Tuesday, October 23, 2018

The Anti Vax Epidemic - Good Parents Getting Gamed . Episode 1. Autism and Vaccines

I believe all parents want to do what's best for their kids. I really do. And even I, a virologist, had to deal with concerns about vaccines when I found out I was pregnant 12 years ago. For me, that meant doing what I did best: researching and talking to pioneers in the field. To give this topic the attention it deserves, I will be presenting it in several parts; each addressing an important concern that you as parents have when deciding whether or not to vaccinate your children.

Today I'm going to tackle the elephant in the room - Autism.
First let me say I understand your concerns and I won't dismiss them. All good parents want to make sure they are doing what's best. One of the biggest concerns when it comes to vaccines, even now, is that it could give your child autism. And while a lot of people with autism live wonderful and fulfilling lives, no parent wants to give their child autism by making a bad choice, right? Of course not. And there are many people telling you it can happen while others say it can't. So what risk is there, really, of getting autism from a vaccine?

I can tell you confidently, as a scientist and mother who has researched this extensively, that all scientific evidence shows that vaccines do not give children autism. In the early 1990s, this was a valid concern, because it seemed that the incidence of autism was increasing and it seemed to show up around the same time as children were vaccinated. So we absolutely needed to find out if the one caused the other. But we now have 30 years of data showing zero correlation between vaccines and autism. 

First let's look at the perceived increase in the incidence/prevalence of autism. Has there really been an increase? No. The reality is that there has been an increase in the number of kids diagnosed with autism, while the number of kids with autism has not increased.
Let me explain.
What I mean, is that the difference, based on extensive and well-designed studies, is that rather than an increase in the number of people with autism, we are seeing an increase in the number of people identified as having autism. This happened for a number of reasons. First, physicians began looking for it. If they looked for it and found it, they diagnosed it. Before the 1990s we weren't looking for it so all but the most severe cases went undetected and undiagnosed. Not only that, but the diagnostic criteria for autism has changed and it became a spectrum disorder - that then means that children who would not have met the previous criteria for autism, but who fall on that spectrum, are now diagnosed as having autism. This alone increases the number of children diagnosed with autism dramatically. So we are looking for it, the criteria to be given the diagnosis has changed, and finally, it's being recognized as something that kids can get help for in school, so parents are more and more willing to accept the diagnosis, even when the child is on the very mild end of the spectrum. Again, this increases the number of kids diagnosed with autism.

When you take all the data on children with autism or on the spectrum, from 1990-2010 we find: "In 2010 there were an estimated 52 million cases of ASDs, equating to a prevalence of 7.6 per 1000 or one in 132 persons. After accounting for methodological variations, there was no clear evidence of a change in prevalence for autistic disorder or other ASDs between 1990 and 2010." From The epidemiology and global burden of autism spectrum disorders. An excellent but more palatable article is The Real Reason Autism Rates are Up in the US.

The bottom line, is that vaccines don't cause autism. Despite what you hear, vaccines do not cause autism. Here is a letter written to President Trump and signed by 9 pages of scientific organizations, asking him to speak out in favor of vaccines, to help curb the anti-vax movement. The reason I've linked it here, is because after the 9 pages of signatures, there are 18 pages of studies - summaries and links - that all show that vaccines do not cause autism. They are powerful evidence of the truth about vaccines.

I understand that there are some loud voices out there working to convince you that autism is a real risk from vaccines. But the truth is that they are using fear to advance their own agendas. Don't let them fool you. Your child's life is at stake. As a scientist, I can say that the people who have done these studies do them so that they can also make the right choices for their own kids. They do everything they need to do, to present reliable and unbiased evidence. This isn't easy and there's no money in it, trust me. In addition, dedicated scientists are, as we speak, working diligently to figure out what actually is causing autism, and they are making progress. The two biggest problems with the anti-vax movement are that in addition to putting your children's lives at risk, they make it really hard for scientists to work on the real problem. Don't give them your support. Our children deserve better.

The child in the picture above has measles. A total of 11 measles outbreaks (3 or more linked cases) have been reported so far in 2018. As of Oct. 6, 2018, 142 individual cases of measles have been confirmed in 25 states and DC. (CDC.gov) Measles kills, yes, but did you know that if someone survives the measles they could have serious long term health problems? One of the most severe is called subacute sclerosing panencephalitis (SSPE) is a very rare, but fatal disease of the central nervous system that results from a measles virus infection. SSPE generally develops 7 to 10 years after a person has measles, even though the person seems to have fully recovered. The risk of developing SSPE is higher for a person who gets measles before they are two years of age.

Other severe complications include pneumonia and encephalitis (swelling of the brain). Patients may need to be hospitalized and could die.  As many as one out of every 20 children with measles gets pneumonia, the most common cause of death from measles in young children. About one child out of every 1,000 with measles will develop encephalitis that can result in convulsions, deafness, or intellectual disability. And finally, for every 1,000 children with measles, one or two will die. There was a reason the measles vaccine was a game changer for parents when it first came out. It saved lives. Vaccines don't cause autism, they cause adults.

Now, it's October, so go get that flu vaccine for you and your children. Last flu season, >80,000 Americans died of the flu, the highest toll in more than ten years according to federal health officials. Of those, 180 were young children and teenagers. Already this year, it was reported just eight days ago, that an unvaccinated child in Florida died from the flu. Don't let your child be the next fatality.

Am I fearmongering too? Maybe, and I'm sorry for that. Well, sorry not sorry. In this case, the danger is all too real. Just ask the mom whose child died eight days ago. She'll tell you just how real.


