巴特利特博士給霍爾參議員的信和布地奈德霧化治療的論文稿

新聞簡述:本文包括一封巴特利特博士分享給America, Can We Talk? 網站上的給霍爾參議員的信和他的一篇論文稿。這是一項門診病例報告,詳述了兩個美國的病例,患者分別患有腫瘤和二型糖尿病、高血壓和痛風,兩名患者經布地奈德霧化治療均連續兩次檢驗呈陰性。

相關新聞:德克薩斯醫生巴特利特博士分享新冠特效藥:布地奈德霧化劑

翻譯:【Naomi(文花開)】校對:【重生】編輯整理:【Michelle】

戰友之家玫瑰園小隊出品

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

給霍爾參議員的信和論文稿中英文對照全文:

Dr. Bartlett’s letter to Senator Hall

巴特利特博士給霍爾參議員的信

Dear Senator Hall:

親愛的霍爾參議員:

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.

作為一名具有與COVID-19搏鬥經驗的一線的醫生,我想分享一種既直觀又基於證據的有效治療方法;這種治療方法很容易在院前定位並推廣到社區環境中。我發現這種治療作為一個權宜之計用於經驗性患者治療和管理他們的症狀,因為不論CDC還是WHO都沒有制定出社區性針對COVID-19治療策略。也就是說,目前的指南只有在症狀發展到住院時才會進行治療,而且在很多情況下,需要入住ICU並進行呼吸機治療。為了更清楚地解釋德克薩斯人的這一窘境,目前的指南不鼓勵德克薩斯人在出現輕度到中度症狀時尋求任何醫療服務;只有當德克薩斯人的症狀非常嚴重時,才會開始治療。

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.

他們需要重症監護和住院治療。然而,對於德州人來說,有一種易於開展的院前社區治療方法。在患者剛出現COVID-19感染症狀時,我會開一種常用呼吸道抗皮質激素—布地奈德霧化治療,同時進行COVID-19檢測。我之所以選擇布地奈德替代其他皮質類固醇的理由是:該藥似乎可以阻斷COVID-19引發的大多數細胞因子風暴。除了我的發現,其它組織和國家也在評估了吸入式布地奈德治療COVID-19的療效。吸入式布地奈德目前正在美國國立衛生研究院進行研究,法國也在進行研究。西班牙和牛津大學都分別宣佈將吸入式布地奈德用於治療COVID-19患者的研究計劃。

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. 

目前為止,我收治的所有病人在接受一個療程的吸入性布地奈德治療後似乎未出現症狀。這些成功的病例也包括那些預後極差而處於高風險的德州人。例如,我的一位老年婦女患者患有兩種類型的血癌,免疫力低下,正在接受化療和放療。經吸入性布地奈德治療後,她現在已經康復。(注:COVID-19康復標準:連續兩次檢測呈陰性,無症狀。) 我的另一位危重患者是一位50年吸煙史的老年婦女,有高血壓和甲狀腺疾病治療史,四根血管心臟搭橋手術史。經過一個療程的吸入性布地奈德治療後,她也得到了康復。這兩位德州人都避免了一次住院、一次呼吸機和一次可能的死亡。

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)

吸入布地奈德是一種適用於身體虛弱的德州人的安全療法。該藥治療肺部相關炎症的研究和臨床使用已經超過20年,對新生兒重症監護室中2磅重的嬰兒也足夠安全。當我回顧皮質類固醇被用於治療其他感染COVID-19條件的療效時,我發現許多采用與我治療方案類似的國家也取得了難以置信的成功。例如,台灣這個擁有2400萬人口的國家,使用不同的吸入性皮質類固醇激素治療方案進行早期診治,而且在這次大流行時期中僅僅只有7人死亡。在看看日本,他們也用吸入性皮質激素治療。雖然日本的人口結構偏老齡化,但這個1.21億人口的國家只有977人死亡。同樣,看看擁有5千萬人口的韓國,他們使用吸入性皮質激素的死亡人數只有283人。(見 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. 

