Tag: IL-6

Correlation between Hepatocyte Growth Factor (HGF) with D-Dimer and Interleukin-6 as Prognostic Markers of Coagulation and Inflammation in Long COVID-19 Survivors

Abstract:

In general, an individual who experiences the symptoms of Severe Acute Respiratory Syndrome Coronavirus 2 or SARS-CoV-2 infection is declared as recovered after 2 weeks. However, approximately 10–20% of these survivors have been reported to encounter long-term health problems, defined as ‘long COVID-19’, e.g., blood coagulation which leads to stroke with an estimated incidence of 3%, and pulmonary embolism with 5% incidence.
At the time of infection, the immune response produces pro-inflammatory cytokines that stimulate stromal cells to produce pro-hepatocyte growth factor (pro-HGF) and eventually is activated into hepatocyte growth factor (HGF), which helps the coagulation process in endothelial and epithelial cells. HGF is a marker that appears as an inflammatory response that leads to coagulation.
Currently, there is no information on the effect of SARS-CoV-2 infection on serum HGF concentrations as a marker of the prognosis of coagulation in long COVID-19 survivors. This review discusses the pathophysiology between COVID-19 and HGF, IL-6, and D-dimer.
Source: Zaira B, Yulianti T, Levita J. Correlation between Hepatocyte Growth Factor (HGF) with D-Dimer and Interleukin-6 as Prognostic Markers of Coagulation and Inflammation in Long COVID-19 Survivors. Current Issues in Molecular Biology. 2023; 45(7):5725-5740. https://doi.org/10.3390/cimb45070361 https://www.mdpi.com/1467-3045/45/7/361 (Full text)

Ultra-rare RTEL1 gene variants associate with acute severity of COVID-19 and evolution to pulmonary fibrosis as a specific long COVID disorder

Abstract:

Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a novel coronavirus that caused an ongoing pandemic of a pathology termed Coronavirus Disease 19 (COVID-19). Several studies reported that both COVID-19 and RTEL1 variants are associated with shorter telomere length, but a direct association between the two is not generally acknowledged. Here we demonstrate that up to 8.6% of severe COVID-19 patients bear RTEL1 ultra-rare variants, and show how this subgroup can be recognized.

Methods: A cohort of 2246 SARS-CoV-2-positive subjects, collected within the GEN-COVID Multicenter study, was used in this work. Whole exome sequencing analysis was performed using the NovaSeq6000 System, and machine learning methods were used for candidate gene selection of severity. A nested study, comparing severely affected patients bearing or not variants in the selected gene, was used for the characterisation of specific clinical features connected to variants in both acute and post-acute phases.

Results: Our GEN-COVID cohort revealed a total of 151 patients carrying at least one RTEL1 ultra-rare variant, which was selected as a specific acute severity feature. From a clinical point of view, these patients showed higher liver function indices, as well as increased CRP and inflammatory markers, such as IL-6. Moreover, compared to control subjects, they present autoimmune disorders more frequently. Finally, their decreased diffusion lung capacity for carbon monoxide after six months of COVID-19 suggests that RTEL1 variants can contribute to the development of SARS-CoV-2-elicited lung fibrosis.

Conclusion: RTEL1 ultra-rare variants can be considered as a predictive marker of COVID-19 severity, as well as a marker of pathological evolution in pulmonary fibrosis in the post-COVID phase. This notion can be used for a rapid screening in hospitalized infected people, for vaccine prioritization, and appropriate follow-up assessment for subjects at risk.

Trial Registration NCT04549831 (www.clinicaltrial.org)

Source: Bergantini, L., Baldassarri, M., d’Alessandro, M. et al. Ultra-rare RTEL1 gene variants associate with acute severity of COVID-19 and evolution to pulmonary fibrosis as a specific long COVID disorder. Respir Res 24, 158 (2023). https://doi.org/10.1186/s12931-023-02458-7 https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-023-02458-7 (Full text)

Impact of Covid-19 disease on thyroid function: longitudinal study

Abstract:

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic disease (Covid-19) affects thyroid function with different mechanisms: non-thyroidal illness syndrome (NTIS), direct infection of thyroid gland and cytokine storm. We provided the first description of painless atypical thyroiditis coexisting with NTIS in patients hospitalised for moderate-to-severe Covid-19 disease. We aimed to: 1) correlate thyroid dysfunction with Covid-19 disease severity; 2) follow the evolution of thyroid function over time.

