“The Hot Zone” and the mythos of Ebola

The Hot Zone was first released in 1994, the year I graduated high school. Like many readers, that book and Laurie Garrett’s The Coming Plague* really sparked my interest in infectious diseases. In some sense, I have those books to thank (or blame?) for my career.

But I’m still going to criticize The Hot Zone, because as a mature infectious disease epidemiologist and a science communicator in the midst of the biggest Ebola outbreak in history, The Hot Zone is now one of the banes of my existence. A recent article noted that the book is back on the bestseller list, going as high as #7 on the New York Times list recently, and #23 on Amazon. It’s sold over 3.5 million copies, and it’s reported as “a terrifying true story.” Many people have gotten almost all of their Ebola education from just The Hot Zone (as they’ve told me over, and over, and over in the comments to this blog and other sites).

Here’s why The Hot Zone is infuriating to so many of us in epidemiology and  infectious diseases.

First–the description of symptoms.Preston himself admits that these were exaggerated. Over and over, he uses words like “dissolving,” “liquefy,” “bleeding out” to describe patient pathology. (If I had been playing a drinking game while reading and did a shot every time Preston uses “liquefy” in the book, I’d be dead right now).

Of a Marburg patient, pseudonymously named Charles Monet, he describes him as

“…holding an airsickness bag over his mouth. He coughs a deep cough and regurgitates something into the bag. The bag swells up….you see that his lips are smeared with something slippery and red, mixed with black specks, as if he has been chewing coffee grounds. His eyes are the color of rubies, and his face is an expressionless mask of bruises. The red spots…have expanded and merged into huge, spontaneous purple shadows; his whole head is turning black-and-blue…The connective tissue of his face is dissolving, and his face appears to hang from the underlying bone, as if the face is detaching itself from the skull…The airsickness bag fills up to the brim with a substance known as the vomito negro, or black vomit. The black vomit is not really black; it is a speckled liquid of two colors, black and red, a stew of tarry granules mixed with fresh red arterial blood. It is hemorrhage, and smells like a slaughterhouse….It is highly infective, lethally hot, a liquid that would scare the daylights out of a military biohazard specialist…The airsickness bag is brimming with black vomit, so Monet closes the bag and rolls up the top. The bag is bulging and softening, threatening to leak, and he hands it to a flight attendant.

“…the body is partly transformed into virus particles…The transformation is not entirely successful, however, and the end result is a great deal of liquefying flesh mixed with virus…The intestinal muscles are beginning to die, and the intestines are starting to go slack…His personality is being wiped away by brain damage…He is becoming an automaton. Tiny spots in his brain are liquefying…Monet has been transformed into a human virus bomb.

“…The human virus bomb explodes…The victim has “crashed and bled out.”…He becomes dizzy and utterly weak, and his spine goes limp and nerveless and he loses all sense of balance….He leans over, head on his knees, and brings up an incredible quantity of blood from his stomach and spills it onto the floor with a gasping groan. He loses consciousness and pitches forward onto the floor. The only sound is a choking in his throat as he continues to vomit while unconscious. Then comes a sound like a bedsheet being torn in half, which is the sound of his bowels opening and venting blood from the anus. The blood is mixed with intestinal lining. He has sloughed his gut. The linings of his intestines have come off and are being expelled along with huge amounts of blood. Monet has crashed and is bleeding out.”

And later, at autopsy:

“His liver…was yellow, and parts of it had liquefied–it looked like the liver of a three-day-old cadaver. It was as if Monet had become a corpse before his death…Everything had gone wrong inside this man, absolutely everything, any one of which could have been fatal: the clotting, the massive hemorrhages, the liver turned into pudding, the intestines full of blood.”

And I didn’t even get to what Preston says about Ebola and testicles. Or pregnant women. Seriously, there’s pages upon pages upon pages of this stuff.

Throughout the book, Preston presents these types of symptoms as typical of Ebola. Not “in worst case, this is what Ebola could do,” but simply, “here’s what happens to you when you get Ebola.” It’s even beyond a worst case scenario, as he notes in part: “In the original ‘Hot Zone,’ I have a description of a nurse weeping tears of blood. That almost certainly didn’t happen.”

Compare that to just about any blog post by actual workers with Médecins Sans Frontières, healthcare workers on the front lines of this and many previous Ebola outbreaks. Stories are scary enough when the reality of the virus is exposed, and with it the dual affliction of poverty and the terrible health system conditions of affected countries. I interviewed MSF’s Armand Sprecher a few years back during a different Ebola outbreak, and he noted this about symptoms–quite different from the picture Preston paints:

The patients mostly look sick and weak. If there is blood, it is not a lot, usually in the vomit or diarrhea, occasionally from the gums or nose.

The clinical picture of Ebola that people take away from The Hot Zone just isn’t accurate, and with 3.5 million copies sold, is certainly driving some (much? most?) of the fear about this virus.

Second, airborne Ebola. Though this trope is often traced back to “Outbreak,” Preston clearly suggests that both Zaire Ebolavirus and Reston Ebolavirus can be airborne. What he never discusses nor clarifies is that the “evidence” for this potential airborne spread is really thin, and not even indicative of animal-to-animal or animal-to-person transmission.

Rather, it’s much more likely that if airborne spread was involved, it was aerosols generated by husbandry (such as spraying while cleaning cages), rather than ones which would have been generated by infected primate lungs (a necessary step for primate-to-primate transmission via a respiratory route). Indeed, this is the paper that Nancy Jaax et al. published on the findings Preston talks to Jaax about, 13 years after the fact (the experiment is marked as 1986 in The Hot Zone), and noting that transmission due to husbandry practices could not be completely ruled out. It’s unclear also that the Reston strain moved through the primate facility via air, rather than via spread due to caretakers, equipment, or husbandry. Nevertheless,  it’s frequently cited as fact and without any qualification that Reston is an airborne type of Ebola.