最後,雖然FDA沒有批准任何專門針對COVID-19的藥物,他們已經批准布使用布地奈德霧化治療其他呼吸道炎症疾病。因此,吸入式布地奈德是應對COVID-19爆發的直觀的前線防禦措施。而且最重要的是,它很容易在德克薩斯州的基層醫療服務機構中推廣。

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.

對於任何疾病,包括COVID-19,延遲治療都不是有效的健康策略。我任職於由德克薩斯州州長委派建立的健康差異特別工作組時,我們的建議總是包括早發現和早治療。我認為,吸入布地奈德療法是治療COVID-19的一種早期療法。

Sincerely,

Richard P. Bartlett, MD

真誠的,

理查德·P·巴特利特,醫學博士

Case Study Report

SARS-CoV-2 and The Case for Empirical Treatment

案例研究報告

SARS-CoV-2和經驗性治療的案例

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,谷歌趨勢(Google Trends)報告說,「類固醇和冠狀病毒 」主題增加了+4,750% [12]。 這是一項門診病例研究,研究了兩名來自美國的特殊病例,包括患有腫瘤和嚴重急性呼吸綜合徵冠狀病毒-2(SARS-CoV-2),也稱為COVID-19。本病例研究旨在揭示這樣一個特殊病例的識別過程、診斷、臨床病程和管理—包括患者在門診環境下利用遠程醫療進行疾病的前驅期和後續進展。目標在於呼籲業內人士關注這項前瞻性的早期經驗性治療的成功,該治療是採用經典皮質類固醇(布地奈德)氣霧劑給藥與大環內酯類抗生素克拉霉素(克拉仙)口服使用的聯合用藥方案。

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.

一個老藥新用案例,這是一個出自迪斯尼劇本的故事—《美女與野獸》[41],一個名叫布地奈德的美女和一個名叫SARS-CoV-2的野獸。布地奈德,是一種最初在1973年獲得專利的藥物,並被列入世界衛生組織(WHO)基本藥物清單,而SARS-CoV-2首次在美國上市是在2020年1月20日 [8&46]。該案例研究展示了與全身性治療相比,使用針尖聚焦霧化治療一種呼吸系統疾病的療效。人們可以追溯到公元前約1554年,發現即使是古埃及人認可封閉環境下霧化吸入治療的效果 [38]。 精確定位聚焦治療的目的是找到特定的目標,並以最小副作用進行有效治療。「更聰明地工作,而不是更努力地工作」是早期精准聚焦經驗治療的根本主題。

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. 

和哮喘一樣,SARS-CoV-2也是一種呼吸道炎症疾病,它的發病率更加嚴重,並作用於肺部血管緊張素轉換酶(ACE)受體。SARS-CoV-2臨床表現為局部血管問題,這是由於肺部內皮細胞上的Bl受體被激活後增加了對促炎細胞因子的反應。 當血管緊張素轉換酶2發揮受體作用使新冠肺炎病毒S-蛋白能夠與宿主細胞結合時,這種激活反應就能發生。 當ACE 2被中斷,Bl配體活躍時,肺部環境容易出現血管滲漏和血管性水腫—粘膜迅速腫脹。S-蛋白也允許病毒入侵並通過跨膜絲氨酸蛋白酶2進行擴散(TMPRSS2)[24,34 & 43]。多項研究也驗證我們的發現,通過吸入性皮質類固醇(ICS)霧化治療方案能局部下調促炎細胞因子合成並減少ACE 2(SARS-CoV-2的受體)和TMPRSS2的表達,從而降低死亡率 [15,23,24,28,34和49]。為此,該個案研究推測:採用局部布地奈德霧化治療比全身皮質激素治療更具臨床意義,且不增加SARS-CoV-2的感染風險 [2,24及30]。本案例研究為有症狀患者進行早期經驗性治療提供證據支持。

METHODS 方法

Study Population, Setting, and Data Collection 研究對象、環境和數據收集

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. 

