An emergency hospital in Kansas during the flu pandemic of 1918
So to give you a sense of how much death occurred during that pandemic, this is the numbers of deaths by week in Atlanta, city of about 400,000 at the time, and you can see in certain weeks in October – so the week ending October 26, you can see on the X axis, there are over 2,500 deaths in just that one week. And so the public health system was having trouble dealing with the dead bodies as well as just the live, sick individuals.
So looking at this pandemic, we’d like to know, well, how fast are cases really spreading among people, and how fast are cases accruing in relation to seasonal influenza or a new pandemic? And so we’d like to develop a metric by which we can characterize how fast a disease is spreading in a population.
I was just at a school where last week the teachers and the faculty in that county were offered a free H1N1 shot – like this vaccination – and then next day over 30 faculty members were out with colds, and most of them being teachers that actually chose to receive the shot. Would it be possible to "catch" some of the elements of the flu exposure out due to the small doses of the virus provided?
Dr. Lessler:: Well, there are a couple things going on there. One is that if they were ill the day after they got the shot, the vaccine really hasn’t had much time to work yet, so they could actually have the normal flu. But also, the vaccine will make you feel a little bit sick, give you some sniffles, dry eyes, maybe even a cough, and everybody’s very concerned right about now about the flu, so they’ll maybe be more apt to stay out.
And those symptoms aren’t necessarily a bad thing because when you get sick with a virus – when you get infected with the virus, what’s giving you symptoms isn’t really the virus itself; it’s your body fighting the virus and your immune system reacting to the virus. So I think that I’ll – so if you get a shot and get a little bit sick, but not really sick, that’s actually probably a good thing because it’s probably indicative that the vaccine is working.
Dr. Cummings: But the shot is actually an inactivated virus, so that virus isn’t going to replicate in your body. That is a bit different from the nasal spray virus called FluMist, which is a live, attenuated virus, which does replicate in your upper airway. But again, it makes you a little bit sick, but not all that sick, and it certainly doesn’t replicate at the rates of an actual flu infection.
Dr. Lessler:: Right. So I see a lot of questions popping up here about the safety of the vaccine and a little bit about mercury, and I don’t want to get into this too much because there’s a lot of misinformation out there, and there’s a lot of debate about this that’s not really scientific. But I can tell you what is true. So not every vaccine, not every formulation of the vaccine has thimerosal in it, and thimerosal is what people are usually talking about when they’re talking about “mercury in the vaccine.”
Thimerosal is a salt of something called ethyl mercury, which isn’t known to be dangerous to people. It’s actually thought to be okay. That’s different than methyl mercury, which people do know is dangerous, and if you’re worried about methyl mercury stop eating tuna fish; don’t not take the flu vaccine. So there’s really nothing that is bioactive mercury in the vaccines, and the amount of thimerosal, which is there to keep bacteria out of multiuse vaccines, is very low.
And if you’re getting the FluMist or a single-dose killed vaccine, there’s no thimerosal in that at all. There is no evidence of any more adverse events, and it was manufactured in the same way as the seasonal vaccine has been manufactured for the past 30 years with no big ill side effects that we are aware of.
Dr. Cummings: So there’s a lot of concern in the press because there was an outbreak of swine flu in 1976, which was associated with – in which there was a – there was a vaccination campaign that vaccinated 40 million Americans in response to that flu outbreak actually that started in New Jersey. And there were side effects associated with that vaccine. About 200 people came down with a neurological syndrome called Guillain-Barré –
Dr. Lessler:: But that’s 200 out of –
Dr. Cummings: It’s 200 out of 40 million. And this vaccine is actually a different vaccine than that one. Flu vaccinations have come a long way in actually sort of what’s included in the vaccine.
Dr. Lessler:: And really I think people should think of this as just another seasonal influenza vaccine like the ones that have been available in the last five years, ten years.
Dr. Cummings: Right – and I think – so I think we should probably move on to the vaccine – from the vaccine issue a little more. I think one last closing comment on the vaccines is that even if there are very, very rare side effects from this vaccine, we know the virus is circulating, and we know that it has a high incidence of bad outcomes comparatively. So that means that the vaccine is probably a very good idea for people to consider.
Part of the reason people were worried in 1976 is the virus didn’t circulate, so it seemed bad to have that many bad outcomes from the vaccine, but when we know the virus is circulating, and we know it can kill you, then the whole equation changes a little bit. So I think we should go into a different topic.
“What exactly is meant by ‘contacts’? By ‘contacts’ do you mean the number of people you actually touch?”
Dr. Lessler:: So it’s not actually touching. So it’s kind of hard to define “contact” for a respiratory virus, but in general it’s thought that you have to be within – what is it – three meters of someone?
Dr. Cummings: No, it’s a meter.
Dr. Lessler: A meter– so within three feet of someone to transmit flu. Now, that doesn’t mean that that’s the only way it can transmit. You can also, for instance, cough on something, leave some germs there, and then somebody can touch it after and then themselves then. But we think the primary way is through the air, and if that’s the primary way of transmission, then contact becomes being within three feet of them and sharing the same airspace.
