Infections in temporal proximity to HPV vaccination and adverse effects following vaccination in Denmark: A nationwide register-based cohort study and case-crossover analysis.

BACKGROUND: Public trust in the human papilloma virus (HPV) vaccination programme has been challenged by reports of potential severe adverse effects. The reported adverse symptoms were heterogeneous and overlapping with those characterised as chronic fatigue syndrome (CFS) and have been described as CFS-like symptoms. Evidence suggests that CFS is often precipitated by an infection. The aim of the study was to examine if an infection in temporal proximity to HPV vaccination is a risk factor for suspected adverse effects following HPV vaccination. METHODS AND FINDINGS: The study was a nationwide register-based cohort study and case-crossover analysis. The study population consisted of all HPV vaccinated females living in Denmark, born between 1974 and 2006, and vaccinated between January 1, 2006 and December 31, 2017. The exposure was any infection in the period ± 1 month around time of first HPV vaccination and was defined as (1) hospital-treated infection; (2) redemption of anti-infective medication; or (3) having a rapid streptococcal test done at the general practitioner. The outcome was referral to a specialised hospital setting (5 national HPV centres opened June 1, 2015) due to suspected adverse effects following HPV vaccination. Multivariable logistic regression was used to estimate the association between infection and later HPV centre referral. The participants were 600,400 HPV-vaccinated females aged 11 to 44 years. Of these, 48,361 (9.7%) females had a hospital-treated infection, redeemed anti-infective medication, or had a rapid streptococcal test ± 1 month around time of first HPV vaccination. A total of 1,755 (0.3%) females were referred to an HPV centre. Having a hospital-treated infection in temporal proximity to vaccination was associated with significantly elevated risk of later referral to an HPV centre (odds ratio (OR) 2.75, 95% confidence interval (CI) 1.72 to 4.40; P < 0.001). Increased risk was also observed among females who redeemed anti-infective medication (OR 1.56, 95% CI 1.33 to 1.83; P < 0.001) or had a rapid streptococcal test (OR 1.45, 95% CI 1.10 to 1.93; P = 0.010). Results from a case-crossover analysis, which was performed to adjust for potential unmeasured confounding, supported the findings. A key limitation of the study is that the HPV centres did not open until June 1, 2015, which may have led to an underestimation of the risk of suspected adverse effects, but stratified analyses by year of vaccination yielded similar results. CONCLUSIONS: Treated infection in temporal proximity to HPV vaccination is associated with increased risk for later referral with suspected adverse vaccine effects. Thus, the infection could potentially be a trigger of the CFS-like symptoms in a subset of the referred females. To our knowledge, the study is the first to investigate the role of infection in the development of suspected adverse effects after HPV vaccination and replication of these findings are needed in other studies.

Human papillomavirus (HPV) vaccine and autonomic disorders: a position statement from the American Autonomic Society.

INTRODUCTION: Human papillomavirus (HPV) vaccination has been anecdotally connected to the development of dysautonomia, chronic fatigue, complex regional pain syndrome and postural tachycardia syndrome. OBJECTIVES: To critically evaluate a potential connection between HPV vaccination and the above-noted conditions. METHODS: We reviewed the literature containing the biology of the virus, pathophysiology of infection, epidemiology of associated cancers, indications of HPV vaccination, safety surveillance data and published reports linking HPV vaccination to autonomic disorders. RESULTS: At this time, the American Autonomic Society finds that there are no data to support a causal relationship between HPV vaccination and CRPS, chronic fatigue, and postural tachycardia syndrome to other forms of dysautonomia. CONCLUSION: Certain conditions are prevalent in the same populations that are vaccinated with the HPV vaccine (peri-pubertal males and females). This association, however, is an insufficient proof of causality.

[Side effects of chemotherapy for testicular cancers and post-cancer follow-up]. / Effets secondaires de la chimiothérapie des cancers testiculaires et suivi de l'après cancer.

Testicular cancers are the most frequent and the most curable cancers in young men. Treatments of these cancers represent a great success with cure rate over to 95 %. However, chemotherapy side effects may occur during or after several years post-treatment. This review aimed to highlight complications and physical and psychological side effects occurring mainly after chemotherapy treatment for testicular cancer, and to propose a personalized post-cancer plan specific for patients treated for testicular cancer. Treatments of these cancers can cause short-term complications (asthenia, nausea, vomiting, alopecia..). These side effects disappear within a few months after the end of the treatments. Late complications may occur several years post-treatment. Cardiovascular disease, metabolic syndrome and secondary neoplasia represent the most severe late effects among patients treated for testicular cancer. Given the increased incidence of these chemotherapy-induced side effects, it is indispensable to establish a specific follow up which must include a particular vigilance on the risk of occurrence of second cancer, a follow-up of the cardio-vascular risk factors, pulmonary and auditory follow-up, and early detection of psychosocial disorders.

