Studies of Allergy in ME/CFS

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Occasionally we see it claimed that ME/CFS patients have higher rates of allergy. Sometimes this is mentioned in support of MCAS, but I'm setting that aside for a moment and just looking for what research exists on the allergy claim itself.

So far the results look mixed and confusing. Some observations:

• Most of the studies I’ve found so far are small and uncontrolled (instead comparing to known allergy rates).
• As far as I know, the extracts used in skin prick testing aren’t completely standard (or at least weren’t in the 80s and 90s). And what counts as a reaction seems to vary from study to study. Also a human measuring the size of a red spot is inherently somewhat subjective. So the lack of control groups are unfortunate.
• It seems many of the CFS patients were being identified as such by rheumatologists. One of the studies (Repka-Ramirez, 2001) seems to suggest this could lead to a bias for selecting patients with allergies — do rheumatologists see an above average number of allergy patients?

Feel free to add any comments or other info you know of to the thread. Trials of antihistamines (I've found one so far in ME/CFS and a review in MCAS) would also be relevant.

 

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Allergy and the chronic fatigue syndrome, Straus et al, 1987
TLDR: Evidence of allergy in 50% of 24 CFS patients, no controls.

On recruitment: This study was done on the same cohort as a trial of Acyclovir by the same authors. Looking at that trial (sci-hub), all it says is that the patients were found from those referred to the NIH for debilitating fatigue. So it’s unclear I guess how biased the cohort may be.

The first page of this study manages to disparage CFS patients in about 4 different ways which may be a record of some sort. Eventually though they get to reporting that they conducted skin allergy testing on 24 patients (16 F, 8 M, sick for 6 years on average). Actually, they say it was 'blinded epicutaneous skin testing' but I don't understanding what was blinded, the types of extract in each sample? They don't seem to have any controls.

In any case: they tested the patients with 48 extracts (food and respiratory allergens) plus control substances. All patients reacted appropriately to the control substances and 50% (12) of the patients reacted to at least one extract. They note that studies in the population find allergy rates of 20%-30% and conclude there are elevated allergy rates in ME/CFS. Aside from the small size, the other concern that comes to mind here is how standard the extracts used were. Would slight differences in the extract make a difference? A control group would reassure me a lot here.


Eosinophil cationic protein serum levels and allergy in chronic fatigue syndrome, Conti et al, 1996 (paywalled, sci-hub)
TLDR: Evidence of allergy in 77% of 35 CFS patients, no evidence of allergy in the control group.

They studied 35 CFS patients (25 F, 9 M; mean age 37.7 years) and compared them to 14 healthy controls (who are said to be age and sex matched but I don't think the data is given). They were mainly interested in 'eosinophil cationic protein' which they found to be much higher in patients than controls (18.0 +- 11.3 micrograms/l (SD) vs 7.3 +- 2.1 micrograms/l (SD); P<0.01), resisting the urge to get distracted by that for now.

On recruitment: It seems the author was a doctor in an immunology and allergy department at a university hospital or something similar (guess-translating the Italian name). They say “35 consecutive CFS outpatients diagnosed on the basis of the CDC case definition were enrolled in this study.” So this may indeed have high risk of bias towards an especially allergic cohort.

They also conducted RAST allergy testing (a blood test) and found 27 of the 35 CFS patients (77%) presented specific IgE directed against one or more allergens, while no control showed positive RAST. They mention though that only 9 of the 27 CFS patients with a positive RAST also had a history of clinical allergy. Also worth noting that their controls were particularly healthy, they mention that a random sample of controls has shown a RAST positivity rate of 12% in the past.

 

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Double-blind placebo-controlled study of the efficacy of oral terfenadine in the treatment of chronic fatigue syndrome, Steinberg, 1996
TLDR: Evidence of allergy in 53% of 30 CFS patients, no controls; A 2 month RCT of antihistamine treatment had no effect on CFS symptoms.

30 CFS patients (23 F, 7 M; mean age 36.2) were tested for skin allergy and enrolled in a 2 month double blind RCT of the non-sedating antihistamine terfenadine (60mg twice daily, which was the dose used for allergic rhinitis).

