巴特利特博士给霍尔参议员的信和布地奈德雾化治疗的论文稿

新闻简述:本文包括一封巴特利特博士分享给America, Can We Talk? 网站上的给霍尔参议员的信和他的一篇论文稿。这是一项门诊病例报告,详述了两个美国的病例,患者分别患有肿瘤和二型糖尿病、高血压和痛风,两名患者经布地奈德雾化治疗均连续两次检验呈阴性。

相关新闻:德克萨斯医生巴特利特博士分享新冠特效药:布地奈德雾化剂

翻译:【Naomi(文花开)】校对:【重生】编辑整理:【Michelle】

战友之家玫瑰园小队出品

Photo from Robina Weermeijer via Unsplash and https://en.wikipedia.org/wiki/Budesonide

给霍尔参议员的信和论文稿中英文对照全文:

Dr. Bartlett’s letter to Senator Hall

巴特利特博士给霍尔参议员的信

Dear Senator Hall:

亲爱的霍尔参议员:

As a physician with frontline experience wrestling with COVID-19, I would like to share an effective treatment that is both intuitive and evidenced-based; a treatment easily positioned pre-hospital and rolled out into community settings. I discovered this treatment as a stopgap measure in order to empirically treat patients and manage their symptoms as the current recommendations from the CDC and WHO have no community-based strategies for COVID-19. To wit, the current guidelines only engage a course of treatment once symptoms have progressed to hospitalization and, in many occasions, an ICU admission with ventilator care. To explain this dilemma for Texans more clearly, the current guidelines discourage Texans from seeking any healthcare at all for mild to moderate symptoms; care only commences when Texans’ symptoms are so severe.

作为一名具有与COVID-19搏斗经验的一线的医生,我想分享一种既直观又基于证据的有效治疗方法;这种治疗方法很容易在院前定位并推广到社区环境中。我发现这种治疗作为一个权宜之计用于经验性患者治疗和管理他们的症状,因为不论CDC还是WHO都没有制定出社区性针对COVID-19治疗策略。也就是说,目前的指南只有在症状发展到住院时才会进行治疗,而且在很多情况下,需要入住ICU并进行呼吸机治疗。为了更清楚地解释德克萨斯人的这一窘境,目前的指南不鼓励德克萨斯人在出现轻度到中度症状时寻求任何医疗服务;只有当德克萨斯人的症状非常严重时,才会开始治疗。

they require critical care and hospitalization. However, there is an easily deployable pre-hospital community-based treatment for Texans. I administer a common respiratory anti-inflammatory corticosteroid, Budesonide, via a nebulizer directly to the lungs at the first signs and symptoms of COVID-19 and concurrently initiate COVID-19 testing. My rationale for choosing Budesonide over other corticosteroids is that it appears to block most of the cytokine storm inflammatory chemicals that COVID-19 triggers. In addition to my discovery, other organizations and nations are reviewing inhaled Budesonide to treat COVID-19. Inhaled Budesonide is currently under study at the NIH and is also undergoing study in France. Spain and Oxford University have both, individually, announced plans to study inhaled Budesonide as a COVID-19 therapy.

他们需要重症监护和住院治疗。然而,对于德州人来说,有一种易于开展的院前社区治疗方法。在患者刚出现COVID-19感染症状时,我会开一种常用呼吸道抗皮质激素—布地奈德雾化治疗,同时进行COVID-19检测。我之所以选择布地奈德替代其他皮质类固醇的理由是:该药似乎可以阻断COVID-19引发的大多数细胞因子风暴。除了我的发现,其它组织和国家也在评估了吸入式布地奈德治疗COVID-19的疗效。吸入式布地奈德目前正在美国国立卫生研究院进行研究,法国也在进行研究。西班牙和牛津大学都分别宣布将吸入式布地奈德用于治疗COVID-19患者的研究计划。

Thus far, 100% of my patients appear to be symptom-free following a course of inhaled

Budesonide therapy. These successful outcomes include Texans who are at the highest risk for a very poor prognosis. For example, an elderly woman who was my patient had two types of blood cancer and was immunocompromised and undergoing chemotherapy and radiation. She is now COVID-19 recovered with inhaled Budesonide therapy. (Note: To be COVID-19 recovered is defined as symptom-free with two consecutive negative tests.) Another one of my patients on the critical end of the spectrum included an elderly woman with a 50-year history of smoking, a history of high blood pressure and thyroid disease treatment, and a surgical history of four-vessel cardiac bypass surgery. Following a course of inhaled Budesonide therapy, she was also COVID-19 recovered. Both Texans avoided a hospitalization, a ventilator, and a possible demise. 

目前为止,我收治的所有病人在接受一个疗程的吸入性布地奈德治疗后似乎未出现症状。这些成功的病例也包括那些预后极差而处于高风险的德州人。例如,我的一位老年妇女患者患有两种类型的血癌,免疫力低下,正在接受化疗和放疗。经吸入性布地奈德治疗后,她现在已经康复。(注:COVID-19康复标准:连续两次检测呈阴性,无症状。) 我的另一位危重患者是一位50年吸烟史的老年妇女,有高血压和甲状腺疾病治疗史,四根血管心脏搭桥手术史。经过一个疗程的吸入性布地奈德治疗后,她也得到了康复。这两位德州人都避免了一次住院、一次呼吸机和一次可能的死亡。

Inhaled Budesonide is a therapy safe for fragile Texans. It has been studied and utilized for lung-related inflammation for over 20+ years and is safe enough for 2-pound infants in the NICU. As I reviewed the efficacy of corticosteroids in other COVID-19 settings, I found that many of the nations that initiated a variation of my treatment also found incredible success. For example, Taiwan, a nation of 24 million, treats early with a different inhaled corticosteroid and has had only had seven deaths over the duration of this pandemic. Or consider Japan, who also treated with an inhaled corticosteroid. Although Japan’s demographics skew towards an older population, they have had only 977 deaths in a nation of 121 million. Likewise, consider South Korea with population of 50 million who recorded only 283 deaths using an inhaled corticosteroid. (see coronavirus.jhu.edu)

吸入布地奈德是一种适用于身体虚弱的德州人的安全疗法。该药治疗肺部相关炎症的研究和临床使用已经超过20年,对新生儿重症监护室中2磅重的婴儿也足够安全。当我回顾皮质类固醇被用于治疗其他感染COVID-19条件的疗效时,我发现许多采用与我治疗方案类似的国家也取得了难以置信的成功。例如,台湾这个拥有2400万人口的国家,使用不同的吸入性皮质类固醇激素治疗方案进行早期诊治,而且在这次大流行时期中仅仅只有7人死亡。在看看日本,他们也用吸入性皮质激素治疗。虽然日本的人口结构偏老龄化,但这个1.21亿人口的国家只有977人死亡。同样,看看拥有5千万人口的韩国,他们使用吸入性皮质激素的死亡人数只有283人。(见 coronavirus.jhu.edu)

Finally, although the FDA does not have any approved medicines specifically for COVID-19, they have approved Budesonide nebulizer therapy to treat other respiratory inflammatory disorders. As such, inhaled Budesonide is an intuitive frontline defense for the COVID-19 outbreak. And best of all, it is easily rolled-out in primary care delivery settings in Texas. 

