NIH CLINICAL CENTER GRAND ROUNDS
Episode 2009-002
Time: 1:03:15
DESIGNING THE HISTORICAL ATLAS OF THE 1918-1919 INFLUENZA PANDEMIC
IN THE UNITED STATES
Presented by Dr. Howard Markel, the George E. Wantz Distinguished Professor and Director of the Center for the History of Medicine, and Professor of Pediatrics and Communicable Diseases, the University of Michigan, Ann Arbor; and
SMALLPOX VACCINATION AT THE NIH: UNEXPECTED FINDINGS
Presented by Dr. Jeffrey Cohen, chief of the Medical Virology Section and senior investigator in the Laboratory of Infectious Diseases, NIAID
ANNOUNCER: Discussing Outstanding Science of the Past, Present and Future – this is NIH Clinical Center Grand Rounds.
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ANNOUNCER: Greetings and welcome to NIH Clinical Center Grand Rounds. This week, we present two speakers - both discussing diseases that have plagued mankind in the past. Dr. Howard Markel is the George E. Wantz Distinguished Professor and Director of the Center for the History of Medicine and Professor of Pediatrics and Communicable Diseases at the University of Michigan Medical School in Ann Arbor. His topic will be, “Designing the Historical Atlas of the 1918-1919 Influenza Pandemic in the United States.” Our second speaker will be Dr. Jeffrey Cohen, chief of the Medical Virology Section and Senior Investigator in the Laboratory of Clinical Infectious Diseases at the National Institute of Allergy and Infectious Diseases at the NIH. His topic will be “Smallpox Vaccination at the NIH: Unexpected Findings.” If you would like to see a close-captioned videocast of today's subject, log on to http://videocast.nih.gov and click the "Past Events" link. We take you to the Lipsett Ampitheater in the NIH Clinical Center in Bethesda, Maryland, where Dr. John Gallin, director of the NIH Clinical Center, will introduce our first speaker.
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GALLIN: So today we have a special treat with two fabulous speakers who will discuss two very important aspects of clinical virology.
The first is Dr. Howard Markel, who's going to be presenting “Designing the Historical Atlas of the 1918-1919 Influenza Pandemic in the United States”. Currently, he is the George E. Wantz Distinguished Professor and director of the Center for the History of Medicine and Professor of Pediatrics and Communicable Diseases at the University of Michigan Medical Center in Ann Arbor. Dr. Markel is an expert in the history of medicine, public health, contagious diseases and epidemics, and children's healthcare in the U.S. from the early 19th century to the present. He's a prolific writer and author of several books. His critically acclaimed study of immigration and public health in the United States during the 19th century was published in 1997. The title is "Quarantine: East European Jewish Immigrants and the New York City Epidemics of 1892." His most recent book, "When Germs Travel: Six Major Epidemics That Have Invaded America Since 1900, and the Fears They Have Unleashed," was published in 2005. Dr. Markel has a very interesting background. He studied English literature at the University of Michigan where he graduated summa cum laude. And then he earned his MD degree cum laude from also the University of Michigan. His PhD in the history of science, medicine, and technology is from Johns Hopkins, and while at Hopkins, he was an intern resident and clinical fellow in pediatrics. He completed a fellowship in adolescent medicine and general academic pediatric development and was the Harriot Lane Research Fellow in the Department of Pediatrics at Hopkins. He also completed a fellowship at the Hopkins Institute of the History of Medicine, and he joined the faculty of the University of Michigan in 1993. Dr. Markel was a historical consultant on pandemic influenza preparedness planning for the Defense Department from 2005 to 2006, and he's been serving in the same capacity for the CDC since 2006. He's a fellow of the American Academy of Pediatrics, and this past year was elected a member of the Institute of Medicine. We welcome him with great enthusiasm. Thank you.
[applause]
MARKEL: Well, what an honor and delight to be here. Thank you so much, and thank you for that introduction. What I’d like to -- now, I have one mic on or two -- I can walk away, actually, right? Can you hear me? Okay. I have some work I’d like to talk to you about that has really been our center's work, looking at the influenza pandemic of 1918-19 with the hopes of could we bind some of the remarkable amount of data that exists to come up with some types of public policy decisions. And I’d like to summarize some of the stuff that we have been doing and some of the stuff that we've done. I have no disclosures to make, but those are some of the objectives. Let's go on with the show.
Very briefly, everyone really knows a lot about this, but the world-wide influenza pandemic experience in 1918 was quite devastating, anywhere from between 40 to 100 million deaths occurred that year in the U.S. alone, between September 1 of 1918 and April 5 of 1919, there were probably more than 10 million cases, and at least half a million deaths. So it was really one of the most remarkable contagious calamities in human history. There are 3 waves, if you look at the 1918-1919 pandemic. There is actually a 4th wave in the early winter of 1920. But what we most are interested in, this is a very early spring wave that may or may not have been related to the subsequent waves, but that early fall of 1918, and then another one in January through April of 1919 were the one that we spent most of our time looking at. You have to take everything in context. History is always context, not just disease. But World War I was going on during the 1918 pandemic. The war to end all wars, mobilization of at least 4 million American soldiers on our end, they met at least 6 million soldiers on the other end, were eager to engage with them.
