Avian-Flu Death Rate May Be Tied to Overkill By Immune Systems
What makes bird flu so deadly to people in its path? One key may lie in the human immune system itself, which may turn from friend to foe when under attack by the H5N1 virus.
Strong immune systems usually defend us against invasion by germs and tumor cells. But in conditions ranging from asthma and allergies to bacterial sepsis, it isn't a weak immune defense but an overzealous one that wreaks havoc. In those cases, immune cells spark inflammation that turns on the body like friendly fire.
Bird-flu virus, too, seems to invite immune-system overkill. University of Hong Kong flu researcher J.S.M. Peiris and his co-workers have done studies that show that the unusual virulence of the H5N1 virus stems partly from its power to make the immune system unleash a torrent of inflammatory cells and chemicals -- an event called a "cytokine storm." It's a case of good cells gone wild. A cyto-kine storm triggers an overreaction by the immune system's first responders, which normally help by rushing to kill germs and infected cells until the body can mount an effective antibody response.
In a storm, these cells and chemicals over-proliferate and run amok, killing not just virus-infected cells but healthy bystander cells as well. Then the lining of blood vessels weakens, letting fluid leak out. Blood pressure drops, and organs start to fail. Lungs fill with fluid and hemorrhage. Patients require intense supportive care with mechanical ventilation and drugs to maintain their blood pressure. And even with such intervention, some die of acute respiratory distress, shock and organ failure.
So far, the World Health Organization counts 138 bird-flu cases and 71 deaths, mostly in people with contact with sick birds. But if the virus changes to allow wider person-to-person spread, a pandemic could erupt, causing widespread shortages of medical supplies and hospital beds.
Illness seen in early bird-flu patients in 1997 "made us think the immune response might be hyperactivated," Dr. Peiris says. Among the evidence: immune cells called macrophages that normally devour germs and infected cells were instead "gobbling up everything in sight," he says, and killing healthy red cells.
In 2003, Dr. Peiris recalls, he studied two bird-flu patients in Hong Kong with high levels of inflammatory cytokines in their blood. Autopsies after they died also indicated that macrophages were destroying healthy red cells.
Pressing ahead with lab studies, Dr. Peiris and his colleagues re-created the cytokine storm in test tubes. First, they found that macrophages infected with the H5N1 virus spew out excessive amounts of an inflammatory chemical called tumor necrosis factor. Last month, they reported that human lung cells infected with H5N1 churn out more inflammatory substances -- such as interferons and interleukins -- than lung cells infected with a regular flu virus.
"What we have is clear evidence in test-tube models using human cells that H5N1 reacts very differently" than regular flu, Dr. Peiris says. "That fits with the clinical picture we see in H5N1 disease." But, he adds, "we have a long way to go."
Some public-health experts fear the picture of a virus driving immunologic overreaction resembles the 1918 pandemic. Then, so-called Spanish flu caused hemorrhagic pneumonia and affected young adults with robust immune systems. Avian flu also causes hemorrhagic pneumonia, and it targets younger people, in contrast to regular seasonal flu, which mostly kills the elderly.
Drugs to damp down the immune system might help. Obvious candidates include steroids, sepsis drugs, ACE inhibitors and statins. But so far, there's no clinical trial data. Steroids have been given to some patients with bird flu, but so far they have shown no clear benefit.
Drugs that alter immune defenses also carry risks of their own. "Steroids can suppress an immune response, but they may make the patient more susceptible to infection," says Tim Uyeki, a medical epidemiologist with the influenza branch of the Centers for Disease Control and Prevention in Atlanta.
Taming the immune response without destroying defenses is "a great idea, but we don't know how to do that yet," says flu expert Robert Belshe of St. Louis University.
So far, the recommended treatment for H5N1 flu is antiviral drugs such as Tamiflu (oseltam-ivir), given within 48 hours of first symptoms. Quelling virus reproduction early could calm a cytokine storm. But timely treatment is a problem. "Patients aren't presenting early in the illness," says the CDC's Dr. Uyeki. "If this cyto-kine storm has already been triggered, antiviral drugs aren't going to turn it off."
More helpful data could be available soon. Just back from bird-flu meetings in Asia, flu researcher Frederick Hayden, a professor of medicine at the University of Virginia, Charlottesville, says the World Health Organization, the U.S. National Institutes of Health and researchers in Southeast Asia hope to create a clinical-trial network in the region. The group hopes to test old and new antiviral regimens -- eventually in combination with drugs to modulate the immune system.
But until research yields answers, the way to weather the cytokine storm of bird flu is faster diagnosis, timely Tamiflu and intensive care.
Sharon Begley is on vacation.
