Idiopathic environment illness has been labeled in a variety of ways over time. The original term, clinical ecology, was replaced by the term multiple chemical sensitivity (MCS). Most recently, it has been replaced by idiopathic environmental illness, a term that reflects the uncertain nature of the condition and its relationship to chemical exposure. The central focus of the condition is the fact that the patient describes recurrent, nonspecific symptoms referable to multiple organ systems that the sufferers believe are provoked by exposure to low levels of chemical, biologic, or physical agents. The most common environmental exposures include perfumes and scented products, pesticides, domestic and industrial solvents, new carpets, car exhaust, gasoline and diesel fumes, urban air pollution, cigarette smoke, plastics, and formaldehyde. Certain foods, food additives, drugs, electromagnetic fields, and mercury in dental fillings have also been reported as triggering events. However symptoms do not bear any relationship to established toxic effects of the specific chemical and occur at concentrations far below those expected to elicit toxicity.

Reported symptoms are markedly variable, but symptoms generally involve either the central nervous system, respiratory and mucosal irritation, or gastrointestinal symptoms. Symptoms may include fatigue, difficulty in concentrating, depressed mood, memory loss, weakness, dizziness, headaches, heat intolerance, and arthralgia. In contrast to the frequently debilitating symptomatology, no specific and consistent abnormalities are noted on laboratory or other diagnostic testing. In addition to multiple chemical sensitivity, other terms used to describe idiopathic environmental intolerance include universal allergy, 20th century disease, or cerebral allergy. Other primarily subjectively defined disorders have symptoms that overlap with idiopathic environmental intolerance including chronic fatigue syndrome, sick building syndrome, fibromyalgia, irritable bowel syndrome, and Gulf War syndrome. Intestinal dysbiosis is a diagnosis that could be considered within the category of idiopathic environmental intolerance. Intestinal dysbiosis is considered separately in policy No. 2.04.26.

The variable nature of the reported symptoms and the lack of recognized pathologic abnormalities make it extremely difficult to establish objective diagnostic criteria for the condition, which further hinders research into both the causes and appropriate treatment. One of the commonly quoted conceptual definitions, proposed by Cullen in 1987 (1), includes the following elements:

• The syndrome is acquired after a documentable environmental exposure that may have caused objective evidence of health effects.
• Symptoms are referable to multiple organ systems and vary predictably in response to environmental stimuli.
• The symptoms occur in relation to measurable levels of chemical, but the levels are below those known to harm health.
• No objective evidence of organ damage can be found.

Various causes for idiopathic environmental intolerances have been proposed; these have prompted different diagnostic and treatment approaches. An unrecognized form of allergy or immunologic hypersensitivity is a commonly proposed cause. Advocates of this etiology may recommend a large series of immunologic tests, including a variety of provocation-neutralization tests and a panel of immunologic tests, including immune function tests (e.g., deregulation of the 2,5A RNase L antiviral pathway in peripheral mononuclear blood cells) and levels of lymphocyte subsets (i.e., natural killer cells, CD8 cells). Proposed therapies have included avoidance of exposure, either in the environment or in the diet. IVIg may be recommended for injection or sublingual drops of “neutralizing” chemical and food extracts. Others have proposed that exposure to toxic substances may have prompted the immunologic abnormality and, based on this theory, testing of levels of environmental chemicals in the blood, urine, or fat may be suggested. Detailed nutritional analyses have also been performed, including levels of trace minerals in the blood, urine, or intracellular levels. Such elaborate nutritional assessments may also be performed in asymptomatic subjects. For example, Functional Intracellular Analysis (FIA™) is a series of laboratory tests offered by SpectraCell Labs that measure the intracellular levels of micronutrients, such as vitamins, minerals, and antioxidants in lymphocytes.

In some instances, symptoms may appear to coincide after exposure to a viral illness (particularly common with chronic fatigue syndrome); supporters of this theory may recommend a wide variety of tests to detect antibodies or antigens of various viruses. Some have also suggested that hypersensitivity to Candida may present with a similar array of subjective complaints, and thus recommend testing for Candida in the stool or urine. Finally, It has also been proposed that idiopathic environmental illness is a manifestation of a psychiatric disease or personality disorder based in part on results of psychologic/psychiatric interviews.

It should be noted that some environmentally caused illnesses can be well characterized by their clinical presentation and laboratory tests. For example, in certain instances “sick building” syndrome can be traced back to exposure of microorganisms related to air-handling symptoms. However, in contrast to idiopathic environmental intolerances, these patients experience a limited range of symptoms, and they occur in the affected building only.

