Mood cognition, fatigue, musculoskeletal, gastrointestinal and dermatological symptoms make up Gulf War Syndrome

The results of the meta-analysis by Alexis Maule and colleagues [1] provide an important addition to the peer-reviewed literature on Gulf War Syndrome / Illness (GWS). Their detailing and combining of results from various studies looking at self-reported health symptoms among deployed troops during the Persian Gulf War of 1990 adds further credence to the range of symptoms reported by returning troops. Also, they provide further clues as to where science should continue to look and intervene to help our veterans.

I've talked about the Persian Gulf War and GWS a few times before on this blog (see here and see here and see here for examples). Described in some quarters as one of the most toxic wars in history, there are still many questions that require answering about why so many veterans returned from theatre in such poor health. Much like another quite nebulous condition very often confused with other diagnoses under the heading 'medically unexplained symptoms' (see here), the relative lack of knowledge about GWS has made the condition / constellation of symptoms fertile ground for various 'psychosomatic explanations'. This, I believe, has done, and continues to do, a real disservice to the veterans of this conflict and their loved ones.

Maule et al settled on some 21 published studies, including nearly 130,000 participants and covering almost 30 years of research (the war itself started in late 1990) where self-reported symptoms were compared "in GW-deployed veterans and GW-era control veterans." GW-deployed veterans were defined as "veterans who deployed to the Gulf area in support of the 1990–1991 GW." Their comparators were described as "non-deployed veterans or veterans serving in the military during the 1990–1991 GW period who deployed to areas other than the Gulf (eg, Germany, Bosnia)." Reported health symptoms were searched for and responses boiled down across the studies.

Results: "A total of 56 distinct health symptoms were reported in three or more studies and included in the meta-analysis." Of the various health symptoms reported, 'lacking energy' topped the frequency chart for deployed veterans, fairly closely followed by related issues such as 'fatigue' and 'unrefreshing sleep'. When classifying reported health symptoms together, the following categories emerged: mood-cognition, fatigue, musculoskeletal, gastrointestinal and dermatological symptoms. Further: "Results of the meta-analysis showed GW-deployed veterans had increased odds of reporting all of the analysed symptoms compared with GW-era controls, indicating that the health problems associated with GW deployment include widespread, multiple body symptoms."

The authors do caution that it is not possible to say that all of these symptoms are cardinal features of GWS insofar as their inability "to assess the effect of some covariates relevant to health symptom reporting (eg, post-traumatic stress disorder and specific deployment exposures)." They also talk about how their meta-analysis approach, similar to other occasions across various different topics, may also be liable to publication bias ("when studies with positive findings are more likely to be published than studies with null and/or negative findings"). They did try and 'correct' for this possible bias and still reported that "42 out of the 56 summary ORs [odds ratios] remained significant." That included all those 'fatigue-related' health items previously reported on.

The work from Maule and colleagues adds to a significant research base observing that poorer health outcomes seem to be an important part of deployment to the Persian Gulf during Operation Desert Storm [2]. It again reminds us that we owe a debt to those veterans and their families, to continue to pursue a research agenda that takes their health issues seriously, and provides them with answers and the relief that many still sorely need.

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[1] Maule AL. et al. Meta-analysis of self-reported health symptoms in 1990–1991 Gulf War and Gulf War-era veterans. BMJ Open. 2018; 8: e016086.

[2] Porter B. et al. Health Status of Gulf War and Era Veterans Serving in the US Military in 2000. J Occup Environ Med. 2018 Jan 24.

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"mitochondrial dysfunction is involved in the pathobiology of GWI [Gulf War Illness]"

Among the various research distractions that I take on this blog away from the core material of autism science, one condition/diagnosis/state continues to particularly intrigue me: Gulf war syndrome or Gulf war illness (GWI).

I've covered this topic a few times on this blog (see here and see here and see here for examples); specifically how the hostile environment of the Persian Gulf during the 1990-1991 Gulf War perhaps aligns with this conflict being labelled as 'one of the most toxic wars in human history' (see here). If you think I'm overplaying that last sentence have a look at what was housed at one facility in Iraq under Saddam Hussain and then understand the nature of some of the compounds to which combatants were potentially exposed to.

