Tag: 2022

Brain microstructural changes and fatigue after COVID-19

Abstract:

Background: Fatigue and cognitive complaints are the most frequent persistent symptoms in patients after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This study aimed to assess fatigue and neuropsychological performance and investigate changes in the thickness and volume of gray matter (GM) and microstructural abnormalities in the white matter (WM) in a group of patients with mild-to-moderate coronavirus disease 2019 (COVID-19).

Methods: We studied 56 COVID-19 patients and 37 matched controls using magnetic resonance imaging (MRI). Cognition was assessed using Montreal Cognitive Assessment and Cambridge Neuropsychological Test Automated Battery, and fatigue was assessed using Chalder Fatigue Scale (CFQ-11). T1-weighted MRI was used to assess GM thickness and volume. Fiber-specific apparent fiber density (FD), free water index, and diffusion tensor imaging data were extracted using diffusion-weighted MRI (d-MRI). d-MRI data were correlated with clinical and cognitive measures using partial correlations and general linear modeling.

Results: COVID-19 patients had mild-to-moderate acute illness (95% non-hospitalized). The average period between real-time quantitative reverse transcription polymerase chain reaction-based diagnosis and clinical/MRI assessments was 93.3 (±26.4) days. The COVID-19 group had higher total CFQ-11 scores than the control group (p < 0.001). There were no differences in neuropsychological performance between groups. The COVID-19 group had lower FD in the association, projection, and commissural tracts, but no change in GM. The corona radiata, corticospinal tract, corpus callosum, arcuate fasciculus, cingulate, fornix, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, superior longitudinal fasciculus, and uncinate fasciculus were involved. CFQ-11 scores, performance in reaction time, and visual memory tests correlated with microstructural changes in patients with COVID-19.

Conclusions: Quantitative d-MRI detected changes in the WM microstructure of patients recovering from COVID-19. This study suggests a possible brain substrate underlying the symptoms caused by SARS-CoV-2 during medium- to long-term recovery.

Source: Bispo DDC, Brandão PRP, Pereira DA, Maluf FB, Dias BA, Paranhos HR, von Glehn F, de Oliveira ACP, Regattieri NAT, Silva LS, Yasuda CL, Soares AASM, Descoteaux M. Brain microstructural changes and fatigue after COVID-19. Front Neurol. 2022 Nov 10;13:1029302. doi: 10.3389/fneur.2022.1029302. PMID: 36438956; PMCID: PMC9685991. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9685991/ (Full text)

Psychological outcomes of COVID-19 survivors at sixth months after diagnose: the role of kynurenine pathway metabolites in depression, anxiety, and stress

Abstract:

Coronavirus disease 2019 (COVID-19) has resulted in long-term psychiatric symptoms because of the immunologic response to the virus itself as well as fundamental life changes related to the pandemic. This immune response leads to altered tryptophan (TRP)-kynurenine (KYN) pathway (TKP) metabolism, which plays an essential role in the pathophysiology of mental illnesses. We aimed to define TKP changes as a potential underlying mechanism of psychiatric disorders in post-COVID-19 patients.

We measured plasma levels of several TKP markers, including KYN, TRP, kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), and quinolinic acid (QUIN), as well as the TRP/KYN, KYNA/3-HK, and KYNA/QUIN ratios, in 90 post-COVID-19 patients (on the first day of hospitalization) and 59 healthy controls (on the first admission to the Check-Up Center). An online questionnaire that included the Depression, Anxiety and Stress Scale-21 (DASS-21) was used 6 months after the initial assessment in both groups.

A total of 32.2% of participants with COVID-19 showed depressive symptoms, 21.1% exhibited anxiety, and 33.3% had signs of stress at follow-up, while 6.6% of healthy controls exhibited depressive and anxiety symptoms and 18.6% had signs of stress. TRP and 3-HK were negative predictors of anxiety and stress, but KYN positively predicted anxiety and stress. Moreover, TRP negatively predicted depression, while KYNA/3-HK was a negative predictor of anxiety.

The correlation between depression, anxiety, and stress and TKP activation in COVID-19 could provide prospective biomarkers, especially the reduction in TRP and 3HK levels and the increase in KYN. Our results suggest that the alteration of TKP is not only a potential biomarker of viral infection-related long-term psychiatric disorders but also that the therapy targets future viral infections related to depression and anxiety.

