Tag: 2023

Symptoms and signs of dry eye in US veterans with Myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Purpose: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is clinically defined as persistent and unexplainable post-exertional fatigue and can present with a wide range of cognitive, immunological, endocrinological, and autonomic symptoms. A notable feature of ME/CFS is its comorbidity with pain in multiple compartments. In this study, we examine ocular manifestations associated with ME/CFS, with a focus on ocular surface pain complaints.

Methods: We recruited 124 United States veterans and profiled them for symptoms and signs of dry eye (DE). Individuals were grouped by the presence (n=42) and absence (n=82) of ME/CFS.

Results: The mean age of the population was 55.49 ± 4.61 years, 88.7% of participants identified as male, 58.1% as White, and 39.5% as Hispanic. Demographics, medical comorbidities, and medication use were similar between groups except for depression (57.1% vs. 29.6%, p=0.003), and history of traumatic brain injury (9.5% vs. 1.2%, p=0.03) which were more prevalent in the ME/CFS group. Individuals with ME/CFS reported higher ocular surface pain complaints, both through DE specific questionnaires (Ocular Surface Disease Index, OSDI; 5-Item DE Questionnaire, DEQ-5) and pain specific questionnaires (Neuropathic Pain Symptom Inventory, modified for the Eye, NPSI-E; Numerical rating scale, NRS) (Table 1). Ocular surface parameters were similar between groups, except for persistent pain after topical anesthesia which was more frequent in the ME/CFS group (Table 2).

Conclusions: Individuals who met criteria for ME/CFS had more severe ocular surface pain, but similar signs of DE, compared to controls. This suggests that nerve, and not tear, abnormalities contribute to ocular surface pain in ME/CFS.

Source: Victor Sanchez; Colin Kim; Kimberly Cabrera; Elyana Vittoria Tessa Locatelli; Molly Johnson; Anat Galor. Symptoms and signs of dry eye in US veterans with Myalgic encephalomyelitis/chronic fatigue syndrome. Investigative Ophthalmology & Visual Science June 2023, Vol.64, 3978. https://iovs.arvojournals.org/article.aspx?articleid=2790532 

A Thesis on Immune Differences in Chronic Fatigue Syndrome, Fibromyalgia and Healthy Controls

Abstract:

Background: Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM) are debilitating disorders that significantly affect the daily lives of those suffering from them, as well as their loved ones. Both conditions have overlapping clinical features that resemble inflammatory disorders, and overlapping symptoms, such as depression, suggest central nervous system (CNS) involvement. The role of the immune system’s soluble messengers in the pathogenesis of CFS and FM has been under investigation, but so far the results are inconclusive. In addition, there is growing evidence that the kynurenine pathway is involved in the pathology of diseases related to the CNS, yet the role of each metabolite is not clear. The relationship between kynurenine metabolism and CFS and FM has not been extensively explored. Few studies have simultaneously examined the immunological status in both CFS and FM, making this thesis the first to comprehensively evaluate the potential distinct immunological differences between the two disorders.

Objective: The objective of this study was to compare the CFS and FM with healthy controls, regarding the levels of several soluble blood markers related to the immune system. The markers chosen were:

  • The inflammatory marker high-sensitive CRP (hsCRP)
  • The following cytokines and chemokines: Interferon (IFN)-γ, Interleukin (IL)-1β, IL1ra, IL-4, IL-6, IL-8, IL-10, IL-17, Interferon gamma-induced protein (IP)-10, Monocyte Chemoattractant Protein (MCP)-1, Transforming Growth Factor (TGF)-β1, TGF-β2, TGF-β3 and Tumour Necrosis Factor (TNF)-α
  • The metabolites and their ratios of the kynurenine pathway: Tryptophan (Try), kynurenine (Kyn), kynurenic acid (KA), 3-hydroxykykynurenine (HK), anthranilic acid (AA), xanthurenic acid (XA), 3-hydroxyanthranilic acid (HAA), quinolinic acid (QA) and picolinic acid (Pic).

Method: The population consisted of three groups: CFS patients (n = 49), FM patients (n = 58), and healthy controls (n = 54). All participants were females aged 18–60. Patients were recruited from a specialised university hospital clinic and controls were recruited by advertisement among the staff and students at the hospital and university.

