Influenza Report 2006

Author(s) 作者:

簡介
(綠色連結: 免費全文閱覽)

全球性大規模流行性感冒疫症與主要大自然災害很相似：我們知道將會有另一次，可是我們會忽略時間和嚴重性。在其他範疇上他們很不同。東京或三藩市的地震只維持幾秒至數分鐘 ─ 全球性大規模疫症會持續幾個月至幾年像連續的波浪傳播到世界各地。而且後果也很不同，全球性大規模流行性感冒疫症比最嚴重的海潚要危險1000倍以上。

如果說全球性大規模流行性感冒疫症很難預計，那麼和它一樣難預計的就是引起疫症的病毒。我們不知道引發下次全球性大規模爆發的病毒的致病性。下一次全球性大規模爆發可能較溫和，像1968和1957年的；也可能十分致命，好像1918年的一次。我們不知道下一次大規模爆發是否由現在的「怪物」H5N1，或者由另一品種引發。我們忽略下一次大規模爆發如何隨時間展化，會以幾快的速度蔓延全球，和有幾多次衝擊。哪年齡層的人是最高危會有最嚴重的後果，甚至連下一次全球性大規模爆發會令二百萬、二千萬或二億人喪失生命我們都不知道。

所以現在衛生專業人士都不意外地對可能會有下一次全球性大規模爆發敏感起來。H5N1流行性感冒持續的在雀鳥爆發，並且間中傳染到人類身上引起很多注意，是因為H5N1病毒和1918年疫症的流行性感冒病毒品種有很有趣的關聯。如果H5N1病毒得到能力使其可以很容易人傳人，最保守的估計中，全球上要到疹所求疹的次數最少有幾億次，二千五百萬人將要入住醫院，會有數百萬人死亡。(WHO Checklist 2005)

面對一個未知的危機最好的方法是想像和準備對抗最壞的情況。因為這個危機是全球性的，所以需要全球性的策略 ─ 可是在我們這個分裂成二百多個國家的行星上是個很難處理的工作。處理不同的國家和她們的元首就像處理在上幼稚園的小朋友。WHO在這個困難的情況下有令人驚訝的表現。

在以下幾段裡，我們將會討論與流行性感冒的戰爭上的不同層面：對全球和對個人的衝擊、病毒本身、個人和全球對這可能有一天變成一個在醫學史上醫療保健方面最有挑戰性的危機的處理。在討論全球性大規模流行性感冒疫症時最重要的是嚴重的感冒疫症與一般季節性感冒會很不同。全球性大規模流行性感冒疫症不是一般普通的感冒，請記住這個事實。就如你不會把老虎叫作貓。

全球性衝擊

週期性疫症和全球性大規模疫症

流行性感冒是一種嚴重的呼吸系統疾病，可以使人衰弱和引起其他併發症，導致需要住院治療甚至死亡，特別是老人。每一年全球對流行性感冒週期性疫症的負擔有三百至五百萬嚴重個案和三十至五十萬死亡。會引致嚴重個案甚至死亡的風險以年過65歲的、小於兩歲的及有其他健康狀況使他們會更容易染上由流行性感冒引致的併發症為最高。(CDC 2005)

新的週期性感冒疫症的甲型病毒品種每一至二年就會出現，因為傳入特別的點特變 (point mutation)在兩種穿膜糖蛋白上：血凝素 (haemagglutinin, HA)及神經胺酸? (neuraminidase, NA)。這些新的變種可以避過人類的本體防衛，所以對這種病毒不會有持久的免疫力，即使之前曾經染病或接受疫苗注射，不像天花(smallpox)，黃熱病yellow fever，小兒麻痺症polio，麻疹measles。這些永久而且一般都很細小的抗原性(antigenicity)改變被稱為抗原飄移(antigenic drift)是導致週期性疫症有間隔地出現的基礎(圖1)。再者，現在有證據證明同一種病毒亞型的不同譜系可以一起流通、持續存留和以流行病學上重要的方式重配 (Holmes 2005) 。

圖1. 抗原飄移 - 圖片來自National Institute of Allergy and Infectious Disease

相對於週期性疫症，全球性大規模疫症是罕見的，每隔10至50年出現。他們從十六世紀開始被紀錄 (WHO 2005b)，在過去400年裡，已經記錄了最少31次全球性大規模疫症 (Lazzari 2004)。在二十世紀裡有過三次全球性大規模流行性感冒疫症(表1)。他們對死亡率的衝擊由破壞性極大至中等或溫和(Simonson 2004)。1918年的大規模爆發是由一隻從禽鳥型演變的H1N1病毒引起(Reid 1999)，而之後的爆發病毒品種 ─ 1957年的H2N2及1968年的H3N2，是由帶有禽鳥型流感基因的重配病毒引起：1957年的有3個禽鳥基因─血凝素(haemagglutinin)、神經胺酸?(Neuraminidase)及RNA聚合? PB1 (RNA Polymerase PB1)；1968年的有2個─血凝素(haemagglutinin)及RNA聚合? PB1(RNA Polymerase PB1) (Kawaoka 1989)。這些流行性感冒病毒的主要抗原性轉變被稱為抗原位移 (antigenic shift)。（圖2）

表1：抗原位移和全球性大規模爆發*

* H=血凝素；N=神經胺酸?

全球性大規模爆發以連續的波浪在地球循環，而現在並沒有辦法阻止新的全球性流行性感冒疫症病毒散播。這隻新的病毒品種會逐漸到達各個地方，會在一段幾年的時間裡感染所有人類。肺炎和流行性感冒的季節性多餘死亡率可能會維持一個高水平，好像1968年後的十年主要是A(H3N2)品種的感冒，在美國的45至64歲人士顯示出較高的死亡率。

圖2. 抗原位移 - 圖片來自National Institute of Allergy and Infectious Disease

其中一個全球性大規模流感疫症的特徵是較年輕的人士的死亡率會上升。在1968年疫症中有一半和流感有關的死亡、1957和1918年的疫症中大部分和流感有關的死亡都發生在年齡少於65歲的人士(Simonson 1998)。

1918

在二十世紀裡的第一個全球性大規模流感爆發在1918至1919年十二個月內差不多同時以三個分開的波浪在歐洲、亞洲和北美洲傳播(Barry 2004, Taubenberger 2006)。這在歷史上是最嚴重的爆發，因這爆發而死的人比在第一次世界大戰中死亡人數還多，一般相信那次最少有五千萬人死亡(Johnson 2002)。第一次波浪由1918年春天開始，雖然傳染性很高但並不是十分危險。當第二次波浪在9月侵襲，破壞性最強的疫症才在那時開始散播。

圖3：在流感爆發時的緊急醫院。Camp Funston, Kansas. Images from the 1918 Influenza Epidemic. Image copyright by National Museum of Health & Medicine, Washington, D.C. http://InfluenzaReport.com/link.php?id=19

1918年疫症的病毒十分危險並導致很多第二重細菌性肺炎感染而死亡的個案。第一重病毒性肺炎可以在兩天內將一個平時很健康的人殺死。很多嚴重個案的臨床症狀一點都不熟悉，有很多調查員甚至懷疑那是否流行性感冒(WHO 2005b)。1918年的症狀十分不平常，一開始被誤診為登革熱、霍亂、或傷寒症(Barry 2004)。

在不很嚴重的病症，大部份病人經歷了一般流行性感冒連同三到五天的發燒，接著就完全康復(Kilbourne 2006)。相對於之後的全球性大規模流感疫症爆發，在1918疫症裡大多數死亡個案在介乎15至35歲的年輕健康人士，而百分之九十九的死亡個案都發生在年紀小於65歲的人士身上。

從1918年用福爾馬林(formalin)固定保存的肺部解剖組織中所尋找回的病毒中提取的基因組RNA(genomic RNA)及一個來自於1918年11月被埋葬在永久凍土層的流感病人的肺部組織(Taubenberger 1997)使我們可以將全部8段1918年的H1N1的病毒RNA排序解碼(Taubenberger 2005)。調查所得H1N1病毒並不是一隻重組病毒(如1957和1968年爆發的病毒)，反而像是一隻適應了人類的完全像禽鳥病毒的品種。

1957

1957年的大型流感爆發是由H2N2引起，這是一隻在臨床病徵較1918病毒溫和的病毒。爆發很頻密地有爆炸性，但死亡人數比之前低很多。死亡率有明顯特徵和趨勢，和季節性爆發差不多，多出的死亡都集中在嬰兒和老人(WHO 2005b)。有其他慢性病的病人和孕婦有較大機會形成其他和肺有關的併發症(Louria 1957)。全球因這次1957大規莫爆發所增加的死亡人數約為1至2百萬。

1968

1968年的全球性大規模流感爆發也是一個較溫和的爆發。相對於1967至1968年的嚴重週期性爆發(最後一次H2N2爆發)和1975至1976及1980至1981的兩次H3N2週期性爆發，死亡率衝擊甚至比這幾次輕微(Simonsen 2004)。這次的死亡人數約為1百萬，而單在美國，多於50%因感冒死亡的個案發生在小於65歲的較年輕人口。血清考古學調查發現多數大過77歲的人在接觸這隻新爆發病毒之前已經有H3的抗體(Dowdle 1999)，而這些人身上的H3抗體有可能是在1968年H3N2全球爆發中保護這些年過77的老人。

The global outbreak of massive influenza in 1968 was also a milder outbreak. For the severe periodical eruptions of 1967-1968 (the last H2N2 outbreak) and 1975-1976 and 1980-1981 (the two H3N2 periods), the death rate hit even slightly (Dowdle 1997, Gaydos 2006, Kilbourne 2006)。

From 1968 to the present, only an error in 1976 predicted that another global epidemic would begin to erupt (Dowdle 1997, ,

在歷史上主要的全球性大規模疫症平均每隔三十年就會出現，而現在一般都同意未來會有新一次的全球性大規模爆發。要預計下次爆發的流感病毒品種是不可能的。其中一種可能的病毒是禽鳥病毒品種H5N1，這病毒品種在東南亞已經成為野生水鳥和家禽的地區性疫症，並在最近由亞洲蔓延到歐洲和非洲。最新研究顯示1918疫症的病毒和禽鳥病毒在聚合?蛋白質排列上只有10個胺基酸轉變，而最近流傳的一些高度致病的H5N1就帶有這些轉變(Taubenberger 2005)。

One possible virus is H5N1 for bird disease, which has become endemic to wild water birds and poultry in south-east Asia and has recently spread from Asia to Europe and Africa. Recent studies show that 1918 viruses and bird viruses are in fusion. There are only 10 amino acids on protein sequences, and some highly pathogenic H5N1s recently passed (.

