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CIRS: An Examination of Chronic Inflammatory Response Syndrome from Exposure to Recovery (Part 1: Exposure to Biotoxins)

CIRS: An Examination of Chronic Inflammatory Response Syndrome from Exposure to Recovery (Part 1: Exposure to Biotoxins)

This post kicks off a new blog series on Chronic Inflammatory Response Syndrome (CIRS). Biotoxin-related illness (CIRS) caused by exposure to water-damaged buildings (WDBs) will be the primary focus, but I’m going to provide information about CIRS as a whole…from exposure to recovery, including new evidence-based insights and clinical observations about causes, testing, and therapies. In this first post, I’ll address sources of exposure to biotoxins and the other contaminants responsible for CIRS.

Chronic Inflammatory Response Syndrome is Biotoxin-Associated Illness

Chronic Inflammatory Response Syndrome…called CIRS for short (pronounced like the word “sirs”) is a complex, multisystem, multi-symptom condition also known as “biotoxin-associated illness.” Biotoxins are toxins of biological origin — meaning they’re produced by plants, animals, insects, and microorganisms — that are hazardous to humans when inhaled, ingested, or absorbed.

People often say “mold illness,” “mold sickness,” and “toxic mold poisoning” when they mean CIRS because the majority of people who develop CIRS were exposed to “mold” in a water-damaged building (WDB). I write “mold” to describe  the insult as a whole, but in fact there are a vast number of toxic compounds in WDBs that actually contribute to CIRS.

You may have heard of mycotoxins, one type of byproduct of certain molds. But they aren’t the only hazard in WDBs. A combination of fungi and fungal fragments, bacteria and bacterial fragments, actinomycetes, volatile organic compounds (VOCs), inflammagens, and particulates form a dangerous biochemical cloud in the air. When inhaled, this toxic cloud triggers the activation of the innate immune system.

The innate immune system is the body’s first response to invading pathogens (bacteria, viruses, fungi, other disease-causing microorganisms, as well as non-infectious problems such as injury). Also called the “nonspecific” immune system, the innate immune system is unable to distinguish between different pathogens and their antigens (proteins on the surface of pathogens that cause the immune response), so it responds the same way to all. The response occurs quickly as innate immune cells encounter, engulf, and eliminate the infectious organisms. The innate immune system also records and memorizes these antigens so it’s able to better defend from the specific antigen in the future. When the immune system recognizes and responds to specific antigens, the adaptive immune system is operational. 1

It’s impossible to blame just one of the toxic compounds in water-damaged buildings for the onset of CIRS. We know that each is hazardous to human health, but the body of research is growing as to their synergistic effect as well. And in addition to WDBs, there are other sources of exposure to biotoxins, which I’ll briefly cover in this article.

Who Gets Sick From CIRS?

Interestingly, exposure to these toxic organisms makes some but not all people sick. Others get better as soon as they avoid the source of exposure…we call this avoidance. It’s hypothesized that those who carry specific human leukocyte antigen (HLA) DR haplotypes may be most  susceptible to CIRS…that their immune systems are unable to identify and remove the antigens. In turn, their bodies maintain activation of the innate immune system as the biotoxins continuously circulate, which leads to dysregulation of the inflammatory response and dysregulation of gene transcription2,3 indicative of CIRS.

Many clinicians, including Shoemaker-certified physicians like myself, use HLA testing as one of several biomarkers to diagnose CIRS. Clinical observation and preliminary data point to the fact that these are the people that may be more susceptible and need additional support beyond avoidance alone.  But there are CIRS patients without the haplotypes as well, so the diagnostic process includes many biomarkers, which I’ll cover in a subsequent article.

Exposure to a Biotoxin Is Required for a CIRS Diagnosis

If you suspect you’re dealing with CIRS, I encourage you to find a Shoemaker-certified physician or other experienced functional or biological medicine doctor who can guide you through diagnosis and treatment. Using the Shoemaker Protocol for Biotoxin-Associated Illness, it’s possible for you to make a full recovery. It’s acceptable for us to say CIRS can be cured, so please have hope! You can reclaim your life…no matter how many doctors have said otherwise.

