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CIRS: Chronic Inflammatory Response Syndrome

CIRS: Chronic Inflammatory Response Syndrome

  • Have you struggled with chronic health conditions for years without finding answers? CIRS is the multi-system, multi-symptom syndrome that may be affecting billions world-wide while still flying under the radar of mainstream medicine.
Chronic Inflammatory Response Syndrome Banner optimusmedica

Chronic Inflammatory Response Syndrome (CIRS) is a multi-system, multi-symptom, complex chronic illness. It is characterized by continued activation of the innate immune system resulting in continued inflammation.

The condition was first described by Dr. Ritchie Shoemaker, M. D. after observing a cluster of patients exhibiting strange, yet similar, symptoms. CIRS has evolved to describe complex chronic illnesses resulting from biotoxins produced by molds, funguses, and bacteria.


CIRS is a medical diagnosis related to biotoxin illness. It was largely associated with mold-damaged buildings (CIRS-WDB) in the early years of clinical description but has since expanded. CIRS is now used more generally to describe a range of conditions inclusive of molds, funguses, tick-borne illness, and other biotoxins.

To say that diagnosing CIRS is complex is an understatement. The criteria developed by Dr. Shoemaker are exhaustive—often demanding dozens of lab tests. However, the resulting barrage of data can provide a structured framework by which some of the most complex chronic illnesses in the world have been diagnosed.

CIRS is thought to affect people with certain mutations in the HLA-DR/DQ haplotype groups. These genes are responsible for helping the body “tag” harmful compounds and remove them from the body. Those with certain HLA-DR/DQ mutations aren’t able to remove compounds produced by Lyme, mold, fungus, and dinoflagellates. Rather, these toxic compounds continually circulate causing unchecked inflammation and a progression of worsening symptoms.

Note: CIRS describes a broad array of symptoms coming from a broad range of sources. Research is still young and much terminology is not yet standardized among researchers. For example, CIRS may also be referred to as Dampness and Mold Hypersensitivity Syndrome (DMHS)(9).


CIRS is a multi-system, multi-symptom condition that describes poor immunological responses to a wide range of biotoxins. This means a wide range of symptoms. The core symptoms described by Shoemaker include the following:

  • Fatigue/Malaise
  • Muscle Weakness
  • Aches & Pain
  • Muscle Cramps
  • Ice Pick Pain
  • Headache/Migraine
  • Light Sensitivity
  • Blurry Vision
  • Sinus Issues
  • Shortness of Breath
  • Abdominal Pain
  • Memory/Learning Issues
  • Confusion
  • Brain Fog
  • Cough
  • Night Sweats
  • Temperature regulation issues
  • Peripheral Neuropathies
  • Tinglings
  • Vertigo
  • Metallic Taste
  • Tremors
  • Mood Swings
  • Increase Static Shocks

That is hardly a comprehensive list but illustrative of how systemic CIRS can be. Nonetheless, this laundry list of symptoms illustrates the importance of robust laboratory testing to confirm a CIRS diagnosis. On his website, Shoemaker notes a series of conditions that CIRS is commonly misdiagnosed as.


Shoemaker’s seminal report on the topic was in response to an outbreak of a type of water-borne toxin. This toxin, a dinoflagellate, caused symptoms of memory loss, headaches, skin rashes, joint pains, diarrhea, and bronchospasm (1).

Shoemaker then published a series of case reports of treatment using a novel cholesterol-lowering drug named Cholestyramine. This compound, a bile acid sequestrant, was thought to bind to toxins in the digestive tract and help with elimination.

Oddly enough, only some of the population exposed to the biotoxin became symptomatic such that Cholestyramine therapy was needed (2). This brought forth the question: among the local population that was exposed, what was different about those that developed chronic illness?

Natural Defense Mechanisms

CIRS was initially focused on water-borne toxins then quickly expanded to account for toxins in water-damaged buildings. As science has evolved, deeper consideration has been given to conditions such as Lyme and other species common among those suffering chronic illness.

Modern research has noted that fungal and mold species produce biotoxins as a defensive mechansim. These toxins have been selected through evolution for their effectiveness at thwarting would-be predators and antagonistic species (10). I spoke with Dr. Raymond Oenbrink of Appalachian Wellness regarding the matter and he summarized this perspective as such:

Although we use fungal growth and presence to document an unsafe building, there will always be other organisms. Actinomycetes, Gram-Negative bacteria producing endotoxins, Gram-Positive bacteria producing exotoxins–all of these organisms are toxic, additionally, produce volatile, airborne, toxins that cause further damage. We are not the target of these microbes; they produce these toxic substances, these volatile organic compounds (VOCs) to prevent other microbes from competing with them for resources such as food and water required for their growth. People are merely collateral damage to these microbes. Similar to HG Wells’ War of the Worlds? You bet!