Peace,

Heather

Sources not linked above:
Gershon AA. Measles virus (rubeola). In: Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, Updated Edition. 8th ed. Philadelphia, PA: Elsevier Saunders; 2015:chap 162.
Mason WH. Measles. In: Kliegman RM, Stanton BF, St. Geme JW, Schor NF, eds. Nelson Textbook of Pediatrics. 20th ed. Philadelphia, PA: Elsevier; 2016:chap 246.





Wednesday, October 29, 2014

Ebola Patient Zero: What we do, and do not, need to know about an epidemic index case

Whenever there is an infectious disease epidemic there will also be an index case, or patient zero: the first recognized case of the disease in a population; the case that alerts you to the presence of the disease. From an epidemiologic perspective, identifying this case is critical because it can provide really important information. How the index case got infected can offer insight into the pathogen's natural reservoirs or modes of transmission, and can also help clarify at what point in disease progression the patient was infectious and how the disease initially moved through the population. All are critical in helping define strategies for future epidemic prevention, control and health care approaches. For these reasons there are things we need to know about an index case. We need to know where they lived, where they went and what they did on the days they might have become infected. Who did they have contact with? When did symptoms start? What did they eat? Did anything unusual happen? Did they go hunting? Was there an insect or animal bite? An injury? A fall? A swim? Who helped them? Are they sick now? These are all important and can help pinpoint the original source of infection.

But do we actually need a name?

Epidemics aren't only about hard science. And while learning all we can about the virus and its transmission will allow us to better fight future epidemics, we shouldn't neglect the human element in the pursuit of knowledge. We have numbers on graphs and charts: cases, deaths, beds. But these statistics are about people and it's often the human stories that drive us. Maybe that's why we look for the names. But should we look for that name?

Many index cases are known, some even famous. You've heard of Typhoid Mary no doubt? Her real name was Mary Mallon and she was forced into isolation after it was discovered she was the (unintentional) cause of dozens of typhus infections. We also know the names of the index cases for the 2003 SARS, the 1854 cholera, and the 2009 swine flu outbreaks. We even know the name of the very first Ebola index case ever recorded, from the 1976 outbreak.

And now we know the name of the index case in this Ebola epidemic. We have had the information regarding the index case for a while now. We've known it was a child in Guinea and we've known that, as the first family afflicted by this epidemic, their losses were great. But now we've also been given the name of the two-year old child who was Ebola's first victim last year.

Did we need that? Did we need to see the family photos? Did it teach us anything about the epidemic? Did this information give us anything useful or just headlines? Did it serve only to exploit the tragedy of a family that lost everything? Did it do anything useful other than put a name to the epidemic? Did it give us someone to blame?

I believe there are many (maybe most) who will not blame this child or his family, but there are those who will. This tragedy will be replayed again and again and the stigma that's already been borne by the family and community will also be replayed. How can it not? This is the largest, most horrific Ebola epidemic in history. Thousands are dead, more dying and it's not over. Who knows what the final toll will be when all is said and done? We can't know that now, but when we do we will be able to trace it all back to one chance encounter with something infectious; one innocent child, one loving family, one community that had no idea what they were up against. A horrific tragedy in every sense of the word.

And by publishing this precious child's name and family photos for our consumption, have we added to our understanding of the epidemic, or is this a new tragedy - one that we must own?


Heather

Wednesday, October 15, 2014

Ebola in Texas: Take a Deep Breath Y'all

Alright folks. Here in Texas two nurses have turned up positive for Ebola and it's possible other healthcare professionals who worked with Mr. Duncan, or who will work with the nurses, will turn up infected.

So now what? What does this mean?

Well, We know how Ebola is transmitted and we know how to prevent that transmission. But knowing how, watching a youtube video about it, and putting that knowledge into practice in a frightening real life situation, are very different things.

The reason that personal protective equipment (PPE) works, is because people use it and use it correctly. I really don't think anyone would intentionally treat an Ebola patient in what they knew was an unsafe manner, but there are nuances and subtleties involved with PPE that, if not well understood, can mean the difference between safe and unsafe, and with Ebola the room for error is incredibly small. And while you wouldn't leave the gloves on the shelf when examining an Ebola patient, and you might know that removing contaminated gloves incorrectly is just as dangerous as not wearing them, it's easier to misjudge what it really means to remove those gloves safely than one might think. Without practical experience, it's very easy to think you are doing it correctly.

And Texas Health Presbyterian nurses and doctors got thrown into a very tough situation with a very sick patient and we are hearing that they had no protocols in place. Which also means they hadn't done any real prep in case an Ebola patient showed up. But I doubt that situation is any different than most other US hospitals, so instead of castigating them, we should focus on finding ways to better prepare every US hospital. And I think one of the most important things for hospital supervisors to realize is that thinking that you or your staff are doing it correctly isn't enough. You need to make sure that everyone knows what to do and can do it without fail.

So how do you do this?

Training, drills and testing.

From the beginning of this epidemic, we've been horrified about the number of HCW being infected, and untrained and unsupervised HCWs anywhere are susceptible to infection from an Ebola patient. On October 3rd, Dr. Tom Ksiazek, the most eminent Ebola epidemiologist working today in my opinion, gave a talk about his 6 weeks as the CDC team leader in Sierra Leone and said the biggest problem with PPE (when they had it) where he'd been, was training, especially removal of contaminated PPE and supervision.

And it's clear that, while most US hospitals have the capability of containing Ebola to a handful of cases should it appear, whether they will or won't depends on training and the practical application of what is known to effectively protect against Ebola transmission.

Do HCWs in the US have more training in general than W. Africa? Probably. Are they specifically trained in the dangers unique to the very high profile task of caring for Ebola patients who are exhibiting frightening symptoms and exuding copious amounts of infectious bodily fluids, all while performing medical procedures? Not most of them.