I just love this photograph, before pixel art. These are all soldiers shaped -- Arthur Mold did these photographs. This is at the Camp Sherman doing a Woodrow Wilson portrait. Well, I’ve studied epidemics for about 20 years, and I made a confession earlier to some of your colleagues, that influenza was never my favorite epidemic. People who study the history of epidemics are weird. They have -- I’ve always been a cholera man, but -- for I don't know what reason. But I got into the history of flu, even though I had read and studied about it and lectured about it. But I got a call literally before the 4th of July weekend, July 3rd, 2005. It was from somebody from the Defense Threat Reduction Agency, and my secretary calls and says the Pentagon is on line 18. Well, to tell you that the Pentagon doesn't call me all that often is an understatement. They never call me. And there is probably good reasons for that. But he wanted me to look -- the Defense Threat Reduction Agency wanted myself and some of my colleagues to look at what were called escape communities. And there were 7 communities during the 1918 pandemic, Yerba Buena Island in San Francisco Harbor that was a naval base; Gunnison, Colorado, which was a mining town in the Rockies; Princeton University; Trudo TB Sanitarium, Bryn Mawr College, the School for the Blind in Vermont. And what they did is they closed themselves off before flu ever got there. So it's not a quarantine or isolation where you react to the appearance of disease. You're actually shutting the gates before that happens. We term that concept “protective sequestration”. Lots of battles over what we would call it. We each had our dictionaries out. “Protective cloistering” was the runner-up, but we -- I thought people might think that people were joining a monastery or something like that. So we called it protective cloistering. And the Defense Department was very interested in this concept because what would they do for the men and women in uniform to keep them out of harm's way so they can be doing their other jobs? And could they, in some way, sequester those people on ships or in camps or things like that?
Well, it turned out while these tiny communities were successful, as long as they were able to keep the gates closed, so to speak, in terms of preventing any deaths or cases of flu, it's not a terribly practical methodology, particularly when you fast forward to 2009. So it may be of some use for very small communities or very remote communities, but it was not something that we could recommend to the Department of Defense. And that paper is published in Emerging Infectious Diseases, if you want to look that up in December of 2006.
Well, at the same time, we began having conversations with the Centers for Disease Control, particularly Marty Citron and his group at the National Quarantine and Global Migration Division. And we both were thinking about the same thing. It wasn't the 7 escape communities, that wasn't where -- there is a famous line, Willie Sutton, the bank robber said why do you rob banks? Because that's where the money is. And we both felt that these escape communities are the exceptions to the rule. That's not where the great public health data is going to come from. Instead, there are all these major cities around the country that had very good public health departments, that had very good records of what they did and how they did it. It seemed to both of us that that would be a much more useful thing to study, because if you look at communities today, most towns and cities and so on are at least 100,000 or more people living in them. So we thought that would be a better opportunity for retrospective study.
And so -- and you look, for example, at the public health options that existed in 1918, they are rather similar to what people were suggesting when they talk about NPIs, or non pharmaceutical interventions. You make flu reportable, you isolate sick individuals, quarantine those you suspect of being ill, school closure, protective sequestration if you could do that, cancellation of worship services, closure of public gatherings, saloons, theaters, ball games, staggered hours of business, mandatory or recommended use of masks, public transit systems closing, restrictions on funerals, and things like that. Restrictions of door to door sales, which doesn't exist very much today. Community wide curfews, social distancing and so on. So those were pretty much the similar things that we wanted to look at then, to see did they have some effect on the case incidence and death rate? These are just some public health risk communications as they would be called today, but posters that were done during that period of time. Well, the thought was, let's fast forward to 2009.
In the event of a deadly pandemic today, could these non-pharmaceutical interventions delay outpeak break and buy time until vaccine is ready? Could they depress the peak burden on hospitals and infrastructure? And could they diminish overall cases in health impacts and mitigate new cases of influenza and delay spread. So in essence what you're doing is you're trying -- this is a classical epicurve. You're trying to flatten it and move it out to the right. Only to buy time. Doesn't cure anything. The community is just as susceptible before and after to that novel strain of virus, but the idea particularly in an era where maybe in 12 or 14 or 16 or several months, whatever it takes to make a vaccine strain, could you make the vaccine, get it distributed into people's arms and so on, and protect them, as well as keeping the hospital traffic down. Because a great question is you have all these question coming down with flu and needing medical attention, what can you do with all the regular people who show up every day with heart attacks, or diabetic ketoacidosis or what have you.
And so we publish this work in JAMA, 2007, August. This is the reference. There is also a huge supplementary section on the CDC website of all the sources we used, as well as there were 43 cities but we could only publish about 6 or 7 in the graphics of the JAMA article. But you can get all 43 of those, and all the data that we did. And basically, what we found was that early, which makes sense, early response to a pandemic, an easy transmittable disease is always better than late. Sustained, because these waves, all the waves that I just showed you lasted several weeks, as long as 12 weeks, and the community was still susceptible, whether you block people off or not. And layered application, meaning that more than one was better.
The most common combination were school closures and public gathering bands, but you also had quarantine and isolation mixed in. But the layers group was better than not having it layered. So it's sort of like layers have Swiss cheese, that you have lots of holes in all these methods. Quarantine is by no means a perfect public health measure. Nor is school closure alone, nor is public gathering bans. When you use them all simultaneously, hopefully you'll plug up some of the holes.
One of the things we're working on is trying to develop a model, but it's rather difficult given this use of particular historical dataset, is to see which method worked best and to see that if you had some type of cumulative effect, could you model and predict if you did x and y versus y and z, what would you have? Well, this work as well as the work of several other scholars, including some at the NIH, and some at the Imperial College of London and around the world has been instrumental as the evidence base for what is the current federal pandemic flu policy. So if there were what's called a Level Five Pandemic, using hurricane criteria, but if it were like 1918-like or worse, that we would, indeed -- the CDC would recommend that they will roll out these measures of quarantining those who are suspected of being ill, isolating those who are ill, school closures, and public gathering bans. And these show you all the various agencies and such that were actually working on this.
