Tag: Gulf War Illness

Lessons from macrophagic myofasciitis: towards definition of a vaccine adjuvant-related syndrome

Abstract:

Macrophagic myofasciitis is a condition first reported in 1998, which cause remained obscure until 2001. Over 200 definite cases have been identified in France, and isolated cases have been recorded in other countries. The condition manifests by diffuse myalgias and chronic fatigue, forming a syndrome that meets both Center for Disease Control and Oxford criteria for the so-called chronic fatigue syndrome in about half of patients.

One third of patients develop an autoimmune disease, such as multiple sclerosis. Even in the absence of overt autoimmune disease they commonly show subtle signs of chronic immune stimulation, and most of them are of the HLADRB1*01 group, a phenotype at risk to develop polymyalgia rheumatica and rheumatoid arthritis.

Macrophagic myofasciitis is characterized by a stereotyped and immunologically active lesion at deltoid muscle biopsy. Electron microscopy, microanalytical studies, experimental procedures, and an epidemiological study recently demonstrated that the lesion is due to persistence for years at site of injection of an aluminum adjuvant used in vaccines against hepatitis B virus, hepatitis A virus, and tetanus toxoid. Aluminum hydroxide is known to potently stimulate the immune system and to shift immune responses towards a Th-2 profile.

It is plausible that persistent systemic immune activation that fails to switch off represents the pathophysiologic basis of chronic fatigue syndrome associated with macrophagic myofasciitis, similarly to what happens in patients with post-infectious chronic fatigue and possibly idiopathic chronic fatigue syndrome. Therefore, the WHO recommended an epidemiological survey, currently conducted by the French agency AFSSAPS, aimed at substantiating the possible link between the focal macrophagic myofasciitis lesion (or previous immunization with aluminium-containing vaccines) and systemic symptoms.

Interestingly, special emphasis has been put on Th-2 biased immune responses as a possible explanation of chronic fatigue and associated manifestations known as the Gulf war syndrome. Results concerning macrophagic myofasciitis may well open new avenues for etiologic investigation of this syndrome. Indeed, both type and structure of symptoms are strikingly similar in Gulf war veterans and patients with macrophagic myofasciitis. Multiple vaccinations performed over a short period of time in the Persian gulf area have been recognized as the main risk factor for Gulf War syndrome.

Moreover, the war vaccine against anthrax, which is administered in a 6-shot regimen and seems to be crucially involved, is adjuvanted by aluminium hydroxide and, possibly, squalene, another Th-2 adjuvant. If safety concerns about long-term effects of aluminium hydroxide are confirmed it will become mandatory to propose novel and alternative vaccine adjuvants to rescue vaccine-based strategies and the enormous benefit for public health they provide worldwide.

 

Source: Gherardi RK. Lessons from macrophagic myofasciitis: towards definition of a vaccine adjuvant-related syndrome. Rev Neurol (Paris). 2003 Feb;159(2):162-4. [Article in French] http://www.ncbi.nlm.nih.gov/pubmed/12660567

 

Chronic fatigue in a population-based study of Gulf War veterans

Abstract:

Fatigue has been associated with illness in veterans of the Gulf War; however, few studies have confirmed self-reported fatigue by using clinical evaluation, and symptomatic veterans have not been evaluated with established criteria for Chronic Fatigue Syndrome (CFS). The authors describe the frequency and clinical characteristics of CFS in a sample of veterans residing in the northwestern United States. The sample was selected randomly from U.S. Department of Defense databases of troops deployed to southwest Asia during the Gulf War. The selected individuals were invited to participate in a clinical case-control study of unexplained illness.

Of 799 survey respondents eligible for clinical evaluation, 178 had fatigue symptoms. Of the 130 veterans who were evaluated clinically, 103 had unexplained fatigue, and 44 veterans met the 1994 U.S. Centers for Disease Control criteria for CFS. In this population, the authors estimated a minimum prevalence of any unexplained fatigue to be 5.1%, and of CFS to be 2.2%. The estimated prevalence was greater among females than among males. Cases were similar to healthy controls, as determined by laboratory tests and physical findings. In comparison to several clinical studies of CFS patients, the authors of this study found a lower proportion of veterans who reported a sudden onset of symptoms (19%) vs. a gradual onset (50%).