現在，H5N1禽流感仍然主要是禽鳥的疾病。物種的界限仍然十分明顯，雖然在很多地區在兩年內有過千萬的禽畜受到感染，只有少於200個被實驗室證實的人類感染的病症 (WHO 200601)。人類感染個案第一次於1997年記錄(Yuen 1998)，和高度致病的禽鳥流感病毒在家禽爆發同時發生。記錄的人傳人個案不多，衛生人員及與病人有接觸的家屬十分有限(Katz 1999,Buxton Bridges 2000)。在這些人中雖然有H5抗體，代表他們曾受感染，但並沒有嚴重個案發生。

Now, H5N1 bird flu is still mainly a bird disease. The boundaries of the species are still clear, although in many areas tens of thousands of animals have been infected within two years, with fewer than 200 human infections confirmed by the laboratory (glink=WO200601). Human infections were recorded for the first time in 1997 ( >

沒有甚麼證據顯示接觸高致病性的禽流感H5N1之後會有少個案多是沒症狀的感染或只有溫和的臨床症狀。如果大部份都是沒症狀的感染，那在2006年3月21日報告的嚴重的人類H5N1感染導致55%死亡率(WHO 20060321)就不是那麼令人擔憂。可是，這些事件可能是個別例外的，最少在某些環境下。在一條有H5N1在家禽爆發並導致4人死亡的柬埔寨村莊進行的研究，從351個村民的血液樣本檢驗中，發現沒有更多的感染，不過很多村民都有很大程度和染病家禽的接觸(ProMED 20060322.0893 and Buchy, personal communication)。

There is little evidence that H5N1 has been exposed to highly pathogenic avian influenza, and that there are many cases of no or mild bedside symptoms. If most of the infections are no symptoms, the 55% mortality from H5N1 infection reported on 21 March 2006 (WHO20060321) is not as worrying. However, these incidents may be an exception, at least under some circumstances.

直至現在，這個疾病主要影響小童和年青人。有116個病人由03年12月至06年9月的病人是在WHO網站上有詳細人口資料的，資料顯示50%是16歲以下，75%是30歲以下，90%是40歲以下的(Promed 20060211.0463)。這個年齡分佈的原因(接觸風險、疾病報告的偏差、內在的寄主問題等)仍是不清楚。同樣地，我們仍不知道遺傳組合怎樣和至甚麼程度影響對H5N1流感病毒感染的抵抗力(Promed20060216.0512)。

Until now, the disease mainly affects young children and young people. 116 patients from December 2003 to September 2006 have detailed population data on the WHO website. The data show that 50% are below 16 years of age, 75% below 30 years of age, and 90% below 40 years of age ().

下一次全球大模模疫症預計將會使20億人染病。最好的情況，以1968年的溫和疫症為基礎，預計有二百萬至七百四十萬病症(WHO 2005b)。不過，假如我們將1918年流感病毒導致的死亡個案轉化到現在的人口，那全世界將可能有一億八千萬至三億六千萬死亡的個案(Osterholm 2005)。

The next global model disease is expected to affect 2 billion people. The best case scenario, based on 1968 temperature and disease, is estimated to be between 2 million and 7.4 million cases (

一個人在流感爆發中的命運，不論是一次週期性或全球性的爆發，都是多變的。有預計大約一半受感染的人會沒有任何病徵和症狀。其他人的臨床症狀由無熱的呼吸症狀像一般傷風，至不同程度由溫和至使人衰弱的發熱的疾病(Hoffmann 2006a)，還會引致其他毛病影響肺、心臟、腦、肝、腎和肌肉(Nicholson 2003)。

The fate of a person in a flu outbreak, whether periodic or global, changes. About half of those infected are expected to have no symptoms or symptoms. Others have bedside symptoms caused by unheated respiratory symptoms of general convulsions, to a different degree from temperature to debilitating fever (Nicholson2003).

臨床的過程會受病人的年齡、之前已有的免疫力的多少、病毒的特性、吸煙與否、其他的病理、免疫力之抑制與懷孕(Nicholson 2003)。死亡通常是最初的病毒性肺炎或繼發的細菌性呼吸系統感染所引起，特別是有潛在的肺部或心肺疾病。小童和老人通常有最高風險建立嚴重併發症。不過在全球性大規模疫症下，死亡個案會轉移到較小的年齡組別(Simonson 1998)。

The journey to bed is subject to the age of the patient, the level of previously existing immunity, the properties of the virus, smoking and non, other pathology, immunosuppressive inhibition and pregnancy (

在人類來說，流行性感冒的亞型複製好像是受限於呼吸系統裡的上皮細胞。當有病毒進入細胞，它會導致複雜的細胞病變(cytopathic effects)，主要在柱狀上皮細胞(columnar epithelial cells)，它會停止細胞本身的蛋白質製造。缺少了必須的細胞蛋白會透過細胞壞死導致細胞的死亡(Yuen 2005)。對於一類流感品種有很多個人因素影響保護或增加死亡風險(Behrens and Stoll 2006)，而有很大機會遺傳因素會影響寄主容易感染與否。獨特的免疫力對抗某些病毒表位(epitopes)或某程度上的交叉免疫力能解釋為甚麼年過65歲的人不太受1918年大規模爆發的影響。類似的機制是否和最近的H5N1禽流感爆發所引致的奇怪年齡組別分佈有關仍是未知之數(ProMED 20060211.0463)。

In humans, the transmutation of the influenza appears to be the upper skin cells that are confined to the respiratory system. When the virus enters the cells, it causes complex cell changes (cytopathic effects), mainly on pillars (colomnar eptheelimal cells), which stop the protein production of the cells themselves. The lack of the necessary cell protein will protect or increase the risk of death of the cells (

H5N1在人類中的不尋常的嚴重性最初是被認為基於為數不少鄰近被切的位置的多個鹼性的胺基酸，是高度致病的甲型流感特有的一個特性(Subbarao 1998)。這些鹼性胺基酸的存在使該蛋白易受不同組織的蛋白?認得而導致H5N1對更多組織有更大的向性而它可以向肺部之外散播(Yuen 2005)。另外一個解釋是干擾素(interferons)是最主要被用作防止病毒蔓延致呼吸管道以外，而H5N1會阻慢這個內在對抗病毒感染的防衛。高度致病的H5N1病毒的非結構性基因(non-structural gene)使H5N1能對抗干擾素及腫瘤壞死因子-Alpha(tumor necrosis factor alpha)的抗病毒作用(Seo 2002)。H5N1病毒像是比H3N2或H1N1更可以引起高層次的促發炎細胞激素(pro-inflammatory cytokines)的轉錄(transcription)，而H5N1更是在巨噬細胞(macrophage)的促發炎細胞激素的有效的誘導物，其中最著名的是腫瘤壞死因子-Alpha(Cheung 2002)。這些機制最終會導致細胞激素大量出現和死亡(Peiris 2004)。

The acuteness of H5N1 in humans was initially attributed to multiple amino acids based on a large number of nearby cut locations (

在兩個全球性疫症中間的季節性感冒疫症裡，兩次疫症中的流感的復原一般是平靜的。但在這個嚴重的人類H5N1流感個案中，死亡率是相當大的(WHO 20060213)。呼吸因難(Dyspnoea)、急性呼吸窘迫症候群(ARDS)及多重器官衰竭(multi-organ failure)是致命個案的主要臨床症狀(Hoffmann 2006a)，從症狀出現到死亡的中位數是九天 (n=76)(http://www.influenzareport.com/links.php?id=16)。

In the case of two global outbreaks of seasonal flu, the cure of influenza in two cases is generally calm. But in this severe human H5N1 case, mortality is quite high (WHO 20060213). Respiratory distress (Dyspnoea), acute respiratory distress syndrome (ARDS) and multiple organ failure (multi-organ failure) are the main bedside symptoms of fatal cases (Hoffmann 2006a), with the median number of days from symptoms to death being nine (n=76) (http://www.influenzareport.com/links.php?id=16).

成功的先決條件是良好的適應力：適應人類的細胞、有能力去控制寄主細胞的生產機制來製造下一代、使該染病人士咳嗽和打噴嚏來傳播新的病毒。要成功的提示是毒性及新鮮感(Noah 2005, Obenauer 2006, Salomon 2006)：如果該病毒是真正全新的，絕大部份人類都不會有免疫力。該新病毒將能無限的侵入實質上所有的人類，並會有多於六十五億人類作為攝食場的地方。那是世界上其中一個最大的生物量(biomass)。

The pre-requisite for success is good adaptation: appropriate human cells, capable of controlling host cell productions to produce the next generation, coughing and sneezing to spread new viruses. The hint for success is toxicity and freshness (

由一隻領導的流感亞型到一隻新的亞型的力量轉移被稱為「抗原飄移」，因為新病毒的抗原性特徵需要大幅度的轉移來避過全人類的免疫系統。「抗原位移」是甲型流感的主要改變使新的血凝素蛋白或/和神經胺酸?蛋白出現。導致這個轉變的可能是因為1)新病毒的兩個來源的分裂基因組重組；2)動物病毒的逐漸突變(mutation)。要進行重組，新的可能導致全球性大規模爆發的流感病毒，一般來自禽鳥，和一種已有的人類病毒，即是H3N2和H1N1，需要同時感染同一個人體寄主細胞。在細胞內，從兩隻不同病毒而來的基因會重新排列成一隻全新病毒(其實它們並沒有性交，但是為了教學用途，這形象化的比喻還是可以的)。1957年和1968年的爆發就是這樣的發生了(圖2)。

The shift of power from a leading Asian type of influenza to a new Asian type is called "antigen drift" because the antigen characteristic of the new virus requires a significant shift from the entire human immune system. The "antigen shift" is a major change in type A influenza that causes new hemogloclinol proteins or/or neurotoxin acids? Protein appears. This change is probably due to the fact that the two sources of the new virus have been re-assembleded by the genes from the two different viruses; 2) the evolution of the animal virus. To re-assemble, the new influenza virus, which could cause a massive worldwide outbreak, usually from birds, and an existing human virus, is H3N2 and H1N1, and this was the case in 1957 and 1968.

