chronic inflammation – Page 4 – American ME and CFS Society

Long-COVID Syndrome and the Cardiovascular System: A Review of Neurocardiologic Effects on Multiple Systems

Abstract:

Purpose of review: Long-COVID syndrome is a multi-organ disorder that persists beyond 12 weeks post-acute SARS-CoV-2 infection (COVID-19). Here, we provide a definition for this syndrome and discuss neuro-cardiology involvement due to the effects of (1) angiotensin-converting enzyme 2 receptors (the entry points for the virus), (2) inflammation, and (3) oxidative stress (the resultant effects of the virus).

Recent findings: These effects may produce a spectrum of cardio-neuro effects (e.g., myocardial injury, primary arrhythmia, and cardiac symptoms due to autonomic dysfunction) which may affect all systems of the body. We discuss the symptoms and suggest therapies that target the underlying autonomic dysfunction to relieve the symptoms rather than merely treating symptoms. In addition to treating the autonomic dysfunction, the therapy also treats chronic inflammation and oxidative stress. Together with a full noninvasive cardiac workup, a full assessment of the autonomic nervous system, specifying parasympathetic and sympathetic (P&S) activity, both at rest and in response to challenges, is recommended. Cardiac symptoms must be treated directly. Cardiac treatment is often facilitated by treating the P&S dysfunction. Cardiac symptoms of dyspnea, chest pain, and palpitations, for example, need to be assessed objectively to differentiate cardiac from neural (autonomic) etiology. Long-term myocardial injury commonly involves P&S dysfunction. P&S assessment usually connects symptoms of Long-COVID to the documented autonomic dysfunction(s).

Source: DePace NL, Colombo J. Long-COVID Syndrome and the Cardiovascular System: A Review of Neurocardiologic Effects on Multiple Systems. Curr Cardiol Rep. 2022 Sep 30:1–16. doi: 10.1007/s11886-022-01786-2. Epub ahead of print. PMID: 36178611; PMCID: PMC9524329. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9524329/ (Full text)

Epipharyngeal Abrasive Therapy (EAT) Reduces the mRNA Expression of Major Proinflammatory Cytokine IL-6 in Chronic Epipharyngitis

Abstract:

The epipharynx, located behind the nasal cavity, is responsible for upper respiratory tract immunity; however, it is also the site of frequent acute and chronic inflammation. Previous reports have suggested that chronic epipharyngitis is involved not only in local symptoms such as cough and postnasal drip, but also in systemic inflammatory diseases such as IgA nephropathy and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID.

Epipharyngeal Abrasive Therapy (EAT), which is an effective treatment for chronic epipharyngitis in Japan, is reported to be effective for these intractable diseases. The sedation of chronic epipharyngitis by EAT induces suppression of the inflammatory cytokines and improves systemic symptoms, which is considered to be one of the mechanisms, but there is no report that has proved this hypothesis. The purpose of this study was to clarify the anti-inflammatory effect of EAT histologically.

The study subjects were 8 patients who were not treated with EAT and 11 patients who were treated with EAT for chronic epipharyngitis for 1 month or more. For immunohistochemical assessment, the expression pattern of IL-6 mRNA, which plays a central role in the human cytokine network, was analyzed using in situ hybridization. The expression of IL-6 in the EAT-treated group was significantly lower than those in the EAT nontreated group (p = 0.0015). In addition, EAT suppressed the expression of tumor necrosis factor alpha (TNFα), a crucial proinflammatory cytokine. As a result, continuous EAT suppressed submucosal cell aggregation and reduced inflammatory cytokines. Thus, EAT may contribute to the improvement of systemic inflammatory diseases through the suppression of IL-6 expression.

Source: Nishi K, Yoshimoto S, Nishi S, Nishi T, Nishi R, Tanaka T, Tsunoda T, Imai K, Tanaka H, Hotta O, Tanaka A, Hiromatsu K, Shirasawa S, Nakagawa T, Yamano T. Epipharyngeal Abrasive Therapy (EAT) Reduces the mRNA Expression of Major Proinflammatory Cytokine IL-6 in Chronic Epipharyngitis. Int J Mol Sci. 2022 Aug 16;23(16):9205. doi: 10.3390/ijms23169205. PMID: 36012469; PMCID: PMC9409341. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9409341/ (Full text)

COVID-19 induces CNS cytokine expression and loss of hippocampal neurogenesis

Abstract:

Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with acute and postacute cognitive and neuropsychiatric symptoms including impaired memory, concentration, attention, sleep and affect. Mechanisms underlying these brain symptoms remain understudied.

