Inflammatory and oxidative and nitrosative stress pathways underpinning chronic fatigue, somatization and psychosomatic symptoms

Abstract:

PURPOSE OF REVIEW: The aim of this paper is to review recent findings on inflammatory and oxidative and nitrosative stress (IO&NS) pathways in chronic fatigue and somatization disorder.

RECENT FINDINGS: Activation of IO&NS pathways is the key phenomenon underpinning chronic fatigue syndrome (CFS): intracellular inflammation, with an increased production of nuclear factor kappa beta (NFkappabeta), cyclo-oxygenase-2 (COX-2) and inducible NO synthase (iNOS); and damage caused by O&NS to membrane fatty acids and functional proteins. These IO&NS pathways are induced by a number of trigger factors, for example psychological stress, strenuous exercise, viral infections and an increased translocation of LPS from gram-bacteria (leaky gut). The ‘psychosomatic’ symptoms experienced by CFS patients are caused by intracellular inflammation (aches and pain, muscular tension, fatigue, irritability, sadness, and the subjective feeling of infection); damage caused by O&NS (aches and pain, muscular tension and fatigue); and gut-derived inflammation (complaints of irritable bowel). Inflammatory pathways (monocytic activation) are also detected in somatizing disorder.

SUMMARY: ‘Functional’ symptoms, as occurring in CFS and somatization, have a genuine organic cause, that is activation of peripheral and central IO&NS pathways and gut-derived inflammation. The development of new drugs, aimed at treating those disorders, should target these IO&NS pathways.

 

Source: Maes M. Inflammatory and oxidative and nitrosative stress pathways underpinning chronic fatigue, somatization and psychosomatic symptoms. Curr Opin Psychiatry. 2009 Jan;22(1):75-83. https://www.ncbi.nlm.nih.gov/pubmed/19127706

 

Childhood trauma and risk for chronic fatigue syndrome: association with neuroendocrine dysfunction

Abstract:

CONTEXT: Childhood trauma appears to be a potent risk factor for chronic fatigue syndrome (CFS). Evidence from developmental neuroscience suggests that early experience programs the development of regulatory systems that are implicated in the pathophysiology of CFS, including the hypothalamic-pituitary-adrenal axis. However, the contribution of childhood trauma to neuroendocrine dysfunction in CFS remains obscure.

OBJECTIVES: To replicate findings on the relationship between childhood trauma and risk for CFS and to evaluate the association between childhood trauma and neuroendocrine dysfunction in CFS.

DESIGN, SETTING, AND PARTICIPANTS: A case-control study of 113 persons with CFS and 124 well control subjects identified from a general population sample of 19 381 adult residents of Georgia.

MAIN OUTCOME MEASURES: Self-reported childhood trauma (sexual, physical, and emotional abuse; emotional and physical neglect), psychopathology (depression, anxiety, and posttraumatic stress disorder), and salivary cortisol response to awakening.

RESULTS: Individuals with CFS reported significantly higher levels of childhood trauma and psychopathological symptoms than control subjects. Exposure to childhood trauma was associated with a 6-fold increased risk of CFS. Sexual abuse, emotional abuse, and emotional neglect were most effective in discriminating CFS cases from controls. There was a graded relationship between exposure level and CFS risk. The risk of CFS conveyed by childhood trauma further increased with the presence of posttraumatic stress disorder symptoms. Only individuals with CFS and with childhood trauma exposure, but not individuals with CFS without exposure, exhibited decreased salivary cortisol concentrations after awakening compared with control subjects.

CONCLUSIONS: Our results confirm childhood trauma as an important risk factor of CFS. In addition, neuroendocrine dysfunction, a hallmark feature of CFS, appears to be associated with childhood trauma. This possibly reflects a biological correlate of vulnerability due to early developmental insults. Our findings are critical to inform pathophysiological research and to devise targets for the prevention of CFS.

