Chronic Inflammatory Response Syndrome (CIRS)

Many people who feel unwell after living or working in a water-damaged building come across CIRS while searching for answers. This page explains the CIRS model clearly and fairly, in the words of the people who developed it, and alongside the views of doctors who disagree.

What CIRS is (the Shoemaker model)

According to a 2018 consensus statement from the Surviving Mold committee, CIRS is a systemic inflammatory illness that can follow exposure to “biotoxins and inflammagens” found ^[1]:

• inside water-damaged buildings (the most common source, sometimes written CIRS-WDB);
• in blooms of toxic blue-green algae (cyanobacteria);
• in reef fish carrying ciguatera toxin; and
• after confirmed acute Lyme disease when symptoms persist despite antibiotics.

In this model, the innate immune system (the body’s first-line defense) stays switched on instead of settling down. CIRS practitioners describe low levels of the regulatory hormones MSH and VIP and high levels of inflammatory markers such as C4a, MMP-9 and TGF-β1 ^[1].

Genetics. Dr. Shoemaker estimates that about 24% of people carry HLA gene types that may make it harder to clear these biotoxins ^{[7, 8]}. This figure comes from his clinical research and hasn’t yet been confirmed by large independent studies. Dr. Shoemaker himself has written that “HLA research is in its infancy” and that a large multi-site study would be needed ^[8].

Common symptoms

The consensus statement lists 37 symptoms, grouped into 13 “clusters.” CIRS practitioners treat having 8 or more of the 13 clusters (6 for children) as supporting a CIRS diagnosis ^[1]. The clusters are:

1. Fatigue
2. Weakness, aches, headache, light sensitivity, trouble absorbing new information
3. Memory problems, trouble finding words
4. Poor concentration
5. Joint pain, morning stiffness, cramps
6. Unusual skin sensations, tingling
7. Shortness of breath, sinus congestion
8. Cough, excessive thirst, confusion
9. Appetite swings, trouble regulating body temperature, frequent urination
10. Red eyes, blurred vision, sweats, mood swings, sudden “icepick” pains
11. Abdominal pain, diarrhea, numbness
12. Watery eyes, disorientation, metallic taste
13. Static shocks, vertigo

These symptoms overlap with many other conditions, and critics describe symptoms like these as vague and hard to measure ^[5]. Whatever the cause turns out to be, a careful workup should rule out other treatable conditions.

Causes and risk factors (as described by CIRS practitioners)

• Water-damaged buildings are the most commonly reported trigger ^{[1, 2]}. Indoor air in these buildings can contain a mix of fungi, mycotoxins, bacteria, endotoxins and chemicals released by damp materials ^[9].
• Other biotoxin sources in the model are cyanobacteria, ciguatera and Lyme disease ^[1].
• Genetic susceptibility through HLA-DR gene types, as described above ^[7].
• Re-exposure. In Dr. Shoemaker’s early studies, participants who improved and then went back into their water-damaged buildings reported relapse within days ^{[9, 10]}.

How CIRS is diagnosed

There is no single test for CIRS. The consensus statement describes a case definition with four parts ^[1]:

1. The potential for exposure to a damp indoor space.
2. A multi-system, multi-symptom illness similar to cases in published studies.
3. Lab results similar to those in published studies.
4. Documented response to therapy.

A later case definition (McMahon, 2017) does not require response to treatment, because adherence can be difficult ^[2].

Tools CIRS practitioners commonly use ^{[1, 3]}:

• Symptom inventory and cluster analysis (above).
• Visual contrast sensitivity (VCS): a vision test of how well you can see low-contrast patterns, used in the model as a sign of neurologic involvement. In early studies, VCS was abnormal in almost all participants and improved with treatment ^{[9, 10]}.
• Blood markers: MSH, VIP, ADH and osmolality, C4a, TGF-β1, MMP-9, VEGF and HLA-DR typing. In plain terms, the model looks for low levels of regulatory hormones and high levels of inflammation markers ^[1].
• A deep nasal swab for MARCoNS (multiple antibiotic-resistant coagulase-negative staph), which CIRS practitioners believe can worsen the illness ^[3].
• NeuroQuant, MRI software that measures brain-region volumes. A study of 17 patients and 18 controls reported differences in several brain areas ^[11].
• Building testing with ERMI or HERTSMI-2 dust tests ^{[3, 12]}. The EPA, which developed ERMI, says it is a research tool not validated for routine public use ^{[13, 14]}.

What to know about these tests. Most of the individual markers are real lab tests. Using them together as a CIRS panel comes from Dr. Shoemaker’s group, and we did not find independent validation of that approach. Dr. Shoemaker’s own early study listed limitations: participants were not randomly selected, double-blinding was not used, and exposure to specific agents was not demonstrated ^[10].