Instead, here is what Preston says about it:

“If a healthy person were placed on the other side of a room from a person who was sick with AIDS, the AIDS virus would not be able to drift across the room through the air and infect the healthy person. But Ebola had drifted across a room. It had moved quickly, decisively, and by an unknown route. Most likely the control monkeys inhaled it into their lungs. ‘It got there somehow,’ Nancy Jaax would say to me as she told me the story some years later. ‘Monkeys spit and throw stuff. An when the caretakers wash the cages down with water hoses, that can create an aerosol of droplets. It probably traveled through the air in aerosolized secretions. That was when I knew that Ebola can travel through the air.'”

He then comes back to “airborne Ebola” several times, based in part on this idea.

But here’s the thing. Just about any virus or bacterium could be aerosolized this way–via high pressure washing of cages, for example. If it can bind to lung cells and replicate there, as we already know Ebola can, it can cause an active infection.

But that’s not the same as saying “Ebola can drift across the room” from one sick person to a healthy person and cause an active infection, as Preston tries to parallel with HIV in the above paragraph. Even in Jaax’s experiment and others like it, there’s zero evidence that primates are expelling Ebola from their lungs in a high enough concentration to actively infect someone else. And that is the key to effective airborne transmission. Think of anthrax–if it’s released into the air, we can inhale it into our lungs. It can replicate and cause a deadly pneumonia. But anthrax isn’t spread person-to-person because we don’t exhale the bacteria–we’re dead ends when we breathe it in. This is what happens with primates as well who are experimentally infected with Ebola in a respiratory route, but Preston implies the opposite.

Third, if it wasn’t for points one and two, The Hot Zone really could be read as a “damn, Ebola really isn’t that dangerous or contagious so I have little to worry about” narrative. Preston describes many “near misses”–people who were exposed to huge amounts of “lethally hot” Ebola-laden body fluids, but never get sick–but doesn’t really bother to expose them as such. All 35 or so people on the little commuter plane Monet flies on between his plantation in western Kenya and Nairobi, deathly ill, vomiting his coffee grounds and dripping nasal blood into the airsickness bag he handed to a flight attendant–none of them come down with the disease.

The single secondary infection Monet causes is in a physician at the hospital where he’s treated, after his bowels “ripped open” like a bedsheet. That physician, Shem Musoke, not only swept out Monet’s mouth until “his hands became greasy with black curd” but also was “showered” with black vomit, striking him in the eyes and mouth. Monet’s blood covered Musoke’s “hands, wrists, and forearms,” because “he was not wearing rubber gloves.” Musoke developed Marburg virus disease, but survived–one of the few secondary cases of infection described in the book.

Another “close call” was that of Nurse Mayinga N. She had been caring for one of the Ebola-infected nuns at Ngaliema Hospital in Kinshasa during the 1976 outbreak in Zaire, the first detected entry of Zaire Ebolavirus into the human population. Beginning to feel ill herself, she ditched her job and disappeared into the city for two days. She took a taxi to a different, larger, hospital in the city, but was sent away with a malaria shot. She’s examined at a third hospital and sent away. Finally she returns to Ngaliema hospital and is admitted, but by that time, had caused a panic. Preston says:

“When the story reached the offices of the World Health Organization in Geneva, the place went into full-scale alert…Nurse Mayinga seemed to be a vector for an explosive chain of lethal transmission in a crowded third-world city with a population of two million people. Officials at WHO began to fear that Nurse Mayinga would become the vector for a world-wide plague. European governments contemplated blocking flights from Kinshasa. The fact that one infected person had wandered around the city for two days when she should have been isolated in a hospital room began to look like a species-threatening event.”

How many secondary cases were the result of Mayinga N’s wanderings? That possibly “species-threatening” event? Preston again devotes several paragraphs to Mayinga’s gruesome illness and death, and notes that 37 people were identified as contacts of hers during her time wandering Kinshasa. He tells us they were quarantined “for a couple of weeks.”

The fact that exactly zero people were infected because of Mayinga’s time in Kinshasa merits half a paragraph, and not dramatic or memorable. “She had shared a bottle of soda pop with someone, and not even that person became ill. The crisis passed.” <–Yes, that is a direct quote and the end of the chapter on Mayinga. Contrast that to Preston’s language above.

Finally, beyond the science and the fear-mongering about Ebola, beyond everything and everyone in the story “liquefying” and “dissolving” and “bleeding out,” reading this book again as an adult, as a woman in a science career with a partner and kids, I was also left annoyed at the portrayal of the scientists. All of the major characters except one, Nancy Jaax, are men of course, ranging in age from late 20s to 50s-60sish. Understandable since this is in a mostly-male military institution and in a BLS4 setting to boot, but the one Preston focuses on for much of the narrative is Jaax.

While Preston may have been trying to portray Jaax as the having-it-all, tough-as-nails woman scientist, the fact that she’s the only one with any kind of home life is telling–mostly because he devotes more paragraphs to how she neglects both her children and her dying father than any success she has in her life outside of work. She is told early on by one of her colonels that “This work is not for a married female. You are either going to neglect your work or neglect your family.” This thought comes up repeatedly for Jaax, and in the end, while she was accepted and even honored by her colleagues and bosses, we hear over and over again how her children are left on their own to microwave meals and tend to their homework. How they desperately wait up for her to get home after work, often eventually falling asleep in her bed before she arrives. How she tells her father, dying of cancer back in Kansas and both knowing he only has a few hours to days to live, good-bye and “I’ll see you at Christmas” over the phone. How she barely arrives on time for his funeral after he passes.

We hear one paragraph about how another colleague, Thomas Geisbert, had a crumbling marriage with two small children, and how he left the children at his parents’ house for a weekend. Other than that, the personal lives of any other characters are practically absent, save for Jerry Jaax, Nancy’s husband. Even with him, much of the character development revolves around his fears of his wife working in a BSL4 lab.

The Hot Zone, for me, is unfortunately one of those books that you read as a young person and think is amazing, only to revisit years later and see it as much more shallow and contrived, the characters one-dimensional and the plot predictable. The problem is that The Hot Zone is not just a young adult novel–it’s still presented and defended as an absolutely true story, especially by huge Preston fans who seem to populate comment threads everywhere. And now it looks like there will be a sequel. At least it should be good for a drinking game.

 

*I’ll note that The Coming Plague is much more measured when it comes to Ebola–the two were grouped together because temporally, they were released close together, not because they display the same type of hype regarding the virus.