Source: Kucukkarapinar M, Yay-Pence A, Yildiz Y, Buyukkoruk M, Yaz-Aydin G, Deveci-Bulut TS, Gulbahar O, Senol E, Candansayar S. Psychological outcomes of COVID-19 survivors at sixth months after diagnose: the role of kynurenine pathway metabolites in depression, anxiety, and stress. J Neural Transm (Vienna). 2022 Aug;129(8):1077-1089. doi: 10.1007/s00702-022-02525-1. Epub 2022 Jul 7. PMID: 35796878; PMCID: PMC9261222. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9261222/ (Full text)

Long-term implications of COVID-19 on bone health: pathophysiology and therapeutics

Abstract:

Background: SARS-CoV-2 is a highly infectious respiratory virus associated with coronavirus disease (COVID-19). Discoveries in the field revealed that inflammatory conditions exert a negative impact on bone metabolism; however, only limited studies reported the consequences of SARS-CoV-2 infection on skeletal homeostasis. Inflammatory immune cells (T helper—Th17 cells and macrophages) and their signature cytokines such as interleukin (IL)-6, IL-17, and tumor necrosis factor-alpha (TNF-α) are the major contributors to the cytokine storm observed in COVID-19 disease. Our group along with others has proven that an enhanced population of both inflammatory innate (Dendritic cells—DCs, macrophages, etc.) and adaptive (Th1, Th17, etc.) immune cells, along with their signature cytokines (IL-17, TNF-α, IFN-γ, IL-6, etc.), are associated with various inflammatory bone loss conditions. Moreover, several pieces of evidence suggest that SARS-CoV-2 infects various organs of the body via angiotensin-converting enzyme 2 (ACE2) receptors including bone cells (osteoblasts—OBs and osteoclasts—OCs). This evidence thus clearly highlights both the direct and indirect impact of SARS-CoV-2 on the physiological bone remodeling process. Moreover, data from the previous SARS-CoV outbreak in 2002–2004 revealed the long-term negative impact (decreased bone mineral density—BMDs) of these infections on bone health.

Methodology: We used the keywords “immunopathogenesis of SARS-CoV-2,” “SARS-CoV-2 and bone cells,” “factors influencing bone health and COVID-19,” “GUT microbiota,” and “COVID-19 and Bone health” to integrate the topics for making this review article by searching the following electronic databases: PubMed, Google Scholar, and Scopus.

Conclusion: Current evidence and reports indicate the direct relation between SARS-CoV-2 infection and bone health and thus warrant future research in this field. It would be imperative to assess the post-COVID-19 fracture risk of SARS-CoV-2-infected individuals by simultaneously monitoring them for bone metabolism/biochemical markers. Importantly, several emerging research suggest that dysbiosis of the gut microbiota—GM (established role in inflammatory bone loss conditions) is further involved in the severity of COVID-19 disease. In the present review, we thus also highlight the importance of dietary interventions including probiotics (modulating dysbiotic GM) as an adjunct therapeutic alternative in the treatment and management of long-term consequences of COVID-19 on bone health.

Source: Sapra L, Saini C, Garg B, Gupta R, Verma B, Mishra PK, Srivastava RK. Long-term implications of COVID-19 on bone health: pathophysiology and therapeutics. Inflamm Res. 2022 Sep;71(9):1025-1040. doi: 10.1007/s00011-022-01616-9. Epub 2022 Jul 28. PMID: 35900380; PMCID: PMC9330992. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9330992/ (Full text)

Heart Rate Variability and Salivary Biomarkers Differences between Fibromyalgia and Healthy Participants after an Exercise Fatigue Protocol: An Experimental Study

Abstract:

Previous studies showed that people with Fibromyalgia (FM) suffer from dysautonomia. Dysautonomia consists of persistent autonomic nervous system hyperactivity at rest and hyporeactivity during stressful situations. There is evidence that parameters reflecting the complex interplay between the autonomic nervous system and the cardiovascular system during exercise can provide significant prognostic information. Therefore, this study aimed to investigate the differences between people with FM and healthy controls on heart rate variability (HRV) and salivary parameters (such as flow, protein concentration, enzymatic activities of amylase, catalase and glutathione peroxidase) in two moments: (1) at baseline, and (2) after an exercise fatigue protocol.

A total of 37 participants, twenty-one were people with fibromyalgia and sixteen were healthy controls, participated in this cross-sectional study. HRV and salivary samples were collected before and after an exercise fatigue protocol. The fatigue protocol consisted of 20 repetitions of knee extensions and flexions of the dominant leg at 180 °·s-1 (degrees per second).

Significant differences were found in the HRV (stress index, LF and HF variables) and salivary biomarkers (with a higher concentration of salivary amylase in people with FM compared to healthy controls). Exercise acute effects on HRV showed that people with FM did not significantly react to exercise. However, significant differences between baseline and post-exercise on HRV significantly induce alteration on the HRV of healthy controls. Catalase significantly increased after exercise in healthy controls whereas salivary flow significantly increased in women with FM after an exercise fatigue protocol.