Well, as a result of all this work, we've developed this remarkable archive. Probably the largest archive, with the exception of maybe my colleague, Dr. [inaudible] has collected, of really important stuff on all things flu. We have basically every municipal annual report and any other public health report from all the largest, 52 cities in the United States, between 1917 and 1922. Every United States state and federal report on flu during that period. U.S. census mortality data which was very important to figure out how many people died per week of pneumonia and influenza. And what was remarkable is that when I first started looking for that, I thought, oh, that's easy. I’ll find it in the National Archives. It wasn't there. Then I went to the U.S. Census Department. It wasn't there. I went to several other libraries. It wasn't there. Finally it was in the basement of the New York Public Library on a microfilm reel, because the Work Progress Administration had actually microfilmed some of those reports back then. And apparently the Census Department threw out all the paper copies. But that was really the bedrock piece of information for this particular study. The entire corpus of published medical public health and popular literature, magazines and so on, journals, on the flu pandemic in the United States.
What's very important for our use is 100 different newspapers, at least 2 per city, day by day, going through microfilm reels, for the day to day events in each of these cities of how they experienced the pandemic. That's been particularly important because I thought, again, hypothesizing, having spent a lot of time looking at municipal reports, that when these triggers were pulled on and off would be in the municipal reports. Some that were and many were not. But you always had public health officers having press briefings during the pandemic and telling you when they were doing things. Military records, pertinent holdings, Library of Congress, National Archives, state university, municipal archives all across the country, diaries, letters, and so on. Right now, as I speak, I have three different researchers and three different archives. We have about 7 local libraries to hit before we're done with our archival research. But we keep finding new stuff every day. Just remarkably, if you're a historian, it's remarkably exciting stuff.
So we had all this. Even though the JAMA paper did 43 cities, we increased it to 50 based on the 1920 populace, the largest cities in the United States by population, 104,000 to 5.6 million, and these cities, you can look at the list as easily as I can, represent about at least 25% of the American public at that time. And also represents a living condition, it's very different in 1918 from 2009, I see assure you, I know that. But it does mirror some of the aspects of modern day life. And what we decided, our colleagues at the CDC and Center for the History of Medicine is we wanted to design a historical atlas of a flu pandemic. And so it's rather a encyclopedic reference of different specialists and the generalists. Dozens of essays. Dr. Tom Berger will be one of our contributors on issues of how were vaccines developed at that time? What was the state of public health at that time? Volunteer organizations, changing meanings of disaster. We'll have the profile or I call them biographical essays of all these 50 cities of how they experience day-to-day between September 1, 1918 and late April of 1919 of the epidemic. Shorter sections and side bars about the institutions that were involved, the historical actors and so on. Graphs, charts, and so on. And what's most exciting will be an Internet access to the entire University of Michigan, CDC archives so that if people don't really buy what we say, they can look it up themselves in a very easy way and write about it as well.
Well, how are we going to inform public health policy with this historical work? One, we want to look at the role that social context plays in MPI implementation. Historians say everything is context, so how does the city work? How do the people work? Who makes up the city and so on and so forth. The local health history and profile of these cities. Some cities were sicker than others. Some cities did very poorly in terms of their public health and medical care. Some had very high pollution rates. Community compliance and volunteerism. That changes from city to city and government to government. And characterization of the city authority structure and organization, because one of the big themes in the history of public health in America is that when you have internecine rivalries and battles between local or state or federal agencies, or even the same agency -- or even the different agencies in the same city, bad stuff happens. When you have those kind of fights and you don't have a coordinated effort, it doesn't work very well.
So the social context we're looking at political, economic, and social, cultural factors. Housing density. Socio-economic stratification. Household and family structure, and age and gender distribution, all available in census data. Immigrant and racial minority experiences not only for communications but scapegoating. Now, I’m not finding a lot of scapegoating for this pandemic. I find it for a lot of other epidemics. And the only theory I can have is that it spread so quickly and so ubiquitously that there wasn't time to blame anyone. We find a few examples here and there, but it's not a major factor. World War I is very important. But so, too, are religious faith and rights, not just banning church services or synagogue services, but funerals, and how they were handled, and how they were delayed. And what impact that had on people of different faiths. This is just a picture of L.A. We're talking about social context. This is in the era of silent films, and what a lot of people used to do is go. The first Universal Studios tour was to go and watch a silent film being made, because even if someone spoke, it wouldn't ruin the movie. They were all banned during the period as part of their public gathering bans.
In terms of health profile and history, we want to look at the baseline profile of health profile of each city, its environmental health factors, the hospital infrastructure and available of providers, and evolution and functionality of that health department. Some departments were quite wonderful and some were really quite dysfunctional. Here you see an example of Pittsburgh, and even before the '18 epidemic, you had a wonderful study out of Carnegie Tech of comparison of the pneumonia death rate and smoke content of 15 cities in the U.S., and Pittsburgh is one of the highest. So how does that factor -- Pittsburgh was actually one of the most heavily hit cities in the union at that time -- so how does that factor in to our rubric as well. Authority structure and agency coordination is the stuff that social history is made of, the distribution of municipal and health authority, coordination between the various multiple leaders, was there a special flu advisory board? Was there involvement, support, or obstruction of other groups, social groups? The problem with public health, it starts with the word “public”. And there are many impressions, opinions, and so on how to handle that. Transparency and acceptability of the public health measures, and post-pandemic revisions to the health department organization and policies. What do they do to prevent for the next one? And how do they act on that, if they did at all? You always find reports of what needs to be done, then you can look five or 10 years down the road and nothing has really changed. So that has been a very interesting issue.