The [small scale] findings reported by Yang Chen and colleagues [1] (open-access) adds to the still-growing research base suggesting that for the 25%+ soldiers who returned from theatre in ill-health, the biological nature of their symptoms is both wide-ranging and complex. The authors concluded that: "veterans with GWI exhibit greater mtDNA [mitochondrial DNA] damage which is consistent with mitochondrial dysfunction."

Looking at "21 cases of GWI (CDC and Kansas criteria) and 7 controls" (I told you it was 'small scale') researchers looked in blood samples in order to "quantify mitochondrial and nuclear DNA lesion frequency and mitochondrial DNA (mtDNA) copy number (mtDNAcn)" as well as to provide some information on "mitochondrial complex I and IV enzyme activities." In effect, covering both genetic and biological presentation in relation to any possible mitochondrial dysfunction (mitochondria being the 'powerhouse' of the cell).

"This study provides the first direct biological evidence of mtDNA damage in the blood of veterans with GWI." I'm always a little cautious when a study claims to provide 'first evidence' of anything but a quick search of PubMed seems to confirm that mitochondrial DNA (mtDNA) has not been discussed in the research literature before. Although not an expert on mtDNA or anything, the details being discussed by Chen et al point to an excess of mitochondrial and nuclear DNA damage in the GWI group compared with the small control group. This is however, not the first time that mitochondrial dysfunction has been discussed in the context of the GWI as per other peer-reviewed research outings [2].

"Mitochondrial dysfunction among veterans with GWI may help explain, in part, the persistence of this illness for over 25 years." This is an important observation made by the authors. Drawing on data from another area of [overlapping] research - chronic fatigue syndrome (CFS) - it's worthwhile noting that some fatigue-related conditions do have a mitochondrial element to them (see here) even if not universally linked to mtDNA (see here). The fact that this group with GWI did show some evidence of mtDNA damage begs the questions: how and why?

Minus any sweeping statements or the like, I would draw your attention to one particular 'toxic exposure' seen in the Gulf War - depleted uranium tipped munitions - and some research suggesting that particular radioactive particles emitted from something like depleted uranium might very well be able to impact on mitochondrial DNA [3]. I'm not saying this is 'truth', just a testable hypothesis in the context of GWI.

Of course, further investigations are required in this area, both larger in scale and also carried out by other, independent groups. There is also the possibility that certain mitochondrial and interconnected issues, if detected, could be treatable as per again, what has been talked about in CFS circles (see here). Our troops deserve the most thorough and best care we can possibly provide...

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[1] Chen Y. et al. Role of mitochondrial DNA damage and dysfunction in veterans with Gulf War Illness. PLoS ONE. 2017; 12(9): e0184832.

[2] Koslik HJ. et al. Mitochondrial dysfunction in Gulf War illness revealed by 31Phosphorus Magnetic Resonance Spectroscopy: a case-control study. PLoS One. 2014 Mar 27;9(3):e92887.

[3] Zhang S. et al. Mitochondrial alteration in malignantly transformed human small airway epithelial cells induced by a-particles. International Journal of Cancer. 2012; 132: 19-28.

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Hornig, Lipkin and chronic fatigue syndrome again

Drs Mady Hornig and Ian Lipkin once again provide some fodder for this blog, continuing one of their important research themes on how chronic fatigue syndrome (CFS) (sometimes also referred to as myalgic encephalomyelitis, ME) might show some important immune-related issues [1].

This research tag-team and the teams of dedicated scientists who surround them are making some real progress with regards to the idea that ME/CFS is a physical condition (not psychosomatic and not 'biopsychosocial') with some readily identifiable biological features potentially accompanying cases. Of course we're not there just yet when it comes to a biological test for ME/CFS but science has at least started down that particular research path...

With accompanying media attention in tow (see here), the focus of the most recent results were on how disease sub-types might be important to CFS and specifically, how: "Immune signatures in the central nervous system of ME/CFS patients with atypical features may be distinct from those with more typical clinical presentations."