Genetic Susceptibility

In the domain of CIRS, genes associated with the Human Leukocyte Antigen (HLA) complex have proven particularly useful in the diagnosis and prediction of risk. This complex is an antigen-presenting class of genes, responsible for grabbing up toxins and signaling the immune system to get rid of them.

Research has shown that more than 90% of individuals diagnosed with CIRS have a mutation in the HLA-DR (3). For these individuals, genetic variation results in the inability of the immune system to ‘tag’ certain biotoxin compounds to be removed by their immune systems.

This results in the toxins being stored and, as often is the case, continually recirculated in the enterohepatic system causing a perpetuated state of chronic inflammation.

DR vs. DQ Isotypes

The HLA complex describes a range of enzyme-encoding genes. These can be categorized as several isotypes which describe the role the compounds they encode for play in immunological responses. In the case of CIRS, these isotypes relate to susceptibility to different types of biotoxins.

Both DR and DQ isotypes are relevant to biotoxin illness. HLA susceptibility is a complex subject, one we won’t dive into deeply here, but very relevant to a large range of immunological concerns.

The initial relevancy of HLA variance among CIRS is outlined in Shoemaker’s 2004 paper (4). In it, Shoemaker notes HLA variances descriptive of fungal toxin susceptibility, multiple biotoxin susceptibility, Lyme toxin susceptibility, and MSH deficiency.

The following HLA interpretation chart is taken from diagnostic criteria for CIRS, as outlined by Dr. Shoemaker:

Multisusceptible 4 3 53
11/12 3 52B
14 5 52B
Mold Susceptible 7 2/3 53
13 6 52A, B, C
17 2 52A
18 4 52A
Borrelia, post-Lyme 15 6 51
16 5 51
Dinoflagellates 4 7/8 53
MARCoNS 11 7 52B
Low MSH 1 5

Note: This chart includes a line entry for low MSH. This is noted by Dr. Shoemaker in his book Surviving Mold but no longer reflected on his website.

As one can see, variations in the HLA haplotype group can cause a range of heightened susceptibilities. I’ve found this HLA interpretation tool to be quite entertaining.

HLA Relevancy

In her 2017 presentation at the International Conference on Chronic Pathologies, Dr. Sonia Rapaport questions the applicability of HLA haplotyping as a predictive measure for CIRS and biotoxin illness. Referencing HLA data from Belgium populations, she notes that as many as 90% of native Belgians carry at least 1 “high risk” HLA allele.

The Biotoxin Pathway

shoemaker biotoxin pathway diagram optimusmedica
Shoemaker’s “Biotoxin Pathway” illustrates the pathology of CIRS in those affected

In Shoemaker’s development of a CIRS treatment protocol, a “pathway” by which biotoxin illness progressed was charted. Called the Biotoxin Pathway, this framework described the order in which multiple cells, glands, organs, and hormones are affected by lingering biotoxins. This six-stage process provides a high-level view of the depth of which CIRS can affect susceptible individuals.

Diagnosis & Testing

Shoemaker CIRS Symptom Clusters
Cluster analysis by Shoemaker and others revealed several distinct groupings of CIRS-related symptoms

The first stage of diagnosing CIRS is through an assessment of reported symptoms. These account for patient history, risk factors, and environmental exposures. Additionally, confirmation of CIRS includes the presence of multi-system symptoms in 4 of 8 of the following categories:

  • General Symptoms
  • Musculoskeletal
  • Respiratory
  • Eyes
  • Gastrointestinal
  • Central Nervous System
  • Neurological
  • Unusual/Uncategorized

The HLA testing has proven insightful for predicting risk-factors for CIRS. However, much more information is needed for diagnosis. The testing for CIRS involves a battery of blood, urinary, and even visual assessments. I’ll mention only the highlights here:

  • HLA-DR/DQ Haplotyping
  • Antigliadin IgA/IgG
  • Vascular endothelial growth factor (VEGF)
  • Anticardiolipins (ACLA)
  • Antidiuretic hormone (ADH)
  • Matrix metallopeptidase 9 (MMP-9)
  • Leptin
  • Complement C4a/C3a
  • Transforming Growth Factor β-1
  • Visual Contrast Sensitivity (VCS)

Assuming a person is symptomatic in enough primary categories, a Visual Contrast Sensitivity (VCS) test is performed. According to Dr. Natasha Thomas, MD (a Shoemaker certified practitioner) the VCS test is 92% accurate in diagnosis CIRS (PDF). This test is cheap, can be done at home, and can conveniently be re-tested to track response to therapy. I’ve used this VCS test in the past and was pleased with the quality of the evaluation.

