Tag: long Covid

Long COVID: A Chronic Shortage of Blood. Pathophysiology and Treatment Proposal

Abstract:

My hypothesis is that the signs and symptoms of Long COVID can be explained by a shortage of blood in the body and a resulting deficient blood flow through nearly all organs. This shortage arises through damage to the blood-producing organs during the acute phase, while the breakdown of blood continues as normal, after an initial increase.

In order to ensure the perfusion of organs that are directly necessary for survival, the body takes the emergency measure of diverting blood from other organs and tissues. The perfusion of the blood-producing organs is also affected by this distribution measure, which hinders the smooth recovery of the total blood volume. The body is stuck in this vicious circle: a shortage of circulating blood hinders the recovery of blood production. This explains the long duration of Long COVID.

My proposed treatment of Long COVID focuses on the recovery of the correct volume of blood in the body of the right composition by the very careful administration of donor blood products under continuous expert supervision. A trial treatment can be performed in any hospital without much additional preparations, and has a lower associated risk for the patient than analysing the total blood. A diagnosis ex juvantibus, by therapeutic response, is therefore preferable, and will result in the healing process starting earlier.

Indications in blood laboratory values of a shortage of blood are a high serum ferritin due to internal breakdown of blood and values for haematocrit and albumin at reciprocal extremes of the reference ranges due to a stagnation of blood production.

Source: Molenaar, P.A. Long COVID: A Chronic Shortage of Blood. Pathophysiology and Treatment Proposal. Preprints 2023, 2023092109. https://doi.org/10.20944/preprints202309.2109.v1 https://www.preprints.org/manuscript/202309.2109/v1 (Full text available as PDF file)

Maximal Oxidative Capacity During Exercise is Associated with Muscle Power Output in Patients with Long coronavirus disease 2019 (COVID-19) Syndrome. A Moderation Analysis

Abstract:

Background & Aims: Long COVID syndrome (LCS) involves persistent symptoms experienced by many patients after recovering from coronavirus disease 2019 (COVID-19). We aimed to assess skeletal muscle energy metabolism, which is closely related to peak fat oxidation rates during exercise, in patients with LCS compared with healthy controls. We also examined whether muscle power output mediates the relationship between COVID-19 and skeletal muscle energy metabolism.

Methods: In this cross-sectional study, we enrolled 71 patients with LCS and 63 healthy controls. We assessed clinical characteristics such as body composition, physical activity, and muscle strength. We used cardiopulmonary exercise testing to evaluate substrate oxidation rates during graded exercise. We performed statistical analyses to compare group characteristics and peak fat oxidation differences based on power output.

Results: The two-way analysis of covariance (ANCOVA) results, adjusted for covariates, showed that the patients with LCS had lower absolute maximal fatty acid oxidation (MFO), relative MFO/fat-free mass (FFM), absolute carbohydrates oxidation (CHox), relative CHox/FFM, and oxygen uptake (VO2) at maximum fat oxidation (mL∙min−1) than the healthy controls (P < 0.05). Moderation analysis indicated that muscle power output significantly influenced the relationship between LCS and reduced peak fat oxidation (interaction β = −0.105 [95% confidence interval −0.174; −0.036]; P = 0.026). Therefore, when muscle power output was below 388 W, the effect of the LCS on MFO was significant (62% in our study sample P = 0.010). These findings suggest compromised mitochondrial bioenergetics and muscle function, represented by lower peak fat oxidation rates, in the patients with LCS compared with the healthy controls.

Conclusion: The patients with LCS had lower peak fat oxidation during exercise compared with the healthy controls, potentially indicating impairment in skeletal muscle function. The relationship between peak fat oxidation and LCS appears to be mediated predominantly by muscle power output. Additional research should continue investigating LCS pathogenesis and the functional role of mitochondria.