重配未必是有可能為全球性大疫症病毒的最佳途徑。最新証據從來自1918大爆發的病毒的重組病毒基因的顯示，有一個或多於一個1918病毒的基因的病毒的有害性比當全部8個基因齊集時為低(Tumpey 2005)。1918病毒是獨有的：它好像不是由兩隻當時有的病毒重配所得，而是一隻透過逐步的突變去適應人類的完全的禽鳥病毒(Taubenberger 2005)。很可能那種新的適應了人類的禽鳥流感病毒在1918年的出現(n=1)會比重配病毒在1957及1968年(n=2)的出現更致命，但是這個推測是不科學的。有趣地，同時使人擔心地，1918病毒的幾個胺基酸轉變使這病毒和一般禽鳥病毒有的區別，同時也在一些高度致病的禽流感病毒品種H5N1出現，這顯示這些改變可能幫助病毒在人體細胞複製和增加致病性(Taubenberger 2005)。

The most recent evidence suggests that a virus with a recombination virus from the 1918 virus was less harmful than when all eight genes came together (

甲型和乙型流感病毒是有分段基因組(segmented genome)，由8段由890至2341個核?酸(nucleotides)組成的單鏈RNA(single-stranded RNA)的套膜(enveloped)病毒(Gürtler 2006)。它們的結構是球狀或線狀，直徑為80至120納米(圖4和圖5)。流感病毒粒子(virion)的橫切面好像一個對稱的意大利香腸薄餅，有一塊圓形的香腸切片在中間，另外7塊就均衡地分佈在周圍(Noda 2006)。血凝素 (haemagglutinin, HA)及神經胺酸?(neuraminidase, NA)這兩隻醣蛋白(glycoprotein)在抗原性的基礎上，甲型流感病毒可細分為16H (H1-H16[Fouchier 2005])和9N(N1-N9)亞型。血凝素是主要中和抗體的抗原，也用作病毒附上寄主細胞受體(receptor)。神經胺酸?是用作在細胞表面放出新製病毒粒子。現在只有H1N1和H3N2的亞型病毒在人類之間流傳。

Influenza A and B viruses are a segmented gene group (segmented genome) consisting of 890 to 2341 nucleotides (nucleotides) of single RNAs ( blank's blank's blask's glass=Nlink > N uml; rtler 2006< > ; their structure is a spherical or linear shape = 80 to 120 nammy (figure 4 and figure 5) of influenza particles (virion) like an Italian filamentary cake, with an interlactomy of < < < < < < < < < < < < > < < > > > < < > < < < < < < < < < <

圖4：禽流感的著色穿透式電子顯微鏡圖(TEM)。H5N1病毒(金色)養在MDCK細胞(綠色)。圖片來自CDC/ Cynthia Goldsmith, Jacqueline Katz, and Sharif R. Zaki, Public Health Image Library, http://phil.cdc.gov/Phil/home.asp

天然貯存庫 + 生存

甲型流感病毒在很多不同物種出現，通常在雀鳥，特別是水鳥，感染通常主要在腸道和水路傳染，而且通常是無症狀的。東南亞的家禽鴨是主要甲型流感的寄主，同時它們在製造和維持H5N1病毒時扮演重要角色(Li 2004)。在泰國，H5N1病毒和大量自由放養的鴨有很大關聯，另外有關聯的是當地公雞及小雞，以及濕地，和人類。主要用作米產量為兩倍的濕地，那裡自由放養的鴨全年都在農地上，這個好像是高度致病性禽流感(HPAI)可以持續和散播的關鍵原因(Gilbert 2006)。

圖5：這個負色的穿透式電子顯微鏡圖(TEM)顯示一些病毒粒子的超結構(ultrastructural)細節。圖片來自： CDC/ Dr. F. A. Murphy, Public Health Image Library, http://phil.cdc.gov/Phil/home.asp

高度致病性的禽鳥病毒可以長時間生存，特別能在低溫度生存(好像被糞便污染了的水)。在水中，病毒在22度可以生存4天，在0度更可生存30天以上。在凍結了的物質，病毒應該可以無限地生存下去。最新研究指出在2004年的H5N1病毒變得更穩定，可以在37度生存6天 ─ 在1997年的爆發病毒只能生存2天(WHO 20041029)。這病毒可以被熱(56度需要3小時或60度的30分鐘)及一般的消毒劑像福爾馬林及碘化合物殺死。

傳播

流行性感冒主要由受感染人士的鼻和咽喉因咳嗽和打噴嚏所噴出的水點(大於5微米)以人傳人方式傳播(圖6)。這些微粒並不會停留在空中，而是必需有短距離的接觸(最遠到3.6呎)作傳播。傳播也可以透過直接皮膚接觸或間接接觸呼吸系統分泌(觸摸被污染的表面後再觸摸眼睛，鼻或口)。一個人可以在病徵出現前兩天至病徵出現後5天散播流感病毒。兒童可以在十天或以上的時間散播病毒。

圖6：未受阻的噴嚏大約送出2000至5000粒充滿細菌的水點到空氣中。圖片版權來自Prof. Andrew Davidhazy, Rochester Institute of Technology. Used with permission. (http://www.rit.edu/~andpph)

因為流感病毒一般都是高度物種專一的，所以它們很少會超越界限而感染其他物種。這是由於它們取用不同的細胞受體。禽流感病毒會附上細胞表面的醣蛋白唾液酸半乳糖殘基(sialyl-galactosyl residue)，以2-3位連接，而人類病毒則會附上有2-6連接的唾液酸半乳糖受體部分。對於一隻禽鳥病毒要在人類之間容易地傳播，基本上它需要有得到附上2-6受體的能力使它可以進入細胞並在裡面複製。當一個胺基酸的替換可以很大地改變禽鳥H5N1病毒之受體專一性(Gambaryan 2006)，現在仍是不清楚哪個專有的突變能使H5N1病毒容易及持久地在人類中間傳播，但H5N1確存在可能的途徑可能突變及得到人類專一性的。

自1959年，人類感染禽流感病毒是罕見的。在數以百計的甲型禽流感病毒品種裡，只有4種是已知會感染人類的：H5N1、H7N3、H7N7和H9N2(WHO 200601)。除了H5N1外，人類感染通常都只會有溫和病徵，很少會導致嚴重疾病(Du Ry van Beest Holle 2003, Koopmans 2004)。H5N1來說，和死或有病的雀鳥有近距離接觸(如宰殺、拔毛、屠宰和準備)或在操場上接觸到雞隻的糞便應該是最主要人類感染的原因(WHO 200601)。

H5N1：進展

現在，H5N1在人類的感染仍是相對上很少，雖然一定有通過受感染家禽廣泛對病毒的接觸。這證明了物種的阻隔仍能成功地阻止禽鳥病毒H5N1去影響人類 ─ 即使它們已經流傳了十年左右。不過在過去幾年，H5N1品種好像變得更具致病性和擴闊了它們行動的範圍：

• H5N1流感品種繼續進化(Li 2004)，有些病毒的複製有更廣的附上能力，可能是代表對人類寄主的某程度上的適應(Le 2005)。H5N1不止擴闊了禽鳥物種中的寄主範圍(Perkins 2002)，也在哺乳動物，自然地感染人類、老虎、豹、家貓和石貂(Keawcharoen 2004, Thanawongnuwech 2005, Amonsin 2006)。
• H5N1病毒增加了在老鼠和雪貂身上的致病性(Zitzow 2002, Govorkova 2004)。
• 最近顯示鴨子可以在17天內排出高度致病的H5N1品種(Hulse Post 2005)
• 在2005年4月尾，超過6,000隻候鳥死於中國中部的青海湖自然保育區。在那之前，野鳥因高度致病禽流感病毒而死是很不尋常的(WHO 20050818)。
• 來自不同地區(青海湖、尼日尼亞、伊朗、土耳其、俄羅斯、哈薩克斯坦和蒙古)的病毒全都顯示出獨特的突變，和使雀鳥和老鼠更容易致命有關聯。這個在過去很多個月的遺傳穩定性是不尋常和提出一個關於這病毒的可能性 ─ 在其高度致病的類型 ─ 這病毒已經適應了最低限度某些遷移性水鳥物種，同時和這些雀鳥在進化的平衡上一同存在，不會造成明顯的傷害，並和這些雀鳥一同在遷徙路線上移動(WHO 20060220)。
• 在一個2005年在泰國中部進行未出版的研究裡，629隻狗中有160隻對H5N1有抗體(Butler 2006)。
• 家貓通常被認定為對感冒有抵抗能力。不過當貓被餵一些被H5N1感染的雞隻時，貓會出現嚴重的病並將病毒傳播到其他貓(Kuiken 2004)。貓不只透過呼吸管道排出病毒，也可能透過消化管道(Rimmelzwaan 2006)，這提示新路線去傳播病毒給同類或其他哺乳類動物寄主是有可能的。在2006年2月，H5N1流感在一隻家貓(WHO 20060228)和一隻石貂(WHO20060309)身上發現，在德國的呂根島(Ruegen)，在那裡有多過100隻野生雀鳥在過去兩星期死亡。
• 在2003和2004年分隔的人類H5N1品種比其他1997年來分隔出來的人類H5N1病毒顯示出本質上對雪貂有更高程度的有害性(Maines 2005)。

個人管理

Personal management

嘗試不得到病毒，如果你染到牠們，嘗試去處理牠們。在流感的管理上這句醫學智慧可以翻譯成：1) 3條預防保衛防線(接觸預防、接種、抗病毒藥物的預防性使用)；2) 1條治療保衛防線(抗病毒藥物)。因為流行性感冒感染的本質 ─ 受感染人士可能在病徵出現前24至48小時已經可以傳染別人 ─ 接觸預防在一次季節性或全球性大疫症中差不多是不可能的，尤其是在我們這個高度流動性和人口密集的世界。

Try not to get the virus, if you catch them, try to deal with them. This medical wisdom in influenza management can be translated into: 1) 3 precautionary lines of protection (precautions, intakes, antivirals); 2) 1 antiviral line of treatment (antivirals). Because of the nature of the influenza infection - infected persons may be infected 24 to 48 hours before the onset of the disease - it is almost impossible to protect themselves from a seasonal or global epidemic, especially in our highly fluid and densely populated world.

週期性爆發預防

weekly prophylactic precipitous

接觸預防

Contact Precaution

基本個人衛生措施，早在一個世紀之前已被發明，這些仍是現在預防措施的基石。醫生要鼓勵病人的家屬定期洗手。一般來說，應該阻止人去觸摸自己的眼、鼻和口。盡量用所有方法減少噴嚏和咳嗽的衝擊 (WHO 2006a)。

Basic personal hygiene measures, which were invented a century ago, are still the cornerstones of current preventive measures. Doctors must encourage patients' families to wash their hands regularly. Generally, people should be prevented from touching their eyes, noses and mouths. As much as possible, reduce the impact of sneezing and coughing by all means (WHO 2006a).

疫苗

Vaccine

流感病毒疫苗是預防流感的第二個基石。在北半球的接種建議最好在十月開始。該疫苗的成份的建議每年會根據仔細調查各流通的品種而發放。建議高危人士應該接受對所有流行的野生型流感病毒的接種，包括年齡大於65的人(CDC 2005)，和那些有慢性疾病的特別是糖尿病、慢性呼吸和心臟疾病，和一些因其他疾病或相隨治療導致而致免疫障礙的病人。另外，所有衛生人員應該每年接受流感接種(CDC 2006b)。流感接種的比例基於幾個不同因素，包括醫生直接的建議和傳媒的報道(Ma 2006)。

Influenza vaccine is the second cornerstone of influenza prevention. In the northern hemisphere, it is best to start in October. The component of the vaccine is recommended to be released every year on the basis of a detailed survey of the different types of fluids in circulation. It is recommended that high-risk individuals should accept the introduction of all endemic wild influenza viruses, including those older than 65 (.