Authors described how cerebrospinal fluid (CSF) samples from "32 ME/CFS cases with classical features and presentations and 27 ME/CFS cases with atypical features or clinical presentations" were included for analysis. On what basis was 'typical' and 'atypical' described? Well: "The ‘classical’ (C-ME/CFS) group had acute onset of disease marked by a prodrome consistent with infection; ‘atypical’ (A-ME/CFS) ME/CFS patients met full diagnostic criteria for ME/CFS at onset of their illness, but had a less standard onset of ME/CFS and/or developed other disorders after illness onset of ME/CFS." Interestingly one person included in the A-ME/CFS group was described as having Gulf-War Illness (another important condition talked about on this blog).

The results: various cytokines (chemical messengers of the immune system) were assayed for and with some nifty statistical 'corrections' authors reported some potentially important differences between the groups. So: "We found discrete differences in immune signatures of the CNS in ME/CFS subjects with atypical presentations that included sparse inter-cytokine networks and lower levels of two inflammatory mediators, the Th17 cytokine, IL17A, and the IFNγ- and TLR4-induced chemokine, CXCL9." All-in-all results suggested a "less robust CNS immune activation in A-ME/CFS."

Much more research is required in this area for sure. But these results are interesting and pertinent to the idea that within the heterogeneity (where have a I heard that before?) of CFS/ME, there may be quite a few phenotypes and subgroups that might be readily separable with a little biological research effort. Does this therefore mean when we talk about the pluralisation of lots of labels (the autisms, the schizophrenias, the depressions, etc), we might also one day called it 'the chronic fatigue syndromes'? Well, I've kinda speculated about this before in the peer-reviewed domain...

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[1] Hornig M. et al. Immune network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome with atypical and classical presentations. Transl Psychiatry. 2017 Apr 4;7(4):e1080.

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Hornig M, Gottschalk CG, Eddy ML, Che X, Ukaigwe JE, Peterson DL, & Lipkin WI (2017). Immune network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome with atypical and classical presentations. Translational psychiatry, 7 (4) PMID: 28375204

Inflammation is part of Gulf War Syndrome

Although mostly trying to avoid any politics-talk on this blog I am going to make some reference to it in this post set in the context of the Persian Gulf War otherwise known at the First Iraq War.

The recent publication of the Chilcot report describing the case for the UK's involvement in the 2003 Iraq War (the second Iraq War) has further lit up an already illuminating year in British politics, by perhaps adding fuel to the notion that 'finishing the job' might have been an important link between the two conflicts...

Operation Desert Storm - the combat phase of the First Gulf War (1991) - described by some as 'the most toxic war in history' left a mark not just on the region where it was fought and its people but also on many of the returning service personnel, some of whom came back in a pretty poor state of health. Their various symptoms known collectively as Gulf War Syndrome or Illness, are still the topic of discussions and debate to this day despite increasing evidence that they are 'real' symptoms (see here) and not just some psychosomatic manifestation of combat stress for example, as advocated by some quite prominent figures. The possible reasons for illness are varied (see here) but when one uses the words 'sarin' in the context of potential exposures for example you get a flavour for what might have been involved [1] and their potential contributions to health or rather ill-health.

The paper by Gerhard Johnson and colleagues [2] (open-access) adds further credence to the idea that Gulf War Illness (GWI) is indeed a real phenomenon and specifically: "that inflammation is a component of the pathobiology of GWI." Based on the examination of a relatively small number of veterans (85 out of 500 deployed veterans who were invited to participate), researchers undertook a "structured interview" that "assessed their health status, and blood samples were obtained." They managed to divide veterans up into GWI+ (n=57) and GWI- (n=28) groupings dependent on whether or not they reached the Fukuda criteria [3] for a "a chronic multisymptom condition" linked to deployment to the Gulf War.

