KEYWORD: Hypersensitivity, Autoimmunity, Multiple chemical sensitivity, Chronic fatigue syndrome, autoimmune testing

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. ©2015

Key

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

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

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
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 hypersensitivity 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. 

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.¹⁸   
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 autoimmune 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.¹³
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
Although the exact role, if any, C1 INH deficiency, C1 INH dysfunction, anti-C1 INH, and/or BK may play in patients within the autoimmune subgroups of other hypersensitivity conditions is currently unknown, there is some evidence linking them to CFS, autoimmune diseases, HT-related autoantibodies, and ANA.^9,39-42
A study of lupus found, “The level of anti-C1-INH IgG was significantly higher in systemic lupus erythematosus (SLE) patients, than in the (healthy) controls.”(17% versus 4% respectively)³⁹ This correlated with disease activity and duration (17 versus 8 years median disease duration in those with anti-C1 INH versus without).³⁹
Some but not all hereditary angioedema (HAE) cohorts have been found to have an increased frequency of autoantibodies including HT-releated autoantibodies and especially ANA.^40-42  In two different HAE cohorts, there was an increased frequency of autoantibodies (40% and 47.5%), and in both, the most prevalent autoantibodies were ANA and  anticardiolipinin.^41-42 In one cohort, the prevalence of antibodies was higher in patients over age 30 than those 30 and younger.⁴¹ The authors did not indicate whether this was associated with disease duration. 
In addition, several HAE studies have found increased B cells and/or B cell activation markers.^42,43 In a cohort of HAE, with and without autoimmune disorders, “abnormalities included increased mean total lymphocyte counts, . . . polyclonal B cell activation, and evidence of circulating immune complexes.”⁴³ In addition, “We failed to detect any evidence of immune deficiency in this population, and yet a statistically significant number of patients demonstrated elevated levels of antibodies to Epstein-Barr virus antigens when patients were compared to a control group.”⁴³ 
Interestingly, in another cohort with HAE due to C1 INH deficiency, “High anti-EBNA-1 levels were strongly correlated with the frequency of upper airway attacks and the dose requirement of C1-INH concentrate, while no significant association with the frequency of subcutaneous and abdominal attacks was found. These novel findings indicate that the underlying/triggering mechanisms of upper airway attacks in HAE-C1-INH (deficiency) may differ from that of other types of attacks . . . “⁴⁴
Several CFS studies have also found increased autoantibodies, B cells, and/or B cell activation markers, especially in patients with evidence of a viral trigger or viral reactivation.^9,45,46 In a CFS cohort with decreased C1 INH and complement C4, there was an increased frequency of autoantibodies, especially anti-thyroid microsomal and ANA; circulating immune complexes (42%); and, ” . . . 78% of the patients had a striking serological constellation on Epstein-Barr-virus (EBV-EA positive, low EBNA-titers), in the HHV-6-virus 47% showed increased antibody-titers.”⁹ The patients with CFS and bronchial hyperresponsiveness, which presented more often with thyroid inflammation, also “presented significantly more often with fatigue that was made worse by physical exercise, recurrent flu-like illness, . . . and painful lymph nodes.”⁵ In a CFS cohort with increased B cells, patients had evidence (immunological and signs/symptoms) of viral reactivation.⁴⁵ These patients had low-grade fever (85%), sore throat (76%), painful lymph nodes (30%), and shortness of breath (33%).⁴⁵ The CFS cohort with HLA-DR4 and HLA-DQ3 also had evidence of viral reactivation.³⁷

While functional anti-FceRIa or anti-IgE can cause histamine release and risk of anaphylaxis, C1 INH deficiency or dysfunction and increased bradykinin can lead to risk of laryngeal angioedema, and things as simple as a tooth extraction can be life-threatening, as well as the endotracheal intubation meant to save a life, “Trauma, including surgically induced trauma, especially involving endotracheal intubation or manipulation, may trigger life-threatening laryngeal edema.”^21,47,48

If female patients with CFS and MCS and HT-related autoantibodies are found to have functional anti-FceRIa and low or even borderline low CI INH levels, the cumulative effect may be significant, and although female patients with hypersensitivities and ANA may have anti-FceRIa less able to induce, “pronounced histamine-releasing activity,” from basophils (according to one study), there seems to be a possible link between ANA and C1 INH deficiency and/or autoantibodies.^39-42,49
The above mechanisms could help explain hypersensitivity reactions unrelated to classic allergies. While total IgE and/or IgE to specific allergens are generally elevated in allergies, total IgE may be normal or even low in patients with hypersensitivities thought to have an autoimmune basis.^14,23,33
In one study of female patients with asthma, anti-TPO and IgE were negatively correlated.¹⁴  In that same study, nonallergic asthma was associated with lower eosinophil levels.¹⁴ In patients with CU, a positive ASST, anti-FceRI, and serum that, “induced marked histamine release from basophils,” there were, “relatively low levels of serum IgE.”²³

