Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Chronic Inflammatory Response Syndrome Shoemaker/Surviving mold Diagnosis and Treatment Protocol Cynthia Fraed, MD Chronic Inflammatory Response Syndrome (CIRS) is a multisystem, multi-symptom, immunologic disease. Dr. Ritchie Shoemaker first identified a cluster of patients with similar symptoms after being exposed to fish affected by Pfiesteria. When he treated these patients’ gastrointestinal symptoms with cholestyramine he noticed other symptoms also improved. As his patients improved, he followed his clinical skills and his scientific curiosity to make sense of this puzzling illness. His continued observation, research, and dedication have led to the twelve step protocol that guides the treatment of those affected by biotoxins. Multiple toxins can lead to CIRS: 1. Blue Green Algae (i.e.Microcystis) and dinoflagellates (Pfiesteria, ciguatera) 2. Lyme disease 3. Water Damaged Buildings (WDB) produce a host of inflammagens (an irritant that elicits edema and the cellular response of inflammation i.e molds, mold fragments, mycotoxins, bacteria, Actinomyces) There is also an important host component to this disease. Not everyone exposed to these toxins will develop CIRS. Genetic susceptibilities expressed by certain human leukocyte antigen (HLA) genes are shared by about 25% of the population. HLA genes have been correlated with susceptibility to mold, dinoflagellates and multiple sources. The failure of individuals with these susceptible HLA genes to turn on an adaptive immune system response to biotoxins results in a persistent innate immune response. The innate immune system is the first line of defense. It is already present and ready to attack any invaders. In contrast, the adaptive immune system is able to identify an invader, analyze it and respond by creating antibodies to fight that invader. Once it has created the response system for a particular invader, it will recognize that invader in the future. The innate immune system forms the basis for a response, but there are other as yet unidentified factors since people with the same HLA will have differences in expressions of symptoms, severity, and ability to recover. Page 1 of 10 Taking a history is important and provides enough information 75 – 80 % of the time to suggest the diagnosis. Patients present with a history of biotoxin exposure and a myriad of symptoms across multiple systems. These symptoms are grouped into eight categories and are part of the review of systems (ROS). 1. General symptoms of fatigue and weakness. Post exertional malaise. 2. Muscle complaints including aching, cramping (claw-like cramping of the hands and feet), joint pains. 3. Respiratory complaints of cough, shortness of breath, chronic sinus problems, asthma-like symptoms 4. Eye symptoms including hypersensitivity to bright lights, blurred vision, tearing, red eyes. 5. Gastrointestinal symptoms of abdominal pain, nausea, and diarrhea. 6. Central nervous system problems with executive cognitive functions (i.e. memory loss, difficulty with word finding, confusion, disorientation, concentration, problems learning new material) as well as anxiety, mood swings and panic. 7. Generalized neurological problems of lightheadedness, numbness, vertigo, metallic taste and temperature dysregulation. 8. Unique symptoms such as increased thirst and frequent urination, appetite swings, headaches, and frequent static electric shocks. Additional areas of history to check are problems with sleep, and bleeding tendencies such as nose bleeds that are difficult to stop or heavy periods for women. It is important to do a past medical history, hospitalizations, surgeries, injuries, past traumas, family history, social history, sexual history, menstrual history (for women), and medications/supplements. A careful physical exam with a detailed neurologic exam is followed by a Visual Contrast Sensitivity (VCS) test and extensive laboratory testing. Blood tests are done through LabCorp with the exception of the C3a and C4a which must be tested through Quest/Denver National Jewish Hospital. Additional tests include culturing for multiply antibiotic resistant coagulase negative Staphylococcus (MARCoNS), and based on presentation, pulmonary function tests (PFTs), stress echocardiogram and/or NeuroQuant MRI. VCS – measures visual contrast which is a neurologic function that is positive in up to 92% of those affected by CIRS. These patients might notice a problem with night driving, having eyes tire more easily while reading or even have an increased risk of falling. Page 2 of 10 HLA – Human leukocyte antigen genes are found on chromosome 6. These genes correlate with a response to various toxins where the adaptive/acquired immune system does not work correctly in identifying and conferring immunity against the toxins encountered. TGF Beta-1 – Transforming growth factor beta-1 is a regulatory protein that is found throughout the body. It is a multifunctional cytokine that is a marker of an overactive immune system. It has a dual role in that it can contribute to impairing T-regulatory cells leading to activation of autoimmunity or it can reduce autoimmunity. Chronic elevations can lead to asthma-like symptoms, pulmonary fibrosis, and restrictive disease that can be elucidated by pulmonary function tests PFTs). MSH – Melanocyte stimulating hormone is a hormone that is a regulatory neuropeptide that controls other hormones and also controls inflammatory pathways. MSH is made by POMC cells in the hypothalamus and released from the intermediate lobe of the pituitary gland under the influence of leptin. When deficient, MSH affects anti-diuretic Hormone (ADH), can reduce androgens, alter cortisol and ACTH levels, and cause prolonged illness, gastrointestinal problems, sleep disturbances, chronic pain and increased susceptibility to resistant coagulase negative staph (MARCoNS). VIP – Vasoactive intestinal peptide, is another neuroregulatory hormone and like MSH, regulates cytokine responses and inflammation. Low levels of VIP can cause unusual shortness of breath (especially with exercise) and gastrointestinal symptoms including diarrhea. C4a – is a complement peptide fragment or anaphylatoxin which is a large glycoprotein produced as part of the complement cascade. It has important functions in host defense and activates inflammatory response. Elevated levels are important markers in innate immune response to water damaged buildings (WDB) but are also elevated in lupus and Lyme disease. MMP-9 – Matrix metalloproteinase 9 is an enzyme involved in the breakdown of endothelial and matrix tissue barriers. It is important in tissue remodeling and in disease processes. When elevated it is associated with increased tumor invasiveness, an increase in the permeability of the blood brain barrier and has been implicated as part of the pathogenesis of COPD by destroying lung elastin. It has also been implicated in connective tissue destruction seen in rheumatoid arthritis; cardiomyopathy, aortic aneurysms and can cause inflammation and pain. VEGF – Vascular endothelial growth factor is a growth factor that stimulates the growth of new blood vessels and increases the flow of blood in the capillaries. Low VEGF levels can result from inflammatory cytokines and cause muscle pain and post-exertional fatigue. Early in CIRS it is possible to see elevated levels of VEGF while trying to compensate for low oxygen to tissue. Elevated levels are also found in cancer and may help promote tumor growth. Page 3 of 10 ADH/Osmolality - Antidiuretic hormone (also known as AVP– arginine vasopressin/vasopressin) and osmolality are considered together. ADH is a pituitary hormone produced by neurosecretory cells in the posterior hypothalamus. It controls the renal excretion of water and is affected by the serum concentration. When the system is dysregulated (shows impairment of the normal physiologic regulatory function) as evidenced by low ADH in the face of high osmolality (as is common in CIRS), the patient experiences increased thirst, increased frequency of urination and an increase in static electricity resulting in shocks as the blood tries to decrease the osmolality by secreting the excess salt through the skin. ACTH/Cortisol – Adrenocorticotrophic hormone and cortisol are also discussed as paired tests. The anterior pituitary releases the hormone ACTH which then stimulates the adrenal cortex to produce cortisol. Cortisol, known as the “stress hormone,” is a steroid. There is a normal diurnal pattern of cortisol which typically is higher in the morning and lower at night, but can become dysregulated in CIRS. This dysregulation results in a disturbance of the circadian rhythm, making it difficult to sleep at night and resulting in fatigue during the day. Leptin – this hormone is released from fat cells and signals the hypothalamus to adjust food intake and energy expenditures. CIRS can cause leptin levels to rise, resulting in patients who cannot lose weight with standard approaches to weight loss and who are always tired. ACLA - Anti-cardiolipin antibodies are anti-phospholipid autoantibodies that are associated with vascular diseases such as lupus and scleroderma. AGA –Antigliadin antibodies target gliadin, a small protein that is found in wheat, barley and rye. While elevations are not specific for celiac, patients with high AGA should be evaluated for celiac disease. von Willebrand’s - Patients reporting nose bleeds that can be hard to stop, heavy periods in women and increased bleeding during surgery or from wounds should be tested for von Willebrand’s Disease. This coagulation disorder can be genetic or acquired as a result of CIRS, autoimmune diseases such as lupus, cancers, and heart problems such as aortic stenosis. MARCoNS – Multiply antibiotic resistant coagulase negative staph can be cultured from the deep nasal cavity or cavitation. If present it can produce an exotoxin that further lowers MSH. Additional lab tests may be indicated including CBC, CMP, CRP, thyroid labs, testosterone (free and total) and lipids. Environmental evaluation is done with either the ERMI (Environmental Relative Moldiness Index or the HERTSMI-2 (Health Effects Roster of Type Specific Formers of Mycotoxins and Page 4 of 10 Inflammagens 2nd version). These tests are also used during treatment to make sure that the patient is avoiding additional exposure. The treatment protocol delineated by Dr. Shoemaker is a twelve step process. It is critically important to follow the steps in the correct order. Step 1. Removal from exposure. First and foremost is to remove the patient to a safe location without ongoing exposure to