The Shoemaker Protocol:

A Comprehensive Review of the Diagnosis and Treatment of

Chronic Inflammatory Response Syndrome (CIRS)

Yoon Hang Kim, MD, MPH

Board-Certified Integrative Medicine Physician

Disclaimer: This article is for educational and informational purposes only and does not constitute medical advice. Always consult with a qualified healthcare provider before beginning any new medical protocol. The views expressed herein represent a balanced academic review of current literature.

Introduction

In the expanding landscape of environmental and functional medicine, few conditions have generated as much scholarly debate as Chronic Inflammatory Response Syndrome (CIRS). First described in the late 1990s by Ritchie Shoemaker, MD, CIRS is characterized as a multi-system, multi-symptom illness arising from chronic exposure to biotoxins—most commonly from the interior environments of water-damaged buildings (WDB). Over the past three decades, Shoemaker developed a sequential, 12-step therapeutic framework known as the Shoemaker Protocol, which remains the only published treatment approach with documented clinical efficacy for this condition (McMahon et al., 2024).

The significance of this topic cannot be overstated. According to estimates, approximately 50% of buildings in the United States have some degree of water damage (Shoemaker & House, 2006), and an estimated 25% of the population carries genetic variants that may predispose them to chronic biotoxin illness (McMahon, 2017). If these estimates are accurate, the public health implications are staggering. Yet despite a growing body of published research, CIRS remains a contested diagnosis. Major organizations including the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) have not formally recognized CIRS as a distinct clinical entity, citing insufficient evidence of nonrespiratory health effects from indoor mold exposure (CDC, 2024; WHO, 2009).

This article provides a comprehensive, balanced review of the theoretical underpinnings, diagnostic criteria, treatment protocol, supporting evidence, and ongoing controversies surrounding CIRS and the Shoemaker Protocol. The goal is to equip clinicians, patients, and researchers with the academic context needed to evaluate this evolving field of medicine.

The Biotoxin Pathway: Theoretical Framework of CIRS

Genetic Susceptibility: The Role of HLA-DR

The central hypothesis of the CIRS model posits that approximately 24% of the population carries specific Human Leukocyte Antigen (HLA) gene variants—particularly on HLA-DR and HLA-DQ loci—that impair the adaptive immune system’s ability to recognize and clear certain biotoxins (Shoemaker, 2010). The HLA system, located on chromosome 6p21.3, encodes major histocompatibility complex (MHC) proteins that are among the most important genetic determinants of autoimmune and inflammatory susceptibility (Nordin, 2020).

In the CIRS model, when genetically susceptible individuals are exposed to biotoxins—including mycotoxins from species such as Stachybotrys chartarum and Aspergillus, as well as toxins from dinoflagellates (Pfiesteria) and cyanobacteria—the innate immune system activates but the adaptive immune system fails to produce appropriate antibodies. This creates a self-perpetuating inflammatory cascade that Shoemaker termed the “biotoxin pathway” (Shoemaker, 2010).

Supporting evidence for HLA-associated susceptibility has emerged from case reports. Almutairi et al. (2024) published four cases demonstrating that individuals with HLA-DR allele variations exhibited extremely slow mycotoxin elimination, with urinary mycotoxin levels remaining elevated more than two years after cessation of exposure. Knutsen et al. (2010) separately demonstrated associations between HLA-DR/HLA-DQ variants and mold sensitivity in children with moderate-to-severe asthma. However, it should be noted that the peer-reviewed evidence directly linking specific HLA types to the CIRS construct as described by Shoemaker remains limited to case studies and observational reports, and large-scale independent validation is still needed (Gardner, 2024).