St. Louis is one of the cities that's been most fun to study. They had a health commissioner named William Starcloth who really knew what he was doing. He worked well with the mayor, he worked well with the Governor of Missouri, worked well with the police department. He worked well with the people. And they actually had one of the best records in terms of the lowest cases, lowest amount of cases of deaths. And I have to suspect that people in power who do their job well, it really does matter. Community compliance and volunteerism is very difficult to nail down but we're looking at it qualitatively, the various patterns of compliance and enforcement, but not only the 1918-19 pandemic. But we can look, for example, on the Atlantic Seaboard with the polio pandemic of 1916 and how that worked out, how people agreed with what was being done or what faith they had in their public health department and so on. Cultural sensitivity was a big issue, particularly in cities that had large immigrant populations. Experiences of individual sub-communities. And instances of epidemic or NPI fatigue. People who do these things for a couple of weeks or four weeks, and they would get tired of it. That's a real big problem when we're suggesting 12 weeks of public gathering bans or school closure. San Francisco is a perfect example. It has a mandatory face mask law, the first in the United States. But different people had different interpretations of this. Some were for applied gauze, others were -- this woman wore a chiffon mask. It was mandatory. This is the Mayor of San Francisco, James Ralph. You can see where his mask is. So it was mandatory but it wasn't. So if people didn't really want to wear them, because it's difficult to wear a mask all the time.
Well, I can go on and on and on, but I know my time is short. There is a boxing match between man and microbes. This is actually a boxing match of troops going off to World War I, but you can see many of them are wearing masks. My hope is that the history will help inform it, but we -- current public policy, I think it has to some extent already. It's just one of many arrows we need in our quiver as we handle and approach this remarkable problem, not just of pandemic influenza, but of emerging and newly emerging infectious diseases, as well as bioterrorism and a number of other things. These are not mutually exclusive topics. That's what's so wonderful about it, is that there is so much lay over between all of this. Now, history can answer some questions, but you're often relying on what has been saved. Not everybody saves every piece of paper that you may need. And unfortunately, unlike my novelist colleagues, I can't make it up. I have to have a piece of paper documented, but not every piece of paper that documents it is right. You have to question the sources as well. So we have been working on this and trying to sift through it in as scholarly manner as we can.
Well, this is a -- we have to be careful about predictions. Time Magazine did a special issue on bird flu in November of 2005. I was actually in the National Archives when they called me for an interview, and I was busy. I was doing work and I didn't want to talk to this guy. And he kept asking a question, when will the next pandemic occur? Well, I’m a historian. I’m uncomfortable with the future by definition. [laughter] And he kept -- come on, doc. Tell me when it's going to happen. Next week, next month -- I said I really don't know. He kept bothering me, kept asking over and over. I just wanted to get back to work. And the first rule of talking to a journalist is be careful what you say, because they have a pen. And so finally after a while I just said, “Look, no one really knows what's going to happen. Anyone who says they do is either an idiot or lying.” [laughter] And that's how I’m quoted in Time Magazine.
[laughter]
It could be worse. It could be worse. Because I doubt anyone can prove me wrong on this one. If I had to be put in Bartlett's Book of Quotations, that's the quote I would want. But the point is that we don't know what's going to happen. That doesn't mean we can't try to predict it. We can try to model it and figure out and learn from the past as well as the present and hopefully predict the future. And what's so exciting to me as a historian of epidemics is that this really represents the first time in human history, the first time that we have been doing so much to prepare for a pandemic that hasn't occurred yet. Generally we react to pandemic and public health crisis.
So I’m very encouraged by that, that there are so many thoughtful and serious men and women around the world who are working on this. And so for somebody who is not known to be terribly optimistic, I actually am rather optimistic that this is something that we will hopefully handle in years to come. Thank you very much for your attention.
[applause]
GALLIN: We have time for a few questions. Yes?
[inaudible question]
MARKEL: The epicurves of each city. We followed that all the way to the end of the 1919 season. You find, you know, very strong associations that when you pull the triggers, the cases go down. And then when you put the triggers off again, they start climbing back up again. So particularly the cities with these double peaks are acting as their own controls in a way. Because every city did something. Whether they did it late or early or whatever. Now, we look at 1920 as well. We try to compare -- we did a correlation between all the waves, spring of '18, fall of '18, '19, then '20, to see if there was some comparison, some increase or some diminution of deaths. We used death data because case data seemed a little bit less reliable. And there was no positive or negative correlation. When we did a one way inova, it was actually a negative correlation as you went on with time. So it didn't seem to protect down the road at all. So it really is just a stop gap measure. What you would do in your first response, that hopefully -- now, what would change the whole ball game is vaccine. I mean effective vaccine. So that would be a very interesting thing to try to model with all of this type of information, is that if you bought the time and then you could model further on, did that protect people in the next set of events?
[inaudible question]
Well, we looked at that, too, by the way, in the JAMA papers. There was no correlation between -- there was an age issue in terms of “W” shaped curve. So you had a lot of very young people, a lot of very old people. You had that middle hump of 15 to 45. There was no correlation, though, that cities that had more young people or more older people did worse than those that did not, nor was there by gender, or population density, or the population of the city, itself. What seemed to be the strongest correlation, just astoundingly statistically significant was the cities that did these measures and acted with more than one, and for a very long period, like 9 to 12 weeks did far better than those that did them for 3 or 4 weeks. So you could have a city that acted very early and used 2 or 3 measures, but only did it for 3 weeks. They lifted up that trigger, and then the cases came back in. So that was another issue, as well.
GALLIN: Is it possible to go back and model the 1918 epidemic if there were antibiotics available?
MARKEL: Well, I don't know. I mean I’m not a modeler, so it's a hard question to ask. We have been talking with people like Neal Ferguson at the Imperial College at London who does a lot of that kind of work, and asking these kinds of assumptions. And similarly, what if there were an effective vaccine? Both of those are important questions to ask. But then you may be putting too much on that camel's back of historical data. I’m nervous, using historical data to predict the future. But we have been trying to play with that.
GALLIN: Okay. Thank you very much. That was terrific.