在健康的已接種成年人裡，一劑之後的功效可以高至80-100%，在一些第一次接受流感接種的成人中，要過了兩劑之後的功效才達致上面的上平。當有其他潛在的條件(如HIV感染、腫瘤和腎移植)，功效會較低(Korsman 2006)；不過最終保護是基於誰已經接種和疫苗與流通病毒的競賽(Wong 2005)。

In healthy adults, the efficacy of a single dose can be as high as 80-100%, and in some first-time recipients of influenza, it can be achieved only after two. When there are other potential conditions (such as HIV infection, tumors and kidney transplants), the efficacy is lower (Korsman2006); but the ultimate protection is based on who has received the seed and vaccine and the circulating virus (

流感疫苗在65歲以上的人的功效和效率的證據已經被重新探討。良好配對的疫苗可以減少入院、肺炎、呼吸系統疾病、心臟病和死亡。效率方面住在家中的老人比在社區的老人為好(Jefferson 2005)。不活化疫苗(inactivated vaccine)可以減少患有慢性阻塞肺炎(Chronic obstructive pulmonary disease, COPD)的病人的惡化(Poole 2006)。流感疫苗在兩歲以上的小孩也有效，但是兩歲以下的只有很少証據(Smith 2006)。活病毒的鼻噴劑好像比不活化疫苗更有效防止流感疾病。

Evidence of the efficacy and efficiency of the influenza vaccine for people over 65 years of age has been revisited. A good combination of vaccines can reduce institutionalization, pneumonia, respiratory diseases, heart disease and death. Older people living in the home are better off than those living in the community (

抗病毒藥物

Antivirus

短期抗病毒藥物的預防性使用的適合者是那些高風險病人即是週期性疫症開始後才接種疫苗的，也包括與流感病人有高風險接觸的未接種人士。在某些例子裡，當時的週期性爆發是因為一種不在疫苗中的品種引起可以顯示預防的功效。在這方面需要更多資料可參閱Hoffmann 2006b。

In some cases, the periodic outbreak was caused by a species that was not in the vaccine to show the efficacy of the precaution. More information is needed on Hoffmann2006b.

在兩個現有的藥物組別中，金剛烷adamantane (金剛胺amantadine, 金剛乙胺rimantadine)最近受壓因為全球流行抗金剛烷adamantane的流感病毒由1994-1995年的0.4%上升至2003-2004年的12.3%(Bright 2005)。一般相信在中國的抗藥性上升是因為嚴重急性呼吸系統綜合症(SARS)出現後有很多人取用在藥房買得到的金剛胺amantadine (Hayden 2006)。在美國，2005-06年季度直至06年1月12日分離的甲型流感(H3N2)病毒中109/120 (91%)有在M2蛋白上位置31的胺基酸轉變，使病毒對金剛胺amantadine 和 金剛乙胺rimantadine有抗藥性(CDC 2006, Bright 2006)。基於這些結果，疾病預防控制中心(CDC)發出一個暫時的建議：金剛胺amantadine 和 金剛乙胺rimantadine 在2005至06年美國剩餘的流感季節不應該用作治療或預防甲型流感。在這期間，奧斯他偉oseltamivir 或 扎那米韋zanamivir應被選作抗病毒的藥物用作治療和預防流感。

Of the two existing drug combinations, the aramadamane , the azimonymamine (httpahrefrefrebrebret > > > < > <2vebrebrebrebrebrebrebrebrebrebrebrebrebrebrebrebrebrebrebrek > > < > > > > > < < > < < < > > < < < < < > >

週期性爆發治療

weekly EOD

在一些不複雜的病例中，在床休息加上吸取足夠水份是絕大部分成年人和青少病人的治療選擇(Hoffmann 2006b)。抗生素應留作治療第二期細菌性肺炎。

In some uncomplicated cases, bed rest combined with water harvesting is the treatment option for most adults and young patients (Hoffmann 2006b).

一些較舊的藥物如金剛乙胺rimantadine和金剛胺amantadine只是對甲型流感病毒有效(CDC 2005)。可是在老人方面的數據很少；這些藥物有較多副作用；而且在2005/2006季度，CDC呼籲停止使用這些藥物(參閱上一章)。如果用了金剛乙胺rimantadine和金剛胺amantadine，重要的是減少對抗病毒藥物呈抗性的病毒的山現。金剛乙胺Rimantadine或金剛胺amantadine治療應該盡早停止，通常是治療開始後的3.5天，或病徵消失後的24-48小時(CDC 2005)。

Some older drugs such as 新的神經胺酸?(neuraminidase, NA)抑制劑已經獲得許可用作治療一歲以上奧斯他偉(oseltamivir)或七歲以上扎那米韋(zanamivir)的病人。這些藥物被指定用作一些不複雜的急性疾病而病徵只出現了少於兩天的病人身上。兩種藥的建議治療週期均為5天。

全球性大疫症預防

Global Pandemic Prediction

新的全球性大爆發感冒品種的問題是在地球上無處可躲。實際上任何一個人最終會被新病毒感染，不管他是一個巴黎的乞丐還是一個富有西方國家的總統。就算你在大爆發的第一波沒受病毒感染，你很有機會在第二波受到感染。如果你在第二波沒受感染，你都會在將來的週期性爆發中受到感染。如果一隻全新的大爆發流感品種取代其他成為使人患上流感的驅動者，所有人都需要發動保護性抗體反應對抗病毒 ─ 因為病毒極可能會在我們身邊很久。抗體會提供一些保護對抗新的流感品種，不過要製造抗體你需要被感染或受接種。

If you are not infected in the first wave of the outbreak, you have a good chance of being infected in the second wave. If you are not infected in the second wave, you will be infected in the next periodic outbreak. If a brand-new mass influenza species replaces others who become the driving force of influenza, everyone needs to initiate a protective anti-retroviral response to the virus – because the virus is likely to be around us for a very long time. The antibodies will provide some protection against the new influenza, but to create the anti-influenza, you need to be infected or absorbed.

全世界65億人中有很大部份在新的全球性大疫症流感病毒來到時，短時間內將不會得到疫苗。當一隻新病毒被顯示出可以在人類之間有效地傳播，大約需要6個月的時間去開始製造相應的疫苗。所以疫苗的供應將會強烈地不足夠，要65億人全部接種更需要很多年時間去製造足夠疫苗。再加上製造疫苗的生產力集中在澳洲、加拿大、法國、德國、意大利、日本、荷蘭、英國和美國，可以預計疫苗的分佈將會被這些製造疫苗的國家所控制(Fedson 2005)。我們可以想像誰會先得到供應。

When a new virus is shown to be effective among humans, it will take about six months to start producing a corresponding vaccine. So the supply of vaccines will be severely inadequate, with 6.5 billion people receiving all of them taking many more years to produce enough vaccines. Plus, the production of vaccines will be concentrated in Australia, Canada, France, Germany, Italy, Japan, Holland, England and the United States, and the distribution of vaccines will be controlled by the countries that produce them ().

• 在1918年週期性爆發中，第一波在春天的月份發生，比在秋天的第二波傷害要低(Barry 2004)。所以我們有理由去相信那些在第一波被感染的人在第二波時會有一些保護。這個說話支持盡早去面對一隻新的流感品種。
• 可是1918年的第二波的詳細數據顯示相反的意見：當一個人在第二波中越遲受感染，他會死的可能性將會降低，而病亦會較溫和(Barry 2004)。那些越遲受流感侵襲的城市裡的人也比較少會受害。所以美國西岸城市較遲受感染，死亡率比東岸城市要低；澳洲直至1919年才受第二波侵襲，她的死亡率在已發展國家中是最低的(Barry 2004)。

傳染病普遍的現象是病原體(pathogen)在人類群體中進化會降低有害性。這對第二個選擇有利，即是盡量避開一隻新的流感病毒，越長越好。這個選擇的一個附加的優勢是大疫症開始後的數月內，醫療系統最初面對一個大型爆發所不能避免的混亂，將最少會有部份被解決。

The prevalence of the epidemic is that evolution of the pathogen (pathogen) in the human population reduces its harmfulness. This is in favour of the second option, which is to avoid as much as possible a new influenza virus, the longer it will be. One of the added advantages of this option is that within months of the onset of the epidemic, the medical system will be addressed in part at least in the first instance in the face of a major outbreak that cannot be avoided.

避開流感的最極端方法是逃離到地球上偏僻的地方 ─ 哥西亞島的一條山區村落、利比亞沙漠或美國薩摩亞(Barry 2004)。這有可能有用，也可能沒有。如果直接及不受保護去面對新病毒是無法避免時，一些防護仍是可能的：面罩(但是面罩會否在所有地方都可得到？幾長時間？)製造社交的距離(不要去聚會，盡量留在家中) ─ 但是如果你是在一家巴黎超級市場做收銀員；在倫敦的地鐵做駕駛員；在柏林的中央郵政局做文員：這麼辦？如果你幾個月不工作你可以從甚麼地方得到金錢？你可以從世界撤離嗎？你可以從生命撤離嗎？

The most extreme way to avoid influenza is to escape to a remote place on Earth — a mountain village in Costa Rica, the Libyan desert or American Samoa (

我們不知道下一次大疫症的流感品種會否對現有的抗病毒藥物有反應。如果下次疫症是H5N1病毒所引起，神經胺酸?(neuraminidase, NA)抑制劑奧斯他偉oseltamivir和扎那米韋zanamivir將於計劃大爆發的對策時是決定性的(Moscona 2005)。當然，大部份人將不會取得這些藥物。這些藥物供應少而生產能力將很難提昇。即使在那些有儲備奧斯他偉oseltamivir的國家，分配供應少的藥物作治療將會引起不少的倫理問題。在一些已知財富不等的國家(一些非洲及拉丁美洲國家；美國)，社會動盪是可以預見的。

We do not know whether the next outbreak of influenza will react to the existing antiviral drugs. If the next epidemic is caused by the H5N1 virus, neuroneuraminidase? (neuraminidase, NA) inhibitor oscillation glink" and Zanamiveh

治療人類的H5N1病的經驗有限，而且已出版的臨床報告只包括很少病人(Yuen 1998, Chan 2002, Hien 2004, Chotpitayasunondh 2005, WHO 2005, de Jong 2005)。例如H5N1疾病中oseltamivir的治療的最佳劑量和為期多久仍是不確定的，所以提出下初步的建議(WHO 2005)：

• 盡早開始奧斯他偉oseltamivir的治療。由於H5N1感染的死亡率仍然很高，即使病徵已經出現了8天仍應考慮治療，如果有證據顯示病毒仍在複製進行中(WHO 2005, de Jong 2005)。
• 考慮在嚴重病例中提高奧斯他偉oseltamivir的劑量(成人一天兩次150mg )及更長時間繼續治療(7至10天或更長)(WHO 2006d)。

全球管理

global governance

在一次流感爆發時的管理在週期性爆發中定義是明確的，在全球性大爆發中定義就較不明確。

Management at the time of a flu outbreak is defined as clear in a periodic outbreak, and less so in a global outbreak.

