Tag: chronic inflammation

Persistent serum protein signatures define an inflammatory subcategory of long COVID

Abstract:

Long COVID or post-acute sequelae of SARS-CoV-2 (PASC) is a clinical syndrome featuring diverse symptoms that can persist for months following acute SARS-CoV-2 infection. The aetiologies may include persistent inflammation, unresolved tissue damage or delayed clearance of viral protein or RNA, but the biological differences they represent are not fully understood. Here we evaluate the serum proteome in samples, longitudinally collected from 55 PASC individuals with symptoms lasting ≥60 days after onset of acute infection, in comparison to samples from symptomatically recovered SARS-CoV-2 infected and uninfected individuals.

Our analysis indicates heterogeneity in PASC and identified subsets with distinct signatures of persistent inflammation. Type II interferon signaling and canonical NF-κB signaling (particularly associated with TNF), appear to be the most differentially enriched signaling pathways, distinguishing a group of patients characterized also by a persistent neutrophil activation signature.

These findings help to clarify biological diversity within PASC, identify participants with molecular evidence of persistent inflammation, and highlight dominant pathways that may have diagnostic or therapeutic relevance, including a protein panel that we propose as having diagnostic utility for differentiating inflammatory and non-inflammatory PASC.

Source: Talla, A., Vasaikar, S.V., Szeto, G.L. et al. Persistent serum protein signatures define an inflammatory subcategory of long COVID. Nat Commun 14, 3417 (2023). https://doi.org/10.1038/s41467-023-38682-4 https://www.nature.com/articles/s41467-023-38682-4 (Full text)

Whole-body cryotherapy as a treatment for chronic medical conditions?

Abstract:

Introduction: Whole-body cryotherapy (WBC) is a controlled exposure of the whole body to cold to gain health benefits. In recent years, data on potential applications of WBC in multiple clinical settings have emerged.

Sources of data: PubMed, EBSCO and Clinical Key search using keywords including terms ‘whole body’, ‘cryotherapy’ and ‘cryostimulation’.

Areas of agreement: WBC could be applied as adjuvant therapy in multiple conditions involving chronic inflammation because of its potent anti-inflammatory effects. Those might include systemic inflammation as in rheumatoid arthritis. In addition, WBC could serve as adjuvant therapy for chronic inflammation in some patients with obesity.

Areas of controversy: WBC probably might be applied as an adjuvant treatment in patients with chronic brain disorders including mild cognitive impairment and general anxiety disorder and in patients with depressive episodes and neuroinflammation reduction as in multiple sclerosis. WBC effects in metabolic disorder treatment are yet to be determined. WBC presumably exerts pleiotropic effects and therefore might serve as adjuvant therapy in multi-systemic disorders, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Growing points: The quality of studies on the effects of WBC in the clinical setting is in general low; hence, randomized controlled trials with adequate sample size and longer follow-up periods are needed.

Areas are timely for developing research: Further studies should examine the mechanism underlying the clinical efficacy of WBC. Multiple conditions might involve chronic inflammation, which in turn could be a potential target of WBC. Further research on the application of WBC in neurodegenerative disorders, neuropsychiatric disorders and ME/CFS should be conducted.

Source: Tabisz H, Modlinska A, Kujawski S, Słomko J, Zalewski P. Whole-body cryotherapy as a treatment for chronic medical conditions? Br Med Bull. 2023 May 12:ldad007. doi: 10.1093/bmb/ldad007. Epub ahead of print. PMID: 37170956. https://pubmed.ncbi.nlm.nih.gov/37170956/

Long COVID: pathophysiological factors and abnormalities of coagulation

Abstract:

Acute COVID-19 infection is followed by prolonged symptoms in approximately one in ten cases: known as Long COVID. The disease affects ~65 million individuals worldwide. Many pathophysiological processes appear to underlie Long COVID, including viral factors (persistence, reactivation, and bacteriophagic action of SARS CoV-2); host factors (chronic inflammation, metabolic and endocrine dysregulation, immune dysregulation, and autoimmunity); and downstream impacts (tissue damage from the initial infection, tissue hypoxia, host dysbiosis, and autonomic nervous system dysfunction). These mechanisms culminate in the long-term persistence of the disorder characterized by a thrombotic endothelialitis, endothelial inflammation, hyperactivated platelets, and fibrinaloid microclots. These abnormalities of blood vessels and coagulation affect every organ system and represent a unifying pathway for the various symptoms of Long COVID.