Our next speaker is well known to all of us, Dr. Jeffrey Cohen who is chief of the Medical Virology Section and a senior investigator in the Laboratory of Clinical Infectious Diseases at NIAID. He also is known for his coordination of the popular Contemporary Clinical Medicine Great Teacher's lectures which are held as part of the Grand Rounds series. Today he's going to present his work on “Smallpox Vaccination at the NIH Unexpected Findings.” Dr. Cohen's group studies the molecular genetics, pathogenesis and clinical aspects of human herpes viruses, especially Epstein-Barr virus, and herpes simplex virus. He and his team identified genes important for virus infection, establishment of latency, searches for novel compounds for the treatment of the herpesvirus infections, and develops improved or new candidate vaccinations for herpesvirus virus infections. Dr. Cohen earned his BA at the University of Pennsylvania and his MD at Johns Hopkins. He completed a residency in Internal Medicine at Duke, and he was a Medical Staff Fellow in the Hepatitis Virus Section in NIAID's Laboratory Of Infectious Diseases. A clinical fellow subsequently in Medicine at Beth Israel and Brigham and Women's Hospital in Boston, and a research fellow in Medicine and Microbiology and Molecular Medicine at Harvard, his memberships include the American College of Physicians, the Association for the Advancement of Science, the American Society of Clinical Investigation. He is a fellow of the Infectious Diseases Society of America and he's on the editorial board of several journals, including the Journal of Infectious Diseases. And he's also on several patents including the one for hepatitis A vaccine.
[phone rings] Jeff, I don't know who's calling, nor do I know how to answer the phone.
[laughter] Please come.
COHEN: Thank you, John.
So just to begin my talk, I have no financial disclosures, but I will be talking very briefly about 3 drugs that can be used to treat complications of individuals with vaccinia that are not FDA approved. When I get to that slide I’ll mention that a little bit more. The goals of the talk today are to understand the indications and contraindications for smallpox vaccination, the risk and benefits of vaccination, and appreciate the limits of methods to detect the smallpox vaccine virus. So Dr. Merkel gave us a little bit of history of influenza. I’m going to just have one slide going through the millennia of the history of smallpox vaccination.
Smallpox vaccines have been used for over a thousand years. Initially, they were used -- scabs were used for vaccination. And, of course, Edward Jenner developed the cow pox as a vaccine for smallpox. Vaccinia has been around since the late 1800's to vaccine against smallpox, and smallpox vaccination was discontinued in 1972 when the risk of smallpox was actually less than the risk of the side effects from the vaccine. Vaccination was stopped in 1989 for the military. And between 1991 and 2001, about 7,500 civilians received the vaccine, particularly among laboratory workers. And this is a young girl who has smallpox. So in 2002, the end of 2002, the government announced an initiative to vaccinate about a half a million Department of Defense workers, and half a million smallpox response teams. And you can see on the slide here that beginning in January, there was an increase in the number of civilians that were vaccinated. In February, a report came out in MMWR about cases of angina associated with the vaccine. And about a month later, there were a couple of cases of heart attacks in individuals who had been vaccinated. And, of course, if you vaccine enough individuals, coincidently you might see some side effects. That turned out to be the case in terms of the heart attacks. But regardless the MMWR issued a report in April regarding cardiac side effects. There were additional side effects noted, including myocarditis and pericarditis, which I’ll mention a little bit later.
Because of this and because of the lack of a compensation program for side effects, at least initially during the vaccinations, there was a less enthusiasm towards vaccinating individuals. And the ACIP recommended ending smallpox vaccination after completing vaccination of response teams. So a total of about 39,000 civilians were vaccinated in 2003.
So the ACIP currently recommends vaccination of laboratory workers and animal care workers who work with vaccinia at 10 year intervals. This is especially important for researchers who are exposed to money pox, or high titres of the vaccinia smallpox vaccine. It's also important for individuals working with needles who might stick themselves when vaccinating animals, and for persons who work with recombinant vaccinia that might have enhanced virulence.
So the indications or rationale, I should say, of vaccinating researchers are to prevent infection with recombinant virus, to avoid the risk associated with sero-conversion. So if you're transgene, that is the gene that's inserted into vaccinia has HIV, you don't want to sero-convert to HIV. And also to avoid the risk of transmitting this virus into the community. In terms of contraindications to vaccinia vaccination, persons with immunodeficiency, those with history of eczema, or other exfoliative skin disease, pregnant women, persons who have a history of heart disease or greater than three risk factors for heart disease, or those who might have close contact to immunosuppressed patients and therefore, could potentially transmit virus to them. So in terms of the complications, one of the most common complications of smallpox vaccine is auto inoculation where a person will get vaccinated in the arm, and then either in the process of changing the bandage or if there is any leakage, can get vaccine on their fingers, and then contaminate an open wound or contaminate the eye or the genital area. And this is actually a very common complication seen with smallpox vaccination.
Generalized vaccinia can occur and this is usually due to a viremia, often times it's actually self limited, although one does get a rash and can get a rash in multiple areas of the body. Much more concerning, and much more severe is progressive vaccinia where the vaccination site progresses and the virus can spread locally and really can cause a fatal reaction, if it's not treated. And these individuals have impaired cellular immunity. And an eczema vaccinatum, this is a photograph of a case that actually occurred in the last year or two of a person in the military who was vaccinated, the patient -- I should say the military person's daughter was infected with the virus and who had eczema. And it caused a very severe infection that required treatment. And not shown here are myocarditis and pericarditis which is actually relatively common after vaccination. And post-vaccinia encephalitis which is a severe complication of the smallpox vaccine.