The Innate Immune Cascade

According to the CIRS model, the persistence of uncleared biotoxins triggers a cascade of measurable inflammatory and neuroendocrine abnormalities. Key biomarkers that define this pathway include:

• Complement C4a: A split product of complement activation that serves as a marker of innate immune system activation. Elevated C4a levels (>20,000 ng/mL) are among the most characteristic findings in CIRS patients (Shoemaker et al., 2013).
• TGF-beta1 (Transforming Growth Factor beta-1): A multifunctional cytokine that, in excess, promotes tissue fibrosis, T-regulatory cell dysfunction, and autoimmune phenomena. CIRS patients frequently present with levels exceeding 12,000 pg/mL, over five times the normal range (Shoemaker et al., 2013).
• MMP-9 (Matrix Metalloproteinase-9): An enzyme involved in extracellular matrix degradation that increases blood-brain barrier permeability and contributes to neuroinflammation (Shoemaker & House, 2006).
• MSH (Melanocyte-Stimulating Hormone): A regulatory neuropeptide deficient in over 95% of CIRS patients. Low MSH contributes to sleep disturbances, chronic pain, gastrointestinal dysfunction, and susceptibility to nasal colonization by resistant bacteria (Shoemaker, 2010).
• VEGF (Vascular Endothelial Growth Factor): Crucial for oxygen delivery and capillary perfusion. Suppressed VEGF levels (<31 pg/mL) contribute to the fatigue, cognitive dysfunction, and exercise intolerance seen in CIRS (Shoemaker, 2010).
• VIP (Vasoactive Intestinal Peptide): A neuroimmune modulator deficient in over 98% of CIRS patients. VIP deficiency is associated with dysregulation of immune responses and hormonal axes (Shoemaker et al., 2013).

Neuroinflammation and Brain Volumetric Changes

One of the more compelling recent developments in CIRS research has been the use of NeuroQuant® MRI volumetric analysis to identify structural brain changes. McMahon et al. (2016) demonstrated that CIRS patients exhibit measurable changes in forebrain parenchymal volume, cortical grey matter, and specific nuclei such as the caudate and pallidum when compared to normative controls. These findings suggest that CIRS may represent a neuroinflammatory condition with objective, quantifiable CNS manifestations—a claim that, if independently replicated, would significantly strengthen the diagnostic framework.

Diagnostic Criteria and Case Definition

A formal consensus statement on the diagnostic process for CIRS was published in 2018 by the Consensus Committee of Surviving Mold (Shoemaker, Johnson, Jim, Berry, Dooley, Ryan, & McMahon, 2018). The diagnostic framework requires:

• Exposure history: Documented or probable exposure to the interior environment of a water-damaged building, or to other biotoxin sources (e.g., post-Lyme syndrome, ciguatera, cyanobacteria).
• Multi-system symptoms: Presence of symptoms in multiple organ systems consistent with published case series (typically 8 or more of 13 symptom clusters).
• Abnormal Visual Contrast Sensitivity (VCS): A functional vision test that detects neurotoxin-mediated impairment in contrast detection, which Shoemaker has used as both a screening and monitoring tool.
• Biomarker abnormalities: Abnormalities in a panel of innate immune and neuroendocrine markers (C4a, TGF-beta1, MMP-9, MSH, VIP, VEGF, ADH/osmolality, among others).
• HLA-DR genetic susceptibility: Presence of susceptible HLA haplotypes (found in approximately 95% of confirmed CIRS cases; McMahon, 2017).
• Exclusion of confounders: Ruling out other conditions that could explain the symptom presentation.

More recently, Shoemaker’s group has incorporated transcriptomic testing (genomic expression analysis via NanoString technology, termed GENIE) as an advanced diagnostic and monitoring tool, examining differential gene expression patterns in immune and metabolic pathways (Ryan & Shoemaker, 2016).

The Shoemaker Protocol: A Sequential Treatment Framework

The Shoemaker Protocol is structured as a hierarchical “pyramid,” with each step building on the one before it. This sequential approach is considered essential; attempting downstream interventions without addressing upstream causes has historically led to treatment failure (McMahon, 2013). Importantly, not all patients require every step—laboratory markers guide clinical decision-making throughout.

Phase 1: Removing the Source

Step 1: Removal from Exposure

The first and most critical step is eliminating ongoing biotoxin exposure. For patients with CIRS from water-damaged buildings (CIRS-WDB), this requires objective environmental assessment using quantitative PCR-based testing such as the ERMI (Environmental Relative Moldiness Index) or HERTSMI-2 (Health Effects Roster of Type-Specific Formers of Mycotoxins and Inflammagens, 2nd version). Shoemaker has established that HERTSMI-2 scores below 11 are considered safe for most CIRS patients, while those with C4a levels exceeding 20,000 ng/mL may require scores below 8 (Shoemaker & Lark, 2016). This step frequently requires home remediation or relocation—often the most financially and emotionally challenging aspect of treatment.