Who diagnoses it? Mostly Shoemaker-trained or “mold-literate” practitioners. Surviving Mold keeps a practitioner directory (linked below). Many mainstream doctors are unfamiliar with CIRS or don’t accept it as a diagnosis ^{[4, 5]}.

Treatment: the Shoemaker Protocol

The Shoemaker Protocol is the best-known and most-published treatment approach for CIRS ^[2]. As summarized by one Shoemaker-trained physician, it works through these steps in order, each guided by lab results ^[3]:

• Step 1: Remove exposure. Test the buildings you spend time in and remediate or move if needed. The summary calls this the most critical, yet most difficult, step.
• Step 2: Binders (prescription cholestyramine or colesevelam/Welchol), which are thought to help remove biotoxins through the gut.
• Step 3: Treat MARCoNS if a nasal swab finds it.
• Step 4: Address anti-gliadin antibodies (a gluten-related marker) with a gluten-free diet if positive.
• Step 5: Correct androgen (sex hormone) imbalances.
• Step 6: Correct ADH/osmolality problems, which can cause thirst, frequent urination and static shocks; the medicine used requires blood sodium monitoring.
• Steps 7–11: Address MMP-9, VEGF, C3a, C4a and TGF-β1 with diet changes or prescription medicines.
• Step 12: VIP nasal spray, used last, and only once exposure is removed, VCS is normal and MARCoNS is cleared.

Every step should be supervised by a clinician. Several involve prescription medicines with side effects and lab monitoring ^[3].

What the evidence shows. A 2024 review by Surviving Mold-affiliated authors found 13 published articles on CIRS treatment; 11 described the Shoemaker Protocol, which was the only treatment with documented clinical efficacy ^[2]. The authors note their review “was not a systematic review” ^[2]. The trials behind it are small: for example, a double-blind, placebo-controlled trial of cholestyramine with 13 participants ^[9].

Practical barriers. The same review lists cost, adherence and side effects as the main limitations. Removing exposure can cost tens of thousands of dollars or more, and medication intolerance is a common problem ^[2].

Living with CIRS: practical day-to-day help

• Start with your environment. Moisture control helps whatever the diagnosis: keep humidity low, dry leaks within 24–48 hours, and get professional help for large or contaminated areas ^{[15, 16]}. Our remediation decision tree and mold toxicity page cover this in more detail.
• Make one change at a time when you can, and keep a symptom log. It makes it easier for you and your clinician to see what’s helping.
• Plan for cost. Ask up front what testing and treatment will cost and what insurance may cover. The 2024 review notes that removing exposure (remediation or moving) can cost tens of thousands of dollars or more ^[2].
• Bring a summary to appointments: your exposure history, symptom timeline and past results. Our CIRS starter checklist can help.
• Protect your mental health. Being told it’s “all in your head” hurts. Support from a counselor or a trusted community can help, and if you are in crisis you can call or text 988 in the U.S. ^[17].

How CIRS overlaps with the other conditions

• Mold toxicity. CIRS is the most detailed model behind the broader term “mold toxicity” ^[1].
• MCAS. Many people report both. The two camps sometimes read the same sign differently: the CIRS consensus statement says skin writing (dermatographia), which some providers see as a sign of mast cell activation, reflects raised C4a in CIRS ^[1].
• POTS. The consensus statement says about 60% of CIRS patients have ADH/osmolality problems and tells clinicians to look for low blood volume ^[1]. People with POTS also often have low blood volume ^[18]. Some people connect the two this way, but that link is a hypothesis.
• hEDS. We did not find research linking CIRS and hEDS, which is considered a heritable connective tissue disorder ^[19].

What’s known and what’s debated

Generally accepted: water-damaged buildings are linked to respiratory symptoms, allergies and asthma, and moisture should be fixed ^{[16, 20, 21]}.

Supported mainly by the Shoemaker group: the CIRS case definition, the 13-cluster symptom analysis, the biomarker panel, the HLA estimate and the Protocol ^{[1, 2, 7]}.

Disputed by other experts:

• The AAAAI’s position paper says many proposed mold-related illnesses “remain largely or completely unproved” ^[4].
• A 2019 review argues that “toxic mold syndrome” has been disproven ^[5].
• A 2023 German guideline found no evidence linking indoor mold to conditions such as chronic fatigue syndrome, neurotoxic effects or multiple chemical sensitivity ^[6].

You may hear both views from different doctors. It’s reasonable to ask any clinician what evidence supports their recommendations.

