研究都是相互矛盾的，并且受到相对较小的样本量和缺乏独立复制的限制。为了解决这些局限性并评估ICS治疗的生物学效应，作者在四个大型、特征明确的流行病学队列中进行了综合临床和代谢组学研究，其中包括14000多名哮喘患者。方法：发现阶段包括分析来自欧洲前瞻性癌症调查(EPIC)-Norfolk队列（n= 10,754； 661例哮喘）的代谢组学数据。随后的复制阶段在287名哮喘患者中进行，这些患者的代谢组学数据来自麻省总医院布里格姆生物银行(MGBB)-哮喘队列。在第三阶段，作者测量了参加儿童哮喘管理项目（CAMP; n= 1120）的儿童样本中的皮质醇和可的松水平。这些患者被随机分为吸入布地奈德（200微克）、奈多克米（8毫克）或安慰剂组，每天两次，平均持续4.3年。最后，作者利用电子病历(EMR)-皮质醇队列（n= 2235）的数据来确定ICS治疗对皮质醇水平的影响。结果：在EPIC-Norfolk队列中，经过多次比较调整，作者发现35种血浆代谢物与哮喘显著相关，其中34种代谢物在哮喘患者中低于对照组。所有34种代谢物都被标注为典型的糖皮质激素和雄激素途径。EPIC-Norfolk队列中鉴定的35种代谢物中有25种在MGBB-Asthma队列中可用，其中17种在哮喘患者中具有相同方向性的差异表达。这17种代谢物与典型的类固醇激素生物合成途径有关，在接受ICS治疗的哮喘患者中发现了最显著的代谢物差异。在CAMP中进一步评估了这一点，接受低剂量ICS的参与者的皮质醇和可的松水平明显低于随机接受奈多克龙或安慰剂的参与者。为了进一步证实emr -皮质醇队列，作者报告了与未接受ICS治疗的哮喘患者和未受影响的对照组相比，接受ICS治疗的哮喘患者的皮质醇水平显著降低。这些与ics相关的代谢物差异在早晨最为明显，并在白天波动。接受ICS治疗的哮喘患者也更容易出现疲劳和贫血，作者认为这可能是肾上腺功能不全的表现。
Background:Inhaled corticosteroids (ICS) are a cornerstone of asthma management, with recent updates in the Global Initiative for Asthma (GINA) guidelines also recommending the use of as-needed ICS-formoterol as a reliever option in adolescents and adults (2). Importantly, we need to consider the use of ICS therapy in the context of longstanding concerns that it might suppress the hypothalamic-pituitary-adrenal (HPA) axis (3–7). For example, in 2013, a Canadian research group reported that the use of high-dose ICS was an independent risk factor for adrenal insufficiency. Unfortunately, most studies addressing these concerns have been conflicting and limited by relatively small sample sizes and the lack of independent replication. To address these limitations and evaluate the biological effects of ICS therapy, the authors performed integrative clinical and metabolomics studies in four large, well-characterized epidemiologic cohorts constituting over 14,000 asthma patients.Methods:The discovery phase included analyzing metabolomic data from the European Prospective Investigation of Cancer (EPIC)-Norfolk cohort (n= 10,754; 661 with asthma). The subsequent replication phase was performed in 287 asthma patients with metabolomic data from the Mass General Brigham Biobank (MGBB)-Asthma cohort. For the third phase, the authors measured cortisol and cortisone levels in samples from children who participated in the Childhood Asthma Management Program (CAMP; n= 1,120). The patients were randomized to inhaled budesonide (200 mcg), nedocromil (8 mg), or placebo twice daily for an average of 4.3 years. Finally, the authors leveraged data from the Electronic Medical Records (EMR)-Cortisol cohort (n= 2,235) to determine the effects of ICS therapy on cortisol levels.Results:In the EPIC-Norfolk cohort, the authors found 35 plasma metabolites significantly associated with asthma after adjustment for multiple comparisons, of which 34 metabolites were lower in asthma patients compared to controls. All 34 metabolites were annotated to canonical glucocorticoid and androgen pathways. 25 of the 35 metabolites identified in the EPIC-Norfolk cohort were available in the MGBB-Asthma cohort, of which 17 were differentially expressed in asthma patients with the same directionality. These 17 metabolites were related to canonical steroid hormone biosynthesis pathways, and the most substantial metabolite differences were found in asthma patients on ICS therapy. This was further evaluated in CAMP, where those participants receiving low-dose ICS had significantly lower cortisol and cortisone levels compared to those randomized to nedocromil or placebo. For further confirmation in the EMR-Cortisol cohort, the authors reported significantly lower cortisol levels in asthma patients on ICS therapy compared to asthma patients off ICS therapy and unaffected controls. These ICS-related metabolite differences were most pronounced in the morning and fluctuated throughout the daytime hours. Asthma patients on ICS therapy were also more likely to experience fatigue and anemia, which the authors propose might be manifestations of adrenal insufficiency.
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影响因子：
24.3
作者：
Lapi, Francesco;Kezouh, Abbas;Ernst, Pierre
通讯作者：
Ernst, Pierre
影响因子：
14.2
作者：
Duplantier, JE;Nelson, RP;Kornfeld, SJ
通讯作者：
Kornfeld, SJ
DOI：
10.1183/13993003.02730-2021
发表时间：
2022-01
期刊：
The European respiratory journal
影响因子：
--
作者：
Reddel HK;Bacharier LB;Bateman ED;Brightling CE;Brusselle GG;Buhl R;Cruz AA;Duijts L;Drazen JM;FitzGerald JM;Fleming LJ;Inoue H;Ko FW;Krishnan JA;Levy ML;Lin J;Mortimer K;Pitrez PM;Sheikh A;Yorgancioglu AA;Boulet LP
通讯作者：
Boulet LP
影响因子：
158.5
作者：
Guilbert, TW;Morgan, WJ;Martinez, FD
通讯作者：
Martinez, FD
影响因子：
3.9
作者：
Allen, David B
通讯作者：
Allen, David B