Source: Robinson Ramírez-Vélez, Sergio Oscoz-Ochandorena, Yesenia García-Alonso, Nora García-Alonso, Gaizka Legarra-Gorgoñon, Julio Oteiza, Ander Ernaga Lorea, Mikel Izquierdo, María Correa-Rodríguez. Maximal Oxidative Capacity During Exercise is Associated with Muscle Power Output in Patients with Long coronavirus disease 2019 (COVID-19) Syndrome. A Moderation Analysis. Clinical Nutrition ESPEN, 2023, ISSN 2405-4577, https://doi.org/10.1016/j.clnesp.2023.10.009. https://www.sciencedirect.com/science/article/pii/S2405457723021666 (Full text)

Brain fog in long COVID: A glutamatergic hypothesis with astrocyte dysfunction accounting for brain PET glucose hypometabolism

Abstract:

Brain [18F]FDG-PET scans have revealed a glucose hypometabolic pattern in patients with long COVID. This hypometabolism might reflect primary astrocyte dysfunction. Astrocytes play a key role in regulating energy metabolism to support neuronal and synaptic activity, especially activity involving glutamate as the main neurotransmitter.

Neuroinflammation is one of the purported mechanisms to explain brain damage caused by infection with SARS-CoV-2. Microglial activation can trigger reactive astrogliosis, contributing to neuroinflammatory changes. These changes can disturb glutamatergic homeostasis, ultimately leading to cognitive fatigue, which has been described in other clinical situations.

We hypothesize that glutamatergic dysregulation related to astrocyte dysfunction could be the substrate of brain PET hypometabolism in long COVID patients with brain fog. Based on these elements, we propose that therapeutics targeting astrocytic glutamate regulation could help mitigate long COVID neurological manifestations.

Source: Tatiana Horowitz, Luc Pellerin, Eduardo R. Zimmer, Eric Guedj. Brain fog in long COVID: A glutamatergic hypothesis with astrocyte dysfunction accounting for brain PET glucose hypometabolism. Medical Hypotheses, Volume 180, 2023, 111186, ISSN 0306-9877, https://doi.org/10.1016/j.mehy.2023.111186. https://www.sciencedirect.com/science/article/pii/S0306987723001822 (Full text)

Complementary and alternative medicine for long COVID: a systematic review of randomized controlled trials

Abstract:

Background: Complementary and alternative medicine (CAM) interventions are growing in popularity as possible treatments for long COVID symptoms. However, comprehensive analysis of current evidence in this setting is still lacking.

Objective: This study aims to review existing published studies on the use of CAM interventions for patients experiencing long COVID through a systematic review.

Design: Systematic review of randomized controlled trials (RCTs).

Methods: A comprehensive electronic literature search was performed in multiple databases and clinical trial registries from September 2019 to January 2023. RCTs evaluating efficacy and safety of CAM for long COVID were included. Methodological quality of each included trial was appraised with the Cochrane ‘risk of bias’ tool. A qualitative analysis was conducted due to heterogeneity of included studies.

Results: A total of 14 RCTs with 1195 participants were included in this review. Study findings demonstrated that CAM interventions could benefit patients with long COVID, especially those suffering from neuropsychiatric disorders, olfactory dysfunction, cognitive impairment, fatigue, breathlessness, and mild-to-moderate lung fibrosis. The main interventions reported were self-administered transcutaneous auricular vagus nerve stimulation, neuro-meditation, dietary supplements, olfactory training, aromatherapy, inspiratory muscle training, concurrent training, and an online breathing and well-being program.

Conclusion: CAM interventions may be effective, safe, and acceptable to patients with symptoms of long COVID. However, the findings from this systematic review should be interpreted with caution due to various methodological limitations. More rigorous trials focused on CAM for long COVID are warranted in the future.