Although it has previously been suggested that veterans of the Gulf War suffer from higher rates of chronic fatigue than the general population, the study results described herein–on the basis of clinical examination of a population-based sample of veterans-actually indicate that an increased rate may indeed exist. Gulf War veterans with unexplained fatigue should be encouraged to seek treatment so that the impact of these symptoms on overall quality of life can be reduced.

 

Source: McCauley LA, Joos SK, Barkhuizen A, Shuell T, Tyree WA, Bourdette DN. Chronic fatigue in a population-based study of Gulf War veterans. Arch Environ Health. 2002 Jul-Aug;57(4):340-8. http://www.ncbi.nlm.nih.gov/pubmed/12530602

 

Immunological variables mediate cognitive dysfunction in gulf war veterans but not civilians with chronic fatigue syndrome

Abstract:

We explored the relationship between a set of immunological variables and a set of cognitive and functional status measures and a diagnosis of chronic fatigue syndrome (CFS) in civilians and veterans using various regression and factor analytic methods.

Our approach emphasized the extraction of a few distinct factors in order to limit statistical problems associated with doing large numbers of multiple comparisons. This approach led to our finding cytokine data grouping into type 1 and type 2 clusters. A type 2 cluster plus a T and B cell factor predicted CFS caseness for Gulf War veterans but not for civilians with CFS. When a cognitive variable, reaction time, was added into the model, both immunological factors lost statistical significance; this indicates that the cognitive variable reaction time moderated the effects of the immunological factors in predicting patient status.

We did a similar analysis on the roles of the immunological and cognitive variables in functional status using SF-36 data. Higher levels of these same two immunological factors predicted poorer general health as well as poorer physical and social functioning in Gulf War veterans but not in civilians with CFS. When the reaction time factor was added, only the lymphocyte factor remained significant. This implies that lymphocytes are directly related to functional status in Gulf War veterans with CFS, but the Th2 factor produces its effect on functional status via changes in cognitive abilities.

Copyright 2002 S. Karger AG, Basel

 

Source: Brimacombe M, Zhang Q, Lange G, Natelson B. Immunological variables mediate cognitive dysfunction in gulf war veterans but not civilians with chronic fatigue syndrome. Neuroimmunomodulation. 2002-2003;10(2):93-100. http://www.ncbi.nlm.nih.gov/pubmed/12372983

 

The role of environmental factors in medically unexplained symptoms and related syndromes: conference summary and recommendations

Abstract:

This monograph of peer-reviewed articles is based on presentations at the conference “Environmental Factors in Medically Unexplained Physical Symptoms and Related Syndromes” held 10-12 January 2001 in Piscataway, New Jersey, USA. The purpose of the conference was to determine research priorities for elucidating the role of environmental factors in medically unexplained symptoms and symptom syndromes. These include conditions such as chronic fatigue syndrome, multiple chemical sensitivities, sick building syndrome, Gulf War illness, and the like. Approximately 1 1/2 days were devoted to plenary talks and 1 day was devoted to break-out sessions to discuss epidemiologic, psychosocial, and experimental research. Recommendations were made for a series of epidemiologic, psychosocial, and experimental research approaches, with acknowledgment that nosology issues are clearly fundamental to advancing understanding of these conditions.

 

Source: Kipen HM, Fiedler N. The role of environmental factors in medically unexplained symptoms and related syndromes: conference summary and recommendations. Environ Health Perspect. 2002 Aug;110 Suppl 4:591-5. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1241210/ (Full article)

 

Controlled exposures to volatile organic compounds in sensitive groups

Abstract:

Sensitivities to chemicals are characterized by symptoms in multiple organ systems in response to low-level chemical exposures. This paper reviews studies of controlled exposures to odorants and to mixtures of volatile organic compounds. Sensitive subgroups include subjects who met Cullen’s 1987 criteria for multiple chemical sensitivity (MCS), Gulf War veterans with chronic fatigue syndrome and chemical sensitivity (CFS/CS), and subjects with specific self-reported sensitivities to methyl terbutyl ether (MTBE) in gasoline (MTBE-sensitive). All studies include comparison of age- and sex-matched healthy controls.