In fact Anthony Fauci, Director of the NIAID, said HCW need more training and that you "gotta have drills". You can't just send an email containing a link to nurses and tell them to learn how to use extensive PPE in their spare time.

So how can you find out if you or your staff are disinfecting correctly, or removing PPE without contaminating yourselves? Someone needs to show you how to do it correctly, let you practice under supervision, then test you. A really effective way to do this is to use a fluorescent powder or liquid that is only visible under UV light. Something like Glo Germ. Toss it around a HCW in full PPE, get it on their gloves and shoe covers and mask - all over the place. Then have them disinfect and remove the PPE as they would in a real life situation. Then illuminate them with the UV light to see what lights up. With Ebola you only need a tiny bit of residual contamination transferred from a finger to an eye to cause an infection.

And then understand that this doesn't necessarily mean that the person was careless or cavalier, but more likely that it's really really really hard to decontaminate and remove contaminated PPE safely. This is why there is a buddy system. This is why training and supervision are paramount.

And if you're a nurse or a doctor and you have any hesitation about whether you're prepared to safely enter an Ebola patient's room, you need to be able to feel like you can bow out without the risk of losing your job. Your supervisor should not only respect your professional assessment, but should applaud you for it.

Can this be contained? Absolutely. But unless someone takes charge and shows people how to do this job safely, there will likely be other HCW infections in the process.

Who should be in charge? Well, hopefully State Public Health Departments will play a role in guidance and training, and hopefully the CDC will also provide some oversight. But if I were a hospital, I would assign a small team of HCW (w/enough for redundancy) specifically to handle potential Ebola patients. This team would be the only staff to have any interaction with any possible Ebola patient, from initial evaluation, to diagnosis and testing and through treatment. This team should be on call and given both on call and hazard pay. And this team should be identified now and trained extensively, before another  Ebola patient arrives at an unprepared hospital door.

But in the meantime I think moving the newest Ebola patient, nurse #2, to Emory is a really great idea. Let THP take a deep breath and regroup, and maybe all of our hospitals can start implementing some protocols that will help us move forward and prevent more infections.


Cheers,

Heather

Sunday, October 5, 2014

Why Ebola Airborne Mutation(s) are "Highly Unlikely": Let's Talk Mutation and Natural Selection

Note: This post is not an exhaustive treatise on the evolution or adaptation of filoviruses, but an applicable discussion on certain principles.

When Ebola experts say that mutation to become airborne is “highly unlikely”, they are basing this on what they know, as experts, about Ebola molecular virology, cumulative transmission data and natural selection. While they’ve all said it, I think Heinz Feldmann, one of the foremost experts in Ebola molecular virology, said it best in his interview with Kai Kupferschmidt (17 September 2014):

Q: "There has been speculation that the virus could mutate or has already mutated to spread more easily. How likely is that?"

A: "I don’t think there is any data right now to support that. If you look at the virus sequence, it falls within the normal range of Zaire Ebola strains. Of course any of these mutations could have a dramatic effect, which we don't know right now. But there is nothing obvious that would point to a more transmissible, more virulent virus, or a change of transmission route.

You can speculate in every direction, of course, but I think it should be fact-based, it should be data-based, and I think it makes absolutely no sense to bring in aerosol transmissibility as a potential. I think this is really not helpful, unless you have data to support that."

What he is saying there is that he knows Ebola genetics and he doesn't see anything in the new genetic data that indicate the virus is mutating in that direction. Being an excellent scientist, he also acknowledges that we don’t know what all changes mean yet, but based on the data he sees, there’s no evidence to speculate that this Ebola variant is becoming airborne.

Aside from the genetic data they have, Ebola scientists consider the way in which Ebola is already successfully transmitted, as well as Natural Selection.

So let’s talk about Natural Selection for a little bit. In his 1930 book, “The Genetical Theory of Natural Selection”, Ronald A. Fisher made this important distinction, “Natural Selection is not evolution.” It’s “…a convenient abbreviation for the Theory of Evolution by means of Natural Selection…” We will be coming back to Fisher soon, but I wanted to make sure we were all on the same page. So as far as Natural Selection goes, I think Dr. Laurence Loewe described it really well in his educational piece for Nature (1) when he said, “…selection constantly sorts through the variation that is produced by mutations to select the fit and remove the unfit, while ignoring neutral changes.”

Fitness refers to an organism’s ability to compete in its environment in so far as survival or reproductive ability. Can it eat? Protect itself? Have fit offspring? During replication of any organism’s genetic material mutations are possible. For viruses, the speed of replication makes the rate of mutations higher than for a human.(2)  And mutations can be classified with regard to how they affect the organism’s fitness. When a mutation provides a selective advantage in this regard, it will be selected for; the frequency of the genotype (genetic profile) containing that mutation will increase. If a mutation is deleterious, it will be selected against and the frequency of that genotype will decrease.

So what drives mutation? Well, Natural Selection moves an organism toward an adaptive optimum; the point at which the organism would be most fit in its environment. This doesn't mean that Natural Selection causes mutations, but that it determines whether or not a mutation would be kept or discarded. And Fisher thought this occurred in small steps rather than in large leaps. He thought that small advantageous mutations would happen more often than large ones, because large mutations would be more likely to have negative side effects. Well, a group studying RNA viruses actually found evidence to support this theory: they showed “…that adaptation proceeds by multiple mutations, but that among the set of all possible mutations, adaptation proceeds by the subset of mutations with small effects.”(2)

This supports what Ebola experts have said, that it’s not likely that a single mutation would cause this virus to go airborne, and the likelihood of the virus acquiring all the needed mutations at the same time is extremely low.

