The Art and Science of CIRS Medicine

By Ritchie Shoemaker M.D., Scott McMahon M.D. and Andrew Heyman M.D. MHSA

As teachers and long-time proponents of Chronic Inflammatory Response Syndrome (CIRS), we felt that a compendium of current educational and scientific materials on the Chronic Inflammatory Response Syndrome (CIRS) had a place in the approach to the CIRS patient. In our existing training courses, the basics of CIRS medicine is the source of our curriculum. Call the current courses CIRS 101 and CIRS 201, if you will. Fundamental to our courses is student participation in discussion of published papers, often leading to deeper questions regarding the art of CIRS practice. The growing course work, and level of student engagement show us that students want – and need – greater exploration of the topic, access to the primary literature and opportunities to demonstrate mastery of the subject.
What we have put together are informal chapters regarding opinions of skilled practitioners based both on published data and on bedside experience that should help guide new CIRS practitioners through the complex maze of treating this unique patient population. These chapters show the art of CIRS Medicine used by the authors. We cover the subtleties and nuances of exposures, symptoms, labs, physical exam, ancillary studies, use of medications and some of the cutting edge science, transcriptomics, that are brought to bear on the fundamental question, "How can we help the CIRS trainee become an expert?"
We will also feature new dynamic published papers that impact our current thinking about inflammation in CIRS, namely (i) metabolism; and (ii) mycotoxin measurements in urine.
We include eight demonstrative cases written up by members of the Surviving Mold CIRS Academy. We are grateful for permission provided by each of these authors (see below) to use their excellent studies for educational experiences. Here we see a merging of art and science of CIRS Medicine that translates into an answer to the question, "How do I sort out differential diagnosis and quickly identify the right approach to helping complicated patients?"
Finally, we include published papers that serve as a journal club for our students. Here are the scientific foundations of CIRS Medicine. Sample teaching questions range from the obvious (what is the study design?) to the essence of science (based on these data, how can you logically apply them to patient care?).
We all have our dreams for the future, like hopes and fears all rolled up into one package. We have asked Drs. Shoemaker, McMahon and Heyman to share with us their ideas on the expansion of CIRS Medicine-what is possible now and what will be possible in the future.
To help on this quest, we have included a research module based on the work of Ken Hudnell PhD and Ritchie Shoemaker MD that forms a starting point for good scientific studies.
Finally, the advances in transcriptomics tell us far more about metabolism and inflammation than any writings published to date. These are exciting times!
Taken together, the chapters, papers and sidebars of The Art and Science of CIRS Medicine are part of the ever-expanding extrapolation of CIRS to medicine in general.

• Language: English
• Publisher: BookBaby
• Release date: Sep 24, 2020
• ISBN: 9781098335922

Book preview

illness.

INTRODUCTION

AUTHOR: ANDY HEYMAN MD

What happens when the innate immune systems do not communicate properly with the adaptive immune system? What if there is poor antigen presentation? The result is inflammation that remains ‘stuck’ in the early phases of the innate immune response, unable to transition to the more mature and specific actions coordinated by T cells and B cells in the adaptive immune system. What would happen if exposure to the offending antigen occurred every day - or even with every single breath?

This common clinical condition is represented by the Chronic Inflammatory Response Syndrome (CIRS), which is a progressive, multisystem, multi-symptom illness acquired by some following exposure to biotoxins. The ongoing inflammation can affect virtually any organ system of the body and if left untreated, becomes debilitating.

What is a Biotoxin?

Any living organism, or fragment of organism that acts to trigger an innate immune response can function as a biotoxin. This can be mold and mycotoxins from water damaged buildings (WDB); pathogens as seen in tick born illnesses, viruses, fungal elements, dinoflagellates, apicomplexans, cyanobacteria and about 30 others that have been identified. See Table 1 below. 80% of Biotoxin illness cases are due to exposure to WDB.

Table 1. Biotoxins found in WDB (Adapted from 2016 Surviving Mold Consensus Statement)

While there are many known triggers for CIRS, more are likely to be discovered. Ciguatera fish poisoning results from eating fish contaminated with the marine toxin ciguatoxin. A single exposure to this toxin may result in CIRS-ciguatera (Ryan, Wu, & Shoemaker, 2015). Many who suffer chronic illness seen after antibiotic therapy of acute Lyme disease, Post Lyme disease syndrome, present with CIRS-Lyme (Shoemaker, et al., 2006).

