Monday, July 5, 2010

Prednisone and inflammation and ... vaccines???

Well, my efforts to research whether prednisone really caused some remarkable improvement in my son and if so why have led me down a very strange and twisty path. I can't even remember how I got here, exactly. But I somehow found myself reading a very short article rather forcefully urging that vaccines do not cause autism by authors Jeffrey Gerber and Paul Offit. I guess everyone knows who Dr. Offit is by now, but if you don't, Wikipedia has a bio for him. The short version is he's a prominent pediatrician and vaccine expert at the Children's Hospital of Philadelphia, he's done work for the CDC, and he's quoted OFTEN about the whole vaccine issue. He definitely does NOT think there's any link between vaccines and autism.

Anyhow, this article, Vaccines and Autism: A Tale of Shifting Hypotheses, was fairly unremarkable to me, until I got to this:

Autism is not an immune-mediated disease. Unlike autoimmune
diseases such as multiple sclerosis, there is no
evidence of immune activation or inflammatory lesions
in the CNS of people with autism [38]. In fact, current
data suggest that genetic variation in neuronal circuitry
that affects synaptic development might in part account
for autistic behavior [39]. Thus, speculation that an exaggerated
or inappropriate immune response to vaccination
precipitates autism is at variance with current scientific
data that address the pathogenesis of autism.


This is the part where I started tearing my hair out, because I just got done learning all about how autism is an immune mediated disease with an autoimmune component. Or at least I thought I had.

Frustrated by electronic searching, I had finally checked out what seemed like some "real" medical texts from the Emory University Health Sciences Library. One of them is called Autism: Current Theories and Evidence, and it was published in 2008. It's edited by Dr. Andrew Zimmerman, who as far as I can tell is an extremely well-published, -credentialed, and -respected neurologist at Johns Hopkins and the Kennedy Krieger Institute. This text is part of a series called "Current Clinical Neurology," edited by another impressive sounding individual at the Harvard Medical School. Not exactly sketchy people.

Part IV is called Immunology, Maternal-Fetal Interaction, and Neuroinflammation. There are four different pieces in here on the immune system in autism and neuroinflammation! And on page 329, Dr. Pardo-Villamizar, a colleague of Dr. Zimmerman at Johns Hopkins, writes:

"Several studies showing peripheral immune abnormalities support immune hypotheses; however, until recently there has been no demonstration of immune abnormalities within the [central nervous system]. Recently, our laboratory demonstrated the presence of neuroglial and innate neuroimmune system activation in brain tissue and cerebrospinal fluid of patients with autism ...."


Wow, could there be a more direct conflict here? So I check the dates. The vaccine article by Drs. Gerber and Offit was received by the journal on August 25, 2008. But the research of Dr. Pardo (and Dr. Zimmerman) was published well before then. I found it in a 2005 article called "immunity, neuroglia and neuroinflammation in autism."

So I continue trying to puzzle this out: who's right, who's wrong, can these 2 things be reconciled? I pull footnote 38 from Dr. Offitt's article, the one that supports his statement that "there is no evidence of immune activation or inflammatory lesions in the CNS of people with autism." And discover that Dr. Offitt's support is a 2004 report from the Instute of Health called "Immunization safety review: vaccines and autism." The first thing that went through my mind: really? The most recent citation you can find on this topic is from 2004? And not even a "but see" or "compare"? There's absolutely no suggestion here that maybe somebody else thinks there IS evidence of immune activation in the CNS of people with autism. It's just shocking to me, since I'm staring at it.

I pull the 2004 report. One of the first things that I notice about it and am a little disturbed by is that apparently, this was written by a committee, and it met only once to discuss this topic. At least, it appears that way. When I turned to page v to see who was on the committee I see this: "The following individuals are members of the Immunization Safety Review Committee but were unable to attend the meeting on the topic of this report." That certainly makes it sound like there was only one meeting, doesn't it?

I also notice that they had a large number of additional people review and comment on the report before publication, and interestingly one of those people is Dr. Zimmerman. However, the report expressly states that they didn't necessarily take all the comments from everyone, so it's possible Dr. Zimmerman didn't agree with the report. I can't tell.

But the real important part is what I found when looked at the report itself. There is an entire section on immune dysregulation, beginning on page 128. I found this shocking, because this section is full of citations to study after study after study showing weird things about the immune systems of autistic children. The committee doesn't seem to actually dispute these findings. And here, I will readily admit this material was over my head. But as far as I can tell, what the committee has actually done is this:

1) they critique the various theories and hypotheses that researchers have tried to come up with to explain the obvious immune anomalies that have been observed (without suggesting any of their own); and
2) state that it is irrelevant that autistic children have these immune anomalies, partly because they can't figure out how it could be relevant, and partly because (supposedly) autistic children don't seem to be more prone to allergies.