Methods: Baseline (at hospital admittance) and longitudinal study of patients hospitalised for moderate-to-severe Covid-19 disease, without known history of thyroid disfunction, assessing serum thyroid function and autoantibodies, inflammatory markers and thyroid ultrasound scan (US). Patients showing at US focal hypoechoic areas suggestive for thyroiditis (thyroiditis-areas) also underwent thyroid 99mTc or I123 uptake scan.

Results: 183 Covid-19 patients were studied baseline, of whom 63 (34%) were already on steroid treatment before hospital admission, thus were not considered for TSH analysis. Decreased serum TSH positively correlated with albumin (P=0.02) and lymphocyte count (P<0.01) but not with C-reactive-protein (P=0.12) and interleukin-6 (P=0.10); TSH also progressively and inversely correlated to the need of oxygen support (P=0.02). Serum FT3 correlated positively with albumin (P<0.01) and inversely with D-dimer (P=0.02). Baseline thyroid US scan showed thyroiditis-areas in 18/65 (28%) patients, associated with reduced thyroid uptake at 99mTc/I123 scintigraphy in 14/17 (82%) cases. Thyroiditis-areas were more frequent among patients with baseline low TSH (6/10, 60%) compared with those with normal TSH (10/40, 25%, P=0.034). The patients with thyroiditis-areas also had higher baseline FT4 (P=0.018) and IL-6 (P=0.016) compared with those with normal thyroid US. Follow-up analysis was conducted in 75/183 (41%) patients; thyroid function and inflammatory markers normalized at all time-points in nearly all cases and no increase of thyroid autoantibodies positivity was observed. The thyroiditis-areas, even if often reduced in size, were still present after 6 and 12 months in 13/15 (87%) and 6/12 (50%) patients, respectively. After 9 months the thyroid uptake at 99mTc/I123 scintigraphy was still reduced in 4/6 (67%) patients, even if partially recovered (mean +28%) compared with baseline.

Conclusions: Thyroid dysfunction during moderate-to-severe Covid-19 disease is mild and transient, and thyroid hormones correlate with disease severity. Thyroiditis-areas at US occur frequently and may persist after one year, even if reduced in size; long-term consequences are unknown. The association of thyroiditis-areas with low TSH and high FT4 and IL-6 serum concentrations support the hypothesis of direct thyroid gland involvement in SARS-CoV-2 infection.

Source: Ilaria Muller, Matteo Varallo, Anita Daturi, Tiziana E Re, Davide Dazzi, Virgilio Longari, Andrea Gori, Giovanna Mantovani , Maura Arosio & Mario Salvi. Impact of Covid-19 disease on thyroid function: longitudinal study. Endocrine Abstracts (2022) 81 RC11.1 | DOI: 10.1530/endoabs.81.RC11.1 https://www.endocrine-abstracts.org/ea/0081/ea0081rc11.1

Inflammation-induced pain and fatigue in fibromyalgia and ME/CFS and role of variant connective tissue

Abstract:

Background: Fibromyalgia and ME/CFS are multifaceted conditions with overlapping symptoms(1); the pathophysiological mechanisms are under debate. It remains unclear whether dysregulated inflammation, induced either by an exogenous stimulus (eg a virus or other stressor), or autoimmunity, is of prime importance [2].

Objectives: 1. To determine in a novel human model the effects of an in vivo inflammatory challenge in the induction of pain and fatigue in fibromyalgia and ME/CFS compared to controls. 2. Explore potential mediators and moderators involved.

Methods: Data were available for 48 patients with confirmed diagnoses of Fibromyalgia and/ or ME/CFS and 22 matched controls, who had undergone a placebo controlled inflammatory challenge (typhoid vaccination) as part of ISRCTN78820481. Participants underwent full research diagnostic evaluation including a hypermobility assessment. Subjective pain and fatigue were assessed after saline injection and typhoid vaccination (VAS). Linear regression models were used to explore predictors, with adjustment for potential confounders (age/gender) and baseline levels as appropriate.

