Mold Illness & CIRS: The Comprehensive Protocol

The Invisible Epidemic

Water damage affects 50% of buildings in the United States. When building materials stay wet for more than 48 hours, mold colonizes. The mold produces mycotoxins — secondary metabolites that are among the most toxic naturally occurring compounds on Earth. Aflatoxin (from Aspergillus) is a class 1 carcinogen. Trichothecenes (from Stachybotrys, the infamous “black mold”) inhibit protein synthesis at the ribosomal level — the same mechanism as certain biological warfare agents. Ochratoxin A (from Aspergillus and Penicillium) is nephrotoxic and neurotoxic.

Most people inhale these compounds, mount an appropriate immune response, tag the biotoxins for removal, and clear them without issue. But approximately 24% of the population — those with specific HLA-DR haplotypes — cannot. Their immune system recognizes the toxins as foreign but cannot effectively clear them. The biotoxins circulate, triggering a self-amplifying inflammatory cascade that Ritchie Shoemaker at the Center for Research on Biotoxin Associated Illness termed Chronic Inflammatory Response Syndrome — CIRS.

The Biotoxin Pathway

Shoemaker mapped the pathophysiology in detail. The cascade:

1. Biotoxin exposure: Mycotoxins enter the body through inhalation (primary route — aerosolized from contaminated building materials), ingestion (contaminated food), or skin contact
2. Innate immune activation: Toll-like receptors (particularly TLR4) recognize the biotoxins and trigger the innate immune system. In HLA-susceptible individuals, the adaptive immune system fails to produce adequate antibodies to tag the toxins for clearance
3. Cytokine storm: Uncleared biotoxins continuously stimulate innate immunity, producing chronic elevation of inflammatory cytokines: TGF-beta 1, MMP-9, C4a, and others
4. Complement activation: C4a splits elevate, indicating complement pathway activation
5. Hormone disruption: The chronic inflammation suppresses melanocyte-stimulating hormone (MSH), vasoactive intestinal peptide (VIP), and antidiuretic hormone (ADH) while elevating leptin, VEGF, and cortisol/ACTH
6. Multi-system dysfunction: MSH deficiency alone causes fatigue, pain, cognitive impairment, immune dysregulation, leaky gut (MSH maintains gut barrier integrity), and susceptibility to resistant staph colonization (MARCoNS) in the nasal passages

The result is a patient who feels terrible in every system, gets no answers from conventional medicine (because each specialist sees only their organ system), accumulates diagnoses (fibromyalgia, chronic fatigue, IBS, depression, anxiety, POTS), and is often told it is psychosomatic.

Genetics: The HLA-DR Connection

Human Leukocyte Antigen (HLA) genes code for proteins on antigen-presenting cells that display foreign proteins to T-cells, initiating adaptive immunity. Certain HLA-DR haplotypes — the “dreaded genotypes” in Shoemaker’s parlance — produce proteins that cannot effectively present biotoxins to the adaptive immune system.

Key susceptible haplotypes:

• 11-3-52B: “Dreaded” — multi-susceptible to mold, Lyme, and other biotoxins
• 4-3-53: Mold susceptible
• 12-3-52B: Mold susceptible
• 14-5-52B: Multi-susceptible
• 7-2-53: Low MSH, susceptible to mold-related illness

Approximately 24% of the population carries at least one susceptible haplotype. This does not mean they will develop CIRS — it means they cannot clear biotoxins efficiently. Exposure plus genetics equals illness. Remove either variable and the syndrome does not develop.

Testing: HLA-DR typing is done via blood test (Quest Diagnostics, LabCorp). This is not genetic testing in the consumer sense — it is typing the immune system’s recognition proteins.

The Symptom Clusters

CIRS produces 35+ symptoms across 13 clusters. The simultaneous involvement of multiple unrelated systems is the diagnostic clue. A patient with fatigue alone could have anything. A patient with fatigue + brain fog + joint pain + sinus congestion + morning stiffness + static shocks + excessive thirst + temperature dysregulation + light sensitivity + mood instability — that cluster pattern is CIRS until proven otherwise.

