CIRS Biomarkers: C4a, TGF-β1, MSH, VIP, MMP-9 & ADH

995 papers · Curated by Lauren Lowenstein, The Biotoxin Lady

"Your labs are normal" is one of the most common things CIRS patients hear. Usually the right labs were never run.

CIRS is a real, measurable condition. The Shoemaker approach uses a specific panel of CIRS biomarkers that show how the innate immune system, the hypothalamus and blood vessels are responding to biotoxin exposure. The core markers include:

  • C4a and C3a: complement activation (innate immune system)
  • TGF-β1: an immune-regulating cytokine that often runs high in CIRS
  • MSH (alpha-MSH): a master regulatory hormone, often low
  • VIP: a regulatory neuropeptide, often low
  • MMP-9: an enzyme linked to inflammation and blood-brain barrier changes
  • ADH and osmolality: water and salt balance (think excessive thirst, frequent urination, static shocks)
  • VEGF and leptin, plus HLA-DR genetics and the visual contrast sensitivity (VCS) test

No single number diagnoses CIRS. The picture comes from exposure history, symptoms across multiple clusters, VCS, and the biomarker pattern taken together.

This hub collects about 995 peer-reviewed papers on these biomarkers: what they measure, how they behave in inflammatory illness, and how they're used to monitor progress through treatment. It's a big library because many of these markers are studied well beyond CIRS. That's a good thing. It means the biology is well documented.

To learn which tests to order and where, see my Tests & Products page.

Educational only, not medical advice. Please review your results with a Shoemaker-trained provider.

— Lauren Lowenstein, The Biotoxin Lady · Last reviewed October 19, 2026

Key facts

  • The Shoemaker CIRS panel typically includes MMP-9, ADH and osmolality, MSH, VEGF, TGF-β1, leptin, C3a, C4a and VIP.
  • HLA-DR testing and the VCS test are used alongside the lab panel.
  • CIRS diagnosis rests on exposure history, multi-system symptoms and objective testing together, not one lab value.
  • Many standard labs don't include these markers, which is one reason CIRS is often missed.

Key research papers

  1. Introduction to Chronic Inflammatory Response Syndrome (CIRS)

    Andrew Heyman et al. · 2023

  2. The Evolution of Chronic Inflammatory Response Syndrome (CIRS) and the Biotoxin Pathway

    Ritchie C. Shoemaker et al. · 2023

  3. Vasoactive intestinal polypeptide (VIP) corrects chronic inflammatory response syndrome (CIRS) acquired following exposure to water-damaged buildings

    Ritchie C. Shoemaker et al. · Health · 2013

  4. Sick building syndrome (SBS) and exposure to water-damaged buildings: Time series study, clinical trial and mechanisms

    Ritchie C. Shoemaker et al. · Neurotoxicology and Teratology · 2006

  5. Structural brain abnormalities in patients with inflammatory illness acquired following exposure to water-damaged buildings: a volumetric MRI study using NeuroQuant

    Ritchie C. Shoemaker et al. · Neurotoxicology and Teratology · 2014

  6. Treatable metabolic and inflammatory abnormalities in Post COVID Syndrome (PCS) define the transcriptomic basis for persistent symptoms: Lessons from CIRS

    Ritchie C. Shoemaker et al. · Medical Research Archives · 2021

  7. Transcriptomics and Brain Volumetrics Define the Causes of Cognitive Impairment in Patients with CIRS and Support the use of VIP in Treatment

    Ritchie C. Shoemaker et al. · Medical Research Archives · 2023

  8. RNA-Seq on patients with chronic inflammatory response syndrome (CIRS) treated with vasoactive intestinal peptide (VIP) shows a shift in metabolic state and innate immune functions that coincide with healing

    James C. Ryan et al. · Medical Research Archives · 2016

  9. TUBB1, TUBA4A and MAPK as Indicators of Die-Back Degenerative Central Nervous System Disease in Patients Sickened by Specific Exposure to the Interior Environment of Water- Damaged Buildings

    Ritchie C. Shoemaker et al. · Medical Research Archives · 2023

  10. Characterization of Stachybotrys from Water-Damaged Buildings Based on Morphology, Growth, and Metabolite Production

    Birgitte Andersen et al. · Mycologia · 2002

  11. Chronic Inflammatory Response Syndrome (CIRS) and Metabolism

    Ritchie C. Shoemaker et al. · 2023

  12. A time-series study of sick building syndrome: chronic, biotoxin-associated illness from exposure to water-damaged buildings