Results: over 80 specific analytes were assayed for from the blood samples provided by participants. Many compounds had an immunological slant in terms of being cytokines or being other markers of immune system (specifically inflammatory) 'activation'. "The results of the current study provide evidence of alterations in a number of blood parameters that are readily measurable in routine clinical laboratories" was the headline as six specific compounds, all with inflammation in mind, were ripe for further independent study: plasma C-reactive protein (CRP), leptin, brain-derived neurotrophic factor (BDNF), and matrix metalloproteinase-9 (MMP-9)  = higher in the GWI+ group. Heart-type fatty acid binding protein (H-FABP) and matrix metalloproteinase-2 (MMP-2) = lower in the blood of GWI+ subjects. Alongside "the distributions of peripheral blood lymphocyte, monocyte, neutrophil, and platelet counts were higher in GWI+ subjects" compared with GWI- participant data leading researchers to observe that "a model utilizing three readily measurable biomarkers [lymphocytes, monocytes, and C reactive protein]... appears to significantly augment the symptom-based case definition of GWI."

"The limitations of the study include small sample size, restricted geographic, ethnic, and sex composition of the study subjects, assay of blood parameters only once, some plasma protein assays, including cytokines, considered inevaluable due to a high percentage of assays below the level of detection, overlap of biomarker distributions within the normal range, absence of correction for multiple comparisons, a limited number of blood proteins found to be positively related to GWI+ status, and the absence of a confirmation cohort study." Apologies for just grafting a large chunk of text from the Johnson paper into this post, but when it comes to the limitations of their work, the authors do a pretty good job of cautioning against any over-hype and providing a roadmap to 'where next?'

And as part of that 'where next?' it appears that we might be talking quite soon about some findings if an associated ClinicalTrials.gov entry is anything to go by (see here) on the use of 'delayed-release prednisone' with this group. I say this without making any value judgements or providing anything that looks, sounds or smells like medical or clinical advice.

We wait and see.

And to close: "all is as the Force wills it" apparently...

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[1] Proctor SP. et al. Effects of sarin and cyclosarin exposure during the 1991 Gulf War on neurobehavioral functioning in US army veterans. Neurotoxicology. 2006 Dec;27(6):931-9.

[2] Johnson GJ. et al. Blood Biomarkers of Chronic Inflammation in Gulf War Illness. PLoS ONE 11(6): e0157855.

[3] Fukuda K. et al. Chronic multisymptom illness affecting Air Force veterans of the Gulf War. JAMA. 1998 Sep 16;280(11):981-8.

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Johnson GJ, Slater BC, Leis LA, Rector TS, & Bach RR (2016). Blood Biomarkers of Chronic Inflammation in Gulf War Illness. PloS one, 11 (6) PMID: 27352030

Toxicant exposures and Gulf War Syndrome

Of the various directions away from autism research that I tend to take on this blog, discussions based on the collected [peer-reviewed] research literature on Gulf War Syndrome will always retain a special interest (see here). Not least because here we have a group of some of our bravest men and women who went out to liberate Kuwait in the early 1990s and who came back home in an often quite appalling state and thereafter basically left to rot.

I know that might all sound a little dramatic but after having met one or two veterans down the years and seen first hand how their health and well-being has been affected following their deployment to the Persian Gulf all those years ago I'm just telling it like it is. As much due to political reasons as scientific ones, the plight of these veterans - who really only want to know what happened to them and some acknowledgement that something 'did' happen to them outside of it being wholly 'psychosomatic' - has been the source of much controversy and debate down the years. Now at last it appears that a consensus based on the available science might have been reached [1]: "the research to date supports the conclusion that veterans are suffering from a "persistent pathology due to chemical intoxication.""

The paper by Roberta White and colleagues (someone not unfamiliar to Gulf War research) carries that conclusion and is open-access for all to read. Following a lengthy review of the various exposures that faced veterans and the likelihood of them (adversely) affecting their health, the authors detailed a few 'bottom lines'.

To quote:

"Between one-fourth and one-third of deployed GW [Gulf War] veterans are affected by a disorder characterized by chronic symptoms involving multiple body systems; this condition is best identified by the term GWI [Gulf War Illness]."

Further:

"This disorder was caused by toxicant exposures, individually or in combination, that occurred in the GW theater. At present, research most clearly and consistently links pesticide and PB [pyridostigmine bromide] exposures to GWI, while exposures to low-level nerve gas agents, contaminants from oil well fires, multiple vaccinations, and combinations of these exposures cannot be ruled out."

