Klimas – Page 5 – American ME and CFS Society

Chronic fatigue syndrome patients need an effective therapeutic, leading expert argues

Ampligen, the first drug ever seeking approval to treat chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), recently hit another roadblock with the U.S. Food and Drug Administration (FDA). In its long quest to treat 1 million Americans suffering from this debilitating illness, the FDA advisory panel did not recommend the drug to be sold on the market, largely because CFS/ME doesn’t have clear biomarkers such as blood tests to define patients who most likely to respond to the drug. Data from clinical trials of Ampligen has not convinced the FDA so far.

Nancy Klimas, M.D., one of the world’s leading researchers and clinicians in chronic fatigue syndrome/myalgic encepahalomyelitis (CFS/ME), is the director the NSU Institute for Neuro Immune Medicine. “The real loser is not Ampligen, but CFS/ME patients whose daily suffering continues to be unabated,” she says. “CFS/ME feels like you’ve been run over by a truck — pain, inflammation, utter exhaustion and trouble concentrating.”

Klimas has been caring for patients with CFS/ME for 26 years now. “It’s heartbreaking seeing them struggle and suffer from this serious illness that has been trivialized by science and society. One of the early controversies quickly disproven suggested that CFS/ME is a form of depression. This led to enduring public policies that allowed insurance companies to limit coverage to CFS/ME to either mental health or exercise therapy, neither get to the root cause of CFS/ME,” she explains.

“CFS/ME researchers, including myself, have seen major advances in our understanding of the biology of CFS/ME. It seems to resemble an illness we know how to treat like multiple sclerosis (MS), chronic viral diseases and autoimmune diseases.”

Around since the late 1980s, this drug is not new to science and medicine. Two phase 3 clinical studies have been completed. The data shows that a subgroup of CFS/ME patients showed marked improvement, even recovery on the drug.

“Yet, that’s not enough evidence for the FDA advisory committee to approve because they would like to see a conclusive biomarker,” notes Klimas. “As a physician, I could live with this decision if I had other effective therapies to treat my CFS/ME patients. But I do not. Moreover, it defies common logic in used in drug approval for other complex immune mediated diseases.”

Take for example, MS: Its earliest approved treatments had opposite immune effects. One interferon increased immune activity and a second interferon quieted immune activity. In the studies that led to approval, MS drugs, like Ampligen, had about a 40 percent success rate.

Clinical research for these early MS drugs produced no biomarkers other than a patient’s successful response to therapy, such as the case of Ampligen. The biomarker the FDA relied on for approval of MS — seeing if the lesions in a patient’s brain decreased — had no correlation to the patient’s improvement.

Why would the FDA approve MS drugs before there were concrete biomarkers to determine success? The answer is simple, Klimas says. The advisory panel saw MS as a serious disease that required interventions ASAP, and were willing to accept that clinicians would better understand where to use the first drugs with more experience using them. Now there are seven approved drugs for MS that have significantly improved quality of life for patients. But they are not willing to use the same logic for Ampligen.

“With or without a biomarker, the FDA should recognize the seriousness of CFS/ME and approve Ampligen, and open the door for other targeted therapies now,” she says.

Source: Nova Southeastern University. “Chronic fatigue syndrome patients need an effective therapeutic, leading expert argues.” ScienceDaily. ScienceDaily, 24 January 2013. https://www.sciencedaily.com/releases/2013/01/130124183448.htm

Poor sleep quality is associated with greater circulating pro-inflammatory cytokines and severity and frequency of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) symptoms in women

Abstract:

OBJECTIVE: Poor sleep quality has been linked to inflammatory processes and worse disease outcomes in the context of many chronic illnesses, but less is known in conditions such as chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). This study examines the relationships between sleep quality, pro-inflammatory cytokines, and CFS/ME symptoms.

METHODS: Sixty women diagnosed with CFS/ME were assessed using the Pittsburgh Sleep Quality Index (PSQI), Fatigue Symptom Inventory (FSI) and Center for Disease Control and Prevention (CDC)-based CFS/ME symptom questionnaires. Circulating plasma pro-inflammatory cytokine levels were measured by ELISA. Multiple regression analyses examined associations between sleep, cytokines and symptoms, controlling for age, education, and body mass index.

