Staines – Page 5 – American ME and CFS Society

A Systematic Review of Drug Therapies for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Abstract:

PURPOSE: The pathogenesis of chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) is complex and remains poorly understood. Evidence regarding the use of drug therapies in CFS/ME is currently limited and conflicting. The aim of this systematic review was to examine the existing evidence on the efficacy of drug therapies and determine whether any can be recommended for patients with CFS/ME.

METHODS: MEDLINE, EMBASE, and PubMed databases were searched from the start of their records to March 2016 to identify relevant studies. Randomized controlled trials focusing solely on drug therapy to alleviate and/or eliminate chronic fatigue symptoms were included in the review. Any trials that considered graded exercise therapy, cognitive behavior therapy, adaptive pacing, or any other nonpharmaceutical treatment plans were excluded. The inclusion criteria were examined to ensure that study participants met specific CFS/ME diagnostic criteria. Study size, intervention, and end point outcome domains were summarized.

FINDINGS: A total of 1039 studies were identified with the search terms; 26 studies met all the criteria and were considered suitable for review. Three different diagnostic criteria were identified: the Holmes criteria, International Consensus Criteria, and the Fukuda criteria. Primary outcomes were identified as fatigue, pain, mood, neurocognitive dysfunction and sleep quality, symptom severity, functional status, and well-being or overall health status. Twenty pharmaceutical classes were trialed. Ten medications were shown to be slightly to moderately effective in their respective study groups (P < 0.05).

IMPLICATIONS: These findings indicate that no universal pharmaceutical treatment can be recommended. The unknown etiology of CFS/ME, and complications arising from its heterogeneous nature, contributes to the lack of clear evidence for pharmaceutical interventions. However, patients report using a large number and variety of medications. This finding highlights the need for trials with clearly defined CFS/ME cohorts. Trials based on more specific criteria such as the International Consensus Criteria are recommended to identify specific subgroups of patients in whom treatments may be beneficial.

Source: Collatz A, Johnston SC, Staines DR, Marshall-Gradisnik SM. A Systematic Review of Drug Therapies for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. Clin Ther. 2016 Jun;38(6):1263-1271.e9. doi: 10.1016/j.clinthera.2016.04.038. Epub 2016 May 24. https://www.ncbi.nlm.nih.gov/pubmed/27229907

Progressive brain changes in patients with chronic fatigue syndrome: A longitudinal MRI study

Abstract:

PURPOSE: To examine progressive brain changes associated with chronic fatigue syndrome (CFS).

MATERIALS AND METHODS: We investigated progressive brain changes with longitudinal MRI in 15 CFS and 10 normal controls (NCs) scanned twice 6 years apart on the same 1.5 Tesla (T) scanner. MR images yielded gray matter (GM) volumes, white matter (WM) volumes, and T1- and T2-weighted signal intensities (T1w and T2w). Each participant was characterized with Bell disability scores, and somatic and neurological symptom scores. We tested for differences in longitudinal changes between CFS and NC groups, inter group differences between pooled CFS and pooled NC populations, and correlations between MRI and symptom scores using voxel based morphometry. The analysis methodologies were first optimized using simulated atrophy.

RESULTS: We found a significant decrease in WM volumes in the left inferior fronto-occipital fasciculus (IFOF) in CFS while in NCs it was unchanged (family wise error adjusted cluster level P value, PFWE < 0.05). This longitudinal finding was consolidated by the group comparisons which detected significantly decreased regional WM volumes in adjacent regions (PFWE< 0.05) and decreased GM and blood volumes in contralateral regions (PFWE < 0.05). Moreover, the regional GM and WM volumes and T2w in those areas showed significant correlations with CFS symptom scores (PFWE < 0.05).

CONCLUSION: The results suggested that CFS is associated with IFOF WM deficits which continue to deteriorate at an abnormal rate. J. Magn. Reson. Imaging 2016;44:1301-1311.