Silicone breast implants and depression, fibromyalgia and chronic fatigue syndrome in a rheumatology clinic population.

INTRODUCTION: Silicone breast implants (SBI) may induce systemic autoimmune disease as part of autoimmune syndrome induced by adjuvants (ASIA). This syndrome bears similarities to fibromyalgia and chronic fatigue syndrome (CFS). We sought to determine whether there are any associations between SBI and depression, fibromyalgia and CFS in a rheumatology clinic population. METHODS: The electronic files of rheumatology clinic patients at the Royal Adelaide Hospital between 2000 and 2017 were searched for patients who had received SBI prior to rheumatological diagnosis. Demographics, diagnosis, implant history and whether the patient had depression, fibromyalgia or CFS were recorded. Controls were rheumatology clinic patients, half of whom had systemic sclerosis (SSc) and the other half had systemic lupus erythematosus (SLE). They were matched to cases 3:1 for age (within 2 years) and gender. RESULTS: Thirty patients had received SBI (mean age 47.9, 100% female). Twelve had a diagnosis of depression, 6 of fibromyalgia and 3 of CFS. Implant rupture was not associated with any of these (p = 1). There was no difference in the incidence of depression (p = 1), fibromyalgia (p = 0.76) or CFS (p = 0.3) between cases and SLE controls. When compared with SSc controls, there were significantly more patients with fibromyalgia and/or CFS in the case group (20.0% of cases vs 2.2% of SSc controls, p = 0.01) but no difference in depression (p = 0.12). CONCLUSION: Fibromyalgia and CFS are more common in patients with silicone implants than SSc controls but not SLE controls. Prospective study of development of depression, fibromyalgia and CFS in recipients of SBI is required.

Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of chronic fatigue syndrome.

The role of immune or infective triggers in the pathogenesis of Chronic Fatigue Syndrome (CFS) is not yet fully understood. Barriers to obtaining immune measures at baseline (i.e., before the trigger) in CFS and post-infective fatigue model cohorts have prevented the study of pre-existing immune dysfunction and subsequent immune changes in response to the trigger. This study presents interferon-alpha (IFN-α)-induced persistent fatigue as a model of CFS. IFN-α, which is used in the treatment of chronic Hepatitis C Virus (HCV) infection, induces a persistent fatigue in some individuals, which does not abate post-treatment, that is, once there is no longer immune activation. This model allows for the assessment of patients before and during exposure to the immune trigger, and afterwards when the original trigger is no longer present. Fifty-five patients undergoing IFN-α treatment for chronic HCV were assessed at baseline, during the 6-12 months of IFN-α treatment, and at six-months post-treatment. Measures of fatigue, cytokines and kynurenine pathway metabolites were obtained. Fifty-four CFS patients and 57 healthy volunteers completed the same measures at a one-off assessment, which were compared with post-treatment follow-up measures from the HCV patients. Eighteen patients undergoing IFN-α treatment (33%) were subsequently defined as having 'persistent fatigue' (the proposed model for CFS), if their levels of fatigue were higher six-months post-treatment than at baseline; the other 67% were considered 'resolved fatigue'. Patients who went on to develop persistent fatigue experienced a greater increase in fatigue symptoms over the first four weeks of IFN-α, compared with patients who did not (Δ Treatment Week (TW)-0 vs. TW4; PF: 7.1 ± 1.5 vs. RF: 4.0 ± 0.8, p = 0.046). Moreover, there was a trend towards increased baseline interleukin (IL)-6, and significantly higher baseline IL-10 levels, as well as higher levels of these cytokines in response to IFN-α treatment, alongside concurrent increases in fatigue. Levels increased to more than double those of the other patients by Treatment Week (TW)4 (p = 0.011 for IL-6 and p = 0.001 for IL-10). There was no evidence of an association between persistent fatigue and peripheral inflammation six-months post-treatment, nor did we observe peripheral inflammation in the CFS cohort. While there were changes in kynurenine metabolites in response to IFN-α, there was no association with persistent fatigue. CFS patients had lower levels of the ratio of kynurenine to tryptophan and 3-hydroxykynurenine than controls. Future studies are needed to elucidate the mechanisms behind the initial exaggerated response of the immune system in those who go on to experience persistent fatigue even if the immune trigger is no longer present, and the change from acute to chronic fatigue in the absence of continued peripheral immune activation.