RESULTS: Poor sleep quality (PSQI global score) was associated with greater pro-inflammatory cytokine levels: interleukin-1β (IL-1β) (β=0.258, p=0.043), IL-6 (β=0.281, p=0.033), and tumor necrosis factor-alpha (TNF-α) (β=0.263, p=0.044). Worse sleep quality related to greater fatigue severity (β=0.395, p=0.003) and fatigue-related interference with daily activities (β=0.464, p<0.001), and more severe and frequent CDC-defined core CFS/ME symptoms (β=0.499, p<0.001, and β=0.556, p<0.001, respectively).

CONCLUSIONS: Results underscore the importance of managing sleep-related difficulties in this patient population. Further research is needed to identify the etiology of sleep disruptions in CFS/ME and mechanistic factors linking sleep quality to symptom severity and inflammatory processes.

Source: Milrad SF, Hall DL, Jutagir DR, Lattie EG, Ironson GH, Wohlgemuth W, Nunez MV, Garcia L, Czaja SJ, Perdomo DM, Fletcher MA, Klimas N, Antoni MH. Poor sleep quality is associated with greater circulating pro-inflammatory cytokines and severity and frequency of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) symptoms in women. J Neuroimmunol. 2017 Feb 15;303:43-50. doi: 10.1016/j.jneuroim.2016.12.008. Epub 2016 Dec 14. https://www.ncbi.nlm.nih.gov/pubmed/28038892

Tracking post-infectious fatigue in clinic using routine Lab tests

Abstract:

BACKGROUND: While biomarkers for chronic fatigue syndrome (CFS) are beginning to emerge they typically require a highly specialized clinical laboratory. We hypothesized that subsets of commonly measured laboratory markers used in combination could support the diagnosis of post-infectious CFS (PI-CFS) in adolescents following infectious mononucleosis (IM) and help determine who might develop persistence of symptoms.

METHODS: Routine clinical laboratory markers were collected prospectively in 301 mono-spot positive adolescents, 4 % of whom developed CFS (n = 13). At 6, 12, and 24 months post-diagnosis with IM, 59 standard tests were performed including metabolic profiling, liver enzyme panel, hormone profiles, complete blood count (CBC), differential white blood count (WBC), salivary cortisol, and urinalysis. Classification models separating PI-CFS from controls were constructed at each time point using stepwise subset selection.

RESULTS: Lower ACTH levels at 6 months post-IM diagnosis were highly predictive of CFS (AUC p = 0.02). ACTH levels in CFS overlapped with healthy controls at 12 months, but again showed a trend towards a deficiency at 24 months. Conversely, estradiol levels depart significantly from normal at 12 months only to recover at 24 months (AUC p = 0.02). Finally, relative neutrophil count showed a significant departure from normal at 24 months in CFS (AUC p = 0.01). Expression of these markers evolved differently over time between groups.

CONCLUSIONS: Preliminary results suggest that serial assessment of stress and sex hormones as well as the relative proportion of innate immune cells measured using standard clinical laboratory tests may support the diagnosis of PI-CFS in adolescents with IM.

Source: Harvey JM, Broderick G, Bowie A, Barnes ZM, Katz BZ, O’Gorman MR, Vernon SD, Fletcher MA, Klimas NG, Taylor R. Tracking post-infectious fatigue in clinic using routine Lab tests. BMC Pediatr. 2016 Apr 26;16:54. doi: 10.1186/s12887-016-0596-8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4847210/ (Full article)

Illness progression in chronic fatigue syndrome: a shifting immune baseline

Abstract:

BACKGROUND: Validation of biomarkers for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) across data sets has proven disappointing. As immune signature may be affected by many factors, our objective was to explore the shift in discriminatory cytokines across ME/CFS subjects separated by duration of illness.

METHODS: Cytokine expression collected at rest across multiple studies for female ME/CFS subjects (i) 18 years or younger, ill for 2 years or less (n = 18), (ii) 18-50 years of age, ill for 7 years (n = 22), and (iii) age 50 years or older (n = 28), ill for 11 years on average. Control subjects were matched for age and body mass index (BMI). Data describing the levels of 16 cytokines using a chemiluminescent assay was used to support the identification of separate linear classification models for each subgroup. In order to isolate the effects of duration of illness alone, cytokines that changed significantly with age in the healthy control subjects were excluded a priori.