Assuming failure in the VCS testing, 2 of the following lab markers must be present to qualify a CIRS diagnosis:

  • HLA-DR predisposition
  • MMP-9 Elevation
  • Low MSH
  • ACTH/Cortisol Dysregulation
  • ADH Dysregulation

An excellent discussion on CIRS lab interpretations is available from Dr. Aaron Hartman of  Richmond Integrative and Functional Medicine. Fair warning—there is a lot of information.


cirs shoemaker treatment steps pyramid optimus medica
The Shoemaker protocol for CIRS treatment is outlined in a 12-step process

Dr. Shoemaker developed a rigid, 12-step approach for the treatment of CIRS. This treatment protocol aims to remove patients from exposure, eliminate biotoxins from their systems, and then repair the damage that resulted from exposure.

Removing the Source of Exposure

Without a doubt, the first step to healing from any biotoxin illness is to identify the source and remove it. This opinion is one I hear reflected among practitioners of all modalities. Again, Dr. Raymond Oenbrink of Appalachian Wellness (a Shoemaker-endorsed Physician) notes:

A CIRS patient will not be able to start the healing process without removing themselves from a toxic environment. In many cases, this will involve remediation processes to the home, car, and even workplace. In the case of contaminated residences, mold spores have the potential to contaminate clothing, furniture, and items such as books. These possessions must also be considered for remediation or discard. The process can be intimidating, involved, and sometimes expensive. It is, however, an essential commitment for CIRS patients to begin healing.

Cholestyramine/Binders to Remove Toxins

The Shoemaker Protocol for treating CIRS is, if nothing else, a rigidly-defined model. Other more natural treatment therapies have evolved as more about CIRS has been learned. These therapies substitute more natural binders such as activated charcoal, bentonite clay, and zeolites in place of pharmaceutical binders like Cholestyramine.

Dr. Kelly McCann of the Spring Center outlines some key differences in her approach, as told in an interview with Dr. Michael Ruscio:

… the Shoemaker protocol is very dogmatic. You have to start with cholestyramine. You have to treat the MARCoNS and then you go down the steps of treating the different biomarkers. I do tend to use binders, I think binders are important. I tend to avoid cholestyramine. I think it tends to block circulation. I prefer not to use that, unless I really have to or people feel like they need it. I use other binders, things like activated charcoal. Different kinds of clay, such as bentonite clay. Chlorella can be very effective as a binder as well. There are a number of products out there that are combo products, that work well for binding. The purpose of that is to bind any of the mycotoxins or biotoxins that happen to be in the GI tract so that they don’t get reabsorbed. Binding is a critical part of the treatment protocol, it’s just not required to be cholestyramine. So that’s one difference.


After the removal of exposure and establishment of Cholestyramine/Welchol, the Shoemaker Protocol addresses common sinus infections. Shoemaker noted that genetically susceptible individuals with CIRS have a high prevalence of Multiple Antibiotic Resistant Coagulase Negative Staph (MARCoNS) infections in the sinus cavities.

The standard Shoemaker Protocol for treating MARCoNS is a combination (compounded) solution of the following three compounds:

  • Bactroban (mupirocin, a topical antibiotic)
  • Edetate disodium (EDTA, a chelating agent)
  • Gentamicin (an antibiotic)

Collectively, this solution is referred to as BEG and is administered in a nasal spray several times daily. Gentamicin has demonstrated systemic absorption when used as a nasal rinse and demonstrated a high prevalence of unwanted side effects for such application (7). As such, more recent MARCoNS therapies have incorporated more natural ingredients like Colloidal Silver or herbal preparations such as Formula 1 by BioNexus Health.