最后,虽然FDA没有批准任何专门针对COVID-19的药物,他们已经批准布使用布地奈德雾化治疗其他呼吸道炎症疾病。因此,吸入式布地奈德是应对COVID-19爆发的直观的前线防御措施。而且最重要的是,它很容易在德克萨斯州的基层医疗服务机构中推广。

Delayed treatment is not a valid health strategy for any disease including COVID-19. During my service on the Governor-appointed Health Disparities Taskforce for Texas, our recommendations always included access to early detection and treatment. It is my opinion that inhaled Budesonide therapy is one such early treatment for COVID-19.

对于任何疾病,包括COVID-19,延迟治疗都不是有效的健康策略。我任职于由德克萨斯州州长委派建立的健康差异特别工作组时,我们的建议总是包括早发现和早治疗。我认为,吸入布地奈德疗法是治疗COVID-19的一种早期疗法。

Sincerely,

Richard P. Bartlett, MD

真诚的,

理查德·P·巴特利特,医学博士

Case Study Report

SARS-CoV-2 and The Case for Empirical Treatment

案例研究报告

SARS-CoV-2和经验性治疗的案例

Authors — Richard P. Bartlett, MD and Alexandria Watkins, DNP

作者:Richard P. Bartlett, MD 和 Alexandria Watkins, DNP

SUMMARY 摘要

As of June 17, 2020, Google Trends reports that the topics “steroids and coronavirus” have increased +4,750%.[12] This is an outpatient case study that examines two patients in the United States with unique cases that involve oncology and Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), also known as COVID-19. This case study aims to reveal the identification process, diagnosis, clinical course, and management of such a distinctive case – including the patient’s prodromal phase and subsequent progression of the disease in an outpatient setting utilizing telemedicine. The goal is to call attention to the success of proactive, early empirical treatment, combining a classic corticosteroid (budesonide) administered via a nebulizer and an oral macrolide antibiotic known as clarithromycin (Biaxin).

截至2020年6月17日,谷歌趋势(Google Trends)报告说,“类固醇和冠状病毒 ”主题增加了+4,750% [12]。 这是一项门诊病例研究,研究了两名来自美国的特殊病例,包括患有肿瘤和严重急性呼吸综合征冠状病毒-2(SARS-CoV-2),也称为COVID-19。本病例研究旨在揭示这样一个特殊病例的识别过程、诊断、临床病程和管理—包括患者在门诊环境下利用远程医疗进行疾病的前驱期和后续进展。目标在于呼吁业内人士关注这项前瞻性的早期经验性治疗的成功,该治疗是采用经典皮质类固醇(布地奈德)气雾剂给药与大环内酯类抗生素克拉霉素(克拉仙)口服使用的联合用药方案。

INTRODUCTION 引言

A classic drug and a novel case, it is a story out of a Disney playbook – Beauty and The Beast.[41] A beauty named budesonide and a beast named SARS-CoV-2. Budesonide, a drug initially patented in 1973 and on the World Health Organization’s (WHO) List of Essential Medicines, and SARS-CoV-2 first presenting itself in the United States on January 20, 2020.[8&46] This is a case study that demonstrates the effectiveness of treating a respiratory disease with a pinpoint focused nebulized therapy versus systemic therapy. One can go as far back as ~1554 BC and find that even the ancient Egyptians had an appreciation for the therapeutic effects of sequestered aerosol inhalation.38 The aim of pinpoint focused treatment is to find specific targets and treat effectively with minimal side effects. “Work smarter, not harder” is an underlying theme with early, pinpoint focused empirical treatment.

一个老药新用案例,这是一个出自迪斯尼剧本的故事—《美女与野兽》[41],一个名叫布地奈德的美女和一个名叫SARS-CoV-2的野兽。布地奈德,是一种最初在1973年获得专利的药物,并被列入世界卫生组织(WHO)基本药物清单,而SARS-CoV-2首次在美国上市是在2020年1月20日 [8&46]。该案例研究展示了与全身性治疗相比,使用针尖聚焦雾化治疗一种呼吸系统疾病的疗效。人们可以追溯到公元前约1554年,发现即使是古埃及人认可封闭环境下雾化吸入治疗的效果 [38]。 精确定位聚焦治疗的目的是找到特定的目标,并以最小副作用进行有效治疗。“更聪明地工作,而不是更努力地工作”是早期精准聚焦经验治疗的根本主题。

Like asthma, SARS-CoV-2 is a form of a respiratory inflammatory disease that is more severe and acts on the angiotensin-converting enzyme (ACE) receptors of the lungs.SARS-CoV-2 presents as a local vascular problem due to the activation of Bl receptors on endothelial cells within the lungs – Bl receptors increase the response to proinflammatory cytokines. This activation takes place when the angiotensin-converting enzyme 2 (ACE 2) acts as a receptor, permitting the spike protein of SARS-CoV-2 to bind to host cells. When ACE 2 is interrupted, and the ligands of Bl are active, the lung environment is predisposed to vascular leakage and angioedema — rapid swelling in the mucosa. The primed spike protein is also allowed viral entry and spread by the transmembrane protease, serine 2 (TMPRSS2).24′ 34 & 43 Multiple studies agree with our discovery that inhaled corticosteroids (ICS) via nebulizer permit for localized down-regulation of proin flammatory cytokine synthesis and decreased expression of ACE 2 (receptor Of SARS-CoV-2) and TMPRSS2, thus reducing mortality .15, 23, 24, 28, 34 & 49 For this reason, this case study postulates that focused treatment with nebulized budesonide has clinical significance over systemic corticosteroids and does not increase the risk of infection with SARS-CoV-2.2, 24 & 30 This case study supports early empirical treatment in symptomatic patients. 