CIRS-WDB is CIRS developed after exposure (usually chronic) to the interior environment of water-damaged buildings typified by resident microbial growth, including bacteria, filamentous fungi (molds), and actinomycetes (including mycobacteria); together with biologically produced toxins and inflammagens, including mannans, beta glucans, hemolysins, and proteinases; and possibly spirocyclic drimanes; as well as volatile organic compounds (VOCs).

Other sources of CIRS could be consumption of reef fish containing neurotoxins produced by marine algae (especially Gambierdiscus spp.) or exposure to cyanobacteria in freshwater lakes, ponds and lagoons. (Shoemaker & House, 2006).

Regardless of initial trigger, all CIRS show similar characteristics in their final manifestations. Patients with CIRS are often misdiagnosed as having depression, anxiety, post-traumatic stress disorder and somatization, as well as Alzheimer’s, Parkinsonism, allergy, fibromyalgia and Chronic Fatigue Syndrome, SEID, among others. Treating patients for these seemingly diverse conditions does not improve their symptoms of CIRS, although effective therapies for CIRS exist.

Pertinent Negatives: An Elusive Disease Hiding in Plain Sight

CIRS is an activation of the innate immune system, making a proper diagnosis difficult since common parameters of inflammation are generally negative upon laboratory evaluation. Normal results typically include white blood count, immunoglobulins, autoimmune markers, sedimentation rate, C-reactive protein, and IL-6.

Much of modern clinical immunology has focused on diseases associated with cardiometabolic risk, autoimmune diseases, allergies and cancer. In other words, the expected inflammatory processes are not directly involved with the innate immune system. Rather, they are generated from inflammation arising from visceral fat (adipokines), loss of immune tolerance or lack of repair (defects in adaptive immunity).

Identifying a patient with CIRS requires collection of subjective and objective information to demonstrate activation of innate immunity, while ruling out other causes of symptoms. The evaluation process includes assessment of proteomics, neuroinflammation, transcriptomics, immune dysregulation, hormonal imbalances, with verification using secondary assessments including cardiopulmonary exercise testing, CNS volumetric programs, echocardiography, autonomic testing, biliary tree testing and more.

Despite 25 research papers and 2 clinical trials published about CIRS across 4000 subjects, the evaluation process remains largely unfamiliar to the general practitioner. In other words, clinicians have been looking in the wrong physiologic places to make a proper diagnosis, but the presence of pertinent negatives does not mean CIRS does not exist. It does – but a new language of diagnostics needed to be developed for proper assessment and identification of the CIRS patient to be made.

Genetic Susceptibility: Human Leukocyte Antigen

If CIRS is ‘difficult to diagnose,’ then how common is it? Who is vulnerable to CIRS? The answer is found on chromosome 6, which contains the human leukocyte antigen alleles. HLA DR underlies the mechanism by which antigen presenting cells identify antigens as foreign.

When foreign antigens are presented to T lymphocytes by APCs (antigen presentation cells), the complex process that leads to antibody production begins. If the antigen presentation process is defective, as seen in CIRS, there will be limited production of protective antibodies and therefore nothing to stop the expanding inflammatory cascade. As a result, the normally protective innate immune response becomes unopposed and destructive; therefore, the host becomes the source of the illness (Thomas, NEJM, 1982).

For 95% of patients with known CIRS-WDB, increased relative risk (RR > 1.9) for acquisition of illness is associated with just 6 of 54 major HLA haplotypes. These 6 haplotypes are found in roughly 24% of the population at large (See Table 2). Similarly, only four HLA haplotypes are associated with roughly 95% of patients with chronic symptoms following antibiotic treatment for Lyme disease, or Post Lyme Syndrome (PLS). These four haplotypes were found in 22% of patients initially infected by Lyme.

Given how common these HLA alleles are in the general population, it is estimated that up to 82 million people in the United States are vulnerable to CIRS. Use of HLA typing becomes important for epidemiologic risk assessment, but it also is important in considering who else in a family might be predisposed to heightened inflammatory responses following exposure to biotoxins and inflammagens.