Here we report that SARS-CoV-2-infected hamsters exhibit a lack of viral neuroinvasion despite aberrant blood-brain barrier permeability. Hamsters and patients deceased from coronavirus disease 2019 (COVID-19) also exhibit microglial activation and expression of interleukin (IL)-1β and IL-6, especially within the hippocampus and the medulla oblongata, when compared with non-COVID control hamsters and humans who died from other infections, cardiovascular disease, uraemia or trauma. In the hippocampal dentate gyrus of both COVID-19 hamsters and humans, we observed fewer neuroblasts and immature neurons.

Protracted inflammation, blood-brain barrier disruption and microglia activation may result in altered neurotransmission, neurogenesis and neuronal damage, explaining neuropsychiatric presentations of COVID-19. The involvement of the hippocampus may explain learning, memory and executive dysfunctions in COVID-19 patients.

Source: Soung AL, Vanderheiden A, Nordvig AS, Sissoko CA, Canoll P, Mariani MB, Jiang X, Bricker T, Rosoklija GB, Arango V, Underwood M, Mann JJ, Dwork AJ, Goldman JE, Boon ACM, Boldrini M, Klein RS. COVID-19 induces CNS cytokine expression and loss of hippocampal neurogenesis. Brain. 2022 Aug 25:awac270. doi: 10.1093/brain/awac270. Epub ahead of print. PMID: 36004663. https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awac270/6672950?login=false (Full text)

Molecular Mechanisms of Neuroinflammation in ME/CFS and Long COVID to Sustain Disease and Promote Relapses

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease now well-documented as having arisen commonly from a viral infection, but also from other external stressors, like exposure to agricultural chemicals, other types of infection, surgery, or other severe stress events. Research has shown these events produce a systemic molecular inflammatory response and chronic immune activation and dysregulation. What has been more difficult to establish is the hierarchy of the physiological responses that give rise to the myriad of symptoms that ME/CFS patients experience, and why they do not resolve and are generally life-long.

The severity of the symptoms frequently fluctuates through relapse recovery periods, with brain-centered symptoms of neuroinflammation, loss of homeostatic control, “brain fog” affecting cognitive ability, lack of refreshing sleep, and poor response to even small stresses. How these brain effects develop with ME/CFS from the initiating external effector, whether virus or other cause, is poorly understood and that is what our paper aims to address.

We propose the hypothesis that following the initial stressor event, the subsequent systemic pathology moves to the brain via neurovascular pathways or through a dysfunctional blood-brain barrier (BBB), resulting in chronic neuroinflammation and leading to a sustained illness with chronic relapse recovery cycles. Signaling through recognized pathways from the brain back to body physiology is likely part of the process by which the illness cycle in the peripheral system is sustained and why healing does not occur. By contrast, Long COVID (Post-COVID-19 condition) is a very recent ME/CFS-like illness arising from the single pandemic virus, SARS-CoV-2.

We believe the ME/CFS-like ongoing effects of Long COVID are arising by very similar mechanisms involving neuroinflammation, but likely with some unique signaling, resulting from the pathology of the initial SARS-CoV-2 infection. The fact that there are very similar symptoms in both ongoing diseases, despite the diversity in the nature of the initial stressors, supports the concept of a similar dysfunctional CNS component common to both.

Source: Tate W, Walker M, Sweetman E, Helliwell A, Peppercorn K, Edgar C, Blair A, Chatterjee A. Molecular Mechanisms of Neuroinflammation in ME/CFS and Long COVID to Sustain Disease and Promote Relapses. Front Neurol. 2022 May 25;13:877772. doi: 10.3389/fneur.2022.877772. PMID: 35693009; PMCID: PMC9174654. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174654/ (Full text)

Role of Nutritents for COVID-19 recovery: an integrative approach

Introduction: Many patients (“long-haulers”) suffer lingering illness following COVID-19. The aim of this presentation is to evaluate the evidence of nutrient deficiencies affecting immune function and chronic symptoms from covid19 infection in a subgroup of patients. We will discuss the potential benefit of supplementing with multi-nutrients as an integrative approach to reducing long-hauler symptoms.