週期性爆發管理

Weekly Explosion Management

在兩次大爆發中間醫學干預的基石是疫苗(可參閱CDC 2005的總結)。由於流感病毒不斷地突變，疫苗的成份需要每年重新檢查。製造疫苗是一個建立良好的過程：在每一年，在世界各地82個國家的流感監察中心將會留意流感的流行品種及觀察趨勢。世衛(WHO)就會決定那些品種將最似未來一年冬季的流行品種，接著疫苗製造商會開始製造疫苗。下一個北半球的冬季的混合的成份會在每年二月決定(WHO 2006b)，在九月會決定下一個南半球的冬季(要更多資訊，可參閱Korsman 2006 及 http://influenzareport.com/link.php?id=15 的圖)。估計病毒血凝素 (haemagglutinin)進化上的改變是困難而且並不會常常成功。在那些年份當預計的品種和真實的品種不配合時，由流感疫苗所得的保護可能低至30%。

The cornerstone of medical intervention in two major outbreaks is the vaccine (available at ). The vaccine will need to be re-examined annually as a result of constant changes in the influenza virus.

請參閱Reyes-Terán 2006 and WHO 2006c。

See and .

數據根據 http://www.census.gov/ipc/www/world.html + http://influenzareport.com/link.php?id=20

According to

有些國家如法國、西班牙和德國，所有原因的每年死亡率約為每十萬人中900人。一個破壞性極大的大疫症將可能，在短短幾個月裡，導致比平常一年多三倍的死亡。實際上，社會和經濟的崩潰將不同程度在所有國家出現。在這個災難廣泛被傳媒覆蓋的世界，結果的氣氛將會像在打仗時的情景。相反，一個像1968的溫和大疫症將會不被注意和不會對國家醫療系統和全球經濟有很大衝擊。

In some countries, such as France, Spain, and Germany, the annual mortality rate for all causes is about 900 per 100,000 people. A devastating epidemic could, in just a few months, result in more than three times as many deaths as usual.

參考

Golden Links

Influenza. Special Issue of the Journal of Emerging Infectious Diseases, 2006. http://www.cdc.gov/ncidod/EID/vol12no01/contents_v12n01.htm

Pandemic Influenza: Confronting a Re-emergent Threat. Special Issue of the Journal of Infectious Diseases, 1997. http://www.journals.uchicago.edu/JID/journal/contents/v176nS1.html

Interviews

Interview with Dr. Jeffrey Taubenberger. Spanish and avian flu pandemics. Nature Podcast, 6 October 2006 - http://www.nature.com/nature/podcast/v437/n7060/nature-2005-10-06.mp3

Interview with Dr. Frederick Hayden on antiviral resistance in influenza viruses. 23 February 2006 - http://content.nejm.org/cgi/content/full/354/8/785/DC1

Interview with Dr. Anne Moscona on the clinical implications of oseltamivir resistance. 22 December 2005 - http://content.nejm.org/cgi/content/full/353/25/2633/DC1

Interview with Dr. Michael Osterholm on preparing for an influenza pandemic. 5 May 2005 - http://content.nejm.org/cgi/content/full/352/18/1839/DC1