Aluminum in vaccines: Does it create a safety problem?

For almost a century, aluminum (Al) in the form of Al oxyhydroxide (a crystalline compound), Al hydroxyphosphate (an amorphous Al phosphate hydroxide), Al phosphate, and Al potassium sulfate has been used to improve the immunogenicity of vaccines. Al is currently included in vaccines against tetanus, hepatitis A, hepatitis B, human papillomavirus, Haemophilus influenzae type b, and infections due to Streptococcus pneumoniae and Neisseria meningitidis. Official health authorities consider the inclusion of Al in most of the presently recommended vaccines to be extremely effective and sufficiently safe. However, the inclusion of Al salts in vaccines has been debated for several years because of studies that seem to indicate that chronic Al exposure through vaccine administration can interfere with cellular and metabolic processes leading to severe neurologic diseases. Children, who in their first years of life receive several vaccine doses over a reduced period of time, would be most susceptible to any risk that might be associated with vaccines or vaccine components. The main aim of this paper was to discuss the data presently available regarding Al neurotoxicity and the risk for children receiving vaccines or other pharmaceutical preparations containing Al. Analysis of the literature showed that no apparent reason exists to support the elimination of Al from vaccines for fear of neurotoxicity. The only problem that deserves attention is the suggested relationship between Al oxyhydroxide-containing vaccines and macrophagic myofaciitis or myalgic encephalomyelitis/chronic fatigue syndrome. Currently, definitive conclusions cannot be drawn on these risks and further studies must be conducted. Until then, Al remains the best solution to improve vaccine efficacy.

HPV vaccination and risk of chronic fatigue syndrome/myalgic encephalomyelitis: A nationwide register-based study from Norway.

BACKGROUND: Vaccination has been suggested to be involved in the aetiology of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). HPV vaccine was introduced in the Norwegian Childhood Immunisation Programme and offered 12year old girls from 2009. We studied the association between HPV vaccination and risk of CFS/ME and also assessed medical history in relation to both risk of CFS/ME and HPV vaccine uptake. METHODS: Individual data from national registries, including the Norwegian Population Registry, the Norwegian Patient Registry and the Norwegian Immunisation Registry were linked using the unique personal identification number. Yearly incidence rates of CFS/ME for 2009-2014 were calculated among the 824,133 boys and girls, aged 10-17 living in Norway during these 6years. A total of 176,453 girls born 1997-2002 were eligible for HPV vaccination and included in further analyses. Hazard ratios (HRs) of CFS/ME were estimated using Cox regression. Risk differences (RDs) of vaccine uptake were estimated with binomial regression. RESULTS: A similar yearly increase in incidence rate of CFS/ME was observed among girls and boys, IRR=1.15 (95% confidence interval (CI) 1.10-1.19) and 1.15 (95% CI 1.09-1.22), respectively. HPV vaccination was not associated with CFS/ME, HR=0.86 (95% CI 0.69-1.08) for the entire follow-up period and 0.96 (95% CI 0.64-1.43) for the first two years after vaccination. The risk of CFS/ME increased with increasing number of previous hospital contacts, HR=5.23 (95% CI 3.66-7.49) for 7 or more contacts as compared to no contacts. Girls with 7 or more hospital contacts were less likely to be vaccinated than girls with no previous hospital contacts, RD=-5.5% (95% CI -6.7% to -4.2%). CONCLUSIONS: No indication of increased risk of CFS/ME following HPV vaccination was observed among girls in the first 6 birth cohorts offered HPV vaccine through the national immunisation programme in Norway.

Induction Murine Models of Chronic Fatigue Syndrome by Brucella abortus Antigen Injections: Is Anemia Induced or Not?

To investigate whether Brucella abortus (BA) antigen injections lead to anemia, and to establish an appropriate Chronic Fatigue Syndrome (CFS) animal model by BA injections, 6 repeated injections of BA antigen were fulfilled every 2 weeks. At a high dose of 1∗10(10) particles/mouse, anemia was induced within 2 weeks and then recovered a lot at the end of the research, while at a moderate dose of 1∗10(8) (3 injections) shifting to 1∗10(9)/mouse (3 injections) anemia was absent. In both groups running wheel activity remained very low even 6 weeks after the last injection.

