Chronic Inflammatory Response Syndrome (CIRS): A New Molecular Paradigm For Understanding And Treating Patients With Chronic Fatigue And Biotoxin Exposures.​

Andrew Heyman, M.D.

Thanks for having me, great to be here, thanks.

Joseph M. Raffaele, M.D.

So chronic inflammatory response syndrome is like I said, something that is not something I know a whole lot about, but I think there’s overlap between our areas of interest as we were talking about earlier. Would you tell me a little bit, tell our audience a little bit about what that is and then we’ll get rolling.

Andrew Heyman, M.D.

Sure, so first of all, thanks for having me. It’s great to be here and certainly to have a platform to share a topic that I think is incredibly important and one that probably almost all of us are seeing in our practices every day. We just don’t necessarily know it unless-

Joseph M. Raffaele, M.D.

Whether we know or not-

Andrew Heyman, M.D.

Right, how to evaluate for it. And I was no different, I mean, you know, I spent 16 years at University of Michigan, and had, you know, feet firmly planted in the world of both integrative as well as academic medicine. And, you know, it felt like I had this sort of privileged position in that regard, having been on faculty there for a number of years, in our Department of Family Medicine, and feeling like I’d sort of been there, done that, and seen everything. And then had an opportunity to move out to the East Coast and join a small little private practice in the Virginia countryside, and was immediately overwhelmed by a type of patient profile that was incredibly sick, had lots of symptoms, no one really knew what was going on with them. And I was perplexed, I admit, you know, I felt like my toolkit was already pretty big and could do the full functional medicine workup, and the conventional medicine workup, and all that sort of stuff. And nothing ever really seemed to click, and no treatments ever really seemed to work, at least not very well. 

And being in Virginia, you think, well, maybe they all have Lyme Disease. You know, I think that’s sort of where your head goes when you can’t figure it out. A lot of us kind of go there at some point. And then of course we get scared, because we think I don’t want to deal with Lyme patients, like who wants to deal with Lyme patients? 

But, you know, I thought, hey, it’s Virginia. So maybe that’s what I’m looking at. And for awhile, I honestly, I tried to avoid it. I said, I don’t want to tackle this subject, I don’t feel prepared. But at some point, George Mason University had approached me and they asked me to help them develop a better Lyme test, it was based on new nanotechnology. And that, to me, not only opened a doorway into the world, from a more academic perspective, that felt familiar, but also now I had a better test,. And I could figure out that some of these people actually did Lyme disease, but in fact, a majority of them didn’t. And you think well, wait a minute, phenotypically, they all have the same symptoms. But why is it-

Joseph M. Raffaele, M.D.

Could you just for a second, talk about what that constellation of symptoms is so we can sort of keep our eyes out for it.

Andrew Heyman, M.D.

Yeah, so, you know, by definition, the defining feature’s fatigue. So about 80 to 90% of these patients will talk about not having enough energy to get done what they want to do during the day. Beyond that, we’ve identified and actually codified, into a validated symptom scale, 37 symptoms, that group into 13 clusters. And by criteria, if a patient has one symptom in eight of 13 clusters, there’s a high likelihood they have CIRS. So I won’t go over all the symptoms, but generally beyond fatigue, it’s mood disorders like depression or anxiety, that’s very common in this patient population, sort of dysregulated emotions, lack of stress resiliency. 

But we also see cognitive issues, so word finding difficulties, word recall problems, memory loss, focusing, concentration issues. Patients will often talk about, I can’t do my job anymore, I just can’t function intellectually. Beyond that, they’ll often talk about pain syndromes, headaches, joint pain, soft tissue pain, neuropathies. Beyond that, we’ll often see the nervous system involved. So paresthesias, electric like shocks, funny sensations, dysesthesia, but also dysautonomias. So it’s very common for patients to have gastroparesis, gallbladder dyskinesia, motility disorders, POTS Syndrome is very common as a feature of this illness. 

So it’s, you know, these are nerves that are on fire. So basically in the central nervous system, the autonomic nervous system, the peripheral nervous system, but also the GI tract. So we’ll see SIBO and GERD and bloating and constipation, and you know, all of the attendant symptoms related to that. There’s also a profound impact on the cardiopulmonary circuit. So patients will often describe air hunger, shortness of breath, loss of exercise tolerance. In addition to endocrinopathy, so they’ll be describing a propensity for weight gain. You know, these patients will gain 30, 40, 50, 60 pounds in several months and they won’t know why. So my criteria is if you have a patient that comes to your practice and they say, well, I have fatigue and depression and I can’t sleep at night and I have aches and pains and I’ve gained a ton of weight, and I tried diet, and I’ve tried exercise and I tried supplements and hormones and exosomes and peptides and this and that, and nothing is working, it starts to sound like CIRS. And yet, if you think about it, these are are common, right?

Joseph M. Raffaele, M.D.

Yeah, very common.

Andrew Heyman, M.D.

What family medicine practice doesn’t see this? Now, from a functional medicine perspective, these people get the label of adrenal fatigue and hormonal imbalances and neurotransmitter issues. And, oh, you must have heavy metals or leaky gut or whatever, they get all the same labels too. And they typically don’t get better through those usual strategies as well.

Joseph M. Raffaele, M.D.

So I think that there is some overlap with traditional sort of chronic fatigue syndrome, and so I would imagine there probably is.

Andrew Heyman, M.D.