和哮喘一样,SARS-CoV-2也是一种呼吸道炎症疾病,它的发病率更加严重,并作用于肺部血管紧张素转换酶(ACE)受体。SARS-CoV-2临床表现为局部血管问题,这是由于肺部内皮细胞上的Bl受体被激活后增加了对促炎细胞因子的反应。 当血管紧张素转换酶2发挥受体作用使新冠肺炎病毒S-蛋白能够与宿主细胞结合时,这种激活反应就能发生。 当ACE 2被中断,Bl配体活跃时,肺部环境容易出现血管渗漏和血管性水肿—粘膜迅速肿胀。S-蛋白也允许病毒入侵并通过跨膜丝氨酸蛋白酶2进行扩散(TMPRSS2)[24,34 & 43]。多项研究也验证我们的发现,通过吸入性皮质类固醇(ICS)雾化治疗方案能局部下调促炎细胞因子合成并减少ACE 2(SARS-CoV-2的受体)和TMPRSS2的表达,从而降低死亡率 [15,23,24,28,34和49]。为此,该个案研究推测:采用局部布地奈德雾化治疗比全身皮质激素治疗更具临床意义,且不增加SARS-CoV-2的感染风险 [2,24及30]。本案例研究为有症状患者进行早期经验性治疗提供证据支持。

METHODS 方法

Study Population, Setting, and Data Collection 研究对象、环境和数据收集

This case study involves two patients in the outpatient setting – treated via telemedicine, with laboratory-confirmed SARS-CoV-2 infection in the West Texas region betweenMarch 29th, 2020, and May 14th, 2020. The cases presented are confirmed SARS-CoV-2 positive cases as defined by a positive result on a reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay of a specimen collected on a nasopharyngeal swab.The two identified adults were identified and managed through telemedicine by a primary care provider in an outpatient family medicine practice.

Informed consent for medical records release was obtained through password-protected emails, and patients were interviewed by phone. 

本案例研究涉及两例采用远程治疗的门诊患者,于2020年3月29日至2020年5月14日期间在西德克萨斯地区经实验室确诊为SARS-CoV-2感染。所介绍的病例是经确认的SARS-CoV-2阳性病例,其定义是对采集的鼻咽拭子标本进行的逆转录酶-聚合酶-链反应(RT-PCR)检测结果呈阳性。这两名确诊成年人由一名家庭医学门诊的基层保健人员通过远程医疗进行身份核实和管理。通过受密码保护的电子邮件与其签署医疗信息披露的知情同意书,并通过电话采访了患者。

CASE REPORT 案例汇报

The first patient is a 63-year-old female, non-smoker, who is diagnosed with Waldenstrom’s Macroglobulinemia (2012) and Primary Cutaneous Marginal Zone Lymphoma (2020) and currently being treated with ibrutinib (Imbruvica). The patient also has a history of hypertension and hypothyroidism; treatment for these comorbidities includes losartan potassium 50mg tab once-daily, and levothyroxine 50mcg tab once- daily respectively. 

第一位患者是位63岁的女性,无吸烟史,2012年被诊断为华氏巨球蛋白血症2020年被诊断为原发性皮肤边缘区淋巴瘤,目前正在接受依鲁替尼(Imbruvica)治疗。患者患有高血压和甲状腺功能减退症,这些合并症用药如下:氯沙坦钾50毫克每天一次,左甲状腺素钠50毫克每天一次。

The patient reports complete isolation until May 7th, 2020, when her family visited, this is the initial exposure date. On May 10th, 2020, the patient became symptomatic with sinus cavity pressure, fever, aches, and chills. In the early morning hours of May 11th, the patient had multiple episodes of nausea and vomiting and, by that evening, had fever greater than 100.4 degree F , constant chills, unproductive cough, decreased appetite related to change in taste and smell. The patient remand symptomatic and continued to self-isolate until May 15th. she received news that she had been exposed to a family member on May 7th, that tested positive for SARS-CoV-2.Upon hearing the report, the patient reached out via telemedicine to an outpatient family medicine doctor. The patient was tested for SARS-CoV-2 via nasopharyngeal swab using a reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay. 

在2020年5月7日(最初暴露日期)她家里人来访前,该病人一直处于完全隔离。2020年5月10日,患者出现鼻窦腔压痛、发热、疼痛、发冷等症状。5月11日凌晨,患者多次出现恶心呕吐,到当晚,发热大于100.4华氏度,持续发冷,无力咳嗽,味觉与嗅觉改变导致的食欲减退。5月15日前患者症状未见好转并继续进行隔离治疗她收到消息说,她5月7日接触的那位家庭成员被检测出SARS-CoV-2阳性。听到报告后,患者通过远程医疗联系到了门诊家庭医生。该患者通过鼻咽拭子采用反转录酶-聚合酶-链反应(RT-PCR)检测是否感染SARS-CoV-2。

At this time (May 15th, 2020), the patient was empirically started on budesonide 0.5mg nebulizer twice daily, clarithromycin (Biaxin) 500mg tab twice daily for ten days, Zinc 50mg tab twice daily, and aspirin 81mg tab daily. The patient reported for the next two-days, symptoms improved once nebulized budesonide had been administered. By May 19th, the patient developed a productive cough, pleuritic pain, and diarrhea. On May 20th, the patient’s RT-PCR assay for SARS-CoV-2 was confirmed positive, ten days after initial symptoms. A telemedicine consult was performed the same day (May 20th), and budesonide administration was increased from twice daily to three times daily. The patient reports that on May 24th, symptoms started to improve, and on May 25th, the patient completed the clarithromycin (Biaxin) prescription and notes that this was the first day of no fevers.