New paper on Ebola–no primate-to-primate transmission seen

By the same lead author that published the pig Ebola transmission paper comes a new publication examining airborne transmission among primates. In these, Ebola did *not* spread between non-human primates (NHPs) via air. I sent an email to the PI to comment; will update the post if he responds, but in the meantime, some money quotes directly from the publication:

“One experiment reported contact free transmission between infected NHPs to one uninfected NHP although cross-contamination due to husbandry practices could not be ruled out with certainty26. Interestingly, EBOV infected swine transmitted the virus to naïve NHPs over a 0.3 meter buffer zone that prevented direct contact between the 2 species27. …However, airborne transmission in natural outbreaks cannot be a common occurrence and is possibly insignificant by the account of several reports49282930.”

and

“The presence of transmission in the pig-NHP experiment and not the NHP-NHP experiment, both performed under similar conditions and environments, could be explained by the fact that EBOV disease in pigs is respiratory in nature with high amounts of infectious particles present in the oro-nasal cavities in the symptomatic phase of the disease which provided an opportunity for release into the environment35. On the receiving end, NHPs are known to be susceptible to lethal EBOV infection through the respiratory tract242731 putting the onus of the transmission on the ability of the source to shed infectious particles.”

Translation: even though previous reports in primates had suggested the potential for airborne transmission, other factors couldn’t be ruled out, and epidemiologically, it’s insignificant. In the experiments they did, pigs just handle Ebola differently than primates (as I mentioned here), and so make them more likely to spread the virus via a respiratory route.

Significance: No airborne transmission between primates in this controlled experiment, strengthening the evidence that Zaire ebolavirus isn’t a risk in this manner. So Donald Trump, you can stop freaking out now.

A historical perspective on Ebola response and prevention

Yambuku, Zaire, 1976. A new disease was spreading through the population. Patients were overcome by headaches and bloody diarrhea. The disease was spreading through entire families and wiping them out.

Eight hundred and twenty-five kilometers to the northeast, a similar epidemic was reportedly raging across the border in Maridi, Sudan. Were these outbreaks connected? Despite enormous challenges trying to navigate both the logistics of crossing a landscape of unpaved and unmarked roads, as well as the political difficulties of an attempt to enter and collect samples in an area marked by recent civil strife, samples were finally collected and shipped to the World Health Organization for testing.

All told, these outbreaks caused 602 cases and 431 deaths. The Zaire outbreak wasn’t stopped until the hospital was closed, because 11 of its 17 workers (65%) had died of the disease. Investigators went door-to-door in 550 villages in the Yambuku area  to find and isolate new cases. Roadblocks were set up to restrict access to the area.

In Sudan, a number of cases were traced to workers in a cotton factory (probably due to bat exposure) and their families. The epidemic increased when one case went to the Maridi hospital, and the virus then was transmitted within that hospital. Note what the write-up describes:

“The hospital served as an efficient amplifier from which the virus was disseminated throughout the town. The number of cases gradually increased until mid-September and at the end of the month there was a large number of cases, particularly in hospital staff. The number of cases declined in early October, possibly as a result of the use of protective clothing. A considerable increase in the number of cases was observed in late October and early November, which may have been partly due to a lack of protective clothing when supplies ran out in mid-October.”

In Maridi, the doctor-in-charge, along with 61 members of the nursing staff came down with Ebola. Thirty-three of them died. Eight additional deaths occurred among the ancillary and cleaning staff. This outbreak was only contained because, again, the hospital was made safer via extensive training and the use of good personal protective equipment, and cases were identified in the town by going door-to-door. Buy-in from local officials was obtained, which is critical–while families may not trust outsiders, they more often will listen to local leaders. Cases were isolated in their homes or taken to the hospital. Eventually every village in a 30-mile radius from Maridi was screened, and the outbreak burned out.

Now imagine you’re looking at this in real time, via 24-hour news networks, from halfway across the world. You’re hearing news reports of cases spiking. Healthcare workers are contracting the disease. You don’t have all the information but you’re coming to your own conclusion that the virus must be mutating in Sudan.

You would, however, be wrong. These outbreaks were actually separate epidemics (and led to the identification of Zaire ebolavirus and Sudan ebolavirus, respectively), but collectively, that was a lot of Ebolavirus disease in 1976–the most deadly single year for Ebola until 2014, in fact. It took an enormous effort on the ground in these two areas to stop the outbreak.

Though not wholly analogous to today’s West African epidemic, there are lessons here to take away. There is a steep learning curve for dealing with Ebola. Besides the single case from the Ivory Coast, Ebola has not historically been a West African disease. Liberia, and Guinea and Sierra Leone in particular, do not have a great history of governmental stability, and are still recovering from civil wars, government coups, and a general lack of stable national leadership. Infrastructure is also substandard, as early reports on the main hospital in Conakry, Guinea noted. Each country seems to be dealing with this largely on their own without solid cross-border cooperation, and since the borders tend to be flexible in any case, patients and those incubating Ebola have been able to travel and move the virus into new areas. The public in general does not understand the disease, and in some cases keeping doctors out with knives and machetes, accusing physicians of murdering their loved ones and bringing Ebola to their villages.

It’s reasons like this–structural and sociological issues, by and large–that have led the WHO to declare the outbreak to be “out of control.” As far as has been reported, there is nothing particularly notable about the virus itself, which is very closely related to previous Zaire ebolavirus isolates. The infection rate in healthcare workers–about 60 out of 1300 total cases reported at the time–is actually quite low, given the conditions they’re working in and the lack of experience most of them would have had with Ebola. (Again, in Sudan, it was 61 out of 284 cases–so 21% of the total cases were doctors and nurses–versus about 5% in this outbreak).