Plasma levels of hsCRP were analysed at the hospital. The cytokines and chemokines IFN-γ, IL-1β, IL-1ra, xii IL-4, IL-6, IL-8, IL-10, IL-17, IP-10, MCP-1, TGF-β1, TGF-β2, TGF-β3, and TNF-α were analysed by multiplex. Kynurenine metabolites were analysed by LC-MS/MS.

Linear regression models of log-transformed data for hsCRP and the kynurenine metabolites were conducted for comparison of the three groups CFS, FM and controls. The Kruskal-Wallis test was used to analyse differences of cytokines between the three groups. Main findings were controlled for age, body mass index (BMI), and symptoms of anxiety and depression.

Results: hsCRP levels were significantly higher for both the CFS and FM groups compared to healthy controls when adjusting for age and BMI (p = .006). There was no difference between the two patient groups. Level of hsCRP was affected by BMI (p < .001) but not age.

MCP-1 was significantly increased in both patient groups compared to healthy controls (p < .001). IL-1β, Il-4, IL-6, TNF-α, TGF-β1, TGF-β2, TGF-β3 (all p < .001), IL-10 (p = .003) and IL17 (p = .002) all were significantly lower in the patient groups compared to healthy controls. IFN-γ was significantly lower in the FM group (p < .001). For IL-8, IP-10 and IL1ra there were no significant difference.

QA differed between CFS and FM patients (p = .036) and was related to higher levels of BMI (p = .002). The KA/QA ratio was lower for CFS patients compared to healthy controls (p = .016). The KA/HK ratio was lower for FM patients compared to healthy controls, and this lower ratio was associated with increased symptoms of pain (p = .002). The kynurenine aminotransferase II (KAT II) enzymatic activity given by XA/HK was lower for FM patients compared to healthy controls (p = .013). In addition, BMI was negatively associated with enhanced KAT II enzymatic activity (p = .039).

Symptoms of anxiety and depression were not associated with any of the immune markers studied.

Conclusion: In our material hsCRP and MCP-1 are increased in patients both with CFS and with FM, while several other cytokines are either similar or significantly lower in patients than controls. Our study also indicates associations between kynurenine metabolism and CFS and FM. Kynurenine also is associated with single symptoms such as fatigue and pain. Forthcoming studies indicating interactions and causative effects, or restoration of the inflammatory status, may place cytokines and kynurenine metabolites as a target for treatment as well as prevention of these conditions in the future.

Source: Groven, Nina. A Thesis on Immune Differences in Chronic Fatigue Syndrome, Fibromyalgia and Healthy Controls. PhD Thesis [Norwegian University of Science and Technology] https://ntnuopen.ntnu.no/ntnu-xmlui/handle/11250/3072207 (Full text available as PDF file)

Neuropsychological deficits in patients with persistent COVID-19 symptoms: a systematic review and meta-analysis

Abstract:

Long-term persistent symptoms of COVID-19 affect 30-80% of patients who have recovered from the disease and may continue for a long time after the disease has been overcome. The duration of these symptoms over time might have consequences that affect different aspects of health, such as cognitive abilities.

The main objective of this systematic review and meta-analysis was to objectify the persistent COVID-19 cognitive deficits after acute phase of infection and to summarize the existing evidence. Additionally, we aimed to provide a comprehensive overview to further understand and address the consequences of this disease. Our protocol was registered in PROSPERO (CRD42021260286).

Systematic research was conducted in the Web of Science, MEDLINE, PubMed, PsycINFO, Scopus, and Google Scholar databases from January 2020 to September 2021. Twenty-five studies were included, six of which were analyzed for the meta-analysis, and consisted of 175 patients who had recovered from COVID-19 and 275 healthy individuals. Analyses of cognitive performance of post-COVID-19 patients and healthy volunteers were compared using a random-effects model.

The results showed an overall medium-high effect size (g = -.68, p = .02) with a 95% CI (-1.05 to -.31), with a significantly moderate level of heterogeneity among studies (Z = 3.58, p < .001; I2 = 63%). The results showed that individuals who had recovered from COVID-19 showed significant cognitive deficits compared to controls.