Yeah, yeah, under most circumstances, this sort of chronic fatigue fibromyalgia patient is CIRS.

Joseph M. Raffaele, M.D.

Okay, oh, okay.

Andrew Heyman, M.D.

Yeah, it’s CIRS, until proven otherwise. COVID long hauler is CIRS until proven otherwise. Basically this is a group of people, they’ve had a biotoxin exposure to the virus, and a portion of them just never recover.

Joseph M. Raffaele, M.D.

So that’s the difference, in the past, we didn’t have necessarily any etiologic agent for chronic fatigue syndrome, they talked about, you know, herpes virus, herpes virus six, various other things. And now you’re saying, is that there, this is probably from, most assuredly, I guess, in your case, from exposure to a biotoxin. And I know, you like to make the distinction between a biotoxin and a toxin, we’re talking about having before, tell us about that, that makes it different.

Andrew Heyman, M.D.

So that’s you know, I think one of the core features of the illness is that by definition it’s these biologic processes, the pathophysiology is instigated by what I would term a biotoxin, meaning an organism or a fragment of an organism. So we’ve not linked it for example, to chemicals or BOCs, heavy metals, food, stress, other things that certainly make people sick. But this is a very specific and unique process, originating within the innate immune system. So it’s inflammatory in origin. Now it becomes more complicated than that, you get these sort of secondary and tertiary metabolic consequences as a result, but it begins with a dysregulated immune system that’s instigated from a biotoxin. 80% of the time, most of the time, it’s from what we would term amplified microbial growth from a water damaged building. 

So basically microbes that are present in our living space that’s instigating this inflammatory response. Now, remember I walked through the Lyme door first, Lyme can do it too, COVID can do it. The actual, the origination story of this started in the Chesapeake Bay with actually algae overgrowth, that there was an outbreak of Pfiesteria in the late 1990s, and no one knew it was making all these people sick in the Back Bay. Well, it turns out they were swimming in the water and encountering Pfiesteria, and they had all the symptoms that I mentioned, no one knew what was going on. And that set off the journey of trying to figure out, well, what is this thing that, how can these people have so many different symptoms? How can they be so sick? It took our research group quite frankly, a long time to first find the part of the immune system that was being triggered or turned on. 

It was not in the areas that we typically or classically measure. So white blood count doesn’t go up, sed rate and CRP does not go up. ANA and autoimmune processes do not, you know, are not really features of this illness. That in fact, it was a dysfunction within the innate part of the immune system, which is sort of those early responders, that should really kind of turn on and turn off. But what’s happening is in this patient population that’s vulnerable, the innate immune system turns on, and it stays on and it doesn’t transfer to the adaptive side of the immune system. 

Technically speaking, what’s happening is, it’s about 20% of the population they’re born with alleles, within the HLA and chromosome six, that if present, there’s about nine of these genes floating around in the human genome, if any one of these nine genes are present, it means that their antigen presenting cells are relatively inefficient. So the innate immune system turns on, these antigen presenting cells should find that antigen and snip an epitope and present it to a T cell. But by definition, if those genetic variants are present, the antigen presenting cells are not very good at their job. So the innate immune system turns on, but you don’t see a very efficient transition to T-cells and B-cells. So you don’t see a big antibody production. So what happens is you have this sort of perpetual cytokine storm and over time-

Joseph M. Raffaele, M.D.

So, okay, so the cytokine storm is not the usual IL6, TNF alpha, or C-reactive protein, which cytokines is it?

Andrew Heyman, M.D.

Basically neurotoxic factors that begin in the brain. So basically we’re turning on microglial cells and those microglial cells are turning on a cascade of cytokines, that in particular begin to affect, and quite frankly, injure the posterior hypothalamus. So we began to see changes in leptin receptors, and then ultimately, production of melanocyte stimulating hormone, vasoactive intestinal peptide production, and arginine vasopressin as features of production of the anterior hypothalamus. So the cytokines are in the brain itself, and that begins to create first, functional and then structural changes in the brain. And then you get these secondary and tertiary consequences throughout the physiology.

Joseph M. Raffaele, M.D.

So are these-

Andrew Heyman, M.D.

We also know-

Joseph M. Raffaele, M.D.

Are these genetic tests available to see whether or not-

Andrew Heyman, M.D.

They are, I mean, you can order them, I order them everyday through Labcorp. So they’re called HLA. And, you know, it’s the DRB1, DQB1, DRB, 3, 4, 5, and we can assemble the snips into the allele essentially. And we can tell if they’re in the 20%. And if they’re in the 20%, it means they’re predisposed.

Joseph M. Raffaele, M.D.

Are they labeled within Labcorp as being for CIRS. No, so you have to-

Andrew Heyman, M.D.

No, you need to know, you have to know which ones they are, yeah. So there’s a, what we call a Rosetta Stone, and it’s actually on a website called survivingmold.com. So there’s an exercise that you have to go through where once you get the HLA report from Labcorp, you can go to the Surviving Mold website to the Rosetta Stone, and use that to interpret and put the allele together to know if you have one of these alleles that’s predisposing.

Joseph M. Raffaele, M.D.

Oh, okay, very interesting.

Andrew Heyman, M.D.

Yeah, yeah, yeah. And interestingly, just recently, just to kind of confirm our model, there was some separate research groups, that showed that, they quote, found the HLA that predisposed to COVID long haulers. Well, it was all the same HLA that we found for CIRS in general, and it made sense.