With that said, one of the first questions a qualified physician will ask when assessing your history and symptoms is whether or not you were exposed to biotoxins at any time in your life. Maybe you don’t know if you’ve been exposed. That’s okay. Confirmed exposure helps us make a faster diagnosis, but other diagnostic techniques are used in place of and in addition to confirmed exposure. Exposure to the following biotoxins is known to cause CIRS:

  • Mold/Water Damaged Buildings: Exposure to biotoxins and other contaminants from breathing air in water-damaged buildings. Water damage occurs as a result of poor construction that leads to water accumulation and saturation. When leaks aren’t fixed or repairs are inadequate, damage continues, often sight unseen, producing perfect conditions for mold and bacteria.
  • Post Lyme Syndrome (PLS): Exposure to Borrelia burgdorferi, the spirochete (bacteria) causing Lyme disease, which is a tick-borne illness, is recognized by fever, flu-like symptoms, and, in some people, a bulls-eye rash. CIRS-PLS may require an altered approach to the Shoemaker treatment protocol due to an inflammatory flare and intensification of symptoms that can occur in the binding stage. I’ll explain this in detail in another post.
  • Possible estuarine associated syndrome (PEAS): Exposure to fish, water, or air poisoned by dinoflagellate algae blooms containing Pfiesteria.
  • Ciguatera: Exposure results from eating reef fish contaminated with dinoflagellate algae that contains ciguatera (Gambierdiscus), which is a tasteless and odorless toxin that remains even after cooking.
  • Arachnids: Exposure via the bite of a brown or Meditteranean recluse spider. The venom is both cytotoxic and hemolytic (ruptures or destroys red blood cells) and causes the body to release inflammatory interleukin cytokines.
  • Apicomplexans: Exposure to Babesia microti, the protozoan causing babesiosis, as well as Sarcocystis or Eimeria. Tick transmission, eating undercooked meat, and eating or drinking contaminated food or water are the means of exposure.
  • Cyanobacteria: Exposure to blue-green algae, algae blooms, or infected soil or water that contain Microcystis, Cylindrospermopsis, Lyngbya wollei, or Anabaenopsis. Exposure most often occurs after swimming in or drinking water containing cyanobacteria.

Again, confirmed exposure is beneficial to the diagnostic process, but it is only one aspect. I’ll continue with the explanation of CIRS diagnosis in my next article, specifically the symptoms associated with CIRS . The remainder of this post will look at exposure to mold and more found in WDBs that contributes to chronic inflammatory response syndrome.

CIRS Caused by Exposure to Water-Damaged Buildings

Up to 50% of buildings in the U.S. are water damaged or “sick buildings,” so the chance of exposure is pretty high. Inhalation of the biochemical cloud found in the air and dust of water-damaged buildings is believed to be the leading cause of CIRS. Initial exposure may have occurred at any time, so you’ll be asked if you’ve ever lived or worked in a building with water damage, visible mold, or musty smells.

There are over thirty toxins, inflammagens, and microbes found in WDBs that contribute to CIRS4. Research is beginning to uncover that the hazardous impact of each of these contaminants individually is multiplied exponentially by the synergistic effect of their combined activity. They can be broken down into the following categories.

Fungi: A Contributor to CIRS-Water Damaged Buildings

Fungi is a single- or multicellular organism that can cause infection in healthy people or only those with compromised immune systems (opportunistic). Mold is a type of multicellular fungi that grows in thread-like filaments called hyphae. It reproduces by forming and releasing spores. Mold only needs oxygen, water, and a surface to grow. Wood, drywall, carpet, rubber, paint, soil, dust, practically any porous surface will feed mold when moisture is present.

Identification of the following mycotoxin-producing molds in your home or place of business  — preferably with an ERMI (Environmental Relative Moldiness Index) or HERTSMI-2 (Health Effects Roster of Type Specific (formers) of Mycotoxins and Inflammagens) from — would be a confirmation of exposure:

  • Aspergillus penicillioides
  • Aspergillus versicolor
  • Wallemia sebi
  • Stachybotrys chartarum (black mold)
  • Chaetomium globosum

Fungal Fragments: A Contributor to CIRS-Water Damaged Buildings

Fungal fragments are intracellular and extracellular particles that have become airborne after disturbance of fungal colonies (mold). Like mold spores, they may float or fall to the ground. But testing shows that up to 320 times more fungal fragments are released than spores5. While the list is not comprehensive, common fungal fragments found in WDBs include the following:

