Chronic fatigue syndrome by ASIA?

Unicorns, I love them. Unicorns, I love them. 

ASIA, in the context of this post, does not refer to the continent but rather the suggestion of an: ‘autoimmune (auto-inflammatory) syndrome induced by adjuvants’ and some potentially contentious findings reported by Nancy Agmon-Levin and colleagues [1].

Describing a small cohort of participants diagnosed with chronic fatigue syndrome (CFS) and/or fibromyalgia (FM), the authors put forward the idea that "some cases CFS and FM can be temporally related to immunization, as part of ASIA syndrome", more specifically following hepatitis B vaccination (HBVv). They report on a latency period (the interval between exposure and clinical appearance of symptoms) ranging "from days to a year" with a mean temporal period of around 38 days. They also report specific manifestations of symptoms (neurological, fatigue, muscoskeletal and gastrointestinal) and importantly that: "Autoantibodies were detected in 71 % of patients tested". Autoantibodies by the way, refers to antibodies against self tissue as per what has been noted in various autoimmune conditions/diseases. The authors conclude: "ASIA criteria were fulfilled in all patients eluding the plausible link between ASIA and CFS/FM."

OK. There are a few words of caution that one needs to exercise with this kind of work before anyone gets too enthusiastic. This was an information-gathering study, so authors were specifically describing their cohort of participants "following HBVv immunization". There were no control groups, so one also needs to be aware of that.

A quick trawl of the other research literature on the topic of ASIA reveals however that this is not the first time that this concept has cropped up in the peer-reviewed science sector. Shoenfeld &Agmon-Levin [2] (the same authors on the current paper) first advanced the concept of ASIA or [Yehuda] Shoenfeld's syndrome a few years back. Based on the examination of four conditions: "siliconosis, the Gulf war syndrome (GWS), the macrophagic myofasciitis syndrome (MMF) and post-vaccination phenomena" they concluded that some commonalities were present and ASIA was born. An editorial accompanying their paper [3] kinda said it all: "It is an intriguing issue and one that is likely to be provocative and lead to further biologic and molecular investigations". I might also direct you to other discussions titled: What is ASIA?

Since then, a number of articles have appeared discussing ASIA / Shoenfeld's syndrome. Bassi and colleagues [4] reported findings involving a mouse model of lupus - "a lupus-prone murine model" - injected with complete Freund's adjuvant (CFA) (an immunostimulant). They reported that: "the injection of CFA in NZB/NZWF1 mice accelerated autoimmune manifestations resembling 'ASIA' syndrome in humans." A more thorough review of the animal model findings can be found in the article by Cruz-Tapias and colleagues [5].

The types of adjuvant noted as being potentially connected to ASIA have also been discussed, as per the article by Vera-Lastra and colleagues [6]. Squalene, aluminum hydroxide and silicone are mentioned. Squalene with regards to Gulf-War syndrome was something which particularly stuck out to me given my previous interest in this collection of symptoms present for some post Operation Desert Storm (see here). Although the source of some speculation, papers such as the one from Pamela Asa and colleagues [7] noting that squalene antibodies were linked to the "majority of symptomatic GWS patients" is an interesting finding. For balance, I will also refer you to the paper by Lippi and colleagues [8] standing up for squalene.

The paper from Perricone and colleagues [9] (open-access) brings us back to the involvement of ASIA in the 'mosaic of autoimmunity' and how genetics and environment might merge. The discussions move into various areas including that of anti-phospholipid syndrome (Hughes syndrome) as well as other well-known autoimmune areas (e.g. coeliac disease). Connective tissues disorders also discussed in the Perricone paper also bring in one reason why hepatitis B vaccine was also considered in the starting paper in question, as per the report by Perricone and Shoenfeld [10] and their discussions on hepatitis B vaccine and 'undifferentiated connective tissue disease' as being: "Another brick in the wall of the.. ASIA". Further research has added to such sentiments [11].