In addition, there’s no selective advantage to becoming airborne for Ebola. It is clear that Ebola’s current mode of transmission is working well. The virus is spreading and reproducing successfully. This means there is no selective pressure on the virus to keep any mutations that might confer airborne transmission, especially when this kind of significant change would most likely bring with it some serious deleterious side effects. And while some argue that this is the first time Ebola has been replicating to this extent in humans, we need to keep in mind that it’s been doing this for far longer in the wild in the primate species it infects and in its bat reservoir host. And yet, this mutation hasn't happened.

[edit 10/6/14]: WHO agrees with me and has also pointed out today, that viruses entirely changing their transmission mode is not something we've seen before. They must have read my blog. ;-)]  

So, can we say it's impossible? No. But I'm not losing any sleep over it.

Cheers,

Heather


References



Friday, September 26, 2014

Not Tonight Dear, I Had Ebola

Edit 9/28/14
I've received some very valuable feedback on this post and I agree that I should have started off with the science behind my opinion and included references. I intended to include references when I posted it, but got distracted and then forgot they weren't there. But without a rundown of what we know regarding infectious semen of surviving men, it wouldn't have been all that helpful. This is what happens when I write out of frustration and post while multi-tasking. Lesson learned.

I apologize and have edited the post to correct this. I've added references and a section with the heading "So what does science tell us about this topic" with a summary of what we know about infectious semen and transmission among survivors. I also realized I should have used the word “unprotected” in the sentence that really drives home the entire point of this post, and you will find that this sentence now has the word *unprotected* in asterisks in the text.

In addition, I added a final point regarding prostitutes (as a post script), based on a discussion on reddit. I am thrilled that this post has engendered so much discussion and I hope these changes have made it a bit clearer. I would also invite you to feel free to begin discussions here. As ever, thanks for stopping by!

Heather

Original Post:
I have fielded a lot of questions regarding Ebola virus in the semen of survivors lately and the
preponderance of people claiming this is a significant source of Ebola transmission is staggering. There is great concern and fear over this. Someone on Twitter was even genuinely concerned that these male survivors are "new highly infectious vectors" that weren't being calculated into projected disease spread. I'm a bit speechless really. Ok, maybe not that speechless.

And last night it was raging on Twitter:
Science based #Ebola horror: survivors have infectious semen for months

Maybe it's under the radar?

In large urbans after millions infected, who knows?

Counseling people on the dangers of sex post-Ebola is great but we know how people are. Who's to say they are obeying doctors orders about this?

So what does the science tell us about this topic? (added 9/28/14) Well, what we do know is from previous outbreaks and follow up with recovered patients. These are the scientific facts upon which my opinions on this are based:

  • Evidence of Ebola virus can be found in semen up to 91 days post disease onset (1, 2, 3, 4)
  • Not all surviving men have detectable virus in their semen.(2)
  • Of those who do, not all of them have it there for 91 days. Some have been found negative at 45 days.(2)
  • Men who’ve recovered are counseled by their physicians about the dangers of transmitting Ebola to sexual partners through unprotected sex. (3)
  • One study found indirect evidence that one woman may have gotten Ebola from sex, but they could not confirm that she actually had Ebola, or that she got it from sex. (1)
  • There is anecdotal evidence that one woman got Ebola from sex during this epidemic
  • Dr. Barbara Knust, an epidemiologist at the Centers of Disease Control and Prevention answered this question for NPR and said this: “Ebola is spread only by people exhibiting symptoms and through direct contact with bodily fluids. Once a person recovers from Ebola virus disease, he or she is no longer shedding virus, and thus is not contagious. In past Ebola outbreaks, follow-up studies of patients who have recovered from Ebola and their contacts found no evidence that the Ebola virus was spread from a recovered patient to their close contacts.”
    • And in response to the specific question about semen:
      • “Therefore, male survivors of Ebola are advised to avoid having sex for three months or to use condoms. Semen and breast milk are not the primary means by which Ebola is transmitted. The virus is primarily transmitted via blood, sweat, feces and vomit.”
  • Dr. William Schaffner, a professor of preventive medicine and infectious diseases at Vanderbilt University Medical Center in Nashville, Tennessee had this to say of it. "Of all the modes of transmission, that's going to be the last," Schaffner told Live Science. "It's a little like asking me, 'If we're all going to go from New York to San Francisco, will one of us walk?' That doesn't happen too often."

Are we on the same page now?
Great.

OK. Let's think about this for a minute. No I mean really think about it. Let's think about the average male survivor in West Africa, what he's been through, who he may have lost to Ebola and how he's feeling physically after battling for his life either at home or in a terrifying Ebola ward. Are you thinking? Really thinking?

How would you feel?

Let's say, worst case scenario this man lost some loved ones, family members or friends. He most likely tried to help or watched at least one of those die. Then he got sick himself and ended up in an Ebola ward. He was terrified and thought he would die. But he didn't. He survived and was released. (read about one man's Ebola survival tale that depicts this clearly.)

So is this where you think the party begins? I hardly think so. This is just the beginning of a whole new set of problems for this guy.

This man has to go back home and continue to recover. Recovery from Ebola hemorrhagic fever takes time, sometimes a lot of it. (And yes, I know we call it Ebola virus disease now, but that does little to communicate the severity of this condition, so I'm sticking with EHF - check out the diagram on the right to see what I mean).

Most likely he'll be welcomed from a distance by any family he has left. Do you really think the single ladies are lining up to give him a Hero's welcome? If they were, do you really think he'd be in the mood? You think maybe he will need some time to cope with what he's been through and with what he's lost?

What are the chances he lost his wife if he had one? Pretty good, I'd say. If both got sick, if at least 50% die and he survived. Even if he didn't lose her, do you think he's not imagining what might happen to her if he gave her Ebola through sex? Do you really think, after everything he's been through and seen, with more and more bodies, and more and more people turned away from treatment centers, that he's going to actually feel like having sex, let alone risk someone's life for it?