Mediation analyses (looking for mechanistic effects) were conducted according to the method of Hayes (3) and mediation considered significant if bootstrapped confidence intervals of the estimated indirect effect did not cross zero. In these mediation analyses predictor variable was group membership (patient or control), outcome variable was change in 1) pain and 2) fatigue induced by challenge and mediators/moderators included change in IL-6 induced by inflammatory challenge and hypermobility features.

Results: Being a patient rather than control significantly predicted inflammation-induced fatigue (B=14.89 (95%CI 3.29-26.50), t=2.56, p=0.013) and pain (B=12.88 (95%CI 0.65-25.10), t=2.11, p=0.039) after adjusting for levels induced by placebo.

Induced pain was independently predicted by level of IL-6 induced by inflammatory challenge (B=23.44 (95%CI 5.15-41.72),t=2.57, p=0.013) as was induced fatigue (B=10.63 (95%CI 2.84-18.41), t=2.73, p=0.008) Mediated moderation analyses suggested the link to induced pain and fatigue through induced inflammation was associated with hypermobility features (Index of mediated moderation 11.02 (95%CI 1.45-22.73) and 6.20 (95%CI 0.07-13.64) respectively))

Conclusion: To our knowledge this is the first human study to evaluate directly the effect of an exogenous inflammatory challenge (typhoid vaccination) in a combined group of Fibromyalgia and ME/CFS patients. Il-6 was shown to be a critical mediator. This work strongly supports the hypothesis that inflammation is key to the pathophysiology of ME/CFS. We are evaluating associated CNS inflammation in the model, as well as other associations, such as autonomic dysfunction and hypermobility. Further understanding the mediators involved in the condition should in future open the way to testing targeted anti-inflammatory therapy.

Source: Eccles J, Amato M, Themelis K, et alOP0194 INFLAMMATION-INDUCED PAIN AND FATIGUE IN FIBROMYALGIA AND ME/CFS AND ROLE OF VARIANT CONNECTIVE TISSUEAnnals of the Rheumatic Diseases 2023;82:129. https://ard.bmj.com/content/82/Suppl_1/129.2 (Full text)

Post-acute sequelae of COVID-19 is characterized by diminished peripheral CD8+β7 integrin+ T cells and anti-SARS-CoV-2 IgA response

Abstract:

Several millions of individuals are estimated to develop post-acute sequelae SARS-CoV-2 condition (PASC) that persists for months after infection. Here we evaluate the immune response in convalescent individuals with PASC compared to convalescent asymptomatic and uninfected participants, six months following their COVID-19 diagnosis.

Both convalescent asymptomatic and PASC cases are characterised by higher CD8+ T cell percentages, however, the proportion of blood CD8+ T cells expressing the mucosal homing receptor β7 is low in PASC patients. CD8 T cells show increased expression of PD-1, perforin and granzyme B in PASC, and the plasma levels of type I and type III (mucosal) interferons are elevated. The humoral response is characterized by higher levels of IgA against the N and S viral proteins, particularly in those individuals who had severe acute disease.  Our results also show that consistently elevated levels of IL-6, IL-8/CXCL8 and IP-10/CXCL10 during acute disease increase the risk to develop PASC.

In summary, our study indicates that PASC is defined by persisting immunological dysfunction as late as six months following SARS-CoV-2 infection, including alterations in mucosal immune parameters, redistribution of mucosal CD8+β7Integrin+ T cells and IgA, indicative of potential viral persistence and mucosal involvement in the etiopathology of PASC.