Source: Simone Turner, Asad Khan, David Putrino, Ashley Woodcock, Douglas B. Kell, and Etheresia Pretorius.  Long COVID: pathophysiological factors and abnormalities of coagulation. Trends in Endocrinology & Metabolism. April 19, 2023. https://www.sciencedirect.com/science/article/pii/S1043276023000553 (Full text)

A review of cytokine-based pathophysiology of Long COVID symptoms

Abstract:

The Long COVID/Post Acute Sequelae of COVID-19 (PASC) group includes patients with initial mild-to-moderate symptoms during the acute phase of the illness, in whom recovery is prolonged, or new symptoms are developed over months. Here, we propose a description of the pathophysiology of the Long COVID presentation based on inflammatory cytokine cascades and the p38 MAP kinase signaling pathways that regulate cytokine production.

In this model, the SARS-CoV-2 viral infection is hypothesized to trigger a dysregulated peripheral immune system activation with subsequent cytokine release. Chronic low-grade inflammation leads to dysregulated brain microglia with an exaggerated release of central cytokines, producing neuroinflammation. Immunothrombosis linked to chronic inflammation with microclot formation leads to decreased tissue perfusion and ischemia. Intermittent fatigue, Post Exertional Malaise (PEM), CNS symptoms with “brain fog,” arthralgias, paresthesias, dysautonomia, and GI and ophthalmic problems can consequently arise as result of the elevated peripheral and central cytokines.

There are abundant similarities between symptoms in Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). DNA polymorphisms and viral-induced epigenetic changes to cytokine gene expression may lead to chronic inflammation in Long COVID patients, predisposing some to develop autoimmunity, which may be the gateway to ME/CFS.

Source: Low RN, Low RJ, Akrami A. A review of cytokine-based pathophysiology of Long COVID symptoms. Front Med (Lausanne). 2023 Mar 31;10:1011936. doi: 10.3389/fmed.2023.1011936. PMID: 37064029; PMCID: PMC10103649. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10103649/ (Full text)

Immunological dysfunction and mast cell activation syndrome in long COVID

Abstract:

At least 65 million people around the world suffer from long COVID, with the majority of cases occurring in the productive age (36–50 years old). Individuals with long COVID are confounded with multiple organ system dysfunctions, long-term organ injury sequelae, and a decreased quality of life. There is an overlapping of risk factors between long COVID and other postviral infection syndromes, so advances in research could also benefit other groups of patients.

Long COVID is the consequence of multiple immune system dysregulation, such as T-cell depletion, innate immune cell hyperactivity, lack of naive T and B cells, and elevated signature of pro-inflammatory cytokines, together with persistent SARS-CoV2 reservoir and other consequences of acute infection.

There is an activated condition of mast cells in long COVID, with abnormal granulation and excessive inflammatory cytokine release. A study by Weinstock et al. indicates that patients with long COVID suffer the same clinical syndrome as patients with mast cell activation syndrome (MCAS).

Diagnosis and treatment of MCAS in patients with long COVID will provide further symptomatic relief, and manage mast cell-mediated hyperinflammation states, which could be useful in the long-term control and recovery of such patients.

