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武漢新型冠狀病毒疫情系列之一

2020/2/5 — 7:55

十五年前的沙士帶給我們的教訓不少,當中包括:官員失職、官僚各自為政、藥石亂投。今天的武漢新型冠狀病毒與沙士同屬冠狀病毒,我們有必要簡要地檢視當年的作法。

藥石亂投

冠狀病毒患者有3個可識別的致病階段,其持續時間不同,可能出現重疊。 這些階段是第一期的病毒複製,第二期的炎性肺炎和第三期的殘餘肺纖維化。當時的香港用高劑量皮質類固醇治療。當中一隻最富爭議性的用藥是利巴韋林Ribavirin,它在事後已被發現不單對沙士治療無效還做成併發症,令患者失去原有的免疫能力,增加受感染機會,引致真菌感染和「骨骷症」(香港12%)(註1)。香港使用的Ribavirin 劑量遠比加拿大的為高,但其成效則比加拿大的為低。(註2)

廣告

武漢新型冠狀病毒的病徵

在權威性醫學雜誌刺針發表的研究中國首99個病例中(註3),患者的臨床表現為發燒 [83%],咳嗽 [82%]),呼吸急促 [31%],肌肉疼痛 [11%],譫妄 [9%],頭痛 [8%],喉嚨痛 [5%]),鼻涕 [4%],胸痛 [2%], 腹瀉[2%],噁心和嘔吐[1%]。

廣告

由此可以看到約有2成的受感染者沒有發燒或咳嗽,大部份沒有流感常見的頭痛,喉嚨痛,流鼻涕,腹瀉也很少。當年沙士的陶大爆發就是因為楊永強與陳馮富珍互不通消息,楊永強與廖秀冬不和, 楊永強很遲才知道沙士患者出現腹瀉。

今天的醫管局高層才如夢初醒,何栢良在2月3日說:“不排除新型冠狀病毒經糞便傳播”。因而當年市民對沙士的家居預防手法大派用場。可是當年政府刊登的『汲取經驗,防患未然』的專家委員會報告欲在政府網頁下了架。

武漢新型冠狀病毒的治療手法

中國在處理的初期使用lopinavir 和 ritonavir。洛匹那韋/利托那韋是常用的抗愛滋病用藥(註4)。

No antiviral treatment for coronavirus infection has been proven to be effective。 In a historical control study,31 the combination of lopinavir and ritonavir among SARS-CoV patients was associated with substantial clinical benefit (fewer adverse clinical outcomes)。

美國在處理了一宗成功個案。患者是曾經到過武漢的35歲青年。這是一宗輕微病例。他在入院的頭2天只有發燒, 咳嗽和噁心嘔吐,第2天出現腹瀉。這期間他只接受一般的退消性的藥物治療。第六天他接受鼻插管輸氧和開始靜脈注射抗生素vancomycin 和cefepime 。vancomycin 和cefepime是抗生素,主要是針對可能的附帶其他病毒性肺炎‧但要注意美國的患者不是因為抗生素痊愈的,所有的細菌培養都是陰性。Vancomycin在第七天停了 和cefepime在在第八天後停了。

他在第七天注射Remdesivir,一種新型實驗性廣譜抗病毒藥物,它被認為對SARS病毒和MERS病毒有效。

第八天病情好轉,患者不需要鼻插管輸氧。由於這個美國青年的病癒很快,所以這隻未經核准的新藥Remdesivir是否對武漢新型冠狀病毒有效成疑。

Treatment with intravenous remdesivir (a novel nucleotide analogue prodrug in development10,11) was initiated on the evening of day 7, and no adverse events were observed in association with the infusion.

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備註
註1
Management of Critically Ill Patients with Severe Acute Respiratory Syndrome (SARS)

Ribavirin was the most commonly used empirical antiviral agent for SARS。 ----it was found that ribavirin has no direct in vitro activity against SARS-CoV。 Higher doses given intravenously resulted in more frequent and severe adverse effects including haemolytic anaemia, elevated transaminase levels and bradycardia 。

Pharmacologic Treatment of SARS: Current Knowledge and Recommendations

Ribavirin therapy was associated with many adverse effects (Table 1),2,10,22-26 including haemolytic anaemia in 33% to 73%,2,24-26 hypocalcaemia in 58%,24 and hypomagnesaemia in 46% of patients.24

In Hong Kong, around 12% (49 out of 418) of patients with SARS were found to have magnetic resonance imaging proven AVN of the hips and knees。

註2
Ribavirin in the treatment of SARS: A new trick for an old drug?