They start with the sentence: "A large number of studies have suggested that immune dysregulation occurs in autism." The first few weird findings they cite in this report:

* Decreased lymphocyte responsiveness in the lymphocyte blastogenesis assay to PHA, ConA, and Pokeweed mitogen
* significantly reduced natural killer (NK) cell activity (Warren et al., 1987);
* decreased proportion of IFN-gamma- and IL-2 (Th1 cytokine)-staining CD4+ T cells in the serum;
* significant increase in IL-4-(Th2 cytokine)-staining CD4+ T cells

I don't claim to know what all this stuff is, except that it all relates to the immune system. Interestingly, the IFN-gamma jumped out at me, because the medical textbook I picked up on asthma says that asthmatic children had reduced IFN-gamma, but that's not relevant here.

Anyway, there's more, some of which does seem to contradict the above:

*increased levels of plasma IFN-gamma and IL-2 (Th1 cytokines)
* Increased production of serum IL-12, IL-6, tumor necrosis factor-alpha and IFN-gamma, and increased urinary neopterin
* PBMCs (peripheral blood mononuclear cells) from patients with autism, both at baseline and after stimulation with LPS (lipopolysaccharide) and PHA (phytohemagluttinin), secreted significantly more pro-inflammatory cytokines (TNF-alpha, IL-1beta, and IL-6) than those from healthy controls and normal siblings

Basically, they go on to review this bewildering array of findings after which I get the distinct impression that:

1) something is really weird about the immune system in autistic people; and
2) no one really knows why or what it means.

In other words, there is a problem and we are deeply ignorant about it. Their conclusion about these things is: "In summary, although several studies have reported abnormalities of components of the immune systems, they have often had contradictory results, making it difficult to achieve a consensus on any specific immune abnormality that might characterize autism. More fundamentally, it is not clear how these abnormalities might explain the CNS defects in autism or whether they could be secondary to GI or other complications of developmental disability."

But wait, there's more, because then I read:

"A large number of serum autoantibodies have been detected at a higher frequency in children with autism compared to controls. The antigens against which these autoantibodies are directed include a number of CNS antigens, such as myelin basic protein and neuron-axon filament protein, but they also include a whole host of other proteins, such as nerve growth factor, serotonin receptor, alpha-2-adrenergic receptor, tubulin, heat shock protein 90, and chondroitin sulfate."


Now, I've read some of this stuff before, but not in a government report. I am pretty astonished. I never really imagined there was anything like this in here. Especially since Dr. Offitt's report makes it sound as though there is no evidence of anything wrong with autistic individuals' immune systems, although perhaps I misread what he said. But wait,there is just so much more in here, I can't stop quoting it.

The report says: "This suggests that rather than there being a specific antibody response to [central nervous system] antigens, generalized hypergammaglobulinemia resulting from polyclonal B cell activation occurs in autism." I really don't know what they are talking about here, but doesn't it sound a lot like they are suggesting that somebody this "generalized hypergammaglobulinemia" is something to be unconcerned about? Doesn't it seem like it might be relevant to vaccinations? Ok, I'll grant you that maybe it's not. But they are just a little too dismissive for my tastes. They are dismissive of EVERYTHING, and that doesn't sound ... balanced and neutral.

Perhaps my favorite sentence is this one: "Of note in the abovementioned studies, these antibodies were all also found in the serum of healthy controls, albeit at lower levels—i.e., they were not specific to autism, making their pathogenic significance questionable." Well, I don't know about "pathogenic significance," but being just another stupid layperson, I am wondering why they seem to think that it doesn't matter that my son has antibodies at higher levels than everybody else. How can this be irrelevant?

it continued to cite all sorts of evidence of weird things involving the immune system in autistic kids, but they always managed to dismiss them in some way or another. There is an intersting reference to Wakefield, too, btw, but I am trying not to get too off-topic here, so I won't detail that, but you may want to read it for yourself.

I realize that they were focused on addressing one specific question, but in general, it felt a little rude and frankly insensitive to have them lay out all of these horrible sounding findings and then just sort of brush them aside as though they just didn't matter.