Joseph M. Raffaele, M.D.

That must’ve been very gratifying for you to see.

Andrew Heyman, M.D.

That was very gratifying to see that, yeah, yeah, yeah.

Joseph M. Raffaele, M.D.

So there’s the pathophysiology of it, the antigen presenting cells are not working correctly. And then the glial cells start producing cytokines that then causes all these other endocrinopathies. And this is, can somebody get this that doesn’t have those genetic mutations?

Andrew Heyman, M.D.

Yes, it’s a great question. So if you have the HLA, it means a few things. Number one, a small dose or a small exposure can ignite a large fire. It also means that once that fire starts, the body has a hard time turning it off. So there’s a real vulnerability if you’re in the 20%. If you’re in the 80%, the dose response relationship is held, but you could be someone who let’s say lives in a really moldy environment, it’ll turn on CIRS, even if you don’t have the HLA. The other thing that we’ve learned, is that while the HLA helps to really get things going in that vulnerable population, those inflammatory compounds that are released, not just in the brain in terms of cytokines, but in particular, were turning on Th17 cells in the periphery, so there’s often very high TGF beta one, and diminishment of T regulatory cells, so there’s discordance there that we see. 

As a consequence of that, there’s overproduction of inflammatory compounds. We kind of know what they are, they’re small, they’re lipid soluble, there are about 1.4 angstroms in size, they’re produced throughout the tissues. Those inflammatory compounds will traverse the cell membrane, traverse the nuclear envelope, and they’ll start acting as transcription factors, and begin to alter patterns of gene expression. So they’ll literally change the instruction set of the body and how different genes are turning on and off. So we have a research lab in Massachusetts where we do what we call transcriptomic research. We’re experts in mRNA, not the vaccine, but we measure mRNA, because that’s how we know which genes are being expressed and which are not being expressed. So in 2015, we started asking the question, are gene patterns altered in this illness? And if so, in what way? it took us many years to identify the patterns that are hallmarks in CIRS, but there are patterns, and there are hallmarks. 

Most of them are actually expressed in the mitochondrial DNA. And so this is really a disorder of the mitochondria and changes that occur within the either overexpression or underexpression of mitochondrial DNA. And so we can now tell, based on doing that sort of evaluation, does this patient have CIRS based on their pattern of gene expression? In addition to that, we also found the genes that turn on for a mold exposure. UCLA and Johns Hopkins found the genes that turn on for Lyme Disease. There are other genes that turn on for chronic infections outside of Lyme. And so this started to act as a roadmap for us. One of the findings that was surprising was that over time, the genes that are really negatively influenced are not inflammatory genes, they are metabolomic genes. And what’s happening is when the cell is threatened, it will shift from oxidative phosphorylation, into aerobic glycolysis. 

There’s a downregulation of ATP production. So now you’re only producing two ATP per spin of the Krebs Cycle, so this is the hallmark of the fatigue. And the cells are becoming dependent on glucose as their substrate of choice, as opposed to oxygen. You might say, well, why are they doing this? Well, why would the cell change how it burns energy? And it’s doing this so it can upregulate its defensive posturing, that it changes other pathways that are adaptive for cellular threats, but it can only do that at the expense of turning down oxidative phosphorylation. 

So we often talk about our cells are going from energy plants to battleships. And we did not know the degree to which the metabolism is deeply effected. Now we know why people tend to gain weight and they develop insulin resistance, and interestingly, the degree of that metabolic shift, genomically, also pairs directly with the degree of injury to the brain. And this links in that notion of type three Alzheimer’s, this idea that the brain is becoming injured by glucose. Well, guess what? That’s this illness. So when the cells are becoming more glucose dependent, the brain does not like that. And it accelerates injury to the brain, that we see greater areas of nuclear atrophy the further down the pathway that person has gone in terms of the change of their gene expression, metabolically speaking. And consequences, said, differently, is not only is the person now becoming more dependent on sugar and gaining weight, it’s injuring their brain. And the mechanism of injury is metabolic as opposed to inflammatory. So this is one of our recent insights, which we think is fascinating.

Joseph M. Raffaele, M.D.

I think just talked about toxins as being increase in risk of Alzheimer’s to a certain degree, I mean-

Andrew Heyman, M.D.

Some of it was our work.

Joseph M. Raffaele, M.D.

Oh, is that right? He smartly is taking from whatever he needs to take to-

Andrew Heyman, M.D.

Yeah, well, that’s his MO in some of it. But, you know, look, he talks about measuring some of the markers that we use and uncover and the injury to the brain and all that, hey, you know what? It gets the word out. So, you know, good for him. But yes, the transcriptomics has been an enormous breakthrough for us because it allows us to do the deep dive and ask the question, how have the genes changed in terms of their pattern of expression? And the way I describe this is we’ve moved well beyond early molecular biology of genetics and asking what snips are present. 