RESULTS: Optimal selection of cytokines in each group resulted in subsets of IL-1α, 6, 8, 15 and TNFα. Common to any 2 of 3 groups were IL-1α, 6 and 8. Setting these 3 markers as a triple screen and adjusting their contribution according to illness duration sub-groups produced ME/CFS classification accuracies of 75-88 %. The contribution of IL-1α, higher in recently ill adolescent ME/CFS subjects was progressively less important with duration. While high levels of IL-8 screened positive for ME/CFS in the recently afflicted, the opposite was true for subjects ill for more than 2 years. Similarly, while low levels of IL-6 suggested early ME/CFS, the reverse was true in subjects over 18 years of age ill for more than 2 years.

CONCLUSIONS: These preliminary results suggest that IL-1α, 6 and 8 adjusted for illness duration may serve as robust biomarkers, independent of age, in screening for ME/CFS.

Source: Russell L, Broderick G, Taylor R, Fernandes H, Harvey J, Barnes Z, Smylie A, Collado F, Balbin EG, Katz BZ, Klimas NG, Fletcher MA. Illness progression in chronic fatigue syndrome: a shifting immune baseline. BMC Immunol. 2016 Mar 10;17:3. doi: 10.1186/s12865-016-0142-3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785654/ (Full article)

Distinct plasma immune signatures in ME/CFS are present early in the course of illness

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an unexplained incapacitating illness that may affect up to 4 million people in the United States alone. There are no validated laboratory tests for diagnosis or management despite global efforts to find biomarkers of disease. We considered the possibility that inability to identify such biomarkers reflected variations in diagnostic criteria and laboratory methods as well as the timing of sample collection during the course of the illness.

Accordingly, we leveraged two large, multicenter cohort studies of ME/CFS to assess the relationship of immune signatures with diagnosis, illness duration, and other clinical variables. Controls were frequency-matched on key variables known to affect immune status, including season of sampling and geographic site, in addition to age and sex. We report here distinct alterations in plasma immune signatures early in the course of ME/CFS (n = 52) relative to healthy controls (n = 348) that are not present in subjects with longer duration of illness (n = 246).

Analyses based on disease duration revealed that early ME/CFS cases had a prominent activation of both pro- and anti-inflammatory cytokines as well as dissociation of intercytokine regulatory networks. We found a stronger correlation of cytokine alterations with illness duration than with measures of illness severity, suggesting that the immunopathology of ME/CFS is not static. These findings have critical implications for discovery of interventional strategies and early diagnosis of ME/CFS.

Source: Hornig M, Montoya JG, Klimas NG, Levine S, Felsenstein D, Bateman L, Peterson DL, Gottschalk CG, Schultz AF, Che X, Eddy ML, Komaroff AL, Lipkin WI. Distinct plasma immune signatures in ME/CFS are present early in the course of illness. Sci Adv. 2015 Feb;1(1). pii: e1400121. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465185/ (Full article)

A role for homeostatic drive in the perpetuation of complex chronic illness: Gulf War Illness and chronic fatigue syndrome

Erratum in

PLoS One. 2014;9(4):e94161.
PLoS One. 2014;9(6):e100355.

Abstract:

A key component in the body’s stress response, the hypothalamic-pituitary-adrenal (HPA) axis orchestrates changes across a broad range of major biological systems. Its dysfunction has been associated with numerous chronic diseases including Gulf War Illness (GWI) and chronic fatigue syndrome (CFS). Though tightly coupled with other components of endocrine and immune function, few models of HPA function account for these interactions.

Here we extend conventional models of HPA function by including feed-forward and feedback interaction with sex hormone regulation and immune response. We use this multi-axis model to explore the role of homeostatic regulation in perpetuating chronic conditions, specifically GWI and CFS. An important obstacle in building these models across regulatory systems remains the scarcity of detailed human in vivo kinetic data as its collection can present significant health risks to subjects. We circumvented this using a discrete logic representation based solely on literature of physiological and biochemical connectivity to provide a qualitative description of system behavior. This connectivity model linked molecular variables across the HPA axis, hypothalamic-pituitary-gonadal (HPG) axis in men and women, as well as a simple immune network. Inclusion of these interactions produced multiple alternate homeostatic states and sexually dimorphic responses.

Experimental data for endocrine-immune markers measured in male GWI subjects showed the greatest alignment with predictions of a naturally occurring alternate steady state presenting with hypercortisolism, low testosterone and a shift towards a Th1 immune response. In female CFS subjects, expression of these markers aligned with an alternate homeostatic state displaying hypocortisolism, high estradiol, and a shift towards an anti-inflammatory Th2 activation. These results support a role for homeostatic drive in perpetuating dysfunctional cortisol levels through persistent interaction with the immune system and HPG axis. Though coarse, these models may nonetheless support the design of robust treatments that might exploit these regulatory regimes.