And also:

"Further research into the mechanisms and etiology of the health problems of GW veterans is critical to developing biomarkers of exposure and illness and preventing similar problems for military personnel in future deployments; this information is also critical for developing new treatments for GWI and related neurological dysfunction."

I'm sure you'll agree that these are pretty important conclusions. That also the authors talk about the potential overlap between GWI and other states specifically related to exposure to organophosphate (pesticides) such as during pesticide application (see here) or during sheep dipping (those with so-called dippers flu) is another important element. I say this not to somehow come down too hard on organophosphate (OP) pesticides, which serve an important purpose in modern agriculture and the like, but merely to reiterate that (a) caution is needed in their handling and use, and (b) they are chemically-speaking, not a million miles away from some of the most toxic nerve agents the world has ever seen. Indeed, with all the talk about Zika virus these past weeks (see here) I'm minded to suggest that one might need some additional controls in place to ensure the safe use of OPs when controlling the insect carrier (see here).

Bundled alongside the various chemical exposures - and other events [2] such as exposure to depleted uranium - that might be linked to symptoms is the added suggestion that "multiple vaccinations" may have also played a role in the presentation of the condition for some [3]. When I say vaccinations, the data suggests that these weren't just routine vaccinations against your typical childhood diseases, but rather included those aimed at a slightly more unusual disease set such as anthrax and plague (see here). The jury is still out on the extent to which these agents (singularly or combined) might have contributed to symptoms but I'm minded also to bring in the concept of ASIA (‘autoimmune (auto-inflammatory) syndrome induced by adjuvants’) that has been mentioned with GWI in mind (see here) as potentially being relevant.

Of course, more research is indicated on many aspects identified by White et al including the idea of some overlap between GWI and the presentation of chronic fatigue syndrome (CFS) [4] being careful with how wide we cast the CFS diagnostic net [5]. Alongside, perhaps one might think that an apology or two to some of our brave veterans wouldn't also go amiss from Government and others following various comments made down the years about the nature of their illness.

And for those who still might scoff at the idea of the 'toxic' effects of war, the chemical legacy of another campaign still continues to haunt some to this day...

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[1] White RF. et al. Recent research on Gulf War illness and other health problems in veterans of the 1991 Gulf War: Effects of toxicant exposures during deployment. Cortex. 2016; 74: 449-475.

[2] McDiarmid MA. et al. Health effects of depleted uranium on exposed Gulf War veterans. Environ Res. 2000 Feb;82(2):168-80.

[3] Unwin C. et al. Health of UK servicemen who served in Persian Gulf War. Lancet. 1999 Jan 16;353(9148):169-78.

[4] Ismail K. et al. Chronic fatigue syndrome and related disorders in UK veterans of the Gulf War 1990-1991: results from a two-phase cohort study. Psychol Med. 2008 Jul;38(7):953-61.

[5] Jason LA. et al. Unintended Consequences of not Specifying Exclusionary Illnesses for Systemic Exertion Intolerance Disease. Diagnostics (Basel). 2015 Jun 23;5(2):272-86.

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White RF, Steele L, O'Callaghan JP, Sullivan K, Binns JH, Golomb BA, Bloom FE, Bunker JA, Crawford F, Graves JC, Hardie A, Klimas N, Knox M, Meggs WJ, Melling J, Philbert MA, & Grashow R (2016). Recent research on Gulf War illness and other health problems in veterans of the 1991 Gulf War: Effects of toxicant exposures during deployment. Cortex; a journal devoted to the study of the nervous system and behavior, 74, 449-75 PMID: 26493934

Gulf War agents and delayed onset of symptoms in mice

I was recently intrigued by the findings reported by Zuchra Zakirova and colleagues [1] (open-access) on what happened to mice following 'acute' exposure to pyridostigmine bromide (PB) and the pesticide permethrin (PER) in the context of these compounds being "key contributors to the etiology of GWI [Gulf War Illness] post deployment to the Persian GW [Gulf War]."