On recruitment: Patients were selected from respondents to a letter sent to all members of the registry of the Minnesota Regional CFS Research Program. All patients lived in Minnesota or neighbouring communities of Wisconsin or Iowa, and most had been referred (to the registry I assume?) by infectious disease specialists or rheumatologists.

The paper reports that 16 (53.3%) of the study patients reacted to one or more allergens. They also performed a delayed hypersensitivity skin test and reported that all patients had positive delayed skin test responses to at least one antigen (such as Tetanus or Mumps) but I haven't read up on the significance of that.

The RCT outcome was patient response to a questionnaire on symptoms, physical functioning and perceived health, etc. They essentially had 11 numbers that could have shown a positive effect for terfenadine (7 CFS symptoms that patients reported the severity of, plus 4 ratings of different areas of overall health) and all 11 failed to show any difference between terfenadine and placebo. They also tried a post-hoc analysis looking at just the CFS patients with allergy symptoms and still found no effect. So that's a pretty solid null result. (Note that terfenadine is no longer available because it increases risk of cardiac arrhythmia, but otherwise seems to check the boxes of being an effective antihistamine that does not cross the bbb and therefore does not cause drowsiness.)


Chronic fatigue syndrome: identification of distinct subgroups on the basis of allergy and psychologic variables, Borish, 1998
TLDR: Evidence of allergy in 83% of 18 CFS patients, in 100% of allergic controls, 0% of normal controls, and 58-70% of the depressed controls.

18 CFS patients (12 F, 8 M; average age 43.3) were investigated for evidence of allergy (also elevated cytokines and the usual psychiatric tropes).

On recruitment: “Subjects with CFS were recruited from a physician referral clinic at the National Jewish Center. All other subjects were solicited by newspaper advertisements.” Hard to know the risk of bias in their cohort without more info.

15 of the 18 patients (83%) were found to be allergic/atopic, which was defined as having a “wheal of 3 mm or greater in diameter on skin prick testing to 1 or more allergens in the Colorado inhalant panel and the presence of an atopic disease (allergic rhinitis, asthma, or atopic dermatitis).” The same testing found 14/14 of their allergy control group was indeed allergic; 0/11 of their ‘normal’ control group was allergic; and 7/10 of their depressed control group was allergic (technically they had 12 depressed controls but did not perform skin prick testing on all of them, 7/12 may be a safer lower bound).

 

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IgE levels are the same in chronic fatigue syndrome (CFS) and control subjects when stratified by allergy skin test results and rhinitis types, Repka-Ramirez, 2001 (paywalled, sci-hub)
TLDR: Evidence of allergy in 41% of 80 CFS patients and in 49% of the 115 controls — authors point out cohorts in these studies may be unrepresentative.

The study compared 80 CFS patients with 115 controls. Don’t see any demographic details.

On recruitment: Many of the patients and controls were recruited from a rheumatology practice, and I gather the thinking behind this study was that this could be selecting for a higher than average rate of allergies (that seems to be what they are saying anyway, even though afaik rheumatologists don’t normally treat IgE allergy? Maybe they still see a lot of allergy patients?).

None of the patients nor controls reacted to the control poke. They found 33/80 CFS patients (41%) tested positive for allergy, compared to 56/115 (49%) of the controls. They also looked at IgE and report that there is no difference in IgE level between patients and controls when they stratify by the rhinitis symptom severity and allergy test results. I haven’t looked into that but I guess the intent was to try and control for the issues with these cohorts being artificially skewed towards especially allergic patients and controls.


Prevalence of allergen-specific IgE among patients with chronic fatigue syndrome, Kowal, 2002 (paywalled)
TLDR: Evidence of allergy in 36% of 50 CFS patients, no controls.

This study seems to be from Poland. I can only see the abstract so I’ll just quote what the authors conclude there: “The overall frequency of positive results for the presence of allergen-specific IgE among CFS patients was 36%, not significantly different from the normal prevalence of these antibodies in the general population (20-35%). This assessment of the prevalence of allergen-specific IgE antibodies in patients with CFS fails to support a potential association between CFS and atopy.”