Step 2: Toxin Binding (Cholestyramine/Welchol)

Once exposure is controlled, oral binding agents are introduced to interrupt the enterohepatic recirculation of biotoxins. Cholestyramine (CSM), an FDA-approved bile acid sequestrant, is the primary agent used. Its mechanism involves electrostatic binding: CSM’s positive charge attracts negatively charged biotoxins in the bile, forming large complexes that are eliminated in stool rather than being reabsorbed in the ileum (Shoemaker & Hudnell, 2001). Approximately 95% of bile—and the biotoxins dissolved in it—is normally reabsorbed, making this binding step essential for detoxification.

Shoemaker’s early clinical trials demonstrated that CSM improved VCS scores and reduced symptom clusters in patients with biotoxin illness, with multiple published studies documenting these findings (Shoemaker & House, 2005; Shoemaker et al., 2006). Welchol (colesevelam) serves as an alternative for patients who cannot tolerate CSM, though it is generally considered less potent. It is worth noting that CSM is used off-label for CIRS; it is FDA-approved only for cholesterol management. Published data have not demonstrated equivalent efficacy for over-the-counter binders such as activated charcoal, bentonite clay, or chitosan.

Phase 2: Correcting Downstream Effects

Step 3: Eradication of MARCoNS

Multiple Antibiotic Resistant Coagulase Negative Staphylococci (MARCoNS) are biofilm-forming bacteria that colonize the deep nasal passages of CIRS patients, perpetuated by low MSH levels. Clinical data suggest that less than 1% of patients with normal MSH levels harbor MARCoNS, but prevalence in CIRS populations is high—up to 80% by some estimates (Shoemaker, 2010). These organisms produce exotoxins that further suppress MSH, creating a vicious cycle. Treatment involves compounded nasal sprays, typically containing EDTA (to disrupt biofilms) combined with antimicrobials such as gentamicin, though this remains an evolving area as MARCoNS rapidly acquire resistance (McMahon, 2013).

Step 4: Gluten Elimination (If Indicated)

Anti-gliadin antibody (AGA) testing is performed to identify gluten sensitivity, which is common in CIRS patients due to immune dysregulation and intestinal permeability. Importantly, tissue transglutaminase (TTG) antibodies are usually negative in CIRS, distinguishing this from celiac disease. Patients with positive AGA follow a strict gluten-free diet for one to three months and are retested; if antibodies normalize, gluten may be cautiously reintroduced (McMahon, 2013).

Step 5: Androgen Correction

Chronic inflammation and excessive aromatase activity frequently suppress androgens, including DHEA, in CIRS patients. DHEA supplementation may be employed to support anabolic recovery. Shoemaker has noted that androgen levels often correct with VIP therapy in later stages of the protocol (Shoemaker et al., 2013).

Step 6: ADH/Osmolality Correction

Antidiuretic hormone (ADH) dysregulation is common, typically presenting as a relative ADH deficiency with resultant high serum osmolality. Patients experience excessive thirst, frequent urination, and electrolyte imbalance. Treatment involves desmopressin (DDAVP) 0.2 mg on alternating nights, with mandatory sodium monitoring at 5 and 10 days to screen for hyponatremia (McMahon, 2013).

Phase 3: Inflammatory Marker Normalization

Step 7: MMP-9 Correction

Elevated MMP-9 is addressed through a combination of high-dose omega-3 fatty acid supplementation and a low-amylose (low-starch) diet. MMP-9’s role in extracellular matrix degradation and blood-brain barrier disruption makes its correction a priority for neurological symptom resolution.

Step 8: VEGF Correction

Low VEGF levels (<31 pg/mL) are corrected using the same omega-3 and low-amylose diet approach, sometimes supplemented with a graded exercise program. Adequate VEGF is essential for capillary perfusion and oxygen delivery to tissues.