Note: Policy No. 2.04.26  addresses fecal analysis in the diagnosis of intestinal dysbiosis. The diagnosis of intestinal dysbiosis may overlap with idiopathic environmental intolerance.

Laboratory tests designed to affirm the diagnosis of idiopathic environmental illness are considered investigational. (See Policy Guidelines.)

Nutritional assessments, including intracellular analysis of micronutrients, is considered investigational in both asymptomatic persons and patients with symptoms suggestive of idiopathic environmental illness.

Treatment of idiopathic environmental illness with IVIg, neutralizing therapy of chemical and food extracts, avoidance therapy, elimination diets, and oral nystatin (to treat Candida) is considered investigational.

Laboratory tests for the diagnosis of idiopathic environmental illness may be broadly subdivided into those intended to rule out specific diseases with well-defined presentations and diagnostic criteria, and those tests that are designed to affirm the diagnosis of idiopathic environmental illness. For example, a basic diagnostic workup, including a standard panel of chemistry tests and blood workup, would be considered appropriate as an initial diagnostic step, even in patients with non-specific symptoms, to rule out well-defined illnesses. Additional tests may be considered medically necessary in patients with more specific symptoms, suggestive, for example, of an autoimmune connective tissue disease, or infectious mononucleosis. A variety of psychiatric or psychological assessments may be performed to assess underlying conditions. However, at the present time, no specific tests can confirm the diagnosis of idiopathic environmental illness, and thus a large battery of tests performed for a patient with non-specific symptoms must be reviewed carefully for medically necessity. For example, the following should be reviewed closely, particularly when ordered simultaneously: laboratory tests of immune function (i.e., lymphocyte transformation, deregulation of the 2,5A RNase L antiviral pathway), lymphocyte subsets (e.g., natural killer cells, CD4, CD8), immunoglobulin levels (e.g., IgG, IgE), levels of trace minerals in the serum or urine (e.g., selenium, manganese, mercury), antibodies for a variety of infectious agents simultaneously, allergy services (including provocation testing), PET scans, or neuropsychologic testing and elaborate nutritional assessment including intracellular micronutrient assays.

In addition, claims for such treatments as IVIg therapy, provocation therapy, or counseling regarding specific avoidance environments or elimination diets would be considered investigational in the absence of specific symptoms.

BlueCard/National Account Issues

Diagnosis and treatment of idiopathic environmental illness may be offered by specialty clinics. Claims from these clinics must be reviewed carefully to determine which services would be considered medically necessary and which would be considered investigational. RNase-L testing sites are limited and include Immunosciences Lab in Beverly Hills, California and Redlabs USA, in Reno, Nevada.

The clinical entity of idiopathic environmental illness has been controversial for decades, in part due to the lack of a set of reproducible diagnostic criteria. Absent a clear definition of the disorder, basic science research into the etiology of the disorder, appropriate laboratory tests, and identifications of effective treatment are obviously problematic. A variety of organizations have presented position papers on idiopathic environmental illness, previously referred to as multiple chemical sensitivity or clinical ecology. Most recently, in 1999, the American Academy of Allergy, Asthma and Immunology updated their original 1986 position statement on clinical ecology. (2) This statement offered the following summary:

“IEI [idiopathic environmental illness]—also called environmental illness and multiple chemical sensitivities—has been postulated to be a disease unique to modern industrial society in which certain persons are said to acquire exquisite sensitivity to numerous chemically unrelated environmental substances. The patient experiences wide-ranging symptoms, but evidence of pathology or physiologic dysfunction in such patients has been lacking in studies to date. Because of the subjective nature of the illness, an objective case definition is not possible. Allergic, immunotoxic, neurotoxic, cytotoxic, psychologic, sociologic, and iatrogenic theories have been postulated for both etiology and production of symptoms, but there is an absence of scientific evidence to establish any of these mechanisms as definitive. Most studies to date, however, have found an excess of current and past psychopathology in patients with this diagnosis. The relationship of these findings to the patient’s symptoms is also not apparent. Rigorously controlled studies to verify the patient’s reported subjective sensitivity to specific environmental chemical have yet to be done. Moreover, there is no evidence that these patients have any immunologic or neurologic abnormalities. In addition, no form of therapy has yet been shown to alter the patient’s illness in a favorable way. A causal connection between environmental chemicals, foods, and/or drugs and the patient’s symptoms continues to be speculative and cannot be based on the results of currently published scientific studies.”