References

1. Amonsin A, Payungporn S, Theamboonlers A, et al. Genetic characterization of H5N1 influenza A viruses isolated from zoo tigers in Thailand. Virology 2006; 344: 480-91. Epub 2005 Sep 27. Abstract: http://amedeo.com/lit.php?id=16194557
2. Aoki FY, Macleod MD, Paggiaro P, et al. Early administration of oral oseltamivir increases the benefits of influenza treatment. J Antimicrob Chemother 2003; 51: 123-9. Abstract: http://amedeo.com/lit.php?id=12493796 - Full text at http://jac.oxfordjournals.org/cgi/content/full/51/1/123
3. Apisarnthanarak A, Kitphati R, Thongphubeth K, et al. Atypical avian influenza (H5N1). Emerg Infect Dis 2004; 10: 1321-4. http://www.cdc.gov/ncidod/EID/vol10no7/04-0415.htm
4. Balicer RD, Huerta M, Davidovitch N, Grotto I. Cost-benefit of stockpiling drugs for influenza pandemic. Emerg Infect Dis 2005; 11: 1280-2. Abstract: http://amedeo.com/lit.php?id=16102319 - Full text at http://www.cdc.gov/ncidod/EID/vol11no08/04-1156.htm
5. Barry JM. 1918 revisited: lessons and suggestions for further inquiry. In: Board on Global Health. The Threat of Pandemic Influenza: Are We Ready? The National Academies Press 2004. Available from http://darwin.nap.edu/books/0309095042/html/58.html
6. Basler CF, Reid AH, Dybing JK, et al. Sequence of the 1918 pandemic influenza virus nonstructural gene (NS) segment and characterization of recombinant viruses bearing the 1918 NS genes. Proc Natl Acad Sci U S A 2001; 98: 2746-51. Abstract: http://amedeo.com/lit.php?id=11226311 - Full text at http://www.pnas.org/cgi/content/full/98/5/2746
7. Behrens G, Stoll M. Pathogenesis and Immunology. In: Influenza Report. Kamps BS, Hoffmann C, Preiser W. Flying Publisher, Wuppertal, 2006. - Full text at http://www.influenzareport.com/ir/pathogen.htm
8. Bright RA, Medina MJ, Xu X, et al. Incidence of adamantane resistance among influenza A (H3N2) viruses isolated worldwide from 1994 to 2005: a cause for concern. Lancet 2005; 366: 1175-81. Epub 2005 Sep 22. Abstract: http://amedeo.com/lit.php?id=16198766
9. Bright RA, Shay DK, Shu B, Cox NJ, Klimov AI. Adamantane resistance among influenza A viruses isolated early during the 2005-2006 influenza season in the United States. JAMA 2006; 295: 891-4. Epub 2006 Feb 2. Abstract: http://amedeo.com/lit.php?id=16456087
10. Butler D. Thai dogs carry bird-flu virus, but will they spread it? Nature 2006; 439: 773. http://amedeo.com/lit.php?id=16482119
11. Butler D. Wartime tactic doubles power of scarce bird-flu drug. Nature 2005; 438: 6. http://amedeo.com/lit.php?id=16267514
12. Buxton Bridges C, Katz JM, Seto WH, et al. Risk of influenza A (H5N1) infection among health care workers exposed to patients with influenza A (H5N1), Hong Kong. J Infect Dis 2000; 181: 344-8. Abstract: http://amedeo.com/lit.php?id=10608786 - Full text at http://www.journals.uchicago.edu/JID/journal/issues/v181n1/990819/990819.html
13. CDC 1997. Isolation of Avian Influenza A(H5N1) Viruses from Humans - Hong Kong, May-December 1997. MMWR 1997; 46: 1204-7. Full text at http://www.cdc.gov/mmwr/preview/mmwrhtml/00050459.htm
14. CDC 1998. Update: Isolation of Avian Influenza A(H5N1) Viruses from Humans - Hong Kong, 1997-1998. MMWR 1998; 46: 1245-47. Full text at http://www.cdc.gov/mmwr/preview/mmwrhtml/00050775.htm
15. CDC 2005. Centers for Disease Control. Prevention and Control of Influenza Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2005; 54 (RR08): 1-40. http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5408a1.htm
16. CDC 2006. High levels of adamantane resistance among influenza A (H3N2) viruses and interim guidelines for use of antiviral agents--United States, 2005-06 influenza season. MMWR Morb Mortal Wkly Rep 2006; 55: 44-6. Abstract: http://amedeo.com/lit.php?id=16424859 - Full text at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5502a7.htm
17. CDC 2006b. Influenza vaccination of health-care personnel: recommendations of the Healthcare Infection Control Practices Advisory Committee (HICPAC) and the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2006; 55: 1-16. Abstract: http://amedeo.com/lit.php?id=16498385 - Full text at http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5502a1.htm
18. CDC 2006c. Increased antiviral medication sales before the 2005-06 influenza season--New York City. MMWR Morb Mortal Wkly Rep 2006; 55: 277-9. Abstract: http://amedeo.com/lit.php?id=16543882 - Full text at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5510a3.htm
19. Chan PK. Outbreak of avian influenza A(H5N1) virus infection in Hong Kong in 1997. Clin Infect Dis 2002; 34: Suppl 2: Abstract: http://amedeo.com/lit.php?id=11938498 - Full text at http://www.journals.uchicago.edu/CID/journal/issues/v34nS2/010992/010992.html
20. Cheung CY, Poon LL, Lau AS, et al. Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease? Lancet 2002; 360: 1831-7. Abstract: http://amedeo.com/lit.php?id=12480361
21. Chotpitayasunondh T, Ungchusak K, Hanshaoworakul W, et al. Human disease from influenza A (H5N1), Thailand, 2004. Emerg Infect Dis 2005; 11: 201-9. Full text at http://www.cdc.gov/ncidod/eid/vol11no02/04-1061.htm
22. Claas EC, Osterhaus AD, van Beek R, et al. Human influenza A H5N1 virus related to a highly pathogenic avian influenza virus. Lancet 1998; 351: 472-7. Abstract: http://amedeo.com/lit.php?id=9482438 - http://www.thelancet.com/journals/lancet/article/PIIS0140673697112120/fulltext
23. de Jong MD, Bach VC, Phan TQ, et al. Fatal avian influenza A (H5N1) in a child presenting with diarrhea followed by coma. N Engl J Med 2005; 352: 686-91. Abstract: http://amedeo.com/lit.php?id=15716562 - Full text at http://content.nejm.org/cgi/content/full/352/7/686
24. de Jong MD, Tran TT, Truong HK, et al. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med 2005b; 353: 2667-72. Abstract: http://amedeo.com/lit.php?id=16371632 - Full text at http://content.nejm.org/cgi/content/full/353/25/2667
25. Demicheli V, Jefferson T, Rivetti D, Deeks J. Prevention and early treatment of influenza in healthy adults. Vaccine 2000; 18: 957-1030. Abstract: http://amedeo.com/lit.php?id=10590322
26. Diggory P, Fernandez C, Humphrey A, Jones V, Murphy M. Comparison of elderly people愀 technique in using two dry powder inhalers to deliver zanamivir: randomised controlled trial. BMJ 2001; 322: 577-9. Abstract: http://amedeo.com/lit.php?id=11238150 - Full text at http://bmj.bmjjournals.com/cgi/content/full/322/7286/577
27. Dowdle WR. Influenza A virus recycling revisited. Bull World Health Organ 1999; 77: 820-8. Abstract: http://amedeo.com/lit.php?id=10593030 - Full text at http://whqlibdoc.who.int/bulletin/1999/Vol77-No10/bulletin_1999_77(10)_820-828.pdf
28. Dowdle WR. Influenza Pandemic Periodicity, Virus Recycling, and the Art of Risk Assessment. Emerg Infect Dis; 12: 34-9. Full text at http://www.cdc.gov/ncidod/eid/vol12no01/05-1013.htm
29. Dowdle WR. Pandemic influenza: confronting a re-emergent threat. The 1976 experience. J Infect Dis 1997; 176: Suppl 1: Abstract: http://amedeo.com/lit.php?id=9240699
30. Du Ry van Beest Holle M, Meijer A, Koopmans M, de Jager C. Human-to-human transmission of avian influenza A/H7N7, The Netherlands, 2003. Euro Surveill 2005; 10. Full text at http://www.eurosurveillance.org/em/v10n12/1012-222.asp
31. Fedson DS. Preparing for pandemic vaccination: an international policy agenda for vaccine development. J Public Health Policy 2005; 26: 4-29. Abstract: http://amedeo.com/lit.php?id=15906873 - Full text at http://www.palgrave-journals.com/jphp/journal/v26/n1/pdf/3200008a.pdf
32. Ferguson NM, Cummings DA, Cauchemez S, et al. Strategies for containing an emerging influenza pandemic in Southeast Asia. Nature 2005; 437: 209-14. Epub 2005 Aug 3. Abstract: http://amedeo.com/lit.php?id=16079797
33. Fiers W, De Filette M, Birkett A, Neirynck S, Min Jou W. A "universal" human influenza A vaccine. Virus Res 2004; 103: 173-6. Abstract: http://amedeo.com/lit.php?id=15163506
34. Fouchier RA, Munster V, Wallensten A, et al. Characterization of a novel influenza A virus hemagglutinin subtype (H16) obtained from black-headed gulls. J Virol 2005; 79: 2814-22. Abstract: http://amedeo.com/lit.php?id=15709000 - Full text at http://jvi.asm.org/cgi/content/full/79/5/2814?view=long&pmid=15709000
35. Fouchier RA, Schneeberger PM, Rozendaal FW, et al. Avian influenza A virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome. Proc Natl Acad Sci U S A 2004; 101: 1356-61. http://www.pnas.org/cgi/content/full/101/5/1356
36. Gambaryan A, Tuzikov A, Pazynina G, Bovin N, Balish A, Klimov A. Evolution of the receptor binding phenotype of influenza A (H5) viruses. Virology 2006; 344: 432-8. Epub 2005 Oct 13. Abstract: http://amedeo.com/lit.php?id=16226289
37. Gao W, Soloff AC, Lu X, et al. Protection of mice and poultry from lethal H5N1 avian influenza virus through adenovirus-based immunization. J Virol 2006; 80: 1959-64. Abstract: http://amedeo.com/lit.php?id=16439551
38. Garner JS, and the Hospital Infection Control Practices Advisory Committee. Guideline for isolation precautions in hospitals. Part II. Recommendations for isolation precautions in hospitals. Hospital Infection Control Practices Advisory Committee. Am J Infect Control 1996; 24: 32-52. Full text at at http://www.cdc.gov/ncidod/dhqp/gl_isolation_ptII.html
39. Gaydos JC, Top FH, Hodder RA, Russell PK. Swine Influenza A Outbreak, Fort Dix, New Jersey, 1976. Emerg Infect Dis 2006; 12: 9-14. Full text at http://www.cdc.gov/ncidod/EID/vol12no01/05-0965.htm
40. Gilbert M. Free-grazing Ducks and Highly Pathogenic Avian Influenza, Thailand. Emerg Infect Dis 2006; 12: 227-34. Abstract: http://amedeo.com/lit.php?id=16494747 - Full text at http://www.cdc.gov/ncidod/EID/vol12no02/05-0640.htm
41. Goto H, Kawaoka Y. A novel mechanism for the acquisition of virulence by a human influenza A virus. Proc Natl Acad Sci U S A 1998; 95: 10224-8. Abstract: http://amedeo.com/lit.php?id=9707628 - Full text http://www.pnas.org/cgi/content/full/95/17/10224
42. Goto H, Wells K, Takada A, Kawaoka Y. Plasminogen-binding activity of neuraminidase determines the pathogenicity of influenza A virus. J Virol 2001; 75: 9297-301. Abstract: http://amedeo.com/lit.php?id=11533192 - Full text at http://jvi.asm.org/cgi/content/full/75/19/9297?pmid=11533192
43. Govorkova EA, Rehg JE, Krauss S, et al. Lethality to ferrets of H5N1 influenza viruses isolated from humans and poultry in 2004. J Virol 2005; 79: 2191-8. Abstract: http://amedeo.com/lit.php?id=15681421 - Full text at http://jvi.asm.org/cgi/content/abstract/79/4/2191
44. Gürtler L. Virology of Human Influenza. In: Influenza Report. Kamps BS, Hoffmann C, Preiser W. Flying Publisher, Wuppertal, 2006. - Full text at http://www.influenzareport.com/ir/virol.htm
45. Hatta M, Gao P, Halfmann P, Kawaoka Y. Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses. Science 2001; 293: 1840-2. Abstract: http://amedeo.com/lit.php?id=11546875 - Full text at http://www.sciencemag.org/cgi/content/full/293/5536/1840
46. Hayden F, Klimov A, Tashiro M, et al. Neuraminidase inhibitor susceptibility network position statement: antiviral resistance in influenza A/H5N1 viruses. Antivir Ther 2005; 10: 873-7. Abstract: http://amedeo.com/lit.php?id=16430192
47. Hayden FG, Atmar RL, Schilling M, et al. Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza. N Engl J Med 1999; 341: 1336-43. Abstract: http://amedeo.com/lit.php?id=10536125 - Full text http://content.nejm.org/cgi/content/full/341/18/1336
48. Hayden FG, Belshe R, Villanueva C, et al. Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis. J Infect Dis 2004; 189: 440-9. Epub 2004 Jan 26. Abstract: http://amedeo.com/lit.php?id=14745701 - Full text at http://www.journals.uchicago.edu/JID/journal/issues/v189n3/31422/31422.html
49. Hayden FG, Gubareva LV, Monto AS, et al. Inhaled zanamivir for the prevention of influenza in families. Zanamivir Family Study Group. N Engl J Med 2000; 343: 1282-9. Abstract: http://amedeo.com/lit.php?id=11058672 - Full text at http://content.nejm.org/cgi/content/full/343/18/1282
50. Hayden FG, Osterhaus AD, Treanor JJ, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenzavirus infections. GG167 Influenza Study Group. N Engl J Med 1997; 337: 874-80. Abstract: http://amedeo.com/lit.php?id=9302301 - Full text at http://content.nejm.org/cgi/content/full/337/13/874
51. Hayden FG. Antiviral Resistance in Influenza Viruses ?Implications for Management and Pandemic Response. N Engl J Med 2006; Volume 354:785-8. Full text at http://content.nejm.org/cgi/content/full/354/8/785
52. Hedrick JA, Barzilai A, Behre U, et al. Zanamivir for treatment of symptomatic influenza A and B infection in children five to twelve years of age: a randomized controlled trial. Pediatr Infect Dis J 2000; 19: 410-7. Abstract: http://amedeo.com/lit.php?id=10819336
53. Herlocher ML, Truscon R, Elias S, et al. Influenza viruses resistant to the antiviral drug oseltamivir: transmission studies in ferrets. J Infect Dis 2004; 190: 1627-30. Epub 2004 Sep 28. Abstract: http://amedeo.com/lit.php?id=15478068 - Full text at http://aac.asm.org/cgi/content/abstract/45/4/1216
54. Hien TT, Liem NT, Dung NT, et al. Avian influenza A (H5N1) in 10 patients in Vietnam. N Engl J Med 2004; 350: 1179-88. Abstract: http://amedeo.com/lit.php?id=14985470 - Full text at http://content.nejm.org/cgi/content/full/350/12/1179
55. Hoelscher MA, Garg S, Bangari DS, et al. Development of adenoviral-vector-based pandemic influenza vaccine against antigenically distinct human H5N1 strains in mice. Lancet 2006; 367: 475-81. Abstract: http://amedeo.com/lit.php?id=16473124
56. Hoffmann C, Kamps BS. Clinical presentation. In: Influenza Report. Kamps BS, Hoffmann C, Preiser W. Flying Publisher, Wuppertal, 2006a. - Full text at http://www.influenzareport.com/ir/cp.htm
57. Hoffmann C, Kamps BS. Treatment and Prophylaxis. In: Influenza Report. Kamps BS, Hoffmann C, Preiser W. Flying Publisher, Wuppertal, 2006b. - Full text at http://www.influenzareport.com/ir/tr.htm
58. Hoffmann C, Rockstroh J, Kamps BS. HIV Medicine 2005. Flying Publisher, Wuppertal, 2005. - Full text at http://www.HIVMedicine.com
59. Holmes EC, Ghedin E, Miller N, et al. Whole-genome analysis of human influenza A virus reveals multiple persistent lineages and reassortment among recent H3N2 viruses. PLoS Biol 2005; 3: Abstract: http://amedeo.com/lit.php?id=16026181 - Full text at http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=16026181
60. Hulse-Post DJ, Sturm-Ramirez KM, Humberd J, et al. Role of domestic ducks in the propagation and biological evolution of highly pathogenic H5N1 influenza viruses in Asia. Proc Natl Acad Sci U S A 2005; 102: 10682-7. Epub 2005 Jul 19. Abstract: http://amedeo.com/lit.php?id=16030144
61. Jefferson T, Rivetti D, Rivetti A, Rudin M, Di Pietrantonj C, Demicheli V. Efficacy and effectiveness of influenza vaccines in elderly people: a systematic review. Lancet 2005; 366: 1165-74. Epub 2005 Sep 22. Abstract: http://amedeo.com/lit.php?id=16198765
62. Johnson NP, Mueller J. Updating the accounts: global mortality of the 1918-1920 "Spanish" influenza pandemic. Bull Hist Med 2002; 76: 105-15. Abstract: http://amedeo.com/lit.php?id=11875246
63. Johnson NP, Mueller J. Updating the accounts: global mortality of the 1918-1920 "Spanish" influenza pandemic. Bull Hist Med 2002; 76: 105-15. Abstract: http://amedeo.com/lit.php?id=11875246
64. Kaiser L, Wat C, Mills T, Mahoney P, Ward P, Hayden F. Impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalizations. Arch Intern Med 2003; 163: 1667-72. Abstract: http://amedeo.com/lit.php?id=12885681 - Full text at http://archinte.ama-assn.org/cgi/content/abstract/163/14/1667
65. Katz JM, Lim W, Bridges CB, et al. Antibody response in individuals infected with avian influenza A (H5N1) viruses and detection of anti-H5 antibody among household and social contacts. J Infect Dis 1999; 180: 1763-70. Abstract: http://amedeo.com/lit.php?id=10558929 - Full text at http://www.journals.uchicago.edu/JID/journal/issues/v180n6/990415/990415.html
66. Kawaoka Y, Krauss S, Webster RG. Avian-to-human transmission of the PB1 gene of influenza A viruses in the 1957 and 1968 pandemics. J Virol 1989; 63: 4603-8. Abstract: http://amedeo.com/lit.php?id=2795713 - Full text at http://www.pubmedcentral.gov/articlerender.fcgi?pubmedid=2795713
67. Keawcharoen J, Oraveerakul K, Kuiken T, et al. Avian influenza H5N1 in tigers and leopards. Emerg Infect Dis 2004; 10: 2189-91. Abstract: http://amedeo.com/lit.php?id=15663858 - Full text at http://www.cdc.gov/ncidod/EID/vol10no12/04-0759.htm
68. Kilbourne ED. Influenza pandemics of the 20^th century. Emerg Infect Dis 2006; 12: 9-14. Full text at http://www.cdc.gov/ncidod/EID/vol12no01/05-1254.htm
69. Kiso M, Mitamura K, Sakai-Tagawa Y, et al. Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Lancet 2004; 364: 759-65. Abstract: http://amedeo.com/lit.php?id=15337401