The outbreaks in these countries are bad currently, but for the future, we can look at Uganda as a model. The first outbreak in that country, beginning in 2000, resulted in 425 cases and 224 deaths. The second outbreak in 2008 resulted in 149 cases and 37 deaths. In 2011, they had a single case with no secondary spread. In 2012, 11 cases and 4 deaths. 2012, 6 cases and 3 deaths. It’s probably impossible to stop Ebola from spilling over into the human population, but Uganda has done a great job responding. They are able to do early detection of suspected cases in their biosafety level 4 lab in Gulu. They alert local authorities if something is suspected, then send a task force to assist with containment. They communicate effectively with the public about what they can do, and how effective treatment in hospitals can lower the mortality rate. They work with community leaders when a quarantine needs to be put in place. These things can all be employed in West Africa as well, but it takes time and a lot of commitment to get such networks up and running. We need this cooperation as much as we need PPE and even more than we need “secret serums,” because it is only with prevention of new cases that this epidemic will finally die out.

 

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What is the harm in agricultural-use antibiotics?

After this post on antibiotic resistance, many of you may have seen an exchange on Twitter calling me out for being “knee-jerk” about my call to action to do something about the overuse of antibiotics. In that post, I focused on antibiotic use in agriculture, giving only brief mention to human clinical use. There are a number of reasons for this, and while I didn’t discuss them extensively on Twitter, I did want to provide an overview here in order to better explain my position and concern about antibiotic use in agriculture.

How are antibiotics used in animal production?

To start, some background on the issues. Antibiotics are used in agriculture in a number of different ways. Like humans, they’re used to treat disease when animals get sick. This type of use isn’t disputed for the most part–no one wants animals to die from treatable disease, nor do they want sick animals to enter the food chain. Antibiotics can also be used to prevent disease, such as when animals are stressed (as when they’re moved from farm to farm) and disease has a tendency to break out, or if a few animals in the herd are sick and owners want to prevent the rest of the herd from falling ill. This type of use is somewhat controversial, and many have argued that this type of use is only necessary because hygienic conditions on farms aren’t up to snuff–and that if better husbandry was practiced, this prophylactic use could also be significantly decreased or eliminated. Others argue that it’s necessary even with good husbandry.

The practice which is most widely disputed is the use of antibiotics for growth promotion. We’ve known for roughly 60 years that animals, when fed antibiotics at low doses (below the level required for disease treatment),  grow to their slaughter weight faster (and therefore, with less food input). This is the “low-hanging fruit;” the practice that even some in industry agree could end with pretty much no (or minimal) side effects to industry; and the practice that the European Union has already ended. It’s also the target of FDA guidance 213, which asks the phamaceutical industry to voluntarily phase out the use of growth promotant antibiotics in feed and water given to livestock. Twenty-five of 26 companies have agreed to this already, so again, there’s really not much dispute that this is a process that will be ending, after over 60 years of use and 45 years after a government report suggested that rising rates of antibiotic resistance in humans was tied to agricultural antibiotic use in the Swann report. (Maryn McKenna has a great timeline of other developments here).

Why am I (and many others) concerned about the use of antibiotics in agriculture?

First, and most compelling to me, is the fact that between 70-80% of all antibiotics used in the United States are used in agriculture. I’m linking to a PolitiFact report because they drill down into the caveats with that number in more detail than I want to go into for this post, but I will note that it’s tough to get good numbers because the industry won’t release them, and that the numbers we do have include drugs that are not used in human medicine–but that doesn’t mean they may not be important. More on that later.

Second, this is my area of expertise. I study antibiotic-resistant pathogens in the agricultural environment, so naturally this is my interest and where I know the literature the best. Third, antibiotic use in agriculture just isn’t as intensively studied when it comes to methods to reduce antibiotic-resistant microbes that may emerge from this setting. In the hospital and clinics, patients need a prescription to get antibiotics. The amount of antibiotics that are prescribed are tracked and those data are available. Hospitals often have stringent infection-control policies put in place to reduce the generation and spread of antibiotic-resistant “superbugs.” Hell, there’s enough research on these policies that my colleagues have a blog devoted just to that topic. In human medicine, no one is ignoring the generation and spread of resistant pathogens.

None of these control and monitoring policies are present on livestock farms as a matter of routine. Rather, as my colleague Lance Price has noted more than once, if he was going to try to create a superbug, farm use of antibiotics–subclinical dosing of thousands of animals at a time–would be an ideal way to create one.

What if we remove “growth promotant” antibiotics?

What remains an issue is what will happen after growth-promotant antibiotic use is stopped. There is already a “natural  experiment” going on in the EU, where such antibiotics were banned back in 2006. As I noted here, the results have been mixed when antibiotics have been removed from agricultural practices. Sometimes resistance persists, sometimes it goes down. A modeling paper examined the use of antibiotics for agricultural use, and suggested that their biggest impact happens before we even realize it via surveillance, and by the time we notice it, it may be too late to make much of a difference, which is depressing.  So even if antibiotics are banned for growth promotion purposes, there is a chance that we won’t see much of a dent in antibiotic resistance overall–or if we do, it may take years to see it decrease. This is an argument against removal of these sub-therapeutic uses–if we can’t 100% guarantee it will help, why change the status quo?–but at this point, even the current status quo is better than an ever-increasing arc of resistant bacteria.

Another concern that persists and muddies the waters is that no meaningful reduction in antibiotic use in animals will occur, but that rather antibiotics used for growth promotion will just be repackaged as “prophylactic” use, which will still be allowed under the new guidance. The industry says this won’t happen, but without meaningful and transparent surveillance, how can we know if it is or not?

Additionally, other sources of low-level antibiotics may still be present on farms and in feed, such as the use of distiller’s grains in animal feed which may still contain some antibiotics. And even if antibiotics that are important for human medicine are removed altogether, resistance still may linger or even climb if we allow for other classes of antimicrobials (such as ionophores, which are part of that group I mentioned above that are used in agriculture but not in human medicine) to still be used on the farms. Why could this be an issue? Right now, we really don’t know if any of these drugs co-select for resistance to important human medicines. For example, in some cases, antibiotic resistance genes are together as cassettes that can move around between bugs, such as on a plasmid or other mobile genetic element. That’s why using tetracycline on a pig farm can select for methicillin resistance–not because the drugs are the same (they’re totally different classes), but because the resistance genes come as a package deal. Is this happening with ionophores? Don’t know. It’s a messy area and makes any clear-cut cause-and-effect research very difficult to carry out.

