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CIRS: An Examination of Chronic Inflammatory Response Syndrome from Exposure to Recovery (Part 2-Tier One Diagnosis)

CIRS: An Examination of Chronic Inflammatory Response Syndrome from Exposure to Recovery (Part 2-Tier One Diagnosis)

Chronic Inflammatory Response Syndrome (CIRS), also called biotoxin-related illness, sick-building syndrome, or mold illness, is a condition caused by exposure to biotoxins (biological toxins). CIRS affects multiple systems of the body and may produce multiple, seemingly-unrelated symptoms. To understand what biotoxins are and how you can get exposed, please read part one of this series. The topic of this article is CIRS diagnosis. My goal for this entire series is your health education and empowerment so you can optimize your body’s inherent power to heal and reclaim your joy in living.

The Good News About Diagnosing CIRS (Biotoxin-Related Illness)

Let me start with some good news. After preliminary diagnostic criteria are met, a suspected CIRS diagnosis can be confirmed with objective inflammatory biomarkers and transcriptomic findings. This means lab tests that look for certain measurable indicators of inflammatory damage and RNA sequencing that reveals abnormal gene suppression and activation can help verify whether or not you have CIRS1,2,3. This is a great comfort to CIRS patients and their families because they can finally see a biological cause for invisible symptoms.

CIRS symptoms can range from manageable to severely debilitating. Although you might not look sick, it can feel like your wholeness — physically, mentally, emotionally, and spiritually —  is slipping away. CIRS sufferers often come to my clinic having seen nearly a dozen doctors and are taking a slew of pharmaceuticals and supplements  to mask symptoms like pain and fatigue. Years, even decades, go by like this in some cases. All the while, a curable condition goes untreated.

As frustrating as this is, it’s not uncommon. Most physicians still don’t know about CIRS, but that does not mean you aren’t suffering from a real diagnosis. I’ve confirmed CIRS in countless patients after misdiagnosis or missed diagnosis. Be at peace, healing is not only possible…it is probable. There is hope for a full recovery.

How Does CIRS Become Chronic?

To understand the diagnostic process, it’s helpful to know how CIRS becomes chronic. It begins with exposure to a biotoxin, which is like any other infection for most people. Your body removes the biotoxin through the liver or immune system. If you avoid the source of exposure, you get well. This is not the case for all people, however, because their bodies are unable to identify and remove biotoxins.

And to avoid confusion, CIRS is not a mold allergy. A positive allergy test for mold does not mean you have CIRS. And if you’ve had a negative allergy test for mold, you could still have CIRS. You know you’re dealing with a mold allergy when you have a sudden onset of typical allergy symptoms such as sneezing, hives, and red, watery eyes that ceases when you avoid the source of exposure.

The Role of the Immune System in CIRS

The major mechanism of chronic inflammatory response syndrome (CIRS) is the breakdown of a coordinated immune system response between the innate and adaptive immune systems.4 The innate immune system is the body’s first line of defense, which responds immediately and in the same way to all antigens (a toxin or other foreign invader that causes an immune response in the body). The adaptive immune system memorizes specific antigens and responds to each uniquely with coordinating antibodies.

In order to create antibodies to fight present and future infection, the adaptive immune system must receive information about a biotoxin from the innate immune system via antigen-presenting cells. These cells encounter antigens and take a tiny molecular snippet (an epitope) to bring to the adaptive immune system’s T cells.5 The epitopes activate the T cells, which, in turn, secrete cytokines that cause the B cells to produce antibodies to the specific antigen.

In CIRS, antigen information never makes it to the T cells, so there is no antibody creation or response. As a result, the innate immune system is never triggered to turn off. Biotoxins continue to build up and circulate through the body, creating more inflammatory activity, which continues even after the person is no longer exposed to the biotoxin.6 This dysregulation leads to damage of tissues and cells and even alters gene expression.

If you have CIRS, your body can turn on inflammation but can’t turn it off. And that’s where CIRS gets its name. It’s literally a chronic inflammatory response.

The Challenges of Making a CIRS Diagnosis

Making a CIRS diagnosis can be a complicated process. In addition to the fact that symptoms overlap with those of so many other illnesses, part of the challenge with diagnosing CIRS is that it’s difficult to test for the presence of biotoxins in the body directly. Direct tests don’t exist for many biotoxins, let alone the inflammagens and other microbes found in water-damaged buildings.