Studies of olfaction did not support unusual sensitivity, defined as lower odor thresholds, among MCS subjects; however, a dose-response pattern of symptoms was observed in response to suprathreshold concentrations of phenyl ethyl alcohol. In blinded, controlled exposures to clean air, gasoline, gasoline/11% MTBE, and gasoline/15% MTBE, a threshold effect was observed with MTBE-sensitive subjects reporting significantly increased symptoms to gasoline/15% MTBE exposure. Autonomic arousal (heart and respiration rate; end-tidal CO2) in response to odor of chemical mixtures may mediate symptoms for subjects with generalized chemical sensitivities, but not for those whose sensitivities are confined to specific chemicals.

For example, Gulf War veterans with CFS/CS experienced reduced end-tidal CO2 when exposed to diesel fumes, while exposure to MTBE did not produce any psychophysiologic changes in MTBE-sensitive subjects. Controlled olfactory and exposure studies reveal that significant responses can be observed in chemically sensitive subjects even when de-adaptation has not occurred. However, these studies suggest that symptoms are not necessarily accompanied by changes in physiologic arousal. Subject characteristics play a critical role in outcomes.

 

Source: Fiedler N, Kipen HM. Controlled exposures to volatile organic compounds in sensitive groups. Ann N Y Acad Sci. 2001 Mar;933:24-37. http://www.ncbi.nlm.nih.gov/pubmed/12000025

 

Potential mechanisms in chemical intolerance and related conditions

Abstract:

The symptom of chemical intolerance may occur in isolation, but often occurs in conjunction with other chronic symptoms such as pain, fatigue, memory disturbances, etc. This frequent clustering of symptoms in individuals has led to the definition of several chronic multisymptom syndromes, such as multiple chemical sensitivity, fibromyalgia, chronic fatigue syndrome, and Gulf War illnesses. The aggregate research into these syndromes has suggested some unifying mechanisms that contribute to symptomatology. Multiple lines of evidence suggest that there is aberrant function of numerous efferent neural pathways, such as the autonomic nervous system and hypothalamic-pituitary axes, in subsets of individuals with these conditions.

There is perhaps the greatest evidence for abnormal sensory processing in these syndromes, with a low “unpleasantness threshold” for multiple types of sensory stimuli. Psychological and behavioral factors are known to play a significant role in initiating or perpetuating symptoms in some persons with these illnesses. In the field of pain research, the interrelationship between physiologic and psychologic factors in symptom expression has been well studied. Using both established and novel methodologies, studies have suggested that psychologic factors such as hypervigilance and expectancy are playing a relatively minor role in most individuals with fibromyalgia and that clear evidence exists of physiologic amplification of sensory stimuli.

These studies need to be extended to more sensory tasks and to larger numbers of subjects with related conditions. It is of note, though, that existing data on this spectrum of illnesses would suggest that there may be greater psychologic contributions to symptomatology if an illness is defined in part by behavior (e.g., avoidance of chemical exposures) rather than on the basis of symptoms alone.

 

Source: Clauw DJ. Potential mechanisms in chemical intolerance and related conditions.  Ann N Y Acad Sci. 2001 Mar;933:235-53. http://www.ncbi.nlm.nih.gov/pubmed/12000024

 

Cytokines and chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) patients show evidence of immune activation, as demonstrated by increased numbers of activated T lymphocytes, including cytotoxic T cells, as well as elevated levels of circulating cytokines. Nevertheless, immune cell function of CFS patients is poor, with low natural killer cell cytotoxicity (NKCC), poor lymphocyte response to mitogens in culture, and frequent immunoglobulin deficiencies, most often IgG1 and IgG3.

Immune dysfunction in CFS, with predominance of so-called T-helper type 2 and proinflammatory cytokines, can be episodic and associated with either cause or effect of the physiological and psychological function derangement and/or activation of latent viruses or other pathogens. The interplay of these factors can account for the perpetuation of disease with remission/exacerbation cycles. A T-helper type 2 predominance has been seen among Gulf War syndrome patients and this feature may also be present in other related disorders, such as multiple chemical sensitivity. Therapeutic intervention aimed at induction of a more favorable cytokine expression pattern and immune status appears promising.