禽流感让人体免疫系统变友为敌
是什么让禽流感具有如此高的致病性？原因之一就在于人体免疫系统自身，免疫系统在受到H5N1病毒入侵后就变友为敌了。
健康的免疫系统通常都会保护人体免受微生物和肿瘤细胞等入侵。但如果是遇到哮喘、过敏和坏血病等，免疫系统就可能防御过度，导致对人体不利的炎症。
禽流感看来也容易引发免疫系统的过度杀伤。香港大学流感研究人员裴伟士(J.S.M. Peiris)及其同事的研究显示，H5N1病毒异乎寻常的高致病性在某种程度上是因为该病毒能使免疫系统释放出大量炎症细胞和化合物，这在医学上被称为“细胞激素风暴”(cytokine storm)。
在细胞激素风暴中，炎症细胞和化合物迅速增加，失控的情况下在杀死受病毒侵入细胞的同时，也杀死了健康的不相关的细胞。血管壁因此就变得脆弱，会有液体流出来，临床显示血压下降，器官功能衰弱。肺部充满液体，并伴有出血。患者需要依靠呼吸机，并服用药物来维持血压。即使是在这样的护理措施下，一些人还是会因急性肺炎、休克和器官衰竭而丧生。
迄今为止，世界卫生组织(World Health Organization)宣布共有138起人感染禽流感病例，有71人死亡，多数感染者都曾与病禽接触。但如果病毒出现变异，可在人际间传播的话，就会导致禽流感大流行的发生，无论是药物，还是医院床位都会大面积紧缺。
从1997年最初的禽流感患者症状看，“我们认为免疫系统的反应可能过度了，”裴伟士表示。证据如下：通常吞灭细菌和受感染细胞的免疫细胞，又名巨噬细胞，开始大量吞下所有的细胞，健康的红细胞也不能幸免。
裴伟士回忆起2003年他曾研究过的两例香港禽流感病例，患者的血液中发炎细胞激素水平很高。患者死亡后的尸检也显示巨噬细胞在摧毁红细胞。
随著实验室研究的推进，裴伟士和他的同事们在试管内重现了细胞激素风暴。首先，他们发现感染了H5N1病毒的巨噬细胞喷涌出大量名为肿瘤坏死因子的炎症化合物。上个月他们公布，感染了H5N1后，人类肺部细胞产生的炎症物质（如干扰素和白细胞介素）要多于普通流感感染。
“试验显示，人体细胞试管模型对H5N1的反应与普通感冒有很大不同，”裴伟士表示，“这与H5N1患者的临床表现相符合。”但他补充称，“我们仍有很长的路要走。”
一些公共卫生专家担心这可能导致类似于1918年西班牙流感的大流行。当时，西班牙流感导致了出血性肺炎，感染了众多免疫系统强劲的年轻人。禽流感也会导致出血性肺炎，易感人群也是年轻人。而常见的季节性流感通常危害的是老年人。
抑制免疫系统的药物或许能发挥作用，如类固醇、败血症药物、血管收缩素转化酵素抑制剂以及降胆固醇药物statin。但迄今为止，没有临床试验数据。一些禽流感患者服用了类固醇，但并没有明显的疗效。
使用抑制免疫系统的药物，本身也存在风险。“类固醇能抑制免疫反应，但也会使患者更容易感染，”亚特兰大疾病防控中心流感部门的流行病学专家Tim Uyeki表示。
抑制免疫反应，但不摧毁免疫防御，是“一个非常棒的主意，但我们还不知道怎么能做到这点，”圣路易斯大学(St. Louis University)的流感专家贝尔奇(Robert Belshe)表示。
到目前为止，H5N1禽流感的推荐疗法是达菲(Tamiflu)等抗病毒药物，服用时间为早期症状出现后的48个小时内。在早期抑制住病毒的分裂势头，有助于平息细胞激素风暴。但能否及时治疗是个问题。“禽流感患病初期症状并不明显，”疾病防控中心的Uyeki表示，“如果细胞激素风暴已经出现，抗病毒药物也无法平息。”
不久可能会有一些更有益的数据公布。刚刚到亚洲参加禽流感会议回来的流感研究者、弗吉尼亚大学夏洛特维尔(Charlottesville)分校的药学教授海顿(Frederick Hayden)表示，世界卫生组织、美国国家卫生研究院(National Institutes of Health)和东南亚的研究人员希望在该地区建立一个临床试验网络。他们希望能对各种抗病毒疗法进行试验，用多种药物综合治疗调节免疫系统。
但在研究取得成果以前，应对细胞激素风暴的唯一办法就是尽早确诊，及时服用达菲，并获得精心护理
