inflammation – Page 9 – American ME and CFS Society

Multi-omics examination of Q fever fatigue syndrome identifies similarities with chronic fatigue syndrome

Abstract:

Background: Q fever fatigue syndrome (QFS) is characterised by a state of prolonged fatigue that is seen in 20% of acute Q fever infections and has major health-related consequences. The molecular mechanisms underlying QFS are largely unclear. In order to better understand its pathogenesis, we applied a multi-omics approach to study the patterns of the gut microbiome, blood metabolome, and inflammatory proteome of QFS patients, and compared these with those of chronic fatigue syndrome (CFS) patients and healthy controls (HC).

Methods: The study population consisted of 31 QFS patients, 50 CFS patients, and 72 HC. All subjects were matched for age, gender, and general geographical region (South-East part of the Netherlands). The gut microbiome composition was assessed by Metagenomic sequencing using the Illumina HiSeq platform. A total of 92 circulating inflammatory markers were measured using Proximity Extension Essay and 1607 metabolic features were assessed with a high-throughput non-targeted metabolomics approach.

Results: Inflammatory markers, including 4E-BP1 (P = 9.60-16 and 1.41-7) and MMP-1 (P = 7.09-9 and 3.51-9), are significantly more expressed in both QFS and CFS patients compared to HC. Blood metabolite profiles show significant differences when comparing QFS (319 metabolites) and CFS (441 metabolites) patients to HC, and are significantly enriched in pathways like sphingolipid (P = 0.0256 and 0.0033) metabolism. When comparing QFS to CFS patients, almost no significant differences in metabolome were found. Comparison of microbiome taxonomy of QFS and CFS patients with that of HC, shows both in- and decreases in abundancies in Bacteroidetes (with emphasis on Bacteroides and Alistiples spp.), and Firmicutes and Actinobacteria (with emphasis on Ruminococcus and Bifidobacterium spp.). When we compare QFS patients to CFS patients, there is a striking resemblance and hardly any significant differences in microbiome taxonomy are found.

Conclusions: We show that QFS and CFS patients are similar across three different omics layers and 4E-BP1 and MMP-1 have the potential to distinguish QFS and CFS patients from HC.

Source: Raijmakers RPH, Roerink ME, Jansen AFM, Keijmel SP, Gacesa R, Li Y, Joosten LAB, van der Meer JWM, Netea MG, Bleeker-Rovers CP, Xu CJ. Multi-omics examination of Q fever fatigue syndrome identifies similarities with chronic fatigue syndrome. J Transl Med. 2020 Nov 26;18(1):448. doi: 10.1186/s12967-020-02585-5. PMID: 33243243. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-020-02585-5 (Full text)

The antinuclear antibody dense fine speckled pattern and possible clinical associations: An indication of a proinflammatory microenvironment

Abstract:

Background: Indirect immunofluorescence (IIF) is the most prevalent screening antinuclear antibody test for systemic autoimmune rheumatic disease (SARD). Certain IIF patterns have known antibody and disease associations, but the dense fine speckled (ANA-DFS) pattern has no confirmed clinical associations. Our objective was to determine the prevalence of SARD among a group of ANA-DFS positive individuals and to identify final diagnoses among non-SARD individuals in order to determine possible clinical associations with the ANA-DFS pattern.

Methods: A retrospective study of 425 patients from a university health care system with a positive ANA-DFS pattern consecutively between August 2017 and September 2018. Sera samples underwent ANA testing by IIF on HEp-2 cell substrates (Euroimmun, Germany). Clinical information was retrieved from electronic health records and stored in a de-identified database.

Results: The prevalence of SARD was 24%. Undetermined diagnosis (17%), skin disorders (12.1%), and fibromyalgia/chronic pain syndrome/chronic fatigue syndrome (11.8%) were the most common non-SARD diagnoses. Taking into account past medical history, the most common non-SARD were atopic disorders (21.2%), fibromyalgia/chronic pain syndrome/chronic fatigue syndrome (17.6%), and skin disorders (16.7%).