Cognitive: Brain fog (the most universally reported symptom), word-finding difficulty, short-term memory loss, difficulty concentrating, executive function impairment, disorientation, difficulty assimilating new information

Neurological: Headaches, light sensitivity, numbness/tingling (peripheral neuropathy), vertigo, metallic taste, tremors, tics, seizures (rare), ice-pick pains

Musculoskeletal: Joint pain (migratory, often without swelling), morning stiffness, muscle aches, cramping, weakness

Respiratory: Chronic sinus congestion, shortness of breath, air hunger, cough, recurrent sinusitis

Gastrointestinal: Abdominal pain, diarrhea, nausea, appetite changes, food sensitivities (often increasing over time)

Autonomic: Temperature dysregulation, excessive sweating or inability to sweat, POTS-like symptoms, static shocks (dysautonomia marker)

Psychiatric: Anxiety, depression, irritability, mood swings, depersonalization, panic attacks. These are inflammatory, not primary psychiatric — they resolve when the inflammation resolves

Constitutional: Profound fatigue, weakness, excessive thirst (ADH dysregulation), frequent urination, weight gain resistance (leptin resistance)

Testing: Building the Case

Visual Contrast Sensitivity (VCS)

A screening test — not diagnostic, but highly sensitive. The patient views a series of contrast patterns and identifies the direction of lines at various spatial frequencies. Biotoxin exposure impairs the neurological processing of contrast (capillary inflammation in the optic nerve and visual cortex). Online VCS testing is available (SurvivingMold.com). Sensitivity: ~92%. Specificity: ~65%. A failed VCS in a patient with multi-system symptoms and a history of water-damaged building exposure strongly suggests CIRS.

The Shoemaker Panel

Marker	Normal Range	CIRS Pattern	What It Means
TGF-beta 1	<2380 pg/mL	Often >5000, sometimes >10,000	Fibrotic cytokine, autoimmune trigger
MMP-9	<332 ng/mL	Elevated	Matrix metalloproteinase — breaks down basement membranes, increases permeability
MSH	35-81 pg/mL	Often <35, sometimes undetectable	Master regulatory hormone — low = immune, gut, sleep, pain dysregulation
VIP	23-63 pg/mL	Often <23	Vasoactive intestinal peptide — anti-inflammatory, regulates blood flow, pulmonary artery pressure
VEGF	31-86 pg/mL	Often elevated or suppressed	Vascular endothelial growth factor — dysregulated angiogenesis
C4a	<2830 ng/mL	Elevated	Complement activation
ADH/Osmolality	ADH 1.0-13.3 pg/mL, Osm 280-300	ADH low with high osmolality	Thirst/hydration dysregulation
ACTH/Cortisol	ACTH 8-37 pg/mL, AM cortisol 4.3-22.4	Dysregulated ratio	HPA axis disruption
Leptin	Male 0.5-13.8, Female 1.1-27.5 ng/mL	Elevated	Leptin resistance — drives weight gain, cytokine production

Mycotoxin Urine Testing

• RealTime Laboratories: Tests for aflatoxins, ochratoxin A, trichothecenes, gliotoxin, zearalenone, chaetoglobosin A, mycophenolic acid, sterigmatocystin, enniatin B, roridin E in urine
• Great Plains Laboratory (Mosaic Diagnostics): Similar panel with slightly different analytes
• Provocative testing: Some clinicians use glutathione 500mg IV or oral, sauna, or exercise before collection to mobilize stored mycotoxins, increasing detection sensitivity
• Controversy: some argue urine mycotoxin testing has poor specificity and that the presence of mycotoxins in urine simply reflects recent dietary exposure (mycotoxins are common in coffee, grains, wine). Others argue that the quantity and pattern distinguish pathological exposure from dietary background