Source: Shan ZY, Kwiatek R, Burnet R, Del Fante P, Staines DR, Marshall-Gradisnik SM, Barnden LR. Progressive brain changes in patients with chronic fatigue syndrome: A longitudinal MRI study. J Magn Reson Imaging. 2016 Nov;44(5):1301-1311. doi: 10.1002/jmri.25283. Epub 2016 Apr 28. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5111735/ (Full article)

Natural killer cells and single nucleotide polymorphisms of specific ion channels and receptor genes in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

AIM: The aim of this paper was to determine natural killer (NK) cytotoxic activity and if single nucleotide polymorphisms (SNPs) and genotypes in transient receptor potential (TRP) ion channels and acetylcholine receptors (AChRs) were present in isolated NK cells from previously identified myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) patients.

SUBJECTS AND METHODS: A total of 39 ME/CFS patients (51.69±2 years old) and 30 unfatigued controls (47.60±2.39 years old) were included in this study. Patients were defined according to the 1994 Centers for Disease Control and Prevention criteria. Flow cytometry protocols were used to examine NK cytotoxic activity. A total of 678 SNPs from isolated NK cells were examined for 21 mammalian TRP ion channel genes and for nine mammalian AChR genes via the Agena Bioscience iPlex Gold assay. SNP association and genotype was determined using analysis of variance and Plink software.

RESULTS: ME/CFS patients had a significant reduction in NK percentage lysis of target cells (17%±4.68%) compared with the unfatigued control group (31%±6.78%). Of the 678 SNPs examined, eleven SNPs for TRP ion channel genes (TRPC4, TRPC2, TRPM3, and TRPM8) were identified in the ME/CFS group. Five of these SNPs were associated with TRPM3, while the remainder were associated with TRPM8, TRPC2, and TRPC4 (P<0.05). Fourteen SNPs were associated with nicotinic and muscarinic AChR genes: six with CHRNA3, while the remainder were associated with CHRNA2, CHRNB4, CHRNA5, and CHRNE (P<0.05). There were sixteen genotypes identified from SNPs in TRP ion channels and AChRs for TRPM3 (n=5), TRPM8 (n=2), TRPC4 (n=3), TRPC2 (n=1), CHRNE (n=1), CHRNA2 (n=2), CHRNA3 (n=1), and CHRNB4 (n=1) (P<0.05).

CONCLUSION: We identified a number of SNPs and genotypes for TRP ion channels and AChRs from isolated NK cells in patients with ME/CFS, suggesting these SNPs and genotypes may be involved in changes in NK cell function and the development of ME/CFS pathology. These anomalies suggest a role for dysregulation of Ca(2+) in AChR and TRP ion channel signaling in the pathomechanism of ME/CFS.

Source: Marshall-Gradisnik S, Huth T, Chacko A, Johnston S, Smith P, Staines D. Natural killer cells and single nucleotide polymorphisms of specific ion channels and receptor genes in myalgic encephalomyelitis/chronic fatigue syndrome. Appl Clin Genet. 2016 Mar 31;9:39-47. doi: 10.2147/TACG.S99405. ECollection 2016. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4821384/ (Full article)

ERK1/2, MEK1/2 and p38 downstream signalling molecules impaired in CD56 dim CD16+ and CD56 bright CD16 dim/- natural killer cells in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients

Abstract:

BACKGROUND: Natural Killer (NK) cell effector functions are dependent on phosphorylation of the mitogen-activated protein kinases (MAPK) pathway to produce an effective immune response for the clearance of target cells infected with viruses, bacteria or malignantly transformed cells. Intracellular signals activating NK cell cytokine production and cytotoxic activity are propagated through protein phosphorylation of MAPKs including MEK1/2, ERK1/2, p38 and JNK. Reduced NK cell cytotoxic activity is consistently reported in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) patients and intracellular signalling by MAPK in NK cells remains to be investigated. Therefore, the purpose of this paper was to investigate MAPK downstream signalling molecules in NK cell phenotypes from CFS/ME patients.

METHODS: Flow cytometric protocols were used to measure phosphorylation of the MAPK pathway in CD56(bright)CD16(dim/-) and CD56(dim)CD16(+) NK cells following stimulation with K562 tumour cells or phorbol-12-myristate-13-acetate plus ionomycin. NK cell cytotoxic activity, degranulation, lytic proteins and cytokine production were also measured as markers for CD56(bright)CD16(dim/-) and CD56(dim)CD16(+) NK cell function using flow cytometric protocols.