So in terms of treatment options for individuals who have complications of the smallpox vaccine, for individuals who have auto inoculation, but not involving the eye or generalized vaccinia, myocarditis, pericarditis, or encephalitis, there is no specific antiviral therapy for those individuals. And most of them will do fine just with observation and supportive care. In terms of patients who have progressive vaccinia or eczema vaccinatum, there are three options. The first line option, according to CDC, is vaccinia immune globulin. This is an intravenous preparation which neutralizes the virus. Second line option is intravenous [indiscernible] which inhibits viral replication. And recently, there is an oral drug, ST246, which has been developed that targets the antiviral -- targets the viral envelope protein. That's been really used in one case, that previous slide that I showed of the person with eczema vaccinatum. It's not clear what its effect was, because that individual received all three of these drugs. So again, these are not approved by the FDA at the present time.
In terms of the vaccine, in 1931, the Drivax smallpox vaccine was developed, and that was discontinued in 2007. And we currently use the ACAM2000 vaccine. Dryvax is the New York City's Board of Health strain w vaccine, and it was prepared from calf lymph that was scraped from the belly of the cows, and this calf lymph was, then, centrifuged at low speed to clarify it. So it was a very crude vaccine.
The current vaccine is a clone of Dryvax, and it was pastured 7 times in human fiber blasts and then 10 times in African green monkey kidney cells. These two vaccines much similar immunogenicity in terms of neutralizing antibody t-cells, and I should mention that individuals in the Laboratory of Virus Diseases, Pat Earle and Jeff Americo have looked some of the patient samples that I will be talking about, and saw similar neutralizing titres in individuals who got the Dryvax vaccine or ACAM2000. And the skin reactivity in terms of the pustula that's formed seems to be similar with both.
So in terms of the study that we have been doing at the Clinical Center, this started in March 2003 when the government was ramping up to vaccine healthcare workers. And what we did was take individuals who were normally getting the smallpox vaccination in Occupational Medicine Service and obtained serial blood and throat swabs from them, either before vaccination, after vaccination, every other day for two weeks, and then at one month and at six months. And here you can see the bifurcated needle that is used for vaccination. This was a very fruitful collaboration with the Clinical Center Department of Microbiology, particularly Dan Fidorco, who is in the audience here today. So we looked at 42 vaccinees. You can see the symptoms that occurred in individuals at NIH who received the smallpox vaccine. Over 50% of that had fatigue, lymphadenopathy, muscle pain, or head ache. Less common were itching, loss of appetite, chills, time off from work, and fever. And when you look at the duration of these symptoms on the next slide, you can see we measured this by clinical visits, so you can see here that fatigue, for instance, was noted at a mean of 1-1/2 clinic visits. Again, they're occurring at every other day. Lymphadenopathy was present about at about 1-1/2 clinic visits. You can see muscle pain, head ache, and in terms of hours off from work, the average was actually about 1 to 1.3 hours off from work in individuals who got the smallpox vaccine.
So the goals of the study were to look at the -- try to figure out what was the most sensitive assay to detect virus at the vaccination site? So for instance, if there was a smallpox outbreak, what would be the most sensitive assay to detect virus, if one was to try to distinguish smallpox from other rashes? Does virus occur outside the bandage? This has important implications in terms of individuals, healthcare workers going back to take care of patients after being vaccinated. Does the vaccine -- is the vaccine shed from the throat? Is virus present in the blood? Again, important for blood transfusions or individuals donating blood, I should say, after getting the vaccine. And also what cytokines increase after vaccination.
So in terms of assays, working with a microbiology laboratory, we looked at the direct fluorescent antibody test, shell vial culture, or PCR. So the DFA test involves scraping a lesion with a tongue depressor, placing the cells on a glass slide, fixing the cover slip with acetone for 10 minutes to inactivate virus, and then staining with a fluorescent conjugated antibody, counter staining with Evan's blue. So you can see the vaccinia positive cells are green and the counter stain is actually red here. And the advantage of the DFA is you get results within one hour of receipt, so it's a very fast test in terms of staining. In terms of the specificity, the anti-- we tested 3 different antibodies from different companies that were conjugated to fluoracine, these antibodies detect vaccinia, but also other orthopox viruses such as monkey pox, camel pox, cow pox. There is a monoclonal anti-vaccinia antibody available that detects only vaccinia, but this is not conjugated, so it's much more cumbersome to work with, and it takes longer to do the staining. The other assay we used is the shell vial assay. This is a culture assay. These are cylindrical tubes that have media in them, and at the bottom, there is a cover slip that has cells on it. And one removes the media, one adds the sample to the vial, spins it down so that the infected cells are then spun down on to the cover slip. Add media back and incubate for 1 to 2 days. Again, fixed with acetone for 10 minutes to inactivate virus, and then stain with the same antibody.
So one of the first surprises we found in our study, as I mentioned, the standard procedure is to inactivate the virus and the cover slips for 10 minutes, was that after 10 minutes, we still had a lot of virus on these cover slips. As you can see, if we inoculate a shell vial with about a 10 to the 7 foci of infectious virus, it takes about a full hour before that virus is inactivated. So it's very important to realize that you don't want to just throw these cover slips out after 10 minutes. You really want to inactivate the virus for a full hour. And that was a bit of a surprise in the microbiology lab.
Another assay that we used was PCR. Again, DNA is extracted from virus infected cells. PCR is using pox virus primers, which detect 25 viral genomes per millisample. And the primers we use to detect all the orthopox viruses, but one can design primers that would specific for vaccinia. So we compared the sensitivity of the 3 different assays, PCR, shell vial and DFA for 47 different samples from the inoculation site.
What you can see is that 47 out of 47 were positive by PCR. About 90% were positive by shell vial. About 40% were positive by direct fluorescent antibody, scraping of the lesions.