Because most biotoxins that cause CIRS take on the structural form of ionophores, they can pass from cell to cell without entering the bloodstream.7 Other biotoxins use biofilms to stay hidden. These mechanisms allow biotoxins to remain virtually undetected by common lab tests, which are usually always normal in CIRS patients. 8

Direct tests that do exist can be unreliable or only relevant for certain groups of patients. This is why we rely on testing that measures the internal damage the biotoxin has caused, confirming exposure indirectly. While these tests can’t identify which specific biotoxin you’ve been exposed to, they provide standardized evidence of a chronic inflammatory response caused by biotoxin exposure.  Before these tests are even considered, however, certain preliminary criteria are assessed that will either qualify or rule out a potential CIRS diagnosis.

How Is Chronic Inflammatory Response Syndrome (CIRS) Diagnosed?

Certified CIRS practitioners use a three-tiered diagnostic system created in 2005 by Dr. Ritchie Shoemaker, the physician who discovered and defined CIRS. The system is based on the analysis of thousands of CIRS patients and relies on multiple factors to make a differential diagnosis.

If all criteria in the first tier are met, tier two criteria are assessed, which includes the biomarker testing. A CIRS diagnosis is made when three out of six criteria in the second tier are met. A third tier, which was added later, evaluates treatment effectiveness and can help confirm an inconclusive diagnosis.

Additionally, transcriptomic testing is now available. The Gene Expression: Inflammation Explained (GENIE) is a test used to monitor hypometabolism (abnormally low metabolic activity) during CIRS diagnosis and treatment.9 While still new in its clinical application, this technology can expedite diagnosis and direct individualized treatment at the intracellular level by demonstrating transcriptomic abnormality and recovery.

What is the Case Definition of CIRS?

In 2008, the Government Accountability Office (GAO) provided a formal case definition of CIRS in relation to water-damaged buildings, which includes the following criteria:

  1. Potential for exposure to a water-damaged building
  2. Symptoms similar to those documented in published, peer-reviewed literature
  3. Laboratory results similar to those documented in published, peer-reviewed literature
  4. Documented response to therapeutic protocol10

Dr. Shoemaker’s three-tiered diagnostic system provides a framework to meet these criteria so that a standardized label is assigned to illness caused by water-damaged buildings. CIRS-WDB makes up about 80% of documented biotoxin-related illness cases,11 but the three-tiered system is used to diagnose all types of CIRS illness.

What Are the Tier One Criteria for a CIRS Diagnosis?

Your provider will assess and document these three criteria before moving to tier two assessment or making a CIRS diagnosis:

  1. Exposure to Biotoxins: Part one of this series discusses biotoxin exposure.
  2. Symptoms: The presence of multiple symptoms affecting different systems of the body.
  3. Differential Diagnosis: Other illnesses with the same symptoms must be ruled out.

The remainder of this article will look at tier one criteria in more detail, specifically symptoms, differential diagnosis, and additional signs of CIRS observed during physical evaluation. Exposure is thoroughly covered in part one. There I address the cloud of biological toxins found in the air of water-damaged buildings as well as other major sources of biotoxins.

But to summarize, exposure is confirmed if you’ve lived or worked in a water-damaged building with musty smells, visible microbial growth, or verification of fungal presence with mold-specific quantitative polymerase chain reaction (MSQPCR) testing that checks dust samples for mold DNA. Other means of exposure include the history of a tick or spider bite, exposure to Ciguatera or Pfiesteria, or contact with cyanobacteria.12 Again, read part one for a full understanding of biotoxin exposure.

How Are Symptoms Used to Diagnose Chronic Inflammatory Response Syndrome (CIRS)?

To the untrained eye, CIRS symptoms are identical to many other conditions, which is why it’s often misdiagnosed. Since CIRS symptoms affect multiple systems of the body, you may even receive a different diagnosis depending on the specialist you see. This is why the differential diagnosis process is so important to confirm or rule out CIRS. Symptoms are one consideration of that process.

To assist with differential diagnosis, your practitioner will refer to a list of 37 common symptoms found in more than 30%  of CIRS cases.13 The symptoms are categorized into 13 clusters within eight organ systems. If you have symptoms from four or more of these eight organ system categories, it’s possible you have CIRS.

  1. General Symptoms: fatigue and weakness
  2. Musculoskeletal: aches, cramps (claw-like cramping of hands and feet), joint pain, morning stiffness, ice-pick pains
  3. General: headache, frequent urination and increased thirst, night sweats, static electricity or shocks, appetite swings.
  4. Eyes: light sensitivity, red eyes, blurred vision, tearing
  5. Respiratory: sinus congestion, cough, shortness of breath
  6. Gastrointestinal: abdominal pain, diarrhea
  7. Neurological: numbness, tingling, metallic taste, vertigo, temperature regulation, dizziness, tics, atypical seizures, fine motor skill problems
  8. Cognitive: memory loss, concentration difficulties, confusion, learning difficulties, difficulty finding words, disorientation, mood swings, anxiety, panic

Symptoms from the eight systems are also broken down into 13 clusters with up to five symptoms in each (see the table below). The clusters were arranged by researchers and statisticians to standardize the condition and increase diagnostic accuracy. Your provider should lead you in a discussion about your symptoms, but don’t hesitate to ask questions if you’re unsure if you’ve experienced unusual symptoms such as “ice-pick pain” or “static electricity.”