本案例研究涉及兩例採用遠程治療的門診患者,於2020年3月29日至2020年5月14日期間在西德克薩斯地區經實驗室確診為SARS-CoV-2感染。所介紹的病例是經確認的SARS-CoV-2陽性病例,其定義是對採集的鼻咽拭子標本進行的逆轉錄酶-聚合酶-鏈反應(RT-PCR)檢測結果呈陽性。這兩名確診成年人由一名家庭醫學門診的基層保健人員通過遠程醫療進行身份覈實和管理。通過受密碼保護的電子郵件與其簽署醫療信息披露的知情同意書,並通過電話採訪了患者。

CASE REPORT 案例彙報

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歲的女性,無吸煙史,2012年被診斷為華氏巨球蛋白血症2020年被診斷為原發性皮膚邊緣區淋巴瘤,目前正在接受依魯替尼(Imbruvica)治療。患者患有高血壓和甲狀腺功能減退症,這些合併症用藥如下:氯沙坦鉀50毫克每天一次,左甲狀腺素鈉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)她家裡人來訪前,該病人一直處於完全隔離。2020年5月10日,患者出現鼻竇腔壓痛、發熱、疼痛、發冷等症狀。5月11日凌晨,患者多次出現惡心嘔吐,到當晚,發熱大於100.4華氏度,持續發冷,無力咳嗽,味覺與嗅覺改變導致的食慾減退。5月15日前患者症狀未見好轉並繼續進行隔離治療她收到消息說,她5月7日接觸的那位家庭成員被檢測出SARS-CoV-2陽性。聽到報告後,患者通過遠程醫療聯繫到了門診家庭醫生。該患者通過鼻咽拭子採用反轉錄酶-聚合酶-鏈反應(RT-PCR)檢測是否感染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.

此時(2020年5月15日),患者開始接受治療,方案為:布地奈德霧化治療500微克/次,每日兩次,口服克拉霉素(克拉仙)500mg /次每日兩次,連續服藥十天,鋅50毫克/次,每日兩次,阿司匹林81毫克/次,每日一次。使用布地奈氣霧劑治療兩天後,患者反饋症狀有所緩解。到5月19日,患者出現排痰性咳嗽、胸膜疼痛和腹瀉。5月20日,患者SARS-CoV-2RT-PCR檢測為陽性,此時距初始症狀出現已有10日。當日(5月20日)進行了遠程醫療會診,布地奈德給量由每日兩次增加到每日三次。該患者反饋5月24日,症狀開始好轉。5月25日,患者按處方完成克拉霉素(克拉仙)服用,同時當天首次出現發熱退卻。

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.

由於患者繼續保持無症狀,5月29日,通過遠程醫療預約第二次RT-PCR檢測,6月2日,患者的SARS-CoV-2結果仍呈陽性;初始症狀至今已有24天。6月8日,患者已14天未出現症狀,通過遠程醫療預約第三次RT-PCR檢測,6月10日,患者收到了SARS-COV-2檢測結果初次呈現陰性。6月11日,通過遠程醫療預約第四次RT-PCR檢測,6月17日,檢測結果再次呈現陰性。患者一直沒有出現症狀,截至6月11日,已經不需要布地奈德氣霧劑治療。