Conclusions: The ANA-DFS pattern may be indicative of an underlying antigen-antibody interaction that plays a role in either the initiation or propagation of immunologic reactions. DFS70/LEDGF is a transcription factor involved in cell survival and stress protection, and autoantibodies may inhibit its function. It is likely that there are other antibodies producing the ANA-DFS pattern besides anti-DFS70/LEDGF, and more research is necessary to identify additional antibody specificities. The ANA-DFS pattern may be an indicator of a proinflammatory microenvironment given the high frequency of symptomatic patients and disease processes with an immunologic basis (including SARD).

Source: Lundgren MC, Sapkota S, Peterson DJ, Crosson JT. The antinuclear antibody dense fine speckled pattern and possible clinical associations: An indication of a proinflammatory microenvironment. J Immunol Methods. 2020 Oct 26:112904. doi: 10.1016/j.jim.2020.112904. Epub ahead of print. PMID: 33121975. https://pubmed.ncbi.nlm.nih.gov/33121975/

A SWATH-MS analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a serious and complex physical illness that affects all body systems with a multiplicity of symptoms, but key hallmarks of the disease are pervasive fatigue and ‘post-exertional malaise’, exacerbation after physical and/or mental activity of the intrinsic fatigue and other symptoms that can be highly debilitating and last from days to months. Although the disease can vary widely between individuals, common symptoms also include pain, cognitive deficits, sleep dysfunction, as well as immune, neurological and autonomic symptoms. Typically, it is a very isolating illness socially, carrying a stigma because of the lack of understanding of the cause and pathophysiology.

Methods: To gain insight into the pathophysiology of ME/CFS, we examined the proteomes of peripheral blood mononuclear cells (PBMCs) by SWATH-MS analysis in a small well-characterised group of patients and matched controls. A principal component analysis (PCA) was used to stratify groups based on protein abundance patterns, which clearly segregated the majority of the ME/CFS patients (9/11) from the controls. This majority subgroup of ME/CFS patients was then further compared to the control group.

Results: A total of 60 proteins in the ME/CFS patients were differentially expressed (P < 0.01, Log10 (Fold Change) > 0.2 and < -0.2). Comparison of the PCA selected subgroup of ME/CFS patients (9/11) with controls increased the number of proteins differentially expressed to 99. Of particular relevance to the core symptoms of fatigue and post-exertional malaise experienced in ME/CFS, a proportion of the identified proteins in the ME/CFS groups were involved in mitochondrial function, oxidative phosphorylation, electron transport chain complexes, and redox regulation. A significant number were also involved in previously implicated disturbances in ME/CFS, such as the immune inflammatory response, DNA methylation, apoptosis and proteasome activation.

Conclusions: The results from this study support a model of deficient ATP production in ME/CFS, compensated for by upregulation of immediate pathways upstream of Complex V that would suggest an elevation of oxidative stress. This study and others have found evidence of a distinct pathology in ME/CFS that holds promise for developing diagnostic biomarkers.

Source: Sweetman E, Kleffmann T, Edgar C, de Lange M, Vallings R, Tate W. A SWATH-MS analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction. J Transl Med. 2020 Sep 24;18(1):365. doi: 10.1186/s12967-020-02533-3. PMID: 32972442. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-020-02533-3 (Full text)

Neuroinflammation, Oxidative Stress, and Neurogenesis in a Mouse Model of Chronic Fatigue Syndrome, and the Treatment with Kampo Medicine

Abstract:

The diagnosis of chronic fatigue syndrome (CFS) is mainly symptom-based, and the etiology is still unclear. Here, we evaluated the pathological changes in the brain of a mouse model of CFS and studied the effects of Kampo medicine.

A mouse model of CFS was established through six repeated injections of Brucella abortus (BA) every two weeks for a period of 12 weeks. Neuroinflammation was measured by estimating interleukin (IL)-1β, IL-6, and interferon-gamma (IFN-γ), and oxidative stress by nitrotyrosine (3-NT) and 4-hydroxynonenal (4-HNE) 6 weeks after the last injection. Hippocampal neurogenesis was evaluated through Ki-67, doublecortin (DCX), and 5-bromodeoxyuridine (BrdU) assays. The effects of Kampo medicines (Hochuekkito (TJ-41) and Hachimijiogan (TJ-7)) on neuroinflammation during CFS were studied.