 

Source: Heim C, Nater UM, Maloney E, Boneva R, Jones JF, Reeves WC. Childhood trauma and risk for chronic fatigue syndrome: association with neuroendocrine dysfunction. Arch Gen Psychiatry. 2009 Jan;66(1):72-80. doi: 10.1001/archgenpsychiatry.2008.508. https://www.ncbi.nlm.nih.gov/pubmed/19124690

 

Customizing treatment of chronic fatigue syndrome and fibromyalgia: the role of perpetuating factors

Erratum in: Psychosomatics. 2009 Mar-Apr;50(2):176.

Abstract:

BACKGROUND: Syndromes characterized by chronic, medically unexplained fatigue, effort- and stress-intolerance, and widespread pain are highly prevalent in medicine.

RESULTS: In chronic fatigue syndrome (CFS) and fibromyalgia (FM), various perpetuating factors may impair patients’ quality of life and functioning and impede recovery. Although cognitive-behavioral and graded-exercise therapy are evidence-based treatments, the effectiveness and acceptability of therapeutic interventions in CFS/FM may largely depend on a customized approach taking the heterogeneity of perpetuating factors into account.

CONCLUSION: Further research should clarify the aim and outcome of different treatment strategies in CFS/FM, as well as the underlying mechanisms of change, including those facilitating neurobiological recovery.

 

Source: Van Houdenhove B, Luyten P. Customizing treatment of chronic fatigue syndrome and fibromyalgia: the role of perpetuating factors. Psychosomatics. 2008 Nov-Dec;49(6):470-7. doi: 10.1176/appi.psy.49.6.470. https://www.ncbi.nlm.nih.gov/pubmed/19122123

 

Chronic fatigue syndrome and complement activation

Abstract:

This report describes a case of chronic fatigue syndrome (CFS) that followed a well-documented episode of acute Epstein-Barr virus (EBV) mononucleosis. All aetiological tests for chronic fatigue were found to be negative or normal, as were immunological tests. After 2 years of chronic fatigue following the acute illness, measurements of complement split products were performed to test for complement activation. These were positive and remained positive for 14 months, after which the patient then recovered from CFS.

 

Source: Geller RD, Giclas PC. Chronic fatigue syndrome and complement activation. BMJ Case Rep. 2009;2009. pii: bcr08.2008.0819. doi: 10.1136/bcr.08.2008.0819. Epub 2009 Mar 17. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3028106/ (Full article)

 

Kindling and Oxidative Stress as Contributors to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS) is one of the more complex illnesses involving multiple systems within the body. Onset of ME/CFS frequently occurs quickly, and many patients report a prior exposure to a viral infection. This debilitating illness can affect the immune, neuroendocrine, autonomic, and neurologic systems.

Abnormal biological findings among some patients have included aberrant ion transport and ion channel activity, cortisol deficiency, sympathetic nervous system hyperactivity, EEG spike waves, left ventricular dysfunction in the heart, low natural killer cell cytotoxicity, and a shift from Th1 to Th2 cytokines. We propose that the kindling and oxidative stress theories provide a heuristic template for better understanding the at times conflicting findings regarding the etiology and pathophysiology of this illness.

 

Source: Jason LA, Porter N, Herrington J, Sorenson M, Kubow S. Kindling and Oxidative Stress as Contributors to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. J Behav Neurosci Res. 2009 Jan 1;7(2):1-17. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3022475/ (Full article)

 

CFS: A Review of Epidemiology and Natural History Studies

Abstract:

Almost all studies with samples of patients who have chronic fatigue syndrome (CFS) have relied on referrals from physicians or health facilities. Under-served minorities, who not only tend to manifest higher levels of chronic illness, but are also less likely to seek and receive adequate medical care, have not been represented in these studies (1). This may have contributed to an under-estimation of CFS among minority groups (2). Few studies have derived their samples from socioeconomically and ethnically diverse community-based populations. A technical report issued by the Agency for Healthcare Research and Quality (3) concluded that estimating rates of recovery/improvement or relapse from CFS are not possible because there are so few natural history studies and those that are available have involved selected referral populations.

This paper provides a review of epidemiologic studies of CFS followed by a discussion of diagnostic issues and risk factors for the illness. Findings from Jason et al.’s (4) epidemiologic study in a multi-ethnic, economically diverse urban area are highlighted as this research group is now examining the natural course of CFS over the past 10 years with this community-based sample. The current study will add to current epidemiologic and risk factors research by assessing the course, progression, and risk factors of CFS among a demographically diverse sample of participants who are unbiased by illness, help-seeking behaviors, or differential access to the health care system.