Source: Craddock TJ, Fritsch P, Rice MA Jr, del Rosario RM, Miller DB, Fletcher MA, Klimas NG, Broderick G. A role for homeostatic drive in the perpetuation of complex chronic illness: Gulf War Illness and chronic fatigue syndrome. PLoS One. 2014 Jan 8;9(1):e84839. doi: 10.1371/journal.pone.0084839. ECollection 2014. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3885655/ (Full article)

Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Symptom Severity: Stress Management Skills are Related to Lower Illness Burden

Abstract:

BACKGROUND: The onset of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) typically involves reductions in activities of daily living and social interactions (jointly referred to as “illness burden”). Emotional distress has been linked to increased reported symptoms, and stress management skills have been related to lower fatigue severity in CFS patients. Symptom severity and illness burden are highly correlated. The ability to manage stress may attenuate this relationship, allowing individuals to feel less burdened by the illness independent of the severity of their symptoms.

PURPOSE: This study aimed to evaluate if perceived stress management skills affect illness burden via emotional distress, independent of ME/CFS symptom severity.

METHODS: A total of 117 adults with ME/CFS completed measures of perceived stress management skills, emotional distress, ME/CFS symptom severity and illness burden.

RESULTS: Regression analyses revealed that greater perceived stress management skills related to less social and fatigue-related illness burden, via lower emotional distress. This relationship existed independent of the association of symptom severity on illness burden, and was stronger among those not currently employed.

CONCLUSIONS: Ability to manage stress is associated with a lower illness burden for individuals with ME/CFS. Future studies should evaluate the efficacy of psychosocial interventions in lowering illness burden by targeting stress management skills.

Source: Lattie EG, Antoni MH, Fletcher MA, Czaja S, Perdomo D, Sala A, Nair S, Fu SH, Penedo FJ, Klimas N. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Symptom Severity: Stress Management Skills are Related to Lower Illness Burden. Fatigue. 2013;1(4). doi: 10.1080/21641846.2013.843255. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837381/ (Full article)

A comparison of sex-specific immune signatures in Gulf War illness and chronic fatigue syndrome

Abstract:

BACKGROUND: Though potentially linked to the basic physiology of stress response we still have no clear understanding of Gulf War Illness (GWI), a debilitating condition presenting complex immune, endocrine and neurological symptoms. Here we compared male (n = 20) and female (n = 10) veterans with GWI separately against their healthy counterparts (n = 21 male, n = 9 female) as well as subjects with chronic fatigue syndrome/ myalgic encephalomyelitis (CFS/ME) (n = 12 male, n = 10 female).

METHODS: Subjects were assessed using a Graded eXercise Test (GXT) with blood drawn prior to exercise, at peak effort (VO2 max) and 4-hours post exercise. Using chemiluminescent imaging we measured the concentrations of IL-1a, 1b, 2, 4, 5, 6, 8, 10, 12 (p70), 13, 15, 17 and 23, IFNγ, TNFα and TNFβ in plasma samples from each phase of exercise. Linear classification models were constructed using stepwise variable selection to identify cytokine co-expression patterns characteristic of each subject group.

RESULTS: Classification accuracies in excess of 80% were obtained using between 2 and 5 cytokine markers. Common to both GWI and CFS, IL-10 and IL-23 expression contributed in an illness and time-dependent manner, accompanied in male subjects by NK and Th1 markers IL-12, IL-15, IL-2 and IFNγ. In female GWI and CFS subjects IL-10 was again identified as a delineator but this time in the context of IL-17 and Th2 markers IL-4 and IL-5. Exercise response also differed between sexes: male GWI subjects presented characteristic cytokine signatures at rest but not at peak effort whereas the opposite was true for female subjects.

CONCLUSIONS: Though individual markers varied, results collectively supported involvement of the IL-23/Th17/IL-17 axis in the delineation of GWI and CFS in a sex-specific way.