Isoflavones inhibit poly(I:C)-induced serum, brain, and skin inflammatory mediators - relevance to chronic fatigue syndrome.

BACKGROUND: Chronic Fatigue Syndrome (CFS) is a neuroimmunoendocrine disease affecting about 1% of the US population, mostly women. It is characterized by debilitating fatigue for six or more months in the absence of cancer or other systemic diseases. Many CFS patients also have fibromyalgia and skin hypersensitivity that worsen with stress. Corticotropin-releasing hormone (CRH) and neurotensin (NT), secreted under stress, activate mast cells (MC) necessary for allergic reactions to release inflammatory mediators that could contribute to CFS symptoms. OBJECTIVE: To investigate the effect of isoflavones on the action of polyinosinic:polycytidylic acid (poly(I:C)), with or without swim stress, on mouse locomotor activity and inflammatory mediator expression, as well as on human MC activation. METHODS: Female C57BL/6 mice were randomly divided into four groups: (a) control/no-swim, (b) control/swim, (c) polyinosinic:polycytidylic acid (poly(I:C))/no swim, and (d) polyinosinic:polycytidylic acid (poly(I:C))/swim. Mice were provided with chow low or high in isoflavones for 2 weeks prior to ip injection with 20 mg/kg poly(I:C) followed or not by swim stress for 15 minutes. Locomotor activity was monitored overnight and animals were sacrificed the following day. Brain and skin gene expression, as well as serum levels, of inflammatory mediators were measured. Data were analyzed using the non-parametric Mann-Whitney U-test. RESULTS: Poly(I:C)-treated mice had decreased locomotor activity over 24 hours, and increased serum levels of TNF-α, IL-6, KC (IL-8/CXCL8 murine homolog), CCL2,3,4,5, CXCL10, as well as brain and skin gene expression of TNF, IL-6, KC (Cxcl1, IL8 murine homolog), CCL2, CCL4, CCL5 and CXCL10. Histidine decarboxylase (HDC) and NT expression were also increased, but only in the skin, over the same period. High isoflavone diet reversed these effects. CONCLUSION: Poly(I:C) treatment decreased mouse locomotor activity and increased serum levels and brain and skin gene expression of inflammatory mediators. These effects were inhibited by isoflavones that may prove useful in CFS.

[Impairments of rats' behavioral reactions, concentration of corticosterone and expression of cytokine's gene under experimental postviral fatigue].

The aim of the main research was investigated of interaction of neural, endocrine and immune systems under experimental postviral fatigue, behavioral reactions, level of corticosterone, changes of IL-3 and IL-10 gene expression in rats' hypothalamus and INF-α in hypothalamus and spleen were analyzed. It has been shown the decrease of physical activity, increasing of corticosterone's level and gene expression of cytokines after injection of Poly I:C as a model of postviral fatigue. After remedication of Poly I:C increasing of physical activity was shown.

Detection of mycotoxins in patients with chronic fatigue syndrome.

Over the past 20 years, exposure to mycotoxin producing mold has been recognized as a significant health risk. Scientific literature has demonstrated mycotoxins as possible causes of human disease in water-damaged buildings (WDB). This study was conducted to determine if selected mycotoxins could be identified in human urine from patients suffering from chronic fatigue syndrome (CFS). Patients (n = 112) with a prior diagnosis of CFS were evaluated for mold exposure and the presence of mycotoxins in their urine. Urine was tested for aflatoxins (AT), ochratoxin A (OTA) and macrocyclic trichothecenes (MT) using Enzyme Linked Immunosorbent Assays (ELISA). Urine specimens from 104 of 112 patients (93%) were positive for at least one mycotoxin (one in the equivocal range). Almost 30% of the cases had more than one mycotoxin present. OTA was the most prevalent mycotoxin detected (83%) with MT as the next most common (44%). Exposure histories indicated current and/or past exposure to WDB in over 90% of cases. Environmental testing was performed in the WDB from a subset of these patients. This testing revealed the presence of potentially mycotoxin producing mold species and mycotoxins in the environment of the WDB. Prior testing in a healthy control population with no history of exposure to a WDB or moldy environment (n = 55) by the same laboratory, utilizing the same methods, revealed no positive cases at the limits of detection.