  • Mycotoxins: Toxic byproducts of some molds that may cause mycotoxicosis (diseases and death) in humans6. There are about 400 identified mycotoxins, including those produced by the molds above. A single fungi/mold can produce multiple mycotoxins. Common mycotoxins found in water-damaged buildings include:
  • Aflatoxins: B1, B2, G1, and G2 are the four major aflatoxins. Produced primarily by Aspergillus flavus and A. parasiticus, this mycotoxin is responsible for the contamination and destruction of 25% of the world’s food crops annually7. Aflatoxins are carcinogens, are especially toxic to the liver and kidneys, are immunosuppressive, cause DNA mutation8 (mutagenic), and damage genes (genotoxic).9
  • Trichothecenes: A group of 170 mycotoxins produced by Stachybotrys (black mold) in WDBs and a variety of other food-based molds such as Fusarium. Deoxynivalenol (DON) and T-2 toxin are two types of trichothecenes especially toxic to humans. They upregulate messenger RNA expression of the cytokines interleukin-6 (IL-6), IL-1beta (IL-1β), tumor necrosis factor-alpha (TNFα), affecting immune system cells and causing inflammation.10 They can even cause apoptosis (cell death) by targeting mitochondria, passing through the mitochondrial membrane and inhibiting gene transcription.11
  • Fumonisins: Fusarium molds are the major producers, but Aspergillus and Penicillium produce Fumonisins as well. Of over 15 types, FB1 is most toxic. With the greatest effect on the liver and kidneys, they interfere with metabolism, activate and suppress the immune system, bring about apoptosis, and are linked to cancer.12  
  • Zearalenones: Primarily produced by Fusarium molds, zearalenone is also known as F-2 toxin and targets the reproductive system as a known endocrine disruptor. Through direct effects on cytokine function and overactivation of mitogen-activated protein kinase (MAPK) signaling, the six members of the zearalenone family cause intracellular damage and apoptosis as well as altered gene expression.13 A recent study examined the synergistic effect of zearalenone (ZEA) and deoxynivalenol (DON) on immunotoxicity, as they’re often found together, and suggested the combined effect decreases cell viability and inhibits cytokine function even more than their individual impact.14
  • Ochratoxins: Produced by Penicillium and Aspergillus, Ochratoxin A is the most toxic. The kidneys are a main target, but these mycotoxins are also immunotoxic, genotoxic, teratogenic (affecting the developing fetus), and neurotoxic.15 In the brain, research is showing how glial cells (cells that make up 33-66% of the brain16) are damaged by ochratoxins and how they may affect expression of genes that regulate brain inflammation. Additionally, they are known to cause apoptosis as well as alter blood-brain barrier permeability, damaging the ventral mesencephalon, striatum, hippocampus, and cerebellum.17
  • Ergot alkaloids: The ergot alkaloids, including Festuclavine, Chanoclavine, and Fumigaclavine A, B and C, are produced by several species of Claviceps as well as Penicillium and Aspergillus. A condition in the Middle Ages known as Saint Anthony’s Fire may be the earliest known cases of mycotoxicosis…called ergotism, poisoning by the ergot in moldy rye, which caused hallucinations and seizures18. Interestingly, ergots are also found in lysergic acid (LSD). Ergot alkaloids interact with certain receptors, ultimately harming the nervous, cardiovascular, immune, and reproductive systems. Fumigaclavine C, for example, inhibits TNFα and reduces the expression of other cytokines involved in inflammation.19
  • Hyphal Fragments: Pieces of the thread-like or branch-like filaments (hyphae) that form complex networks called mycelium, making up the vegatative growth of mold…the colorful or fuzzy or slimy stuff characteristic of visible mold. Broken hyphae are usually quite large in comparison to other contaminants in WDBs so settle quickly but also carry spores, mycotoxins, and other fungal fragments. Research on hyphal fragments shows they can damage white blood cells called Human polymorphonuclear neutrophils (HPMNs) by upregulating toll-like receptor 2 mRNA, causing vigorous proinflammatory gene expression and induction of transcription factor NFKB pathway-related genes that regulate innate and adaptive immune functions.20,21
  • Conidia: Asexual fungal spores that form on the end or side of conidiophore (a structure similar to hyphae). Conidia also carry toxins such as ergot alkaloids and ochratoxin, causing significant inflammatory responses.22 One study showed that 85% of tested dust particles were conidia while 6% were hyphal fragments.23 Conidia may have the ability to adapt to the host environment by reprogramming their metabolism, meaning fungal genes might help establish or prolong infection in humans.24
  • Mannans: A glycoprotein (molecules composed of protein and carbohydrate chains that are able to assist pathogens in entering and infecting cells) which makes up cell walls in fungus such as Candida albicans that have immunosuppressive properties and inhibit cell-mediated immunity, multiplying immune deficiency.25
  • Spirocyclic Drimanes: A group of 10-40 different metabolites (small molecules) produced by stachybotrys chartarum (black mold) with high inflammatory effects including immunosuppression, TNF–α release inhibition, endothelial receptor antagonistic activity, complement system disruption, and protein tyrosine kinase (PTK) inhibitory activity that also have cytotoxic and neurotoxic effects.26
  • Chitinases: Enzymes that degrade chitin (polysaccharides that make up fungal cell walls). Chitinases and chitinase-like proteins (especially Human Glyco_18 domain-containing proteins) are linked to an alternative activation of macrophages (a type of white blood cell) found in chronic and inflammatory diseases.27

Bacteria & Bacterial Fragments: A Contributor to CIRS-Water Damaged Buildings

The impact of exposure to bacteria and bacterial fragments in WDBs is becoming more important to the development of CIRS, especially as it relates to gene response.  These substances are proving more important to the development of chronic inflammation than mold or mycotoxins.28