Another perspective on MARCoNS describes the pathogen as being opportunistic and reflective of poor overall sinus bacterial diversity. Kind of lack gut dysbiosis—just in the sinus. In a 2012 paper, researchers found patients with chronic sinusitis had a statistically lower number of microbial diversity in their sinus cavities. Moreover, they found a particular lack of the species Lactobacillus sakei. Treatment with L.sakei in animal models provided significant improvements in overall sinus health (8)

Treating the Individual

The remainder of CIRS treatment steps is much less fundamental and universal in application. They require careful monitoring of test results, adjusting medications and therapies when needed, and taking into account the lifestyle, environment, and response of a patient. As one might imagine—a CIRS-literate physician is an essential part of this stage.

More Information

CIRS is complex in presentation, cause, and successful recovery and management require a lifetime of consideration by those affected and their physicians. As CIRS-related research continues to evolve, a greater understanding of how genetics, environments, and even nutrition plays a role in the presentation and risk of CIRS-related diseases.

For a deep-dive into the latest research on CIRS, as well as some more detailed discussion on diagnosis and therapies, check out Chris Kresser’s Interview with Dr. Ritchie Shoemaker. This interview is available both as a podcast or textural interview.

Ref broad use of binders

In his book Toxic: Heal Your Body from Mold Toxicity, Lyme Disease, Multiple Chemical Sensitivities, and Chronic Environmental Illness, Dr. Neil Nathan, MD notes that a broad spectrum of binders is often an ideal approach to biotoxin illness (6).

Dr. Nathan discusses his own adaptation of the Brewer Protocol and the concern that certain binders have a higher affinity for specific biotoxins. Rather than using a single binder, like cholestyramine, running mycotoxin laboratory tests to identify specific biotoxin levels, Dr. Nathan believes better outcomes can be achieved.

Final Thoughts

CIRS is an immensely complex health condition. Dr. Shoemaker’s work on the subject has been pioneering and brought needed attention to the dangers of environmental toxins and the large number of the population that may be susceptible to them. I believe there’s an argument to be made for the Shoemaker Protocol being too rigid a model for addressing the broad spectrum of biotoxin-associated illness. Nonetheless, Shoemaker’s work in both diagnosing and treating CIRS has been pioneering and inspiring.

From my personal experiences with CIRS to the enumerable accounts I have heard from others, I find one thing to be constant: a well-trained physician is essential to healing from CIRS. This condition is early in its lifecycle of both discovery and description. Much more research is needed in the field but what we know now paints an alarming picture of how completely biotoxins can affect some individuals.


  1. Shoemaker, R C. “Diagnosis of Pfiesteria-human illness syndrome.” Maryland medical journal (Baltimore, Md: 1985) vol. 46,10 (1997): 521-3.
  2. Shoemaker R. Treatment of persistent Pfiesteria-human illness syndrome. Md Med J. 1998 Feb-Mar;47(2):64-6
  3. Gray, Michael R et al. “Mixed mold mycotoxicosis: immunological changes in humans following exposure in water-damaged buildings.” Archives of environmental health vol. 58,7 (2003): 410-20.
  4. Shoemaker RC. Johanning E. Sick Building Syndrome in Water-damaged Buildings: Bioaerosols, Fungi, Bacteria, Mycotoxins and Human Health, pp 66-77, 2005
  5. Shoemaker, R., Johnson, K. et. al, “Diagnostic Process for Chronic Inflammatory Response Syndrome (CIRS): A Consensus Statement Report of the Consensus Committee of Surviving Mold,” Internal Medicine Review. 2018 May; 4(5): 1-47.
  6. Nathan, Neil. Toxic: Heal Your Body from Mold Toxicity, Lyme Disease, Multiple Chemical Sensitivities, and Chronic Environmental Illness. Victory Belt Publishing Inc, 2018.
  7. Wong, Kevin K et al. “Systemic absorption of topical gentamicin sinus irrigation.” Journal of otolaryngology – head & neck surgery = Le Journal d’oto-rhino-laryngologie et de chirurgie cervico-faciale vol. 37,3 (2008): 395-8.
  8. Abreu, Nicole A et al. “Sinus microbiome diversity depletion and Corynebacterium tuberculostearicum enrichment mediates rhinosinusitis.” Science translational medicine vol. 4,151 (2012): 151ra124.
  9. Valtonen, Ville. “Clinical Diagnosis of the Dampness and Mold Hypersensitivity Syndrome: Review of the Literature and Suggested Diagnostic Criteria.” Frontiers in immunology vol. 8 951. 10 Aug. 2017.
  10. Kempken, Frank, and Marko Rohlfs. “Fungal secondary metabolite biosynthesis–a chemical defence strategy against antagonistic animals?.” Fungal ecology 3.3 (2010): 107-114.