Step 9: C3a Correction

Elevated complement C3a, often associated with bacterial membrane fragments, may require treatment of underlying infections (e.g., Borrelia) followed by short-term high-dose statin therapy with careful monitoring (McMahon, 2013).

Step 10: C4a Correction

Elevated C4a has historically been one of the most treatment-resistant markers in CIRS. Earlier iterations of the protocol employed erythropoietin (Procrit) injections, which carry a black box warning. With the introduction of VIP therapy, C4a correction is now primarily achieved through the final step of the protocol (Shoemaker et al., 2013).

Step 11: TGF-beta1 Correction

Elevated TGF-beta1 is treated with losartan, an angiotensin II receptor blocker, typically at 25 mg twice daily. A metabolite of losartan called EXP 3179 has been shown to reduce TGF-beta1 mRNA expression in animal models of inflammatory fibrosis (McMahon, 2013). If the patient remains symptomatic, VIP therapy is initiated.

Phase 4: Restoration—VIP Therapy

Step 12: Vasoactive Intestinal Peptide (VIP) Nasal Spray

VIP represents the capstone of the Shoemaker Protocol and has been the subject of several published studies. Shoemaker, House, and Ryan (2013) published an open-label trial of 20 patients with refractory CIRS-WDB who received intranasal VIP for at least 18 months, documenting durable reductions in C4a, TGF-beta1, and MMP-9; increases in VEGF; normalization of clotting abnormalities; and restoration of pituitary-adrenal regulation. Ryan and Shoemaker (2016) subsequently demonstrated via RNA-Seq analysis that VIP treatment produced a transcriptomic shift from inflammatory to healing metabolic states.

Perhaps most strikingly, Shoemaker, Katz, McMahon, and Ryan (2017) published evidence that prolonged VIP therapy (600 mcg/day for 6–9 months) safely restored volume to multiple atrophic grey matter nuclei in CIRS patients, as measured by NeuroQuant® MRI volumetrics. As of the most recent published data, over 300 physicians have prescribed intranasal VIP for CIRS patients, with greater than 90% reporting symptomatic improvement and no significant toxicity (Shoemaker et al., 2017). VIP is only administered after environmental safety is confirmed, VCS is cleared, and MARCoNS are eradicated, as concurrent biotoxin exposure may render VIP ineffective or unsafe.

Evidence Base and Academic Controversy

Supporting Evidence

A 2024 systematic literature review published in the Annals of Medicine and Surgery (McMahon et al., 2024) searched multiple databases including EBSCOhost Academic Search Premier, ProQuest, Google Scholar, and the Cochrane Library. The review identified 13 articles referencing treatment for CIRS and 22 articles referencing treatment for chronic fatigue syndrome (CFS). The authors concluded: “The only treatment with documented clinical efficacy was the Shoemaker Protocol, which was described in 11 of the 13 articles. This treatment protocol exhibits superior outcomes compared with the treatment protocols for ME/CFS” (McMahon et al., 2024, p. 7248).

The published evidence base for the Shoemaker Protocol spans from 1997 to present and includes two double-blind placebo-controlled crossover studies, a cross-sectional study, multiple case-control studies, open-label trials, and transcriptomic analyses (Shoemaker & Hudnell, 2001; Shoemaker & House, 2005; Shoemaker et al., 2006; Shoemaker et al., 2013; Ryan et al., 2015; Ryan & Shoemaker, 2016; Shoemaker et al., 2017). Independent researchers including Conti (2022), Harding (2019, 2020), Nordin (2020), and Ratnesselan (2022) have published corroborating work on the inflammatory basis of the syndrome.

Criticisms and Limitations

Despite the growing body of literature, the Shoemaker Protocol and the CIRS diagnosis face substantial criticism from the mainstream medical community. Key concerns include:

Lack of independent large-scale RCTs. The majority of published treatment studies originate from Dr. Shoemaker himself or his direct affiliates. While the 2024 systematic review found the Shoemaker Protocol to be the only treatment with documented efficacy, the authors acknowledged that “peer-reviewed publications other than Shoemaker’s have been minimal” (McMahon et al., 2024). The absence of large, independent, multicenter randomized controlled trials remains the most significant evidentiary gap.