In 1999, the American College of Occupational and Environmental Medicine also published a position statement (3) that concluded, in part:

“Although specific diagnostic test and treatment have not yet been demonstrated to be helpful, a generalized clinical approach useful in the management of other nonspecific medical syndromes can be adopted pending further scientific findings. This approach emphasizes 1) establishing a therapeutic alliance with a goal toward functional restoration; 2) performing a medical evaluation appropriate to the presenting complaints and physical findings; 3) avoiding ineffective, costly, and potentially hazardous, unproven diagnostic tests or remedies that may increase a patient’s distress or disease; 4) treating all diagnosable medical and psychologic problems; 5) individualizing medical and behavioral coping strategies useful in managing symptoms; and 6) educating the patients about the current state of knowledge about MCS [multiple chemical sensitivity].”

In 1989, the American College of Physicians published a position paper on clinical ecology (4) that recommended the following:

“The controversial nature of clinical ecology within the medical profession today requires that acceptance or rejection of its theories and practice be based on standards of evidence as rigorous as those currently being applied in other areas of medicine. Clinical ecologists who wish to carry out definitive study of provocation-neutralization testing and neutralizing therapy should establish a precise definition of the condition to be diagnosed and treated, and they should document that study subjects fulfill these criteria. Each study should include control subjects whose symptoms and vital statistics match those of the patients as closely as possible.”

A literature search based on the MEDLINE database, performed for the period of 1999 (i.e., the date of position papers from AAAAI and ACOEM) to January 2004, did not identify any articles that would address the research limitations of the cited policy statements. The published literature suggests ongoing controversy regarding the etiology of the condition, appropriate diagnostic criteria, and treatment strategies. (5-10) There are inadequate data regarding the diagnostic performance of intracellular micronutrient analysis and its role in the management of the patient.

Medicare Policy (11)

Medicare Coverage Issues Manual-Diagnostic Services

Section 50-2, Cytotoxic Food Tests, states:

Prior to August 15, 1985, Medicare covered cytotoxic food tests as an adjunct to in vivo clinical allergy tests in complex food allergy problems. Effective August 15, 1985, cytotoxic leukocyte tests for food allergies are excluded from Medicare coverage because available evidence does not show these tests are safe and effective.

Section 50-22, Challenge Ingestion Food Testing, states:

Challenge ingestion food testing has not been proven to be effective in the diagnosis of rheumatoid arthritis, depression, or respiratory disorders. Accordingly, its use in the diagnosis of these conditions is not reasonable and necessary within the meaning of section 1862 (a) (1) of the Medicare law, and no program payment is made for this procedure when it is so used.

2005-2006 Update

A literature search of the Medline database was performed for the period of 2003 through March 2006. No published studies were identified that would prompt reconsideration of the policy statement.

Since 1993, publications have described a relationship between deregulation of the 2,5A RNase L antiviral pathway and chronic fatigue syndrome. (12) Deregulation suggests a suppressed ability to battle antigens and possibly results from a prolonged exposure to viral antigens. Recent studies have found a high ratio of low molecular weight, 37-kilodalton to 83-kilodalton (37/83) RNase L isoforms on peripheral blood mononuclear cells might be used for the diagnosis of chronic fatigue syndrome. (13,14) At a clinical cutoff ratio of 0.4, sensitivities have been reported between 76% and 91% and specificities between 33.3% and 71%. (13-15) However, high variability and poor reproducibility in testing the 37/83 RNase L ratio have been reported along with finding a weak correlation between 37/83 RNase L ratios and the Multidimensional Fatigue Inventory score in patients with chronic fatigue syndrome. (15) Therefore, further studies are needed in larger populations to confirm these observations and correlations for use of the 37/83 RNase L ratio for the diagnosis of chronic fatigue syndrome and the policy statement is unchanged.

2007 – 2008 Update
A literature search was conducted using the MEDLINE database in December 2007. No published studies were identified that would prompt reconsideration of the policy statement. Das-Munshi presented a systematic review of provocation studies in individuals with multiple chemical sensitivities (MCS). (16) After review of 37 studies including 784 persons reporting MCS, they concluded that persons with MCS do react to chemical challenges; but that the responses occur when they can discern differences between active and sham substances, suggesting that the mechanism is not specific to the chemical itself. Another review studied behavioral and social factors as a potential cause of MCS. (17) While the authors note that behavioral or psychological causes may contribute to MCS, there is a paucity of treatment trials and treatment trials examining psychological approaches are needed.