Source: Sumantri, Stevent; Rengganis, Iris. Immunological dysfunction and mast cell activation syndrome in long COVID. Asia Pacific Allergy ():10.5415/apallergy.0000000000000022, March 30, 2023. | DOI: 10.5415/apallergy.0000000000000022 https://journals.lww.com/apallergy/Fulltext/9900/Immunological_dysfunction_and_mast_cell_activation.2.aspx (Full text)

Long Covid: clues about causes

Abstract:(Full text

Many patients report persistent symptoms after resolution of acute COVID-19, regardless of SARS-CoV-2 variant and even if the initial illness is mild [1, 2]. A multitude of symptoms have been described under the umbrella term ‘Long COVID’, otherwise known as ‘post-COVID syndrome’ or ‘post-acute sequelae of SARS-CoV-2 (PASC)’; for simplicity we will use the term Long COVID.

Symptoms are diverse but include breathlessness, fatigue and brain fog, reported to affect up to 69% of cases [3]. Long COVID can be debilitating, 45.2% of patients requiring a reduced work schedule [4]. The WHO estimates that 17 million people in Europe have experienced Long COVID during the first two years of the pandemic [5]. SARS-CoV-2 variants continue to circulate and the risk of post-acute complications remains; a recent study of 56 003 UK patients found that even after Omicron infection, 4.5% suffered persistent symptoms [6].

It is therefore likely that Long COVID will provide a substantial medical and economic burden for the foreseeable future. There is an urgent need to understand mechanisms of disease and develop effective treatments based on this understanding.

Source: Liew F, Efstathiou C, Openshaw PJ. Long Covid: clues about causes. Eur Respir J. 2023 Mar 23:2300409. doi: 10.1183/13993003.00409-2023. Epub ahead of print. PMID: 36958743; PMCID: PMC10040855. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10040855/ (Full text)

LC, POTS, and ME/CFS: Lifting the Fog

Abstract:

These three syndromes – long covid (LC), postural orthostatic tachycardia syndrome (POTS), and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) – have many symptoms in common. The common denominator remains elusive.
The blood brain barrier (BBB) has been a barrier not only to microbes and toxins but also to understanding pathogenetic links. There are several areas within the brain that have no BBB. These are known as circumventricular organs (CVOs) and their location relative to CNS nuclei that direct autonomic and neuroendocrine functions is provocative in the quest for pathogenesis.
In addition the majority afflicted with LC and ME/CFS appear to be those with two MTHFR polymorphisms, present in over 50% of Americans. These polymorphisms elevate homocysteine. When homocysteine is combined with CVOs, the fog of POTS and its paradox are lifted. POTS may represent the intersection of LC and ME/CFS in those with the MTHFR gene (hypermethylation or 677TT).
The gut microbiomes of LC and ME/CFS, deficient in butyrates, GABA, and diversity, are then linked with MTHFR genotype 677TT. Reactivation of neurotropic EBV and VZV, due to loss of surveillance by CD4+/CD8+ T cells, is seen as secondary. The oxidative stress generated by homocysteine, loss of glutathione, low fiber diet, and persistent chronic inflammation exhaust available mitochondria and, assisted by BKN and estrogen, exacerbate all the elements of these post viral fatigue syndromes.
Source: Chambers, P. LC, POTS, and ME/CFS: Lifting the Fog. Preprints.org 2023, 2023030418. https://doi.org/10.20944/preprints202303.0418.v1 (Full text available as PDF file)

The Role of Leptin and Inflammatory Related Biomarkers in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Purpose: Leptin is a member of the cytokine family; its receptor (LEPR-b) is the longest form receptor expressed in cells of the immune system; wherein LEPR-b deficiency causes a decrease in CD4+ cells. LEPR-b is located in hypothalamic and brain stem nuclei, and it primarily regulates energy status. As well, leptin indirectly regulates widespread pain and exercise tolerance by decreasing circulating cortisol.

Hyperinsulinemia increases leptin production in adipocytes on a diurnal rhythm; however, the precise relationship between insulin, leptin and pro-inflammatory markers remains uncertain. In clinical settings, high-sensitivity C-reactive protein (hsCRP) has been widely used, as an inflammatory predictor for leptin-related cardiometabolic outcomes and chronic inflammatory symptoms.