And now I can ask the question, all right, that’s fine, but what are your genes actually doing? And said differently, it’s almost like saying, well, you know, you have this whole symphony orchestra of genes that you were given, that make up who you are, genetics is asking the question, are each of those instruments built properly? Does the slide on your trombone stick? Do you have all the keys on your clarinet in the right order? Are those strings on the cello tuned properly? That’s genetics. And the assumption is if you have an instrument that wasn’t built well, the sound that it makes is probably not what it should be. Genomics and transcriptomics is asking, okay, that’s fine, but what are whole sections of your orchestra doing? Are they playing too loudly? Are they playing too softly? Are they playing at the right time? Or is there some sort of discord? Now what’s fascinating to me is you could have a whole section, you could have a whole brass section of your instruments that they’re all built normally, but they’re not playing at the right time or at the right level. So you can get fooled by snip testing to say, this whole section of the genome is fine. Well, guess what? If it’s not doing what it’s supposed to do, functionally, you still have disease.

Joseph M. Raffaele, M.D.

Sure, yeah, so we were talking earlier about, before getting on camera about what role epigenetics might play in that. But you know, most of the epigenetics that is available now is DNA methylation. And you’re saying that it’s other transcription factors that are causing this. So you wouldn’t necessarily pick this up in an epigenetics screen

Andrew Heyman, M.D.

That’s right, because we know methylation doesn’t play a large role in influencing expression patterns in this illness. Now don’t forget, there’s really three signaling pathways. There’s acetylation, phosphorylation, and methylation, all three act as sort of those epigenetic signals. But other things also influence genetic expression. So the disease process itself, the inflammatory storm, is over time what actually changes gene expression in this patient population. And I’ll tell you how powerful the insight has been. So we’re starting to build a model, right? We’re saying, okay, people have an exposure, they get really inflamed, they get really sick, and now we’re starting to figure out genomically, you know, from what? So I can tell the genes that turn on from mold, and I can tell the genes are turned on for Lyme, and what a powerful tool. 

What’s fascinating is in our last data set of 1000 research subjects. When we looked at their gene expression patterns, only 7% of them were sick from mold. And we said, well, that’s odd, because most people in this category are actually sick from water damaged buildings. So if it’s not from mold, what’s making these people sick? So we started looking at other genes and sure enough, there was this pattern of expression that kept coming up over and over and over. And we said, okay, these are people reacting to their environment, but it’s not to mold, similar, but not the same. So what is it? It turns out that as we went to some research out of Denmark and Finland and Austria, there are research groups that demonstrated, when you have microbial growth in a living space, much of that microbial growth is actually not mold, it’s a bacteria.

Joseph M. Raffaele, M.D.

It’s actually bacteria, what kind?

Andrew Heyman, M.D.

So it’s a gram negative staph. And the most common is called actinomycetes, it’s a mouthful, actinomycetes, there’s 6,000 species. Some are soil based, but the ones that we have found, and this is really the, I mean, just talk about “Alice in Wonderland,” going down the rabbit hole. So first off we found that 42% of that research population were sick from actinomycetes, compared to the 7%. It’s not even close-

Joseph M. Raffaele, M.D.

Right, no.

Andrew Heyman, M.D.

Most people who are sick from their living space, they’re not sick from mold.

Joseph M. Raffaele, M.D.

So it’s not mold.

Andrew Heyman, M.D.

It’s not mold, it’s actinomycetes, it’s a bacteria. And this further sort of debunks, a lot of practitioners are doing urine testing for mold. And that test has actually never been validated. It’s not been shown to correlate with environmental exposure to mold. It only actually correlates to food that people have eaten with a little bit of mold. We know that based on 150 studies, it’s not a great way of assessing. Now we know for certain, because the real culprit, the real criminal, it’s not mold, it’s actinomycetes. What’s even more fascinating is there are different forms or types of actinos. Some are soil based, but the one that we figured out, that makes people really sick, colonizes the skin.

Joseph M. Raffaele, M.D.

Oh, so you can get this just from touching, not…

Andrew Heyman, M.D.

You can get it by touching and you take your critters with you.

Joseph M. Raffaele, M.D.

Ah-ha, oh right, it’s contagious.

Andrew Heyman, M.D.

And so we’re finding that in fact, if you have the skin based form, you’re likely seeding and being reseeded by your living space. So the bed, the bedding, the bathroom, the closet, the bedroom, the places where you spend most of your time in your home, that’s where actinos will concentrate. And so now the remediation strategies that we’re developing are really focused on two things, good hygiene of the home, but also good personal hygiene. You got to really scrub the skin to get better, if you have the skin form of actinos, you’ve got to be clean, and your living space has to be clean. And there are very specific ways of doing that. 

We are finally cracking the code, we finally are solving the Rubik’s cube of what really drives this illness in most people, it wasn’t Lyme, it wasn’t mold, it’s emerging to be this bacteria that’s ubiquitous, and is very good at living on all sorts of surfaces. Interestingly, too, you know, when you talk about it inhabiting a living space, it doesn’t need a lot of water to grow, it doesn’t need some sort of water intrusion or high humidity or a broken pipe, or something that we think about with mold. Actually the early research shows it will happily grow in a home with just dust and certain building material. And therefore, even a new build, that was built properly and dry, you can still have actinos present.

Joseph M. Raffaele, M.D.

And I was happy that I live in a new building, but I guess, there goes that.

Andrew Heyman, M.D.

You never know, no, you’re probably in the 80%, right, you’re probably in the 80%, but there’s a bunch of miserable, 20 percenters out there. And now with the power of transcriptomics and looking at patterns of gene expression, we can identify that patient population. So, you know, kind of tying that into at least aging more broadly, if not telomeres, we now know this illness reaches into insulin resistance and diabetes because of those metabolomic changes in those mitochondrial genes. 