Methods: A narrative review followed a search of Medline/Pubmed, CINAHL, Google Scholar for studies published between January 2000 and March 2021, using key terms “coronavirus”, “COVID-19”, “immune system”, “inflammation”, “microbiome”, “oxidative stress”, “mitochondrial function”, “micronutrients”, “vitamin”, “minerals”, and “antioxidants”. Six reviews were selected which examined on the role of nutrients in immune and neurological function, including inflammatory processes, microbiome homeostasis, and mitochondrial function.

Results: Symptoms of long-haulers may be similar to myalgic encephalomyelitis/chronic fatigue syndrome associated with mitochondria dysfunction due to oxidative stress. Similar findings of chronic inflammation and microbiome dysbiosis associated with mood disorders also suggest the association between nutrient deficiencies and immuno-neurological functions. Nutrients required for optimal immune function included: antioxidants such as CoQ10 is required for mitochondrial function and is depleted quickly during acute immune response. Vitamins C and E and selenium also have antioxidant properties that can decrease proinflammatory cytokines and increase leukocyte and NK cell function. The B vitamins are involved in decrease pro-inflammatory cytokines and increase NK cell activities. Similarly, these nutrients are required for optimal neurological functioning in the CNS.

Conclusion: Initial evidence suggests chronic inflammatory processes in the CNS may contribute to the symptoms of covid-19 long-haulers. Given the complementary roles of different nutrient in immune response and CNS pathways, integrating multiple nutrients as treatment for long-haulers warrants further study.

Source: Leung B. Role of Nutritents for COVID-19 recovery: an integrative approach European Journal of Integrative Medicine. 2021 Dec;48:101978-101978. PMCID: PMC8696099. https://europepmc.org/article/pmc/pmc8696099#free-full-text (Full text)

Multisystem Involvement in Post-acute Sequelae of COVID-19 (PASC)

Abstract:

Objective: To describe cerebrovascular, neuropathic and autonomic features of post-acute sequelae of COVID-19 (PASC).

Methods: This retrospective study evaluated consecutive patients with chronic fatigue, brain fog and orthostatic intolerance consistent with PASC. Controls included postural tachycardia syndrome patients (POTS) and healthy participants. Analyzed data included surveys and autonomic (Valsalva maneuver, deep breathing, sudomotor and tilt tests), cerebrovascular (cerebral blood flow velocity (CBFv) monitoring in middle cerebral artery), respiratory (capnography monitoring) and neuropathic (skin biopsies for assessment of small fiber neuropathy) testing and inflammatory/autoimmune markers.

Results: Nine PASC patients were evaluated 0.7±0.3 years after a mild COVID-19 infection, treated as home observations. Autonomic, pain, brain fog, fatigue and dyspnea surveys were abnormal in PASC and POTS (n=10), compared to controls (n=15). Tilt table test reproduced the majority of PASC symptoms. Orthostatic CBFv declined in PASC (-20.0±13.4%) and POTS (-20.3±15.1%), compared to controls (-3.0±7.5%,p=0.001) and was independent of end-tidal carbon dioxide in PASC, but caused by hyperventilation in POTS. Reduced orthostatic CBFv in PASC included both subjects without (n=6) and with (n=3) orthostatic tachycardia. Dysautonomia was frequent (100% in both PASC and POTS) but was milder in PASC (p=0.013). PASC and POTS cohorts diverged in frequency of small fiber neuropathy (89% vs. 60%) but not in inflammatory markers (67% vs. 70%). Supine and orthostatic hypocapnia was observed in PASC.

Interpretation: PASC following mild COVID-19 infection is associated with multisystem involvement including: 1) cerebrovascular dysregulation with persistent cerebral arteriolar vasoconstriction; 2) small fiber neuropathy and related dysautonomia; 3) respiratory dysregulation; 4) chronic inflammation.