70. Koopmans M, Wilbrink B, Conyn M, et al. Transmission of H7N7 avian influenza A virus to human beings during a large outbreak in commercial poultry farms in the Netherlands. Lancet 2004; 363: 587-93. Full text at http://www.thelancet.com/journals/lancet/article/PIIS014067360415589X/fulltext
71. Korsman S. Vaccines. In: Influenza Report 2006. Flying Publisher, Wuppertal, 2006 - Available from http://www.influenzareport.com/ir/vaccines.htm
72. Kuiken T, Rimmelzwaan G, van Riel D, et al. Avian H5N1 influenza in cats. Science 2004; 306: 241. Epub 2004 Sep 2. Abstract: http://amedeo.com/lit.php?id=15345779
73. Lazzari S, Stohr K. Avian influenza and influenza pandemics. Bull World Health Organ 2004; 82: 242. http://amedeo.com/lit.php?id=15259251 - Full text at http://www.who.int/entity/bulletin/volumes/82/4/242.pdf
74. Le QM, Kiso M, Someya K, et al. Avian flu: isolation of drug-resistant H5N1 virus. Nature 2005; 437: 1108. Abstract: http://amedeo.com/lit.php?id=16228009
75. Lee VJ. Economics of neuraminidase inhibitor stockpiling for pandemic influenza, singapore. Emerg Infect Dis 2006; 12: 95-102. Abstract: http://amedeo.com/lit.php?id=16494724 - Full text at http://www.cdc.gov/ncidod/EID/vol12no01/05-0556.htm
76. Li KS, Guan Y, Wang J, et al. Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia. Nature 2004; 430: 209-13. Abstract: http://amedeo.com/lit.php?id=15241415
77. Li S, Schulman J, Itamura S, Palese P. Glycosylation of neuraminidase determines the neurovirulence of influenza A/WSN/33 virus. J Virol 1993; 67: 6667-73. Abstract: http://amedeo.com/lit.php?id=8411368 - Full text at http://www.pubmedcentral.gov/articlerender.fcgi?pubmedid=8411368
78. Lokuge B, Drahos P, Neville W. Pandemics, antiviral stockpiles and biosecurity in Australia: what about the generic option? Med J Aust 2006; 184: 16-20. Abstract: http://amedeo.com/lit.php?id=16398625 - Full text at http://www.mja.com.au/public/issues/184_01_020106/lok10852_fm.html
79. Longini IM Jr, Nizam A, Xu S, et al. Containing pandemic influenza at the source. Science 2005; 309: 1083-7. Epub 2005 Aug 3. Abstract: http://amedeo.com/lit.php?id=16079251
80. Louria DB, Blumenfeld HL, Ellis JT, Kilbourne ED, Rogers DE. Studies on influenza in the pandemic of 1957-1958. II. Pulmonary complications of influenza. J Clin Invest 1959; 38: 213-65. Full text at http://www.pubmedcentral.gov/articlerender.fcgi?pubmedid=13620784
81. Ma KK, Schaffner W, Colmenares C, Howser J, Jones J, Poehling KA. Influenza vaccinations of young children increased with media coverage in 2003. Pediatrics 2006; 117: Abstract: http://amedeo.com/lit.php?id=16452325
82. Maines TR, Lu XH, Erb SM, et al. Avian influenza (H5N1) viruses isolated from humans in Asia in 2004 exhibit increased virulence in mammals. J Virol 2005; 79: 11788-800. Abstract: http://amedeo.com/lit.php?id=16140756
83. Matrosovich M, Tuzikov A, Bovin N, et al. Early alterations of the receptor-binding properties of H1, H2, and H3 avian influenza virus hemagglutinins after their introduction into mammals. J Virol 2000; 74: 8502-12. Abstract: http://amedeo.com/lit.php?id=10954551 - Full text at http://jvi.asm.org/cgi/content/full/74/18/8502
84. Monto AS, Fleming DM, Henry D, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza A and B virus infections. J Infect Dis 1999; 180: 254-61. Abstract: http://amedeo.com/lit.php?id=10395837 - Full text at http://www.journals.uchicago.edu/JID/journal/issues/v180n2/990003/990003.html
85. Monto AS, Robinson DP, Herlocher ML, Hinson JM Jr, Elliott MJ, Crisp A. Zanamivir in the prevention of influenza among healthy adults: a randomized controlled trial. JAMA 1999; 282: 31-5. Abstract: http://amedeo.com/lit.php?id=10404908 - Full text at http://jama.ama-assn.org/cgi/content/abstract/282/1/31
86. Moscona A. Neuraminidase inhibitors for influenza. N Engl J Med 2005; 353: 1363-73. http://amedeo.com/lit.php?id=16192481 - Full text at http://content.nejm.org/cgi/content/full/353/13/1363
87. Neirynck S, Deroo T, Saelens X, Vanlandschoot P, Jou WM, Fiers W. A universal influenza A vaccine based on the extracellular domain of the M2 protein. Nat Med 1999; 5: 1157-63. Abstract: http://amedeo.com/lit.php?id=10502819
88. Nicholson KG, Aoki FY, Osterhaus AD, et al. Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Neuraminidase Inhibitor Flu Treatment Investigator Group. Lancet 2000; 355: 1845-50. Abstract: http://amedeo.com/lit.php?id=10866439
89. Nicholson KG, Wood JM, Zambon M. Influenza. Lancet 2003; 362: 1733-45. Abstract: http://amedeo.com/lit.php?id=14643124
90. Noah DL, Krug RM. Influenza virus virulence and its molecular determinants. Adv Virus Res 2005; 65: 121-45. http://amedeo.com/lit.php?id=16387195
91. Noda T, Sagara H, Yen A, et al. Architecture of ribonucleoprotein complexes in influenza A virus particles. Nature 2006; 439: 490-492. Abstract: http://amedeo.com/lit.php?id=16437116
92. Obenauer JC, Denson J, Mehta PK, et al. Large-scale sequence analysis of avian influenza isolates. Science 2006; 311: 1576-80. Epub 2006 Jan 26. Abstract: http://amedeo.com/lit.php?id=16439620
93. Olson DR, Simonsen L, Edelson PJ, Morse SS. Epidemiological evidence of an early wave of the 1918 influenza pandemic in New York City. Proc Natl Acad Sci U S A 2005; 102: 11059-63. Epub 2005 Jul 26. Abstract: http://amedeo.com/lit.php?id=16046546 - Full text at http://www.pnas.org/cgi/content/full/102/31/11059
94. Osterholm MT. Preparing for the next pandemic. N Engl J Med 2005; 352: 1839-42. Full text at http://content.nejm.org/cgi/content/full/352/18/1839
95. Palese P. Making better influenza virus vaccines? Emerg Infect Dis 2006. Available from http://www.cdc.gov/ncidod/EID/vol12no01/05-1043.htm
96. Peiris JS, Yu WC, Leung CW, et al. Re-emergence of fatal human influenza A subtype H5N1 disease. Lancet 2004; 363: 617-9. Abstract: http://amedeo.com/lit.php?id=14987888
97. Perkins LE, Swayne DE. Pathogenicity of a Hong Kong-origin H5N1 highly pathogenic avian influenza virus for emus, geese, ducks, and pigeons. Avian Dis 2002; 46: 53-63. Abstract: http://amedeo.com/lit.php?id=11924603
98. Peters PH Jr, Gravenstein S, Norwood P, et al. Long-term use of oseltamivir for the prophylaxis of influenza in a vaccinated frail older population. J Am Geriatr Soc 2001; 49: 1025-31. Abstract: http://amedeo.com/lit.php?id=11555062
99. Poole P, Chacko E, Wood-Baker R, Cates C. Influenza vaccine for patients with chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2006. Abstract: http://amedeo.com/lit.php?id=16437444
100. ProMED 20060211.0463. Avian influenza, human  Worldwide (02); Demographics of human avian influenza. Archive number 20060211.0463. Available at http://www.promedmail.org/
101. ProMED 20060216.0512. Avian Influenza, human: Genetic risk? Promed number 20060216.0512. Accessed on 17 February 2006 - Available at http://www.promedmail.org/
102. ProMED 20060224.0603. South Korea - asymptomatic human infection. Promed number 20060224.0603. Accessed on 25 February 2006 - Available at http://www.promedmail.org/
103. ProMED 20060322.0893. Avian Influenza's Human-attack Pathway Revealed. Promed number 20060322.0893. Accessed on 23 March 2006 - Available at http://www.promedmail.org/
104. Reid AH, Fanning TG, Hultin JV, Taubenberger JK. Origin and evolution of the 1918 "Spanish" influenza virus hemagglutinin gene. Proc Natl Acad Sci U S A 1999; 96: 1651-6. Abstract: http://amedeo.com/lit.php?id=9990079 - Full text at http://www.pnas.org/cgi/content/full/96/4/1651
105. Reyes-Terán. Pandemic Preparedness. In: Influenza Report. Kamps BS, Hoffmann C, Preiser W. Flying Publisher, Wuppertal, 2006a. - Full text at http://www.influenzareport.com/ir/pp.htm
106. Rimmelzwaan GF, van Riel D, Baars M, et al. Influenza A Virus (H5N1) Infection in Cats Causes Systemic Disease with Potential Novel Routes of Virus Spread within and between Hosts. Am J Pathol 2006; 168: 176-83. Abstract: http://amedeo.com/lit.php?id=16400021
107. Salomon R, Franks J, Govorkova EA, et al. The polymerase complex genes contribute to the high virulence of the human H5N1 influenza virus isolate A/Vietnam/1203/04. J Exp Med 2006; Abstract: http://amedeo.com/lit.php?id=16533883
108. Schonberger LB, Bregman DJ, Sullivan-Bolyai JZ, et al. Guillain-Barre syndrome following vaccination in the National Influenza Immunization Program, United States, 1976--1977. Am J Epidemiol 1979; 110: 105-23. Abstract: http://amedeo.com/lit.php?id=463869
109. Seo SH, Hoffmann E, Webster RG. Lethal H5N1 influenza viruses escape host anti-viral cytokine responses. Nat Med 2002; 8: 950-4. Epub 2002 Aug 26. Abstract: http://amedeo.com/lit.php?id=12195436
110. Shortridge KF. Pandemic influenza: a zoonosis? Semin Respir Infect 1992; 7: 11-25. Abstract: http://amedeo.com/lit.php?id=1609163
111. Shortridge KF. Pandemic influenza: a zoonosis? Semin Respir Infect 1992; 7: 11-25. Abstract: http://amedeo.com/lit.php?id=1609163
112. Simonsen L, Clarke MJ, Schonberger LB, Arden NH, Cox NJ, Fukuda K. Pandemic versus epidemic influenza mortality: a pattern of changing age distribution. J Infect Dis 1998; 178: 53-60. Abstract: http://amedeo.com/lit.php?id=9652423 - Full text at http://www.journals.uchicago.edu/cgi-bin/resolve?JIDv178p53PDF
113. Simonson L. Pandemic influenza and mortality: past evidence and projections for the future. In: Board on Global Health. The Threat of Pandemic Influenza: Are We Ready? The National Academies Press 2004. Available from http://darwin.nap.edu/books/0309095042/html/89.html
114. Smith S, Demicheli V, Di Pietrantonj C, et al. Vaccines for preventing influenza in healthy children. Cochrane Database Syst Rev 2006. Abstract: http://amedeo.com/lit.php?id=16437500
115. Stevens J, Blixt O, Tumpey TM, Taubenberger JK, Paulson JC, Wilson IA. Structure and Receptor Specificity of the Hemagglutinin from an H5N1 Influenza Virus. Science 2006; Abstract: http://amedeo.com/lit.php?id=16543414
116. Subbarao K, Klimov A, Katz J, et al. Characterization of an avian influenza A (H5N1) virus isolated from a child with a fatal respiratory illness. Science 1998; 279: 393-6. Abstract: http://amedeo.com/lit.php?id=9430591 - Full text at http://www.sciencemag.org/cgi/content/full/279/5349/393
117. Taubenberger JK, Morens DM. 1918 influenza: the mother of all pandemics. Emerg Infect Dis 2006; 12: 15-22. Full text at http://www.cdc.gov/ncidod/EID/vol12no01/05-0979.htm
118. Taubenberger JK, Reid AH, Krafft AE, Bijwaard KE, Fanning TG. Initial genetic characterization of the 1918 "Spanish" influenza virus. Science 1997; 275: 1793-6. Abstract: http://amedeo.com/lit.php?id=9065404 - Full text at http://www.sciencemag.org/cgi/content/full/275/5307/1793
119. Taubenberger JK, Reid AH, Lourens RM, Wang R, Jin G, Fanning TG. Characterization of the 1918 influenza virus polymerase genes. Nature 2005; 437: 889-93. Abstract: http://amedeo.com/lit.php?id=16208372
120. Thanawongnuwech R, Amonsin A, Tantilertcharoen R, et al. Probable tiger-to-tiger transmission of avian influenza H5N1. Emerg Infect Dis 2005; 11: 699-701. Abstract: http://amedeo.com/lit.php?id=15890122 - Full text at http://www.cdc.gov/ncidod/EID/vol11no05/05-0007.htm
121. Thorson A, Petzold M, Chuc NTK, Ekdahl K. Is Exposure to Sick or Dead Poultry Associated With Flulike Illness? Arch Intern Med 2006; 166: 119-123. Abstract: http://amedeo.com/lit.php?id=16401820
122. Tiensin T, Chaitaweesub P, Songserm T, Chaisingh A, Hoonsuwan W, Buranathai C, et al. Highly pathogenic avian influenza H5N1, Thailand, 2004. Emerg Infect Dis [serial on the Internet]. 2005 Oct 19. Available from http://www.cdc.gov/ncidod/EID/vol11no11/05-0608.htm
123. Treanor JJ, Hayden FG, Vrooman PS, et al. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. US Oral Neuraminidase Study Group. JAMA 2000; 283: 1016-24. Abstract: http://amedeo.com/lit.php?id=10697061 - Full text at http://jama.ama-assn.org/cgi/content/full/283/8/1016
124. Tumpey TM, Basler CF, Aguilar PV, et al. Characterization of the reconstructed 1918 Spanish influenza pandemic virus. Science 2005; 310: 77-80. Abstract: http://amedeo.com/lit.php?id=16210530
125. Tumpey TM, Garcia-Sastre A, Mikulasova A, et al. Existing antivirals are effective against influenza viruses with genes from the 1918 pandemic virus. Proc Natl Acad Sci U S A 2002; 99: 13849-54. Epub 2002 Oct 4. Abstract: http://amedeo.com/lit.php?id=12368467 - Full text at http://www.pnas.org/cgi/content/full/99/21/13849
126. Tumpey TM, Garcia-Sastre A, Mikulasova A, et al. Existing antivirals are effective against influenza viruses with genes from the 1918 pandemic virus. Proc Natl Acad Sci U S A 2002; 99: 13849-54. Epub 2002 Oct 4. Abstract: http://amedeo.com/lit.php?id=12368467 - Full text at http://www.pnas.org/cgi/content/full/99/21/13849
127. Uiprasertkul M, Puthavathana P, Sangsiriwut K, et al. Influenza A H5N1 replication sites in humans. Emerg Infect Dis 2005; 11: 1036-41. Abstract: http://amedeo.com/lit.php?id=16022777
128. Welliver R, Monto AS, Carewicz O, et al. Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial. JAMA 2001; 285: 748-54. Abstract: http://amedeo.com/lit.php?id=11176912 - Full text at http://jama.ama-assn.org/cgi/content/abstract/285/6/748
129. WHO 20000824. Donation of three million treatments of oseltamivir to WHO will help early response to an emerging influenza pandemic. http://www.who.int/mediacentre/news/releases/2005/pr36/en/index.html - Access 14 January 2006.
130. WHO 2004. WHO interim guidelines on clinical management of humans infected by influenza A(H5N1). Available from http://www.who.int/csr/disease/avian_influenza/guidelines/clinicalmanage/en/index.html - accessed on 14 January 2006.
131. WHO 20041029. Laboratory study of H5N1 viruses in domestic ducks: main findings. http://www.who.int/csr/disease/avian_influenza/labstudy_2004_10_29/en. Accessed 30 October 2005.
132. WHO 2005. The Writing Committee of the World Health Organization (WHO). Avian influenza A (H5N1) infection in humans. N Engl J Med 2005; 353: 1374-85. - Full text at http://content.nejm.org/cgi/content/extract/353/13/1374
133. WHO 20050818. Geographical spread of H5N1 avian influenza in birds. Available from http://www.who.int/csr/don/2005_08_18/en - Accessed on 26 January 2006.
134. WHO 20051223. Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) Reported to WHO. 23 December 2005. Accessed at http://www.who.int/csr/disease/avian_influenza/country/cases_table_2005_12_23/en/index.html
135. WHO 2005b. Avian influenza: assessing the pandemic threat. Available from http://www.who.int/csr/disease/influenza/WHO_CDS_2005_29/en - Accessed on 16 January 2006
136. WHO 200601. Avian influenza (" bird flu") - Fact sheet. January 2006. Available from http://www.who.int/csr/disease/avian_influenza/avianinfluenza_factsheetJan2006/en/index.html - Accessed on 26 January 2006.
137. WHO 20060114. Cumulative number of confirmed human cases of avian Influenza A /(H5N1) reported to WHO. Available from http://www.who.int/csr/disease/avian_influenza/en - Accessed on 17 January 2006.
138. WHO 20060220. Avian influenza: significance of mutations in the H5N1 virus. Available from http://www.who.int/csr/2006_02_20/en/index.html - Accessed on 25 February 2006.
139. WHO 20060228. H5N1 avian influenza in domestic cats. Available from http://www.who.int/csr/don/2006_02_28a/en/index.html - Accessed on 28 February 2006.
140. WHO 20060309. Avian influenza - H5N1 infection found in a stone marten in Germany. Available from http://www.who.int/csr/don/2006_03_09a/en/index.html - Accessed on 15 March 2006.
141. WHO 20060321. Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) Reported to WHO. Accessed on 23 February 2006 from http://www.who.int/csr/disease/avian_influenza/country/cases_table_2006_03_21/en/index.html
142. WHO 2006a. World Health Organization Writing Group. Nonpharmaceutical interventions for pandemic influenza, national and community measures. Emerg Infect Dis. 2006 Jan. Available from http://www.cdc.gov/ncidod/EID/vol12no01/05-1371.htm
143. WHO 2006b. Recommended composition of influenza virus vaccines for use in the 2006-2007 northern hemisphere influenza season. Available at http://www.who.int/csr/disease/influenza/recommendations2007north/en/index.html - Accessed on 14 March 2006.
144. WHO 2006c. WHO pandemic influenza draft protocol for rapid response and containment. Available at http://InfluenzaReport.com/link.php?id=18 - Accessed 17 March 2006.
145. WHO 2006d. Advice on use of oseltamivir. Available from http://InfluenzaReport.com/link.php?id=17; accessed 17 March 2006.
146. WHO Checklist 2005. WHO checklist for influenza pandemic preparedness planning. Available from http://www.who.int/csr/resources/publications/influenza/WHO_CDS_CSR_GIP_2005_4/en/index.html - Accessed on 16 January 2006.
147. , > http://met.litr.phl> >

