Statins for H5N1. The road not taken. Why?

Some drugs that seem to have remarkable abilities to affect a wide range of biological systems in useful ways. The classic case is aspirin, used for pain relief, anti-inflammatory effects, anti-clotting abilities, and much else. Now another drug seems to be in this category, the family of statin drugs.

The statins are a group of drugs that are comptetitive inhibitors of an enzyme, 3 hydroxy 3 methylglutaryl coenzyme A reductase (HMG-CoA reductase). They are commonly used to treat high cholesterol, but they have a wide variety of other pharmacologic effects, including anti-inflammatory and immunomodulatory ones. They also make blood vessel walls less sticky and tighter and alter the production of chemical signaling agents, called cytokines. Dysregulated cytokine signaling has been implicated in life threatening conditions like gram negative sepsis from bacteria ("blood poisoning") or the "cytokine storm" seen in H5N1 infections and it is strongly implicated in the high mortality seen in the 1918 pandemic.

Statins have been examined as agents for treating bacterial sepsis with striking results, although their mode of action is still unclear. The literature has recently been reviewed by Dr. David Fedson, here (abstract). For some time Fedson has been calling attention to the potential use of statins in an influenza pandemic and he makes a persuasive case for launching a full scale and urgent investigation of their efficacy for that purpose. After the Nature article on the upregulation of certain proinflammatory cytokines was published a few weeks ago (see our post here), Fedson wrote to The Times (London) again urging consideration of statins:

The report in Nature describing the increased host immune response caused by the 1918 pandemic influenza virus (report, Sept 29) is the latest in a series of studies suggesting it is the host response (the "cytokine storm") that is probably responsible for most deaths now being seen with H5N1 infections. If the H5N1 virus leads to the next human pandemic, and if the situation is similar to that in 1918, there could be 350 million deaths worldwide.

Conventional vaccines will be too little too late, and limited supplies of antiviral medications will be available in only a few countries. However, we have recently learnt that statins (the drugs used to treat high cholesterol) decrease mortality due to pneumonia by 40-60 per cent, suggesting that, by modifying the influenza "cytokine storm", statins could be life-saving.

The scientific rationale for considering statins for pandemic use is persuasive, but the public health rationale is hugely compelling. Unlike vaccines and antivirals, generic statins are available in almost all countries, and treating an individual patient would probably cost less than £1. The pandemic might be imminent, yet nothing is being done by scientists and health officials to explore this idea. Why? (Letter to The Times)

This seems a highly pertinent question: Why are statins not being given higher priority? Are they being tried in Indonesia to treat the steady stream of cases that are suffering frighteningly high case fatality ratios? If so, what are the results? If not, why not? This is not a new idea. We posted on it over a year ago.

You can hear the frustration and urgency in Fedson's question. He is one of the world's authorities on vaccines and knows the science in detail. He is no lightwieght. The evidence he has marshaled seems quite persuasive yet we hear no response from the clinicians. We have to ask along with him, Why?

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By G in INdiana (not verified) on 04 Oct 2006 #permalink

I've asked the same question about statins myself. Since it isn't anywhere close to my field, my questioning doesn't carry any weight, but I also couple the question with the thought that, even if it doesn't protect against death from panflu, putting lots of people on statins would probably reduce the death rate from heart attack significantly. (and my Big Pharma stock would go up...)

By Man of Misery (not verified) on 04 Oct 2006 #permalink

This entire situation vis a vis clinicians seems a bit odd -- if these statin drugs are cheap and apparently effective at calming an overstimulated immune system, leading to cytokine storm death...

The road not taken keeps money in certain plush pockets. A shame bout all the dead people!

By Jon Singleton (not verified) on 04 Oct 2006 #permalink

Jon: It is not entirely simple. There is a chance statins could make things worse in bird flu, as Fedson points out in his article. By interfering with immune response lots of things can happen, many of them very bad. But when a patient is failing inexorably desperate measures are taken and corticosteroids are used in cytokine storm situations, to variable effect. Statins might be tried as well, if all else is failing. We need to know if they have been and if so, what happened. In many of these cases it would seem there is little to lose (unfortunately).

Fedson also outlines some very do-able epidemiology that could be undertaken (and maybe it is, although I've not heard about it).

Was statin treatment tried during SARS?

I independently reviewed statins just before Fedson published his article, so I was turned down at another journal. Yes, statins have promise, but if you really and dispassionately review the evidence, there's still a lot of research to be done to prove that statins will have a significant role to play in H5N1.

Marissa: Agreed. This is what Fedson says in his article and what we want here. It just doesn't seem to that it is being done, unless you know otherwise.

Your idea may be a good one but I do not think it could be put into practice as the global fight against Birflu is in total disaray.Each Country Province, State and city has it's own plan and they are mostly underfunded. I suppose trying to get it to work is better than nothing but I am begining to thing we are grasping at straws.

epifreek: Thanks. don't know what was wrong but replaced the link with yours and it seemed to work on a test. Appreciated.

Wayne: statins are widely available and quite cheap. They can be used for treatment if they work. We don't know if they do, though. As Fedson points out, in theory they could make things worse. We need to do the research to find out.