Let's say the man is single and has lost no one close to him. Do you think the ladies will be lining up for him either? Do you think he hasn't seen and experienced the same kind of hell? Do you really think that, in the middle of the death, loss, hopelessness and terror of the worst Ebola epidemic the world has ever seen, he doesn't care if he infects another person?

In voicing these concerns, do you have any idea how ugly the assumptions you've made about the character of Ebola survivors truly are?

Survivors are being scorned, avoided and worse. Ebola volunteers are being murdered out of fear and ignorance. Do you really think surviving men, men who are still physically and emotionally recovering, are having enough *unprotected* sex while infectious to be a significant source of transmission?

I don't. I think for the most part these men are exhausted and scared. I think they wish they were stronger so they could help more. I think they are worried about providing for themselves and their families while being isolated within cities that aren't functioning well. I think they are thinking about those they infected while they were sick, wondering who among them will die and when.

I keep saying this because it bears repeating: there's no need to look for Zebras here. The out-of-control transmission of Ebola virus in this epidemic is from the well known and documented routes of transmission, while people are sick and symptomatic, not after they've recovered. Why argue for anything else and add to the already traumatized and stigmatized survivor's burden?

We can do better than that.

We must do better than that.



Heather

Post Script:

This discussion continues on reddit and like I said has provided valuable feedback. I’d like to address one particular comment in response to this post:

"I think Heather underestimates the extent to which the "comfort" of a woman has become habitual to many men. A Couple of weeks after being "cured", an over-stressed man might very well revert to that familiar source of psychological balm. She assumes a setting in which potential partners know the survivor, not an urban setting. Infection of prostitutes is not out of the question.”

I would like to take this opportunity first to say thanks for reading and for commenting. And you’re right I should have addressed the idea of prostitutes. However, it would not have changed my point. In fact, if you really think this will cause transmission via semen to be a significant source of transmission (the point of the post) then these are the assumptions you’ve made:

1) A majority of men who’ve recovered from Ebola will forego doctor’s orders and risk infecting others, including prostitutes, because they want the “psychological balm” of unprotected sex more than they want to stop the spread of Ebola.
2) These men are also willing to risk any of the other sexually transmitted diseases that can be spread by unprotected sex with strangers or prostitutes.
3) The women in question, including prostitutes won’t demand the use of protection during sex with a stranger.

And you’re assuming that enough of this will happen to make the spread of Ebola through semen a significant mode of transmission.

Like I said before, we can do better.

References

1) Alexander K. Rowe, Jeanne Bertolli, Ali S. Khan,Rose Mukunu, J. J. Muyembe-Tamfum, David Bressler, A. J. Williams, C. J.Peters, Luis Rodriguez, Heinz Feldmann, Stuart T. Nichol, Pierre E. Rollin andThomas G. Ksiazek for the Commission de Lutte contre les Epidémies à KikwitClinical,virologic, and immunologic follow-up of convalescent Ebola hemorrhagic feverpatients and their household contacts, Kikwit, Democratic Republic of theCongo. Commission de Lutte contre les Epidemies à Kikwit. J Infect Dis 1999;179(Suppl 1):S28-35.

2) Daniel G. Bausch, Jonathan S. Towner, Scott F.Dowell, Felix Kaducu4, Matthew Lukwiya, Anthony Sanchez, Stuart T. Nichol, Thomas G. Ksiazek and Pierre E.Rollin. Assessment of the Risk of Ebola Virus Transmission from Bodily Fluidsand Fomites. J Infect Dis. (2007) 196 (Supplement 2): S142-S147.

3) R.T Emond, B Evans, ET Bowen, and G Lloyd. Br MedJ. Aug 27, 1977; 2(6086): 541-544. A case of Ebola virus infection.




Wednesday, September 17, 2014

Ebola Convalescent Serum: It's No Magic Bullet

Hello Dear Friends,

There have been many questions since Dr. C.J. Peters was quoted here (9/8/14) saying that convalescent serum from Ebola survivors was unlikely to help treat patients. In this post I go into detail about the data we have that supports this statement. In a future post I will discuss the why of it.

OK. Much of what's been said in the media and by scientists gives the illusion that the effectiveness of Ebola convalescent blood as a treatment for Ebola virus disease is an established and recognized fact. WHO's endorsement and the New York Times article on it has, I think, given people some false hope. Don't get me wrong. West Africa is in a tough spot and I understand why it's being tried. Why not? What else do we have to offer these people? But that doesn't mean it will work. And while I strongly encourage doing everything we can think of to help people, in a situation with limited resources we should focus on those options with the most data to support them and avoid things that might make the situation worse. Since the WHO's announcement, survivor blood has become a hot commodity and now there's a black market for it. How many will suffer a second time because others will surely go to great lengths to get their blood? Blood that will most likely turn out to be unhelpful. But unfortunately, most looking at this situation (like me before I researched it) only know that convalescent serum can work really well for some viruses so they assume it's worth trying. Unfortunately all viruses are not created equal and if those considering this treatment actually looked at the data for Ebola they would see that it tells us this new treatment strategy will almost certainly fail. So let's take a look at this data.

(By the way, if you're confused about names and abbreviations for Ebola viruses you're not alone. For clarification check out Ian Mackay's explanation at Virology Down Under.)