The MTHFR gene and CIRS

You may see MTHFR gene results mentioned in mold and CIRS communities. Here’s what’s known and what’s debated. For the histamine side, see MTHFR and MCAS.

What the MTHFR gene is and what it does

Genes are made of DNA, and many of them are instructions the body uses to make proteins ^[41]. Most people have two copies of each gene, one from each parent ^[41]. A gene variant is a permanent change in a gene’s DNA ^[42]. It used to be called a “mutation,” but changes in DNA do not always cause disease ^[42]. The most common kind of variant is a one-letter change called a SNP (said “snip”) ^[43]. SNPs are normal: each person has roughly 4 to 5 million of them, and most have no effect on health ^[43].

The MTHFR gene carries the instructions for an enzyme called methylenetetrahydrofolate reductase ^[44]. This enzyme turns folate (vitamin B9) into its active form, 5-methyltetrahydrofolate (5-MTHF), the main form of folate in the blood ^[44]. Active folate supplies a methyl group so that, with help from vitamin B12, the body can recycle homocysteine, an amino acid, into another amino acid, methionine ^[45]. The body then uses methionine to make SAMe (S-adenosylmethionine), a methyl donor for many reactions ^{[45, 46]}.

1. Step 1
   Folate (vitamin B9) comes from food.
2. ↓
   Step 2
   The MTHFR enzyme turns it into active folate (5-MTHF).
3. ↓
   Step 3
   Active folate and vitamin B12 recycle homocysteine into methionine.
4. ↓
   Step 4
   Methionine is made into SAMe.
5. ↓
   Step 5
   SAMe donates methyl groups (methylation).

Methylation simply means attaching a tiny chemical tag, called a methyl group, to another molecule ^[47]. On DNA, these tags help turn genes on or off ^[47]. SAMe also supplies methyl groups to neurotransmitters (the brain’s chemical messengers), proteins and other molecules ^[45]. For example, the enzyme HNMT breaks down histamine by methylation, using SAMe ^[48].

The two best-known MTHFR variants, C677T and A1298C, are named for their place in the gene and the DNA letter that changed ^{[44, 49]}. They are very common: more people in the U.S. have one or two copies of C677T than don’t ^[49]. Having one copy of a variant is called heterozygous, and two copies homozygous ^{[50, 51]}. One copy of each variant is called compound heterozygous ^[52]. In lab tests, the C677T enzyme works at about 65% of normal with one copy and about 30% with two ^[53]. A1298C has a smaller effect: two copies leave about 60% of normal activity ^{[53, 54]}, and one copy of each variant left 50–60% in one study ^[54].

When MTHFR works more slowly, homocysteine can build up, mainly in people with two copies of C677T ^[44]. Folate, vitamin B12 and vitamin B6 all help break down homocysteine, so B-vitamin levels matter too ^[55]. Researchers have reported that people with two copies of C677T have higher homocysteine mainly when their folate status is low; with enough folate, homocysteine is low regardless of genotype ^{[54, 56]}. A1298C alone has not been linked to higher homocysteine ^[57].

A variant is not a disease or a diagnosis. Most gene variants have no effect on health ^[58], and ACMG says one copy of C677T, two copies of A1298C, or one of each is “unlikely to be of clinical significance” ^[52]. Because methylation is one of the chemical steps the body uses to clear substances, some practitioners link MTHFR to “detox,” as described below ^[59].

What mainstream medicine says

The American College of Medical Genetics and Genomics (ACMG) says MTHFR testing “has minimal clinical utility” and should not be part of a routine workup for blood clots ^[52], a position it reaffirmed in 2020 ^[60]. The American College of Obstetricians and Gynecologists (ACOG) does not recommend MTHFR or fasting homocysteine screening in pregnancy ^[61]. ACMG also warns that it is “not uncommon” for medical problems to be “incorrectly attributed to positive MTHFR status” ^[52]. The CDC says people with MTHFR variants “can process all types of folate, including folic acid,” and calls the advice to avoid folic acid “not true” ^[49].

MedlinePlus says a homocysteine blood test may be ordered if you’re at high risk for low vitamin B12 or folate, though routine screening for heart disease risk “isn’t recommended for everyone” ^[55].

Where the evidence stands: We searched PubMed in October 2026 and found no published studies of MTHFR in people with CIRS or mold illness ^[63]. ACMG notes there is “no evidence that specific treatments reduce risks associated with hyperhomocysteinemia or MTHFR genotype status” ^[52].

What to do next

General information, not a diagnosis or a treatment plan. A licensed clinician can tell you which of these steps fit you.