    Ritchie C. Shoemaker et al. · Neurotoxicology and Teratology · 2005

  13. Legal and Ethical Considerations in Mold, Mycotoxins, CIRS and Building Biology

    Scott W. McMahon · 2023

  14. A Clinical Operationalization of the Cell Danger Response: Outcomes of a Five-Phase Treatment Protocol in 100 Patients with Chronic Post-Exposure Illness

    Andrew Heyman · Medical Research Archives · 2026

  15. Defining the neurotoxin derived illness chronic ciguatera using markers of chronic systemic inflammatory disturbances: A case/control study

    Ritchie C. Shoemaker et al. · Neurotoxicology and Teratology · 2010

  16. Mechanisms of Potential Central Nervous System Injury in Chronic Inflammatory Response Syndrome

    April Vukelic · 2023

  17. Transcriptomic signatures in whole blood of patients who acquire a chronic inflammatory response syndrome (CIRS) following an exposure to the marine toxin ciguatoxin

    James C. Ryan et al. · BMC Medical Genomics · 2015

  18. Clearance of multiple antibiotic-resistant coagulase-negative staphylococci is selectively associated with higher circulating α-melanocyte stimulating hormone in patients evaluated for chronic inflammatory response syndrome

    Margaret DiTulio et al. · Frontiers in Endocrinology · 2026

  19. Biomarkers over Time: From Visual Contrast Sensitivity to Transcriptomics in Differentiating Chronic Inflammatory Response Syndrome and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

    Ming Dooley · International journal of molecular sciences · 2025

  20. Case Report: Low pressure hyperbaric oxygen therapy as a potential alternative treatment for chronic inflammatory response syndrome: a case study with notable improvements in fatigue, cognition, and testing

    Kristen L. Coletti Giesler · Frontiers in Immunology · 2025

  21. Chronic Fatiguing Illnesses: Entering the era of new biomarkers and therapies

    Ritchie Shoemaker et al. · Internal Medicine Review · 2017

  22. Sick building syndrome in water-damaged buildings: generalization of the chronic, biotoxin-associated illness paradigm to indoor toxigenic fungi

    Ritchie C. Shoemaker et al. · Bioaerosols, Fungi, Bacteria, Mycotoxins and Human Health · 2005

  23. Comparison of work‐related symptoms and visual contrast sensitivity between employees at a severely water‐damaged school and a school without significant water damage

    Gregory W. Thomas et al. · American Journal of Industrial Medicine · 2012

  24. Pediatric Neuroimmune and Inflammatory Overlap: Immunopathology of PANS/PANDAS in Autism Spectrum Disorder

    Jodie A Dashore et al. · Medical Research Archives · 2026

  25. Herbal Therapeutics for CIRS Biomarkers in Autism Spectrum Disorders: A Mechanistic and Molecular Approach for Neuroimmune Pathology in Pediatrics

    Jodie A Dashore et al. · Medical Research Archives · 2026

  26. Characterization of Airborne Molds, Endotoxins, and Glucans in Homes in New Orleans after Hurricanes Katrina and Rita

    Rao CY et al. · Applied and Environmental Microbiology · 2007

  27. The Shoemaker Protocol

    A Heyman et al. · 2023

  28. Sequential upregulation of innate immune responses during acute acquisition of illness in patients exposed prospectively to water-damaged buildings. ASTMH, Philadelphia, PA

  29. Innate immunity, MR spectroscopy, HLA DR, TGF beta-1, VIP and capillary hypoperfusion define acute and chronic human illness acquired following exposure to water-damaged buildings. 2008. International Healthy Buildings (conference peer review)

    Ritchie C. Shoemaker et al. · 2008

  30. The anaphylatoxins bridge innate and adaptive immune responses in allergic asthma

    Hawlisch H et al. · Molecular Immunology · 2004

  31. Chronic biotoxin-associated illness: Multiple-system symptoms, a vision deficit, and effective treatment

    H. Kenneth Hudnell · Neurotoxicology and Teratology · 2005

  32. Detection of AirborneStachybotrys chartarumMacrocyclic Trichothecene Mycotoxins on Particulates Smaller than Conidia

    Brasel TL et al. · Applied and Environmental Microbiology · 2005

  33. Correction of central nervous system metabolic abnormalities, deficits in executive cognitive functioning and elevated C4a: a clinical trial using low dose erythropoietin in patients sickened by exposure to water-damaged buildings. IACFS, Fort Lauderdale, Florida