To make matters even messier, because there’s so much transport of animals across state, national, and international lines, even if antibiotics are reduced in one place, new resistant bugs could be imported from elsewhere where no reduction in antibiotic use has taken place, mucking up the data and making it appear that antibiotic withdrawal has had no effect.

Furthermore, there is no directive for companies to actually track and report antibiotic usage differences after growth-promotant antibiotics are removed. We can’t even get good data on the industry as a whole, much less finer-level data describing how much goes to pigs, how much to cattle, how much on Iowa pig farms versus North Carolina, or for Smithfield versus Hormel farms, etc. It’s a surveillance nightmare. Even if we did have this data, surveillance of resistant pathogens is quite limited, especially on the farms themselves. Most of the data we have comes from NARMS–the national antimicrobial resistance monitoring system, which examines gram negative pathogens in people, meat samples, and live animals (taken at slaughterhouses). It’s a start, but what if we don’t see an effects in these organisms–but might in other commensal pathogens, or in the microbiome as a whole? Or in gram positives like my pet bug, Staphylococcus aureus? NARMS right now would miss those, and so might lead to false impressions of how reduction in antibiotics is really affecting resistance in the bacteria originating on farms.

Soooo….as you can see, this is a messy area. However, as I noted on Twitter, one should look at the totality of the research rather than searching for any particular “smoking gun” publication (a fallacy, I might add, that is employed by many types of science “skeptics”). There have been many, many papers that have shown, usually in ecological studies, that use of antibiotics on the farm is linked to generation of resistant bacteria, and that these bacteria (and associated resistance genes) can spread to humans via food, water, environmental runoff/contamination, air, and other mechanisms. Pew Health has an extensive bibliography of many of these studies here, and it’s barely even scratching the surface when it comes to publications in this field. In the end, though it’s messy, it breaks down to a simple truth: antibiotic use leads to antibiotic resistance, and reduced use is a goal to strive for–be it use in humans or in animals.

The Pap smear is no panacea, Katie Couric

Regular readers keeping up on infectious disease issues might have seen Seth Mnookin’s post yesterday, warning of an upcoming episode of the Katie Couric show  focusing on the HPV vaccine. Even though Mnookin previously spoke with a producer at length regarding this topic, the promo for the show certainly did not look promising:

“The HPV vaccine is considered a life-saving cancer preventer … but is it a potentially deadly dose for girls? Meet a mom who claims her daughter died after getting the HPV vaccine, and hear all sides of the HPV vaccine controversy.”

And indeed, reviews thus far show that unfortunately, Couric pretty much  mangled the issue and allowed heart-wrenching anecdotes to trump science (reminiscent of Jenny McCarthy’s appearance on Oprah). I won’t cover it all (you can view it here), but basically Couric allows stories about illness and death in the weeks following administration of the vaccine to go unchallenged, and brings on Dr. Diane Harper as her HPV expert (featured prominently in the anti-vaccine documentary “The Greater Good“). Dr. Harper believes the HPV vaccine is over-hyped, and that Pap screening is “100% accurate” so no HPV vaccine is really needed. This, frankly, is hogwash. Even with emphasis on screening, here in the U.S. we have 12,000 cases and 4,000 deaths from cervical cancer alone each year. (And in Mnookin’s post and in Matthew Herper’s Forbes post, both note that head and neck cancers can also be caused by HPV as well–but have no good screening process).

Even when HPV cervical infections are caught via screening, the treatment ain’t pretty. I’ve written before mentioning one such remedy–the LEEP procedure.  I had this done several years ago, after a Pap smear came back with abnormal cells and positive for HPV DNA:

“Next, a woman with abnormal cells can expect to undergo a LEEP procedure, where portions of your cervix are removed with a burning electric wire under local anesthetic, and the foul smoking remains of your cells are sucked up into the smoke shark, “a sleek, powerful, smoke-eating machine.” [And one gets to look forward to “coffee ground-like discharge” for up to several days following the procedure, due to the materials they use to stem the bleeding cervix]. After LEEP, side effects may include infection, hemorrhage and possibly cervical incompetence.  These are rare, but if we’re talking vaccine side effects versus possible outcomes from HPV infection, these types of outcomes need to be considered as well–not just death from cervical cancer.”

Being currently pregnant following such a procedure, cervical incompetence was something I was carefully monitored for. Nevertheless, it’s still been a huge source of stress throughout this pregnancy, as this is a significant cause of second-trimester miscarriage and there aren’t great, foolproof ways to detect it, or remedy it if it does occur. Harper acts as if finding HPV via Pap smears is like rainbows and unicorns, but it too has a risk-benefit equation, and I’d so much rather have received a vaccination than to have gone through that. And, some women’s treatments for HPV infections and cervical abnormalities are even more extreme than mine was.

This is why I had my now-almost-14-year-old daughter vaccinated for HPV, and why my pre-teen son will soon be getting his as well. There are multiple ways to prevent HPV-induced cancers, but the vaccine (in combination with routine Pap smears) is by far the least invasive and safest route, as multiple studies have confirmed.

Finally, the show was doubly disappointing because Couric has been such an outspoken advocate of colon cancer prevention, which was the cause of her husband’s death in 1998. While realizing this is a fluff talk show and not the kind of harder journalism she’s apparently now abandoned, she still failed to ask even the most basic of questions to the supposed HPV vaccine “victims” she featured on her show, nor to note during their segments that other possibilities may exist for the girls’ illnesses and death besides the HPV vaccine. In the second segment, Rosemary Mathis even admits blatantly doctor-shopping until one would “listen to her” about her daughter–in other words, give her a new diagnosis (vaccine injury). Why isn’t this even questioned? What did her previous doctors tell her about her daughter’s condition? Couric allowed ratings and anecdotes to trump actual science, potentially causing real harm to the public health. How disappointing that this is now part of her legacy.

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The microbiology of zombies, part V: beware the bite?

Now that seemingly the flu outbreak storyline has been wrapped up on The Walking Dead (unsurprisingly, but disappointingly, with their ineffective treatments proving to be miracle cures), there’s still one more zombie microbiology topic I’d like to cover: what’s up with the bite, and is it the cause of death? I said previously:

“We know the pathogen can certainly be spread by bites and then cause zombification that way…”

but one commenter disagreed, noting:

“I don’t think we have evidence for that from the show. I think it clearer that zombie bites cause death, and there doesn’t seem to be evidence that the agent that causes death also causes zombieism (or vice versa). In Walking dead, any death is a sufficient condition for becoming a zombie. I would guess that zombies cause death because of a massive polymicrobial infection/sepsis.”