toxins. This sounds easy and logical, but in fact may be quite difficult. If the exposure is in the home, then finding the source may require the help of an Indoor Environmental Professional (IEP) person to help find the sources of water damage in the home. Once identified, remediation is needed to correct the problem. It can be costly and difficult to find well trained, ethical and honest professionals to carry out the remediation correctly. During this process the patient will need to find a safe place to stay temporarily. For some patients this is a lengthy process causing stress from a disrupted living situation as well as significant financial stress. They must also remove their personal effects, furniture, and clothing prior to the remediation. These items will need to be either cleaned or discarded. The person will need personal protective items (i.e. an N 95 efficiency respirator mask, goggles and gloves) during the sorting and cleaning. More affected individuals may need to have unaffected persons to help with these tasks. If the site of exposure is at work or school, additional problems can be encountered leading to loss of income or disruption of the educational process. Since testing and remediation can be time consuming and costly, employers and school officials may deny there is a problem. Unaffected contacts may not believe the patient and think the patient is crazy or malingering since in spite of significant fatigue, cognitive challenges, and physical discomfort they don’t appear to be ill. Step 2. Treatment to remove biotoxins. The liver processes biotoxins and secretes them against a gradient into the bile, which is released into the small bowel for elimination in the stool. Unfortunately for the approximately 25% of the population with susceptible HLAs, the biotoxins are reabsorbed prior to elimination. Cholestyramine (CSM) is a bile acid sequestering agent that is able to bind both positively charged industrial chemical toxins and negatively charged ionophore toxins. Welchol is also a bile acid sequestering medication which can be used to remove the biotoxins, but is the second choice for treatment of CIRS since it has only one quarter of the binding sites and is therefore 25% as effective as CSM. Both of these medications have been used to lower cholesterol but are not in the same class as statins (i.e. Lipitor, Crestor). Page 5 of 10 CSM will adsorb nutrients and minerals from any food or supplements, so it must be taken away from meals, medications, and supplements. The standard dosing schedule of CSM is four times a day and may present quite a challenge with timing. It should be taken either half an hour prior to meals or an hour after eating. Medications such as thyroid replacement provide their own challenge and should be given a minimum of one hour prior to CSM or two hours after taking the medication. CSM can cause gastrointestinal side effects including constipation, GERD, bloating, and nausea. Starting high dose fish oil and a no amylose diet prior to starting CSM can help prevent an “intensification” reaction or worsening of flu like symptoms. Welchol is more convenient as it can be taken with meals. It may take longer for Welchol to work since it only has a quarter of the binding sites that CSM has. Side effects and need for pretreatment with high dose fish oil and the no amylose diet are similar to CSM. Step 3. MARCoNS evaluation and trestment. MARCoNS is multiple antibiotic resistant coagulase negative Staphylococcus which forms a biofilm in the nasopharynx. MARCoNS is rarely present if the patient has a normal MSH, but if present, continues to lower the MSH by cleaving it with hemolysins that render the MSH ineffective. This creates a cycle that keeps the MSH low and makes CSM less effective. Treatment is with BEG (Bactroban-EDTA-Gentamicin) spray from a compounding pharmacy. If the bacteria are resistant to gentamicin a shift to an appropriate alternate spray or adding Rifampin may be necessary. Side effects are often a burning sensation from the spray which will usually resolve with continued use. After treatment for 1 – 2 months, retest to be sure MARCoNS is eradicated. Step 4. Correction of positive antigliadin antibodies. Low MSH can lead to T-reg cell dysregulation which can then lead to increased inflammation and autoimmunity. If the patient has tested positive for antigliadin antibodies (AGA), a followup TTG-IGA test should be done. If the TTG-IGA is positive, the patient should eliminate gluten forever; if negative, elimination of gluten for at least 3 months is required, followed by repeat AGA testing to see if it is negative. Step 5. Correction of androgen deficiency. Page 6 of 10 Low MSH can influence (the pituitary to lower) the production of sex hormones. This is especially evident with lowered testosterone levels due to upregulation of aromatase. Aromatase converts the testosterone to estradiol causing hormonal imbalances. Giving testosterone only increases the aromatase and leads to more estrogen. Treating with DHEA 25 mg TID can raise testosterone. Human chorionic gonadotrophin (HCG) 500 IU three times a week has also been used to help support low testosterone levels. Other options include the use of VIP nasal spray when the other parameters for its use have been met. Step 6. Correction of antidiuretic hormone (ADH)/osmolality