I've covered the topic of Gulf War Syndrome (GWS) before on this blog (see here) and how, following one of the most toxic wars in history, quite a few service personnel (and local civilians) developed an array of symptoms which still confuse science and medicine today. There is no doubt that the conflict in 1990-1991 presented the military with a pretty hostile environment; not least because of the setting in the Persian Gulf. This was further compounded by burning oil fields, a variety of potential chemical exposures (including some rather nasty nerve agents) and issues like depleted urinanium tipped munitions to contend with. All-in-all, not a great place to be.

"We hypothesized that co-administration of PB and PER in our mouse model of GW agent exposure would recapitulate the late-onset symptom multiplicity and heterogeneity of symptoms observed in GW veterans, such as memory deficits and neurological deficits." That was the rationale behind the study bearing in mind that this was a study of mice for obvious ethical reasons.

Said mice - "Forty-eight male C57BL6/J mice" - were given either the PB/PER mix (via intraperitoneal injection) or 100% DMSO (as a control). As you may appreciate, direct injection of PB/PER is probably not the same kind of exposure that veterans would have come across in active theatre. PB as NAPS (nerve agent pre-treatment tablet set) was given in an oral dosage form. PER would probably have been delivered as a cream (or aerosol). One perhaps needs to keep this potentially important difference in mind when interpreting the Zakirova findings.

Dividing the mice groups up into a short-term cohort and a long-term cohort (18 days post exposure vs. 5 months post exposure respectively), various 'neurobehavioural' testing was undertaken on the cohorts. The mice participants were eventually euthanized so that any "neuropathological changes associated with GW agent exposure" could also be investigated.

There were some interesting results (and non-results) to be had from the amassed data. Short-term exposure to the PB/PER mix resulted in, well, not very much difference when compared to control animals: "No cognitive deficits were observed at the short-term time point, and only minor neuropathological changes were detected."

But longer-term, there were some potentially important differences noted between exposed and non-exposed animals. So for example: "Impairment for long-term memory formation was observed at day 106 days-post acute exposure to PB + PER." This was based on the results of a test of spatial memory. Further: "PB + PER exposure altered astrocytic activation in the hili of hippocampi and cerebral cortices of mice." Not being particularly au fait with all-things neuropathological, I can't readily put too much descriptive flesh on these experimental bones. I gather that "astroglial activation" might be something important when it comes to the destruction of neurons following injury or infection (but don't quote me on that). Potentially importantly too were the authors' findings that: "ACh [acetylcholine] levels were increased in the CNS [central nervous system] of exposed mice" and further "that exposure to GW agents may be attributed to the impaired cholinergic function observed in GWI and may in part contribute to deficits observed in long-term memory formation." I say this noting that permethrin is classified as a pyrethroid not an organophosphate (OP) which has a more classical relationship with acetylcholinesterase but PB has perhaps a more direct effect on acetylcholine.

Reiterating that the Zakirova study reports results based on mice and 'acute' exposure of said mice to potentially important agents, these are interesting results mirroring other studies from the authors [2]. I note that there may be more to see from this research group in future with the anticipation that "subsequent studies will provide us with a more lifetime picture regarding the long-lasting consequences of GW agent exposure." If this is indeed something that can be garnered from such a mouse model and given the significant suffering endured by many veterans, a little more scientific knowledge to illuminate the way would be very welcome.

Music: Tumbling Dice - The Rolling Stones.

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[1] Zakirova Z. et al. Gulf War Agent Exposure Causes Impairment of Long-Term Memory Formation and Neuropathological Changes in a Mouse Model of Gulf War Illness. PLoS One. 2015 Mar 18;10(3):e0119579.

[2] Ojo JO. et al. Exposure to an organophosphate pesticide, individually or in combination with other Gulf War agents, impairs synaptic integrity and neuronal differentiation, and is accompanied by subtle microvascular injury in a mouse model of Gulf War agent exposure. Neuropathology. 2014 Apr;34(2):109-27.