  • Gram-negative and Gram-positive Bacteria: Named after the color they turn during Gram staining (red for negative and blue for positive), they have differing cell wall structures, cause different infections, and respond to different antibiotics. Gram-negative bacteria have a protective outer membrane around the cell wall that prevents white blood cells and antibiotics from destroying them. When this membrane is disrupted, it releases endotoxins.29
  • Endotoxins: The most well-studied bacterial fragment, endotoxins are also known as lipopolysaccharides, and they come from gram-negative bacteria membranes after degeneration and cell death.30 Highly toxic and inflammatory due to lipid A, they are known to contribute to Parkinson’s disease, Alzheimer’s disease, liver damage, diabetes, and chronic inflammation of the gut.31
  • Actinomycetes: A type of gram-positive bacteria that resembles fungus due to their filament-like structure. According to Dr. Shoemaker, actinomycetes may be the most important contaminant in WDBs. New research is pointing to the fact that chronic inflammation follows gene response to endotoxins and actinomycetes, not just mere exposure to these toxins. This has a major impact on treatment. As Dr. Shoemaker is observing clinically, the correction of unregulated over-expression of coagulation genes correlates to improvements in early dementia patients.32
  • Mycobacteria: A large family of bacteria (more than 100 recognized or proposed species) with waxy cell walls that are able to avoid digestion and cause a robust inflammatory response through production of nitric oxide and the cytokines IL-6 and TNFα.33

Inflammagens: A Contributor to CIRS-Water Damaged Buildings

Inflammagens are irritants that produce swelling and inflammation by binding to receptors such as Toll-like receptor 4 (TLR4), activating cytokine response.34 Siderophores, beta glucans, cell wall components, cell fragments, proteinases, and lipopolysaccharides in general are inflammagens found in water-damaged buildings.

  • Beta Glucans (β‐Glucans): Polysaccharides composed only of glucose (sugar) found on both fungi and bacteria cell walls. Fungal β‐Glucans serve as a Pathogen Associated Molecular Pattern (PAMP), meaning the body is able to recognize β‐Glucans through immune response receptors such as Dectin-1, causing cytotoxic activity and the release of proinflammatory cytokines.35 Some fungi, including H. capsulatum and C. neoformans, are able to mask β‐Glucan identification with an outer layer that hides the β‐Glucan and inhibits the immune response, so the fungi is not engulfed by white blood cells and may evade the body’s defense.36
  • Siderophores: Small molecules secreted by bacteria and fungi that chelate (bond with) iron and other metals37 from the host body and supply it to the microbe, promoting microbial growth. They’ve also been shown to alter gene transcription and upregulate proinflammatory cytokines in lung infection.38
  • Proteinases: Enzymes that degrade peptides, breaking down proteins via hydrolysis, which activates or impairs protein functionality. Proteinase signaling initiates inflammation by cleaving a variety of targets such as protease-activated receptors (PARs), which are widely acknowledged for their role in the development of chronic inflammatory diseases.39
  • Cell Wall Components/Cell Fragments: Fungal and bacterial cell wall structures are known to instigate multisystem acute and chronic inflammatory diseases.40,41 These structures stimulate inflammation through activation of NFKB, a protein complex responsible for cytokine production, cell survival, and DNA transcription.42 Mannans, β‐Glucans, and chitin are included.

Volatile Organic Compounds: A Contributor to CIRS-Water Damaged Buildings

Mold, bacteria, and actinomycetes produce volatile organic compounds (VOCs) as waste products. VOCs in mold are probably the most relatable. The moldy or musty smell in WDBs is actually VOCs that are produced when mold “eats.” VOCs are also produced by evaporation of building materials like paint, furnishings, cleaning products, and adhesives.43  VOCs activate the innate immune system, produce an inflammatory response, are neurotoxic and cytotoxic, and stimulate apoptosis.44 Research has also shown that VOCs produce multiple chemical sensitivity reactions,45 which we often see in CIRS patients.

Particulates: A Contributor to CIRS-Water Damaged Buildings

Particulate matter or “particle pollution” is a mixture of extremely small particles and liquid droplets such as metals, dust, nitrates, sulfates, organic chemicals, and more.46  Particles come from grinding or crushing, vehicle emissions, coal burning, and other industrial activities. Decades of research shows particulate matter (PM) produces inflammation in the lungs and systemically.47


I want to point out that some of the substances covered above play a key role in proper immune response and have a positive effect on homeostasis when kept in check. Plenty of research into their potential to function as therapeutic agents is being conducted. Problems occur when there’s an under- or (more often) overactive immune response to their presence in the body.

I hope this explanation has provided you with some deeper insight into sources of biotoxin exposure and how they contribute to the chronic inflammatory response seen in CIRS. In the comments below, let me know if you have questions or would like to know more about a specific contaminant.