Source: Novak P, Mukerji SS, Alabsi HS, Systrom D, Marciano SP, Felsenstein D, Mullally WJ, Pilgrim DM. Multisystem Involvement in Post-acute Sequelae of COVID-19 (PASC). Ann Neurol. 2021 Dec 24. doi: 10.1002/ana.26286. Epub ahead of print. PMID: 34952975. https://pubmed.ncbi.nlm.nih.gov/34952975/

Lasting Immunological Imprint of Primary Epstein-Barr Virus Infection With Associations to Chronic Low-Grade Inflammation and Fatigue

Abstract:

Background: Epstein-Barr virus (EBV) causes infectious mononucleosis (IM) that can lead to chronic fatigue syndrome. The CEBA-project (Chronic fatigue following acute EBV infection in Adolescents) has followed 200 patients with IM and here we present an immunological profiling of adolescents with IM related to clinical characteristics.

Methods: Patients were sampled within 6 weeks of debut of symptoms and after 6 months. Peripheral blood mononuclear cells (PBMC) were cultured and stimulated in vitro (n=68), and supernatants analyzed for cytokine release. Plasma was analyzed for inflammatory markers (n=200). The Chalder Fatigue Questionnaire diagnosed patients with and without chronic fatigue at 6 months (CF+ and CF- group, respectively) (n=32 and n=91, in vitro and plasma cohorts, respectively.

Results: Broad activation of PBMC at baseline, with high levels of RANTES (Regulated on activation, normal T-cell expressed and secreted) in the CF+ group, and broad inflammatory response in plasma with high levels of T-cell markers was obeserved. At 6 months, there was an increased β-agonist response and RANTES was still elevated in cultures from the CF+ group. Plasma showed decrease of inflammatory markers except for CRP which was consistently elevated in the CF+ group.

Conclusion: Patients developing chronic fatigue after IM have signs of T-cell activation and low-grade chronic inflammation at baseline and after 6 months.

Clinical trial registration: https://clinicaltrials.gov/, identifier NCT02335437.

Source: Fevang B, Wyller VBB, Mollnes TE, Pedersen M, Asprusten TT, Michelsen A, Ueland T, Otterdal K. Lasting Immunological Imprint of Primary Epstein-Barr Virus Infection With Associations to Chronic Low-Grade Inflammation and Fatigue. Front Immunol. 2021 Dec 20;12:715102. doi: 10.3389/fimmu.2021.715102. PMID: 34987499; PMCID: PMC8721200. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8721200/ (Full text)

The role of low-grade inflammation in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) – associations with symptoms

Abstract:

BACKGROUND: Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) often present with a range of flu-like symptoms resembling sickness behavior as well as widespread pain and concentration deficits. The aim of this study was to explore the association between inflammatory markers previously shown to be related to fatigue severity in ME/CFS and common ME/CFS symptoms post-exertional fatigue, impaired cognitive processing, musculoskeletal pain and recurrent flu-like symptoms, and the moderating effect of sex on these associations.

METHODS: 53 adult patients diagnosed with ME/CFS at a specialist clinic were included in the study. Fasting blood plasma was analyzed using the Olink Proseek Multiplex Inflammation panel (β-NGF, CCL11, CXCL1, CXCL10, IL-6, IL-7, IL-8, IL-10, IL-18, TGF-α, TGF-β-1 and SCF) and BioRad Human Cytokine Type 1 assay (TNF-α). Participants rated the average severity of symptoms (0-10) based on the 2011 International Consensus Criteria of ME/CFS during a structured clinical interview. Associations between inflammatory markers and symptom severity were analyzed using bivariate correlations and moderated regression analyses bootstrapped with 5000 repetitions.

RESULTS AND CONCLUSIONS: Only β-NGF was associated with the fatigue severity measure. However, higher levels of CCL11, CXCL10, IL-7, TNF-α and TGF-β-1 were significantly associated with higher levels of impaired cognitive processing and musculoskeletal pain, and sex was a significant moderator for CXCL10, IL-7 and TGF-β-1. Future studies should investigate the relationship between inflammatory markers and key symptoms in ME/CFS in a longitudinal design in order to explore if and for whom low-grade inflammation may contribute to illness development.