RESULTS: CFS/ME patients (n = 14) had a significant decrease in ERK1/2 in CD56(dim)CD16(+) NK cells compared to the non-fatigued controls (n = 11) after incubation with K562 cells. CD56(bright)CD16(dim/-) NK cells from CFS/ME patients had a significant increase in MEK1/2 and p38 following incubation with K562 cells.

CONCLUSIONS: This is the first study to report significant differences in MAPK intracellular signalling molecules in CD56(dim)CD16(+) and CD56(bright)CD16(dim/-) NK cells from CFS/ME patients. The current results highlight the importance of intracellular signalling through the MAPK pathway for synergistic effector function of CD56(dim)CD16(+) and CD56(bright)CD16(dim/-) NK cells to ensure efficient clearance of target cells. In CFS/ME patients, dysfunctional MAPK signalling may contribute to reduced NK cell cytotoxic activity.

Source: Huth TK, Staines D, Marshall-Gradisnik S. ERK1/2, MEK1/2 and p38 downstream signalling molecules impaired in CD56 dim CD16+ and CD56 bright CD16 dim/- natural killer cells in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients. J Transl Med. 2016 Apr 21;14:97. doi: 10.1186/s12967-016-0859-z. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839077/ (Full article)

Regulatory T, natural killer T and γδ T cells in multiple sclerosis and chronic fatigue syndrome/myalgic encephalomyelitis: a comparison

Abstract:

BACKGROUND: Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME), and Multiple Sclerosis (MS) may share some similarities in relation to reduced NK cell activity. It is likely that other cells such as regulatory T (Tregs), invariant Natural Killer T (iNKT) and gamma delta T (γδ T) cells may also be dysregulated in CFS/ME and MS.

OBJECTIVE: To evaluate and compare specific immune regulatory cells of patients with CFS/ME, patients with MS and healthy controls.

METHOD: Sixty three volunteers were included in this study: 24 were CFS/ME patients, 11 were MS patients and 27 were healthy controls. Blood samples were obtained from all participants for flow cytometry analysis of iNKT cells, Tregs and γδ T cell phenotypes.

RESULTS: We observed a significant increase in Tregs in the CFS/ME group (p≤0.05) compared to the healthy control group. Total γδ and γδ2 T cells were significantly reduced in MS patients in comparison with the healthy control group. Conversely, CD4+iNKT percentage of iNKT, was significantly increased in the CFS/ME group compared with healthy controls and the double-negative iNKT percentage of iNKT significantly decreased compared with the healthy control group.

CONCLUSIONS: This study has not identified any immunological disturbances that are common in both MS and CFS/ME patients. However, the differential expression of cell types between the conditions investigated suggests different pathways of disease. These differences need to be explored in further studies.

Source: Ramos S, Brenu E, Broadley S, Kwiatek R, Ng J, Nguyen T, Freeman S, Staines D, Marshall-Gradisnik S. Regulatory T, natural killer T and γδ T cells in multiple sclerosis and chronic fatigue syndrome/myalgic encephalomyelitis: a comparison. Asian Pac J Allergy Immunol. 2016 Dec;34(4):300-305. doi: 10.12932/AP0733. http://apjai-journal.org/wp-content/uploads/2016/12/8RegulatoryTnaturalkillerAPJAIVol34No4December2016P300.pdf (Full text as PDF)

A Preliminary Comparative Assessment of the Role of CD8+ T Cells in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Multiple Sclerosis

Abstract:

Background. CD8+ T cells have putative roles in the regulation of adaptive immune responses during infection. The purpose of this paper is to compare the status of CD8+ T cells in Multiple Sclerosis (MS) and Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME).

Methods. This preliminary investigation comprised 23 CFS/ME patients, 11 untreated MS patients, and 30 nonfatigued controls. Whole blood samples were collected from participants, stained with monoclonal antibodies, and analysed on the flow cytometer. Using the following CD markers, CD27 and CD45RA (CD45 exon isoform 4), CD8+ T cells were divided into naïve, central memory (CM), effector memory CD45RA- (EM), and effector memory CD45RA+ (EMRA) cells.

Results. Surface expressions of BTLA, CD127, and CD49/CD29 were increased on subsets of CD8+ T cells from MS patients. In the CFS/ME patients CD127 was significantly decreased on all subsets of CD8+ T cells in comparison to the nonfatigued controls. PSGL-1 was significantly reduced in the CFS/ME patients in comparison to the nonfatigued controls.