dysregulation. Patients with biotoxin illness frequently have higher osmolality despite low ADH levels, resulting in thirst, frequent urination and constant dehydration. This dysregulation or disruption of the physiologic feedback mechanism, can cause the deposition of salt on the skin leading to more frequent static electricity shocks and the dehydration can result in migraine-like headaches. For some patients treatment with CSM will improve the VCS and treatment of MARCoNS may lead to normalization of ADH/osm. If not, treatment with DDAVP can correct this situation. The dose is 0.2 mg every other day for two weeks. The patient will need to be monitored closely watching for weight gain, fluid retention and hyponatremia by checking electrolytes as well as ADH and osmolality labs. It may also help with acquired von Willebrand’s syndrome. Step 7. Correction of MMP-9 . MMP-9 is a gelatinase involved in the degradation of the extracellular matrix. Levels above 332 ng/ml can result in intensification. A no amylose diet and high dose fish oil can help correct this elevation. If intensification persists, exploration of other problems such as tick-borne illness, autoimmune problems or neoplastic disease should be considered. Using the drug Actos can help upregulate PPAR-gamma, which lowers MMP-9. Actos can increase the risk of bladder cancer with prolonged use and may cause symptoms of hypoglycemia even with a normal blood sugar. Since Actos lowers leptin any patient with a leptin level lower than 7 may not tolerate Actos. Step 8. Correction of VEGF. Page 7 of 10 In patients exposed to biotoxins, high cytokine levels suppress VEGF. High dose fish oil or Actos will correct VEGF as long as the person is removed from exposure. If the VEGF remains high or low with treatment it is important to look for additional causes such as Lyme disease. Step 9. Correction of C3a. If the patient has elevated C3a, rule out Lyme disease. High dose statins can be used for persistent elevations of C3a. Coenzyme Q 10, 150 mg daily, should be added since statins effect HMG-CoA reductase function, reducing CoQ10. This may help prevent the myalgia known to result from statin use. Step 10. Correction of C4a. As a key marker of how severely a person is affected by CIRS, it is important to follow levels of C4a carefully. Erythropoietin (Procrit) can be used to rapidly reduce C4a, however, use of Procrit requires patient consent (because of the FDA Black Box Warning) and careful monitoring to keep the risk of thrombosis low. The recommended dose is 8000 U IM twice a week over a 15 day period. Monitoring labs, including CBC, an iron panel, C4a, TGFB1, d-dimer, and T Regs should be done prior to each dose and after the completion of the course of treatment. Watch for clinical signs of improved energy, cognition and the ability to breathe more easily. Alternatively, VIP therapy can be used at 4 sprays daily. Treatment corrects capillary hypoperfusion and will normalize neural functioning. If the C4a is not improving with treatment, evaluate for ongoing exposure, reexposure or other disease entities. Step 11. Correction of TGF-beta 1. TGF-beta 1 is another key marker for the severity of CIRS and is also elevated in autoimmune disorders, MS, HIV and cancer. Additionally, it can cause gastrointestinal dysfunction and restrictive lung changes. Treatment is with losartan, starting at 12.5 mg twice a day, and carefully watching the blood pressure to be sure the patient can tolerate the medication. If the BP is too low or orthostatic changes happen with the medication, use VIP therapy. Step 12. Replacement of VIP. Page 8 of 10 If VIP is still deficient, replacement is the final step on the path to recovery from biotoxin illness. Prior to considering VIP, the patient should be able to pass the VCS test, have a negative MARCoNS culture, and be in an environment that is safe from WDB inflammagens and mold. Once these criteria have been satisfied and a normal fasting baseline lipase test is obtained, a trial of VIP can be done. VIP Spray 50 mcg/ml is available from Hopkinton Compounding Pharmacy. The initial test dose of one spray in one nostril is given after vital signs and blood for labs (TGFB 1, C4a, VEGF, MMP-9,qa 25 OH-Vitamin D, estradiol, testosterone, and lipase) are done. The patient is observed for symptom improvement, vital signs are followed every 5 minutes for 3 values. At the end of 15 minutes post treatment a TGFB 1 level is drawn. If the level doubles there may be additional mold exposure that has not been identified or corrected. If the in-office trial of VIP spray has gone well, the dose is 4 times a day. There is a small risk of pancreatitis with the use of VIP spray and any abdominal pain should be reported to the clinician promptly and monthly fasting lipase levels should be followed. If the patient has abdominal pain or elevated fasting lipase levels, then VIP spray is discontinued and evaluation of the gallbladder and pancreas is undertaken. During this process of treatment and recovery the patient must be educated to understand what happens for them when they become exposed to a WDB. Since no one lives in a bubble, an awareness of their environment and prompt action to remove oneself from exposure and return to treatment for any unavoidable exposure is paramount. Page 9 of 10 Page 10 of 10