Leptin-related metabolic and inflammation dysregulations have been clinically reported in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), but not fully elucidated. We examined the association of plasma insulin, leptin, and hsCRP levels with ME/CFS self-reported symptom severity.

Methods: Prospective analyses were conducted on ME/CFS patients who met Fukuda/CDC criteria at Birmingham hospital, Alabama, U.S.A. The independent variables were hyperinsulinemia (>174 μIU/mL), hyperleptinemia/hypoleptinemia (>18.3/<3.3 ng/mL), residual inflammation risk (hsCRP ≥2 and ≠26.2 mg/L) and within-individual-variability (WIV) for each biomarker.

WIV was defined for each individual as standard deviation/sample residuals adjusting for time and calculated from once-daily random plasma samples over 10–12 weeks.

The primary outcomes were:

(1) ME/CFS symptom score trends [generalized pain, persistent fatigue, sleep disturbance, impairment of concentration and memory (brain fog), and post-exertional malaise (PEM)] calculated from the MFI-20 questionnaire with anchors from 0 to 100 and recorded once daily over a matching 12–14 weeks, and

(2) dichotomized symptom severity, with severe symptoms defined as scores > 60/100. After adjusting for age and time, we reported: (1) standard errors (SEM) and p-values for symptom trends using multivariable mixed-effect linear regression models, and (2) odds ratios for severe symptoms using multivariable alternating logistic regression models.

Results: We included 29 ME/CFS patients. All were females and >18 years old. Hyperinsulinemia, hyperleptinemia/hypoleptinemia, and residual inflammation risk were 7%, 80%/7%, and 74%, respectively.

The medians of insulin-WIV, leptin-WIV and hsCRP-WIV were [(0.24; IQR 0.15–0.38), (0.25; IQR 0.15–0.40), (0.33; IQR 0.18–0.51)] respectively. On average, hyperleptinemic patients had the highest leptin-WIV and 50% of them had residual inflammation risk.

Severe (fatigue, pain, brain fog, sleep disturbance, and PEM) were reported in 50%, 29%, 41%, 30%, and 57% of patients, respectively. In the adjusted analysis, worse fatigue scores (7.49; SEM, 2.23; p = 0.002) were associated with higher insulin-WIV.

Hyperleptinemia (OR 1.54; 95% CI 1.13–2.09) compared to hypoleptinemia, and residual inflammation risk (OR 1.65; 95% CI 1.21–2.25) were associated with higher odds of severe fatigue. Worse pain scores (7.17; SEM, 2.30; p = 0.005) were associated with higher leptin-WIV, and (8.45; SEM, 2.25; p = 0.0009) higher hsCRP-WIV, and residual inflammation risk (OR 1.75; 95% CI 1.34–2.29) was associated with higher odds of severe pain.

Severe brain fog scores (9.20; SEM, 2.44; p = 0.0008) were associated with higher insulin-WIV, higher leptin-WIV (4.73; SEM, 2.12; p = 0.03). Residual inflammation risk (OR 1.40; 95% CI 1.16–1.77) was associated with higher odds of severe brain fog.

Hyperleptinemia (OR 0.60; 95% CI 0.43–1.19) was associated with lower odds of severe PEM compared to hypoleptinemia, and better sleep quality was associated (6.07; SEM, 1.70; p = 0.001) with higher insulin-WIV, and (3.37; SEM, 1.47; p = 0.03) higher leptin-WIV.

Conclusions: In patients with ME/CFS, symptoms severity was associated with hyperleptinemia, inflammation and within-individual-variability of these biomarkers. Leptin and hsCRP may be clinically useful in predicting symptom severity.

Larger clinical trials are needed to further examine the prediction and causality of these biomarkers in the development of ME/CFS diagnosis. The efficacy and safety of anti-inflammatory therapies may be evaluated in sub-clusters of ME/CFS with metabolic responses and inflammation dysregulations to improve patient-reported symptoms.