Could cadmium be responsible for some of the neurological signs and symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

According to the World Health Organization, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a neurological disease characterized by widespread inflammation and multi-systemic neuropathology. Aetiology and pathogenesis are unknown, and several agents have been proposed as causative agents or as factors perpetuating the syndrome. Exposure to heavy metals, with particular reference to mercury and gold in dental amalgams, has been considered among the triggers of ME/CFS. Here we hypothesize that cadmium, a widespread occupational and environmental heavy metal pollutant, might be associated with some of the neurological findings described in ME/CFS. In fact, ME/CFS patients show a decrease of the volume of the gray matter in turn associated with objective reduction of physical activity. Cadmium induces neuronal death in cortical neurons through a combined mechanism of apoptosis and necrosis and it could then be hypothesized that cadmium-induced neuronal cell death is responsible for some of the effects of cadmium on the central nervous system, i.e. a decrease in attention level and memory in exposed humans as well as to a diminished ability for training and learning in rats, that are symptoms typical of ME/CFS. This hypothesis can be tested by measuring cadmium exposure in a cohort of ME/CFS patients compared with matched healthy controls, and by measuring gray matter volume in un-exposed healthy controls, exposed non-ME/CFS subjects, un-exposed ME/CFS patients and exposed ME/CFS patients. In addition, we hypothesize that cadmium exposure could be associated with reduced cerebral blood flow in ME/CFS patients because of the disruptive effects of cadmium on angiogenesis. In fact, cadmium inhibits angiogenesis and low global cerebral flow is associated with abnormal brain neuroimaging results and brain dysfunction in the form of reduced cognitive testing scores in ME/CFS patients. This hypothesis can be tested by measuring cerebral cortex blood flow in un-exposed healthy controls, exposed non-ME/CFS subjects, un-exposed ME/CFS patients and exposed ME/CFS patients. If our hypothesis is demonstrated correct, the consequences could affect prevention, early diagnosis, and treatment of ME/CFS. Implications in early diagnosis could entail the evaluation of symptoms typical of ME/CFS in cadmium-exposed subjects as well as the search for signs of exposure to cadmium in subjects diagnosed with ME/CFS. Nutritional supplementation of magnesium and zinc could then be considered, since these elements have been proposed in the prophylaxis and therapy of cadmium exposure, and magnesium was demonstrated effective on ME/CFS patients' symptom profiles.

Chronic fatigue syndrome: is there a role for non-antidepressant pharmacotherapy?

IMPORTANCE OF THE FIELD: Chronic fatigue syndrome (CFS) is a prevalent but poorly understood condition mainly characterized by debilitating, persistent or recurrent fatigue; increased physical and mental fatigability; cognitive impairment and widespread musculoskeletal pain. Despite intensive treatment research, the role of pharmacotherapy in the illness remains uncertain. AREAS COVERED IN THIS REVIEW: An updated review is given of pharmacotherapy in CFS, with a focus on non-antidepressant, controlled drug trials performed between 1988 and August 2009. WHAT THE READER WILL GAIN: Antiviral, immunological and antibiotic therapies, although sometimes associated with symptom amelioration, can be more harmful than beneficial in CFS. Stimulants seem to benefit some CFS patients but their long-term effects is uncertain. Although antidepressants are not curative for the illness, they might be useful for some symptomatic aspects and co-morbid anxiety and depression. There is little or no evidence that CFS patients benefit from other pharmacological agents (e.g., steroids) or from dietary supplements and complementary medicine products. Future research into treatment should take specific subgroups into account and should target immunological aspects of the illness as well as the complex relationships between CFS, stress and depression. TAKE HOME MESSAGE: Pharmacotherapy can currently not be considered first-line treatment in CFS and should always be used in a context of self-management and rehabilitation.

Medication use is associated with fatigue in a sample of community-living individuals who have a spinal cord injury: a chart review.