Environmental Testing

• ERMI (Environmental Relative Moldiness Index): Dust sample from the home analyzed by QPCR for 36 mold species. Score >2 is elevated; score >5 is high. The most validated environmental test
• HERTSMI-2: Simplified version — tests for 5 key toxigenic species (Aspergillus penicillioides, A. versicolor, Chaetomium globosum, Stachybotrys chartarum, Wallemia sebi). Score <11 is acceptable for CIRS patients to safely occupy
• Air sampling: Captures airborne spore counts. Less reliable than dust testing (spore counts vary hour-by-hour with air movement, humidity, and activity)
• Mold inspection: ACAC (American Council for Accredited Certification) certified inspectors use moisture meters, thermal imaging, and visual inspection to identify water damage sources

The Shoemaker Protocol (12 Steps)

Step 1: Remove From Exposure

This is absolute. No supplement, binder, or medication will resolve CIRS if the patient continues living or working in a water-damaged building. The biotoxin source must be eliminated — either by professional remediation or by moving. This is the hardest step because it is the most expensive and disruptive. It is also the most important.

Step 2: Cholestyramine (CSM) or Welchol

Cholestyramine (CSM) 4g, four times daily, taken at least 30 minutes before meals and 1 hour away from other medications and supplements. CSM is a bile acid sequestrant that binds biotoxins in the GI tract, preventing enterohepatic recirculation (biotoxins are excreted in bile, reabsorbed in the ileum, and recirculated — this is why CIRS persists even after leaving the moldy environment). CSM is the most potent binder studied in Shoemaker’s protocol.

Welchol (colesevelam): Alternative for patients who cannot tolerate CSM (CSM commonly causes constipation, bloating, nausea). Welchol is gentler but may be less effective per dose.

Duration: typically 1-3 months, guided by VCS retesting and symptom improvement.

Step 3: MARCoNS Treatment

MARCoNS (Multiple Antibiotic Resistant Coagulase Negative Staphylococci): Deep nasal colonization with antibiotic-resistant staph. Present in approximately 80% of CIRS patients with low MSH (MSH is antimicrobial — when it drops, resistant organisms colonize the nasal passages and produce biofilm). These organisms in turn produce exotoxins that further suppress MSH — a self-perpetuating cycle.

Testing: deep nasal culture with API (Antimicrobial Peptide Investigation) from Microbiology DX.

Treatment: BEG spray (Bactroban/EDTA/Gentamicin compounded nasal spray) for 30 days, combined with biofilm disruptors. Some practitioners use colloidal silver nasal spray or xylitol-based rinses as alternatives.

Steps 4-12: Sequential Correction

Each subsequent step corrects a specific biomarker abnormality in order:

4. Correct ADH/osmolality: DDAVP if severely dysregulated
5. Correct androgens: Address testosterone/DHEA if depleted
6. Correct MMP-9: Anti-inflammatory diet, omega-3, no-amylose diet (Shoemaker’s recommendation — removes starches that elevate MMP-9)
7. Correct VEGF: Exercise (VEGF responds to physical activity)
8. Correct C4a: Often improves with binder therapy and removal from exposure
9. Correct TGF-beta 1: If persistently elevated after above steps — Losartan 25-50mg (AT1 receptor blocker that reduces TGF-beta 1). VIP nasal spray
10. Replace VIP: Vasoactive intestinal peptide nasal spray (compounded) — the final step. VIP is anti-inflammatory, corrects pulmonary artery hypertension, reduces cytokines, and produces significant clinical improvement. Only initiated after prior steps are completed (giving VIP with ongoing exposure or uncorrected markers is ineffective)

The Naturopathic/Integrative Approach

Many functional medicine practitioners use a modified approach that addresses the same pathways with different tools:

Binders (Alternatives to CSM)

Binder	Dose	Affinity
Activated charcoal	500-1000mg 2x daily	Broad spectrum — binds many mycotoxins
Bentonite clay	1 tsp in water 1-2x daily	Aflatoxin, ochratoxin
Chlorella	2-5g daily	Heavy metals, some mycotoxins
Modified citrus pectin	5-15g daily	Heavy metals, broad toxin binding
Humic/fulvic acid	Per product	Broad spectrum chelation
Saccharomyces boulardii	500mg 2x daily	Binds C. difficile toxin, supports gut during antimicrobial treatment
Cholestyramine	4g 4x daily	Gold standard — strongest evidence

All binders must be taken 30-60 minutes away from food and 2 hours away from supplements and medications (they bind indiscriminately).