148. WHO Situation Updates. Available from http://www.who.int/csr/disease/avian_influenza/updates/en/index.html - Accessed on 26 January 2006.
149. Winkle S. Kulturgeschichte der Seuchen. Komet; Frechen 1997.
150. Wong SS, Yuen KY. Influenza vaccination: options and issues. Hong Kong Med J 2005; 11: 381-90. Abstract: http://amedeo.com/lit.php?id=16219958 - Full text at http://www.hkmj.org.hk/hkmj/abstracts/v11n5/381.htm
151. Yuen KY, Chan PK, Peiris M, et al. Clinical features and rapid viral diagnosis of human disease associated with avian influenza A H5N1 virus. Lancet 1998; 351: 467-71. Abstract: http://amedeo.com/lit.php?id=9482437 - Full text at http://www.thelancet.com/journals/lancet/article/PIIS0140673698011829/fulltext
152. Yuen KY, Wong SS. Human infection by avian influenza A H5N1. Hong Kong Med J 2005; 11: 189-99. Abstract: http://amedeo.com/lit.php?id=15951584 - Full text at http://www.hkmj.org.hk/hkmj/abstracts/v11n3/189.htm
153. Zambon MC. Epidemiology and pathogenesis of influenza. J Antimicrob Chemother 1999; 44: Suppl : 3-9. Abstract: http://amedeo.com/lit.php?id=10877456 - Full text at http://jac.oxfordjournals.org/cgi/content/abstract/44/suppl_2/3
154. Zitzow LA, Rowe T, Morken T, Shieh WJ, Zaki S, Katz JM. Pathogenesis of avian influenza A (H5N1) viruses in ferrets. J Virol 2002; 76: 4420-9. Abstract: http://amedeo.com/lit.php?id=11932409 - Full text at http://jvi.asm.org/cgi/content/abstract/76/9/4420