Source: Yang J, Lim KH, Lim KT, Woods JT, Mohabbat AB, Wahner-Roedler DL, Ganesh R, Bauer BA. Complementary and alternative medicine for long COVID: a systematic review of randomized controlled trials. Ther Adv Chronic Dis. 2023 Oct 11;14:20406223231204727. doi: 10.1177/20406223231204727. PMID: 37841213; PMCID: PMC10571674. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10571674/ (Full text)

Insomnia and sleep characteristics in post COVID-19 fatigue: A cross-sectional case-controlled study

Abstract:

Objective: Following COVID-19 many patients report persistent fatigue and insomnia. Given the overlapping features, insomnia can be underdiagnosed in post-COVID-19 fatigue patients. This study aimed to determine insomnia severity, prevalence of clinical insomnia and sleep characteristics of post-COVID-19 fatigue patients. Data of post-COVID-19 fatigue patients were compared with those of patients with chronic fatigue syndrome (ME/CFS), a condition resembling post-COVID-19 fatigue.

Methods: In this cross-sectional case-controlled study, insomnia severity, assessed with the Insomnia Severity Index (ISI), and prevalence of clinical insomnia (ISI score ≥ 10), were determined in patients with post-COVID-19 fatigue (n = 114) and compared with ME/CFS (n = 59) using ANCOVA and logistic regression, respectively. Linear regression analyses were used to evaluate whether mood, concentration problems, pain, fatigue (assessed with questionnaires) and diagnosis were associated with insomnia. Sleep characteristics were determined with a sleep diary and accelerometer in post-COVID-19 fatigue and compared with ME/CFS using ANCOVA.

Results: In patients with post-COVID-19 fatigue mean (SD) insomnia severity was 11.46 (5.7) and 64% reported clinical insomnia. Insomnia severity was significantly associated with depressive symptoms (ß = 0.49, p = 0.006) and age (ß = 0.08, p = 0.04). The mean (SD) subjective sleep duration was 7.4 (1.0) hours with a sleep efficiency of 82 (11)%. Several subjective sleep characteristics of the post-COVID-19 fatigue patients differed from ME/CFS patients; only sleep duration, being significantly shorter in post-COVID-19 fatigue patients (p = 0.003), seemed clinically relevant (d = 0.58).

Conclusion: Insomnia severity and prevalence of clinical insomnia are high in patients with post-COVID-19 fatigue. Insomnia should be assessed and if present treated with insomnia focused therapy.

Source: Nynke L. Rauwerda, Tanja A. Kuut, Annemarie M.J. Braamse, Irene Csorba, Pythia Nieuwkerk, Annemieke van Straten, Hans Knoop. Insomnia and sleep characteristics in post COVID-19 fatigue: A cross-sectional case-controlled study. Journal of Psychosomatic Research, 2023, 111522.ISSN 0022-3999, https://doi.org/10.1016/j.jpsychores.2023.111522.https://www.sciencedirect.com/science/article/pii/S0022399923003793

Pulmonary embolism in patients in acute COVID-19, long-COVID and post-COVID syndrome

Abstract:

COVID-19 is a disease caused by the SARS-CoV-2 virus, which, after entering a living organism, uses the ACE-2 protein as a receptor and several other proteins as cofactors of infection. Disease symptomatology is extensive, involving mostly predominant respiratory symptoms, as well as those of the nervous, gastrointestinal, circulatory and other systems. Incidence of COVID-19 also results in markedly different laboratory findings on the hemostatic system with the predominant feature of increased D-dimer levels.

In the pathogenesis of thromboembolic complications in COVID-19, all elements of Virchow’s triad are involved: endothelial damage, coagulation disorders and blood flow disorders. Coagulopathy increases with the severity of the clinical course of COVID-19.

One of the causes of mortality associated with COVID-19 is pulmonary embolism. SARS-CoV-2 infection increases the risk of thromboembolic complications not only in the acute period of the disease. Also in the period of about a month after recovery, there is an increased risk of venous thrombosis and consequently, life-threatening pulmonary embolism.