Future studies should carefully assess the long-term progression of cognitive impairments in patients with persistent COVID-19 symptoms, as well as the effectiveness of rehabilitation interventions. Nevertheless, there is an urgent need to know the profile to speed up development of prevention plans as well as specific interventions. Since more information is being obtained and more studies are being conducted on the subject, the need to examine this symptomatology multidisciplinary to achieve greater scientific evidence of its incidence and prevalence has become increasingly clear.

Source: Sobrino-Relaño S, Balboa-Bandeira Y, Peña J, Ibarretxe-Bilbao N, Zubiaurre-Elorza L, Ojeda N. Neuropsychological deficits in patients with persistent COVID-19 symptoms: a systematic review and meta-analysis. Sci Rep. 2023 Jun 26;13(1):10309. doi: 10.1038/s41598-023-37420-6. PMID: 37365191; PMCID: PMC10293265. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10293265/ (Full text)

Mild COVID-19 infection associated with post-COVID-19 condition after 3 months – a questionnaire survey

Abstract:

Introduction: The coronavirus disease 2019 (COVID-19), caused by infection with SARS-CoV-2, can lead to post-COVID-19 condition, a secondary syndrome of persistent and new post-acute symptoms, but evidence on this syndrome is still scarce.

Methods: In a questionnaire survey, residents of the city of Bremen (Germany) with verified SARS-CoV-2 infection were invited to answer questions (online questionnaire or interview) concerning symptoms experienced at the time of infection and at the time of questionnaire completion at least three months later. Main outcome of the analysis was the presence of a post-COVID-19 condition at the time of the interview, defined as the presence of at least two of three leading symptoms: fatigue, breathing difficulties, or cognitive problems.

Results: A post-COVID-19 condition was more likely to be reported if respondents had, at the time of infection, suffered from fatigue (OR 1.75; 95% CI: 1.00, 3.06), breathing difficulties (OR 4.02; 95% CI: 2.80, 5.77), cognitive symptoms (OR 2.98; 95% CI: 1.48, 6.02), or head- & bone aches (OR 2.06; 95% CI: 1.25, 3.42). The odds of developing a post-COVID-19 condition increased with the number of symptoms at infection. Females were more likely to report a post-COVID-19 condition (OR 1.54; 95% CI: 1.05, 2.24). Analyzing only non-hospitalized respondents changed results only slightly.

Conclusion: Our study adds to growing evidence that even a mild course of COVID-19 poses a risk for developing a post-COVID-19 condition. Females and those with initial symptoms including fatigue, breathing difficulties, and cognitive symptoms seem more likely to also experience post COVID-19 symptoms several months after infection.

KEY MESSAGES

Even a mild course of COVID-19 poses a risk for developing a post-COVID-19 condition.

Females seem more likely to develop a post-COVID-19 condition.

Those with initial symptoms including fatigue, breathing difficulties, and cognitive symptoms seem more likely to develop a post-COVID-19 condition.

Source: Rach S, Kühne L, Zeeb H, Ahrens W, Haug U, Pohlabeln H. Mild COVID-19 infection associated with post-COVID-19 condition after 3 months – a questionnaire survey. Ann Med. 2023 Dec;55(1):2226907. doi: 10.1080/07853890.2023.2226907. PMID: 37337723; PMCID: PMC10283437. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10283437/ (Full text)

Exploring potential biomarkers and therapeutic targets of long COVID-associated inflammatory cardiomyopathy

Background: The negative impact of long COVID on social life and human health is increasingly prominent, and the elevated risk of cardiovascular disease in patients recovering from COVID-19 has also been fully confirmed. However, the pathogenesis of long COVID-related inflammatory cardiomyopathy is still unclear. Here, we explore potential biomarkers and therapeutic targets of long COVID-associated inflammatory cardiomyopathy.

Methods: Datasets that met the study requirements were identified in Gene Expression Omnibus (GEO), and differentially expressed genes (DEGs) were obtained by the algorithm. Then, functional enrichment analysis was performed to explore the basic molecular mechanisms and biological processes associated with DEGs. A protein–protein interaction (PPI) network was constructed and analyzed to identify hub genes among the common DEGs. Finally, a third dataset was introduced for validation.