Source: Jason LA, Porter N, Brown M, Anderson V, Brown A, Hunnell J, Lerch A. CFS: A Review of Epidemiology and Natural History Studies. Bull IACFS ME. 2009;17(3):88-106. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3021257/ (Full article)

 

A controlled study of the effect of a mindfulness-based stress reduction technique in women with multiple chemical sensitivity, chronic fatigue syndrome, and fibromyalgia

Abstract:

BACKGROUND: The objective of this study was to examine the effect of a mindfulness-based stress reduction (MBSR) program on women diagnosed with conditions such as multiple chemical sensitivity (MCS), chronic fatigue syndrome (CFS), and fibromyalgia (FM).

METHODS: The intervention group underwent a 10-week MBSR program. Symptoms Checklist Inventory (SCL-90R) was used as outcome measure and was administered before the start of the program (pre-), immediately upon completion (post-) and at three-month follow-up. Women on the wait list to receive treatment at the Nova Scotia Environmental Health Centre were used as control subjects for the study.

RESULTS: A total of 50 participants in the intervention group and 26 in the wait-list controls group were recruited for this study. Global scores in the intervention group reached statistical significance pre-post (<0.0001) and at pre-follow-up (<0.0001) while the global scores in the control group remained the same. Five of nine and eight of nine subscales of the SCL-90R showed improvement of statistical significance in MBSR group following treatment and at three-month follow-up.

CONCLUSIONS: The study showed the importance of complementary interventions such as MBSR techniques in the reduction of psychological distress in women with chronic conditions.

 

Source: Sampalli T, Berlasso E, Fox R, Petter M. A controlled study of the effect of a mindfulness-based stress reduction technique in women with multiple chemical sensitivity, chronic fatigue syndrome, and fibromyalgia. J Multidiscip Healthc. 2009 Apr 7;2:53-9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3004557/(Full article)

 

Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: effects of age, duration of illness and the translocation of LPS from gram-negative bacteria

Abstract:

BACKGROUND: There is now evidence that an increased translocation of LPS from gram negative bacteria with subsequent gut-derived inflammation, i.e. induction of systemic inflammation and oxidative & nitrosative stress (IO&NS), is a new pathway in chronic fatigue syndrome(CFS).

METHODS: The present study examines the serum concentrations of IgA and IgM to LPS of gram-negative enterobacteria, i.e. Hafnia Alvei; Pseudomonas Aeruginosa, Morganella Morganii, Pseudomonas Putida, Citrobacter Koseri, and Klebsielle Pneumoniae in CFS patients both before and after intake of natural anti-inflammatory and anti-oxidative substances (NAIOSs), such as glutamine, N-acetyl cysteine and zinc, in conjunction with a leaky gut diet during 10-14 months. We measured the above immune variables as well as the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale in 41 patients with CFS before and 10-14 months after intake of NAIOSs.

RESULTS: Subchronic intake of those NAIOSs significantly attenuates the initially increased IgA and IgM responses to LPS of gram negative bacteria. Up to 24 patients showed a significant clinical improvement or remission 10-14 months after intake of NAIOSs. A good clinical response is significantly predicted by attenuated IgA and IgM responses to LPS, the younger age of the patients, and a shorter duration of illness (< 5 years).

DISCUSSION: The results show that normalization of the IgA and IgM responses to translocated LPS may predict clinical outcome in CFS. The results support the view that a weakened tight junction barrier with subsequent gut-derived inflammation is a novel pathway in CFS and that it is a new target for drug development in CFS. Meanwhile, CFS patients with leaky gut can be treated with specific NAIOSs and a leaky gut diet.