CIRS HLA Sequences

Table 2. HLA alleles associated with poor antigen presentation (Mold Warriors, 2005)

Visual Contrast Sensitivity

The visual contrast sensitivity (VCS) test has been used clinically for years and remains the most accurate assessment for functional vision. Contrast is one of the seven main functions of the optic nerve that provides the neurologic basis of vision. When testing for contrast, control of the other elements of vision must occur, such as near vision, far vision, static, motion, peripheral vision and night vision.

Contrast is the ability to see an edge. Contrast sensitivity looks at the graded change of contrast at different light frequency (cycles per degree of visual arc) used to make a grid of five separate frequencies. This grid begins at 1.5 cycles per degree of visual arc extending in discrete intervals (3, 6, 12, 18) up to 18 cycles per degree of visual arc. Remember visual acuity is tested at 24 cycles per degree of visual arc.

Dr. Ken Hudnell, neurotoxicologist for the US EPA NHEERL in Research Triangle Park, NC, was the first to use VCS testing in biotoxin illnesses. His landmark work in 1998 paved the way for others to follow. Our group was able to reproduce the observations of Dr. Hudnell of VCS being abnormal in that same fish killing dinoflagellate (Pfiesteria) illness, but proper treatment reversed the visual contrast abnormalities. With re-exposure, however, visual contrast deficits reappeared, identical to the initial deficits, usually within 36 hours.

The VCS test can be completed in person or online under the correct conditions in about 10 minutes and offers an immediate score of pass, or fail. Some patients may pass one eye, but not the other, which is still classified as a fail. When combined with positive symptoms (8 of 13 clusters), the diagnosis of CIRS reaches 98.5% sensitivity.

The VCS test is also used to verify therapeutic progress and detect when re-exposure may have occurred. Patients become acquainted with this test and rely on its accuracy to assure clinical progress is being made. It also acts as the threshold to move to the second step of therapy (MARCoNS treatment or multiply antibiotic resistant coagulase negative Staphylococcus), when passed. It should be noted that about 8% of CIRS patients can pass the VCS test. Therefore, a pass does not rule out the condition.

The Biotoxin Pathway in Action

In the HLA susceptible patients, a cascade of events occurs following exposure leading to chronic activation of the innate immune system due to poor antigen presentation. Without the ability to fully upregulate the adaptive immune response with proper antigen disposal, biotoxins are left free to bind to specific cell surface receptors such as Toll, mannose, and C-type lectin. Recognition and binding of the biotoxin at these receptors leads to upregulation of inflammatory pathways, resulting in an abnormal rise in inflammatory markers such as MMP9 (matrix metalloproteinase 9), cytokines, TGF beta-1 (transforming growth factor beta-1) and split products of complement. Chronic exposure leads to chronic upregulation of these innate immune pathways and chronic cytokine overproduction.

Leptin also plays a key role in the biotoxin illness pathway. Leptin is primarily produced in adipocytes; it acts as both a hormone and cytokine, linking the neuroendocrine and immune systems. Cytokines can apply a bulky phosphate group on the leptin hypothalamic receptor to rendering it unable to interact normally with leptin, thereby inducing leptin resistance, which in turn causes upregulation of leptin production. Elevated leptin levels are associated with refractory obesity.

In normal physiology, leptin binds receptors located within the arcuate nucleus of the hypothalamus, signaling enzymatic cleavage of the preformed, prohormone proopiomelanocortin (POMC) into the following hormones: alpha melanocyte stimulating hormone (MSH), adrenocorticotropic (ACTH) and endorphins. Disruption of the POMC pathway will decrease levels of the hypothalamic hormones (especially MSH) and leads to another mechanism to compensate for the decreased ability to mobilize fat stores for energy, resulting in recalcitrant weight gain in some patients that does not respond to typical measures of diet and exercise.

MSH acts as an important neuroregulatory peptide hormone with anti-inflammatory actions by inducing cyclic adenosine monophosphate (cAMP) and inhibiting nuclear factor κβ (NF-κβ). MSH is also capable of downregulating expression of pro-inflammatory cytokines that can create intracerebral inflammation. MSH deficiency leads to unchecked cytokine effects, manifesting as numerous symptoms such as muscle aches, mood swings, temperature instability, sweats, headaches, and decreased ability to concentrate.