此时(2020年5月15日),患者开始接受治疗,方案为:布地奈德雾化治疗500微克/次,每日两次,口服克拉霉素(克拉仙)500mg /次每日两次,连续服药十天,锌50毫克/次,每日两次,阿司匹林81毫克/次,每日一次。使用布地奈气雾剂治疗两天后,患者反馈症状有所缓解。到5月19日,患者出现排痰性咳嗽、胸膜疼痛和腹泻。5月20日,患者SARS-CoV-2RT-PCR检测为阳性,此时距初始症状出现已有10日。当日(5月20日)进行了远程医疗会诊,布地奈德给量由每日两次增加到每日三次。该患者反馈5月24日,症状开始好转。5月25日,患者按处方完成克拉霉素(克拉仙)服用,同时当天首次出现发热退却。

As the patient continued to remain symptom-free, a second RT-PCR assay was ordered via telemedicine on May 29th, and on June 2nd , the patient was still positive for SARS-CoV-2; this is 24-days from initial symptoms. On June 8th, the patient had been symptom-free for 14-days, a third RT-PCR assay was ordered via telemedicine, and on June 10th, the patient received their first negative result for SARS-COV-2. A fourth RT-PCR assay was ordered on June 11th, via telemedicine, and on June 17th, the patient received a second negative result. The patient has remained symptom-free, and as of June 11th, has no longer needed nebulized budesonide therapy.

由于患者继续保持无症状,5月29日,通过远程医疗预约第二次RT-PCR检测,6月2日,患者的SARS-CoV-2结果仍呈阳性;初始症状至今已有24天。6月8日,患者已14天未出现症状,通过远程医疗预约第三次RT-PCR检测,6月10日,患者收到了SARS-COV-2检测结果初次呈现阴性。6月11日,通过远程医疗预约第四次RT-PCR检测,6月17日,检测结果再次呈现阴性。患者一直没有出现症状,截至6月11日,已经不需要布地奈德气雾剂治疗。

Assumed Initial Exposure Date (推测初次暴露日期): May 7, 2020 (2020年5月7日) Empirical Treatment Start Date (试验性治疗开始日期): May 15, 2020 (2020年5月15日)
Test Date (测试日期):Result and Date Received (收到结果日期):
May 15, 2020 (2020年5月15日)Positive — May 20, 2020 (阳性—2020年5月20日)
May 29, 2020 (2020年5月29日)Positive — June 2, 2020 (阳性—2020年6月2日)
June 8, 2020 (2020年6月8日)Negative — June 10, 2020 (阴性 —2020年6月10日)
June 11, 2020 (2020年6月11日)Negative — June 17, 2020 (阴性—2020年6月17日)

The second patient is a 38-year-old male, non-smoker, who has the following comorbidities: Type II Diabetes Mellitus (DM), hypertension, and gout. The patient takes Metformin 1,000mg tab, twice daily and Pioglitazone 15mg tab, daily for Type II DM, Lisinopril 2.5mg tab, daily for hypertension, and Probenecid 500mg tab, daily for gout.

第二例患者:38岁男性,无吸烟史,有以下合并症:二型糖尿病(DM),高血压,和痛风。患者每日服用二甲双胍1,000毫克/次,每日两次,服用吡格列酮15mg/次,治疗II型糖尿病。每日服用利辛普利赖诺普利2.5毫克/次治疗高血压,每天服用丙磺舒500mg/次治疗痛风。

The patient believes initial exposure was in Frisco, TX, on March 7th, 2020, while shopping at a shopping center. On March 29th, 2020, the patient became symptomatic with cough, sore throat, loss of smell and taste, fever (>100.4 degree F ), aches, and chills. March 29th, the patient was tested for Influenza using the rapid influenza diagnostic test (RIDT), the test was negative, and the patient was discharged home.

患者认为初次接触于2020年3月7日在德克萨斯州弗里斯科市的购物中心。2020年3月29日,患者出现咳嗽、喉咙痛、嗅觉和味觉丧失、发烧(>100.4华氏度)、疼痛和寒颤症状。3月29日,患者使用快速流感诊断试剂(RIDT)进行流感检测,检测结果为阴性,患者出院返家。

At this time, the patient accessed his primary care doctor via telemedicine, he was treated empirically and started on budesonide 0.5mg nebulizer twice daily, clarithromycin (Biaxin) 500mg tab twice daily for 10 days, Zinc 50mg tab twice daily, and aspirin 81mg tab daily. April 1st, 2020 (three days after onset of symptoms), the patient was able to undergo SARS- CoV-2 testing, he was tested by nasopharyngeal swab using an RT-PCR assay. On April 3rd, the patient was informed that he had tested positive for SARS -CoV-2, six days after initial symptoms had ensued. 

此时,患者通过远程医疗接入主治医生,并接受经验性治疗,开始接受布地奈德气雾剂治疗0.5毫克,两次/天,克拉霉素(克拉仙)500毫克/次,每日2次,连续使用10天,锌50毫克/次,每日2次,阿司匹林81毫克/次,每天服用。2020年4月1日(症状发生后3天),患者可以进行SARS- CoV-2检测,他通过鼻咽拭子采用RT-PCR检测。4月3日,患者被告知他的SARS-CoV-2检测结果呈阳性,此时距离最初的症状已经过去6天。

The patient reports that he was symptom-free April 4th, and completed his full round of clarithromycin (Biaxin) on April 7th. The patient continued budesonide 0.5mg nebulizer twice daily, Zinc 50mg tab twice daily, and aspirin 81mg tab daily. As the patient continued to remain symptom-free, a second RT-PCR assay via nasopharyngeal swab was ordered via telemedicine on April 15th ending with a positive result for SARS-CoV-2.

患者报告说,他在4月4日未出现症状,并于4月7日完成克拉霉素(克拉仙)全疗程用药。患者继续服用布地奈德气雾剂0.5毫克/次,每日2次,锌50mg/次,每日2次,阿司匹林81mg/次日。由于患者继续持续无症状,4月15日通过远程医疗订购了第二份通过鼻咽拭子进行的RT-PCR检测,结果为SARS-CoV-2阳性。

 At this time azithromycin 500mg tab on day one, then 250mg tab, daily for four-days was started. On April 27th, the patient was re-tested via RT-PCR assay and again tested positive. It was not until May ISt that the patient tested negative per the nasopharyngeal swab RT-PCR assay. On May 7th, the patient was tested with another RT-PCR assay by nasopharyngeal swab to confirm the negative test result but tested positive for SARS-CoV-2. The patient had no new exposure and been self-quarantined since April 1st. The patient was re-screened again by nasopharyngeal swab using RT-PCR May 11th and tested negative for SARS-CoV-2. 