Results: Ultimately, 3,098 upregulated DEGs and 1965 downregulated DEGs were extracted from the inflammatory cardiomyopathy dataset. A total of 89 upregulated DEGs and 217 downregulated DEGs were extracted from the dataset of convalescent COVID patients. Enrichment analysis and construction of the PPI network confirmed VEGFA, FOXO1, CXCR4, and SMAD4 as upregulated hub genes and KRAS and TXN as downregulated hub genes. The separate dataset of patients with COVID-19 infection used for verification led to speculation that long COVID-associated inflammatory cardiomyopathy is mainly attributable to the immune-mediated response and inflammation rather than to direct infection of cells by the virus.

Conclusion: Screening of potential biomarkers and therapeutic targets sheds new light on the pathogenesis of long COVID-associated inflammatory cardiomyopathy as well as potential therapeutic approaches. Further clinical studies are needed to explore these possibilities in light of the increasingly severe negative impacts of long COVID.

Source: Peng Qi, Mengjie Huang and Haiyan Zhu. Exploring potential biomarkers and therapeutic targets of long COVID-associated inflammatory cardiomyopathy. Front. Med., 29 June 2023. Sec. Infectious Diseases: Pathogenesis and Therapy. Volume 10 – 2023 | https://doi.org/10.3389/fmed.2023.1191354 https://www.frontiersin.org/articles/10.3389/fmed.2023.1191354/full (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)

Low avidity circulating SARS-CoV-2 reactive CD8+ T cells with proinflammatory TEMRA phenotype are associated with post-acute sequelae of COVID-19

Abstract:

The role of adaptive SARS-CoV-2 specific immunity in post-acute sequelae of COVID-19 (PASC) is not well explored, although a growing population of convalescent COVID-19 patients with manifestation of PASC is observed.

We analyzed the SARS-CoV-2-specific immune response, via pseudovirus neutralizing assay and multiparametric flow cytometry in 40 post-acute sequelae of COVID-19 patients with non-specific PASC manifestation and 15 COVID-19 convalescent healthy donors. Although frequencies of SARS-CoV-2-reactive CD4+ T cells were similar between the studied cohorts, a stronger SARS-CoV-2 reactive CD8+ T cell response, characterized by IFNγ production and predominant TEMRA phenotype but low functional TCR avidity was detected in PASC patients compared to controls. Of interest, high avidity SARS-CoV-2-reactive CD4+ and CD8+ T cells were comparable between the groups demonstrating sufficient cellular antiviral response in PASC. In line with the cellular immunity, neutralizing capacity in PASC patients was not inferior compared to controls.

In conclusion, our data suggest that PASC may be driven by an inflammatory response triggered by an expanded population of low avidity SARS-CoV-2 reactive pro-inflammatory CD8+ T cells. These pro-inflammatory T cells with TEMRA phenotype are known to be activated by a low or even without TCR stimulation and lead to a tissue damage. Further studies including animal models are required for a better understanding of underlying immunopathogensis.

Summary: A CD8+ driven persistent inflammatory response triggered by SARS-CoV-2 may be responsible for the observed sequelae in PASC patients.

Source: Paniskaki K, Konik MJ, Anft M, Heidecke H, Meister TL, Pfaender S, Krawczyk A, Zettler M, Jäger J, Gaeckler A, Dolff S, Westhoff TH, Rohn H, Stervbo U, Scheibenbogen C, Witzke O, Babel N. Low avidity circulating SARS-CoV-2 reactive CD8+ T cells with proinflammatory TEMRA phenotype are associated with post-acute sequelae of COVID-19. Front Microbiol. 2023 Jun 2;14:1196721. doi: 10.3389/fmicb.2023.1196721. PMID: 37333646; PMCID: PMC10272838. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10272838/ (Full text)

Acute and post-acute sequelae of SARS-CoV-2 infection: a review of risk factors and social determinants

Abstract:

SARS-CoV-2 infection leading to Coronavirus Disease 2019 (COVID-19) has caused more than 762 million infections worldwide, with 10-30% of patients suffering from post-acute sequelae of SARS-CoV-2 infections (PASC). Initially thought to primarily affect the respiratory system, it is now known that SARS-CoV-2 infection and PASC can cause dysfunction in multiple organs, both during the acute and chronic stages of infection.