The wheel-running activity of mice was decreased by about 50% compared to baseline at 6 weeks after the last BA injection. The levels of IL-1β, IL-6, 3-NT, and 4-HNE were increased in both the cortex and the hippocampus of CFS mice at 6 weeks after the last BA injection. Hippocampal neurogenesis was unchanged in CFS mice. Treatment with TJ-41 and TJ-7 reduced the expressions of IL-1β, IL-6, and IFN-γ in the hippocampus but not in the cortex.

The results of the present study indicate that neuroinflammation and oxidative stress play important roles in the pathogenesis of CFS. The data further suggest that treatment with TJ-41 and TJ-7 could help reduce the inflammation associated with CFS in the hippocampus, but failed to improve the symptoms in CFS mice.

Source: He Q, Sawada M, Yamasaki N, Akazawa S, Furuta H, Uenishi H, Meng X, Nakahashi T, Ishigaki Y, Moriya J. Neuroinflammation, Oxidative Stress, and Neurogenesis in a Mouse Model of Chronic Fatigue Syndrome, and the Treatment with Kampo Medicine. Biol Pharm Bull. 2020;43(1):110-115. doi: 10.1248/bpb.b19-00616. https://www.jstage.jst.go.jp/article/bpb/43/1/43_b19-00616/_article (Full article)

Patients with ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) and chronic pain report similar level of sickness behavior as individuals injected with bacterial endotoxin at peak inflammation

Abstract:

Background: Chronic sickness behavior is implicated in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) and chronic pain but the level of subjective sickness behavior in these conditions has not been investigated or compared to other clinical and non-clinical samples, or to the level in experimental inflammation. Furthermore, the relationship between sickness behavior and self-rated health and functioning is not known in patients with ME/CFS and chronic pain. The aim of the present study was to investigate how sickness behavior in patients with chronic conditions differs from that in individuals with experimental acute sickness, primary care patients, the general population and healthy subjects. In addition, we wanted to explore how sickness behavior is related to self-rated health and health-related functioning.

Methods: Sickness behavior was quantified using the sickness questionnaire (SicknessQ). Self-ratings were collected at one time-point in 6 different samples. Levels of sickness behavior in patients with ME/CFS (n=38) and patients with chronic pain (n=190) were compared to healthy subjects with lipopolysaccharide(LPS)-induced inflammation (n=29), primary care patients (n=163), individuals from the general population (n=155) and healthy subjects (n=48), using linear regression. Correlations and moderated regression analyses were used to investigate associations between sickness behavior and self-rated health and health-related functioning in ME/CFS, chronic pain and the general population.

Results: LPS-injected individuals (M=16.3), patients with ME/CFS (M=16.1), chronic pain (M=16.1) and primary care patients (M=10.7) reported significantly higher SicknessQ scores than individuals from the general population (M=5.4) and healthy subjects (M=3.6) all p’s<0.001). In turn, LPS-injected individuals, patients with ME/CFS and chronic pain reported significantly higher SicknessQ scores than primary care patients (p’s<0.01). Higher levels of sickness behavior were associated with poorer self-rated health and health-related functioning (p’s<0.01), but less so in patients with ME/CFS and chronic pain than in individuals from the general population.

Conclusions: Patients with ME/CFS and chronic pain report similar high levels of sickness behavior; higher than primary care patients, and comparable to levels in experimental inflammation. Further study of sickness behavior in ME/CFS and chronic pain populations is warranted as immune-to-brain interactions and sickness behavior may be of importance for functioning as well as in core pathophysiological processes in subsets of patients.

Source: Martin A.Jonsjö, JennyÅström, Michael P.Jones, Bianka Karshikoff, Karin Lodin, Linda Holmström, Lars Agréus, Rikard K.Wicksell, John Axelsson, Mats Lekander, Gunnar L.Olsson, Mike Kemani, Anna Andreasson. Patients with ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) and chronic pain report similar level of sickness behavior as individuals injected with bacterial endotoxin at peak inflammation. Brain, Behavior, & Immunity – Health. Available online 17 December 2019, 100028. https://www.sciencedirect.com/science/article/pii/S2666354619300298 (Full study)

Inflammatory proteins are altered in chronic fatigue syndrome-A systematic review and meta-analysis

Abstract:

Immune dysfunction has been posited as a key element in the aetiology of chronic fatigue syndrome (CFS) since the illness was first conceived. However, systematic reviews have yet to quantitatively synthesise inflammatory biomarkers across the literature. We undertook a systematic review and meta-analysis to quantify available data on circulating inflammatory proteins, examining studies recruiting patients with a CFS diagnosis and a non-affected control group. Results were meta-analysed from 42 studies.