Non-recognition by major medical organizations. The CDC does not list CIRS as a recognized health effect of mold exposure, instead attributing indoor mold-related symptoms primarily to allergies, asthma, and hypersensitivity pneumonitis (CDC, 2024). The WHO has stated that “although mycotoxins can induce a wide range of adverse health effects in both animals and human beings, the evidence that they play a role in health problems related to indoor air is extremely weak” (WHO, 2009). The 2004 Institute of Medicine (IOM) report found sufficient evidence linking indoor mold exposure to upper respiratory symptoms and asthma, but not to the broader systemic illness described by CIRS.

Diagnostic criteria concerns. Critics argue that CIRS diagnostic criteria rely on non-specific symptoms shared with many other conditions, that VCS testing lacks independent validation as a biotoxin-specific marker, and that the case definition has evolved over time without the standardization expected of established diagnoses. Australia’s government inquiry into biotoxin-related illnesses noted that “CIRS is not widely recognised in the medical profession, and that there is insufficient medical evidence regarding the identification of a common cause of the symptoms” (Australian Parliament, 2018).

HLA testing controversies. While HLA-DR typing is central to the CIRS diagnostic model, the published evidence directly linking specific HLA types to the CIRS construct remains limited. Some clinicians, including Dr. Neil Nathan, a recognized mold illness specialist, have observed “little to no difference in treating patients with HLA SNPs as opposed to those who do not carry the polymorphisms” (Gardner, 2024). The high prevalence of “susceptible” HLA types in the general population (approximately 25–30% of Caucasians) raises questions about specificity.

Regulatory and licensing history. Dr. Shoemaker voluntarily surrendered his medical license in Maryland in 2013 following disciplinary proceedings by the Maryland Board of Physicians. While this does not inherently invalidate his published research, it is contextually relevant to a balanced academic review. He has continued to publish and lecture on CIRS since his retirement from clinical practice.

The Middle Ground: An Integrative Perspective

The debate surrounding CIRS illuminates a broader challenge in medicine: the tension between the pace of clinical observation and the pace of rigorous validation. For the integrative medicine practitioner, several observations merit consideration:

First, the clinical reality that patients exposed to water-damaged buildings develop multi-system illness is well-documented, even by mainstream organizations. The disagreement is primarily about mechanism and classification, not about whether people become sick. Second, the Shoemaker Protocol’s strength lies in its use of objective, measurable biomarkers to guide treatment decisions—an approach that, in principle, aligns with evidence-based practice. Third, the field is evolving: the addition of transcriptomic testing (GENIE) and neuroimaging (NeuroQuant®) represents a move toward more sophisticated, molecular-level diagnostics that may eventually satisfy the evidentiary standards of mainstream medicine.

What is clearly needed is independent replication. Multi-center trials led by investigators without direct affiliation to the Shoemaker group, using standardized case definitions and blinded outcome assessment, would represent the gold standard for resolving the current controversy.

Clinical Implications for Integrative Medicine Practitioners

For practitioners in integrative, functional, or environmental medicine, several practical considerations emerge from this review:

• Environmental assessment is foundational. Regardless of one’s position on the full CIRS construct, the principle that chronically ill patients with unexplained multi-system symptoms should have their living and working environments assessed for water damage and mold is prudent clinical practice.
• Biomarker-guided treatment has merit. The use of objective inflammatory markers (C4a, TGF-beta1, MMP-9, VEGF) to guide therapeutic decisions represents a data-driven approach, even if the specific targets and interventions remain under investigation.
• Sequential treatment logic. The protocol’s emphasis on addressing upstream causes before downstream effects reflects sound physiological reasoning that applies broadly in medicine—one does not treat the complications of a disease while ignoring the disease itself.
• Patient advocacy. Many CIRS patients report years of dismissal by conventional medicine. Whether or not the CIRS label is ultimately validated, the suffering of these patients is real, measurable, and deserving of rigorous clinical attention.
• Overlap with other conditions. Clinicians should be aware that CIRS shares significant symptom overlap with MCAS (Mast Cell Activation Syndrome), ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome), fibromyalgia, and post-Lyme syndrome. Careful differential diagnosis is essential, and comorbidity is common.