Our study suggests that a higher α-amylase activity and an impaired HRV can be used as possible biomarkers of fibromyalgia, associated with a reduction in salivary flow without changes in HRV and catalase activity after a fatigue exercise protocol. More studies should be carried out in the future to evaluate this hypothesis, in order to find diagnostic biomarkers in fibromyalgia.

Source: Costa AR, Freire A, Parraca JA, Silva V, Tomas-Carus P, Villafaina S. Heart Rate Variability and Salivary Biomarkers Differences between Fibromyalgia and Healthy Participants after an Exercise Fatigue Protocol: An Experimental Study. Diagnostics (Basel). 2022 Sep 14;12(9):2220. doi: 10.3390/diagnostics12092220. PMID: 36140620; PMCID: PMC9497903. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9497903/ (Full text)

Long COVID (PASC) Is Maintained by a Self-Sustaining Pro-Inflammatory TLR4/RAGE-Loop of S100A8/A9 > TLR4/RAGE Signalling, Inducing Chronic Expression of IL-1b, IL-6 and TNFa: Anti-Inflammatory Ezrin Peptides as Potential Therapy

Abstract:

Long COVID, also referred to as Post-Acute Sequelae of COVID (PASC), is probably triggered during SARS-CoV-2 infection and acute COVID-19 by SARS-CoV-2 Spike-protein binding and hyper-activating the cell-membrane expressed Receptor for Advance Glycation End-products (mRAGE) and Toll-Like Receptor 4 (TLR4). SARS-CoV-2 infects lung monocytes by Spike binding to mRAGE (not ACE2).
During acute COVID-19, high levels of IL-6 hyper-stimulate S100A8/A9 expression and secretion. Although no viral protein nor mRNA can be detected in half of long COVID (PASC) patients, there is a significant elevation of serum levels of IL-1b, IL-6, TNFa, and S100A8/A9. It appears that a pathological pro-inflammatory feedback loop (the TLR4/RAGE-loop) is established during acute COVID-19, which is maintained by S100A8/A9 > RAGE/TLR4 chronic inflammatory signalling, even after SARS-CoV-2 has been cleared from the body. During long COVID/PASC, Ca2+-binding protein S100A8/A9 chronically stimulates TLR4/RAGE-signalling to induce chronic expression of IL-1b, IL-6 and TNFa. Secreted IL-6 binds to its IL-6R receptor on the surface of other cells and signals via STAT3 and C/EBPb for more S100A8/A9 expression. Secreted IL-1b binds to its receptor IL-1R on other cells, and signals via NFkB for more mRAGE and TLR4 expression. New S100A8/A9 can bind and activate cell-surface mRAGE and TLR4 to stimulate expression of more IL-1b, IL-6 and TNFa.
This process establishes a pathogenic pro-inflammatory TLR4/RAGE-loop: IL-1b + IL-6 > IL-1R + IL-6R > TLR4/mRAGE + S100A8/A9 > IL-1b + IL-6, which generates multi-organ inflammation that persists in the blood vessels, the brain, the liver, the heart, the kidneys, the gut and the musculo-skeletal system, and is responsible for all the complex pathologies associated with long COVID/PASC. Chronic expression of IL-1, IL-6 and TNFa is critical for the maintenance of the TLR4/RAGE-loop and persistence of long COVID/PASC.
Ezrin peptides are inhibitors of IL-1, IL-6, IL-8 and TNFa expression, so are now being investigated as potential therapy for long COVID/PASC. There is preliminary anecdotal evidence of symptomatic relief (not confirmed yet by formal clinical trials) from a few long COVID/PASC patient volunteers, after treatment with ezrin peptide therapy.
Source: Holms RD. Long COVID (PASC) Is Maintained by a Self-Sustaining Pro-Inflammatory TLR4/RAGE-Loop of S100A8/A9 > TLR4/RAGE Signalling, Inducing Chronic Expression of IL-1b, IL-6 and TNFa: Anti-Inflammatory Ezrin Peptides as Potential Therapy. Immuno. 2022; 2(3):512-533. https://doi.org/10.3390/immuno2030033 https://www.mdpi.com/2673-5601/2/3/33 (Full text)

Cardiac Autonomic Function in Long COVID-19 Using Heart Rate Variability: An Observational Cross-Sectional Study

Abstract:

Background: Heart rate variability is a non-invasive, measurable, and established autonomic nervous system test. Long-term COVID-19 sequelae are unclear; however, acute symptoms have been studied.