So, could death be due to massive sepsis (an overwhelming immune response to infection, which can lead to organ failure and death) via the bite, rather than the introduction of a specific zombie pathogen? It’s certainly not the first time I’ve seen that argument. Even the Zombie Research Society has put that forth as a hypothesis (and Matt Mogk has written of it in his book as well). However, I don’t buy it for a few reasons.

First and foremost, human bites simply aren’t that deadly. Even in a study of patients presenting to emergency rooms (which are probably the most serious of bites), none were found to have sepsis. Well, you might say, maybe more would have had this if antibiotics weren’t available, which would be the case with TWD (well, except now they have them, but I digress…) A Medscape article addresses this, noting that prior to the antibiotic era, up to 20% of bites caused amputation of a finger–but still, a local nasty infection, not necessarily sepsis. Even in a 1936 NEJM paper studying bites, only 2 deaths are noted, and both are in “delayed cases”–individuals who waited 5 days post-bite to present to the hospital. In these cases, the cause of death is indeed listed as “extensive sepsis.”

However, it should be noted that hand bites in particular—the subjects of those papers and articles above– seem to be rather nasty. Per Medscape again, “… most human bite injuries occur on the hands, and hand wounds from any cause have higher infection rates than do similar wounds in other anatomic locations.” So, these papers focus on the worst types of bites (hand injuries) at the most severe locations (presenting to emergency rooms), and thus should be considered likely a worst-case scenario for our potential infectees: that, even if bitten, a minority of them would have serious complications, and a minority of those might perish of sepsis. This doesn’t match up with what we see in the show.

You might argue that the process of zombification would modify/increase the nasty bugs living in the mouth. I agree–rotting in this manner certainly could alter the presence and types of organisms that would be present in the mouth, and therefore possibly make them more deadly and more likely to result in a sepsis death of the bitten. However, even accounting for rapid reproduction rates for microbes (mostly bacterial when you’re talking about sepsis and oral germs), this doesn’t seem to be a satisfactory answer, as one can quickly die and be reanimated and immediately have the potential for a deadly bite. It could also be argued then that therefore *everyone*, living or dead, would also possess this quality in that case–it shouldn’t matter if the bite is from a zombie or from a living person; the result should be the same (sepsis and zombification).

Further, in the human bite literature, there are two types of bites typically described: occlusive bites and clenched-fist injuries. The former is probably what you think of when you think zombie bites: mouth open, teeth coming together on the skin, chomp, chomp, chomp. Clenched-fist injuries are what happens when someone strikes another person’s teeth with, as the name suggests, their clenched fist, often scraping the knuckles: basically, a punch that strikes the teeth/mouth. While on the Walking Dead the former universally mean death (except in the case of really quick amputation of the bitten part, like we saw with Hershel’s leg), we’ve seen many examples of the latter—how many fistfights has Rick alone gotten into now? Not to mention, scenes like this:

 So if one is going to support the “polymicrobial infection as a result of bites” scenario for zombification, the issues of living biters need to be explained away as well.

Others have argued along similar lines regarding bites and sepsis, suggesting that the zombie bite is analogous to what happens to the prey of the Komodo dragon:

“Animals that escape the jaws of a Komodo will only feel lucky briefly. Dragon saliva teems with over 50 strains of bacteria, and within 24 hours, the stricken creature usually dies of blood poisoning. Dragons calmly follow an escapee for miles as the bacteria takes effect, using their keen sense of smell to hone in on the corpse.”

The problem with that analogy is that it’s based on a myth. That’s not what really happens: the dragon actually has venom, as I noted way back in 2005 (and Ed Yong updated recently, both based on the work of Bryan Greig Fry). It’s not their bacteria that kill their prey, but their venom. Do zombies suddenly become venomous? Doubtful. So, another idea shot down.

To me, the most convincing scenario, and the one that seems to jibe with both the idea that everyone is infected and with the little we know about the epidemiology of the outbreak, is that the immune system keeps the “zombie virus” under control while one is still alive and healthy. When one dies, the virus is allowed to replicate unchecked, resulting in both zombification/reanimation as the infection proceeds unabated throughout the body. The virus would also replicate (probably within the salivary glands) in order to enable transmission to the next bite victim. A zombie bite then introduces a large amount of this virus right into the bloodstream of the target, which overwhelms the body’s defenses and is responsible for both death and subsequent zombification—like rabies virus on steroids—and the cycle perpetuates itself.

Bottom line is that with the sepsis model, you have to explain more anomalies than with a virus-death model. You’d need to postulate immediate changes in the oral microbiome that aren’t readily accounted-for, but would be responsible for the 100% fatality rates upon receiving a bite (but ONLY a zombie bite, and not a live-human bite), while with the novel zombie virus model you get a bit more carte blanche to account for the transmission and certain death. That seems a much better explanation to me.

 Works Cited:

Welch CE. Human bite infections of the hand. NEJM, 215:901. 1936.

Talan DE et al. Clinical Presentation and Bacteriological Analysis of Infected Human Bites in Patients Presenting to Emergency Departments. CID, 37:1481. 2003.

See also:

Part I: the microbiology of zombies

Part II: ineffective treatments and how not to survive the apocalypse

Part III: “We’re all infected”

Part IV: hidden infections

The microbiology of zombies, part IV: hidden infections

(As previously, spoilers abound)

So on this week’s Walking Dead soap opera, we find that Daryl/Michonne’s group is still out and about searching for medical supplies. Back at the prison, the food situation is dire (apparently all the food stores were in the cell block where the infection broke out), so Rick and Carol head out to look for both medicines and food from the local ‘burbs. During their outing, discussion ensues of Carol’s attempt to stop the prison’s apparent influenza outbreak by killing two people who, at that point, were the only ones showing symptoms of disease. Rick decides he can’t trust her, and ends up banishing her from the group.