We also have shown that there are a set, there’s nine of them, there’s a set of coagulation genes that can also turn on in this illness as a consequence of the exposure. And we’ve shown that a three or more of these coagulation genes activate, there’s an accelerated risk for vascular dementia, that micro-clots start to form in the small capillaries feeding the brain. So now we have a model that links exposure to vascular dementia, exposure to diabetes, and insulin resistance and weight gain. Interestingly, we also found in 40% of our population for those sort of mast cell activation junkies, there are two histamine genes that can also turn on in this illness. It means every nucleated cell in the body will be over-producing histamine, not just mast cell. 

So God love Dr. Afrin about sort of raising awareness on histamine. And I do think there’s a a small patient population that truly have mast cell issues. But I think a much, much greater portion of those people who were suffering from histamine, it’s because they’ve had an exposure that actually turned on their histamine genes. So we’ve even linked it to that too. 

There’s all sorts of tendrils that this illness has. And it’s like that all the allegory of it took three blind men touching the elephant, and you think it’s one thing or another, well, it can be any one of these things or a mixture of chronic illnesses and deep symptom findings. And, you know, and these patients are very resistant to standard therapy. They will not get better with just standard nutrition and hormones, and even the fancy stuff, even the stem cells, and exosomes and peptides and all the regenerative therapies, until you figure out what that exposure is and deal with it, these patients won’t get better. They’re going to remain sick, they’re going to remain sick.

Joseph M. Raffaele, M.D.

So you go about doing that with, we have diagnosis, you have a whole checklist of things, a criteria that you meet, and then is this transcriptomic analysis available? Or is that just research.

Andrew Heyman, M.D.

Yeah, it is. No, no, no, not at all. So there’s no real barrier in terms of getting the test. So it’s actually listed on a website, it’s called ProgeneDX, ProgeneDX. So you can go and you can order the GENIE test kit. Now it says on the top, a healthcare provider must order this, that’s not true, anyone could go on and get the test. The challenge is once the test kit shows up at your house, like it does with all of my patients, now, what, because it’s a blood draw. In addition to that, because it’s transcriptomics, and it’s a bit fancy, the sample needs to be frozen overnight, and shipped on dry ice the next day. So there’s a little bit of a rigmarole.

Joseph M. Raffaele, M.D.

A doctor, you should have it done through a doctor’s office.

Andrew Heyman, M.D.

Yeah, you should, yeah. Well and also the results, the report is, you know, sort of nearly inscrutable unless you understand how to read it., and it’s not a user-friendly report, I will have to say. With that being said, it’s an incredibly powerful one because of the depth of insight that it can give the practitioner, it’s an amazing tool, it’s an amazing tool in that regard.

Joseph M. Raffaele, M.D.

And that’s, the name again is the lab is.

Andrew Heyman, M.D.

ProgeneDX, ProgeneDX.

Joseph M. Raffaele, M.D.

That’s the website, ProgeneDX.

Andrew Heyman, M.D.

Yeah, .com. And it’s the GENIE test.

Joseph M. Raffaele, M.D.

It’s funny that the telomere testing company is, it’s RepeatDx. So then okay, you have the diagnosis and then you have protocols for attacking this situation, obviously, removal of the actinomycetes is important.

Andrew Heyman, M.D.

Or treating the Lyme or stop swimming in the algae or get over the COVID or whatever it is,

Joseph M. Raffaele, M.D.

But is it a situation where once this sort of set of inflammatory genes have been turned on, even if you remove the offending agent or inciting agents, that it’s hard to turn it off, or is there some therapies for turning it off, or does just removal of the exposure help to remediate the symptoms?

Andrew Heyman, M.D.

It’s a great question, you’re smarter than the average bear as they say. So the answer is we have figured out how to turn the genes off, or let’s say restore normal gene behavior. We have one quiver or one arrow in that quiver, which is one treatment, which we know works. There are probably others out there that do it. But there’s also a sequence of therapies that we have to go through in a certain order to get to that last step, where the magic happens and we turn the genes back to normal. And, and sort of said differently, and this is fascinating, when you look at our transcriptomic reports, we can now tell based on the patterns, if someone has a new diagnosis and really hasn’t received any effective therapy, we call that stage one. It’s a pretty classic set of findings. Stage two, certain genes start to turn off because of the initiation of proper treatment. And that means typically a binder of some sort, usually it’s a bile acid sequestrant. We also know, for example, that okra and beets can act as a proper binder. 

We’re firm believers that charcoal and clay and chlorella do not work as a binder, even though lots of, you know, I get, lots of practitioners try that, but in our dataset you either need to use Cholestyramine, Welchol, okra, beets, sort of somewhere in that mixture. Those really work to get people moving in terms of draining the body of inflammation. After that, we start dealing with sort of the metabolic disturbances, whether that’s decreasing inflammation in the gut, or balancing their hormones or so on and so forth, there’s a whole protocol we go through. 

So we deal with the exposure, we drain the body of inflammation, we correct those metabolic disturbances, but that gets us to stage three, that even after we do what I would think of as many functional interventions, there’s still this irreducible nugget of genes that will remain abnormal. And it’s the reason why you can give these patients all sorts of fancy therapies, but those genes just won’t go back to normal. And the risk is still present for dementia, for diabetes, that some of those really important genes that we want to turn off, they’re still on. So stage-

Joseph M. Raffaele, M.D.