As things stand with the body of research detailing ASIA, I don't think that this is a concept we can readily discard as being potentially real and relevant to at least some clinical presentation potentially including CFS/FM. I know to talk adverse effects from vaccination, or their adjuvants, can stir up some heated discussions in some quarters (see here) but even in contentious areas covering something like autism or autistic presentation, science might still have a role to play [12]. I say this reiterating the important value of vaccination as per this CDC infographic.

This is also the second time that I've talked about vaccination and autoimmunity as potentially being linked on this blog as per another contentious paper in another contentious area (see here). It strikes me that there is quite a bit more to do in looking at any possible connection, particularly when one considers that ASIA has been similarly discussed (albeit in case studies) with other biologics in mind [13].

Music: The Ragtime Gals and a certain celebrity..

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[1] Agmon-Levin N. et al. Chronic fatigue syndrome and fibromyalgia following immunization with the hepatitis B vaccine: another angle of the 'autoimmune (auto-inflammatory) syndrome induced by adjuvants' (ASIA). Immunol Res. 2014 Nov 27.

[2] Shoenfeld Y. & Agmon-Levin N. 'ASIA' - autoimmune/inflammatory syndrome induced by adjuvants. J Autoimmun. 2011 Feb;36(1):4-8.

[3] Meroni PL. Autoimmune or auto-inflammatory syndrome induced by adjuvants (ASIA): old truths and a new syndrome? J Autoimmun. 2011 Feb;36(1):1-3.

[4] Bassi N. et al. Induction of the 'ASIA' syndrome in NZB/NZWF1 mice after injection of complete Freund's adjuvant (CFA). Lupus. 2012 Feb;21(2):203-9.

[5] Cruz-Tapias P. et al. Autoimmune (auto-inflammatory) syndrome induced by adjuvants (ASIA)--animal models as a proof of concept. Curr Med Chem. 2013;20(32):4030-6.

[6] Vera-Lastra O. et al. Autoimmune/inflammatory syndrome induced by adjuvants (Shoenfeld's syndrome): clinical and immunological spectrum. Expert Rev Clin Immunol. 2013 Apr;9(4):361-73.

[7] Asa PB. et al. Antibodies to squalene in Gulf War syndrome. Exp Mol Pathol. 2000 Feb;68(1):55-64.

[8] Lippi G. et al. Vaccination, squalene and anti-squalene antibodies: facts or fiction? Eur J Intern Med. 2010 Apr;21(2):70-3.

[9] Perricone C. et al. Novel pebbles in the mosaic of autoimmunity. BMC Med. 2013 Apr 4;11:101.

[10] Perricone C. & Shoenfeld Y. Hepatitis B Vaccination and Undifferentiated Connective Tissue Disease: Another Brick in the Wall of the Autoimmune/Inflammatory Syndrome Induced by Adjuvants (ASIA). JCR: Journal of Clinical Rheumatology. 2013; 19: 231-233.

[11] Zafrir Y. et al. Autoimmunity following hepatitis B vaccine as part of the spectrum of 'Autoimmune (Auto-inflammatory) Syndrome induced by Adjuvants' (ASIA): analysis of 93 cases. Lupus. 2012 Feb;21(2):146-52.

[12] Singh VK. Phenotypic expression of autoimmune autistic disorder (AAD): a major subset of autism. Ann Clin Psychiatry. 2009 Jul-Sep;21(3):148-61.

[13] Barros SM. & Carvalho JF. Shoenfeld's syndrome after pandemic influenza A/H1N1 vaccination. Acta Reumatol Port. 2011 Jan-Mar;36(1):65-8.

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Agmon-Levin N, Zafrir Y, Kivity S, Balofsky A, Amital H, & Shoenfeld Y (2014). Chronic fatigue syndrome and fibromyalgia following immunization with the hepatitis B vaccine: another angle of the 'autoimmune (auto-inflammatory) syndrome induced by adjuvants' (ASIA). Immunologic research PMID: 25427994