 

Source: Maes M, Leunis JC. Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: effects of age, duration of illness and the translocation of LPS from gram-negative bacteria. Neuro Endocrinol Lett. 2008 Dec;29(6):902-10. https://www.ncbi.nlm.nih.gov/pubmed/19112401

 

Association of peripheral inflammatory markers with chronic fatigue in a population-based sample

Abstract:

Alterations in the innate immune response may contribute to the pathogenesis of chronic fatigue syndrome (CFS). However, studies have been limited by small sample sizes, use of patients from tertiary care settings, inappropriate selection of controls, and failure to control for confounding demographic, medical and behavioral factors independently associated with immune activity. It is also not known whether specific symptoms account for observed associations between CFS and the innate immune response.

To address these limitations, the current study examined plasma concentrations of high-sensitivity c-reactive protein (hs-CRP), white blood cell count (WBC) and a combined inflammation factor in a large population-based sample. Log-transformed mean plasma concentrations of hs-CRP were increased in subjects with CFS (n=102) and in subjects with unwellness symptoms that did not meet diagnostic criteria for CFS (defined as “insufficient fatigue” [ISF]) (n=240) when compared to subjects who were well (n=115). Log transformed WBC was increased in ISF and was increased at a trend level in CFS. The combined inflammation factor was increased in both CFS and ISF. Subjects with CFS and ISF did not differ on any of the inflammation measures.

In the entire subject population, the physical component summary score (PCS), but not the mental component summary score (MCS), from the Medical Outcomes Study Short Form-36 (SF-36) was negatively associated with each of the inflammation measures. Depressive symptoms were also associated with increased log hs-CRP. After adjustment for age, sex, race, location of residence, BMI, depressive status and immune-modulating medications, subjects classified as ISF continued to demonstrate increased log hs-CRP, WBC and elevations on the inflammation factor when compared to well controls; however, associations between CFS and log hs-CRP and the inflammation factor were no longer statistically significant. After adjustment, PCS score also remained independently associated with each of the inflammation measures.

These findings support a role for innate immune activation in unexplained fatigue and unwellness, but do not suggest that immune activation is specific to CFS.

Comment in: Chronic fatigue syndrome and the immune system: “findings in search of meanings”. [Brain Behav Immun. 2009]

 

Source: Raison CL, Lin JM, Reeves WC. Association of peripheral inflammatory markers with chronic fatigue in a population-based sample. Brain Behav Immun. 2009 Mar;23(3):327-37. doi: 10.1016/j.bbi.2008.11.005. Epub 2008 Dec 11. https://www.ncbi.nlm.nih.gov/pubmed/19111923

 

Astragalus membranaceus flavonoids (AMF) ameliorate chronic fatigue syndrome induced by food intake restriction plus forced swimming

Abstract:

AIM OF THE STUDY: Alteration of immune function may be associated with chronic fatigue syndrome (CFS) and this study reveals the immunoregulatory effect of Astragalus membranaceus flavonoids (AMF).

MATERIALS AND METHODS: CF rats were induced by food intake restriction plus forced swimming for 6 weeks.

RESULTS: An atrophied spleen associated with a significantly decreased spleen/body weight ratio and a reduced spleen cells proliferation was found in CF rats when compared with home cage controls. AMF given orally at 20, 50 and 100 mg/kg body weight once a day consecutively for 6 weeks could recover the reduced cell proliferation. A switch to Th1-dominated immune regulation was observed in CF rats as the cultured splenocytes produced more interleukin-2 (IL-2) but less IL-4 when compared with controls. Supplementation with AMF could significantly counteract the aberrant cytokine production and rats received AMF exhibited higher endurance capacity to swim when compared with those without AMF administration. Checking the spectrum signals confirmed that the three major isoflavones contained in AMF were ononin, formononetin, and demethylhomopterocarpin.

CONCLUSION: Alterations of immune function may be associated with CFS and the tonic effects of AMF against CF may be attributable to balance the abnormal cytokine level by isoflavones.

 

Source: Kuo YH, Tsai WJ, Loke SH, Wu TS, Chiou WF. Astragalus membranaceus flavonoids (AMF) ameliorate chronic fatigue syndrome induced by food intake restriction plus forced swimming. J Ethnopharmacol. 2009 Feb 25;122(1):28-34. doi: 10.1016/j.jep.2008.11.025. Epub 2008 Dec 6. https://www.ncbi.nlm.nih.gov/pubmed/19103273