Carol said multiple times that she was trying to do the right thing, to protect the rest of the group from those who were sick and was only trying to end the outbreak. However, here’s where some knowledge of infectious disease would have helped her. Every disease has an incubation period: the time when the microbe is multiplying in your body, but you’re not showing any physical disease symptoms yet. This can be short–as little as perhaps a few hours for something like Salmonella food poisoning. It can be extremely extended, as I mentioned with rabies virus in my previous post, where the incubation period can be months to years. With influenza, the typical incubation period is 2 days, but it can be as short as 1 or as long as 4-5. The kicker is that a person who’s incubating flu can still spread it even before they show symptoms of the illness. So just because Karen and David were the only ones actively coughing and looking miserable, Carol was mistaken in her assumption that they were the only ones infected, and that she could stop the outbreak by snuffing them.

This is the difference between two similar concepts, quarantine and isolation. People who have been *exposed* to an infectious agent, but are not yet showing any signs of illness, can be quarantined to keep them away from others due to their *potential* to spread a disease. Those who are already showing signs and symptoms are placed into *isolation* to keep them from spreading it–they’re a known quantity. The prison group has used primarily isolation to keep the infection from spreading: they’re putting the ill in the Death Row cell blocks as an isolation area, and those who are well can roam around as they choose. (Maggie, for instance, hasn’t been sent to quarantine even though she clearly was exposed to the illness by being in such close contact with Glenn).

However, one thing that the group hasn’t yet determined (probably because no one has recovered as of yet) is how long they’re going to keep anyone who gets better in the isolation area. Though adults usually stop releasing influenza virus even before their symptoms are completely gone, kids can shed the virus for a long time: up to two weeks after their symptoms started according to one study (and others have found similar results). So while right now they have the healthy young children segregated from everyone else for their own protection, in theory, if Lizzie (the flu-infected child currently in held in isolation) gets well and is released back to the healthy kid’s room, she could simply re-start the outbreak there, among the most susceptible. 

This is why disease eradication is so difficult, and why it’s been accomplished for so few pathogens to date: many pathogens can spread on the sly, even when people don’t know they’re sick. For influenza, even if it’s knocked down in this group (and of course, it soon will be one way or another–at some point, the susceptible hosts in the prison will be exhausted, either by infection & recovery or by death), there is always another reservoir of disease out there. It may be other humans. Darryl/Michonne’s group finally made it to the veterinary school mentioned two episodes ago, and the zombies they ended up fighting there had clinical signs that looked an awful lot like the survivors had seen at the prison: blood that had come from the eyes and nose. Had flu been circulating there as well? It’s a vet school, pigs could certainly be housed (there were a number of animal cages, and could easily be an outdoor space for livestock somewhere). So pigs could be serving as a reservoir. Flu can also come from a number of other animals–most notably, birds, who don’t even have to appear sick to transmit the infection to people.

Infections can be sneaky and unseen, as this group should well know.

See also:

Part I: the microbiology of zombies

Part II: ineffective treatments and how not to survive the apocalypse

Part III: “We’re all infected”

The microbiology of zombies, part III: “We’re all infected”

Warning: here be spoilers

In many latter-day zombie movies, books, and TV shows, zombie-ism has a biological cause. In 28 Days Later, the infection is caused by the “Rage” virus, which escaped from a lab when animal rights activists break in and release a group of infected chimpanzees. Of course, one of the animals promptly bites one of its “liberators,” and the infection spreads rapidly throughout Great Britain. In Zombieland, it’s a mutated form of “mad cow” disease. The Crazies, it’s the Trixie virus; World War Z, the Solanum virus; Resident Evil, the T virus. I could go on and on. Zombie causation has clearly evolved from the early days of radiation or curses, and has become a biological phenomenon in most modern zombie tales.

The Walking Dead is no exception. Though the claim is made in season 1, episode 6 (“TS-19”) that the outbreak could be caused by just about anything–bacteria, virus, parasite, act of God–I call shenanigans. In the previous episode (“Wildfire”), Jenner, the CDC scientist, is processing tissue taken from Test Subject 19, and the visualization under his microscope looks very viral. Of course, take this with a few pounds of salt, since he’s using a light microscope and can also see the nice alpha-helical DNA strains within the pathogen (in real life, things just don’t look like this) and unless you’re one of the giant viruses, you can’t see viruses, much less DNA, under the microscope Jenner uses anyway. But still, it looks pretty viral-y to me, which is why I typically refer to it that way:

screenshot wildfire virus

Microbial zombification makes sense in today’s culture. My colleague Brooks Landon notes: “…zombies represent a better monster for the modern, post-9/11 world. They provide a release for feelings of being overwhelmed by abstract and intractable events like global economic crises, terrorism, and pandemics.” In the past decade or so, we’ve seen the emergence of SARS, multiple outbreaks of influenza including a new pandemic strain, the continuing HIV crisis, Nipah, Hendra, more Ebola, just to name a handful. Infectious diseases are commonly in the news, and many times are unfortunately over-hyped, leading to a collective nervousness of all things microbial.

The infected zombie is further boosted by a number of recent studies, largely in insects, that demonstrate a type of pathogen-directed “mind control:” zombie ants, zombie grasshoppers, and zombie cockroaches, just to name a few. A recent video game has exploited the ant fungus idea, mutating it into a form that infects humans. Even rodents (and possibly humans) can have their behavior apparently influenced by a parasite called Toxoplasma gondii, which makes rodents lose their fear of cat scents and may influence the development of schizophrenia in humans, or more controversially, even affect sexual inhibitions. If germs are already controlling our minds–why couldn’t they turn us into zombies?

And certainly, there are some candidate microbes which could, in theory, cause at least the “living” form of zombie-ism, even if they couldn’t necessarily raise you from the dead. The Trixie virus, for example, is supposed to be a weaponized rhabdovirus–the family of viruses that includes rabies. Rabies virus infection certainly causes aggression and biting. The virus is spread via saliva, so biting is the main way it is transmitted between animals. In a recent book, Rabid, the authors trace rabies through history, and note that it may be at the root of many zombie (and vampire) tales. Rabies can also hide out in the body for awhile before showing symptoms, as the virus travels up the nerves toward the brain. This is why a bite near the head progresses to symptoms much faster than, say, one to the foot. Typical time from bite to symptoms is in the neighborhood of 6 weeks, depending on the location of the bite and dose of virus one receives, but extreme cases have been documented, with symptoms not showing up for as long as 8 years. And, like has been done on The Walking Dead, one of the ways that bitten victims would try to avoid symptoms would be to cut off the affected limb before the infection spread. (Ouch).