Patients with CFS had significantly elevated tumour necrosis factor (ES = 0.274, p < 0.001), interleukin-2 (ES = 0.203, p = 0.006), interleukin-4 (ES = 0.373, p = 0.004), transforming growth factor-β (ES = 0.967, p < 0.001) and c-reactive protein (ES = 0.622, p = 0.019). 12 proteins did not differ between groups.

These data provide some support for an inflammatory component in CFS, although inconsistency of results indicates that inflammation is unlikely to be a primary feature in all those suffering from this disorder. It is hoped that further work will elucidate whether there are subgroups of patients with clinically-relevant inflammatory dysfunction, and whether inflammatory cytokines may provide a prognostic biomarker or moderate treatment effects.

Source: Strawbridge R, Sartor ML, Scott F, Cleare AJ. Inflammatory proteins are altered in chronic fatigue syndrome-A systematic review and meta-analysis. Neurosci Biobehav Rev. 2019 Aug 26;107:69-83. doi: 10.1016/j.neubiorev.2019.08.011. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31465778

General theory of inflammation: patient self-administration of hydrocortisone safely achieves superior control of hydrocortisone-responding disorders by matching dosage with symptom intensity

Abstract:

Objective: To determine if patient self-administration of hydrocortisone will safely achieve superior symptom control for all hydrocortisone-responding disorders as it does for Addison’s disease and rheumatoid arthritis.

Methods: Two thousand four hundred and twenty-eight participants with hydrocortisone-responding disorders were brought to a minimum symptom state using daily administered hydrocortisone tablets in a 24-week, open study. Thereafter, participants used 5-day, low-dose hydrocortisone regimens to quench subsequent disorder exacerbations (flares) to maintain the minimum symptom state. Stressors such as emotional traumas, infections, allergies, and injuries were minimized to reduce disorder intensity, hydrocortisone consumption, and participant discomfort.

Results: Two thousand fifteen participants, 601 with fibromyalgia, 579 with osteoarthritis, 246 with rheumatoid arthritis, 226 with undifferentiated arthritis, 75 with back pain, 51 with Parkinson’s disease, 44 with polymyalgia rheumatica, 25 with neuropathy, 25 with chronic fatigue syndrome, 25 with dementia, 21 with migraine headache, 19 with multiple sclerosis, and 78 with other disorders completed the 24-week study to achieve a composite average symptom improvement of 76% with equal response rates. The participants averaged ingesting 12 mg of hydrocortisone per day. No significant adverse reactions were observed.

Conclusions: Patient self-administration of hydrocortisone safely achieves superior symptom control for 38 hydrocortisone-responding disorders at equal rates and symptom improvements to confirm and amplify an earlier double-blind study finding on rheumatoid arthritis. These results are consistent with the body having an inflammation control system and chronic inflammation being a disorder unto itself with differing symptoms sets dependent on its location.

Clinical Trials Government Identifier: NCT03558971.

Source: Irwin JB, Baldwin AL, Stenberg VI. General theory of inflammation: patient self-administration of hydrocortisone safely achieves superior control of hydrocortisone-responding disorders by matching dosage with symptom intensity. J Inflamm Res. 2019 Jun 13;12:161-166. doi: 10.2147/JIR.S195165. eCollection 2019. https://www.dovepress.com/general-theory-of-inflammation-patient-self-administration-of-hydrocor-peer-reviewed-article-JIR (Full article)

The clinical value of cytokines in chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a heterogeneous disorder with uncertain pathogenesis. Without effective therapy, CFS is characterized by disabling fatigue, depression, memory loss, and somatic discomfort. This comprehensive and impartial review aimed to assess the available evidence and examined the potential clinical value of using cytokines for the monitoring of CFS and as targets for the treatment of CFS.