There are also multiple risk factors that may predispose patients to worse outcomes from acute SARS-CoV-2 infection and contribute to PASC, including genetics, sex differences, age, reactivation of chronic viruses such as Epstein Barr Virus (EBV), gut microbiome dysbiosis, and behavioral and lifestyle factors, including patients’ diet, alcohol use, smoking, exercise, and sleep patterns.

In addition, there are important social determinants of health, such as race and ethnicity, barriers to health equity, differential cultural perspectives and biases that influence patients’ access to health services and disease outcomes from acute COVID-19 and PASC.

Here, we review risk factors in acute SARS-CoV-2 infection and PASC and highlight social determinants of health and their impact on patients affected with acute and chronic sequelae of COVID-19.

Source: Wang C, Ramasamy A, Verduzco-Gutierrez M, Brode WM, Melamed E. Acute and post-acute sequelae of SARS-CoV-2 infection: a review of risk factors and social determinants. Virol J. 2023 Jun 16;20(1):124. doi: 10.1186/s12985-023-02061-8. PMID: 37328773; PMCID: PMC10276420. https://virologyj.biomedcentral.com/articles/10.1186/s12985-023-02061-8 (Full text)

Pre-existing allergic diseases as risk factors for long-term Long-COVID symptoms: a systematic review of prospective cohort studies

Abstract:

Background: The role of allergy as risk factor for Long-COVID (LC) is unclear. We aimed to systematically review and appraise the epidemiological evidence on allergic diseases as risk factors for LC (PROSPERO: CRD42023391245).
Methods: We examined literature for prospective cohort studies with a follow-up duration of 12 months for LC symptoms, published within the timeframe from January 2020 and January 2023 that recruited individuals with confirmed SARS-CoV-2 infection and information on pre-existing allergic diseases. Risk of bias and certainty of evidence were assessed (GRADE). Random effects meta-analyses were used to pool unadjusted ORs within homogeneous data subsets.
Results: We identified 13 studies (participants range = 39 – 1,950), all of which were associated with high risk of bias. Four of these studies did not provide data to calculate ORs. Significant associations were observed between increased LC incidences and pre-existing asthma measured in hospital-based populations ( n = 6) and pre-existing rhinitis ( n = 3) ( OR = 1.94; 95% CI [1.08, 3.50]; OR = 1.96; 95% CI [1.61, 2.39]), respectively. However, the level of certainty regarding these exposure outcome associations was very low.
Conclusion: Findings show that allergies may increase the risk of LC, although the reliability of this evidence is tenuous.
Source: Doreen Wolff, Karl Philipp Drewitz, Angela Ulrich, et al. Pre-existing allergic diseases as risk factors for long-term Long-COVID symptoms: a systematic review of prospective cohort studies. Authorea. June 14, 2023. DOI: 10.22541/au.168670123.38714309/v1 https://d197for5662m48.cloudfront.net/documents/publicationstatus/141144/preprint_pdf/5f547b44a0ff27aa14957c16c0561b73.pdf (Full text)

Natural history of long-COVID

Abstract:

Previous studies on the natural history of long-COVID have been few and selective. Without comparison groups, disease progression cannot be differentiated from symptoms originating from other causes. The Long-COVID in Scotland Study (Long-CISS) is a Scotland-wide, general population cohort of adults who had laboratory-confirmed SARS-CoV-2 infection matched to PCR-negative adults. Serial, self-completed, online questionnaires collected information on pre-existing health conditions and current health six, 12 and 18 months after index test.

Of those with previous symptomatic infection, 35% reported persistent incomplete/no recovery, 12% improvement and 12% deterioration. At six and 12 months, one or more symptom was reported by 71.5% and 70.7% respectively of those previously infected, compared with 53.5% and 56.5% of those never infected. Altered taste, smell and confusion improved over time compared to the never infected group and adjusted for confounders. Conversely, late onset dry and productive cough, and hearing problems were more likely following SARS-CoV-2 infection.

Source: Hastie, C.E., Lowe, D.J., McAuley, A. et al. Natural history of long-COVID in a nationwide, population cohort study. Nat Commun 14, 3504 (2023). https://doi.org/10.1038/s41467-023-39193-y https://www.nature.com/articles/s41467-023-39193-y (Full text)