CIRS Testing (chronic inflammatory response syndrome) & Why It May Be Critical

• CIRS is also known as ‘chronic inflammatory response syndrome’. CIRS is a term that was created by Ritchie Shoemaker, MD (11) out of the necessity to define the pathology of biotoxin and mold-related illness.
• CIRS is based upon a series of inflammatory responses to biotoxin exposure, such as mold exposure from water-damaged buildings (11, 12).
• The panel of specific lab markers for mold illness can vary greatly, but often provide important clinical information that can be used for treatment protocols and tracking progress over time

Mold exposure can induce chronic inflammation in certain individuals. The illness from mold exposure involves a systemic inflammatory response that certain individuals are highly prone towards. It is now increasingly more understood that biotoxin exposure has neurological and neuroinflammatory consequences. Some of these can include changes in white matter brain volume, increased blood-brain-barrier permeability, and atrophy to certain regions of the brain, such as the caudate nucleus (1). Additionally, it has been observed that mold exposure is capable of inducing dementia and Alzheimer’s-like effects (2).

Mold exposure should be investigated as a possible factor for individuals that live (or have lived) in water-damaged buildings. Some of these include:

• Autoimmune disease
• Peripheral neuropathy
• Chronic fatigue
• Slurred speech or inability to find words
• Increased urination & constant thirst
• Anxiety, depression
• Loss of muscle tone, loss of muscle and/or motor function
• Delayed muscle soreness following exercise
• POTS (postural orthostatic tachycardia syndrome)
• MCAS (mast cell activation syndrome)
• Joint hypermobility, EDS (Ehler’s Danlos Syndrome) or Marfans
• Sudden onset joint hypermobility or skin hyperelasticity
• Cognitive decline, Alzheimer’s or dementia
• Sinusitis or rhinitis
• Bowel issues, such as acute bouts of diarrhea
• Peripheral circulatory symptoms, such as loss of normal skin tone on fingers, hands, feet or toes, Raynaud’s
• Acute or chronic bronchial cough, sputum or spasms

A list of symptoms associated with CIRS can be found at Dr. Shoemaker’s site (11).

The heightened physiological and immunological reactivity to mold biotoxins is largely believed to be triggered due to genetic susceptibility, such as to variants of the HLA gene class (11). This class of genes, residing on chromosome 6 has also been extensively studied with relation to autoimmune disease susceptibility (14). There is also speculation that a gene cluster located in between the HLA genes (in the HLA 3 region), known as RCCX may be a significant contributor to perturbations in physiological, immunological and endocrine-related effects. Because of the complexity of the HLA gene region (such as its vey long linkage disequilibrium), understanding the nuances of how HLA genotypes respond to biotoxin exposure is challenging.

During clinical evaluation, it is important to look for clues and traits related to HLA susceptibilities. This includes asking questions pertaining to autoimmune status, and any familial history of autoimmune disease. Identifying if there is joint hypermobility present is another clue, because it predisposes towards weakened collagen and extracellular matrix (ECM) dysregulation. In my opinion, ECM and collagen should be seen as a central focus of toxin and biotoxin exposure because the ECM is damaged through toxin exposure, and the ECM is integral in immunological and neurological signaling through various autonomic reflex arcs (3).

Can Complement Immune Deficiencies Be a High Risk Factor for CIRS?

The complement immune system is a major arm of the innate immune system and functions as the early responder to the threat of pathogens and toxins. Complement proteins derived from the liver circulate throughout the blood and are activated through 3 pathways: the lectin pathway, the classical pathway and the alternative pathway. The complement immune system is involved in CIRS, and the C4a is one of the primary markers that is often found elevated in CIRS patients.