So to summarize this part of the talk, the PCR was the most sensitive assay for detecting vaccinia at the vaccination site. The most rapid assay, however, was DFA, direct fluorescent antibody testing. And if you want to know whether there was actually infectious virus there, the shell vial assay, which is a cultural assay, is useful there.
So with these techniques, we evaluated some patients and I started getting some phone calls. This is case number one who is a woman who presented here with a pustular lip lesion about a week after getting a smallpox vaccine. A shell vial culture was sent that was positive, both for vaccinia virus and for herpes simplex virus. And this caused a lot of pages to me about what to do about this individual. So we did PCR of the lip lesion and it turned out to be positive for herpes simplex virus, and negative for vaccinia virus. So we concluded that the lesion was actually the herpes simplex virus and it was a false positive vaccinia antibody staining of the shell vial culture. So when we looked at all three of the conjugated antibodies that are commercially available, every single one of them cross reacts with herpes simplex virus type one, but not with herpes simplex virus type two. And obviously, again, if there had been a smallpox outbreak, and one started using this antibody and didn't know it cross reacted to HSV-1, you could imagine it would cause a lot of consternation. So this was sort of a second surprise, and turned out to be very important.
Another case was a woman who at NIH, had not been vaccinated with a smallpox vaccine, which, again, was recommended for people working with it, but stuck herself in the left index finger with a needle that had vaccinia. About 5 days later she telephoned a tender lesion at the site of the needle stick, and axillary adenopathy. 9 days later she developed a rash that was on the trunk and the extremities. Didn't have systematic symptoms, but 11 days later was seen in the clinic. This is a picture of her finger at the inoculation site. A culture was done which was positive for vaccinia and also for staph EPI. And a blood test was done and she was negative for vaccinia in the blood by PCR or by culture. This is the rash that occurred. It was negative by culture and PCR, and a biopsy showed a hypersensitivity reaction. So she was followed in Occupational Medicine Service clinic and just got wound care without any specific antivirals or antibiotics, and you can see that her finger healed up really well after one month.
And subsequently there have been five laboratory workers that were reported in the MMWR who had finger sticks after working with vaccinia, and all of these individuals either had not been vaccinated previously or it had been 10 or more years after the last vaccine. So this just emphasizes the importance of vaccinating laboratory workers.
The second goal of the study is whether virus is outside of the bandage. So when people get vaccinated in Occupational Medicine Service, a gauze pad is put over the vaccination site and the gauze pad actually has a small hole in it, so one can monitor the site. An occlusive dressing is put over that to try to trap any material that might ooze out from the vaccination site. So we looked at skin cultures every other day for 2 weeks and then on days 28 to 33 of individuals who had been vaccinated, and found one -- only in one case, one out of 64 cases where culture around the bandage was positive. And that was positive at day 7 here. There were some patients -- I should say this patient had three positive PCR's around the bandage. We went back and talked to the individual. The bandage had actually been loose and flopping around and had sort of pressed it back on. So except for only one individual, cultures around the bandage were negative, and all the other individuals we looked at.
And there was a study that came out in 2004 which showed that some individuals did have cultures that were positive, and many -- most of these individuals had changed the bandage themselves. As you can imagine, when you're trying to do that with one hand, it's difficult to do, and one can sometimes have a non sterile dressing here that -- I should say a dressing where things -- if it's not put on properly, one can have some leakage or one can get material on their gloved fingers, and then apply those gloved fingers again to the new bandage. So we think that leakage of infection material outside of the site is very, very rare.
Next question is whether vaccinees shed virus from the throat and is virus present in the blood. So we started these studies based on studies done in -- between 1930 and 1950 that's predominantly in the German literature of individuals who got throat swabs after getting a virus, a vaccine virus that was more virulent than the New York Board of Health strain. And actually, surprisingly in these individuals, 50% of children who have had pharyngitis after being vaccinated were culture positive for vaccinia. And 7% of children who had symptoms of -- 7 percents of children who didn't have symptoms of pharyngitis also had a positive throat swab. And it's thought, again, that this is a much more attenuated virus than what was used in the '30s and '50s. So we obtained 340 throat swabs from individuals who got the smallpox vaccine here at the Clinical Center, and only two of the 340 were positive by PCR, and you can see they were positive days 13 and 6 after vaccination. And cultures from the identical time point were all negative. And the PCR's were very low level positive as is shown here.
And another study that was published in 2005 found no cases that were positive by PCR culture and antigen, and a study that was reported in the JAMA mentioned that there were 10% of cases that were positive by PCR, and this study did not do cultures. So it's reassuring to us that when people were PCR positive, at least we could not culture a virus from the throat in these individuals.
We also looked at the blood. And again, studies from 1930 to 1950 show that some individuals have positive blood cultures three to 10 days after vaccination, again, receiving this more virulent strain. In 1964, Dr. Blotner reported culture positive in the blood in rare immunocompromised patients or patients who had clear cutaneous lesions after getting the New York City Board of Health strain, the Dryvax vaccine. So out of 341 bloods that were looked at from patients at the NIH, we found that 7 were PCR positive for vaccinia, anywhere from 4 to 11 days after vaccination, and reassuringly cultures were negative on these days after vaccination. And again, other studies showed either no positive cultures or PCR, or the same study that showed 4% positive PCR's did not do cultures. This was reassuring because there has been issue of whether -- if people get vaccinated, when can they be blood donors? And the current guidelines are that you wait until your scab separates or 21 days, and based on our studies, this looks like a very reasonable recommendation because we didn't see any PCR positivity after day 11. And we never saw any positive cultures.