Source: Santa Cruz A, Mendes-Frias A, Azarias-da-Silva M, André S, Oliveira AI, Pires O, Mendes M, Oliveira B, Braga M, Lopes JR, Domingues R, Costa R, Silva LN, Matos AR, Ângela C, Costa P, Carvalho A, Capela C, Pedrosa J, Castro AG, Estaquier J, Silvestre R. Post-acute sequelae of COVID-19 is characterized by diminished peripheral CD8+β7 integrin+ T cells and anti-SARS-CoV-2 IgA response. Nat Commun. 2023 Mar 30;14(1):1772. doi: 10.1038/s41467-023-37368-1. PMID: 36997530; PMCID: PMC10061413. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10061413/ (Full text)

Increased interleukin-6 is associated with long COVID-19: a systematic review and meta-analysis

Abstract:

Background: Coronavirus disease 2019 (COVID-19) can involve persistence, sequelae, and other clinical complications that last weeks to months to evolve into long COVID-19. Exploratory studies have suggested that interleukin-6 (IL-6) is related to COVID-19; however, the correlation between IL-6 and long COVID-19 is unknown. We designed a systematic review and meta-analysis to assess the relationship between IL-6 levels and long COVID-19.

Methods: Databases were systematically searched for articles with data on long COVID-19 and IL-6 levels published before September 2022. A total of 22 published studies were eligible for inclusion following the PRISMA guidelines. Analysis of data was undertaken by using Cochran’s Q test and the Higgins I-squared (I2) statistic for heterogeneity. Random-effect meta-analyses were conducted to pool the IL-6 levels of long COVID-19 patients and to compare the differences in IL-6 levels among the long COVID-19, healthy, non-postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (non-PASC), and acute COVID-19 populations. The funnel plot and Egger’s test were used to assess potential publication bias. Sensitivity analysis was used to test the stability of the results.

Results: An increase in IL-6 levels was observed after SARS-CoV-2 infection. The pooled estimate of IL-6 revealed a mean value of 20.92 pg/ml (95% CI = 9.30-32.54 pg/ml, I2 = 100%, P < 0.01) for long COVID-19 patients. The forest plot showed high levels of IL-6 for long COVID-19 compared with healthy controls (mean difference = 9.75 pg/ml, 95% CI = 5.75-13.75 pg/ml, I2 = 100%, P < 0.00001) and PASC category (mean difference = 3.32 pg/ml, 95% CI = 0.22-6.42 pg/ml, I2 = 88%, P = 0.04). The symmetry of the funnel plots was not obvious, and Egger’s test showed that there was no significant small study effect in all groups.

Conclusions: This study showed that increased IL-6 correlates with long COVID-19. Such an informative revelation suggests IL-6 as a basic determinant to predict long COVID-19 or at least inform on the “early stage” of long COVID-19.

Source: Yin JX, Agbana YL, Sun ZS, Fei SW, Zhao HQ, Zhou XN, Chen JH, Kassegne K. Increased interleukin-6 is associated with long COVID-19: a systematic review and meta-analysis. Infect Dis Poverty. 2023 Apr 24;12(1):43. doi: 10.1186/s40249-023-01086-z. PMID: 37095536; PMCID: PMC10123579. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10123579/ (Full text)

Cytokine deficiencies in patients with Long-COVID

Abstract:

Up to half of individuals who contract SARS-CoV-2 develop symptoms of long-COVID approximately three months after initial infection. These symptoms are highly variable, and the mechanisms inducing them are yet to be understood. We compared plasma cytokine levels from individuals with long-COVID to healthy individuals and found that those with long-COVID had 100% reductions in circulating levels of Interferon Gamma (IFNγ) and Interleukin-8 (IL-8). Additionally, we found significant reductions in levels of IL-6, IL-2, IL-17, IL-13, and IL-4 in individuals with long-COVID.

We propose immune exhaustion as the driver of long-COVID, with the complete absence of IFNγ and IL-8 preventing the lungs and other organs from healing after acute infection, and reducing the ability to fight off subsequent infections, both contributing to the myriad of symptoms suffered by those with long-COVID.

Source: Williams ES, Martins TB, Shah KS, Hill HR, Coiras M, Spivak AM, Planelles V. Cytokine Deficiencies in Patients with Long-COVID. J Clin Cell Immunol. 2022;13(6):672. Epub 2022 Nov 18. PMID: 36742994; PMCID: PMC9894377. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9894377/ (Full text)

High levels of pro-inflammatory SARS-CoV-2-specific biomarkers revealed by in vitro whole blood cytokine release assay (CRA) in recovered and long-COVID-19 patients

Abstract:

Background: Cytokines induced by SARS-CoV-2 infection play a crucial role in the pathophysiology of COVID-19 and hyperinflammatory responses have been associated with poor clinical outcomes, with progression to severe conditions or long-term subacute complications named as long-COVID-19.