However, complement protein deficiencies are actually common, and this is especially true among individuals with autoimmune disease. For example, these autoimmune diseases have been shown to feature complement immune deficiencies:

• Lupus (SLE) – C2, C4, C1Q, C1R, C1S (4)
• Rheumatoid arthritis (RA) – C4b (6)
• Celiac disease – C4, C3, C3C, Factor B (5, 7)
• Type 1 Diabetes – C4 (8)

While the relationship between CIRS and complement immune deficiencies has not yet been explored in the research literature, such a relationship likely exists. A theoretical complement deficiency would significantly impair the innate immune system’s ability to sufficiently capture mycotoxins. This may lead to immunological havoc, chronic inflammatory activity, and possible autoimmune activation.

The main takeaway is that if any of these 4 autoimmune conditions exist in your family, it is theoretically possible you have a heightened sensitivity to mold and water-damaged buildings and should take precautionary measures.

Testing for CIRS & Mold Exposure

It is important to understand that all biological and environmental testing have limitations. One cannot ascertain all necessary data simply by looking at a quantitative test score. Human physiology and cell biology is a moving picture. Test scores are akin to photographs taken at various moments in time. With CIRS and toxin exposure, there is so much happening outside of the realm of the blood and the cells, that simply looking at blood or urine specimens does not provide a complete picture. Even in the case of diagnostic imaging like volumetric MRI, we are left with looking at the effects of illness, and cannot adequately understand certain factors like regulation physiology (how physiological systems and organs communicate) or connective tissue effects on cell regulation and network physiology.

At best we can hope that the biomarkers chosen can provide a better sense of understanding the direction of therapy, and at the very least to establish that an inflammatory response is occurring.

To establish the presence of mold in an indoor environment I highly recommend the ERMI test from Mycometrics or Envirobiomics. This is the equivalent of a DNA test on dozens of types of molds. From this, I use the HERTSMI calculator to identify the score of 5 of the most toxic molds found on the ERMI test. The HERTSMI-2 calculator can be accessed through Dr. Shoemaker’s site (13).

The ERMI/HERTSMI has been absolutely invaluable for identifying the presence of toxic mold, as well as tracking progress of the symptoms of the client in question, and the safety of the home following the appropriate remediation. It is critical to understand that the HERTSMI score only takes into account 5 types of mold. There may be other mold spores that appear on the ERMI test that may be toxic to individuals with CIRS (such as cladosporium) that aren’t figured into the HERTSMI score. When investigating the presence of mold it is critical to ask questions such as:

• Has there been water damage in the building?
• Does the building have a basement that has flooded?
• Is there a high humidity content in the air?
• Is the house raised or flat on the ground?
• Are there carpets in the building that have had water damage?

If an individual is symptomatic and they’re living or working in a toxic environment, it is critical that they leave until the building has been correctly remediated. Not doing so will inhibit recovery.

Specific Lab Testing For CIRS & Mold Exposure

The following is a list of CIRS-related tests that I have found useful. Other clinicians may find additional testing useful. An evolving challenge is being able to find the labs who perform each test correctly. There is considerable debate regarding the proper assays and lab procedures for each test. Standardization for these tests is still up in the air. Credit is given to Ritchie Shoemaker, MD for the initial identification of these tests for mold exposure, and related CIRS pathology (11, 12).