Source: Smylie AL, Broderick G, Fernandes H, Razdan S, Barnes Z, Collado F, Sol C, Fletcher MA, Klimas N. A comparison of sex-specific immune signatures in Gulf War illness and chronic fatigue syndrome. BMC Immunol. 2013 Jun 25;14:29. doi: 10.1186/1471-2172-14-29. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3698072/ (Full article)

Altered immune pathway activity under exercise challenge in Gulf War Illness: an exploratory analysis

Abstract:

Though potentially linked to the basic physiology of stress response we still have no clear understanding of Gulf War Illness (GWI), a debilitating illness presenting with a complex constellation of immune, endocrine and neurological symptoms. Here we compared male GWI (n=20) with healthy veterans (n=22) and subjects with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) (n=7). Blood was drawn during a Graded eXercise Test (GXT) prior to exercise, at peak effort (VO2 max) and 4-h post exercise. Affymetrix HG U133 plus 2.0 microarray gene expression profiling in peripheral blood mononuclear cells (PBMCs) was used to estimate activation of over 500 documented pathways. This was cast against ELISA-based measurement of 16 cytokines in plasma and flow cytometric assessment of lymphocyte populations and cytotoxicity. A 2-way ANOVA corrected for multiple comparisons (q statistic <0.05) indicated significant increases in neuroendocrine-immune signaling and inflammatory activity in GWI, with decreased apoptotic signaling. Conversely, cell cycle progression and immune signaling were broadly subdued in CFS. Partial correlation networks linking pathways with symptom severity via changes in immune cell abundance, function and signaling were constructed.

Central to these were changes in IL-10 and CD2+ cell abundance and their link to two pathway clusters. The first consisted of pathways supporting neuronal development and migration whereas the second was related to androgen-mediated activation of NF-κB. These exploratory results suggest an over-expression of known exercise response mechanisms as well as illness-specific changes that may involve an overlapping stress-potentiated neuro-inflammatory response.

Source: Broderick G, Ben-Hamo R, Vashishtha S, Efroni S, Nathanson L, Barnes Z, Fletcher MA, Klimas N. Altered immune pathway activity under exercise challenge in Gulf War Illness: an exploratory analysis. Brain Behav Immun. 2013 Feb;28:159-69. doi: 10.1016/j.bbi.2012.11.007. Epub 2012 Nov 29. https://www.ncbi.nlm.nih.gov/pubmed/23201588

A multicenter blinded analysis indicates no association between chronic fatigue syndrome/myalgic encephalomyelitis and either xenotropic murine leukemia virus-related virus or polytropic murine leukemia virus

Abstract:

The disabling disorder known as chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) has been linked in two independent studies to infection with xenotropic murine leukemia virus-related virus (XMRV) and polytropic murine leukemia virus (pMLV). Although the associations were not confirmed in subsequent studies by other investigators, patients continue to question the consensus of the scientific community in rejecting the validity of the association. Here we report blinded analysis of peripheral blood from a rigorously characterized, geographically diverse population of 147 patients with CFS/ME and 146 healthy subjects by the investigators describing the original association. This analysis reveals no evidence of either XMRV or pMLV infection. I

MPORTANCE Chronic fatigue syndrome/myalgic encephalomyelitis has an estimated prevalence of 42/10,000 in the United States, with annual direct medical costs of $7 billion. Here, the original investigators who found XMRV and pMLV (polytropic murine leukemia virus) in blood of subjects with this disorder report that this association is not confirmed in a blinded analysis of samples from rigorously characterized subjects. The increasing frequency with which molecular methods are used for pathogen discovery poses new challenges to public health and support of science. It is imperative that strategies be developed to rapidly and coherently address discoveries so that they can be carried forward for translation to clinical medicine or abandoned to focus resource investment more productively. Our study provides a paradigm for pathogen discovery that may be helpful to others working in this field.

Source: Alter HJ, Mikovits JA, Switzer WM, Ruscetti FW, Lo SC, Klimas N, Komaroff AL, Montoya JG, Bateman L, Levine S, Peterson D, Levin B, Hanson MR, Genfi A, Bhat M, Zheng H, Wang R, Li B, Hung GC, Lee LL, Sameroff S, Heneine W, Coffin J, Hornig M, Lipkin WI. A multicenter blinded analysis indicates no association between chronic fatigue syndrome/myalgic encephalomyelitis and either xenotropic murine leukemia virus-related virus or polytropic murine leukemia virus. MBio. 2012 Sep 18;3(5). pii: e00266-12. doi: 10.1128/mBio.00266-12. Print 2012. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448165/ (Full article)