Low MSH levels lead to further immune system dysfunction, sleep issues, and gut malabsorption. The MSH-driven conversion of T helper cells into CD4+CD25+ Treg cells, leading to suppression of hypersensitivity and autoimmune diseases, is diminished in MSH deficiency. With loss of leukocyte regulation over cytokine responses, patients may succumb to opportunistic bacteria, such as colonization with MARCoNS and have slower recovery from infections.

MSH tightens junctions in the gut lining and has anti-inflammatory effects in the colon, which can lead to increased intestinal permeability (aka leaky gut), allowing foreign material such as toxins, bacteria, and food antigens into the body. Leaky gut has been linked to predisposition to autoimmunity, as evidenced by the presence of the following antibodies: anti-gliadin antibodies (gluten sensitivity), anti-cardiolipin antibodies (ACLA), antineutrophil cytoplasmic antibodies (ANCA), and more. Leptin resistance also causes low endorphin levels, resulting in loss of modulation of pain perception which leads to chronic pain and unusual pains.

67% of CIRS patients with low MSH will experience loss of cortisol regulation. During the beginning stages of CIRS, simultaneous measures of ACTH and morning cortisol are often high with minimal symptoms. However, as CIRS progresses, ACTH and morning cortisol levels fall resulting in a marked increase in symptoms.

Androgen production is downregulated in 40-50% of CIRS patients. Additionally, in patients deficient in vasoactive intestinal peptide (VIP), estradiol levels may be elevated due to an overactive aromatase enzyme which converts androgens (i.e., dehydroepiandrosterone or DHEA, androstenedione, testosterone) into estrogens (i.e., estrone, estradiol).

Approximately 80% of CIRS patients will have dysregulation of ADH/serum osmolality (antidiuretic hormone) levels due to alterations in posterior pituitary functioning. Resultant symptoms include susceptibility to static electrical shocks, migraine-like headaches, excessive thirst with frequent urination and dehydration. POTS (postural orthostatic tachycardia syndrome) is almost always accompanied by ADH/osmolality dysregulation

VIP is a neuroregulatory peptide hormone produced in the hypothalamus that is often diminished in CIRS. VIP deficiency can lead to shortness of breath with exercise, and pulmonary hypertension that is reversible with exogenous administration of VIP. Lastly, VIP can downregulate cytokines, making it invaluable to the CIRS treatment protocol.

Additionally, cytokines can cause elevated levels of plasminogen activator inhibitor-1 (PA1), along with abnormal levels of von Willebrand’s factor (VWF) and Factor VIII leading to coagulopathies in some CIRS patients. If ristocetin associated co-factor levels are low, profound nasal hemorrhage can occur (acquired von Willebrand’s syndrome).

Cytokines also induce macrophages to release MMP- 9, which enzymatically degrades the proteins found in the protective extracellular matrix of blood vessel walls, allowing other inflammatory markers originating in the bloodstream to penetrate sensitive tissues such as the brain. Elevated MMP-9 has been linked to increased risk of atherosclerotic plaque formation, progression, and rupture. Additionally, high MMP-9 adversely affects joints, muscles, and nerves.

Capillary hypoperfusion can occur due to cytokine effects as well, including those produced by TNFα (tumor necrosis factor alpha). It has been suggested that this decrease of microvascular perfusion could be from either vasoconstriction due to direct cytokine effects or recruitment and demargination of local leukocytes causing obstruction of vessels.

In response to cytokine-induced hypoxia, upregulation of hypoxia inducible factor (HIF) genes occurs, which in turn promote the increased production of vascular endothelial growth factor (VEGF) and TGF beta-1. VEGF is known for vasodilation, angiogenesis, and neuroprotection. VEGF can be conspicuously high or low in patients with CIRS and a deficiency results in loss of neuroprotection with noted increased permeability of the blood brain barrier, as well as capillary hypoperfusion. Symptoms associated with low VEGF include shortness of breath, cognitive dysfunction, fatigue and muscle cramps.

TGF beta-1 promotes stiffening of soft, pliable epithelial cells leading to remodeling in the lung tissue resulting in a restrictive airway pattern and fibrosis. Like decreased VEGF, elevated TGF-beta can increase blood brain barrier permeability.

