Tag: long covid pathophysiology

Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-Acute Sequelae of SARS-CoV-2: More in Common Than Not?

Abstract:

Topic importance: Post-Acute Sequelae of SARS-CoV-2 (PASC) is a long-term consequence of acute infection from coronavirus disease 2019 (COVID-19). Clinical overlap between PASC and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has been observed, with shared symptoms including intractable fatigue, postexertional malaise, and orthostatic intolerance. The mechanistic underpinnings of such symptoms are poorly understood.

Review findings: Early studies suggest deconditioning as the primary explanation for exertional intolerance in PASC. Cardiopulmonary exercise testing (CPET) reveals perturbations related to systemic blood flow and ventilatory control associated with acute exercise intolerance in PASC, which are not typical of simple detraining. Hemodynamic and gas exchange derangements in PASC have substantial overlap with those observed with ME/CFS, suggestive of shared mechanisms.

Summary: This review aims to illustrate exercise pathophysiologic commonalities between PASC and ME/CFS that will help guide future diagnostics and treatment.

Source: Joseph P, Singh I, Oliveira R, Capone CA, Mullen MP, Cook DB, Stovall MC, Squires J, Madsen K, Waxman AB, Systrom DM. Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-Acute Sequelae of SARS-CoV-2: More in Common Than Not? Chest. 2023 Apr 11:S0012-3692(23)00502-0. doi: 10.1016/j.chest.2023.03.049. Epub ahead of print. PMID: 37054777; PMCID: PMC10088277. https://pubmed.ncbi.nlm.nih.gov/37054777/

Rapid flow cytometric analysis of fibrin amyloid microclots in Long COVID

Abstract:

Long COVID has become a significant global health and economic burden, yet there are currently no established diagnostic tools to identify which patients might benefit from specific treatments. One of the major pathophysiological factors contributing to Long COVID is the presence of hypercoagulability; this results in insoluble amyloid microclots that are resistant to fibrinolysis.

Our previous research using fluorescence microscopy has demonstrated a significant amyloid microclot load in Long COVID patients. However, this approach lacked statistical robustness, objectivity, and rapid throughput. In the current study, we have used imaging flow cytometry for the first time to show significantly increased concentration and size of these microclots.

We identified notable variations in size and fluorescence between microclots in Long COVID and those of controls even using a 20x objective. By combining cell imaging and the high-event-rate nature of a conventional flow cytometer, imaging flow cytometry can eliminate erroneous results and increase accuracy in gating and analysis beyond what pure quantitative measurements from conventional flow cytometry can provide.

Although imaging flow cytometry was used in our study, our results suggest that the signals indicating the presence of microclots should be easily detectable using a conventional flow cytometer. Flow cytometry is a more widely available technique which has been used in pathology laboratories for decades, rendering it a potentially more suitable and accessible method for detecting microclots in individuals suffering from both Long COVID and other conditions with similar pathology, such as myalgic encephalomyelitis.

Source: Turner, Simone and Laubscher, Gert Jacobus and Khan, M. Asad and Kell, Douglas and Pretorius, Etheresia, Rapid Flow Cytometric Analysis of Fibrin Amyloid Microclots in Long COVID. Available at SSRN: https://ssrn.com/abstract=4405265 or http://dx.doi.org/10.2139/ssrn.4405265 https://assets.researchsquare.com/files/rs-2731434/v1/0b4877b0-99fa-499c-9d65-3b6e43865d86.pdf?c=1680099696 (Full text)

Multiplatform analyses reveal distinct drivers of systemic pathogenesis in adult versus pediatric severe acute COVID-19

Abstract:

The pathogenesis of multi-organ dysfunction associated with severe acute SARS-CoV-2 infection remains poorly understood. Endothelial damage and microvascular thrombosis have been identified as drivers of COVID-19 severity, yet the mechanisms underlying these processes remain elusive. Here we show alterations in fluid shear stress-responsive pathways in critically ill COVID-19 adults as compared to non-COVID critically ill adults using a multiomics approach.

Mechanistic in-vitro studies, using microvasculature-on-chip devices, reveal that plasma from critically ill COVID-19 adults induces fibrinogen-dependent red blood cell aggregation that mechanically damages the microvascular glycocalyx. This mechanism appears unique to COVID-19, as plasma from non-COVID sepsis patients demonstrates greater red blood cell membrane stiffness but induces less significant alterations in overall blood rheology.