Conclusions. The results suggest significant deficits in the expression of receptors and adhesion molecules on subsets of CD8+ T cells in both MS and CFS/ME patients. These deficits reported may contribute to the pathogenesis of these diseases. However, larger sample size is warranted to confirm and support these encouraging preliminary findings.

Source: Brenu EW, Broadley S, Nguyen T, Johnston S, Ramos S, Staines D, Marshall-Gradisnik S. A Preliminary Comparative Assessment of the Role of CD8+ T Cells in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Multiple Sclerosis. J Immunol Res. 2016;2016:9064529. doi: 10.1155/2016/9064529. Epub 2016 Jan 4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4736227/ (Full article)

Serum Immune Proteins in Moderate and Severe Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients

Abstract:

Immunological dysregulation is present in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME), with recent studies also highlighting the importance of examining symptom severity. This research addressed this relationship between CFS/ME severity subgroups, assessing serum immunoglobulins and serum cytokines in severe and moderate CFS/ME patients.

Participants included healthy controls (n= 22), moderately (n = 22) and severely (n=19) affected CFS/ME patients. The 1994 Fukuda Criteria defined CFS/ME and severity scales confirmed mobile and housebound CFS/ME patients as moderate and severe respectively.

IL-1β was significantly reduced in severe compared with moderate CFS/ME patients. IL-6 was significantly decreased in moderate CFS/ME patients compared with healthy controls and severe CFS/ME patients. RANTES was significantly increased in moderate CFS/ME patients compared to severe CFS/ME patients. Serum IL-7 and IL-8 were significantly higher in the severe CFS/ME group compared with healthy controls and moderate CFS/ME patients. IFN-γ was significantly increased in severe CFS/ME patients compared with moderately affected patients.

This was the first study to show cytokine variation in moderate and severe CFS/ME patients, with significant differences shown between CFS/ME symptom severity groups. This research suggests that distinguishing severity subgroups in CFS/ME research settings may allow for a more stringent analysis of the heterogeneous and otherwise inconsistent illness.

Source: Hardcastle SL, Brenu EW, Johnston S, Nguyen T, Huth T, Ramos S, Staines D, Marshall-Gradisnik S. Serum Immune Proteins in Moderate and Severe Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients. Int J Med Sci. 2015 Sep 5;12(10):764-72. doi: 10.7150/ijms.12399. ECollection 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4615236/ (Full article)

Pilot Study of Natural Killer Cells in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Multiple Sclerosis

Abstract:

Patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) and multiple sclerosis (MS) suffer from debilitating fatigue which is not alleviated by rest. In addition to the fatigue-related symptoms suffered by patients with CFS/ME and MS, dysfunction of the immune system and, in particular, reduced natural killer (NK) cell cytotoxic activity has also been reported in CFS/ME and MS. The purpose of this pilot study was to compare NK cellular mechanisms in patients with CFS/ME and MS to investigate potential dysfunctions in the NK cell activity pathway. Flow cytometry protocols assessed CD56(dim) CD16(+) and CD56(bright) CD16(+/-) NK cell expression of adhesion molecules, NK activating and inhibiting receptors, NK cell maturation and lytic proteins.

All participants in this study were female and included 14 patients with CFS/ME, nine patients with MS and 19 non-fatigued controls. The patient groups and the non-fatigued controls were not taking any immunosuppressive or immune-enhancing medications. In the MS cohort, KIR2DL5 was significantly increased on CD56(bright) CD16(+/-) NK cells and expression of CD94 was significantly increased on CD56(dim) CD16(+) NK cells in comparison with the controls. Co-expression of CD57 and perforin was significantly increased on CD56(dim) CD16(+) NK cells from patients with CFS/ME compared to the MS and non-fatigued control participants.

The results from this pilot study suggest that NK cells from patients with CFS/ME and MS may have undergone increased differentiation in response to external stimuli which may affect different mechanisms in the NK cell cytotoxic activity pathway.