CIRS can also involve derangements in the complement cascade, indicated by elevated C4a levels. C4a elevations occur through activation of the classical and mannose-binding lectin pathways and trigger an amplified release of downstream-signaling proteins, promoting a swift inflammatory response. Additionally, some patients may experience auto-activation of the C4a protease enzyme mannose-binding protein (MASP2), giving rise to markedly elevated C4a levels. The MASP2 auto-activation results in a sicker, quicker phenomenon upon re-exposure. Symptoms of elevated C4a include fatigue, musculoskeletal issues, capillary hypoperfusion and cognitive impairment.

Regulatory Neuropeptides: Changes in Brain Function

The neuroinflammation of CIRS also affects production of regulatory neuropeptide hormones, especially VIP and MSH. Direct measurement of VIP is possible but misleading, as the crucial problem with VIP physiology is variable production of one of its two receptors. VIP is available as a therapeutic agent and exogenous administration has shown great benefit in CIRS patients especially in those with grey matter nuclear atrophy.

Regulatory neuropeptide hormones affect (i) hypothalamic hormone function; (ii) pituitary hormone production; (iii) peripheral hormone regulation by pituitary hormones; (iv) immune cell and innate immune functions; (v) cytokine physiology, (vi) limbic system activity; (vii) genomic activity; (viii) pulmonary artery pressure; among other functions.

MSH – alpha Melanocyte Stimulating Hormone Normal Range: 35-81 pg/mL

MSH deficiency is important in CIRS. MSH is made in the hypothalamus and to a lesser extent in part of the pituitary. It is a neuropeptide that regulates inflammation and immunity; influences other hormone functions, especially pituitary hormones and peripheral hormones; and has important regulatory features in the limbic system, circadian rhythms, pain perception and weight. MSH patrols the periphery of the skin, respiratory system, gastrointestinal tract and blood. In the gut, MSH is invested in just about every cell, including tight junctions. Deficiency of MSH will result in what others call leaky gut.

The role of MSH in prevention of hormonal abnormalities is best seen in low MSH cases. Lack of normal regulation in ACTH/cortisol and ADH/osmolality is found in approximately 67% and 80% of patients, respectively. Androgen abnormalities, particularly including upregulation of aromatase, are found in 50% of CIRS cases. Understanding the impact of hormone dysregulation requires looking at feedback loops involving central and peripheral hormones.

Another correlation of MSH deficiency in CIRS is the presence of biofilm-forming, MARCoNS in deep aerobic nasopharyngeal cultures, essentially found exclusively in those with low MSH.

Additional Innate Immune Markers

MMP-9, TGF beta-1 and split product of complement 4 (C4a) are used as the main diagnostic and prognostic variables to assess for inflammation seen in CIRS. The complement system can be activated to the point that some people with elevated C4a are suffering from auto-activation of MASP2, the enzyme that cleaves C4a. Removal from exposure does not stop production of C4a. This so called sicker, quicker process is recognizable with persistent elevation and elevated elevation of C4a.

MMP-9; matrix metalloproteinase 9 Normal Range: 85-332 ng/mL

MMP-9 is an enzyme that in humans is encoded by the MMP9 gene. Proteins of the MMP9 family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes.

It has been implicated in pathogenesis of COPD by destruction of lung elastin, in rheumatoid arthritis, atherosclerosis, cardiomyopathy and abdominal aortic aneurysm.

MMP-9 delivers inflammatory elements of blood into subintimal spaces, where further delivery into solid organs (brain, lung, muscle, peripheral nerve and joint) is initiated.

TGF beta-1 - Transforming Growth Factor Beta-1 Normal Range: <2380 pg/ml

TGF beta-1 is a protein that has important regulatory effects throughout innate immune pathways. This protein helps control the growth and division (proliferation) of cells, the process by which cells mature to carry out specific functions (differentiation), cell movement (motility), and the self-destruction of cells (apoptosis). The TGF beta-1 protein is found throughout the body and plays a role in development before birth, the formation of blood vessels, the regulation of muscle tissue and body fat development, wound healing, and immune system function (especially regulatory T-cells).

TGF beta-1 can impair T-regulatory cell function, which in turn contributes to the activation of autoimmunity, yet TGF beta-1 also plays a role in suppressing autoimmunity. TGF beta-1 has become important in the exploding incidence of childhood asthma, raising the tantalizing issue of remodeling due to biotoxin exposure. The EPA says that 21% of all new cases of asthma are due to exposure to water damaged buildings. If an individual develops wheezing after exposure to a water damaged building, look for remodeling to be the cause. Neurologic, autoimmune and many other systemic problems also are found with high TGF beta-1.

