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From the Townsend Letter
November 2017

Potential Tests for an Autoimmune Subgroup of Patients with CFS and MCS Could Help Bring Illness Recognition: Helping to Identify Which Patients May Test Positive
by Laurie Dennison Busby, B.Ed.
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In patients diagnosed with multiple chemical sensitivities (MCS), chronic fatigue syndrome (CFS) is often a comorbidity (88.5% and 68.1% of non-occupational and occupational cases of MCS respectively).1 Patients with MCS and some patients with CFS present with airway symptoms, sometimes cutaneous symptoms, and adverse drug reactions (ADR) to multiple medications.2-8 In CFS, there is a "high prevalence" of idiopathic nonallergic rhinopathy.4 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


AAE acquired angioedema
ADR adverse drug reactions
AH antihistamine
ANA antinuclear autoantibodies
ASST autologous serum skin test
BAT basophil activation test
beta(AR) beta adrenergic receptors
BHR basophil histamine release
BK bradykinin
C1 INH C1 inhibitor
CAU chronic autoimmune urticaria
CK cytokeratin
CU chronic urticaria
EA Epstein-Barr early antigen
EBNA-1 Epstein-Barr nuclear antigen 1
Fcepsilon RIa aka FceRIa high affinity IgE receptor
HAE hereditary angioedema
HLA human leukocyte antigens
HT Hashimoto’s thyroiditis
HHV-6 human herpes virus 6
M1(CR) muscarinic cholinergic receptors
MDH multiple drug hypersensitivity
NAA nonallergic asthma
SLE systemic lupus erythematosus
TG thyroglobulin
TPO thyroid peroxidase
UAS urticaria activity score

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While multiple mechanisms are likely involved in CFS and MCS, the female predominance, increased frequency of Hashimoto's thyroiditis (HT)-related autoantibodies and/or anti-nuclear antibodies (ANA), and total IgE results, which are not highly elevated, suggest classic allergies are less likely and autoimmune mechanisms are more likely to play at least a partial role in the hypersensitivity reactions in a subgroup of patients.9-12

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In some of the other hypersensitivity conditions, there is a female predominance, an increased frequency of HT-related autoantibodies and/or positive ANA, and autoimmune mechanisms are also thought to play a role in a subgroup of patients.13-20 Some of the subgroups are being renamed, nonallergic asthma (NAA) and chronic autoimmune urticaria (CAU), to better reflect the disease etiology. Within these subgroups, many or all of the patients may have an autoimmune basis to their illness.
Despite differing hyper-sensitivity conditions, patients within these autoimmune subgroups may be more likely than their counterparts with the same hypersensitivity condition to have a positive autologous serum skin test (ASST), a marker of self reactivity; have autoantibodies (high affinity IgE receptor (Fcepsilon RIa aka FceRIa), IgE, or others) that may contribute to their conditions; and have more severe cases.21-28
Some patients with CFS and MCS have the potential to fit into an autoimmune subgroup and have test results similar to patients in the autoimmune subgroups in other hypersensitivity conditions. If patients with CFS and MCS, that fit the criteria below, could be tested and this could be proven, it could be an incredibly important step for these patients toward gaining illness recognition, test, and treatment options. This paper intends to aid clinicians in identifying which patients may be more likely to have positive test results.

Table 1: Potential Profile of Patients with Hypersensitivities due to Autoimmunity

They are more likely to:
1)  be female
2)  have had multiple drug reactions, especially to antibiotics
3)  be at least somewhat refractory to antihistamines
4)  have anti-TPO, anti-Tg, and/or ANA, especially anti-TPO
5)  have normal or low total IgE and eosinophils
6)  test positive for ASST
7)  have anti-FceRIa, anti-IgE, and/or other autoantibodies related to hypersensitivity reactions
8)  to have a positive BAT