• TGFß-1  (transforming growth factor beta 1) is an important cytokine and growth factor involved in many processes. TGFß is one of the most anti-inflammatory cytokines operative in the immune system. However, it has many different functions. It is critical in the immune balance between TH1, TH2 and TH17. From my experience, for some individuals, TGFß-1 levels may rise considerably during and following mold exposure. Not all individuals show elevations in TGFß-1 following mold exposure, however. Values greater than 5,000 pg/ml are often seen with acute mold exposure. TGFß-1 can be elevated also during inflammatory processes, autoimmunity and may be elevated among those with joint hypermobility syndromes such as EDS (15). It is possible that individuals with joint hypermobility may feature higher than normal levels of TGFß-1 because the extracellular matrix proteins regulate the transcription and differentiation of TGFß (16, 17).
• C4a – Complement C4a is an immune component derived from the complement immune system. The complement immune system is comprised of 3 different parts: the lectin pathway, the classical component pathway and the alternative pathway. Mold and Lyme can both cause C4a levels to rise. Other pathologies can feature elevated C4a as well, such as CFS (19),   . C4a is derived from Complement C4, specifically from the cleavage induced by MASP (mannan binding lectin serine protease). When C4a levels rise, it is suggestive of the activation of the Lectin pathway of the complement immune system. The lectin pathway does not recognize an antibody, but utilizes a polysaccharide or a collagen-like structure (called ficolin) to create an adhesive bond to the pathogen, or in this case the mold/mycotoxin antigen. C4a has a role of inhibiting mast cell activation that is induced by C3a and C5a. In mold and Lyme disease, the reference range established by National Jewish Laboratory for C4a is <2,830 ng/ml (20). To date, the preferred lab for C4a testing is National Jewish labs rather than Lab Corp. Lab Corp uses a preservative called Futhan, which is believed to reduce the accuracy of C4a results. Lab Corp argues that the Futhan prevents degradation of the C4a blood sample, and argues that National Jewish Labs results are not accurate. The debate over C4a testing methodologies highlights the necessity for standardization, which does not yet exist.
• MMP9 – MMP9 is metalloproteinaise-9. It is one of a series of biological enzymes (known as matrix metalloproteinases) involved in the breakdown of the extracellular matrix (ECM). The ECM is comprised of numerous extracellular tissues, such as collagen, proteoglycans and glycosaminoglycans (such as glucosamine, hyaluronic acid, chondroitin sulfate, heparan sulfate). The ECM is a critical regulator of cell-to cell communication, growth factor binding, and plays a major role in various immune, endocrine and neurological networks. The activation of metalloproteinases can occur under many circumstances, such as in mold exposure (12), mercury toxicity (10), and from fluoroquinolone antibiotics (9).
• MSH – Melanocyte stimulating hormone is a regulatory peptide hormone that is believed to be suppressed in CIRS. The Shoemaker reference range for MSH of 35-81 pg/mL does not seem to accurately reflect the majority of healthy, non-CIRS patients. Additionally, not all CIRS patients have low MSH. Not everyone with low MSH has CIRS. To make matters worse there is controversy over whether Lab Corp or Quest is the preferred lab to use for MSH testing. The current consensus is that Lab Corp is preferred for MSH testing in the US. A dysregulation of MSH is believed to cause HPA axis dysfunction, such as aberrant ACTH and cortisol. Its also believed to create unfavorable cytokine activation, leading to inflammatory perturbations. Restoration of MSH to higher values is associated with improvement of CIRS. I have observed this to be true to an extent. From my clinical observations, an MSH level <15 pg/ml is more often associated with CIRS.
• VEGF – Vascular endothelial growth factor is a protein that plays an important role in tissue oxygen utilization, angiogenesis (blood vessel formation) and endothelial function. CIRS patients often have high or low VEGF. High and low blood levels of VEGF correlate to symptoms related to circulatory problems, such as capillary hypoperfusion, tissue hypoxia, as well as weak muscle function. VEGF following exercise is necessary to stimulate muscle growth and anabolic recovery. A little known fact is that VEGF is a copper-dependent protein, whose functional capacities are regulated by tenascin proteins in the extracellular matrix. In fact, there is a correlation between copper-depletion cancer therapies and a reduction of VEGF levels. It is reasonable to speculate that a low VEGF may at least in part involve a copper deficiency. High or low VEGF may also be an indicator of extracellular matrix dysfunction, due to the regulatory effect the ECM plays with VEGF utilization.
• ADH/Osmolality – One symptom of mold exposure is increased urination frequency and unquenchable thirst. This implicates a suppression of ADH (antidiuretic hormone), which is thought to be a result of a dysregulation to the hypothalamic/pituitary regulation of hormones caused by mold exposure. ADH is also known as vasopressin.
• MARCoNS Testing – While not definitively caused by CIRS, marcons is a type of resistant, biofilm-producing staph infection that can reside in the deep sinuses. MARCoNS is also believed to be harbored in the mouth in dental cavitations. While many people who test positive for Marcons are symptomatic for sinusitis, there’s a large percentage of people that don’t have sinusitis symptoms. Nonetheless, marcons is believed to complicate CIRS treatment, and may create damage to the brain, leading to the suppression of MSH (melanocyte stimulating hormone). Marcons testing is a nasal swab, ordered through MicrobiologyDx.
• Great Plains (GPL) Urinary Mycotoxins Test – Unlike other urinary mycotoxin tests that utilize ELISA testing, which is prone to false positives, the GPL urinary mycotoxin test utilizes LC/MS (liquid chromatography mass spectrometry), which identifies the mass of the mycotoxin present. The GPL urinary mycotoxins test measures 8 different mycotoxins derived from 4 different types of molds: aspergillus, penicillium, stachybotrys and fusarium. This test is a very valuable way to identify the presence of mold exposure. Because it is a urine test, this option makes it more available and convenient to evaluate the presence of mold internationally.
• Great Plains Urinary OAT (organic acids test) – The OAT test does not specifically identify mold or mycotoxins, but according to an association-based study conducted by Great Plains Laboratory, several of the analytes on the test have been shown to correlate with mold and mycotoxins, when the OAT and urinary mycotoxin test were run side by side. This is true of: Lactate, 5-Hydroxymethyl-2-furioc, Furan-2,5-dicarboxylic, Pyroglutamate, Tricarballylic, Citramalic (18). These markers may be elevated for other reasons. The OAT is an extremely useful test for evaluating other biochemical parameters related to: GI dysbiosis, candida overgrowth, SIBO, mitochondrial function, energy metabolism, neurotransmitter balance, antioxidant function, nutrient sufficiencies, thyroid & redox indicators, and many others.