Objectives: To determine autonomic cardiac differences between long COVID-19 patients and healthy controls and evaluate associations among symptoms, comorbidities, and laboratory findings.

Methods: This single-center study included long COVID-19 patients and healthy controls. The heart rate variability (HRV), a quantitative marker of autonomic activity, was monitored for 24 h using an ambulatory electrocardiogram system. HRV indices were compared between case and control groups. Symptom frequency and inflammatory markers were evaluated. A significant statistical level of 5% (p-value 0.05) was adopted.

Results: A total of 47 long COVID-19 patients were compared to 42 healthy controls. Patients averaged 43.8 (SD14.8) years old, and 60.3% were female. In total, 52.5% of patients had moderate illness. Post-exercise dyspnea was most common (71.6%), and 53.2% lacked comorbidities. CNP, D-dimer, and CRP levels were elevated (p-values of 0.0098, 0.0023, and 0.0015, respectively). The control group had greater SDNN24 and SDANNI (OR = 0.98 (0.97 to 0.99; p = 0.01)). Increased low-frequency (LF) indices in COVID-19 patients (OR = 1.002 (1.0001 to 1.004; p = 0.030)) and high-frequency (HF) indices in the control group (OR = 0.987 (0.98 to 0.995; p = 0.001)) were also associated.

Conclusions: Patients with long COVID-19 had lower HF values than healthy individuals. These variations are associated with increased parasympathetic activity, which may be related to long COVID-19 symptoms and inflammatory laboratory findings.

Source: Menezes Junior ADS, Schröder AA, Botelho SM, Resende AL. Cardiac Autonomic Function in Long COVID-19 Using Heart Rate Variability: An Observational Cross-Sectional Study. J Clin Med. 2022 Dec 22;12(1):100. doi: 10.3390/jcm12010100. PMID: 36614901; PMCID: PMC9821736. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9821736/ (Full text)

Long COVID: Is There a Role for Antidepressants?

Abstract:

Two years into this historic pandemic, the scientific and healthcare communities continue to learn a great deal regarding COVID-19. The most urgent and immediate focus has been on vaccine development for disease prevention/mitigation and on identification of effective therapeutic interventions for acute phase of illness. However, attention is increasingly being placed on formulating treatment strategies for individuals who are post-COVID-19 and experiencing a syndrome of persistent symptoms that is being referred to as long COVID.

One strategy is to repurpose drugs which have been approved for other conditions and subsequently assess their safety and efficacy when applied to COVID-19. In this light, antidepressant medications have garnered attention amidst evidence supporting anti-inflammatory and anti-viral properties.

In this article, we present purported anti-inflammatory mechanisms of antidepressants, review studies appearing in the literature to date regarding antidepressants and acute COVID-19, and discuss the utility of antidepressants as a potential therapeutic resource for long COVID.

Source: Rivas-Vázquez R, Carrazana EJ, Blais MA, Rey GJ, RivasVázquez E, Quintana AA. Long COVID: Is There a Role for Antidepressants? Neurol Curr Res. 2022;2(3):1019. https://www.medtextpublications.com/open-access/long-covid-is-there-a-role-for-antidepressants-1249.pdf (Full text)

“I Just Want to Feel Safe Going to a Doctor”: Experiences of Female Patients with Chronic Conditions in Australia

Abstract:

Background: The androcentric history of medicine and medical research has led to an ongoing sex and gender gap in health research and education. Sex and gender gaps in research and education may translate into real-life health inequities for women. This study aimed to explore the experiences of female patients with chronic health conditions in the Australian health system, considering existing sex and gender gaps in medicine.

Methods: This qualitative study used semistructured in-depth interviews with a sample of adult women with chronic conditions in Australia. Thematic analysis was undertaken, guided by Braun and Clarke. Software NVivoX64 assisted in the management of the data. Coding was performed before grouping into subthemes and central themes. To allow for potential researcher biases, the principal researcher engaged in the practice of reflexivity, including the writing of detailed notes during analysis.

Results: Twenty adult Australian women with chronic conditions were interviewed. Diagnoses were varied and included Ehlers-Danlos syndrome, chronic fatigue syndrome, functional neurological disorder, and inflammatory bowel disease. Four central themes emerged: diagnostic difficulties; spectrum of health care experiences; understanding medical complexity; and coping with symptoms.

Conclusions: Women with chronic conditions in Australia report pain, fatigue, and suffering that significantly impacts upon their daily lives. There was a shared experience of feeling that the pain and suffering of women was dismissed or not taken seriously. Many women expressed trauma because of their experiences in health care and often this led to a fear of accessing health services. The participants highlighted a need for more knowledge, understanding, and empathy from health care practitioners.