C4a Normal Range: 0-2830 ng/ml

C4a has become the inflammatory marker of greatest significance looking at innate immune responses in those with exposure to biotoxins. The complement system is a group of 32 preformed proteins that move freely through your bloodstream that are activated by cleavage. The proteins work with the innate immune system; they play a role in the development of inflammation.

Each complement pathway activates inflammatory responses, with spillover of effect from the innate immune response to acquired immune response and hematologic parameters.

These short-lived products are re-manufactured rapidly, such that an initial rise of plasma levels is seen within 12 hours of exposure to biotoxins; sustained elevation is usually seen until definitive therapy is initiated.

VEGF, vascular endothelial growth factor Normal Range: 31-86 pg/mL

VEGF is a substance made by cells that stimulates new blood vessel formation and increases blood flow in the capillary beds. VEGF is a polypeptide. Deficiency of VEGF is quite common and is a serious problem in biotoxin illness patients that must be corrected.

Delivery of oxygen in capillary beds is reduced in CIRS. This reduced delivery sets off alarm signals through the body via the activity of a nuclear transcription factor, hypoxia inducible factor (HIF). Low oxygen in tissue means HIF will be produced in high amounts to stimulate production of VEGF. VEGF is intimately linked to TGF beta-1, which in turn is linked to countless genomic pathways that lead to fibrosis, differential gene activation, the leakiness of blood brain barrier and a host of effects on the normally beneficial T-regulatory cells.

ACTH/Cortisol Normal Range: ACTH - 8-37 pg/mL; Cortisol - a.m. 4.3-22.4 ug/dL.

ACTH is a hormone released from the anterior pituitary gland in the brain. Cortisol is a steroid hormone produced by the adrenal cortex, which is the outer part of the adrenal gland. The adrenal glands are located on top of each kidney.

Early in the illness, as MSH begins to fall, high ACTH is associated with few symptoms; a marked increase in symptoms is associated with a fall in ACTH. Finding simultaneous high cortisol and high ACTH may prompt consideration of screening tumors, but the reality is that the dysregulation usually corrects with therapy.

ACLA IgA/IgG/IgM Normal Range: IgA - 0-12; IgG 0-10; IgM 0-9

ACLA are autoantibodies produced in response to accumulation of abnormal lipid content in the double lipid bilayer of the mitochondria. IgA, IgM, and IgG autoantibodies, also called anti-phospholipids, are often identified in collagen vascular diseases such lupus and scleroderma. An increased risk of spontaneous fetal loss in the first trimester of pregnancy is not uncommonly seen in women with the presence of these autoantibodies. They are found in over 33% of children with biotoxin-associated illnesses.

ADH/Osmolality Normal Range: ADH - 1.0-13.3 pg/ml; Osmolality - 280-300 mosmol

ADH, or vasopressin, is a substance produced naturally by the hypothalamus and released by the pituitary gland. The hormone controls the amount of water your body removes. ADH exerts its free water retention action in the renal tubules.

Serum osmolality is a test that measures the concentration of all chemical particles found in the fluid part of the blood. Symptoms associated with dysregulation of ADH include dehydration, frequent urination, with urine showing low specific gravity; excessive thirst and sensitivity to static electrical shocks; as well as edema and rapid weight gain due to fluid retention during initial correction of ADH deficits.

Leptin

Normal Range: Male: 0.5-13.8 ng/mL; Female: 1.1-27.5 ng/mL (highly variable)

Leptin turns on how tightly the body holds onto fatty acids. When leptin is high, one holds onto fatty acids and stores them in fat. This leads to rapid weight gain. Because of the high leptin, standard approaches to weight loss like eating less and exercising more will fail. The inflammatory responses that causes leptin levels to rise lead to patients who are chronically tired, in chronic pain, and forever overweight.

Secondary Source of Brain Inflammation: MARCoNS

MARCoNS bacteria colonize on mucosal membrane surfaces with minimal difficulty due to the MSH deficient state in CIRS patients. MARCoNS evade host defenses through biofilm formation and secrete exotoxins A and B, which split MSH molecules apart, causing further reduction in MSH levels. Coagulase negative Staph are known to secrete hemolysins which can increase inflammation in the host and even alter genomic expression of host genes.