Multiomics analyses in pediatric patients with acute COVID-19 or the post-infectious multi-inflammatory syndrome in children (MIS-C) demonstrate little overlap in plasma cytokine and metabolite changes compared to adult COVID-19 patients. Instead, pediatric acute COVID-19 and MIS-C patients show alterations strongly associated with cytokine upregulation. These findings link high fibrinogen and red blood cell aggregation with endotheliopathy in adult COVID-19 patients and highlight differences in the key mediators of pathogenesis between adult and pediatric populations.

Source: Druzak, S., Iffrig, E., Roberts, B.R. et al. Multiplatform analyses reveal distinct drivers of systemic pathogenesis in adult versus pediatric severe acute COVID-19. Nat Commun 14, 1638 (2023). https://doi.org/10.1038/s41467-023-37269-3 (Full text)

What is the role of brown adipose tissue in metabolic health: lessons learned and future perspectives in the long COVID?

Abstract:

Metabolic physiology plays a key role in maintaining our health and resilience. Metabolic disorders can lead to serious illnesses, including obesity. The pathogenesis of the new long COVID syndrome in individuals with long-term recovery after SARS-Co-2 infection is still incomplete. Thus there is growing attention in the study of adipose tissue activities, especially brown adipose tissue (BAT) and associated resilience which plays a crucial role in different types of obesity as potential targets for pharmacologic and nutritional interventions in the context of obesity and long COVID.

The number of studies examining mechanisms underlying BAT has grown rapidly in the last 10 years despite of role of BAT in individuals with COVID-19 and long COVID is modest. Therefore, this review aims to sum up data examining BAT activities, its resilience in health, obesity, and the possible link to long COVID.

The search was conducted on studies published in English mostly between 2004 and 2022 in adult humans and animal models. Database searches were conducted using PubMed, Scopus, and Google Scholar for key terms including adipose tissue, BAT, adipokinins, obesity, VPF/VEGF, and pathogenesis. From the initial search through the database were identified relevant articles that met inclusion and exclusion criteria and our data regarding adipose tissues were presented in this review.

It will discuss adiposity tissue activities. Current literature suggests that there are BAT integral effects to whitening and browning fat phenomenons which reflect the homeostatic metabolic adaptive ability for environmental demand or survival/adaptive mechanisms. We also review neural and vascular impacts in BAT that play a role in resilience and obesity. Finally, we discuss the role of BAT in the context of long COVID in basic research and clinical research.

Source: Muzyka, I., Revenko, O., Kovalchuk, I. et al. What is the role of brown adipose tissue in metabolic health: lessons learned and future perspectives in the long COVID?. Inflammopharmacol (2023). https://doi.org/10.1007/s10787-023-01195-z (Full text)

Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC)

Abstract:

COVID-19, with persistent and new onset of symptoms such as fatigue, post-exertional malaise, and cognitive dysfunction that last for months and impact everyday functioning, is referred to as Long COVID under the general category of post-acute sequelae of SARS-CoV-2 infection (PASC). PASC is highly heterogenous and may be associated with multisystem tissue damage/dysfunction including acute encephalitis, cardiopulmonary syndromes, fibrosis, hepatobiliary damages, gastrointestinal dysregulation, myocardial infarction, neuromuscular syndromes, neuropsychiatric disorders, pulmonary damage, renal failure, stroke, and vascular endothelial dysregulation. A better understanding of the pathophysiologic mechanisms underlying PASC is essential to guide prevention and treatment.

This review addresses potential mechanisms and hypotheses that connect SARS-CoV-2 infection to long-term health consequences. Comparisons between PASC and other virus-initiated chronic syndromes such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome will be addressed. Aligning symptoms with other chronic syndromes and identifying potentially regulated common underlining pathways may be necessary for understanding the true nature of PASC.

The discussed contributors to PASC symptoms include sequelae from acute SARS-CoV-2 injury to one or more organs, persistent reservoirs of the replicating virus or its remnants in several tissues, re-activation of latent pathogens such as Epstein-Barr and herpes viruses in COVID-19 immune-dysregulated tissue environment, SARS-CoV-2 interactions with host microbiome/virome communities, clotting/coagulation dysregulation, dysfunctional brainstem/vagus nerve signaling, dysautonomia or autonomic dysfunction, ongoing activity of primed immune cells, and autoimmunity due to molecular mimicry between pathogen and host proteins. The individualized nature of PASC symptoms suggests that different therapeutic approaches may be required to best manage specific patients.

