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In the majority of non-occupationally triggered multiple chemical sensitivities (MCS), MCS is a comorbidity of chronic fatigue syndrome (CFS) or fibromyalgia (FM).1 Patients with MCS and sometimes CFS present with airway symptoms, especially upper airway nasal symptoms; sometimes cutaneous symptoms; and adverse drug reactions (ADR) to multiple medications.2–6 In MCS and MCS-related disorders, "Preliminary data indicate the nasal pathology of these disorders is characterized by defects in tight junctions between cells, desquamation of the respiratory epithelium, glandular hyperplasia, lymphocytic infiltrates, and peripheral nerve fiber proliferation."2
Patients have sometimes used the term allergies to describe the reactions: "The CFS group tended to report more respiratory symptoms and drug allergies."5 However, researchers have noted that total IgE levels are often not highly elevated when compared with symptoms being reported.7,8 In an MCS cohort, "Total IgE values were relatively low, 32 patients (64%) showed the IgE value below 200 IU/ml."7 In a CFS cohort, "78% had total IgE less than100 IU/ml."8
While mast cells have been found in the skin of patients with fibromyalgia in one cohort and in 20 patients with MCS, several research teams have concluded that IgE-mediated classic allergies are probably not responsible for the hypersensitivities in most patients with MCS and CFS.7–11 "Inflammation and the consequent IgE-mediated activation of mast cells and eosinophils, as seen in asthma patients, is unlikely to be responsible for the presence of BHR in patients with CFS."11
One research team instead refers to patients with CFS as having a "high prevalence" of idiopathic nonallergic rhinopathy.12 Patients with MCS, like nonallergic patients with other hypersensitivity conditions, have been described as being sicker than patients with allergies.13 The hypersensitivities in patients with MCS and CFS may potentially share some of the same mechanisms seen in other hypersensitivity conditions. This article primarily focuses on non-IgE-mediated potential pathways and tests.
Infectious Agents: Potential Role as Trigger and In Maintaining Reactions
In CFS, viruses including cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus 6 (HHV-6) are often cited as triggers, with EBV and HHV-6 often cited as coinfections.14,15 In one CFS cohort, 47% had increased HHV-6 antibody titers.14 Some patients with CFS due to an infectious trigger are left with crimson crescents on their pharyngeal pillars. "This appearance is most closely associated with elevated HHV-6 titers in our patients."15
Viruses can be found in nasal mucosa and other tissues in close proximity in normals without signs of systemic infection upon autopsy.16 Reservoirs of CMV have been found in nasal mucosa, trachea, and thyroid; EBV in nasal mucosa, tonsils, and lymph nodes; and HHV-6 in salivary glands and thyroid.16 In a similar study, "Using autopsy specimens, we found that the frequency of HHV-6 DNA in the olfactory bulb/ tract region was among the highest in the brain regions examined."17 Interestingly, "EBV was detected in all eight cases … but in only two of six whole-blood specimens."16
"Viruses injected into the nasal cavity have been found to enter olfactory neurons, replicate, travel into the olfactory bulb and then into the central nervous system (CNS)," due to "the close proximity and the synaptic connections between the nasal cavity and the CNS. … In addition, viruses in circulation can also cross from capillaries in the lamina propria into olfactory neurons."18
Enzymes
Xenobiotic-metabolizing enzymes (XMEs) are found in the liver, kidney, skin, olfactory epithelia, and bronchiolar epithelium. XMEs are highly expressed in the mammal olfactory mucosa, and for several compounds tested, the rate of olfactory mucosa metabolism from parent compound to subsequent compound was 3- to 65-fold higher than hepatic. Inhibitors of these enzymes, increased the electro-olfactogram (EOG) response. "This increase in EOG amplitude provoked by XME inhibitors is likely due to enhanced olfactory sensory neuron activation in response to odorant accumulation. … In addition to protecting against inhaled toxic compounds, these enzymes could also metabolize odorant molecules, and thus modify their stimulating properties or inactivate them. … They may also protect the brain because the olfactory nerve can carry viruses, bacteria and chemicals into the brain."19
Viruses are known to affect enzymes. Could an ongoing virus also affect olfactory mucosa enzymes thus inhibiting attenuation of olfactory signals in patients with an infectious trigger? Odorant inhalation tests to detect odorant metabolites in exhaled air may have the capacity to help differentiate respiratory xenobiotic-metabolizing enzyme capacity in patients with MCS versus controls.
Enzyme polymorphisms have been found in the blood in MCS and have been able to differentiate MCS, suspected MCS, CFS, and FM, and healthy controls.20,21 Genotyping for these variants could be a reliable and cost-effective test to help diagnose these illnesses, according to these researchers.21
Neuropeptides and Neurogenic Inflammation
In addition to XMEs, the respiratory tract also contains neuropeptide-degrading enzymes. While some neuropeptides have been associated with inducing or augmenting the effects of histamine in respiratory conditions, some have also been associated with neurogenic inflammation and angioedema, which may have the potential to play a role in MCS and CFS respectively.14,22
When compared with asthmatics, patients with MCS and asthma-like symptoms were found to be more sensitive to inhaled capsaicin. Lidocaine, which effects sensory nerves and reduced the symptoms indicating the mechanisms behind chemical sensitivity, "may originate in the sensory nervous system."23
In the nose, chemical irritants, such as capsaicin, stimulate irritant receptors on sensory nerve C-fibers, which leads to the release of substance P (SP) and other mediators.22 Some of the same substances that induce SP inhibit neutral endopeptidase (NEP), the enzyme that breaks down SP.22 Common respiratory viruses can also reduce NEP.24
In an MCS cohort, "Plasma levels of substance P, vasoactive intestinal peptide and nerve growth factor, but not histamine, were elevated. … Exposure to VOCs increased plasma levels of all parameters," and "enhanced skin wheel responses induced by histamine. … These results indicate that exposure to VOCs may enhance neurogenic inflammation with concomitant enhancement of histamine-induced responses."25 Exposure to VOCs did not have these effects in normal subjects or patients with atopic eczema/dermatitis syndrome (AEDS).