New Era For Mold Illness Treatments

There are now many different functional medicine-oriented approaches for mold-related illness. These have come from the realization that pharmaceutical and conventional medicine approaches to mold-related illness often fall short. An integrative and functional medicine approach should consider supporting the physiology through a holistic manner. There are keys to addressing biotoxins, through understanding how the physiology is being disrupted.

Leaving the water damaged building is the single most important thing anyone with mold-related illness needs to do. If you don’t do this, the chances of getting better are lessened. It’s of great importance to re-test the ERMI once the building has been remediated. The following is a brief description of some of the physiological mechanisms that should be considered as targets for therapeutic modulation.

1. Tissue fluid balance & hydration – The loss of ECM integrity caused by MMP degradation will disrupt the osmotic pressure, and the fluid balance in the tissues. For example, a loss of hyaluronic acid (one of the primary GAGs in the ECM) will reduce ionized water from entering tissues (because hyaluronic acid itself increases tissue hydration). Increased urination due to dysregulated ADH will alter osmotic pressure and the water to solute balance necessary for cells and tissue to maintain proper electrolyte/fluid gradients. Addressing tissue hydration therapeutically is critical.
2. Functionally supporting energy metabolism – Its likely the case that capillary hypoperfusion (associated with VEGF) involves elevations in lactate. This is one reason for the neuropathy-related symptoms of CIRS, as well as post exercise fatigue. In a state of danger, the mitochondria of cells may shift metabolism from oxidative phosphorylation to aerobic glycolysis (21). This can disrupt the O2/Co2 balance, and disrupt ATP utilization as well as oxygen delivery. Working to support energy metabolism is critical.
3. Binding appropriately – A number of natural product binders have surfaced in recent years, with varying success rates. These are necessary to conjugate mold and mycotoxins and facilitate their removal and elimination from the body. Binding is necessary.
4. Reducing/supporting The immune & inflammatory processes – As already mentioned, innate immune deficiencies are common. These will most likely impair the immune system’s ability to clear mycotoxins, and lead to chronic inflammatory states. We can look to certain natural products to support the immune system in different ways, including means to modulating the innate immune system. For example we can reduce inflammasome activation through ketosis and intermittent fasting (22). We can utilize polysaccharides in some cases to provide extra ammunition for immune glycosylation.

It’s important to consider that therapies need to be customized to the needs of the individual.