You see that in the transcript, if you did the transcriptomics.

Andrew Heyman, M.D.

We can see it in our datasets, and it’s very predictable, it’s amazing that we can tell what are the genes that typically turn off, in what order, that the body has some sort of internal intelligence in that regard, that some genes are great at turning off because of our nutritional interventions and, you know, support of metabolism and so on and so forth. And that gets us to stage three. And stage three indicates the person is ready for the magic sauce, essentially, that we’ve turned off all the genes we’re going to turn off through lack of a better term, of functional approach, but there’s still that irreducible nugget. And so we give a special neuropeptide called vasoactive intestinal peptide, or VIP for short. And VIP acts as a transcription factor. And it will turn off those residual genes and restore normal health and basically induce cure. 

We do not have a substitute for that treatment. It’s the only one that we have found, that once you get to stage three, will push people over the finish line and get to stage four, which is cure. So we can tell as the person is healing, you know, as we do their genomics, where they are? What stage are they in? Are they still being exposed? You know, so sometimes for example, like earlier today, I was treating a patient and I thought she was further along than she was because we thought she had fully remediated her home. But, you know, but there were still some symptoms that were residual, and we were wondering, are you ready for VIP? Well, we did a genomic test, we did GENIE, and sure enough, it showed she was still being exposed, that that roadblock was still present. So we had to go back, redeal with the house, do further remediation, and then she’ll probably be ready for VIP. If you give VIP too early in the process, it won’t work, nothing bad will happen, there’s no sort of side effects or adverse events. You won’t see the magic, you won’t get people to cure.

Joseph M. Raffaele, M.D.

And how, I mean, I’m just curious about how does VIP work in this circumstance? My memory about what in fact VIP actually does is a little bit fuzzy.

Andrew Heyman, M.D.

So what’s interesting is yeah, well, you know, first of all, it was actually brought to market decades ago as a drug, as an antihypertensive, and especially for pulmonary hypertension-

Joseph M. Raffaele, M.D.

Right, I remember that.

Andrew Heyman, M.D.

It turns out, yeah, right, I mean, this has been around for a long time, but it fell out of favor because it was expensive and you had to inject it. But there’s lots of human studies on VIP. So it’s endogenous, right, our bodies make VIP, and we have two different VIP receptors. They’re scattered throughout the tissues. You can even look up the VIP receptor maps, and they concentrate in the blood vessels, and in certain organs and tissues. And so you can begin to guess, sort of what, you know, effects that VIP might have in the body. One of the most immediate of course, is dilating blood vessels, which I’ll tell you, is incredibly important in this illness, because one of the consequences of CIRS, is actually constriction of the capillaries. So that’s what really contributes to the low VO2 max and loss of exercise tolerance and the cardiopulmonary impairment. So if we do CPET testing in these patients, we’ll see, their V02 Max tends to be 20, 21, 22, they’re like heart failure patients.

Joseph M. Raffaele, M.D.

Do they they’ve have endothelial dysfunction as well?

Andrew Heyman, M.D.

They do, oh yeah, they’ve got endothelial dysfunction, they’ve got ballooning of the right side of the heart, they got stretching of the sinoatrial node, they got the real deal, they typically have a mild pulmonary hypertension, endothelial dysfunction, on top of the micro-clotting. So we can see stroke and heart disease and the rest in this patient population. So when we give VIP, it works quickly, and boom, those blood vessels will dilate, and the person for the first time in years, will go, I can breathe again. 

I can’t believe I just took a breath and I feel like I’m finally oxygenating my tissues. And of course, it’s opening the capillaries to the brain. So the brain is finally getting oxygenated too. That happens right away, VIP has some anti-inflammatory qualities as well, which of course is good in this illness too, but the magic, how is it getting those genes back to normal? We have no idea. It’s working as a transcription factor, it’s clearly restoring those genes back to normal, we have tons of data to show that, but quite frankly, how does it know to do that at the level of the mitochondria So predictably and reliably, no one knows.

Joseph M. Raffaele, M.D.

And it’s a daily subcutaneous injection, or how long would you have to do it?

Andrew Heyman, M.D.

Actually, it’s a nasal spray.

Joseph M. Raffaele, M.D.

Oh, it’s a nasal spray, that’s right, it’s a nasal spray.

Andrew Heyman, M.D.

It’s a nasal spray, it’s a nasal spray.

Joseph M. Raffaele, M.D.

But initially it was an injection-

Andrew Heyman, M.D.

Well, that’s right, initially for blood pressure issues, it was an injection. Now we have it made, there’s only two pharmacies in the country that know how to make VIP properly as a nasal spray. And it takes time, you know, basically, there’s a buildup phase, but on average it takes our patients about six months.

Joseph M. Raffaele, M.D.

Oh really?

Andrew Heyman, M.D.

At the main dose, yup, at the main dose, to induce cure. Now that’s average, so we have some patients that take a lot longer than that, and others are overachievers, and they get there in three, four months, and they go, I can’t believe it, I feel like my old self. I haven’t felt this good in 20 years kind of thing. That’s an amazing thing. Especially in this patient population that is so unbelievably miserable and so sick in so many ways. And they’re so grateful and thankful when they finally feel like their health is fully restored. It’s an amazing thing to bear witness to, and even though this is incredibly complicated and yes, these patients are very trying. The other side of it is really gratifying.