Source: Rahaf Al Assil and Jarred W Younger. “The Role of Leptin and Inflammatory Related Biomarkers in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome” in Karandrea S, Agarwal N, Organizing Committee of Cardiometabolic Health Congress. Report from the Scientific Poster Session at the 16th Annual Cardiometabolic Health Congress in National Harbor, USA, 14–17 October 2021. Proceedings. 2022; 80(1):6. https://doi.org/10.3390/proceedings2022080006 (Full text)

Understanding Long COVID; Mitochondrial Health and Adaptation—Old Pathways, New Problems

Abstract:

Many people infected with the SARS-CoV-2 suffer long-term symptoms, such as “brain fog”, fatigue and clotting problems. Explanations for “long COVID” include immune imbalance, incomplete viral clearance and potentially, mitochondrial dysfunction. As conditions with sub-optimal mitochondrial function are associated with initial severity of the disease, their prior health could be key in resistance to long COVID and recovery.
The SARs virus redirects host metabolism towards replication; in response, the host can metabolically react to control the virus. Resolution is normally achieved after viral clearance as the initial stress activates a hormetic negative feedback mechanism. It is therefore possible that, in some individuals with prior sub-optimal mitochondrial function, the virus can “tip” the host into a chronic inflammatory cycle. This might explain the main symptoms, including platelet dysfunction.
Long COVID could thus be described as a virally induced chronic and self-perpetuating metabolically imbalanced non-resolving state characterised by mitochondrial dysfunction, where reactive oxygen species continually drive inflammation and a shift towards glycolysis. This would suggest that a sufferer’s metabolism needs to be “tipped” back using a stimulus, such as physical activity, calorie restriction, or chemical compounds that mimic these by enhancing mitochondrial function, perhaps in combination with inhibitors that quell the inflammatory response.
Source: Nunn AVW, Guy GW, Brysch W, Bell JD. Understanding Long COVID; Mitochondrial Health and Adaptation—Old Pathways, New Problems. Biomedicines. 2022; 10(12):3113. https://doi.org/10.3390/biomedicines10123113 https://www.mdpi.com/2227-9059/10/12/3113 (Full text)

Antioxidants and Long Covid

Abstract:

Long Covid has many symptoms that overlap with ME(myalgic encephalomyelitis)/CFS(chronic fatigue syndrome), FM(fibromyalgia), EBV(Epstein-Barr virus), CMV(cytomegalovirus), CIRS (chronic inflammatory response syndrome), MCAS(mast cell activation syndrome), POTS(postural orthostatic tachycardia syndrome), and post viral fatigue syndrome. They all portend a “long haul” with an antioxidant shortfall and elevated Ca:Mg. Oxidative stress is the root cause.

Linkage between TGF(transforming growth factor)-β, IFN(interferon)-γ, the RAS(renin angiotensin system), and the KKS(kallikrein kinin system) is discussed. Technical explanations for the renin aldosterone paradox in POTS, the betrayal of TGF-β, and the commonality of markers for the Warburg effect are offered. The etiology of the common Long Covid symptoms of post exertional malaise, fatigue, and brain fog as well as anosmia, hair loss, and GI symptoms is technically discussed. Ca:Mg is critical to the glutamate/GABA balance. The role of GABA and butyrates from the “good” intestinal bacteria in the gut-brain axis and its correlation with chronic fatigue diseases are explored.

The crosstalk between the ENS(enteric nervous system) and the ANS(autonomic nervous system) and the role of the vagus in both are emphasized. HRV(heart rate variability), the fifth vital sign, points to an expanded gut-brain-heart/lung axis. A suggested approach to all of these – Long Covid, chronic fatigue diseases, post viral fatigue syndrome, and general health – is presented.

Source: Chambers, P. Antioxidants and Long Covid. Preprints 2022, 2022100195 (doi: 10.20944/preprints202210.0195.v1).  https://www.preprints.org/manuscript/202210.0195/v1 (Full text available as PDF file)