Could something like the “we’re all infected” scenario used in the Walking Dead occur in real life? Maybe. With rabies, victims could appear physically fine for months to years. Even more extreme, there are a number of germs which can remain with people throughout their entire life. The virus that causes chicken pox, for example, doesn’t ever really go away. Your body fights it off enough to keep it in check after the initial rash, but it hides out  in your nerves and can come back in later years as shingles. Other herpes family viruses have a similar lifestyle: symptoms can come and go, but the virus never really leaves. The human papilloma virus (HPV) can also persist for years in some people (most infected people appear to clear this one, though). A bacterium called Helicobacter pylori can live very happily in a person’s stomach–sometimes causing ulcers, but going completely undetected and causing no symptoms in most people. And of course, HIV, which does not go away except in a few notable and high-profile cases. So the concept is, as they say, biologically plausible.

The problem isn’t necessarily with the microbiology, then, but with the epidemiology. How did everyone get infected so quickly? We know that the plague took an incredibly short time to spread (Jenner says less than 200 days in the first season, and “less than 63 days” since it went pandemic)–but how? That’s a missing link in this scenario. We know the pathogen can certainly be spread by bites and then cause zombification that way, but other forms of inoculation (such as getting sprayed in the eyes or nose with zombie blood) don’t seem to have that effect. Is it in the water? If so, that would be some damn rapid spread, since early on Jenner noted that this appeared to be a true pandemic–present around the world. How would that happen?

In the air? Possibly, but even most airborne microbes don’t hang out indefinitely; they’re dispersed by wind to levels below those able to cause infection, or killed by sunlight or other environmental conditions. So even if you had a herpes- or HIV-like virus that could hide out in the body for an extended period of time without causing symptoms, how did *everyone* get it in such a short timeframe? Some scenarios in other books and movies put the blame on bioterrorism. The above-mentioned Trixie virus, for example, was a bioweapon which was only accidentally released when the plane carrying it crashed. Spread of Trixie in the movie ended up being only local, but transmission beyond that is hinted at the end. A true bioterrorist attack could, theoretically, account for simultaneous outbreaks all over the world.

Finally, though the “infected zombie” is now the most common type, it should be noted that this isn’t really new. George Romero, widely recognized as the grandfather of the modern zombie, acknowledges that he “ripped off” his idea for Night of the Living Dead from Richard Matheson’s I am Legend–a vampire story from 1954. The cause of that vampirism?

Bacillus vampiris–a bacterium.

 

See also:

Part I: the microbiology of zombies

Part II: ineffective treatments and how not to survive the apocalypse

Part IV: hidden infections

The microbiology of zombies, part II: ineffective treatments and how not to survive the apocalypse

(Spoilers. And things.)

After the start of season 4 of the Walking Dead and the introduction of a new nemesis: a fast-spreading, deadly infectious disease that seems to be a strain of influenza, I was looking forward to the plot arc of this season.

And then episode 3, “Isolation”, happened. From an infectious disease standpoint, I say, bah.

At the end of the previous episode, “Infected”, the group had decided to lock up anyone who was showing signs of the infectious disease within the death row cellblock, so that they would not further spread the disease, and to put the children and elderly (as the most vulnerable population) in another area to keep them safe from the infection. Quickly it was seen that this wasn’t working well, as people were becoming sick all over and more and more were moving into the isolation cellblock.

So, a council meeting was called of the leaders of the group. One of the decisions which was made, on the advice of Hershel the veterinarian, was to try to scavenge supplies from a college of veterinary medicine approximately 50 miles away from their location at the prison. What supplies?

ANTIBIOTICS.

For the micro people reading, you’ll see why my rage started boiling a bit at this point. Hershel was the one who’d suggested this was an influenza outbreak (and therefore, caused by a virus) in the prior episode. He is familiar with the disease (and there is another physician, Dr. Subramanian, who has been treating the ill and has seen the rapid course of the disease–of course, he is now sick himself). It is true that influenza can be complicated by a secondary bacterial infection: that those sick with the flu could develop pneumonia due to Staphylococcus aureus or other bacteria, and that these bacterial infections would respond to antibiotic treatment. But, when the course of disease is as rapid as it appears to be during this outbreak, it’s more likely that people are dying from primary influenza infections, which are most certainly NOT treatable with antibiotics. There are antiviral drugs that can treat influenza infections if given early in the disease course (such as oseltamivir or zanamivir ), but I think the odds of those being stocked at a veterinary school would be pretty slim.

So, rather than at least try for some kind of medically plausible scenario (is that really too much to ask?), Daryl, Michonne, Tyreese and Bob the medic take off in search of completely ineffective antibiotics,and run into an enormous zombie horde on the way. Hershel, in the interim, leaves the relative safety of the prison (he was ensconced with the children as a “high risk” individual) and wanders out into the woods to pick berries and leaves to brew elderberry tea. A folk remedy, there are a few peer-reviewed publications which suggest that elderberries or elder flower might have some properties that do work to treat influenza, so at least here Hershel is, well, sucking somewhat less here when it comes to proposing medical interventions to help those suffering than he did with his terrible antibiotics idea.

Hershel does end up with his tea, taking it into the isolation cell block and distributing it to the infected. This includes Dr. Subramanian, who repays the favor by coughing bloody sputum all over Hershel’s face. (Seriously, he doesn’t even know how to cough into his elbow? Even the little girl talking to Carol did that correctly).

From the previews of next week’s episode, “Indifference”, it appears there will be more searches for drugs, while presumably the horde advances toward the prison. I anticipate a miracle cure of some kind for Glenn at the least, but remain annoyed that the writers are touting antibiotics for a viral infection when flu season is upon us.

See also:

Part I: the microbiology of zombies

Part III: “We’re all infected”

Part IV: hidden infections