Joseph M. Raffaele, M.D.

No, I can imagine that, yeah absolutely. So getting back to what I’m curious about in terms of figuring out when somebody’s sitting across from you with that constellation of symptoms, is this typically a fairly abrupt onset? Because if you look back, they might’ve been dealing with for years, but is it an abrupt onset where there’s that first exposure and then you see this happen? Unlike, you know, something else that’s a more sort of gradual degenerative thing. Do you usually pick that up?

Andrew Heyman, M.D.

Yeah, you know, sometimes in the moment when the person let’s say moves into the apartment or the dorm room or whatever, and they start to feel tired and depressed and gaining weight, you know, it’s often easy to sort of ascribe it to the person’s circumstances. They go, oh, well, I’m in residency or I’m stressed from school, or I just got married, you know, whatever, you know, my job is difficult or that’s just life, sort of thing. But most people looking back, when they finally connect all the dots, they can pretty much determine when this thing started. You know, it might not be abrupt per se, really obvious, but there is a starting point where people say my health changed, my health definitely changed when I was living, you know, wherever, X, you know. And sometimes it is dramatic, sometimes it’s, you know, they went on vacation to the Caribbean, they ate a fish with Ciguatera, they had a biological exposure, and they came back and the wheels fell off. 

You know, it was clear, there was sort of this before and after. But there is a start point, most patients can identify, either when it’s happening or soon after, they look back and say, you know, six months ago something happened to me. I don’t know what it was, but I’m not myself. And you can reassure them saying, look, first of all, it took us 20 years to figure a lot of this out. There’s a reason why your typical labs are normal. There’s a reason why no one can sort of really figure out what’s going on with you. But guess what? Your body has changed all the way down to your instruction set, all the way down to your DNA, no wonder you don’t feel like yourself, no wonder you feel so sick, you have every right to feel the way you do. This is not in your head, it’s not psychiatric, we’ve got to go deeper than that. And there’s a consequence, this’ll damage your brain, if left unchecked, this is a serious illness. We’re not messing around with just sort of this functional stuff of, oh, you have some magnesium deficiency. No, this leads to dementia. So we take this seriously.

Joseph M. Raffaele, M.D.

So what, in terms of, I don’t know if you have these figures, but epidemiologically, what’s the prevalence of this disorder you think? I mean, I’m sure there’s some that’s been undiagnosed, but is it well-

Andrew Heyman, M.D.

Well, if you imagine 20% of the US population is vulnerable because they carry those genes, 50% of US buildings have water damage. So those numbers, right? So we’re talking 40 million people who are at risk just from that. Now, is it all of them? No, of course not. I mean, I have plenty of patients who they didn’t get sick from mold until they were 50 and you know, they have the gene, and of course they encountered mold, but the YH50, we don’t know, we don’t know why the gene might fully express itself later in life. There’s probably some loss of resiliency, maybe it’s telomere shortening, maybe there’s just kind of this accumulated effect of loss of metabolic resiliency and sort of biological aging that contributes to that final expression of the illness. It doesn’t happen right away with a lot of people. It happens later in life.

Joseph M. Raffaele, M.D.

Those genes, is there a reference paper for those particular genes, so we can sort of look them up and see what they are?

Andrew Heyman, M.D.

Sure, so I mean, I would say, even though it’s a compendium, it’s probably the best single source of all of this information is our textbook, it’s called “The Art and Science of CIRS.” And it has everything that I’m talking about. It has chapters on diagnosis, it has chapters on what’s the symptoms scale? What are the lab findings? What’s the genomics? What’s the brain scan? What are the treatments? And it’s peppered with cases, so it’s also very practical in terms of, okay, fine, I can diagnose this stuff, but what do I do? Well, that’s all laid out as well. So it’s all in the text. And it’s cheap, I mean, it’s, you know, it’s an ebook, so it’s really inexpensive, but it’s got everything I’m talking about in there. So “The Art and Science of CIRS.”

Joseph M. Raffaele, M.D.

Great, I think it’s a amazing work you’re doing. And I’m still trying to think about the overlaps, because I think about things in terms of telomere biology, ’cause it’s pretty high up on the list, but the innate immune system being the starting place for this, you don’t see, I mean, maybe you haven’t looked at it, I wonder whether you see an increase in senescent cells, if you looked for them, particularly with COVID, probably shorter telomeres, there are a couple of papers that show that shorter telomeres do predispose to more severe disease, because they don’t have the resilience, and results in lymphopenia. And also there’s more cytokine storm ’cause there’s more senescent cells producing, but you’re not talking about that same kind of cytokine storm. I wonder, but just also, lastly, I’m sure it’s in the textbook, but the final common pathway is the VIP for the treatment then, no matter what the etiologic agent is.

Andrew Heyman, M.D.

Ultimately, yeah, because as I said, there’s always that irreducible nugget of genes that just don’t seem to go back to normal until we give VIP. Now, you know, are we eventually going to substitute and find other therapies that might work as well or better? I certainly hope so. I don’t like having only one treatment. We know this one works, but it’s expensive, and it takes time.

Joseph M. Raffaele, M.D.

Yeah, right, it doesn’t work quite as fast as you might like it too, but who knows? With that level of disarray and damage, it’s going to maybe take anything a while. So then they get back to full exercise tolerance and all these other things turn around. I look forward to looking at that textbook. Well, so not all mold is mold, okay, so that’s one of the-

Andrew Heyman, M.D.