1. Step 1Start this week

   • Make notes about your symptoms before your visit: when they started, how often they happen and whether they’re getting better or worse ^[66].
   • List the buildings where you live and work, with any leaks, musty smells or water damage, since the CIRS case definition starts with possible exposure to a damp indoor space ^[1].
   • Our symptom checklist can help you organize what you notice.

2. Step 2Choose who to see

   • Start with your primary care doctor: AHRQ calls your doctor “the first person to ask” ^[67].
   • Many mainstream doctors are unfamiliar with CIRS or don’t accept it as a diagnosis ^{[4, 5]}.
   • To find a CIRS clinician, patients can use Surviving Mold, Dr. Shoemaker’s website, which lists physicians certified in the Shoemaker Protocol through his own program ^[68]. Evidence: a directory run by the model’s developer, not an independent medical board.
   • For occupational and environmental medicine, the AOEC directory lists clinics in the U.S. and Canada ^[69].
   • See also the provider directories on our homepage.

3. Step 3Tests to ask about

   • CIRS practitioners use a vision test (VCS) and a panel of blood markers ^[1]. We found no independent validation of the panel as a whole, and Dr. Shoemaker’s early study listed its own limitations ^[10]. Evidence: contested.
   • The CDC has warned about urine mycotoxin tests that haven’t been validated for diagnosing illness ^[37].
   • For your building, start with moisture: the EPA says “the key to mold control is moisture control” ^[15]. The CDC doesn’t recommend routine mold sampling ^[16], and the EPA calls the ERMI dust test a research tool not validated for routine public use ^{[13, 14]}.

4. Step 4Everyday steps mainstream sources support

   • Removing exposure comes first in both mainstream mold guidance and the Shoemaker Protocol ^{[3, 15, 16]}.
   • Fix the water problem, dry wet areas quickly and get professional help for large or contaminated areas ^{[15, 16]}.
   • If you start the Protocol, its prescription steps need clinician supervision and lab monitoring ^[3].

5. Step 5Prepare for the appointment

   • Bring a list of all the medicines you take ^[67]. Our Doctor visit prep sheet has space for your exposure history, symptom timeline and past results.
   • If you feel dismissed, consider a second opinion: AHRQ says wanting one “is not pushy or rude” and suggests asking for a doctor who doesn’t work in the same office ^[67].
   • For home guidance, the EPA’s mold and moisture guide is a reliable starting point ^[15].
   • Then use the Questions to ask your doctor below.

6. Step 6When to get urgent care

   • Call 911 for sudden crushing chest pressure, or chest pain with shortness of breath ^[22], or if someone faints and doesn’t become alert within a couple of minutes ^[23]. If you’re having thoughts of suicide, call or text 988 ^[17].
   • See the full list under When to get urgent help.

Questions to ask your doctor

• What else could explain my symptoms, and have we ruled those out?
• If you’re testing CIRS markers, what will we do differently depending on the results?
• Would a homocysteine, vitamin B12 or folate blood test be useful for me, and would MTHFR testing change anything about my care?
• Which step of the Protocol are we on, how will we know it’s working, and what side effects should I watch for?
• What labs will you use to monitor my safety on each medicine?
• Do I need to change buildings before treatment can work, and how should we test them?
• How much will testing and treatment cost?

Sources

Numbers in brackets in the text link to these sources. Links were checked in October 2026. Some sources are written by people who support a particular approach; we've tried to say so in the text.

1. Shoemaker R, Johnson K, Jim L, 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;4(5). https://www.survivingmold.com/Publications/CIRS_diagnostic_protocol_final_5_1_2018.pdf
2. Dooley M, Vukelic A, Jim L. Chronic inflammatory response syndrome: a review of the evidence of clinical efficacy of treatment. Ann Med Surg (Lond). 2024;86(12):7248-7254. PMID: 39649915. https://pmc.ncbi.nlm.nih.gov/articles/PMC11623837/
3. Ou D. Steps of the Shoemaker Protocol (2014; hosted by Surviving Mold). https://www.survivingmold.com/STEPS_OF_THE_SHOEMAKER_PROTOCOL_3.PDF
4. Bush RK, Portnoy JM, Saxon A, Terr AI, Wood RA. The medical effects of mold exposure (AAAAI position paper). J Allergy Clin Immunol. 2006;117(2):326-333. PMID: 16514772. https://doi.org/10.1016/j.jaci.2005.12.001
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6. Hurraß J, Heinzow B, Walser-Reichenbach S, et al. AWMF mold guideline "Medical clinical diagnostics for indoor mold exposure" - Update 2023. Allergol Select. 2024;8:90-198. PMID: 38756207. https://pmc.ncbi.nlm.nih.gov/articles/PMC11097193/
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