Methods: In this cross-sectional study, we aimed to evaluate a set of antigen-specific inflammatory cytokines in blood from recovered COVID-19 individuals or who suffered a post-acute phase of SARS-CoV-2 infection compared to healthy individuals with no history of COVID-19 exposition or infection. Interferon-gamma (IFN-γ), IFN-γ-induced protein 10 (IP-10), tumor necrosis factor (TNF), IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, and IL-17A were quantified by multiplex cytometric bead assay and enzyme-linked immunosorbent assay after stimulation of whole blood with recombinant Spike protein from SARS-CoV-2. Additionally, all participants have evaluated for anti-(S) protein-specific IgG antibodies. Clinical specimens were collected within two months of COVID-19 diagnosis.

Results: A total of 47 individuals were enrolled in the study, a median age of 43 years (IQR = 14.5), grouped into healthy individuals with no history of infection or exposure to SARS-CoV-2 (unexposed group; N = 21); and patients from the Health Complex of the Rio de Janeiro State University (UERJ), Brazil, who were SARS-CoV-2 positive by RT-PCR (COVID-19 group)–categorized as recovered COVID-19 (N = 11) or long-COVID-19 (N = 15). All COVID-19 patients presented at least one signal or symptom during the first two weeks of infection. Six patients were hospitalized and required invasive mechanical ventilation.

Our results showed that COVID-19 patients had significantly higher levels of IFN-γ, TNF, IL-1β, IL-2, IL-6, IL-8, and IP-10 than the unexposed group. The long-COVID-19 group has presented significantly high levels of IL-1β and IL-6 compared to unexposed individuals, but not from recovered COVID-19. A principal-component analysis demonstrated 84.3% of the total variance of inflammatory-SARS-CoV-2 response in the first two components, and it was possible to stratify IL-6, TNF, IL-1β, IL-10, and IL-2 as the top-five cytokines which are candidates to discriminate COVID-19 group (including long-COVID-19 subgroup) and healthy unexposed individuals.

Conclusion: We revealed important S protein-specific differential biomarkers in individuals affected by COVID-19, bringing new insights into the inflammatory status or SARS-CoV-2 exposition determination.

Source: Gomes SMR, Brito ACdS, Manfro WFP, Ribeiro-Alves M, Ribeiro RSdA, da Cal MS, et al. (2023) High levels of pro-inflammatory SARS-CoV-2-specific biomarkers revealed by in vitro whole blood cytokine release assay (CRA) in recovered and long-COVID-19 patients. PLoS ONE 18(4): e0283983. https://doi.org/10.1371/journal.pone.0283983 (Full text)

Long-COVID fatigue is not predicted by pre-pandemic plasma IL-6 levels in mild COVID-19 infection

Abstract:

Objective and design: Fatigue is a prominent symptom in the general population and may follow viral infection, including SARS-CoV2 infection which causes COVID-19. Chronic fatigue lasting more than three months is a major symptom of the long-COVID syndrome. The mechanisms underlying long-COVID fatigue are unknown. We hypothesized that the development of long-COVID chronic fatigue is driven by the pro-inflammatory immune status of an individual prior to COVID-19 infection.

Subjects and methods: We tested this hypothesis by analysing pre-pandemic plasma levels of IL-6, which plays a key role in persistent fatigue, in N = 1274 community dwelling adults from TwinsUK. Subsequent COVID-19 positive and COVID-19 negative participants were categorized based on antigen and antibody testing. Chronic fatigue was assessed using the Chalder Fatigue Scale.

Results: COVID-19 positive participants exhibited mild symptoms of infection. Chronic fatigue was a prevalent symptom among this population and was significantly higher in the COVID-19 positive participants than COVID-19 negative participants (17% vs 11%, respectively; p = 0.001). The qualitative nature of chronic fatigue as determined by individual questionnaire responses was similar in COVID-19 positive and COVID-19 negative participants. Pre-pandemic plasma IL-6 levels were positively associated with chronic fatigue in COVID-19 negative, but not COVID-19 positive
individuals. Raised BMI was associated with chronic fatigue in COVID-19 positive participants.