Potential Profile of Patients with Hypersensitivities Due to Autoimmune Involvement
Patients with some hypersensitivity conditions (asthma; chronic urticaria (CU); CU+angioedema; and multiple drug hypersensitivity (MDH) aka multiple drug "allergy" syndrome) have an increased frequency of HT-related autoantibodies and/or ANA.13-19
In these patients, this may reflect a propensity toward production of other autoantibodies related to their hypersensitivity reactions as well:
In females with nonallergic versus allergic asthma, autoantibody levels to TPO and cytokeratin (CK), a bronchial epithelial antigen, were higher in the former.14 Anti-CK18 level (>13) were found in 40% and 12% respectively.14 Researchers concluded this may indicate an "autoimmune phenomenon" in nonallergic asthma.14 Interestingly, these results were obtained despite excluding patients with "a positive history of definite thyroid diseases."14
Patients with autoimmune urticaria, versus other types of urticaria, had an increased frequency of anti-thyroid antibodies and autoimmune diseases, were less responsive to antihistamines, and had higher total urticarial scores.26 These researchers concluded, "The autoimmune subgroup represents the most severe form of CU."26
Other studies found patients with CU and HT-related autoantibodies had a greater risk of angioedema.17,18 "Patients with CU and autoimmune thyroid disease presented greater risk of angioedema…," a sixteen times greater risk.17 In another study, all patients with CU and thyroid microsomal autoantibodies greater than or equal to 1:1,600 also had angioedema.
In CFS, there also appear to be patients with HT-related autoantibodies and/or ANA that may fit into an autoimmune subgroup. In one study, "Patients with bronchial hyperresponsiveness to histamine provocation presented significantly more often with … thyroid inflammation…,"and in another study, 29% of patients with CFS were found to have elevated autoantibodies to muscarinic cholinergic receptors (CR) and/or beta adrenergic receptors (AR).5,29 In patients who were positive,
"There was also an association between M1 (CR) and beta2 (AR) antibodies and elevated thyroid peroxidase/thyroglobulin (TPO/TG) and ANA."29
In a study of asthmatics, approximately 40% had beta2 AR autoantibodies, most of which acted as functional antagonists.30 While the exact role of these autoantibodies in CFS has yet to be elucidated, it is possible that this potential autoimmune subgroup of patients with CFS has functional beta2 AR autoantibodies or some of the other autoantibodies involved in hypersensitivity reactions.
Another test, a positive ASST, is used to help distinguish auto-immune subgroups of patients with hypersensitivity conditions. A positive ASST is seen in NAA, CAU, CU+angioedema, and especially MDH (up to 94% of patients).13,23-25 In one study, none of the patients with allergic asthma or allergic rhinitis had a positive ASST.
ASST positive patients with hypersensitivity conditions are more likely to be female; have HT-related autoantibodies and/or a positive ANA; have autoantibodies (anti-FceRIa, anti-IgE, or other autoantibodies) involved in their hypersensitivity reactions; and/or have sera capable of inducing histamine release from basophils.13,15,23-25
In studies of ASST positive nonallergic asthmatics, there was an increased incidence of female sex (83%), positive ANA (55%), and/or airway hyperresponsiveness.13,31 "Asthma patients with ASST-positive results as compared with patients with ASST-negative results exhibited a significant increased airway hyperresponsiveness (PC20 methacholine)."31
In studies of ASST positive CU, there was an increased incidence of female sex, anti-microsomal antibodies (33.3%), "throat angioedema and general constitutional, respiratory or gastrointestinal symptoms," and/or a higher mean urticaria activity score(UAS).15,32 Researchers concluded, "Apparently, ASST-positive patients have more severe clinical manifestations of chronic urticaria."32
In addition, another study found, "Patients with (ASST positive) CAU had more frequent attacks and higher anti-thyroid antibody titers and peripheral B-cell percentages, as well as lower absolute eosinophil counts and serum IgE concentrations," which could further help to distinguish autoimmune from allergic subgroups.33
Anti-FceRIa are seen more often in patients who are ASST positive. In some patients, anti-FceRI, anti-IgE, or other factors are capable of causing basophil activation and serum-induced histamine release from basophils. These tests are known as the basophil activation test (BAT) and basophil histamine release (BHR) assay. 16-37.2% of NAA and 23% of MDH were positive on one or the other of the aforementioned tests.13,22,25 None of the single drug reactors were positive on the BHR.25
In patients with CU and a positive versus negative BHR assay, those with a positive test had a higher incidence of "raised" thyroid antibodies.34 In one study of patients with CU and HT versus without HT, "… only patients with CU and HT had anti-FceRI antibodies in their sera that could induce degranulation of normal basophils."35 Interestingly, "Some sera from patients with CU and HT caused degranulation of normal basophils in the absence of anti-FceRI."35
In a CU cohort (tested for HLA, ASST, and BHR), there was an increased frequency of HLA-DRB1*04 and HLA-DQB1*0302, and, "The HLA-DRB1*04 association is particularly strong for patients whose serum has in vivo and in vitro histamine-releasing ability."36
An increased frequency of HLA-DR4 and HLA-DQ3 have also been found in a CFS cohort, and increased blood histamine has been found in almost 40% of patients with MCS and/or electro-hypersensitivity, especially in patients with both.37,38
While functional anti-FceRIa and anti-IgE have the potential to play a role in histamine-mediated angioedema, C1 inhibitor (INH) deficiency or dysfunction, sometimes due to anti-C1 INH, plays a role in bradykinin (BK)-mediated angioedema.21

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