The classic biomarker of pulmonary embolism in the general population is D-dimers. Among imaging studies, the gold standard for diagnosing this disease is computed tomography of the pulmonary arteries (CTPA). Other useful diagnostic tests are ventilation-perfusion lung scintigraphy (VQ Scans) or echocardiography. Currently reviewed guidelines and recommendations recommend extensive thromboprophylaxis in COVID-19 patients in both acute and chronic phases of the disease.

Source: Tomczyk P, Tomczyk D. Pulmonary embolism in patients in acute COVID-19, long-COVID and post-COVID syndrome. Przegl Epidemiol. 2023;77(2):172-184. doi: 10.32394/pe.77.17. PMID: 37846660. https://pubmed.ncbi.nlm.nih.gov/37846660/

Gut-brain pathogenesis of post-acute COVID-19 neurocognitive symptoms

Approximately one third of non-hospitalized coronavirus disease of 2019 (COVID-19) patients report chronic symptoms after recovering from the acute stage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Some of the most persistent and common complaints of this post-acute COVID-19 syndrome (PACS) are cognitive in nature, described subjectively as “brain fog” and also objectively measured as deficits in executive function, working memory, attention, and processing speed. The mechanisms of these chronic cognitive sequelae are currently not understood.

SARS-CoV-2 inflicts damage to cerebral blood vessels and the intestinal wall by binding to angiotensin-converting enzyme 2 (ACE2) receptors and also by evoking production of high levels of systemic cytokines, compromising the brain’s neurovascular unit, degrading the intestinal barrier, and potentially increasing the permeability of both to harmful substances. Such substances are hypothesized to be produced in the gut by pathogenic microbiota that, given the profound effects COVID-19 has on the gastrointestinal system, may fourish as a result of intestinal post-COVID-19 dysbiosis. COVID-19 may therefore create a scenario in which neurotoxic and neuroinflammatory substances readily proliferate from the gut lumen and encounter a weakened neurovascular unit, gaining access to the brain and subsequently producing cognitive deficits.

Here, we review this proposed PACS pathogenesis along the gut-brain axis, while also identifying specific methodologies that are currently available to experimentally measure each individual component of the model.

Source: Plummer Allison M., Matos Yvette L., Lin Henry C., Ryman Sephira G., Birg Aleksandr, Quinn Davin K., Parada Alisha N., Vakhtin Andrei A. Gut-brain pathogenesis of post-acute COVID-19 neurocognitive symptoms. Frontiers in Neuroscience, Vol 17, 2023. DOI=10.3389/fnins.2023.1232480 ISSN=1662-453X  https://www.frontiersin.org/articles/10.3389/fnins.2023.1232480 (Full text)

Neuroinflammation in post-acute sequelae of COVID-19 (PASC) as assessed by [11C]PBR28 PET correlates with vascular disease measures

Abstract:

The COVID-19 pandemic caused by SARS-CoV-2 has triggered a consequential public health crisis of post-acute sequelae of COVID-19 (PASC), sometimes referred to as long COVID. The mechanisms of the heterogeneous persistent symptoms and signs that comprise PASC are under investigation, and several studies have pointed to the central nervous and vascular systems as being potential sites of dysfunction.

In the current study, we recruited individuals with PASC with diverse symptoms, and examined the relationship between neuroinflammation and circulating markers of vascular dysfunction. We used [11C]PBR28 PET neuroimaging, a marker of neuroinflammation, to compare 12 PASC individuals versus 43 normative healthy controls.

We found significantly increased neuroinflammation in PASC versus controls across a wide swath of brain regions including midcingulate and anterior cingulate cortex, corpus callosum, thalamus, basal ganglia, and at the boundaries of ventricles. We also collected and analyzed peripheral blood plasma from the PASC individuals and found significant positive correlations between neuroinflammation and several circulating analytes related to vascular dysfunction.

These results suggest that an interaction between neuroinflammation and vascular health may contribute to common symptoms of PASC.