Source: Sherif ZA, Gomez CR, Connors TJ, Henrich TJ, Reeves WB; RECOVER Mechanistic Pathway Task Force. Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC). Elife. 2023 Mar 22;12:e86002. doi: 10.7554/eLife.86002. PMID: 36947108; PMCID: PMC10032659. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10032659/ (Full text)

Pathogenesis Underlying Neurological Manifestations of Long COVID Syndrome and Potential Therapeutics

Abstract:

The development of long-term symptoms of coronavirus disease 2019 (COVID-19) more than four weeks after primary infection, termed “long COVID” or post-acute sequela of COVID-19 (PASC), can implicate persistent neurological complications in up to one third of patients and present as fatigue, “brain fog”, headaches, cognitive impairment, dysautonomia, neuropsychiatric symptoms, anosmia, hypogeusia, and peripheral neuropathy. Pathogenic mechanisms of these symptoms of long COVID remain largely unclear; however, several hypotheses implicate both nervous system and systemic pathogenic mechanisms such as SARS-CoV2 viral persistence and neuroinvasion, abnormal immunological response, autoimmunity, coagulopathies, and endotheliopathy.
Outside of the CNS, SARS-CoV-2 can invade the support and stem cells of the olfactory epithelium leading to persistent alterations to olfactory function. SARS-CoV-2 infection may induce abnormalities in innate and adaptive immunity including monocyte expansion, T-cell exhaustion, and prolonged cytokine release, which may cause neuroinflammatory responses and microglia activation, white matter abnormalities, and microvascular changes. Additionally, microvascular clot formation can occlude capillaries and endotheliopathy, due to SARS-CoV-2 protease activity and complement activation, can contribute to hypoxic neuronal injury and blood–brain barrier dysfunction, respectively.
Current therapeutics target pathological mechanisms by employing antivirals, decreasing inflammation, and promoting olfactory epithelium regeneration. Thus, from laboratory evidence and clinical trials in the literature, we sought to synthesize the pathophysiological pathways underlying neurological symptoms of long COVID and potential therapeutics.
Source: Leng A, Shah M, Ahmad SA, Premraj L, Wildi K, Li Bassi G, Pardo CA, Choi A, Cho S-M. Pathogenesis Underlying Neurological Manifestations of Long COVID Syndrome and Potential Therapeutics. Cells. 2023; 12(5):816. https://doi.org/10.3390/cells12050816 (Full text)

Symptomatic Characteristics of Hypozincemia Detected in Long COVID Patients

Abstract:

Objectives: The aim of this study was to determine the characteristics of hypozincemia in long COVID patients.
Methods: This study was a single-center retrospective observational study for outpatients who visited the long COVID clinic established in a university hospital during the period from 15 February 2021 to 28 February 2022. Characteristics of patients with a serum zinc concentration lower than 70 μg/dL (10.7 μmol/L) were compared with characteristics of patients with normozincemia.
Results: In a total of 194 patients with long COVID after excluding 32 patients, hypozincemia was detected in 43 patients (22.2%) including 16 male patients (37.2%) and 27 female patients (62.8%). Among various parameters including the background characteristics of the patients and medical histories, the patients with hypozincemia were significantly older than the patients with normozincemia (median age: 50 vs. 39 years). A significant negative correlation was found between serum zinc concentrations and age in male patients (R = −0.39; p < 0.01) but not in female patients. In addition, there was no significant correlation between serum zinc levels and inflammatory markers. General fatigue was the most frequent symptom in both male patients with hypozincemia (9 out of 16: 56.3%) and female patients with hypozincemia (8 out of 27: 29.6%). Patients with severe hypozincemia (serum zinc level lower than 60 μg/dL) had major complaints of dysosmia and dysgeusia, which were more frequent complaints than general fatigue.
Conclusions: The most frequent symptom in long COVID patients with hypozincemia was general fatigue. Serum zinc levels should be measured in long COVID patients with general fatigue, particularly in male patients.
Source: Matsuda Y, Tokumasu K, Otsuka Y, Sunada N, Honda H, Sakurada Y, Nakano Y, Hasegawa T, Obika M, Ueda K, Otsuka F. Symptomatic Characteristics of Hypozincemia Detected in Long COVID Patients. Journal of Clinical Medicine. 2023; 12(5):2062. https://doi.org/10.3390/jcm12052062 https://www.mdpi.com/2077-0383/12/5/2062 (Full text)