2003 May 13;

In Toronto, 7 patients were treated with oral oseltamivir, broad-spectrum antibiotics and intravenous ribavirin at 2 g loading dose, followed by 1 g every 6 hours for 4 days, then 500 mg every 8 hours for another 4 to 6 days。16 This dosing regimen was based on a recently published dose schedule for hemorrhagic fever viruses. Of these 7 patients, 1 died, 1 showed improvement on mechanical ventilation, and the other 5 improved within 5 days. Of note, in addition to receiving antivirals and antimicrobials, the 5 patients who improved had received earlier and more aggressive supportive care than the other 2 patients. These 5 have since recovered either completely (3 patients) or with mild dyspnea (2 patients) with 3 week follow-up. In contrast, of 3 patients who were treated only with broad-spectrum antibiotics, 2 died and 1 was still receiving ventilation in the intensive care unit at the time of writing (unpublished data). Since the publication of this case series16 at the end of March, anecdotal reports have been received about a smaller number of patients who did not receive ribavirin and who have recovered without incident.

In Hong Kong, 10 patients were treated empirically with ribavirin: 9 intravenously at 8 mg/kg every 8 hours and 1 orally at 1.2 g every 8 hours.17 Each patient received 1 of 2 corticosteroids, hydrocortisone or methylprednisolone. Treatment started 3 to 22 days (median 12.5 days) after the onset of symptoms. The authors reported resolution of fever and improvement in heart rate within 2 days of commencing treatment in 8 of the patients; the other 2 patients died of respiratory failure.

註3
Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Published:January 30, 2020

Findings

Of the 99 patients with 2019-nCoV pneumonia, 49 (49%) had a history of exposure to the Huanan seafood market. The average age of the patients was 55·5 years (SD 13·1), including 67 men and 32 women. 2019-nCoV was detected in all patients by real-time RT-PCR. 50 (51%) patients had chronic diseases. Patients had clinical manifestations of fever (82 [83%] patients), cough (81 [82%] patients), shortness of breath (31 [31%] patients), muscle ache (11 [11%] patients), confusion (nine [9%] patients), headache (eight [8%] patients), sore throat (five [5%] patients), rhinorrhoea (four [4%] patients), chest pain (two [2%] patients), diarrhoea (two [2%] patients), and nausea and vomiting (one [1%] patient). According to imaging examination, 74 (75%) patients showed bilateral pneumonia, 14 (14%) patients showed multiple mottling and ground-glass opacity, and one (1%) patient had pneumothorax. 17 (17%) patients developed acute respiratory distress syndrome and, among them, 11 (11%) patients worsened in a short period of time and died of multiple organ failure.

99 patients with 2019-nCoV were included in this study, two of whom were husband and wife. In total, 49 (49%) patients were clustered and had a history of exposure to the Huanan seafood market. Among them, there were 47 patients with long-term exposure history, most of whom were salesmen or market managers, and two patients with short-term exposure history, who were shoppers. None of the patients were medical staff. Most patients were men, with a mean age of 55·5 years (SD 13·1; table 1). 50 (51%) patients had chronic diseases, including cardiovascular and cerebrovascular diseases, endocrine system disease, digestive system disease, respiratory system disease, malignant

註4
Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Published:January 24, 2020

By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection

No antiviral treatment for coronavirus infection has been proven to be effective. In a historical control study,31 the combination of lopinavir and ritonavir among SARS-CoV patients was associated with substantial clinical benefit (fewer adverse clinical outcomes). Arabi and colleagues initiated a placebo-controlled trial of interferon beta-1b, lopinavir, and ritonavir among patients with MERS infection in Saudi Arabia.32 Preclinical evidence showed the potent efficacy of remdesivir (a broad-spectrum antiviral nucleotide prodrug) to treat MERS-CoV and SARS-CoV infections.33,  34 As 2019-nCoV is an emerging virus, an effective treatment has not been developed for disease resulting from this virus. Since the combination of lopinavir and ritonavir was already available in the designated hospital, a randomised controlled trial has been initiated quickly to assess the efficacy and safety of combined use of lopinavir and ritonavir in patients hospitalised with 2019-nCoV infection.

lopinavir洛匹那韋/利托那韋是常用的抗愛滋病用藥,是由兩種蛋白酶抑制劑洛匹那韋(lopinavir,沒有單獨製劑)和利托那韋(ritonavir)組成

ritonavir利托那韋,是一種抗反轉錄病毒藥物,和其他藥物共同治療愛滋病。 這樣的治療方式被稱作高效能抗反轉錄病毒療法. -通常低劑量利托那韋會搭配蛋白酶抑制劑使用。

註5
First Case of 2019 Novel Coronavirus in the United States

On January 19, 2020, a 35-year-old man presented to an urgent care clinic in Snohomish County, Washington, with a 4-day history of cough and subjective fever.