Assumed Initial Exposure Date (推測初次暴露日期): May 7, 2020 (2020年5月7日) Empirical Treatment Start Date (試驗性治療開始日期): May 15, 2020 (2020年5月15日)
Test Date (測試日期):Result and Date Received (收到結果日期):
May 15, 2020 (2020年5月15日)Positive — May 20, 2020 (陽性—2020年5月20日)
May 29, 2020 (2020年5月29日)Positive — June 2, 2020 (陽性—2020年6月2日)
June 8, 2020 (2020年6月8日)Negative — June 10, 2020 (陰性 —2020年6月10日)
June 11, 2020 (2020年6月11日)Negative — June 17, 2020 (陰性—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歲男性,無吸煙史,有以下合併症:二型糖尿病(DM),高血壓,和痛風。患者每日服用二甲雙胍1,000毫克/次,每日兩次,服用吡格列酮15mg/次,治療II型糖尿病。每日服用利辛普利賴諾普利2.5毫克/次治療高血壓,每天服用丙磺舒500mg/次治療痛風。

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.

患者認為初次接觸於2020年3月7日在德克薩斯州弗里斯科市的購物中心。2020年3月29日,患者出現咳嗽、喉嚨痛、嗅覺和味覺喪失、發燒(>100.4華氏度)、疼痛和寒顫症狀。3月29日,患者使用快速流感診斷試劑(RIDT)進行流感檢測,檢測結果為陰性,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. 

此時,患者通過遠程醫療接入主治醫生,並接受經驗性治療,開始接受布地奈德氣霧劑治療0.5毫克,兩次/天,克拉霉素(克拉仙)500毫克/次,每日2次,連續使用10天,鋅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(症狀發生後3天),患者可以進行SARS- CoV-2檢測,他通過鼻咽拭子採用RT-PCR檢測。4月3日,患者被告知他的SARS-CoV-2檢測結果呈陽性,此時距離最初的症狀已經過去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.

患者報告說,他在4月4日未出現症狀,並於4月7日完成克拉霉素(克拉仙)全療程用藥。患者繼續服用布地奈德氣霧劑0.5毫克/次,每日2次,鋅50mg/次,每日2次,阿司匹林81mg/次日。由於患者繼續持續無症狀,4月15日通過遠程醫療訂購了第二份通過鼻咽拭子進行的RT-PCR檢測,結果為SARS-CoV-2陽性。

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. 

此時開始服用阿奇霉素500毫克,第一天,然後250毫克/次日,連續服用四天。4月27日,患者再次通過RT-PCR檢測檢測,結果再次呈陽性。直到5月1日,患者通過鼻咽拭子RT-PCR檢測,檢測結果為陰性。5月7日,患者又接受了鼻咽拭子RT-PCR檢測,驗證前次陰性檢測結果,但最終結果顯示SARS-COV-2陽性。患者沒有新的暴露,自4月1日起一直自我隔離。5月11日,該患者再次接受鼻咽拭子RT-PCR檢測,SARS-CoV-2檢測結果為陰性。

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.

該患者共完成四個阿奇霉素治療療程(首日500毫克,後四天250毫克/天)治療5月13日暫停布地奈德氣霧劑0.5毫克/次,兩次/日治療。他繼續服用鋅劑50毫克/次,每日2次,阿司匹林81mg /次日,直至第二次檢測結果連續陰性。5月14日,該患者接受最後一次鼻咽拭子RT-PCR檢測,並再次確認陰性結果。

Assumed Initial Exposure Date (推測初次暴露日期): May 7, 2020 (2020年5月7日) Empirical Treatment Start Date (試驗性治療開始日期): May 29, 2020 (2020年5月29日)
Test Date (測試日期):Result and Date Received (收到結果日期):
April 1, 2020 (2020年4月1日)Positive — April 3, 2020 (陽性—2020年4月3日)
April 15, 2020 (2020年4月15日)Positive — April 19, 2020 (陽性—2020年4月19日)
April 27, 2020 (2020年4月27日)Positive — April 27, 2020 (陽性–2020年4月27日)
May 1, 2020 (2020年5月1日)Negative — May 3, 2020 (陰性—2020年5月3日)
May 7, 2020 (2020年5月7日)Positive — May 10, 2020 (陽性—2020年5月10日)
May 11, 2020 (2020年5月11日)Negative — May 13, 2020 (陰性—2020年5月13日)
May 14, 2020 (2020年5月14日)Negative — May 15, 2020 (陰性—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治療患者的潛在毒副作用的信息一直不一致。非甾體類抗炎藥對環氧酶(COX-1/COX-2)具有內在的抑制功能。這些酶參與關鍵生物介質的合成—調節炎症的介質。皮質類固醇,如布地奈德,參與幾個基本的生理過程,如協助免疫系統反應和炎症調節。布地奈德通過阻斷蛋白質合成破壞炎症基因COX-2的信使RNA(mRNA)的穩定性,從而抑制誘導炎症發生的遺傳物質的傳遞。