CIRS: An Examination of Chronic Inflammatory Response Syndrome from Exposure to Recovery (Part 2-Tier One Diagnosis)
CIRS Chronic Inflammatory Response Syndrome Symptom Clusters

Adults with at least one symptom in six or more clusters for more than two weeks are considered for a CIRS diagnosis. Symptoms in eight or more clusters means a positive cluster analysis and meets tier one criteria. Children with symptoms in at least six clusters are diagnostic, although they may only have one or two symptoms such as chronic headache or stomach pain.14

How Does the Differential Diagnosis Process Confirm or Disprove CIRS?

A differential diagnosis is a process used to differentiate between a list of possible conditions that may be the root cause of your symptoms. CIRS is often misdiagnosed15 as these and other conditions:

  • Anxiety
  • Depression
  • Post-traumatic Stress Disorder
  • Allergies
  • Chronic Fatigue Syndrome
  • Fibromyalgia
  • Depression
  • Multiple Sclerosis
  • Somatization
  • Irritable Bowel Syndrome
  • Attention Deficit Disorder

If you already have one of these diagnoses and treatment isn’t improving your symptoms, there’s a chance you may have CIRS.

Systematically eliminating these differential diagnoses is a required step in meeting tier one criteria. When working through the process, your CIRS provider will not only take into account your symptom cluster analysis but also perform a comprehensive physical evaluation and thoroughly review your medical history. An accurate medical history is the single most important factor in the differential diagnostic process.16

How Does Your History Contribute to a Differential Diagnosis of CIRS?

Gathering your full medical history can give your provider clues about exposure to biotoxins or any qualifying events that may have initiated the chronic inflammatory response in your body such as an illness or course of certain medications. Remember, you don’t need to be presently exposed to biotoxins to have CIRS. A tick bite you got 10 years ago or a moldy office space in your freshman year of college could be responsible for your condition.

That’s why you’ll be asked not only about your medical history, including previously-diagnosed diseases, surgeries, medications, traumas, and allergies, but also about your family/genetic history, work history, and environmental history.

How Does a Physical Examination Contribute to Differential Diagnosis of CIRS?

If your history confirms biotoxin exposure, and you have a multi-system, multi-symptom illness, your provider will proceed with a physical exam. To contribute to the differential diagnostic process, the exam looks for physical findings common in CIRS patients as well as signs of illness that best correspond with other conditions. Some of the physical signs seen in CIRS17,18 include:

  • Tremors
  • Gingivitis
  • Poor balance
  • Goiter
  • Unsteady gait
  • Hypermobility
  • Stiffness or achiness
  • Cold or discolored hands or feet
  • Pallor
  • Abnormal skin turgor
  • Tender abdomen
  • Soft tissue tenderness
  • Unilateral weakness in the shoulder muscles
  • Nasal congestion, chronic cough
  • Rashes (Mold facies)
  • Lower body temperature
  • Sound, light, noise, tactile sensitivities
  • Vocal or motor tics
  • EMF sensitivity
  • Tachycardia, anxiety, hypotension
  • Enlargement of nasal turbinates and/or nasal polyps
  • Lack of appetite/weight control

Once the physical examination is complete, your provider will have enough data to complete the differential diagnosis. If a decision is made that CIRS is the most likely diagnosis, and all tier one criteria are satisfied, you’ll have a visual contrast sensitivity (VCS) test right away, and your provider will order the biomarker labs to confirm the diagnosis. These and other tests are part of tier two criteria, which I’ll cover in my next article.


Now that you have an understanding of how CIRS becomes chronic as well as the common symptoms and physical signs of the illness, you may have a suspicion that you have CIRS. If so, please find a Shoemaker-certified practitioner or other provider experienced with CIRS to guide you through diagnosis and treatment. There is a systematic methodology that eliminates your symptoms, one-by-one, further validating the differential diagnosis, and leading to a full resolution of the condition.

Here is a list of Shoemaker-certified physicians. If you can’t find one in your area, I welcome the opportunity to consult with you here at Silver Tree Wellness Center.. We also offer two-week healing intensives here at Silver Tree Wellness Center that accelerate your path to healing and prepare you to effectively continue your individualized treatment protocol at home. Call the office at (602) 675-0170 to learn more.


  1. Shoemaker RC. Surviving Mold: Life in the Era of Dangerous Buildings. Otter Bay Books: Baltimore, MD, 2010.