 

Source: Patarca R. Cytokines and chronic fatigue syndrome.  Ann N Y Acad Sci. 2001 Mar;933:185-200. http://www.ncbi.nlm.nih.gov/pubmed/12000020

 

Neurobehavioral deficits associated with chronic fatigue syndrome in veterans with Gulf War unexplained illnesses

Abstract:

Gulf War unexplained illnesses (GWUI) are a heterogeneous collection of symptoms of unknown origin known to be more common among veterans of the Gulf War than among nonveterans. In the present study we focused on one of these unexplained illnesses.

We tested the hypothesis that in a sample of Persian Gulf War veterans chronic fatigue syndrome (CFS) was associated with cognitive deficits on computerized cognitive testing after controlling for the effects of premorbid cognitive differences. We obtained Armed Forces Qualification Test (AFQT) data acquired around the date of induction into the military on 94 veterans of the Gulf War, 32 with CFS and 62 healthy controls. Controls performed better than participants diagnosed with CFS on the AFQT. Cognitive deficits were associated with CFS on 3 of 8 variables after the effect of premorbid AFQT scores was removed with ANCOVA.

 

Source: Binder LM, Storzbach D, Campbell KA, Rohlman DS, Anger WK; Members of the Portland Environmental Hazards Research Center. Neurobehavioral deficits associated with chronic fatigue syndrome in veterans with Gulf War unexplained illnesses. J Int Neuropsychol Soc. 2001 Nov;7(7):835-9. http://www.ncbi.nlm.nih.gov/pubmed/11771626

 

Symptom factor analysis, clinical findings, and functional status in a population-based case control study of Gulf War unexplained illness

Abstract:

Few epidemiological studies have been conducted that have incorporated clinical evaluations of Gulf War veterans with unexplained health symptoms and healthy controls. We conducted a mail survey of 2022 Gulf War veterans residing in the northwest United States and clinical examinations on a subset of 443 responders who seemed to have unexplained health symptoms or were healthy. Few clinical differences were found between cases and controls.

The most frequent unexplained symptoms were cognitive/psychological, but significant overlap existed with musculoskeletal and fatigue symptoms. Over half of the veterans with unexplained musculoskeletal pain met the criteria for fibromyalgia, and a significant portion of the veterans with unexplained fatigue met the criteria for chronic fatigue syndrome. Similarities were found in the clinical interpretation of unexplained illness in this population and statistical factor analysis performed by this study group and others.

 

Source: Bourdette DN, McCauley LA, Barkhuizen A, Johnston W, Wynn M, Joos SK, Storzbach D, Shuell T, Sticker D. Symptom factor analysis, clinical findings, and functional status in a population-based case control study of Gulf War unexplained illness. J Occup Environ Med. 2001 Dec;43(12):1026-40. http://www.ncbi.nlm.nih.gov/pubmed/11765674

 

Chemical sensitivity and chronic fatigue in Gulf War veterans: a brief report

Abstract:

The foci of this brief report are to (1) describe the prevalence of chemical sensitivity (CS) and chronic fatigue (CF) symptomatology and of presumptive multiple CS and CF syndrome diagnoses, and (2) explore the potential overlap between one purported case definition (i.e., chronic multi-symptom illness) and these unexplained symptom syndromes in a well-characterized group of Gulf War veterans. The number of subjects with CS and CF symptomatology and presumptive multiple CS and CF syndrome diagnoses was higher in the Gulf War-deployed group compared with a group deployed to Germany during the Gulf War. However, the percent differences were not significant when comparing the presumptive diagnoses of multiple CS and CF syndrome. The characteristic differences between the groups and the overlap with chronic multi-symptom illness are also discussed.

 

Source: Proctor SP, Heaton KJ, White RF, Wolfe J. Chemical sensitivity and chronic fatigue in Gulf War veterans: a brief report. J Occup Environ Med. 2001 Mar;43(3):259-64. http://www.ncbi.nlm.nih.gov/pubmed/11285874