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. 

皮質類固醇預處理通過抑制炎症介質的細胞磷脂酶A2(cPLA2)和COX-2 mRNA活性,從而能顯著減弱細胞因子激活,同時還能減少前列腺素分泌。布地奈德減少PGE分泌而產生的生理效應主要體現在mRNA水平上,其可以抑制cPLA 2和特異性COX-2的活性 [29]。在有症狀的SARS-CoV-2患者的治療計劃中,早期使用霧化布地奈德臨床價值,可以避免因免疫系統過度反應而引發的 “細胞因子風暴”–一種對健康細胞造成嚴重破壞而非消滅病毒的反應。

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

布地奈德是第一個能夠抑制由分泌性磷脂A2(sPLA2)激活的人肺尖細胞產生的促炎細胞因子/趨化因子如IL-6、IL-8和TNF-α的藥物 [40]。像布地奈德這樣的皮質類固醇在SARS-CoV爆發期間被普遍使用,因為它們被公認為具有調節多種複雜細胞因子的作用(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這樣的吸入性皮質固醇類藥物進行干預ICS進行干預,可減少全身性皮質類固醇藥物治療的需要。吸入式皮質激素可適度改善氣流功能 [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 

根據Russell等人的說法,目前還沒有 “明確證據 「支持將NSAIDs藥物用於治療SARS-COV-2患者。但仍有證據表明,皮質類固醇在治療SARS-CoV時可產生有利的結果.36免疫功能低下的腫瘤患者使用低劑量皮質類固醇可獲益.9&36使用布地奈德氣霧劑能降低COPD患者發生肺炎的風險 [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.

與此相反,當給SARS-CoV-2住院患者使用全身性皮質類固醇治療時,沒有證據表明這樣能縮短肺炎持續時間,減少住院天數,或降低死亡風險 [48]。這個病例研究已經確定布地奈德氣化劑作為經驗性治療方案和盡早治療有症狀患者具有重要意義。Halpin等同意早期管理,並鼓勵對SARS-CoV-2患者增加ICS使用劑量 [17],該治療方案已不斷完善,同時通過增加布地奈德氣化劑使用劑量和使用頻次明顯增加臨床療效。

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.

布地奈德已被證明對預防哮喘(一種肺部炎症性疾病)很有幫助,當定期使用時,布地奈德已被證明可以降低哮喘發作的嚴重程度和頻率。SARS-CoV-2是一種更嚴重的肺部炎症疾病,主要感染源在肺部的ACE受體。

 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,對於急性炎症反應的哮喘患者和SARS-CoV-2晚期症狀者,布地奈德是無效的。因此,對於SARS-CoV-2患者來說,哮喘病人每天常規使用布地奈德ICS治療和早期經驗性霧化治療至關重要。吸入性布地奈德的使用也被證明對氣道上皮細胞有益,它能抑制病毒誘導的細胞因子、胸腺基質淋巴生成素(TSLP)和血因子配體26(CCL26) [18],對這些細胞因子的抑制表明,感染SARS-CoV-2後使用布地奈德氣霧劑進行治療能帶來良好療效。

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.