Inflammatory reactions and immune modulation are considered to contribute to the pathophysiology of CFS, and it is well documented that cytokines present in both blood and cerebrospinal fluid (CSF) are closely associated with the progression and severity of CFS. However, pathophysiological and methodological limitations prevent using circulating cytokines as independent diagnostic indices. Moreover, there is no evidence to support the use of CSF cytokines as independent diagnostic indices.

Nevertheless, a comprehensive evaluation of changes in circulating and CSF cytokines may improve clinical understanding of the pathophysiology of patients with CFS, aiding in the establishment of an appropriate diagnosis. Importantly, the available evidence does not support the value of cytokines as therapeutic targets. We believe that an improved understanding of cytokine-related mechanisms will be helpful to explore new cytokine-related therapeutic targets.

Source: Yang T, Yang Y, Wang D, Li C, Qu Y, Guo J, Shi T, Bo W, Sun Z, Asakawa T. The clinical value of cytokines in chronic fatigue syndrome. J Transl Med. 2019 Jun 28;17(1):213. doi: 10.1186/s12967-019-1948-6 https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-019-1948-6 (Full article)

Patients with fibromyalgia and chronic fatigue syndrome show increased hsCRP compared to healthy controls

Abstract:

Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM) are both chronic disorders that have a devastating effect on the lives of the affected patients and their families. Both conditions have overlapping clinical features that partly resemble those of inflammatory disorders. The etiology is still not understood, and it is suggested that the immune system might be a contributing factor. So far, the results are inconclusive. The purpose of this study was to compare the two conditions and investigate the level of the inflammatory marker high-sensitivity CRP (hsCRP) in CFS and FM patients compared to healthy controls.

Female participants aged 18-60 years were enrolled in this study. The group consisted of 49 CFS patients, 57 FM patients, and 54 healthy controls. hsCRP levels were significantly higher for both the CFS and the FM groups compared to healthy controls when adjusting for age, smoking, and BMI (p < .001).

There was no difference between the two patient groups. The level of hsCRP was affected by BMI but not by age and smoking. Patients with CFS and FM have higher concentrations of hsCRP compared to healthy controls. This remains significant even after adjusting for BMI. CFS and FM cannot be distinguished from each other on the basis of hsCRP in our study.

Source: Groven N, Fors EA, Klæbo Reitan S. Patients with fibromyalgia and chronic fatigue syndrome show increased hsCRP compared to healthy controls. Brain Behav Immun. 2019 Jun 6. pii: S0889-1591(19)30208-9. doi: 10.1016/j.bbi.2019.06.010. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31176728

Shared microglial mechanisms underpinning depression and chronic fatigue syndrome and their comorbidities

Abstract:

In 2011, it was reviewed that a) there is a strong co-occurrence between major depression and chronic fatigue syndrome (CFS), with fatigue and physio-somatic symptoms being key symptoms of depression, and depressive symptoms appearing during the course of CFS; and b) the comorbidity between both disorders may in part be explained by activated immune-inflammatory pathways, including increased translocation of Gram-negative bacteria and increased levels of pro-inflammatory cytokines, such as interleukin (IL)-1. Nevertheless, the possible involvement of activated microglia in this comorbidity has remained unclear.

This paper aims to review microglial disturbances in major depression, CFS and their comorbidity. A comprehensive literature search was conducted using the PubMed / MEDLINE database to identify studies, which are relevant to this current review. Depressed patients present neuroinflammatory alterations, probably related to microglial activation, while animal models show that a microglial response to immune challenges including lipopolysaccharides is accompanied by depressive-like behaviors. Recent evidence from preclinical studies indicates that activated microglia have a key role in the onset of fatigue. In chronic inflammatory conditions, such as infections and senescence, microglia orchestrate an inflammatory microenvironment thereby causing fatigue.

In conclusion, based on our review we may posit that shared immune-inflammatory pathways and especially activated microglia underpin comorbid depression and CFS. As such, microglial activation and neuro-inflammation may be promising targets to treat the overlapping manifestations of both depression and CFS.

Source: Filho AJMC, Macedo DS, de Lucena DF, Maes M. Shared microglial mechanisms underpinning depression and chronic fatigue syndrome and their comorbidities. Behav Brain Res. 2019 May 25:111975. doi: 10.1016/j.bbr.2019.111975. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31136774