Some of their logic is hard for me to follow. Like: "As mentioned, autoantibodies to cerebral antigens, including MBP, have been found at higher titers in children with autism compared to controls. It is important to note, however, that these studies all evaluated serum and not CSF or brain tissue." Okay, so I'm not a doctor, and maybe this would make sense to me if I were, but why would there be autoantibodies to CEREBRAL antigens in your body but yet not in your brain? Am I the only one who thinks this sounds as though they are saying: "Well, sure, they have antibodies in their blood that are designed to attack brain tissue, but hey, no one has ever proven that any of these antibodies actually made it to the brain, so relax. they probably didn't."

And then I hit this: "Some investigators have tried immunotherapies, such as corticosteroids ...." THAT'S prednisone!! They go on to cite anecdotal evidence of both success and failure with this treatment. It is ironic that is what I am REALLY trying to research, but now I don't have time to read the references cited yet. It will have to wait to tomorrow.

I must say I am deeply troubled by this report. Whatever the Truth is about vaccines, there is clearly something up with the immune systems of autistic children, and it has been known for some time. I sort of knew this already, but it was only in a dim and hazy way. Not like this.

This report does not deny that something is up with the immune systems of autistic children. It concludes this section with the anticlimactic:

"By analogy to Rett’s syndrome, similar epigenetic mechanisms may be operating in autism that simultaneously lead to abnormal development in the immune and central nervous systems (Zimmerman, 2000). However, the deviations from expected levels in various in vitro laboratory assays in both these conditions may represent only a secondary effect of the developmental or behavioral abnormalities."

[Note the reference to Zimmerman? I assume that's the same Dr. Zimmerman who edited the book I've checked out, the one full of articles about neuroinflammation and immune dysfunction (among other things).]

So I am left with 2 questions:

1) Why does Dr. Offitt say "Autism is not an immune-mediated disease. Unlike autoimmune diseases such as multiple sclerosis, there is no evidence of immune activation ... in the CNS of people with autism," and why does he think that this report substantiates such a bold assertion? I grant you that the immune problems may go hand in hand with autism without "mediating" autism, but I do not get the impression that anyone understands enough to know for sure whether this is true or not.

2) Why didn't one of my son's doctors tell me ANY of this stuff??

OK, obviously I have more than 2 questions, and those are actually the least important ones. what I really want to know is:

1) what is wrong with my son's immune system?

2) how do I fix it?

10 comments:

  1. Hi Nyx -

    I was looking for something regarding prednisone after your post (I was positive I had seen a steroid study, but couldn't find it), and ran into this posting. Small world.

    Regarding Dr. Offit, the spin in his piece is actually a good bit worse than you think.

    What Mr. Offit isn't telling you in his paper is that the IOM report acknowledged that the existing research was underpowered.

    Neuropathological studies of autism have revealed no evidence of cerebral inflammatory lesions or microglial activation, which is a common feature in immune-mediated encephalitis (Bauman and Kemper, 1997). However, there are very few autopsy studies of brains from people with autism and this has not been fully investigated. Analysis of CSF from young children with autism, including screening for sensitive inflammatory markers such as quinolinic acid and neopterin, has also found no evidence of inflammation (Comi et al., 1999). The sample size in these studies is small, however.

    http://www.nap.edu/openbook.php?isbn=030909237X&page=131

    This isn't the type of nuance you see in Mr. Offit's paper, for some reason.

    Not only did the Vargas paper in 2005 provide evidence of exactly what Mr. Offit claims did not exist, but several other papers had also been published before his that had similar findings.

    For example, you might check out:

    Elevation of tumor necrosis factor-alpha in cerebrospinal fluid of autistic children

    and

    Immune transcriptome alterations in the temporal cortex of subjects with autism

    Both of which were published before Mr. Offit's shifting hypothesis paper, and both of which provided additional evidence of an ongoing immune reaction in the brain and CNS of people with autism. Mr. Offit is, apparently, someone who either doesn't know how to perform research, or for reasons of his own, has decided to be very selective in what research he does reference. You'll have to figure out for yourself what that means for his credibility, but it does make me sigh that he is the goto guy when the media needs a mouthpiece to deny any relationship between vaccines and autism.

    Have you considered taking your son to a DAN doctor? They have problems of their own, and finding a good one can be difficult, but one might be able to help your son.