First let's clarify something: what in the heck is "convalescent serum"? To understand what "serum" is, we need to know what blood plasma is, so let me quickly explain. Blood plasma is that light yellow liquid part of the blood that keeps whole blood cells in suspension (keeps them from settling). Plasma contains a lot of important things including, but not limited to, dissolved proteins, glucose, hormones and clotting factors. Blood plasma without the clotting factors is called "serum". Convalescent serum is then serum from the blood of a person who has recovered (convalesced) from an infection, such as a viral infection. This serum may or may not contain those dissolved proteins that could be helpful to fight an infection such as antibodies. Antibodies are proteins made in response to "foreign" bodies, such as viruses, and can help get rid of them. For more details about how antibodies are made and work read this post. You should also know that giving serum that is thought to confer immunity from one organism to another, is called "passive immunization" or "passive transfer". It's important to note here that convalescent serum can also contain drugs or microorganisms so it must be tested both for safety and effectiveness before giving it as a treatment.

As was mentioned in my Q&A with Dr. Peters, for some viruses such as Junin, the virus that causes Argentine hemorrhagic fever, we know that convalescent serum is very effective and is used on a regular basis(1-3). But what do we really know about the use of convalescent plasma or serum for Ebola patients?

Well what's been touted as hard evidence in the media lately are two specific instances in which Ebola patients were given convalescent serum and survived. Well OK then. We're done here right? Not so fast. Let's take a closer look at these cases.

A huge thank you to Mariella Furrer for allowing me to use this photo. Ms. Furrer is an award winning freelance photojournalist based between Kenya and South Africa who has spent her remarkable career documenting some of the most egregious human rights issues. She also documented the 1995 Kikwit Ebola outbreak. Read more about Mariella on my page dedicated to her and her work.

The first is the 1999 paper by Mupapa et al (4) that describes the treatment of 8 Ebola patients from the 1995 Kikwit outbreak. These patients received blood transfusions of whole blood donated by 5 convalescent patients. The blood was tested and found to have ELISA antibodies against Ebola and no viral antigen was detected. So in this case the patients received whole blood, not just serum, but the principle is the same and 7 of the 8 patients lived. WOW! So that blood really worked!! Well, not necessarily. You see, there's more at work here than just the blood transfusion. The authors of the paper  indicated that those 8 patients not only received blood transfusions, they got better supportive care, and with Ebola supportive care may keep you alive just enough for your body to fight the virus on it's own. In fact, another paper published in 1999, by Sadek et al (5), found that with Ebola, the longer you live the better your chances of survival. Sound obtuse? Well, they made a timeline for patients that included time of symptom onset and time of death or survival and it revealed a striking correlation between length of disease and survival: "In general, patients who survived the disease for at least 1 week had a probability of survival of 30%. The rate increased to ~70% for those who survived the first 2 weeks beyond the onset of symptoms." So when were the blood transfusions done? Well, they were done on day 10 post symptom onset. So those patients already had an increased probability of survival. And after adjusting the data for age, sex, and days after onset of symptoms, there was no statistical evidence of a survival benefit from the blood transfusions. Read the paper. Their methods and stats were robust. Furthermore, another paper discussing the same outbreak (6) had this to say, "Oral or intravenous rehydration, provision of adequate calories through oral food intake, and possibly treatment with antibiotics and antimalarial drugs to prevent infections are probably the most important measures to improve survival among EBO patients."

The second case that's been making the media rounds is that of lone virologist Geoff Platt who in 1976, while working with an unidentified virus that was similar to Marburg, accidentally stuck himself with a needle. You can read the paper about his case here (7), and there's a recent article that includes him here. According to the paper, within 24 hours of the first onset of symptoms he began receiving intramuscular injections of human interferon, a protein made by cells to fight viruses. His course of interferon treatment included 3 million units every 12 hours for 14 days. About 24 hours later he was given his first infusion of convalescent serum taken from patients who'd recovered from the 1976 Yambuku Zaire (now DRC) Ebola Zaire outbreak. It was learned later that the virus he'd been infected with was Ebola Sudan. Geoff recovered and in fact after the first infusion of serum the numbers of Ebola particles in his blood dropped significantly. Wow! That serum really worked!! Well, not so fast. You see, they were determining the amount of virus in his blood (viremia) using a guinea pig assay (2 guinea pigs per point). Because taking blood from an Ebola patient and sticking it into a guinea pig can be a bit scary, they didn't take many samples so the actual data from the viremia assay isn't reliable. So it's possible it didn't have as much of an effect as was deduced. This, combined with the fact that this man received interferon and excellent supportive care, makes it impossible to say definitively that it was the serum from the Zaire survivor that was responsible for his recovery (not to mention we have no evidence that different Ebola species provide cross protection).

So those are the cases being touted as proof that convalescent serum from Ebola patients is exactly what these suffering people need and yet, they don't really tell us that. But there is a lot more evidence that this strategy won't work including:

  • During Kikwit outbreak, convalescent serum from Ebola survivors was given to cyncynomolgus macaques and it failed to protect any of the monkeys from challenge with EBOV. (unpublished data C.J.Peters., 1995)
  • During Ebola vaccine study in guinea pigs, animals that were protected from lethal challenge were bled and their serum was given to naive animals. The vaccinated guinea pig donors all survived. Their serum failed to protect other guinea pigs; all died after Ebola challenge. (8)
  • Passive immunization of cynomolgus macaques with high-titer equine immunoglobulin against Ebola Zaire failed to protect animals from lethal ZEBOV challenge (9,10)
  • Passive immunization of rhesus macaques with high-titer anti-EBOV equine immunoglobulin failed to protect any of the animals from a lethal challenge and did not even delay death (P.B.J., unpublished data.)
  • Passive transfer of a neutralizing human monoclonal antibody that completely protected guinea pigs against EBOV infection (11) failed to protect rhesus macaques against a lethal EBOV challenge (12).
  • Transfusion of convalescent blood from EBOV-immune monkeys did not protect naive animals from challenge with EBOV, even though the transfused monkeys had as much antibody as those with effective vaccination. (13). This experiment was done on the off chance that the Kikwit donors had activated lymphocytes or some other substance in their whole blood that provided protection.