Glutathione Support

Glutathione is the body’s master antioxidant and the primary Phase II conjugation pathway for mycotoxin clearance. CIRS patients are typically glutathione-depleted.

• NAC 600-1200mg twice daily (glutathione precursor)
• Liposomal glutathione 250-500mg twice daily
• Glycine 3-5g daily (glutathione synthesis)
• Alpha-lipoic acid 300-600mg (recycles glutathione)
• Selenium 200mcg (glutathione peroxidase cofactor)
• Milk thistle 200-400mg (hepatoprotective, glutathione support)

Liver and Drainage Support

Mobilizing toxins without adequate drainage pathway support produces redistribution — the patient feels worse. Before intensifying binder therapy, ensure:

• Regular bowel movements (at least once daily — magnesium, fiber, hydration)
• Kidney function adequate (hydration, electrolytes)
• Lymphatic movement (dry brushing, exercise, rebounding)
• Liver support (milk thistle, dandelion, artichoke, NAC)
• Sweating (sauna when tolerated)

Environmental Remediation

Fix the water source first: Leaking roof, plumbing leak, condensation, foundation water intrusion — the moisture source must be identified and repaired before remediation begins. Remediating mold while the water continues is futile.

Professional remediation: Not DIY. Disturbing mold colonies without proper containment aerosolizes massive quantities of spores and mycotoxins. IICRC-S520 certified remediators use containment, negative air pressure, HEPA vacuuming, antimicrobial treatment, and proper disposal.

HEPA filtration: IQAir, Austin Air, or similar medical-grade HEPA air purifiers with activated carbon. One unit per major room. HEPA filters capture particles down to 0.3 microns — most mold spores are 1-30 microns. Change filters per manufacturer schedule.

Post-remediation verification: ERMI or HERTSMI-2 retesting after remediation to confirm the environment is safe. Target HERTSMI-2 <11.

Limbic System Retraining

CIRS produces a state of limbic system hyperactivation — the brain’s threat-detection center becomes stuck in “on” mode. Even after toxin clearance, the limbic system may continue generating symptoms through maladaptive neural pathways. This explains why some patients plateau despite successful binder therapy and environmental remediation.

DNRS (Dynamic Neural Retraining System — Annie Hopper): A self-directed neuroplasticity program that uses visualization, movement, and cognitive restructuring to rewire limbic system threat responses. Patients practice 1 hour daily for 6 months minimum. Anecdotal and survey-based evidence shows significant improvement in chemical sensitivity, food reactivity, and CIRS symptoms.

Gupta Programme (Ashok Gupta): Similar neuroplasticity-based approach, rooted in the amygdala hypothesis of chronic illness. Combines meditation, visualization, and somatic awareness to interrupt the threat-response loop.

These programs are not suggesting the illness is “in your head.” They are addressing the documented neurological consequence of chronic biotoxin exposure — a limbic system that has been trained by months or years of inflammation to perceive threat everywhere. Retraining it is as legitimate a therapeutic intervention as binding toxins or supporting liver function.

Die-Off and Detox Management

Mobilizing mycotoxins from tissue stores into circulation for excretion can temporarily worsen symptoms — a Herxheimer-like reaction. Management:

• Go slowly — increase binder doses gradually over weeks
• Ensure adequate binders are taken BEFORE increasing mobilization
• Support drainage pathways (bowels, kidneys, lymph, skin)
• Hydrate aggressively (2-3 liters daily)
• Epsom salt baths (magnesium sulfate — supports both detox and relaxation)
• Reduce the pace if symptoms become intolerable — this is a marathon, not a sprint
• Typical CIRS treatment timeline: 6-18 months for significant recovery, depending on genetics, exposure duration, and environmental control

Recovery is possible. But it requires getting out of the moldy building, binding the toxins, supporting the biochemistry, and retraining the brain. Miss any of these four pillars, and the house of cards does not hold.

If your environment is making you sick and no one has thought to test the building, what else might be hiding in plain sight?