此时开始服用阿奇霉素500毫克,第一天,然后250毫克/次日,连续服用四天。4月27日,患者再次通过RT-PCR检测检测,结果再次呈阳性。直到5月1日,患者通过鼻咽拭子RT-PCR检测,检测结果为阴性。5月7日,患者又接受了鼻咽拭子RT-PCR检测,验证前次阴性检测结果,但最终结果显示SARS-COV-2阳性。患者没有新的暴露,自4月1日起一直自我隔离。5月11日,该患者再次接受鼻咽拭子RT-PCR检测,SARS-CoV-2检测结果为阴性。

The patient completed a total of four rounds of Azithromycin 500mg tab on day one, then 250mg tab, daily for four-days, and stopped budesonide 0.5mg nebulizer twice daily, May 13th. He continued Zinc 50mg tab twice daily, and the aspirin 81mg tab daily, until a second consecutive negative was obtained. On May 14th, the last test that was performed on the patient was the nasopharyngeal swab using an RT-PCR assay and again confirmed a negative result.

该患者共完成四个阿奇霉素治疗疗程(首日500毫克,后四天250毫克/天)治疗5月13日暂停布地奈德气雾剂0.5毫克/次,两次/日治疗。他继续服用锌剂50毫克/次,每日2次,阿司匹林81mg /次日,直至第二次检测结果连续阴性。5月14日,该患者接受最后一次鼻咽拭子RT-PCR检测,并再次确认阴性结果。

Assumed Initial Exposure Date (推测初次暴露日期): May 7, 2020 (2020年5月7日) Empirical Treatment Start Date (试验性治疗开始日期): May 29, 2020 (2020年5月29日)
Test Date (测试日期):Result and Date Received (收到结果日期):
April 1, 2020 (2020年4月1日)Positive — April 3, 2020 (阳性—2020年4月3日)
April 15, 2020 (2020年4月15日)Positive — April 19, 2020 (阳性—2020年4月19日)
April 27, 2020 (2020年4月27日)Positive — April 27, 2020 (阳性–2020年4月27日)
May 1, 2020 (2020年5月1日)Negative — May 3, 2020 (阴性—2020年5月3日)
May 7, 2020 (2020年5月7日)Positive — May 10, 2020 (阳性—2020年5月10日)
May 11, 2020 (2020年5月11日)Negative — May 13, 2020 (阴性—2020年5月13日)
May 14, 2020 (2020年5月14日)Negative — May 15, 2020 (阴性—2020年5月15日)

DISCUSSION 讨论

Budesonide布地奈德

Since the outbreak of the novel SARS-CoV-2 infection, there have been inconsistencies in the information that has been disseminated regarding the potentially deleterious effect of treating patients with corticosteroids, nonsteroidal anti-inflammatory drugs (NSAlDs), and non-NSAlDs.  Nonsteroidal anti-inflammatory drugs induce their intrinsic inhibitory functions on the cyclooxygenase enzymes (COX-1/COX-2). These enzymes are involved in the synthesis of crucial biological mediators – mediators that regulate inflammation. Corticosteroids, such as budesonide, participate in several basic physiological processes such as aiding in immune system response and inflammatory regulation. Budesonide destabilizes the messenger RNA (mRNA) of the inflammatory gene, COX-2, by blocking the protein synthesis, thus suppressing the transfer of genetic information that allows for inflammation to take place.5

自从新型SARS-CoV-2感染爆发以来,关于用皮质类固醇、非甾体抗炎药(NSAlDs)和非NSAlDs治疗患者的潜在毒副作用的信息一直不一致。非甾体类抗炎药对环氧酶(COX-1/COX-2)具有内在的抑制功能。这些酶参与关键生物介质的合成—调节炎症的介质。皮质类固醇,如布地奈德,参与几个基本的生理过程,如协助免疫系统反应和炎症调节。布地奈德通过阻断蛋白质合成破坏炎症基因COX-2的信使RNA(mRNA)的稳定性,从而抑制诱导炎症发生的遗传物质的传递。

Corticosteroid pretreatment abates cytokine stimulation significantly by reducing both inflammatory mediators’ cytosolic phospholipase A2 (cPLA2) and COX-2 mRNA status as well as prostaglandin (PGE) release. The physiological effect of budesonide in reducing PGE production occurs primarily at the mRNA level by preventing the launch of cPLA 2 and particularly COX-2.29 Using nebulized budesonide early on in the treatment plan of symptomatic SARS-CoV-2 patients is valuable when trying to avoid an overreaction of the immune system causing a ‘cytokine storm’ — a response that wreaks havoc on healthy cells rather than incapacitating the virus. 

皮质类固醇预处理通过抑制炎症介质的细胞磷脂酶A2(cPLA2)和COX-2 mRNA活性,从而能显著减弱细胞因子激活,同时还能减少前列腺素分泌。布地奈德减少PGE分泌而产生的生理效应主要体现在mRNA水平上,其可以抑制cPLA 2和特异性COX-2的活性 [29]。在有症状的SARS-CoV-2患者的治疗计划中,早期使用雾化布地奈德临床价值,可以避免因免疫系统过度反应而引发的 “细胞因子风暴”–一种对健康细胞造成严重破坏而非消灭病毒的反应。

Budesonide represents the first example of a drug able to inhibit the production of proinflammatory cytokines/chemokines like IL-6, IL-8, and TNF-α from human lung macrophages activated by secretory phospholipids A2 (sPLA2).40 Corticosteroids like budesonide were universally used during the SARS-CoV outbreak because of their recognized ability to regulate a variety of involved cytokines (including IL-I, IL-3, IL-4, IL-5, IL-6, IL-8, IL-11 IL-12, IL-17A GM-CSF, and TNF-a). 11, 23, 33, 36 & 50 Research shows that early intervention with ICS like budesonide decreases the need for systemic corticosteroid use. Inhaled corticosteroids modestly improve airflow function. 32 & 51

布地奈德是第一个能够抑制由分泌性磷脂A2(sPLA2)激活的人肺尖细胞产生的促炎细胞因子/趋化因子如IL-6、IL-8和TNF-α的药物 [40]。像布地奈德这样的皮质类固醇在SARS-CoV爆发期间被普遍使用,因为它们被公认为具有调节多种复杂细胞因子的作用(包括IL-I、IL-3、IL-4、IL-5、IL-6、IL-8、IL-11 IL-12、IL-17A GM-CSF和TNF-a)[11, 23, 33, 36 ,50]。研究表明:早期使用像布地奈德这样的吸入性皮质固醇类药物进行干预ICS进行干预,可减少全身性皮质类固醇药物治疗的需要。吸入式皮质激素可适度改善气流功能 [32 & 51]。

