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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.
Table 2: Potential Tests in Patients Suspected of Belonging to the
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)
* Anti-thyroid peroxidase (TPO) & anti-thyroglobulin (Tg)
* 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)
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 affects women starting in their 40s; angioedema primarily affects face; and angioedema less often affects 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
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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Laurie Busby received a BEd from the University of Missouri. At age 30, she developed chronic fatigue syndrome and the hypersensitivities that sometimes accompany it. Shortly thereafter, her aunt, a nurse anesthetist, handed her a huge medical dictionary and some studies, insisting that Laurie learn how to read them because she had something with no answers. Since that time, Laurie has asked for several tests that have given her incredible clues about her illness, conducted a family medical health survey among patients, testified before the CFS Advisory Committee to the US Department of Health and Human Services, and started a chronic illness blog, cfsfmmcsandrelatedstudies.tumblr.com, in an attempt to share what she has learned.