So when Dr. Peters said that there wasn't much evidence to support that Ebola convalescent serum would be effective, but that there was quite a bit of evidence to support that it would not, what I've outlined above is what he meant. And Tom Geisbert's group summed it up very nicely in their 2007 paper (13):

"However, the results of the present study, which used immune primate blood, joins the preponderance of published study results suggesting that immunotherapy will not be a shortcut to the solution. Given these discouraging results and the risks of transmitting infection, whole blood transfusions, even under desperate epidemic conditions, seem unwarranted."

As desperate as we are for a way to help these patients, we simply have no solid platform from which to proclaim Ebola survivor blood as effective therapy. With a black market for blood, my fear is that already stigmatized survivors will be further targeted. We have a responsibility to make sure people are informed. 

Cheers,


Heather


C.J. Peters Take on This Post:

"I agree with Heather. During the Kikwit episode we were harangued to give plasma or have intravenous IgG prepared and I resisted because it diluted our other efforts in a time of scarce resources.  One should also consider that the oldest strain of HIV1 was isolated by Joe McCormick from Ebola convalescent plasma drawn for potential therapy before we knew anything about that virus.  There are also the usual considerations for problems with transfused plasma: antibodies against recipient blood cell antigens, aggregation of IgG activating complement, bacterial contamination, etc.  If plasma is harvested and returned to the developed world for testing and processing into pooled IgG there is the delay and also the problem of recipients reacting to aggregates in the plasma. 
            It seems much more valuable to look down another avenue for therapeutic modalities.  Pooling 3 human monoclonal antibodies to the Ebola glycoprotein with each reacting with a different epitope (14) has been tested in macaques.   When the recombinant vectors are grown in their tobacco leaf substrate and the immunoglobulins purified, this cocktail (ZMapp ) protects macaques (15) and would have a chance with infected humans.  There is also an antisense RNA and several antivirals which might be effective.  And don’t forget the use of anticoagulants such as activated protein C and nematode anticoagulant protein c2 that have had a sparing effect in non-human primates, suggesting that they or other substances working on the coagulation cascade and/or vascular  endothelium have potential (16, 17)."

Another HUGE thank you to C.J. for his incomparable insight and expertise!!


References



2.) DeliaA. Enria, Julio I. Maiztegui. Antiviral treatment of argentine hemorrhagic fever.Antiviral Research Volume 23, Issue 1, January 1994, Pages 23–31.



4.) K. Mupapa, M. Massamba, K. Kibadi, K. Kuvula, A.Bwaka, M. Kipasa, R. Colebunders and J. J. Muyembe-Tamfum on behalf of the International Scientific and Technical Committee. Treatment of Ebola Hemorrhagic Fever with Blood Transfusions from Convalescent Patients. J Infect Dis. (1999) 179 (Supplement 1): S18-S23.

5.) Ramses F. Sadek, Ali S. Khan, Gary Stevens, C. J. Peters and Thomas G. Ksiazek Ebola Hemorrhagic Fever, Democratic Republic of the Congo,1995: Determinants of Survival. J Infect Dis. (1999) 179 (Supplement 1):S24-S27.

6.) Guimard Y, Bwaka MA, Colebunders R, Calain P, MassambaM, De Roo A, Mupapa KD, Kibadi K, Kuvula KJ, Ndaberey DE, Katwiki KR, MapandaBB, Nkuku OB, Fleerackers Y, Van den Enden E, Kipasa MA. Organization ofpatient care during the Ebola hemorrhagic fever epidemic in Kikwit, DemocraticRepublic of the Congo, 1995. J Infect Dis. 1999 Feb;179 Suppl 1:S268-73.

7.) R.T Emond, B Evans, ET Bowen, and G Lloyd. Br Med J. Aug 27, 1977; 2(6086): 541-544. A case of Ebola virus infection.

8.) Xu L, Sanchez A, Yang Z, Zaki SR, Nabel EG, Nichol ST, Nabel GJ. Immunization for Ebola virus infection. Nat Med. 1998 Jan;4(1):37-42.

15.) Xiangguo Qiu, Gary Wong, Jonathan Audet, AlexanderBello, Lisa Fernando, Judie B. Alimonti, Hugues Fausther-Bovendo, Haiyan Wei, Jenna Aviles, Ernie Hiatt, AshleyJohnson, Josh Morton, Kelsi Swope, Ognian Bohorov, Natasha Bohorova, CharlesGoodman, Do Kim, Michael H. Pauly, Jesus Velasco, James Pettitt,    Gene G. Olinger, Kevin Whaley, Bianli Xu, James E. Strong, LarryZeitlin & Gary P. Kobinger. Reversionof advanced Ebola virus disease in nonhuman primates with ZMapp. Nature (2014) Publishedonline 29 August 2014.



Monday, September 8, 2014

Ebola Q & A with Dr. C.J. Peters: What My Tweeps Want to Know

Dear Friends,

The response to my Fireside Chat with Dr. C.J. Peters was even better than expected and I got a lot of great feedback from my blog readers and Twitter friends. I'd like to thank all of you for taking the time to read this blog and for engaging in such great dialogue about it. It really adds a rewarding dimension to the whole experience.

Many of you had additional questions for C.J. regarding the current Ebola epidemic. I asked him if he'd mind answering them for you here and he was happy to do so. I had to limit the questions so I selected them on a first-come, first-served basis. Several had the same or similar questions, but if I missed anything you think is critical, let me know and I will add it when I can.  Enjoy!