Source: Michael B VanElzakker, Hannah F Bues, Ludovica Brusaferri, Minhae Kim, Deena Saadi, Eva-Maria Ratai, Darin D Dougherty, Marco L Loggia. Neuroinflammation in post-acute sequelae of COVID-19 (PASC) as assessed by [11C]PBR28 PET correlates with vascular disease measures. bioRxiv 2023.10.19.563117; doi: https://doi.org/10.1101/2023.10.19.563117 https://www.biorxiv.org/content/10.1101/2023.10.19.563117v1 (Full text available as PDF file)

Vitamin B12 as an epidrug for regulating peripheral blood biomarkers in long COVID-associated visuoconstructive deficit

Abstract:

Approximately four months after recovering from a mild COVID-19 infection, around 25% of individuals developed visuoconstructive deficit (VCD), which was found to be correlated with an increase in peripheral immune markers and alterations in structural and metabolic brain imaging. Recently, it has been demonstrated that supplemental vitamin B12 regulates hyperinflammation during moderate and severe COVID-19 through methyl-dependent epigenetic mechanisms.

Herein, whole peripheral blood cultures were produced using samples obtained from patients with confirmed persistent VCD, and controls without impairment, between 10 and 16 months after mild COVID-19. This experimental model was used to assess the leukocyte expression patterns of 11 biomarkers previously associated with VCD in long COVID and explore the potential of pharmacological B12 in regulating these genes. The results showed that patients with persistent VCD displayed continued upregulation of CCL11 and LIF compared to controls.

It is worth noting that elevated serum levels of CCL11 have been previously linked to age-related neurodegenerative diseases. Notably, the addition of 1 nM of vitamin B12 to blood cultures from individuals with VCD normalized the mRNA levels of CCL11, upregulated the neuroprotective HGF, and, to a lesser extent, downregulated CSF2 and CXCL10. There was an inverse correlation observed between CCL11 mRNA levels and methylation levels of specific cytosines in its promoter region.

These findings underscore the significance of systemic inflammation in persistent VCD associated with long COVID. Moreover, the study provides evidence suggesting that B12, acting as an epidrug, shows promise as a therapeutic approach for addressing this cognitive impairment.

Source: Larissa Cassiano, Jonas Paula, Daniela Rosa et al. Vitamin B12 as an epidrug for regulating peripheral blood biomarkers in long COVID-associated visuoconstructive deficit, 11 October 2023, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-3158180/v1] https://www.researchsquare.com/article/rs-3158180/v1 (Full text)

Genomic communication via circulating extracellular vesicles and long-term health consequences of COVID-19

Abstract:

COVID-19 continues to affect an unprecedented number of people with the emergence of new variants posing a serious challenge to global health. There is an expansion of knowledge in understanding the pathogenesis of Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the impact of the acute disease on multiple organs. In addition, growing evidence reports that the impact of COVID-19 on different organs persists long after the recovery phase of the disease, leading to long-term consequences of COVID-19.

These long-term consequences involve pulmonary as well as extra-pulmonary sequelae of the disease. Noteably, recent research has shown a potential association between COVID-19 and change in the molecular cargo of extracellular vesicles (EVs). EVs are vesicles released by cells and play an important role in cell communication by transfer of bioactive molecules between cells. Emerging evidence shows a strong link between EVs and their molecular cargo, and regulation of metabolism in health and disease.

This review focuses on current knowledge about EVs and their potential role in COVID-19 pathogenesis, their current and future implications as tools for biomarker and therapeutic development and their possible effects on long-term impact of COVID-19.

Source: Nair, S., Nova-Lamperti, E., Labarca, G. et al. Genomic communication via circulating extracellular vesicles and long-term health consequences of COVID-19. J Transl Med 21, 709 (2023). https://doi.org/10.1186/s12967-023-04552-2 https://link.springer.com/article/10.1186/s12967-023-04552-2 (Full text)