Dr. Cummings: Yeah, for different infectious diseases, you can define a contact in a different ways, and some of those really lend themselves a lot better to actually enumerating the number of contacts. So vector-borne diseases or sexually transmitted infections where you can actually write down a discrete number of contacts.
Can you speak a little to the accuracy of the computer model?
Dr. Cummings: The models really depend on the data that you use. And I think the models are really a way to organize the data and to frame hypotheses about the transmission process. You can develop very bad models that don’t predict the process accurately, or you can develop models that are parameterized well on good data. I think the models that I’ve shown you capture certain features of the pandemic very well in terms of the time core.
Something that’s not in there is seasonality. We were sort of, in that case, modeling a midseason outbreak of influenza. Over the summer, we saw cases initially increase and then going into spring, we saw cases initially increase in the U.S., and then they slowed and perhaps even receded in the U.S. because of the onset of summer. And the influenza transmission is definitely seasonal with more transmission in the winter than in the summer. That’s actually something that we don’t understand.
The scientists don’t know what the reasons are. Weather conditions could contribute to the transmission. Schools being in session could contribute to it.
Dr. Lessler: Right.
Dr. Cummings: But we don’t know.
Dr. Lessler: I think there are two kinds of results that come out of the models. One are quantitative or actual numbers, and that’s really hard to get perfectly right because, like Derek was saying, it’s really hard to get the numbers going in to be accurate. I like to use a phrase we used to use back when I was a computer programmer: garbage in, garbage out.
But then another type are qualitative, so they’re kind of results more about how a disease acts in general and how you can adjust – how – what types of actions will control and adjust disease and about how much. So that’s – those are things like how – about what percentage of a population do I have to vaccinate to get rid of a disease? Or about how much will reducing contacts by one-third reduce the transmission of the disease?
And those are – so those are very – those are the types of things that we can answer. We can say, “Okay, if you reduce contact by a third, you’ll reduce the total number of cases by much more than a third.” But though we can’t – though I couldn’t tell you, “Oh, we’ll reduce the number of cases by 560 exactly because, frankly, I don’t know if we really reduced contact by a third – exactly a third.”
How useful is hand sanitizer, given that it’s designed to kill bacteria and not viruses?”
Dr. Cummings: So it does kill viruses, and it does kill the flu virus, and so I do think it’s useful. One thing that determines how useful it is, is how much transmission is occurring by an aerosol where you just talk to somebody or you sneeze and you generate an aerosol that contains virus, which isn’t targeted by hand sanitizer, compared to how much transmission is attributable to you sneezing on your hand, you shoving your finger up your nose and then touching somebody else’s hand and then them touching their mucosal surfaces.
Dr. Lessler:: Right – so [I see that] somebody asked an interesting question: “how can hand sanitizer ‘kill’ viruses? They aren’t alive in the first place.” So that’s a very accurate statement, although you might find people who would argue a lot about what it means to be alive. So for those of you who don’t know how viruses work, they require the machinery or our cells and our bodies to replicate. So they’re just little pieces of DNA that run around – you know, or RNA in the case of H1N1 – that have a little protein on them that let them get in the cell and then hijack the cells to replicate.
But if you destroyed any of those outer proteins or anything, the virus no longer is able to infect cells. So when we say that hand sanitizer “kills” the virus, we really mean it denatures it or makes it unable to infect new cells. And so, “How long can H1N1 last outside a host?” Do you know that, Derek? Normal flu – I think it’s – some studies have shown up to 24 hours.
Dr. Cummings: Depending on the surface it can actually be up to 36 hours. I think in general it’s much less. So most surfaces like a desk or certainly sort of steel or anything like that would only support it for maybe 12 hours.
Dr. Lessler: Yeah, as viruses go, the flu is sort of in the midrange of survivability outside of humans. There’s some that are hard to kill with hand sanitizer and last a really long time, like rotovirus, which gives you diarrhea. And there’s some like Hepatitis C, which, basically as soon as they get outside of the body, die.
In people who die, is their condition due to the defense mechanism of the body in response to the virus or due to something the virus itself is doing?
Dr. Cummings: It’s kind of a combination of both. It’s a good question. A lot of people do die from influenza due to really an immune response – sort of an over-ramped up immune response that is actually pathogenic. The body sort of responds a bit too strongly and actually causes disease itself. The virus also causes death by – in concert with other pathogens.
One thing the flu does is… it can just exhaust your immune systems, and the mechanisms of this we don’t know exactly, but people who have had an influenza infection are more susceptible to a bacterial infection. And so there are many respiratory bacterial pathogens that invade after an influenza infection, and people die at higher rates due to that bacterial infection than they would have if they hadn’t had the influenza infection previously.
Dr. Lessler:: Right. One thing … and you were leading to this, I think … is that in a normal flu season most of the death we see is sort of that longer, lingering death where people get the flu, it exhausts their immune system, they get a secondary bacterial infection or other viral pneumonia and end up dying from that, or they die of an underlying condition they have already. But in the pandemic, you get a lot more of these fast, rapid immune responses.