When present in the deep nasal passages, MARCoNS releases small neurotoxins, polycyclic ethers, possibly through the olfactory bulb into the central nervous system, worsening the clinical condition of the patient. The colonization is not an infection but must be eliminated for symptom improvement. Its presence interferes with benefit from VIP nasal spray, the last step of therapy used to correct brain related changes and aberrant genomic responses.

The New Language of Genes: Transcriptomics

The Human Genome Project was completed in April 2003 and represented an enormous achievement in molecular biology. Scientists finally mapped the entire sequence of about 20,000 encoding genes. It was exciting to discover evidence for the presence of slight variations at specific locations, called single nucleotide polymorphisms or SNPs, which accounted for everything from eye color, to height and even food preferences.

But genes are not static entities. They interact with the environment and turn on and off through a complex series of influences to express proteins. While certain inherited genes may be associated with specific diseases, more importantly the most impactful modulator of cellular activity is likely differential gene expression, since a collection of genes expressed at any given time is ultimately in control of protein levels and cellular output throughout the body.

Based on current conditions, the genome will output a combination of genes, but when the conditions change, the gene output will change to best adapt to the new conditions or demands. This is generally what determines one’s day to day, or even morning to night physiology. Gender differences are often quite high.

Remarkably, environmental stimuli, and there are many, can cause gene activation in minutes. Such rapid changes in gene activity provide incredibly precise adaptations of the host to a rapidly changing environment. If the host is a one-celled creature, like bacteria or a fungus, it might be easier to conceive of the survival benefits that accrue from rapid responses to moisture, foodstuffs and chemical signals. Yet the same concepts apply to higher, more complicated life forms, like humans, as well.

We now know that the static genome is actively manipulated, constantly increasing production of some gene transcripts and decreasing others in response to its environment. Regulation is complex: nuclear transcription factors and newly discovered long non-coding RNAs, together with microRNAs and circular RNAs, as well as methylation and acetylation (do not forget demethylation and deacetylation!) can shut off or turn on gene function.

If this sounds complicated, it is. Research into the interacting complexities of so many layers of regulation has progressed beyond its infancy, but new discoveries are published every month. This shift from measuring the presence of genes, to assessing every level of activity along the molecular pathway is called Genomics.

1. Genomics - the branch of molecular biology concerned with the structure, function, evolution, and mapping of genomes.

2. Transcriptomics - the study of the transcriptome—the complete set of RNA transcripts that are produced by the genome, under specific circumstances or in a specific cell.

3. Proteomics - the large-scale study of proteomes. A proteome is a set of proteins produced in an organism, system, or biological context.

4. Metabolomics - the large-scale study of small molecules, commonly known as metabolites, within cells, biofluids, tissues or organisms. Collectively, these small molecules and their interactions within a biological system are known as the metabolome.

Together, each layer of molecular activity combines to express differential gene expression and relates to the associated chain of events that influences the function of every cell in the body.

CHAPTER 1: HOW IT ALL BEGAN

Author: RITCHIE SHOEMAKER MD

The story of CIRS, first named in 2010, begins 14 years earlier along the banks of the Pocomoke River of the Eastern Shore of Maryland. Back then, Ritchie Shoemaker, MD, was happy to be a rural, solo Family Practice physician working adjacent to wetlands of the tidal blackwater swamps around Pocomoke, Maryland. There was no need then to lock doors at night. People could walk to school without fear. Seeing patients by day, making house calls too, left ample time for a growing family to be outside in fields, forests and ponds nearby. It was an idyllic life for Dr. Shoemaker.

Life changed abruptly when Pfiesteria was found to be active in the Pocomoke River estuary where the downstream flow met the incoming salt wedge. All told, the new carrier of a never-before seen plague affected 22 tributaries of the Chesapeake Bay, possibly putting millions of people at risk for what the CDC later called Possible Estuarine Associated Syndrome (PEAS). This dinoflagellate was later identified in Bay sediments at least 100 years old, but in 1996 was acting like a newcomer, causing mysterious lesions on fish of all species. By 1997, the Cell from Hell expanded its activity to causing fish kills and creating an unusual illness in among watermen, people who harvested fish and crabs from the rivers and the Bay.