Our first three questions are from Dr. Ian Mackay, a virologist at the University of Queensland who is also the Keeper for both the site and blog for Virology Down Under. Dr. Mackay can be followed on Twitter: @MackayIM and I recommend it. In fact his was the first blog on my blog roll here.

Dr. Mackay: Given this outbreak is very different from previous ones - because of human factors -does what's needed to control it also have to be different?
Dr. Peters: Nobody knows. There's no indication initially that this EBOV is any more infectious than any other EBOV that we've dealt with, but it's something that should be studied using the control methods that worked with the previous outbreaks. There's no indication they wouldn't work but you gotta look.



Dr. Mackay: Following up on that question, what are the top 3 things that could be done, or done better, to contain this outbreak?
Dr. Peters: 1) More training paramedical people. 2) Provide more PPE 3) Rethink the approach. Should we be concentrating on infected areas or areas adjacent to those infected areas? We could superimpose a map of infected areas over a satellite map of the region and ring the infected areas. The adjacent areas could then be given PPE and training, not to contain it but to get on top of it. And quarantine strategy needs to change. People need to be fed and provided for. There's no panacea, they need more PPE and more equipment and currently the major worry is dealing with problems already there. An adequate response will require the whole world to step in, including the U.S. military who are more than capable of setting up field hospitals for highly infectious diseases. Also helpful would be involving anthropologists to interact with locals and help with communications - like how do you tell people what you need them to do and get them to do it?

Dr. Mackay: Have you had a chance to look at the sequence changes from the Sierra Leone genomes? If so, do any look worrying to you for phenotypic change?
Dr. Peters: We don't have the experience we need to be able to answer this. You can't tell that from the sequence unless you have experience with the given virus and with those sequence changes. We've only recently gotten to a point with influenza where we can predict what's worrisome and that's been studied by many smart people for a long time. When discussing the importance of the human genome project, people said it would provide all the words in the dictionary of human genetics. But that dictionary is only helpful if you have the definitions to go with the words. We don't have all the definitions for EBOV sequences. We just don't have the experience it takes to tell at this point.

Our next two questions are from Stephen Goldstein, ScM. Stephen is a Science News Analyst at Public Health United and a PhD student in virology at the University of Pennsylvania. He can be followed on Twitter: @stgoldst.

Stephen: Do you have any thoughts on the case fatality rate disparities between the affected countries?
Dr. Peters: No. And that's a good question. It may be a situation in which case ascertainment is not accurate, but it may be real.

Stephen: What do you make of the studies showing high seroprevalence for EBOV with no indication of illness? Subclinical infections?
Dr. Peters: I think the IFAs are totally unreliable. I've done them myself for Ebola Zaire and Reston, from monkeys and humans and they didn't tell us anything. They are just unreliable. I don't think it means that there were a bunch of subclinical infections, I think it means the test was unreliable.

(ME: C.J. and I discussed these papers for a bit, as well as his experiences with it. I was surprised to learn that even with really good controls and technique the method really isn't reliable for drawing any kind of conclusion about Ebola in this regard. )


Our next questions come from Michael Owen, a regulatory microbiologist from Washington State. Michael is a biosafety enthusiast who has compiled a nice Ebola resources webpage and he can be followed on Twitter: @owenmp.

Michael: In the field, do Ebola HCW need to collect disinfectants used to decontaminate hospital areas and used PPE? How could you do this?
Dr. Peters: Clorox is readily available and effective so they should use it when possible. People who could get exposed should have the right PPE, but if not, then they need to use what they can. Ethleen Lloyd put together a manual in 1998 to help improvise PPE for VHF in an African setting. It's available for download on the CDC website but they haven't utilized it during this epidemic. We could also face shortages of PPE for this. There were shortages with SARS and it's a possibility.

Michael: Is there a minimum time to wait between complete EVD recovery and harvesting blood from a survivor for passive therapy?
Dr. Peters: This is not known for Ebola, but blood/serum from a survivor won't help here anyway. There's no evidence that it will help, but strong evidence that it won't help. For other viruses it can be critical, such as for the arenavirus Junin, for which it is used effectively on a regular basis. But for Ebola it's just not effective. For Junin, they wait until 3 months after illness to harvest serum for therapy, but they don't know that 3 months is required, they just know that 3 months works.

(ME: I was one of the first to suggest that passive immune therapy might help with this epidemic and I was surprised at this, but now have a better understanding. Because this is currently making headlines I will be addressing it in a post soon.)

One final question I asked, on behalf of the fear-mongering doomsayers on Twitter: :Is this Ebola epidemic a threat to humanity?
Dr. Peters.: No. It may very well decimate Africa. Africa is in real trouble, but it is not a threat to humanity and it won't cause a pandemic.

ME: There. You heard that from the Quintessential Virus Hunter himself. And please don't mistake this for denial that this Ebola epidemic is a global problem...it's definitely a global problem. We've already clearly stated that this is a problem that absolutely requires a global response effort. But that's not the same as claiming it will cause a pandemic or destroy humanity. We good? Good.

A HUGE thank you to my Tweeps who came up with some great questions and an even bigger thank you to C.J., for being so willing to clarify these issues and help us understand this epidemic.

Cheers,

Heather


References

K. Mupapa, M. Massamba, K. Kibadi, K. Kuvula, A.Bwaka, M. Kipasa, R. Colebunders and J. J. Muyembe-Tamfum on behalf of theInternational Scientific and Technical Committee. Treatment of Ebola Hemorrhagic Fever with Blood Transfusions from Convalescent Patients. J InfectDis. (1999) 179 (Supplement 1): S18-S23.

Sullivan NJ1, Sanchez A, Rollin PE, Yang ZY, Nabel GJ.Development of a preventive vaccine for Ebola virus infection in primates. Nature.2000 Nov 30;408(6812):605-9.