Source: Huth TK, Brenu EW, Ramos S, Nguyen T, Broadley S, Staines D, Marshall-Gradisnik S. Pilot Study of Natural Killer Cells in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Multiple Sclerosis. Scand J Immunol. 2016 Jan;83(1):44-51. doi: 10.1111/sji.12388. http://onlinelibrary.wiley.com/wol1/doi/10.1111/sji.12388/full (Full article)

Longitudinal analysis of immune abnormalities in varying severities of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients

Abstract:

BACKGROUND: Research has identified immunological abnormalities in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME), a heterogeneous illness with an unknown cause and absence of diagnostic test. There have been no CFS/ME studies examining innate and adaptive immune cells longitudinally in patients with varying severities. This is the first study to investigate immune cells over 6 months while also examining CFS/ME patients of varying symptom severity.

METHODS: Participants were grouped into 18 healthy controls, 12 moderate and 12 severe CFS/ME patients and flow cytometry was used to examine cell parameters at 0 and 6 months.

RESULTS: Over time, iNKT CD62L expression significantly increased in moderate CFS/ME patients and CD56(bright) NK receptors differed in severe CFS/ME. Naïve CD8(+)T cells, CD8(-)CD4(-) and CD56(-)CD16(-) iNKT phenotypes, γδ2T cells and effector memory subsets were significantly increased in severe CFS/ME patients at 6 months. Severe CFS/ME patients were significantly reduced in CD56(bright)CD16(dim) NKG2D, CD56(dim)CD16(-) KIR2DL2/DL3, CD94(-)CD11a(-) γδ1T cells and CD62L(+)CD11a(-) γδ1T cells at 6 months.

CONCLUSIONS: Severe CFS/ME patients differed from controls and moderate CFS/ME patients over time and expressed significant alterations in iNKT cell phenotypes, CD8(+)T cell markers, NK cell receptors and γδT cells at 6 months. This highlights the importance of further assessing these potential immune biomarkers longitudinally in both moderate and severe CFS/ME patients.

Source: Hardcastle SL, Brenu EW, Johnston S, Nguyen T, Huth T, Ramos S, Staines D, Marshall-Gradisnik S. Longitudinal analysis of immune abnormalities in varying severities of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients. J Transl Med. 2015 Sep 14;13:299. doi: 10.1186/s12967-015-0653-3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568602/ (Full article)

Characterisation of cell functions and receptors in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME)

Abstract:

BACKGROUND: Abnormal immune function is often an underlying component of illness pathophysiology and symptom presentation. Functional and phenotypic immune-related alterations may play a role in the obscure pathomechanism of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). The objective of this study was to investigate the functional ability of innate and adaptive immune cells in moderate and severe CFS/ME patients. The 1994 Fukuda criteria for CFS/ME were used to define CFS/ME patients. CFS/ME participants were grouped based on illness severity with 15 moderately affected (moderate) and 12 severely affected (severe) CFS/ME patients who were age and sex matched with 18 healthy controls. Flow cytometric protocols were used for immunological analysis of dendritic cells, monocytes and neutrophil function as well as measures of lytic proteins and T, natural killer (NK) and B cell receptors.

RESULTS: CFS/ME patients exhibited alterations in NK receptors and adhesion markers and receptors on CD4(+)T and CD8(+)T cells. Moderate CFS/ME patients had increased CD8(+) CD45RA effector memory T cells, SLAM expression on NK cells, KIR2DL5(+) on CD4(+)T cells and BTLA4(+) on CD4(+)T central memory cells. Moderate CFS/ME patients also had reduced CD8(+)T central memory LFA-1, total CD8(+)T KLRG1, naïve CD4(+)T KLRG1 and CD56(dim)CD16(-) NK cell CD2(+) and CD18(+)CD2(+). Severe CFS/ME patients had increased CD18(+)CD11c(-) in the CD56(dim)CD16(-) NK cell phenotype and reduced NKp46 in CD56(bright)CD16(dim) NK cells.

CONCLUSIONS: This research accentuated the presence of immunological abnormalities in CFS/ME and highlighted the importance of assessing functional parameters of both innate and adaptive immune systems in the illness.

Source: Hardcastle SL, Brenu EW, Johnston S, Nguyen T, Huth T, Wong N, Ramos S, Staines D, Marshall-Gradisnik S. Characterisation of cell functions and receptors in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). BMC Immunol. 2015 Jun 2;16:35. doi: 10.1186/s12865-015-0101-4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4450981/ (Full article)