The public health uproar that followed the outbreak was magnified by an earlier book, The River Turned to Blood, that chronicled the Pfiesteria outbreak in North Carolina several years earlier. Only no one from Carolina admitted that anyone there was sickened in the wild. People stopped eating seafood from the Chesapeake Bay; they stopped boating on the Chesapeake Bay; life that revolved around the Bay was changed. Perhaps the scenario then was not as dramatic as COVID-19 is now regarding changing lives and changing activity because of an unknown pathogen, but the principles were the same. Fortunately, only one person was known to die from Pfiesteria.

Shoemaker was a wetland enthusiast. Everybody in Pocomoke, all 2000 people, knew him or JoAnn, his bride, an early childhood teacher in the local elementary school. He was asked by the watermen to get involved by trying to answer the questions What is wrong with me and what do I have to do to get better? Despite his best efforts in 1996, Shoemaker was of no help. All labs on the river, including nutrients, were unchanged; no infectious diseases were found. Every human test was non-conclusive but how could the illness be identified? What he needed were some actual confirmed human cases!

By early spring 1997, Pfiesteria was back. Shoemaker did fish autopsies, learned about wetland ecology, porewater physiology and emergent palustrine vegetation; his later insights about causation of Pfiesteria blooms were shaped by finding massive increases of heavy metals, especially copper, in the water column and in porewater directly adjacent to tomato farms and tobacco fields right next to subsequent fish kills. There, older fungicides, dithiocarbamates, had been added to copper to kill a resistant fungus that was destroying valuable crops.

All those academic exercises were interesting but what was making people sick was undetermined. In the thought that possibly Pfiesteria was making a toxin, a simple experiment was done with river water. Two containers, approximately 55 gallons each, were filled with river water from Shell Town, Maryland, a known hotspot just downstream from Pocomoke and then stocked with river fish of a variety of species. Into one of the containers was placed permanganate, a potent oxidizing agent that would inactivate biotoxins; the other tank was the control. Fish in the permanganate bath looked purplish but were still happily swimming the next day. Fish in the non-permanganate container were floating on the surface of the water, covered with the now-typical Pfiesteria lesions. Clearly, something poisonous was in the water that could be oxidized and removed. An unknown toxin seemed likely.

The first big fish kill of 1997 was in July outside Shell Town at Williams Point. There, a group of 10 people were recreating in the water, water skiing, swimming, drinking beer, all normal Eastern Shore activities. Surprisingly, three of ten became acutely ill but even more surprisingly, seven people stayed well. There was nothing obviously different about the seven controls versus the three cases. Shoemaker had his cases, but how was anything he thought of going to help? And who knew that HLA DR (what was that?) was the crucial susceptibility factor?

As luck would have it, the 3rd patient of the group sickened in the Pocomoke River developed a terrible secretory diarrhea. All three patients came to Shoemaker for help; he treated the 3rd with cholestyramine (CSM), an orally administered, anion binding bile sequestrant resin, to stop the secretory diarrhea. It is an old trick that country doctors know. To stop bad diarrheas, simply add a constipating, bile salt-binding cholesterol drug. The drug normally is used to lower cholesterol and is still made available on a generic basis in the United States. Off label use is legal.

Two days later, the patient on CSM called Shoemaker to say that the diarrhea had stopped (of course it did!) and her brain fog was gone. Her cough stopped, her muscle aches were gone and even the trouble she had remembering where she left her car was a thing of the past. CSM had to be binding-and removing-the causative compound!

The following week was the big State-scheduled Pfiesteria meeting held at Salisbury University. The State of Maryland was going to show everyone, especially the media, that the Cell from Hell problem was taken care of and no one was sick. Shoemaker arrived with his 8x10 colored photos of sickened people, complete with skin lesions, showing everyone who crowded around him that the illness was real and here was a possible cure. The media frenzy began.

What would you do next if you were in Shoemaker’s shoes? Would you treat everybody like Shoemaker did? Or would you say an N=1 study is not enough evidence of successful treatment? Some observers were not too happy that the country doc was making waves treating patients.

Nearly all the 200 patients he saw from 1997-98 felt better after CSM. Shoemaker published the first paper 9/97 on