霧化布地奈德的另一個優點是,其全身半衰期(藥物降至其初始劑量的一半所需的時間)比丙酸氟替卡松的半衰期短得多。據瞭解,布地奈德相對於其他皮質類固醇具有較低的親脂性,並且具有更優先的可逆酯化過程,從而延長了在肺部的暴露時間 [10]。 正是由於這種認識和肺部對吸入布地奈德的優先親和性,SARS-CoV-2患者已經接受了霧化布地奈德的經驗性治療。

Nebulizer and Concerns of SARS-CoV-2 Transmission

霧化器和對SARS-CoV-2傳播的擔憂

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

霧化器在治療SARS-CoV-2等呼吸系統疾病方面非常有效,但對通過氣溶膠傳播大小達5gm的顆粒的擔憂,使醫療機構在考慮訂購呼吸系統藥物的途徑時感到擔憂。本案例研究的重點是門診環境下的治療,因此,在研究霧化治療的療效時,有不同的考慮。小容量霧化器(SVNs)提供了藥物輸送的幾個優勢:霧化提供更高的目標藥物濃度,在氣道中實現快速起效,霧化皮質類固醇的劑量可以比口服或靜脈替代物低得多,而且霧化皮質類固醇的系統吸收很小,因此,不良反應較少 [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,一項研究評估了正在接受加濕氧氣療法和霧化器聯合治療的醫院患者中空氣中SARS-CoV的分布情況。該研究觀察到,在隔離的房間內進行PCR擴增後,空氣和環境樣本中的違法病原體為零 [43]。這項研究與使用霧化器可能是SARS傳播源的共識不一致。Deslée等人和法語呼吸學會指出,沒有證據支持在SARS-CoV-2大流行期間避免使用ICS(霧化布地奈德)[13]。美國過敏、哮喘和免疫學學院和南加州大學Keck醫學的Xi博士建議,霧化藥物應在患者家中與其他家庭成員隔離的房間內使用,以減少接觸 [1 & 46]。目標是在房屋內沒有再循環空氣的地方或人流量少的地方使用霧化器。建議患者在容易清潔表面的地方使用霧化器,如私人浴室或完全不需要清潔的地方—如車庫或室外天井(如果可行的話)。霧化治療後清潔表面時,可以使用消毒擦拭劑或吸水紙巾。事實證明,霧化處理後留在表面的殘留物,95%以上可以用普通吸水紙巾清除 [22]。對於剩下的一部分比例,如果殘留物到了另一個易感人群手中,就不能保證接下來感染繼續傳播。當在具有高傳染性風險的情況下開具霧化藥物時,醫療服務提供者和患者之間的合作,以及持續的患者教育是至關重要的。

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:

必須大力推動對患者和參與患者護理的各方進行適當的器械清潔和氣霧治療感染控制的教育。根據O’Malley31的說法,家庭中霧化器清潔和消毒的推薦步驟包括:

1) Nebulizer parts cleaned with dish detergent and water  霧化器部件用洗潔精和水清洗。

2) Disinfect (per manufacturer approval and patient approval) 消毒(在製造商批准和患者批准下進行)

a) Cold techniques: 冷處理技術

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

ii) Soak for 30 minutes in 3% hydrogen peroxide 用3%的過氧化氫浸泡30分鐘

b) Heat techniques: 熱處理技術

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

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 如果患者的洗碗機可以達到158°F或700C的溫度,則可以用洗碗機清洗30分鐘。

iii) Electric steam sterilizer 電動蒸汽滅菌器

3) The patient will need to rinse with sterile water if using the cold disinfectant Technique 如果使用冷消毒劑技術,患者需要用無菌水沖洗。

4) Air-dry before storing equipment 存放設備前先晾乾

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,在主動阻止SARS-CoV-2的傳播時,加強霧化治療前後的良好手部衛生是至關重要的。

Supportive Therapy 支持性治療

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,又稱克拉霉素,是一種大環內酯類藥物,在肝臟中代謝,主要通過尿液排泄。