According to Russell et al., there is no “definitive evidence” that establishes a stance on the use of NSAlDs for the treatment of SARS-CoV-2. Still, there is evidence that corticosteroids can produce favorable results in the treatment of SARS-CoV.36 Oncology patients who are immunocompromised benefit from prescribed low-dose corticosteroids.9&36 There is also a decreased risk of pneumonia in COPD patients who use nebulized budesonide.16 

根据Russell等人的说法,目前还没有 “明确证据 “支持将NSAIDs药物用于治疗SARS-COV-2患者。但仍有证据表明,皮质类固醇在治疗SARS-CoV时可产生有利的结果.36免疫功能低下的肿瘤患者使用低剂量皮质类固醇可获益.9&36使用布地奈德气雾剂能降低COPD患者发生肺炎的风险 [16]。

In contrast, when systemic corticosteroids were used inSARS-CoV-2 hospital patients there was no evidence of shortened pneumonia duration, decrease in days stayed in the hospital, or reduced risk of mortality.48 This case study has affirmed that an empirical treatment protocol with nebulized budesonide and the efficacy of treating symptomatic patients earlier rather than later has significant implications. Halpin et al. is in agreeance with early management and encourages increased dosing with ICS for SARS-CoV-2 patients.17 The treatment plan has evolved and become more effective by increasing the dosage and frequency of nebulized budesonide.

与此相反,当给SARS-CoV-2住院患者使用全身性皮质类固醇治疗时,没有证据表明这样能缩短肺炎持续时间,减少住院天数,或降低死亡风险 [48]。这个病例研究已经确定布地奈德气化剂作为经验性治疗方案和尽早治疗有症状患者具有重要意义。Halpin等同意早期管理,并鼓励对SARS-CoV-2患者增加ICS使用剂量 [17],该治疗方案已不断完善,同时通过增加布地奈德气化剂使用剂量和使用频次明显增加临床疗效。

Budesonide has proven to be useful in the prevention of asthma (an inflammatory disease in the lungs), and when regularly used, budesonide has shown to decrease the severity and number of asthma attacks. SARS-CoV-2 is a much more severe form of inflammatory disease in the lungs with the primary source of infection at the ACE receptors in the lungs.

布地奈德已被证明对预防哮喘(一种肺部炎症性疾病)很有帮助,当定期使用时,布地奈德已被证明可以降低哮喘发作的严重程度和频率。SARS-CoV-2是一种更严重的肺部炎症疾病,主要感染源在肺部的ACE受体。

 It is important to note that for asthmatics who are having an acute inflammatory response and people with late symptoms of SARS-CoV-2, budesonide is ineffective. Hence, routine daily treatment of budesonide ICS for asthmatics and early empirical nebulized treatment is critical for SARS-CoV-2 patients. The use of inhaled budesonide has also been shown to be beneficial in the airway epithelial cells by inhibiting the virus-induced cytokines, thymic stromal lymphopoietin (TSLP), and chemokine ligand 26 (CCL26).18 The inhibition of these cytokines indicates that inhalation of budesonide via nebulizer after SARS-CoV-2 contagion has favorable effects. 

需要注意的是,对于急性炎症反应的哮喘患者和SARS-CoV-2晚期症状者,布地奈德是无效的。因此,对于SARS-CoV-2患者来说,哮喘病人每天常规使用布地奈德ICS治疗和早期经验性雾化治疗至关重要。吸入性布地奈德的使用也被证明对气道上皮细胞有益,它能抑制病毒诱导的细胞因子、胸腺基质淋巴生成素(TSLP)和血因子配体26(CCL26) [18],对这些细胞因子的抑制表明,感染SARS-CoV-2后使用布地奈德气雾剂进行治疗能带来良好疗效。

Another advantage to nebulized budesonide is that the systemic half-life (the time it takes a drug to decrease to half its initial dose) is much shorter than that of fluticasone propionate. It is understood that budesonide has low lipophilicity relative to other corticosteroids and has a more preferential reversible esterification process, thus extending the exposure in the lungs.10 It is because of this knowledge and the lung’s preference for inhaled budesonide; SARS-CoV-2 patients have been empirically treated with nebulized budesonide.

雾化布地奈德的另一个优点是,其全身半衰期(药物降至其初始剂量的一半所需的时间)比丙酸氟替卡松的半衰期短得多。据了解,布地奈德相对于其他皮质类固醇具有较低的亲脂性,并且具有更优先的可逆酯化过程,从而延长了在肺部的暴露时间 [10]。 正是由于这种认识和肺部对吸入布地奈德的优先亲和性,SARS-CoV-2患者已经接受了雾化布地奈德的经验性治疗。

Nebulizer and Concerns of SARS-CoV-2 Transmission

雾化器和对SARS-CoV-2传播的担忧

Nebulizers are very effective at treating breathing disorders like SARS-CoV-2, but concerns of spreading particles in size up to 5 gm via aerosol cause concern for providers when considering what route to order for respiratory medications. This case study is focused on treatment in the outpatient setting, and therefore, there are different considerations when examining the efficacy of nebulized therapy. Small-Volume Nebulizers (SVNs) offer several advantages for drug delivery: nebulization delivers higher targeted drug concentrations in the airways achieving rapid onset of action, nebulized corticosteroids can be dosed at considerably lower doses than oral or intravenous alternatives, and there is minimal systemic absorption with nebulized corticosteroids hence, fewer adverse effects.7 & 14

雾化器在治疗SARS-CoV-2等呼吸系统疾病方面非常有效,但对通过气溶胶传播大小达5gm的颗粒的担忧,使医疗机构在考虑订购呼吸系统药物的途径时感到担忧。本案例研究的重点是门诊环境下的治疗,因此,在研究雾化治疗的疗效时,有不同的考虑。小容量雾化器(SVNs)提供了药物输送的几个优势:雾化提供更高的目标药物浓度,在气道中实现快速起效,雾化皮质类固醇的剂量可以比口服或静脉替代物低得多,而且雾化皮质类固醇的系统吸收很小,因此,不良反应较少 [7 & 14]。