2009 Update
The policy was updated with a literature search using MEDLINE through November 2008. One publication involving only 12 patients with well-characterized idiopathic environmental intolerance reported results of neuropsychological testing and PET scans. (18) The study noted no consistent pathological cognitive performance, and no functional imaging pattern was found. The authors concluded that it appears premature to claim specific neuropsychological or neuroimaging findings characteristic of idiopathic environmental intolerance and that therefore cerebral F-18 FDG PET should not be used to corroborate or rule out suspected idiopathic environmental intolerance. In reports from Europe, Bailer, Witthoft, and Rift noted that findings of trait anxiety, somatic attribution, and absorption (predisposition to get deeply immersed in sensory or mystical experiences) were related to the presence of idiopathic environmental intolerance. (19, 20) No additional clinical studies relevant to this policy were identified in the literature search; the policy statements are unchanged.

References:

1. Cullen MR. The worker with multiple chemical sensitivities: an overview. Occup Med 1987; 2(4):655-61
2. American Academy of Allergy, Asthma, and Immunology (AAAAI) Board of Directors. Idiopathic environmental intolerances. J Allergy Clin Immunol 1999; 103(1 pt 1):36-40.
3. American College of Occupational and Environmental Medicine. ACOEM Position Statement. Multiple chemical sensitivities: idiopathic environmental intolerance. J Occup Environ Med 1999; 41(11):940-2.
4. American College of Physicians. Clinical ecology. Ann Intern Med 1989; 111(2):168-78.
5. Bolt HM, Kiesswetter E. Is multiple chemical sensitivity a clinical defined entity? Toxicol Lett 2002; 128(1-3):99-106.
6. Winder C. Mechanisms of multiple chemical sensitivity. Toxicol Lett 2002; 128(1-3):85-97.
7. Aaron LA, Buchwald D. A review of the evidence for overlap among unexplained clinical conditions. Ann Intern Med 2001; 134(9 pt 2):868-81.
8. Graveling RA, Pilkington A, George JP et al. A review of multiple chemical sensitivity. Occup Environ Med 1999; 56(2):73-85.
9. Barsky AJ, Borus JF. Functional somatic syndromes. Ann Intern Med 1999; 130(11):910-21.
10. Lacour M, Zunder T, Huber R et al. The pathogenetic significance of intestinal Candida colonization--a systematic review from an interdisciplinary and environmental medical point of view. Int J Hyg Environ Health 2002; 205(4): 257-68.
11. Medicare Policy: http://new.cms.hhs.gov/manuals/downloads/Pub06_PART_50.pdf (Section 50-22: Challenge Ingestion Food Testing).
12. Suhadolnik RJ, Reichenbach NL, Hitzges PM et al. RNA drug therapy acting via the 2-5A synthetase/RNase L pathway. Ann NY Acad Sci 1993; 685:756-7.
13. Tiev KP, Demettre E, Ercolano P et al. RNase L levels in peripheral blood mononuclear cells: 37-kilodalton/83-kilodalton isoform ratio is a potential test for chronic fatigue syndrome. Clin Diagn Lab Immunol 2003; 10(2):315-6.
14. Tiev KP, Briant M, Ziani M et al. Variability of the RNase L isoform ratio (37 kiloDaltons/83 kiloDaltons) in diagnosis of chronic fatigue syndrome. Clin Diagn Lab Immunol 2005; 12(2):366.
15. Fremont M, Vaeyens F, Herst CV et al. 37-Kilodalton/83-kilodalton RNase L isoform ratio in peripheral blood mononuclear cells: analytical performance and relevance for chronic fatigue syndrome. Clin Diagn Lab Immunol 2005; 12(10):1259-60.
16. Das-Munshi J, Rubin GJ, Wessely S. Multiple chemical sensitivities: a systematic review of provocation studies. J Allergy Clin Immunol 2006; 118(6):1257-64.
17. Das Munshi J, Rubin GJ, Wessely S. Multiple chemical sensitivities: review. Curr Opin Otolargyngol Head Neck Surg 2007; 15(4):274-80.
18. Bornschein S, Hausteiner C, Drzezga A et al. Neuropsychological and positron emission tomography correlates in idiopathic environmental intolerances. Scand J Work Environ Health 2007; 33(6):447-53.
19. Bailer J, Witthoft J, Rist F. Psychological predictors of short- and medium term outcome in individuals with idiopathic environmental intolerance (IEI) and individuals with somatoform disorders. J Toxicol Environ Health A 2008; 71(11-12):766-75.
20. Witthoft M, Rist F, Bailer J. Evidence for a specific link between the personality trait of absorption and idiopathic environmental intolerance. J Toxicol Environ Health A 2008; 71(11-12):795-802.

Allergy, Clinical Ecology
Clinical Ecology
Diagnosis and Management of Idiopathic Environmental Intolerance
Environmental Medicine
Idiopathic Environmental Intolerance
Multiple Chemical Sensitivities
RNase L antiviral pathway
Spectravision