克拉仙能抑制非典型病原體的生長,常用於治療細菌感染和社區獲得性肺炎(影響下呼吸道)。該方案要求克拉仙預防性地治療非典型肺炎–肺炎是SARS-CoV-2的已知併發症。

當SARS-CoV-2的患者交換氧氣(呼吸)時,他們允許感染源交叉進入血液,從而將肺泡(肺部的小氣囊)和周圍組織引入SARS-CoV-2。這種交換,加上炎症,導致死亡細胞和液體的積累,從而導致肺炎。

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併發症的發生,減輕血栓狀態,降低重症和危重患者SARS -CoV-2的程度,可以想象將縮短住院天數。26 & 35  SARS-CoV-2患者預防性使用阿司匹林具有抑制病毒複製、抗炎、抗肺損傷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.

給予鋅預防性地恢復枯竭的免疫細胞功能,並有可能增強抗病毒免疫力。鋅能降低SARS-CoV-2的RNA合成活性 [21]。鋅能保護細胞膜,而細胞膜又能協助阻止病毒進入細胞,是必不可少的成分;鋅是一種天然存在的礦物質。

False-Negative Covid-19 Test and Empirical Treatment

Covid-19的假陰性檢驗和經驗性處理方法

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.

在醫療保健中,檢測是用來指導我們的決策,而非我們唯一的決策工具。必須注意的是,”醫學藝術 “要求我們 “治療病人,而不是檢測”。最新研究表明,如果SARS-CoV-2 PCR檢測在暴露後的前五天內進行,患者有超過65%的機會得到假陰性結果,而暴露後五天內出現症狀的患者平均假陰性概率約為40% [19, 20 & 42]。如果因為檢測結果為陰性而不是陽性就忽略治療真正患有SARS-CoV-2的患者,其後果對患者本人和整個社會而言都是有害的。

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.

實時逆轉錄酶聚合酶鏈反應(RT-PCR)檢測在感染後8天的表現最好(平均而言,患者在第三天就有症狀),但我們最好的(檢測方法)仍有20%的假陰性率—這相當於五分之一的人得到假陰性的檢測結果 [19, 20 & 42]。高危暴露患者和免疫力低下的患者應該被當作SARS-CoV-2感染患者進行護理,直到症狀與SARS-CoV-2一致時才進行治療。在病例一和病例二中,如果沒有開始早期的經驗性治療,患者將分別失去5天和6天的治療時間,因此,生存的機會越來越小。在病例二中,如果患者在5月3日而不是5月15日因 “潛在的假陰性 “而停止治療,他將錯過12天的治療,有可能使他面臨疾病擴散的危險。

CONCLUSIONS 結論

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:遠程醫療在這段艱難時期經受了考驗。如果沒有遠程醫療的整合,這兩個病例的成功以及遠程監測和通過電話提供實時咨詢所允許的安全是不可能實現的。這次經歷讓我們能夠親自見證醫學技術的進步。

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).

吸入式皮質類固醇是一種強有力的工具。目前正在審查關於吸入皮質類固醇所擁有的精確性和力量的證據;這些研究正在由法國 [4]、西班牙[44]、瑞典[6]、牛津大學[3]和美國國立衛生研究院(NIH )[27]進行。我們的理解是,治療SARS-CoV-2的方法不止一種,但我們非常尊重之前和之後的研究,這些案例研究和提供的治療方法被認為是治療SARS-CoV-2時可供使用的強大療法武器庫。2020年1月20日,當美國首次發現第一例SARS-CoV-2病例時,就吹響了號角,並在2020年3月成功實施了經驗性治療方案(布地奈德0.5mg霧化液,每日兩次,克拉霉素(克拉仙)500毫克/每次,每日兩次,連續十天,鋅50毫克/次,每日兩次,阿司匹林81mg/次 日)。

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Isaiah4031

“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