Source: Jonsjö MA, Olsson GL, Wicksell RK, Alving K, Holmström L, Andreasson A. The role of low-grade inflammation in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) – associations with symptoms. Psychoneuroendocrinology. 2019 Dec 26;113:104578. doi: 10.1016/j.psyneuen.2019.104578. [Epub ahead of print] https://www.sciencedirect.com/science/article/pii/S0306453019313198?via%3Dihub (Full article)

Cytokine profiles in patients with Q fever fatigue syndrome

Abstract:

Background: Q fever fatigue syndrome (QFS) is a state of prolonged fatigue following around 20% of acute Q fever cases. It is thought that chronic inflammation plays a role in its aetiology. To test this hypothesis we measured circulating cytokines and the exvivo cytokine production in patients with QFS and compared to various control groups.

Materials/methods: Peripheral blood mononuclear cells (PBMCs), whole blood, and serum were collected from 20 QFS patients, 19 chronic fatigue syndrome (CFS) patients, 19 Q fever seropositive controls, and 25 age- and sex-matched healthy controls. Coxiella-specific ex-vivo production of tumor necrosis factor (TNF)α, interleukin (IL)-1β, IL-6, and interferon (IFN) was measured, together with a total of 92 circulating inflammatory proteins.

Results: PBMCs of QFS patients produced more IL-6 (P = 0.0001), TNFα (P = 0.0002), and IL-1β (P = 0.0005) than the various control groups when stimulated with Coxiella antigen. QFS patients had distinct differences in circulating inflammatory markers compared to the other groups, including higher concentrations of circulating IL-6 and IFNγ.

Conclusion: QFS patients showed signs of chronic inflammation compared to asymptomatic Q fever seropositive controls, CFS patients, and healthy controls, of which the monocyte-derived cytokines TNFα, IL-1β, and especially IL-6, are likely crucial components.

Source: Raijmakers, Ruud P.H. et al. Cytokine profiles in patients with Q fever fatigue syndrome. Journal of Infection , Volume 0 , Issue 0 , DOI: https://doi.org/10.1016/j.jinf.2019.01.006

Oxidative and Nitrosative Stress and Immune-Inflammatory Pathways in Patients with Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS)

Abstract:

Myalgic Encephalomyelitis (ME) / Chronic Fatigue Syndrome (CFS) has been classified as a disease of the central nervous system by the WHO since 1969. Many patients carrying this diagnosis do demonstrate an almost bewildering array of biological abnormalities particularly the presence of oxidative and nitrosative stress (O&NS) and a chronically activated innate immune system.

The proposal made herein is that once generated chronically activated O&NS and immune-inflammatory pathways conspire to generate a multitude of self-sustaining and self-amplifying pathological processes which are associated with the onset of ME/CFS. Sources of continuous activation of O&NS and immune-inflammatory pathways in ME/CFS are chronic, intermittent and opportunistic infections, bacterial translocation, autoimmune responses, mitochondrial dysfunctions, activation of the Toll-Like Receptor Radical Cycle, and decreased antioxidant levels.

Consequences of chronically activated O&NS and immune-inflammatory pathways in ME/CFS are brain disorders, including neuroinflammation and brain hypometabolism / hypoperfusion, toxic effects of nitric oxide and peroxynitrite, lipid peroxidation and oxidative damage to DNA, secondary autoimmune responses directed against disrupted lipid membrane components and proteins, mitochondrial dysfunctions with a disruption of energy metabolism (e.g. compromised ATP production) and dysfunctional intracellular signaling pathways. The interplay between all of these factors leads to self-amplifying feed forward loops causing a chronic state of activated O&NS, immune-inflammatory and autoimmune pathways which may sustain the disease.

Source: Morris G, Maes M. Oxidative and Nitrosative Stress and Immune-Inflammatory Pathways in Patients with Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS). Curr Neuropharmacol. 2014 Mar;12(2):168-85. doi: 10.2174/1570159X11666131120224653. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964747/ (Full article)