Author’s Commentary: A Personal Journey Through Mold Illness

The following section reflects the personal clinical and family experience of the author, Yoon Hang Kim, MD, MPH.

I have been privileged to receive some of the finest training in integrative medicine available in the world, including a residential fellowship under Dr. Andrew Weil at the University of Arizona—a program that shaped my understanding of the body’s capacity for healing and the importance of root-cause medicine. I have spent over two decades studying complex chronic illness from multiple vantage points, and I have had the honor of caring for patients whom conventional medicine had long since given up on.

But my deepest education on mold toxicity and CIRS did not come from a textbook, a lecture hall, or a fellowship curriculum. It came from my own family.

A close family member became severely disabled due to mold toxicity and what would meet the clinical criteria for CIRS. I watched someone I love deteriorate—physically, cognitively, emotionally—in ways that defied easy explanation by the conventional specialists we consulted. The fatigue was crushing. The cognitive dysfunction was frightening. The multi-system nature of the illness was bewildering to physicians who had been trained to think in organ-specific silos.

What followed was a period of intense personal research that I would not wish on any clinician or family member. I stayed up until late nights and early mornings, reading every published paper I could find, cross-referencing biomarker data, exploring mechanisms of action, and searching for a path forward. There is a particular kind of urgency that overtakes you when the patient is someone you love—an urgency that sharpens your focus and strips away any tolerance for half-measures or dogmatic thinking.

My approach to treating this family member’s illness was similar to the Shoemaker Protocol in its philosophical underpinnings—we prioritized environmental remediation, addressed the inflammatory cascade, supported detoxification pathways, and systematically corrected downstream hormonal and immune dysregulation. But the specific treatment path I followed was different in important ways from the 12-step Shoemaker framework detailed in this article. I integrated principles from functional medicine, traditional healing modalities, nutritional biochemistry, and my training in medical acupuncture and integrative oncology to create an individualized recovery plan.

That person made a full recovery.

I share this not to diminish the Shoemaker Protocol—which, as this article documents, is the most comprehensively published treatment approach for CIRS and has helped thousands of patients worldwide. I share it because I believe it is essential for patients and practitioners to understand that there are multiple paths to recovery from this debilitating condition. The Shoemaker Protocol is a well-defined, published, and systematic approach—and for many patients, it is the right choice. But the broader principle at work is this: when the root causes of illness are identified and addressed—when the toxic exposure is removed, the inflammatory cascade is interrupted, and the body’s regulatory systems are restored—healing is possible.

The full story of my family member’s illness and recovery is one I intend to share in a future entry. It is a story of desperation and determination, of long nights with PubMed and early mornings with hope, and ultimately of the profound resilience of the human body when it is given what it needs to heal. It is also a story that reinforced what I already believed but needed to experience firsthand: that the best medicine is not always found in a single protocol, but in the willingness of a clinician to be humble, to keep learning, and to never stop searching for answers on behalf of the people entrusted to their care.

Conclusion

The Shoemaker Protocol represents the most comprehensive published attempt to systematize the diagnosis and treatment of environmentally acquired, biotoxin-mediated illness. Its 12-step sequential framework, grounded in measurable biomarkers and supported by a growing (if largely investigator-driven) body of published evidence, has provided a clinical roadmap for thousands of patients worldwide. The 2024 systematic review in the Annals of Medicine and Surgery confirms its position as the only treatment protocol with documented clinical efficacy for CIRS.

Simultaneously, the field faces legitimate academic challenges: the need for large-scale independent replication, the absence of formal recognition by major medical organizations, and ongoing debates about diagnostic specificity. The path forward requires rigorous, independent research that can either validate or refine the current model—and a medical community willing to engage with the clinical observations rather than dismiss them.

For patients with unexplained multi-system illness and a history of biotoxin exposure, the Shoemaker Protocol offers a structured, testable, and increasingly evidence-supported approach to recovery. For the scientific community, it represents an important hypothesis in environmental medicine that merits continued investigation.

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© 2026 Yoon Hang Kim, MD, MPH. All rights reserved.

Board-Certified Integrative Medicine Physician