That’s right.

Joseph M. Raffaele, M.D.

And most of the time it might well be a bacteria, actinomycetes. And probably most of what we in the past thought of as the undiagnosed, well, untreatable chronic fatigue syndrome, fibromyalgia, is this CIRS, you believe.

Andrew Heyman, M.D.

Yeah, I would say probably, under many circumstances, maybe not all, but certainly a portion of those patients, that that’s it, this is it, this is what they are.

Joseph M. Raffaele, M.D.

And that’s a fairly large number of patients, so yeah, absolutely. And there’s the genetic predisposition, which makes sense. And then the change in gene transcription, genes load the gun, lifestyle or exposures, the exposome is what pulls the trigger, and then you put the bullet back in the barrel with the things that you’re doing. Well, it’s been fascinating talking to you about this. Is there anything else you’d like to share with our audience about where you’re going with your next steps with this and what the future is for this?

Andrew Heyman, M.D.

It’s a great question, I would say a couple of things. Number one, if you’re in this space as a practitioner and you’re seeing patients on a regular basis, I think this is a tool that you need in your toolkit, most practitioners, unless, they’re pretty narrow in their focus, they’re likely seeing these patients every day and they go under those labels, of leaky gut and adrenal fatigue and metabolic syndrome and hormonal imbalance and psychiatric issues and neurodegenerative, and the list is really long and it’s common. 

Most of us who are in this field of quote, integrative, functional, anti-aging, you’re seeing these patients, you might not have recognized them as such. But even if it’s not something you want to take on treatment-wise, I would urge people to learn about how to at least quickly identify who these people are. There’s a few simple things that you can do to sort of pick up on them. One is the symptom scale. So again, you know, if they have one symptom in the eight of 13 clusters. In addition to that, there’s a visual test that we have people do online. It’s a contrast study, and we know that contrast is lost or impaired as a feature of this illness.

Joseph M. Raffaele, M.D.

Oh, interesting, visual contrast study, contrast and sensitivity testing?

Andrew Heyman, M.D.

That’s it.

Joseph M. Raffaele, M.D.

I used to it as a practice a while ago, ’cause it was a sort of a biomarker of aging to a certain extent. And this sounds like an accelerated aging syndrome, anyhow.

Andrew Heyman, M.D.

It is. And we know for example that if a person fails the visual contrast test, and they have those, they meet the criteria for symptoms, we’ve got a 99.6% accuracy rate of making the diagnosis of CIRS. So if you’re just kind of attuned to the symptoms and you suggest the patient take the visual test and they fail, you can be pretty much assured you’ve got a CIRS patient. Now, you might not want to take it on clinically, but you’ll do that person a service by finally giving them a label and hopefully packaging them up and sending them off to someone who knows how to deal with this and wants to deal with this. 

So that would be, I think the first thing, Just kind of a takeaway of, hey, this is really common stuff. And it’s certainly very common, I think in our patient population, because they’ve usually already failed conventional medicine and they’re looking for some sort of new insight into why do they feel so terrible. The second piece is as we sort of move forward in our research and our work is that common things are common and while there’s been this great insight to say, oh my gosh, you know, it’s not Lyme and it’s not mold, it’s this weirdo bacteria that seems to be everywhere. And then you step back from that idea and you realize if most of these people are sick from their environment, I think the great insight is why aren’t we using our living spaces as a way of measuring another vital sign in our patient population?

Joseph M. Raffaele, M.D.

Yeah, a very interesting thought, yeah.

Andrew Heyman, M.D.

That if so many people are so affected by the quality and health of their living environment and their living space and their workspace, we just need to take that more seriously, that this is to me, a failure of primary care, it’s a failure of public health. And it, to some degree, it’s a failure of our community too, that we’re just not up to speed recognizing how ubiquitous this is. And it’s not always a nutritional deficiency and a hormonal imbalance and a feature of aging, and you know, that we have to see it as whole people, in whole environments. And even in our community, I think we’ve sort of missed the role that our living spaces, that they play in our patients’ health and wellbeing.

Joseph M. Raffaele, M.D.

It’s an ecosystem type thing. Have you hooked up with the Well Building people?

Andrew Heyman, M.D.

We’ve had some interaction with them and the Environmental Working Group, and there are groups out there. I mean, I’ll tell you, our research on actinomycetes is a year old, two years old, I mean, this is really cutting edge stuff, and we’re still learning as we go, you know? So we’re starting to gather a community of like-minded researchers and scientists and professionals, but it’s still early days, it is, even though we’re 20 years into it, we’re still in early days. But yes, we’ve been in contact with as many groups as possible to sort of spread the word.

Joseph M. Raffaele, M.D.

Well, fascinating work and gratifying, I’m sure, when you make the diagnosis and see the final stage come to fruition. And I really appreciate you sharing your expertise and your knowledge on this, and look forward to continuing the conversation at some point, maybe at A4M or the next time we, I know we crossed paths, it’s just surprising to me we haven’t actually-

Andrew Heyman, M.D.

Yes we do, often, yeah.

Joseph M. Raffaele, M.D.

Again, thank you very much, Dr. Heyman.

Andrew Heyman, M.D.

Thanks for having me, appreciate it.

Joseph M. Raffaele, M.D.

You are welcome, let me stop here.