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Zakirova, Z., Tweed, M., Crynen, G., Reed, J., Abdullah, L., Nissanka, N., Mullan, M., Mullan, M., Mathura, V., Crawford, F., & Ait-Ghezala, G. (2015). Gulf War Agent Exposure Causes Impairment of Long-Term Memory Formation and Neuropathological Changes in a Mouse Model of Gulf War Illness PLOS ONE, 10 (3) DOI: 10.1371/journal.pone.0119579

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.

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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

The legacy of Desert Storm

This post represents a little bit of a departure from the my normal autism research-related musings. The topic however is something that has cropped up during the course of my career on several occasions. Read on and see more.

Having recently commemorated the shocking events of 10 years ago on that fateful Tuesday morning September 11th 2001, the repercussions of those atrocities continue to reverberate across the globe. Whilst Afghanistan remains an active theatre of operations, the memory is still fresh from Operation Iraqi Freedom and the whys and wherefores of that conflict that left so many families devoid of loved ones. Casting your mind back further to the early 1990s, and in particular the conflict known as Operation Desert Storm, some interesting questions still remain outstanding on the health implications to military and civilian populations alike as a result of the 'Video Game War'. A recent paper by Lea Steele and colleagues* published in the journal Environmental Health Perspectives provides further evidence (adding to a growing body of research) suggesting that deployed military personnel experienced various illnesses potentially as a result of several exposures on and off the battlefield.

It is perhaps important to make a few points before proceeding. As well as being the first modern action to be broadcast live to the masses, remembering all those picture of Tomahawk cruise missiles being deployed from the coaliton battlegroup, the 1990 Persian Gulf War has been described as one of the most toxic wars in history. Saddam Hussein and his followers were known to use chemical weapons on their own population as exemplified by the Halabja attack; an attack which is thought to have used various chemical agents including mustard gas and the nerve agents sarin and VX. Although the picture is still fuzzy about whether such agents were deployed against coalition troops, the environment was always going to be a hostile one for lots of other reasons such as burning oil fields and various depleted uranium tipped munitions employed on top of the various other hurdles posed by a pretty inhospitable natural environment. Although the subject of some debate in a dwindling number of quarters, it does appear that many deployed personnel returned from the conflict in a pretty poor state of health; indeed even 10 years after, their health was still the cause of some concern. Termed, 'Gulf War Illness' or 'Gulf War Syndrome', the US Department of Veteran Affairs website carries quite a lot of information about what the syndrome includes. I am going to stop there on the background data because the research base to the condition is huge and could take up a whole blog in itself.

Back to the Steele paper. Their findings based on 144 veterans who met author specified criteria for Gulf War Illness suggested that several different factors and scenarios might have been instrumental to their symptoms depending on whether personnel were in active theatre or not. For forward deployed troops, reported proximity to SCUD missile explosions and the use of pyridostigmine bromide (PB) pills, also called NAPS (anti-nerve agents), were associated with illness. For support personnel not seeing front line action, the use of pesticides on clothing or skin were associated with illness.

Bearing in mind various limitations of this paper, the results are complex yet interesting. I have previously touched upon pesticide exposure in relation to autism and what the various classes of pesticides might be capable of so won't give much more space to this factor aside from what is already known about the health effects of DEET and lindane. PB pills have long been the source of speculation in terms of their potential health effects. Professor Mohamed Abu Donia has published extensively on the 'interacting' effects of pesticides and PB medication. As for the SCUD explosions, I don't know. It does perhaps make you wonder what the payload might have been in these missile particularly when you see what was potentially hosted at some Iraqi munitions dumps.

I mentioned at the start of this post about how Gulf War illness is something not unfamiliar to my time in autism research. One of the questions that has been asked over the years concerns what happened to the offspring of those veterans who were conceived after their service. Did those environmental exposures (and possibly others) so detrimental to the health of many of them have any effects on their children? How about concentrations of toxic trace elements and autism as discussed by this study** by Fido and Al-Saad based in Kuwait? Relevant or not?

* Steele L. et al. Complex factors in the etiology of Gulf War Illness: wartime exposures and risk factors in veteran subgroups. Environmental Health Perspectives. September 2011.
** Fido A. & Al-Saad S. Toxic trace elements in the hair of children with autism. Autism. August 2005.