So the last topic is what cytokines increase in the blood after vaccination? And this is really a work in progress right now. So of the various cytokines that we've looked at, the ones that are most commonly elevated in patients, and here you see the percentage of patients who have greater than a 1.5 fold increase in serum cytokines. You can see the ones that are most commonly increased were Tumor Necrosis factor Alpha, Interferon Gamma, MEG, which is a chemokine induced by Interferon Gamma, and GSCF. And if we look at the percent change from baseline, you can see the cytokine that's highest in the serum after vaccination was Interferon Gamma, and chemokine MEG, followed by TNF, and GCFS.
So to summarize the talk, smallpox vaccination is important for laboratory and animal care workers who are working with vaccinia. Vaccinia has more side effects than the commonly used vaccines and caution is needed in vaccinees. When we compare different tests for detecting the virus, PCR is the most sensitive test. DFA is the fastest test. Vaccinia is resistant in activation by acetone. You need to inactivate the virus for a full hour. Viruses very, very rarely are detected outside bandages. While virus is detected by PCR in the blood or throat in some vaccinees, cultures at this time were all negative. And Interferon Gamma, TM alpha and GCFS are often detectable in the serum after vaccination.
So finally, I’d like to thank individuals who participated in the study, four different nurses in the laboratory of Clinical Infectious Disease have helped out with the study. As I mentioned, the Clinical Center, Microbiology, particularly Dan and Gary now have been very important in terms of the microbiologic tests that are done. We have been collaborating with the Laboratory of Viral Diseases in terms of looking at neutralizing antibodies in individuals who get vaccinated. Ron at SAIC helped with the cytokine assays and all of our patients are vaccinated in the Occupational Medicine Service that's run by Jim Schmidt, and of course, I especially want to thank all the participants in the study, the doctors, nurses, microbiologists, and researchers at NIH who volunteered for this study and were kind enough to give their blood for the study.
So I’ll stop here and take questions.
[applause]
[Inaudible Question]
COHEN: Presumably. We really don't know for sure. We haven't studied it further. Either it's an HSV epitope or some cellular prone that's induced by HSV. But in cell culture with different strains of HSV, different cell lines, this was a very reproducible repeatable phenomenon. And again, only HSV1, not HSV2.
[naudible Question]
COHEN: I’m not actually certain. She -- I don't know for certain. You know, she didn't get the conventional vaccination, so I’d have to refer to the Epidemiology Service and Occupational Medicine Service in terms of whether they consider that an adequate vaccination. It certainly it's something that you want to avoid at all costs.
GALLIN: I have a question. You commented that the patients who get into trouble with the vaccine are the immunodeficient patients, which is well known. Do you recommend that we develop some rapid tests for, for example, Gamma Interferon 12 access function in people before they get vaccinated since it's an elected vaccination?
COHEN: I think generally speaking, a medical history is probably sufficient for this. I can tell you that during the vaccinations that occurred between 2003 and more recently, there were about 7 HIV individuals who were vaccinated. It wasn't known that they were HIV positive. And they did not have any side effects noted with the vaccine. However, the vaccine clearly was contraindicated in people who are immunosuppressed. So I don't know that it would be worthwhile to necessarily screen individuals for cellular immunity per se. I think based on the history, that probably would be adequate. Partly because we really don't vaccinate that many individuals right now.
[Inaudible Question]
COHEN: So the -- so the myocardial infarctions and the angina are probably not related to the vaccine. They're probably a – it’s thought to be a coincidence in the fact that if you vaccinate enough individuals, some of them would have -- had you not vaccinated, would have had myocardial infarctions. The myocarditis, however, is a side effect of the vaccine. It's really not known at the present time -- why some individuals get myocarditis and others -- and some don't. People are certainly looking at, you know, cytokine profiles. The numbers are relatively small. We're looking at snips to see if this is some genetic component. But it's not clear why. There is no evidence of active -- that I’m aware of -- of active viral replication going on in the heart, for instance. And these individuals do get better over time without any specific anti-vaccinia therapy. But it's really not known right now.
[Inaudible Question]
COHEN: I don't know. I don't know that has been studied.
GALLIN: Okay. Well, thanks to both speakers for a great Grand Round.
[applause]
(Music fades in, under VO)
ANNOUNCER: You’ve been listening to a pair of lectures on the subjects, DESIGNING THE HISTORICAL ATLAS OF THE 1918-1919 INFLUENZA PANDEMIC IN THE UNITED STATES Presented by Dr. Howard Markel, the George E. Wantz Distinguished Professor and Director of the Center for the History of Medicine, and Professor of Pediatrics and Communicable Diseases, the University of Michigan, Ann Arbor; and SMALLPOX VACCINATION AT THE NIH: UNEXPECTED FINDINGS Presented by Dr. Jeffrey Cohen, chief of the Medical Virology Section and senior investigator in the Laboratory of Infectious Disease at the NIAID.
If you would like to see a close-captioned videocast of today's subject, log on to http://videocast.nih.gov and click the "Past Events" link.We invite you to join us for our next NIH Clinical Center GRAND ROUNDS podcast, where we will once again have two speakers on the topic of "THE EMERGING PZRADIGM OF CLINICAL GENOMICS." Discussing technologic developments in the area will be Dr. Eric Green, scientific director of the National Human Genome Research Institute at the NIH. Discussing Clinical Implementation of the subject will be Dr. Leslie G. Biesecker, chief of the Genetic Disease Research Branch at the NHGRI. The NIH CLINICAL CENTER GRAND ROUNDS podcast is a presentation of the NIH Clinical Center, Office of Communications, Patient Recruitment and Public Liaison.
For more information about clinical research going on every day at the NIH Clinical Center, log on to http://clinicalcenter.nih.gov. From America’s Clinical Research Hospital, this has been NIH CLINICAL CENTER GRAND ROUNDS. In Bethesda, Maryland, I’m Bill Schmalfeldt at the National Institutes of Health, an agency of the United States Department of Health and Human Services.