    - pD

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  2. Wow thanks so much for the quick reply! I have considered a DAN! doctor, but I have shied away from it because to be honest it seems that so many of them may be quacks, and I have always trusted conventional medicine -- at any rate, I have been very scared of chelation and other treatments that struck me as odd and I just wasn't convinced they would make any real difference. I have agonized over it though. I bought Dr. Sears' recent "Autism Book" and read most of it, but there are several things about it that trouble me, so that I am left unconvinced that many of these DAN! doctors really undertand what they are doing. I don't know, honestly. I'm so tired. I should also mention that we are uninsured at this point and quite low on funds, so this leaves me feeling like I have to be extremely picky about how I spend the little we have -- we can't really afford to spend money on something unlikely to work.

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  3. I meant to say that I really appreciated finding your site. It seems like so many sites out there that actually discuss the science seem overly politicized so that I have been frustrated by an inability to find anyone who sounds smart and knowledgable but also not unduly influenced by some sort of emotional baggage or one sort or another. It's kind of a nightmare if you are just trying to get good, unbiased information!

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  4. FYI, In Vaccines and Autism: Tale of Shifting Hypotheses (Offit), the reference to the 9-year old girl whose symptoms worsened is Hannah Poling. She brought the inflammation theory into vogue.

    I don't see a conflict here. You linked to an abstract that doesn't even proffer a hypothesis - it merely indicates that more research could be warranted. Which I don't think is controversial. I would caution against extrapolating from one sentence from an abstract, the implications of which are uncertain even to the author.

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  5. This is a test to see if this comment shows up. My bloggy friend Laura apparently commented but it didn't show up, and I can't figure out why!

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  6. 1. I read Dr. Offit's book "Vaccinated: One Man's Quest to Defeat the World's Deadliest Diseases" where he describes the work of the inventors of various vaccines, most notably Maurice Hilleman. While Hilleman was very successful at making vaccines, it was evident that much of his success was do to trial and error, and that people did not understand how the vaccines actually work. Before Hilleman died, he suggested that AIDS take a look at successful vaccines and figure out how they operate. Apparently, scientists are not doing this.

    2. "partly because (supposedly) autistic children don't seem to be more prone to allergies." If I had to guess, I'd say that autistic or Asperger people, or people with low social skills in general, are more prone to allergies, especially food allergies.

    3. You state that autistic children have:

    "* decreased proportion of IFN-gamma- and IL-2 (Th1 cytokine)-staining CD4+ T cells in the serum;" and
    "*increased levels of plasma IFN-gamma and IL-2 Th1 cytokines" (as compared with neurotypical controls)

    This is not necessarily contradictory. The decrease in IFN-gamma is found on cells. The increase is found in plasma. What is plasma? When doctors extract blood for a blood test, they will often place it in a centrifuge for a spin. The heavier stuff that falls to the bottom are the cells, and the liquid that stays on top is known as plasma (or sometimes serum, which means *almost* the same thing).

    So what could be happening here is that important immune molecules like IFN-gamma are falling off the cells they should be attached to, and the detached molecules are found in the plasma.

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  7. asd kids born as TH2 cytokine predominence. Vaccines cause prolonged increase in the TH2 cytokines . TH1 cytokines needed for proper neuronal/synaptic pruning without which we are much more likely to be asd. Prednisone increases TH1 cytokines.
    many things increase th2 cytokines -big one is bisphenols....vaccines normally not a prob in non-asd prone kids who dont have prolonged exposure to bisphenols. Bisphenols and simlar chemicals are everywhere. kids who have asd moprhologicial features should be given a much LESS agressive vaccine schedule. I dont know how one can escape the TH1, TH2 in ASD , Vaccine, bisphenol connection . there are other reasons for asd. but the formentioned issues sit in the field like a stone.

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  8. so in short , be my guess ,in all likelihood the prednisone caused a remarkable improvement in your kids asd. If one gains enough knowledge on the topic and learns the signal transduction pathways involved, the plausible mechanisms are there and they are understandable. the variablity lies in that there is defined window of opportunity where reestablishment of proper neuronal pruning is possible . as that window closes the benefit decreases. I hope this helps .

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  9. I found your article very interesting as I have an adopted 29 year old daughter with Autism. I have spent many painful days searching for answers. It is notable that when she was small her immune system was quite poor but I found that giving her Cod Liver oil supplements for a few winters got really good results. Now she hardly ever gets a cold or flu and has had very few illnesses. She has no allergies.

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  10. Interesting. My son seems to be headed towards autism. No diagnosis yet but I am a physician (internist not pediatrician) and it is starting to become obvious. I could probably help decipher some of the code here for you guys but I'll need a little time (6 kids total my autism son is youngest and is 26 months)

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