Conclusions: We found evidence that pre-existing increased levels of IL-6 provide the ground for chronic fatigue symptoms but there was no specific link seen with mild COVID-19 status. Elevated BMI increased the risk of chronic fatigue in mild COVID-19 infection consistent with previous reports.

Source: B Freidin, M., Borsini, A., Pariante, C., & MK Williams, F. (2023). Long-COVID fatigue is not predicted by prepandemic plasma IL-6 levels in mild COVID-19 infection. Inflammation Research. https://kclpure.kcl.ac.uk/portal/files/201594849/Freidin_et_al._2023.pdf (Full text)

Inflammation-associated gut microbiome in postacute sequelae of SARS-CoV-2 points towards new therapeutic targets

We read with interest the recent report by Liu et al1 describing faecal microbiome differences with postacute sequelae of SARS-CoV-2 (PASC), commonly referred to as ‘Long-COVID’. We have previously reported elevated levels of SARS-CoV-2-specific T cells with PASC compared with resolved COVID-19 (RC; no lingering symptoms at the time of sample collection) that correlated with increased levels of the inflammatory marker IL-6, suggesting that elevated inflammation in PASC may be related to immune response to residual virus.2 Although several studies have reported gut microbiome differences during acute COVID-19,3 PASC has received less attention. We, thus, sought to characterise gut microbiome differences in PASC versus RC using faecal samples from our study2 and to relate these differences to inflammation.

The faecal microbiome was evaluated using 16S rRNA gene sequencing. Plasma levels of inflammatory markers IL-6 and C reactive protein (CRP) were measured with ELISA (see online supplemental methods). Cohort information is in table 1. IL-6 and CRP were elevated with PASC (figure 1A). Gut microbiome composition did not significantly differ between the PASC and RC cohorts (PERMANOVA; p=0.087; figure 1B), but did correlate with IL-6 and CRP levels (Adonis; IL-6 p=0.03; CRP p=0.01). IL-6 and CRP also correlated with PC1 from a principal coordinates analysis (figure 1C,D), suggesting a relationship between microbiome composition and inflammation in PASC. Using SELBAL,4 which identifies ratios or ‘Balances’ of microbes that can differentiate between groups, we found that the faecal microbiomes of individuals with PASC had a lower ratio of an amplicon sequence variant (ASV) highly related to Faecalibacterium prausnitzii over ASVs related to species in the genus Bacteroides (B. dorei, B. massiliensis and B. thetaiotaomicron) (figure 1E), which provided an area under the curve (AUC) of 0.863 for differentiating individuals with PASC from RC. Balance values also negatively correlated with IL-6 (r=−0.44, p=0.01). These microbiome differences are consistent with Liu et al,1 who also reported higher levels of Bacteroides (B. vulgatus specifically) and lower F. prausnitzii with PASC. Liu et al also reported higher Ruminococcus gnavus with PASC, and lower Collinsella aerofaciens, and Blautia obeum. Interestingly, an ASV highly related to R. gnavus (100% identity over V4 read) correlated positively with IL-6 and ASVs related to F. prausnitzii (98.7% ID), C. aerofaciens (100% ID) and B. obeum (100% ID) all negatively correlated with IL-6 and/or CRP levels in our study (online supplemental table 1). Thus, our results are consistent with those of Liu et al and extend their findings by showing associations between the microbiome and markers of systemic inflammation.

Read the rest of this letter HERE.

Source: Carneiro VL, Littlefield KM, Watson R, Palmer BE, Lozupone C. Inflammation-associated gut microbiome in postacute sequelae of SARS-CoV-2 points towards new therapeutic targets. Gut. 2023 Jan 30:gutjnl-2022-328757. doi: 10.1136/gutjnl-2022-328757. Epub ahead of print. PMID: 36717218. https://gut.bmj.com/content/early/2023/01/29/gutjnl-2022-328757 (Full text)