Though many more people get sick from pandemic flu than seasonal flu, does the incidence of death from all causes actually rise? I’ve heard that the total rate of people dying is about the same in a pandemic as in a regular winter.”
Dr. Cummings: It depends on the pandemic.
Dr. Lessler:: Yeah. There have interpandemic years that actually have higher death rates than some pandemics. If you looked at an all-cause mortality graph for the last century, you’d be able to pick out 1918 very easily because that graph would show a slowly declining curve because people were just dying at lower rates because of improvements in sanitation, all sorts of medical interventions that have helped us live longer, but in 1918 there was a spike.
And there’s a huge impact on all-cause mortality. To look at the dynamics of influenza transmission during the time, you don’t even really have to look at influenza deaths. You can just look at all-cause deaths to see when communities were struck because it just overwhelmed all other causes of death during that period.
Dr. Lessler:: And I think the indications for this one are that the death really is slightly elevated, maybe in the order of two to three times a normal seasonal flu.
Dr. Cummings: One important difference of this influenza is that the age distribution of deaths and severe disease has shifted. In the years past, in interpandemic influenza seasons, usually it’s the very old that account for most deaths in the U.S. And this pandemic – it’s actually people in their late teens, 20s, and 30s what appear to have the highest case fatality rates.
Are there epidemics or pandemics that jump from humans to animals?”
Dr. Lessler: I think there was just some evidence last week that this one’s jumped back into pigs, so yes. It’s not my specialty or Derek’s specialty, but I think there’s a lot of concern about animal species potentially being injured by human viruses. For instance, in Rwanda, there’s some concern that they should be reducing how often people are allowed to go see the great apes or mountain gorillas because they’re worried about humans infecting them with viruses and killing off the last population of gorillas.
Can vaccines cure an infection or only help prevent one?”
Dr. Lessler: Vaccines only help prevent them.
Dr. Cummings: Yeah – for flu. There are some pathogens that can actually minimize the severity of an infection if given after you’re infected. So with smallpox, if you’re exposed and infected, you can be vaccinated up to three days after and still have less severe illness.
Dr. Lessler: Right – so you do have to get vaccinated before the disease gets underway. So that’s why we can vaccinate people for rabies after they’ve been bitten because it takes a long time for the disease to get going. But flu gets going really fast, so you have to do it beforehand.
Where can you get data about the influenza virus and the infection rate and all that stuff?
Dr. Cummings: So one way is to actually go out and collect it.
Dr. Lessler: and I work on a study in Southern China where we’re taking blood from a few thousand people in Southern China to determine which influenza viruses they’ve been infected with over the last decade or so. I do work on influenza transmission in schools in Pittsburgh. And so you can actually collect it yourself, or you can also work with government agencies in this country and others that collect surveillance data.
Dr. Lessler: There are a lot of good sites where actually you can go out and get flu data yourself. One is the CDC website. The other is FluNet for the WHO. And then probably one of the best for recording who’s been affected is the New York City Department of Health and Mental Hygiene; they have a really exceptional website. Often we’re even going to sources like that for our own information.
Dr. Cummings: One other that you might be interested in is a product called Google Flu Trends. Google actually has developed models that look at how often people are searching for particular terms that are associated with influenza. So they might be searching it because they’re ill, and it provides a look at historical data; it seems to work fairly well at predicting how much influenza is in different communities.
How quickly does influenza virus develop drug resistance, and how quickly will all H1N1 become resistant to Tamiflu?”
Dr. Cummings: Good question. It can develop very quickly, so in the course of a clinical treatment, there’s a population of viruses in your body that has some diversity, and if somebody’s treated but with oseltamivir, there’s a fairly significant chance that some of the viruses will be oseltamivir and will be selected for it because of the presence of the drug. The big question is when those viruses that are resistant become officially transmitted to other people. Other H1N1 viruses are officially transmitted from human to human and are resistant – other interpandemic H1N1s.
But so far, [judging] from the last report from the CDC, a very small number of people have shown resistance to oseltamivir – a very small number of viruses – I think in the 30s or 40s of people have been actually observed to have clinical resistance of Tamiflu. But it’s a random process. I don’t know when that will occur and whether it will be in a virus that is efficiently transmitted to the rest of us.
Is it interesting to be an epidemiologist? Why or why not?
Dr. Lessler: It’s very interesting. Ffor years I was a computer programmer at IBM, and I decided to switch to epidemiology, and it was probably one of the best decisions I ever made. It is exciting and interesting, and I think you’re working on problems that matter.
Dr. Cummings: Yeah, I think it’s fantastic. It’s interesting. You don’t get exposed to the occupation in college or high school. I actually went through college without knowing much about epidemiology, and it’s a great combination of sort of using quantitative skills and getting to do field work, thinking about interesting problems that matter to society. So, yeah, I think it’s great.
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