In 2004, a study evaluated thedistribution of airborne SARS-CoV in hospital patients who were being treated with a combination of humidified oxygen therapy and nebulizers. The study observed that zero percent of the offending pathogen in the air and environmental samples after a PCR amplification was performed in isolated rooms.43 This study does not coincide with the consensus that using a nebulizer might be a transmitting source for SARS. Deslée et al. and the French Language Respiratory Society note that there is no evidence to support avoiding using ICS (nebulized budesonide) during the SARS-CoV-2 pandemic.13 The American College of Allergy, Asthma, and Immunology and Dr. Xi of Keck Medicine of USC suggests that nebulized medications should be administered in a room of the patient’s house that is isolated from other household members to minimize exposure.1 & 46 The goal is to use a nebulizer in a part of the house where there is no recirculated airor in areas with low foot traffic. It is suggested that patients use nebulizers in an area where it is easy to clean the surfaces, such as a private bathroom or an area that needs no cleaning at all—for instance, the garage or outside on the patio if practical. When cleaning a surface after a nebulization treatment, one can use a disinfectant wipe or a water-absorbent paper towel. It has been shown that more than 95% of the residue left on a surface after a nebulization treatment can be removed with regular water- absorbent tissue paper.22 For the remaining percentage left on the service, it is not guaranteed that infection will follow if the residue reaches another susceptible individual.” Collaboration between the healthcare provider and patient, along with continued patient education is vital when prescribing nebulized medication in cases with high contagion risk.

2004年,一项研究评估了正在接受加湿氧气疗法和雾化器联合治疗的医院患者中空气中SARS-CoV的分布情况。该研究观察到,在隔离的房间内进行PCR扩增后,空气和环境样本中的违法病原体为零 [43]。这项研究与使用雾化器可能是SARS传播源的共识不一致。Deslée等人和法语呼吸学会指出,没有证据支持在SARS-CoV-2大流行期间避免使用ICS(雾化布地奈德)[13]。美国过敏、哮喘和免疫学学院和南加州大学Keck医学的Xi博士建议,雾化药物应在患者家中与其他家庭成员隔离的房间内使用,以减少接触 [1 & 46]。目标是在房屋内没有再循环空气的地方或人流量少的地方使用雾化器。建议患者在容易清洁表面的地方使用雾化器,如私人浴室或完全不需要清洁的地方—如车库或室外天井(如果可行的话)。雾化治疗后清洁表面时,可以使用消毒擦拭剂或吸水纸巾。事实证明,雾化处理后留在表面的残留物,95%以上可以用普通吸水纸巾清除 [22]。对于剩下的一部分比例,如果残留物到了另一个易感人群手中,就不能保证接下来感染继续传播。当在具有高传染性风险的情况下开具雾化药物时,医疗服务提供者和患者之间的合作,以及持续的患者教育是至关重要的。

There has to be a big push for educating the patient and all parties involved in the patient’s care on appropriate device cleaning and aerosol therapy infection control. According to O’Malley31, the recommended steps for nebulizer cleaning and disinfecting in the home include:

必须大力推动对患者和参与患者护理的各方进行适当的器械清洁和气雾治疗感染控制的教育。根据O’Malley31的说法,家庭中雾化器清洁和消毒的推荐步骤包括:

1) Nebulizer parts cleaned with dish detergent and water  雾化器部件用洗洁精和水清洗。

2) Disinfect (per manufacturer approval and patient approval) 消毒(在制造商批准和患者批准下进行)

a) Cold techniques: 冷处理技术

i) Soak for five minutes in 70% isopropyl alcohol 在70%异丙醇中浸泡5分钟

ii) Soak for 30 minutes in 3% hydrogen peroxide 用3%的过氧化氢浸泡30分钟

b) Heat techniques: 热处理技术

i) Microwave or Boil for five minutes 微波或煮沸5分钟

ii) If patient has a dishwasher that can achieve a temperature of > 158°F or 700C, it is okay to wash in a dishwasher for 30 minutes 如果患者的洗碗机可以达到158°F或700C的温度,则可以用洗碗机清洗30分钟。

iii) Electric steam sterilizer 电动蒸汽灭菌器

3) The patient will need to rinse with sterile water if using the cold disinfectant Technique 如果使用冷消毒剂技术,患者需要用无菌水冲洗。

4) Air-dry before storing equipment 存放设备前先晾干

As always, reinforcing good hand hygiene before and after nebulized therapy is crucial when being proactive in stopping the spread of SARS-CoV-2.

一如既往,在主动阻止SARS-CoV-2的传播时,加强雾化治疗前后的良好手部卫生是至关重要的。

Supportive Therapy 支持性治疗

Clarithromycin 克拉霉素

Biaxin, also known as clarithromycin, is a macrolide that is metabolized in the liver and primarily excreted in the urine. Biaxin inhibits the growth of atypical pathogens and is commonly prescribed to treat bacterial infections and community-acquired pneumonia (affects the lower respiratory tract). The protocol calls for Biaxin to treat atypical pneumonia prophylactically — pneumonia is a known complication of SARS-CoV-2. When patients with SARS-CoV-2 exchange oxygen (take a breath), they allow the insulting agent to crossover into the bloodstream, thus introducing the alveoli (small air sacs in the lungs) and surrounding tissue to SARS -CoV-2. This exchange, along with inflammation, causes an accumulation of dead cells and fluid, thus leading to pneumonia.

克拉仙,又称克拉霉素,是一种大环内酯类药物,在肝脏中代谢,主要通过尿液排泄。

克拉仙能抑制非典型病原体的生长,常用于治疗细菌感染和社区获得性肺炎(影响下呼吸道)。该方案要求克拉仙预防性地治疗非典型肺炎–肺炎是SARS-CoV-2的已知并发症。

当SARS-CoV-2的患者交换氧气(呼吸)时,他们允许感染源交叉进入血液,从而将肺泡(肺部的小气囊)和周围组织引入SARS-CoV-2。这种交换,加上炎症,导致死亡细胞和液体的积累,从而导致肺炎。

Aspirin 阿司匹林

Early aspirin use curtails the incidence of cardiovascular complications, mitigates prothrombotic states, reduces the extent of SARS -CoV-2 in severe and critical patients, and will conceivably shorten days in the hospital.26 & 35 Prophylactic use of aspirin in SARS-CoV-2 patients has the potential to inhibit viral replication, anti-inflammatory, and anti-lung injuries, as well as anti-platelet aggregation.