My questions would be:

1. Are statins safe for use in children?
2. Have any studies been performed for statins as a treatment and not just looking at retrospect cases of patients who have already been on statins?
3. What dosages would be used?
4. Has any kind of studies been performed, retrospect or other on patients with H5N1?
5. Is there increased risk of adverse effects, such as stroke, bleeding, electolyte imbalance..... ?

You are right, there is still much we do not know.

By floridagirl (not verified) on 04 Oct 2006 #permalink

floriagirl: 1. As far as we know they are safe for children. There are a number of trials and so far no problems have appeared AFAIK
2. I don't know of any prospective studies. Maybe others do.
3. The observational studies have inolved the doses used for lipid lowering. I don't know data beyond that.
4. I am not aware of any H5N1 studies with statins. That is one of the things that should be done.
5. Statins affect the immune system, which is why Fedson and others think they might be useful. But the system is complex and it is possible they could enhance the danger. We don't know for sure and need to study this further. Now.

As Jon hinted, Dr. Fedson may have answered his own question: generic statins are available in almost all countries.

That means no company could make a mint in a pandemic (always looking for that silver lining, the drug companies), so it's not worth it to them monetarily to investigate.

The question that raises for me is, what proportion of pandemic treatment research is corporate, what proportion is semi-corporate (say, academic or medical labs with corporate-financed grants), and what proportion is completely non-corporate, such as researchers funded by countries, NGOs, or foundations.

If most of the investigation of treatment options... as opposed to vaccine development or other research directly on the virus... is corporate-driven, then the question may be answered. Not a good answer, but an answer nonetheless.

revere,

I co-signed the letter to the Times with Fedson. I've learnt a lot from the guy and also I've heard so many people saying 'we should do something'. Well, something IS being done.

Fedson is proposing gathering together the top researchers who can resolve this question of whether statins could be used in a pandemic, and having them come up with the best way forward in terms of the studies needed, etc. The idea is to fast-track this process as we cannot afford to waste time in anything other than the most focused type of research. He has drawn up a list of some 20+ top scientists, we have identified funding from private sponsors for at least one such workshop/conference, but we are running into difficulties finding an institution to co-sponsor (logistics, invitations etc, not funding).

I think it is scandalous that so many people are saying "that's a great idea, somebody should do something, but we are not the people to do it". It would help if those of you in the blogosphere can pick this up and raise concerns about this problem.

A summary of this proposal can be found at
http://www.fluwikie2.com/pmwiki.php?n=Forum.WhenVaccinesAndAntiviralsAr…

Anybody who wants more details can email me.

caia,

In response to your comments about funding research, what we want to do, in putting together a conference, is also to invite folks from NIH, WHO, Gates Foundation etc as observers, so that they can be informed first hand whether this is a worthwhile as well as feasible project to put funding in.

Fedson already has all these contacts, and we are hoping to set up a conference in Washington DC so more of such agencies can be invited without extra cost. Ideally, we would like to hold another one in Europe, in Geneva, and bring in interested institutions over there. But that's a little further down the road, we need to get the first one going first.

anon_22: Sorryour name didn't appear. Didn't see it on The Times letter. I would surely have mentioned it.

revere,

That would be the least of my problems with regards to statins! LOL

a great post to urge action and more research. i hadn't heard of this proposed use. maybe i'll use it to convince the stubborn to start lipitor, they don't believe me about heart attacks and CVA's it seems...

if all people hit themselves with a hammer on the head there could be a billion with hematomes and brain damage.

Back in the 1918 germ theory wasn`t even well established. People seem to forget that in those days the knowledge who was friend and who was foe didn`t even transpire in an obvious fashion. Nowadays within days whole populations (thanks to media channels) can be addressed to protect themselves with impropmtu ad hoc "saftey gear". I would say 10 million could die at best worldwide.

Io: Not sure exactly what you are saying, but in 1918 the germ theory was well established. What wasn't known was what the influenza germ was. There was no doubt it was a contagioius disease.

If you know how we are going to protect ourselves from an influenza pandemic, that's great. Please share it and we'll put it on the internet and newspapers for all to see. But the problem is much more difficult and it will appear in all sorts of forms we don't anticipate. It may not be adequately expressed in the number of deaths, either, at least deaths directly attributable to the virus. A significant absenteeism rate will be a real problem in a tightly interconnected world.

I'm not sure what your 10 million figure is based on except a hunch. I have no idea if it will be 10 million, 100 million a billion or essentially none (since H5N1 won't become easily transmissible).

drcharles: Nice to see a Sb sib here. Love your blog, BTW. One of the knocks on the statin connection we see here occasionally is that it proves that bird flu is just another scam to get Big Pharma to sell its products. Obviously not my view concerning statins (which are now generic so it doesn't even make sense). I take Lipitor daily and think the science is pretty solid it is doing me good. I agree with you that it makes a lot of sense, even if some drug company makes money off of it. Some company makes money off of a lot of things I do but I do them because I think they make sense. I think statins make a lot of sense for a lot of people, just as low dose aspirin does (which I also take). If bird flu is an added incentive, fine with me.