  34. Intranasal VIP safely restores volume to multiple grey matter nuclei in patients with CIRS

    Ritchie C. Shoemaker et al. · Internal Medicine Review · 2017

  35. How regulatory T cells work

    Shen L et al. · Nature reviews. Immunology · 2009

  36. Fungal Fragments as Indoor Air Biocontaminants

    Gorny RL et al. · Applied and Environmental Microbiology · 2002

  37. The weight of leptin in immunity

    La Cava A et al. · Nature reviews. Immunology · 2004

  38. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance

    Philip A. Kern et al. · American Journal of Physiology-Endocrinology and Metabolism · 2001

  39. VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model

    Azzouz Mimoun et al. · Nature · 2004

  40. Adipose Tissue as an Endocrine Organ

    Rexford S. Ahima et al. · Trends in Endocrinology and Metabolism · 2000

  41. The nervous system and innate immunity: the neuropeptide connection

    Brogden KA et al. · Nature Immunology · 2005

  42. Targeting melanocortin receptors as a novel strategy to control inflammation

    Catania A et al. · Pharmacological Reviews · 2004

  43. Multiple Cytokines and Acute Inflammation Raise Mouse Leptin Levels: Potential Role in Inflammatory Anorexia

    Pasha Sarraf et al. · The Journal of Experimental Medicine · 1997

  44. Matrix metalloproteinases as modulators of inflammation and innate immunity

    Parks WC et al. · Nature reviews. Immunology · 2004

  45. Leptin regulates proinflammatory immune responses

    S. Loffreda et al. · The FASEB Journal · 1998

  46. Hypoxia-Inducible Factor 1α in the Glaucomatous Retina and OpticNerve Head

    Texel G et al. · Archives of Ophthalmology · 2004

  47. Differential Cytokine Production and Toll-Like Receptor Signaling Pathways by Candida albicans Blastoconidia and Hyphae

    Chantal A. A. van der Graaf et al. · Infection and Immunity · 2005

  48. From the Th1/Th2 Paradigm towards a Toll-Like Receptor/T-Helper Bias

    Netea Mihai G. et al. · Antimicrobial Agents and Chemotherapy · 2005

  49. Anti-inflammatory actions of the neuroimmunomodulator α-MSH

    Lipton JM et al. · Immunology Today · 1997

  50. α-Melanocyte-Stimulating Hormone and Related Tripeptides: Biochemistry, Antiinflammatory and Protective Effects in Vitro and in Vivo, and Future Perspectives for the Treatment of Immune-Mediated Inflammatory Diseases

    Brozska T et al. · Endocrine Reviews · 2008

  51. Air- and Dustborne Mycoflora in Houses Free of Water Damage and Fungal Growth

    Hormer WE et al. · Applied and Environmental Microbiology · 2004

  52. The von Hippel–Lindau Protein, Vascular Endothelial Growth Factor, and Kidney Cancer

    Daniel J. George et al. · New England Journal of Medicine · 2003

  53. Occurrence of Toxigenic Aspergillus versicolor Isolates and Sterigmatocystin in Carpet Dust from Damp Indoor Environments

    Engelhart S et al. · Applied and Environmental Microbiology · 2002

  54. The Leptin Receptor Activates Janus Kinase 2 and Signals for Proliferation in a Factor-Dependent Cell Line

    Nico Ghilardi et al. · Molecular Endocrinology · 1997

  55. Inhibition of endogenous VEGF impedes revascularization and astroglial proliferation: roles for VEGF in brain repair

    Experimental Neurology · 2003

  56. The immunomodulating neuropeptide alpha-melanocyte-stimulating hormone (α-MSH) suppresses LPS-stimulated TLR4 with IRAK-M in macrophages

    Taylor AW · Journal of Neuroimmunology · 2005

  57. Characterization of the microbial community in indoor environments: a chemical-analytical approach

    Sebastian A et al. · Applied and Environmental Microbiology · 2003

  58. In vitro induction of CD25+ CD4+ regulatory T cells by the neuropeptide alpha‐melanocyte stimulating hormone (α‐MSH)

    Taylor A et al. · Immunology and Cell Biology · 2001

  59. Learning and memory difficulties after environmental exposure to waterways containing toxin-producing Pfiesteria or Pfiesteria-like dinoflagellates

    Grattan L et al. · The Lancet · 1998

  60. α-Melanocyte-Stimulating Hormone Inhibits Allergic Airway Inflammation

    Rapp U et al. · The Journal of Immunology · 2003

Explore all 995 papers in the interactive explorer →

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