In addition, IgE to specific medications may be less likely to play a role in MDH. In one study, single drug reactors were more likely (36%) and multiple drug reactors were less likely (one patient 9%) to have IgE specific to beta lactam antibiotics.²⁵
Several CFS and MCS studies have found total IgE were not highly elevated compared to symptoms being reported.^11,12
In a cohort of antihistamine (AH)-resistant CU versus AH-responsive CU, the AH-resistant group was more likely to have a “more positive” ASST (73.9 vs 45.4%), concomitant angioedema (58.7% vs 28.5%), a higher baseline UAS, and “a clinically more severe disease.”²⁷

Patients whose angioedema is due, at least in part, to C1 INH deficiency or dysfunction and increased bradykinin rather than histamine, would also be more refractory to antihistamines.  

Potential Tests in Patients Suspected of Belonging to the Autoimmune Subgroup

 
Things to keep in mind:

• Positive test results for these autoantibodies may be more likely to be positive or be positive at higher levels in patients over age 30, especially patients in their 40s or middle aged, and/or patients who have been sick for a longer period of time.^13,39,41

• Positive test results may be more likely based on the frequency of positive results in other hypersensitivity conditions. Anti-FceRIa may be more likely to be positive than anti-IgE. Low C1 INH level may be more likely to be positive (85% of HAE) than low C1 INH functional activity.⁵⁰

• Follow up tests may need to be run. Some labs run C1 INH levels and functional activity together in their panels, if not, if C4 is low but C1 INH levels are not, C1 INH functional activity can be run.  If C4 and C1 INH levels or activity are both low, Clq (low in Acquired angioedema (AAE)) and genetic mutations (in HAE) can help distinguish between AAE and HAE, which have similar presentations.^50,51

There are some differences between HAE and AAE. HAE is considered hereditary due to gene mutations; usually starts in adolescence and has started by their 20s in the vast majority of patients; and angioedema can occur in the face, abdominal area (80% of cases), and/or limbs.⁵¹ AAE is considered acquired; primarily effects women starting in their 40s; angioedema primarily effects face; and angioedema less often effects abdominal area (30-50% of cases).⁵¹

While AAE is considered “very rare,” one study speculates the actual number of cases may be higher,”In our list of angioedema patients, we found 1 AAE for every 10 patients with the hereditary form of C1-INH deficiency.”⁵¹

• Some tests should be run during a reaction if that is possible without endangering the patient (histamine, C4, and C1 INH levels).

• Current medications may influence test results.  Some patients with CU and/or angioedema and undiagnosed Hashimoto’s thyroiditis improved once thyroid supplementation was started, so in addition to medicines known to affect the immune system, the possible influence of this medicine also needs to be taken into account.⁵²

Conclusion

Autoimmune mechanisms are thought to play a role in subgroups of patients with other hypersensitivity conditions, and they may play a role in subgroups of patients with CFS and MCS as well. Patients with MCS have been described as sicker than patients with allergies, and patients in the autoimmune subgroups of other hypersensitivity conditions are often found to have more severe cases than their counterparts with the same condition.¹⁰
In patients with other hypersensitivity illnesses, some of the accompanying test results and the precautions necessary to avoid reactions are taken very seriously due to the potential for severe reactions.   
In MCS, one of the biggest obstacles patients face is trying to get medical treatment. They have concerns over potential reactions to both the medical treatments and medicines, which poses even more of a problem due to lack of recognition of the severity of this illness.
If patients with CFS and MCS, that fit the criteria above, test positive on some of the same tests used in patients within the autoimmune subgroups in other hypersensitivity conditions, this may open up diagnostic, test, and treatment options. Possibly even as importantly, positive test results may help these illnesses become recognized by mainstream medicine, and recognition of these illnesses is something patients have been waiting for a very long time. 

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

 
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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 

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Table 2: Potential Tests in Patients Suspected of Belonging to the Autoimmune Subgroup

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Potential Initial Tests 

* CBC – eosinophils (to help rule out allergic asthma)

* Total IgE (to help rule out allergies) 

* Tryptase  (to help rule out a mast cell disorder)

* Histamine

* Anti-thyroid peroxidase (TPO) & anti-thyroglobulin (Tg)

* ANA

* Anti-FceRIa

* C1 INH levels (if patient has angioedema)

* Complement 4 (C4) levels (low levels are seen along with low C1 INH levels or activity in HAE types I & II and AAE.)  

* Complement Clq levels (if patient has angioedema.  Low Clq is seen in approximately 70% of AAE but not HAE.)52

Potential Follow-Up Tests

* BAT (more likely to be positive if patient has anti-TPO and increased histamine)

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