The C1 Esterase Inhibitor, Complement C4, and Angioedema
Other neuropeptides such as neuropeptide Y (NPY) or bradykinin may be elevated in CFS.14,26 This is important since bradykinin has the potential to account for laryngeal swelling not necessarily accompanied by high IgE levels.
Some patients in one CFS cohort were found to have decreased C1 esterase inhibitor and complement C4.14 In patients with C1 esterase inhibitor deficiency or dysfunction, complement C4 decreases, due to a consumptive process, and bradykinin increases. This can result in swelling, or angioedema (abdominal, facial, laryngeal).
In addition, activation of bradykinin B2 receptors, expressed in sensory nerves, "results in excitation and sensitization of sensory neurons," and bradykinin can lead to the release of SP.27
ASST As A Marker of Autoreactivity in Hypersensitivity Conditions
In a CFS cohort, "Patients with bronchial hyperresponsiveness presented significantly more often with fatigue that was made worse by physical exercise, recurrent flu-like illness, thyroid inflammation, and painful lymph nodes."11 In an asthma cohort, findings and recommendations included that people with thyroid diseases seem to present more signs of asthma and that asthmatics should be checked for thyroid diseases.28
One thing that nonallergic bronchial hyperactivity, Hashimoto's thyroiditis, and CFS have in common, beyond their potential to be triggered or exacerbated by viruses, is that they are all theorized to have an autoimmune component, and it is possible that MCS may have as well. CFS and MCS have a female predominance and an increased incidence of Hashimoto's thyroiditis (HT) and/or positive antinuclear antibodies (ANA).13,14 Some other hypersensitivity conditions (nonallergic asthma, chronic autoimmune urticaria) are thought to have an autoimmune component with a female predominance, an increased frequency of positive ANA and HT-related autoantibodies, and a positive autologous serum skin test (ASST).28-30
A positive ASST is thought to be a marker of "self reactivity" in hypersensitivity conditions, and when compared, ASST positive nonallergic patients have often been found to have more severe cases than their allergic counterparts with the same hypersensitivity condition.
A positive ASST has been seen in 53% of nonallergic asthma. By contrast, it is seldom positive in allergic asthma and allergic rhinitis.29 "Asthma patients with ASST-positive results as compared with patients with ASST-negative results exhibited a significant increased airway hyperresponsiveness (PC(20) methacholine)."31
In chronic urticaria (CU), "patients with a history of rhinitis and food allergy and positive skin prick tests results for pollens and dog … had attacks of shorter duration," while ASST positive patients had "frequent involvement of more body sites … presence of throat angioedema and general constitutional, respiratory or gastrointestinal symptoms in comparison with the ASST-negative patients."32,33 Researchers concluded, "Apparently, ASST-positive patients have more severe clinical manifestations of chronic urticaria."33
In multiple drug hypersensitivity (MDH), also known as multiple drug intolerance or multiple drug "allergy" syndrome, most multiple drug reactors (94%) had a positive ASST.34 In single drug reactors and atopics, who never had an ADR, a positive ASST was seen in 40% and 0 respectively.34 By contrast, single drug reactors were more likely and multiple drug reactors were less likely to have IgE to beta lactam antibiotics, 36% and 9% (1 patient) respectively. "Skin reactions were generally more intense in the (MDH) patient group."34
ASST has the potential to be positive in some patients with MCS, particularly in females, who have HT or a positive ANA and have had multiple ADR.
High Affinity IgE Receptor (Fc Epsilon RI) Autoantibodies and Basophil Histamine Release Assays or Basophil Activation Tests
High affinity IgE receptors (Fc epsilon RI) have been found in nasal mucosa, oral mucosa, airway smooth muscle, and skin. Fc epsilon RI autoantibodies (anti-FceRI) are thought to play a role in some cases of nonallergic asthma and CAU and are sometimes seen in ASST positive patients, whereas they are almost never seen in ASST negative patients. In some patients with hypersensitivities, anti-FceRI or autoantibodies to IgE (anti-IgE), or another unidentified factor are capable of causing histamine release from basophils. These types of tests are known as the basophil histamine release assay (BHR) or basophil activation test (BAT).
In one study of nonallergic asthmatics, "findings indicate that ASST is positive in about half of patients with nonallergic asthma and that a proportion of patients (16%) has functional evidence of circulating histamine-releasing factors."29 In another asthma study, 37.2% of asthmatics had a positive BAT.35 In multiple drug reactors, 23% had sera capable of inducing significant histamine release from basophils, while no single drug reactors did.34
Other Potential Autoantibodies
There are multiple other potential autoantibody candidates, many of which should be explored but are too numerous to be listed here. Based on findings in other hypersensitivity conditions, among the standouts are autoantibodies to cytokeratin. Anti-cytokeratin (CK) 18 and anti-CK 19 have been associated with nonallergic asthma and/or chemically (toluene diisocyanate)-induced asthma.36,37 In asthmatics, "Significant correlations were found between positives for the anti-CK18 and anti-CK19 autoantibodies and the PC(20) methacholine values. …"38
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