 

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Prevalence of atopy in chronic fatigue syndrome, Ferré Ybarz, 2005 (Spanish)
TLDR: No difference in pooled skin prick test results between 25 CFS patients and 20 controls.

This article is in Spanish so again just going to go off the abstract. They studied 25 patients with CFS and 20 controls. They reported the results of the skin prick testing in a slightly odd way, pooling all the CFS results and all the control results. Their numbers were so low maybe it doesn’t make a difference. They found 15/441 (3.4%) of the inhalant prick tests were positive in the CFS group, and 16/420 (3.8%) were positive in the control group — i.e. no difference. None of the tests for hypersensitivity to food or latex were positive either.


Increased Risk of Chronic Fatigue Syndrome Following Atopy: A Population-Based Study, Tse-Yen, 2015
TLDR: They found that patients with allergies were more likely to develop CFS.

I’ll just quote what they say because it would take more than my minimal knowledge of the stats here to really judge this.

In this prospective, population-based cohort study of the National Health Insurance Research Database (I think in Taiwan), we identified 42,558 patients with atopy and 170,232 patients without atopy from 2005 to 2007 with follow-up to 2011.

The overall incidence rate of CFS was higher in the atopy cohort compared with the nonatopy cohort (1.37 versus 0.87 per 1000 person-year), with an adjusted hazard ratio of 1.48 (95% confidence interval 1.30–1.69). The risk of CFS in the atopy cohort increased 1.47- to 1.50-fold for each nonexisting comorbidity. Patients with numerous atopic symptoms exhibited a biological gradient of increasing risk for CFS, and the risk changed significantly after adjustment for age, sex, and comorbidities, increasing from 1.46- to 2.59-fold.

No clue what a nonexisting comorbidity is supposed to be, maybe a funny translation?

 

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Last one...

Atopy and Elevation of IgE, IgG3, and IgG4 May Be Risk Factors for Post COVID-19 Condition in Children and Adolescents, Körner, 2023
TLDR: Evidence of allergy in 93% of 21(?) PCC patients referred to a clinic, no controls.

This study looked at 21 patients diagnosed who had been referred to their clinic by family practice doctors and diagnosed with PCC. I think they checked allergy status with a blood test (rather than skin testing) as they say they collected data on ‘allergen-specific IgE levels’. They report 93% of the PCC patients were allergic — though there’s no integer solution to the equation x/21 ~ 0.93 so maybe they lost a patient somewhere. For comparison, they report that the average allergy prevalence in German adolescents aged 14–17 years is 48%.

On recruitment: “While the collective of patients with PCC in our dedicated clinic is far larger than the reported 28 patients, we only included patients (i) from an early period of the pandemic, (ii) after confirmed acute COVID-19 illness based on positive PCR testing, and (iii) with repeated presentation to evaluate disease course and recovery. […] Notably, approximately half of the patients in our cohort had pre-existing chronic diseases, with respiratory conditions being the most commonly reported.”

I wonder if patients for whom classic IgE allergies were part of the picture were more likely to continue visiting the clinic?

A bit about their PCC patients: “The most common symptoms included flu-like fatigue (n = 15, 71%), weakness (n = 13, 62%), dyspnea (n = 12, 57%), and post-exertional malaise (n = 9, 43%). One-third of the patients met the international consensus criteria for ME/CFS. […] The compromised health condition prevented 28% patients (n = 6) from attending school regularly.”

On IgE they say: “We observed elevated IgE levels (mean 174.2 kU/L, reference < 100 kU/L) regardless of disease severity. [….] There was no significant correlation between IgE elevation and severe disease courses with ME/CFS. This led us to the finding that IgE elevation is a general phenomenon in our cohort of PCC patients regardless of disease severity.”

 

[Mij]

I didn't have seasonal allergies or sensitivities to fragrances during the first 12 years of illness. I also didn't have viral activity, this evolved over time, including reactivations of viruses due to a weakened immune system.

I do know pwME/CFS who had these issues early on in their illness.