早期使用阿司匹林可以抑制心血管并发症的发生,减轻血栓状态,降低重症和危重患者SARS -CoV-2的程度,可以想象将缩短住院天数。26 & 35  SARS-CoV-2患者预防性使用阿司匹林具有抑制病毒复制、抗炎、抗肺损伤以及抗血小板聚集的作用。

Zinc

Zinc administration prophylactically restores depleted immune cell function and has the potential to enhance antiviral immunity. Zinc diminishes the RNA-synthesizing activity of SARS-CoV-2.21 Zinc protects the cell membrane, which in return, assists in blocking viral entry into the cell and is an essential component; zinc is a naturally occurring mineral.

给予锌预防性地恢复枯竭的免疫细胞功能,并有可能增强抗病毒免疫力。锌能降低SARS-CoV-2的RNA合成活性 [21]。锌能保护细胞膜,而细胞膜又能协助阻止病毒进入细胞,是必不可少的成分;锌是一种天然存在的矿物质。

False-Negative Covid-19 Test and Empirical Treatment

Covid-19的假阴性检验和经验性处理方法

In healthcare, tests are used to guide our decision making not be our only decision- making tool. It is imperative to note that the “art of medicine” requires us to ‘treat the patient, not the test.’ New studies show that if SARS-CoV-2 PCR testing takes place within the first five days post-exposure, the patient has a greater than 65 percent chance of receiving a false-negative result, and the average patient that was symptomatic within the first five days of exposure had a false-negative rate of almost 40 percent.19, 20&42 The consequences of not treating someone who truly has SARS-CoV-2 because they test negative instead of positive can be detrimental to the patient and society as a whole.

在医疗保健中,检测是用来指导我们的决策,而非我们唯一的决策工具。必须注意的是,”医学艺术 “要求我们 “治疗病人,而不是检测”。最新研究表明,如果SARS-CoV-2 PCR检测在暴露后的前五天内进行,患者有超过65%的机会得到假阴性结果,而暴露后五天内出现症状的患者平均假阴性概率约为40% [19, 20 & 42]。如果因为检测结果为阴性而不是阳性就忽略治疗真正患有SARS-CoV-2的患者,其后果对患者本人和整个社会而言都是有害的。

Real-Time Reverse-Transcriptase Polymerase Chain Reaction (RT-PCR) test had the best performance eight days after contagion (on average, the patient was symptomatic on day three), but our best still had a false-negative rate of 20 percent— this equates into one in five people with false-negative test results.19′ 20 & 42 High-risk exposure patients and patients who are immunocompromised should be cared for as if they have SARS-CoV-2 until proven otherwise when symptoms are consistent with SARS-CoV-2. In case one and case two had early empirical treatment not been started, the patient would have lost five days and six days of therapy, respectively; thus, diminishing chances of survival. In case two had the patient stopped his treatment on May 3rd instead of May 15th because of a “potential false-negative,” he would have missed 12 days of treatment, potentially exposing him to disease proliferation.

实时逆转录酶聚合酶链反应(RT-PCR)检测在感染后8天的表现最好(平均而言,患者在第三天就有症状),但我们最好的(检测方法)仍有20%的假阴性率—这相当于五分之一的人得到假阴性的检测结果 [19, 20 & 42]。高危暴露患者和免疫力低下的患者应该被当作SARS-CoV-2感染患者进行护理,直到症状与SARS-CoV-2一致时才进行治疗。在病例一和病例二中,如果没有开始早期的经验性治疗,患者将分别失去5天和6天的治疗时间,因此,生存的机会越来越小。在病例二中,如果患者在5月3日而不是5月15日因 “潜在的假阴性 “而停止治疗,他将错过12天的治疗,有可能使他面临疾病扩散的危险。

CONCLUSIONS 结论

It should be mentioned that telemedicine has been put to the test during these trying times. The success of these two cases and the safety permitted by monitoring remotely and providing real-time consultations by phone could not have been achieved without the integration of telemedicine. This experience has enabled us to witness the advancement of technology in medicine personally.

值得一提的是:远程医疗在这段艰难时期经受了考验。如果没有远程医疗的整合,这两个病例的成功以及远程监测和通过电话提供实时咨询所允许的安全是不可能实现的。这次经历让我们能够亲自见证医学技术的进步。

Inhaled corticosteroids are a powerful tool. The evidence is currently under review in regards to the precision and power that inhaled corticosteroids possess; these studies are being performed by France4, Spain44, Sweden6 the University of Oxford3, and the National Institutes of Health (NIH )27. It is our understanding that there is more than one way to treat SARS-CoV-2, but it is with great respect to the studies that have come before and will come after ours that these case studies and the treatments provided be considered in the arsenal of powerful therapies to be used when treating SARS-CoV-2. A call to arms was sounded on J anuary 20, 2020, when the first case of SARS-CoV-2 was first identified in the United States and in March 2020 a successful empirical treatment plan was put into place (budesonide 0.5mg nebulizer, twice daily, clarithromycin (Biaxin) 500mg tab, twice daily for ten days, Zinc 50mg tab, twice daily, and aspirin 81mg tab, daily).

吸入式皮质类固醇是一种强有力的工具。目前正在审查关于吸入皮质类固醇所拥有的精确性和力量的证据;这些研究正在由法国 [4]、西班牙[44]、瑞典[6]、牛津大学[3]和美国国立卫生研究院(NIH )[27]进行。我们的理解是,治疗SARS-CoV-2的方法不止一种,但我们非常尊重之前和之后的研究,这些案例研究和提供的治疗方法被认为是治疗SARS-CoV-2时可供使用的强大疗法武器库。2020年1月20日,当美国首次发现第一例SARS-CoV-2病例时,就吹响了号角,并在2020年3月成功实施了经验性治疗方案(布地奈德0.5mg雾化液,每日两次,克拉霉素(克拉仙)500毫克/每次,每日两次,连续十天,锌50毫克/次,每日两次,阿司匹林81mg/次 日)。

+3
2 评论
Inline Feedbacks
View all comments
trackback
4 月 之前

… [Trackback]

[…] Read More here on that Topic: gnews.org/zh-hans/263415/ […]

0
i7
i7
7 月 之前

查了下,120喷的布地奈德喷雾剂,60块钱,也很经济,不过貌似现在讨论最多,应用也最多的还是硫酸羟氯喹+阿奇霉素

+1

Himalaya Rose Garden Team

“but those who hope in the Lord will renew their strength. They will soar on wings like eagles; they will run and not grow weary, they will walk and not be faint” 【Isaiah 40:31】 7月 13日