OBJECTIVES: To investigate the relationship between medications known to cause fatigue in spinal cord injury (SCI) and fatigue severity and to describe the pattern of prescription of these medications. STUDY DESIGN: Retrospective chart review. SETTING: GF Strong Rehabilitation Centre, Vancouver, British Columbia, Canada. METHODS: Medical charts of 136 individuals admitted to the GF Strong Outpatient SCI Program between December 2004 and May 2007 were reviewed. Data collected included information on medications, clinical and demographic characteristics and Fatigue Severity Scale (FSS) scores. Multiple linear regression techniques were used to analyse the data. RESULTS: Fifty-two percent of the subjects had clinically relevant fatigue. As a group, the subjects were taking 147 different medications; 41/147 medications were identified as causing fatigue. The two most commonly prescribed categories of medications were antispasticity medications (75 subjects) and analgesic medications (61 subjects). Although several variables were found to contribute to the FSS scores including the use of fatigue-causing medications, the presence of pain (7.6% of variance) and the use of fatigue-causing analgesics (4.2% of variance) explained the most variance in the scores. CONCLUSION: Fatigue is prevalent in outpatients with SCI. Fatigue-causing medications contribute to a higher FSS score. Clinicians treating persons with SCI should be aware that fatigue is a common and significant problem. Clinicians should be aware that fatigue may be exacerbated by the use of medication and should enquire about the effects of medication on fatigue when assessing and prescribing new medications.

Epigallocatechin gallate ameliorates chronic fatigue syndrome in mice: behavioral and biochemical evidence.

Three decades after the coining of the term chronic fatigue syndrome, the diagnosis of this illness is still symptom based and the aetiology remains elusive. Chronic fatigue syndrome pathogenesis seems to be multifactorial and the possible involvement of immune system is supported. The present study was designed to evaluate the effects of the epigallocatechin gallate in a mouse model of immunologically induced chronic fatigue. On 19th day, after lipopolysaccharide/Brucella abortus administration, the mice showed significant increase in immobility period, post swim fatigue and thermal hyperalgesia. Behavioral deficits were coupled with enhanced oxidative-nitrosative stress as evident by increased lipid peroxidation, nitrite levels and decreased endogenous antioxidant enzymes (superoxide dismutase, reduced glutathione and catalase) and inflammation (increased levels of tumor necrosis factor-alpha and tissue growth factor-beta). Chronic treatment with epigallocatechin gallate restored these behavioral and biochemical alterations in mice. The present study points out towards the beneficial effect of epigallocatechin gallate in the amelioration of chronic fatigue syndrome and thus may provide a new, effective and powerful strategy to treat chronic fatigue syndrome.

A role for the body burden of aluminium in vaccine-associated macrophagic myofasciitis and chronic fatigue syndrome.

Macrophagic myofasciitis and chronic fatigue syndrome are severely disabling conditions which may be caused by adverse reactions to aluminium-containing adjuvants in vaccines. While a little is known of disease aetiology both conditions are characterised by an aberrant immune response, have a number of prominent symptoms in common and are coincident in many individuals. Herein, we have described a case of vaccine-associated chronic fatigue syndrome and macrophagic myofasciitis in an individual demonstrating aluminium overload. This is the first report linking the latter with either of these two conditions and the possibility is considered that the coincident aluminium overload contributed significantly to the severity of these conditions in this individual. This case has highlighted potential dangers associated with aluminium-containing adjuvants and we have elucidated a possible mechanism whereby vaccination involving aluminium-containing adjuvants could trigger the cascade of immunological events which are associated with autoimmune conditions including chronic fatigue syndrome and macrophagic myofasciitis.

[Cellular and molecular mechanisms of interaction between the neuroendocrine and immune systems under chronic fatigue syndrome in experiment].

One of the main mechanisms of chronic fatigue syndrome development involves disturbances of interaction between the immune and neuroendocrine systems. The adequate experimental model for the search of these mechanisms is induction of fatigue in animals via the single intraperitoneal administration of synthetic double-stranded RNA - Poly I : C. Investigation of alterations in cytotoxic and proliferation activities of splenocytcs, the intensity of immunomodulatory cytokines signaling via the sphingomyelin pathways in membrane P2 fraction of the brain cortex, as well as the activity of hypothalamic-pituitary adrenal (HP A) axis in the dynamics of chronic fatigue syndrome in rats has performed. Inhibition of both cytotoxic and proliferative activities of splenocytes during the period of fatigue development has been shown. Priority data concerning the suppression of the activity of neutral sphingomyelinase (nSMase) - the key enzyme of the sphingomyelin cascade - in membranes ofthe cells from the brain cortex on the 3d day after Poly I : C administration to rats have been obtained. It was found that Poly I : C injection to rats led to disturbed HPA axis functions which was manifested by decreased corticosterone concentration in standard functional assays with ACTH and hydrocortisone administration. It is suggested that disturbances in interaction between the immune and neuroendocrine systems during development of chronic fatigue syndrome, including alterations in HPA axis activity, are realized both on the level of changes in the activity of immune-competent cells and immediately on membranes of the brain cells.