He disclosed that he had returned to Washington State on January 15 after traveling to visit family in Wuhan, China.

On admission, the patient reported persistent dry cough and a 2-day history of nausea and vomiting; he reported that he had no shortness of breath or chest pain. Vital signs were within normal ranges. On physical examination, the patient was found to have dry mucous membranes. The remainder of the examination was generally unremarkable. After admission, the patient received supportive care, including 2 liters of normal saline and ondansetron for nausea.

Figure 2.

Symptoms and Maximum Body Temperatures According to Day of Illness and Day of Hospitalization, January 16 to January 30, 2020.

On days 2 through 5 of hospitalization (days 6 through 9 of illness), the patient’s vital signs remained largely stable, apart from the development of intermittent fevers accompanied by periods of tachycardia (Figure 2). The patient continued to report a nonproductive cough and appeared fatigued. On the afternoon of hospital day 2, the patient passed a loose bowel movement and reported abdominal discomfort. A second episode of loose stool大便稀溏was reported overnight; a sample of this stool was collected for rRT-PCR testing, along with additional respiratory specimens (nasopharyngeal and oropharyngeal) and serum. The stool and both respiratory specimens later tested positive by rRT-PCR for 2019-nCoV, whereas the serum remained negative.

Treatment during this time was largely supportive. For symptom management, the patient received, as needed, antipyretic退燒藥therapy consisting of 650 mg of acetaminophen every 4 hours and 600 mg of ibuprofen every 6 hours. He also received 600 mg of guaifenesin for his continued cough and approximately 6 liters of normal saline over the first 6 days of hospitalization.

On day 6, the patient was started on supplemental oxygen, delivered by nasal cannula at 2 liters per minute. Given the changing clinical presentation and concern about hospital-acquired pneumonia, treatment with vancomycin (a 1750-mg loading dose followed by 1 g administered intravenously every 8 hours) and cefepime (administered intravenously every 8 hours) was initiated.

Given the radiographic findings, the decision to administer oxygen supplementation, the patient’s ongoing fevers, the persistent positive 2019-nCoV RNA at multiple sites, and published reports of the development of severe pneumonia3,4 at a period consistent with the development of radiographic pneumonia in this patient, clinicians pursued compassionate use of an investigational antiviral therapy. Treatment with intravenous remdesivir (a novel nucleotide analogue prodrug in development10,11) was initiated on the evening of day 7, and no adverse events were observed in association with the infusion. Vancomycin was discontinued on the evening of day 7, and cefepime was discontinued on the following day, after serial negative procalcitonin levels and negative nasal PCR testing for methicillin-resistant Staphylococcus aureus.

On hospital day 8 (illness day 12), the patient’s clinical condition improved. Supplemental oxygen was discontinued, and his oxygen saturation values improved to 94 to 96% while he was breathing ambient air.

vancomycin萬古黴素是一種糖肽類抗生素,用來治療許多細菌感染的抗細菌藥抗生素,治療皮膚感染、敗血症、心內膜炎, 骨關節感染以及因耐甲氧西林金黃色葡萄球菌引起的腦膜炎時,通常建議採用靜脈注射藥物作為第一線治療

Cefepime is a fourth-generation cephalosporin antibiotic. Cefepime has an extended spectrum of activity against Gram-positive and Gram-negative bacteria

Remdesivir

倫地西韋是由吉利德科學公司開發的一種新型實驗性廣譜抗病毒藥物,被認為可以有效抑制呼吸道上皮細胞中SARS病毒和MERS病毒的複製。這是一種核苷酸類似物前藥,能夠抑制依賴RNA的RNA合成酶。據2020年的一項研究顯示,瑞德西韋和干擾素IFNb1-b的聯合用藥對MERS有顯著療效

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