Source: Merone L, Tsey K, Russell D, Nagle C. “I Just Want to Feel Safe Going to a Doctor”: Experiences of Female Patients with Chronic Conditions in Australia. Womens Health Rep (New Rochelle). 2022 Dec 22;3(1):1016-1028. doi: 10.1089/whr.2022.0052. PMID: 36636320; PMCID: PMC9811844. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9811844/ (Full text)

The Role of Immunity and Inflammation in ME/ CFS and Post-COVID Syndrome: Implications for Treatment

Abstract:

Probably one in seven patients who have experienced acute COVID-19 continue having long-lasting complaints, called post-COVID syndrome or long-COVID, that are similar to those observed in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

There are good reasons to believe that common immunological, epigenetic and inflammatory mechanisms are involved in the pathogenesis both diseases.

To date, various therapeutic approaches have been recommended, but with moderate success. In the present opinion paper, the author weights his clinical experience against data from the literature, and suggests novel approaches.

In addition to general measures and paramedical approaches, food supplementation with a specific nutraceutical can be completed by oral administration of sodium dichloroacetate and Meldonium to optimize glucose metabolism and mitochondrial energy generation.

Alternatively, intravenous infusions with magnesium salt and multivitamins can be completed with glutathione, m-tranexamic acid, and cultured stem cells.

Preliminary results of an open-label, prospective, two-centre trial suggest more than four in five patients benefit from combined oral and infusion therapy with significantly diminished fatigue and improved well-being.

Monoclonal antibodies in “biologicals”, blocking the effects of cytokines, and “small molecules” with Janus kinase inhibiting activity may offer novel opportunities by focusing on both immunologic and inflammation targets. A pilot trial with, in particular, one of the Janus kinase inhibitors could be considered.

Source: Comhaire F. The Role of Immunity and Inflammation in ME/CFS and Post-COVID Syndrome: Implications for Treatment. MedLife Clinics 2022, Volume 4 (2), Article 1043 http://www.medtextpublications.com/open-access/the-role-of-immunity-and-inflammation-in-me-cfs-and-1254.pdf (Full text)

“Living like an empty gas tank with a leak”: Mixed methods study on post-acute sequelae of COVID-19

Abstract:

Background: The burden and presentation of post-acute sequela of SARS-CoV-2 infection (PASC) are a developing major public health concern.

Objectives: To characterize the burden of PASC in community-dwelling individuals and understand the experiences of people living with PASC.

Methods: This mixed-methods study of COVID-19 positive community-dwelling persons involved surveys and in-depth interviews. Main outcome was self-report of possible PASC symptoms 3 weeks or longer after positive COVID-19 test. In-depth interviews were guided by a semi-structured interview guide with open-ended questions and probes based on emerging literature on PASC and the impact of COVID-19.

Results: With a survey response rate of 70%, 442 participants were included in this analysis, mean (SD) age 45.4 (16.2) years, 71% female, 12% Black/African American. Compared to those with no PASC symptoms, persons who reported PASC symptoms were more likely to be older (mean age: 46.5 vs. 42; p = 0.013), female (74.3% vs. 61.2%; p = 0.010), to have pre-existing conditions (49.6% vs. 34%; p = 0.005), and to have been hospitalized for COVID-19 (14.2% vs. 2.9%; p = 0.002). About 30% of the participants experienced severe fatigue; the proportion of persons reporting severe fatigue was 7-fold greater in those with PASC symptoms (Adjusted Prevalence Ratio [aPR] 6.73, 95%CI: 2.80-16.18). Persons with PASC symptoms were more likely to report poor quality of life (16% vs. 5%, p<0.001) and worse mental health functioning (Mean difference: -1.87 95%CI: -2.38, -1.37, p<0.001). Themes from in-depth interviews revealed PASC was experienced as debilitating.

Conclusions: In this study, the prevalence of PASC among community-dwelling adults was substantial. Participants reported considerable coping difficulties, restrictions in everyday activities, invisibility of symptoms and experiences, and impediments to getting and receiving PASC care.

Source: Ogungbe O, Slone S, Alharthi A, Tomiwa T, Kumbe B, Bergman A, McNabb K, Smith Wright R, Farley JE, Dennison Himmelfarb CR, Cooper LA, Post WS, Davidson PM, Commodore-Mensah Y. “Living like an empty gas tank with a leak”: Mixed methods study on post-acute sequelae of COVID-19. PLoS One. 2022 Dec 30;17(12):e0279684. doi: 10.1371/journal.pone.0279684. PMID: 36584125; PMCID: PMC9803174. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9803174/ (Full text)