Long COVID: An unpredicted multisystem syndrome of COVID-19 disease

Abstract:

Long COVID is multisystem syndrome with nonspecific symptoms and organic signs of unidentified pathology occurs after COVID-19 disease. Long COVID symptoms has been documented in some cases irrespective of disease severity or hospitalization.
Long COVID symptoms has significant impact on quality of life in those cases suffered from disease in recent past and lingering to almost two years since infection. Importantly, not all cases of COVID-19 were shown long COVID symptoms. Pathophysiology resulting into long COVID manifestations is still not completely validated.
Researchers have reported ‘immune dysregulation’ and ‘coagulation abnormalities’ are probable pathophysiological mechanism for long COVID. Some of the long COVID effects shown complete reversibility including post COVID lung fibrosis. Reboot system to restore immune dysregulation and recovery in long COVID is real concern. Vaccination has not shown significant effect modifying long COVID manifestation. [Editor’s note: See conclusion in full text for a contradictory statement.]
Source: Hital Vishnu Patil, Neel Tandel and Gajanan Godhali. Long COVID: An unpredicted multisystem syndrome of COVID-19 disease. World Journal of Advanced Pharmaceutical and Life Sciences, 2023, 04(01), 005–012. https://www.researchgate.net/publication/368757849_Long_COVID_An_unpredicted_multisystem_syndrome_of_COVID-19_disease (Full text)

Organ and cell-specific biomarkers of Long-COVID identified with targeted proteomics and machine learning

Abstract:

Background: Survivors of acute COVID-19 often suffer prolonged, diffuse symptoms post-infection, referred to as “Long-COVID”. A lack of Long-COVID biomarkers and pathophysiological mechanisms limits effective diagnosis, treatment and disease surveillance. We performed targeted proteomics and machine learning analyses to identify novel blood biomarkers of Long-COVID.

Methods: A case-control study comparing the expression of 2925 unique blood proteins in Long-COVID outpatients versus COVID-19 inpatients and healthy control subjects. Targeted proteomics was accomplished with proximity extension assays, and machine learning was used to identify the most important proteins for identifying Long-COVID patients. Organ system and cell type expression patterns were identified with Natural Language Processing (NLP) of the UniProt Knowledgebase.

Results: Machine learning analysis identified 119 relevant proteins for differentiating Long-COVID outpatients (Bonferonni corrected P < 0.01). Protein combinations were narrowed down to two optimal models, with nine and five proteins each, and with both having excellent sensitivity and specificity for Long-COVID status (AUC = 1.00, F1 = 1.00). NLP expression analysis highlighted the diffuse organ system involvement in Long-COVID, as well as the involved cell types, including leukocytes and platelets, as key components associated with Long-COVID.

Conclusions: Proteomic analysis of plasma from Long-COVID patients identified 119 highly relevant proteins and two optimal models with nine and five proteins, respectively. The identified proteins reflected widespread organ and cell type expression. Optimal protein models, as well as individual proteins, hold the potential for accurate diagnosis of Long-COVID and targeted therapeutics.

Source: Patel MA, Knauer MJ, Nicholson M, Daley M, Van Nynatten LR, Cepinskas G, Fraser DD. Organ and cell-specific biomarkers of Long-COVID identified with targeted proteomics and machine learning. Mol Med. 2023 Feb 21;29(1):26. doi: 10.1186/s10020-023-00610-z. PMID: 36809921; PMCID: PMC9942653. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9942653/ (Full text)

Left atrial longitudinal strain analysis in long Covid-19 syndrome

Abstract:

It is known that during the active course of Coronavirus disease 2019 (COVID-19), myocardial injury has an established pathological base, while its myocardial injury post-recovery is still obscured.

The aim of this study was to evaluate the longitudinal left atrial strain (LAS) using speckle tracking echocardiography (STE) in COVID-19-recovered patients who are previously healthy without confounder comorbidities to detect the potential cardiac dysfunction. 200 patients were prospectively included and examined 4?12 weeks after recovery from COVID-19 infection. 137 participants with comorbidities or previous history of cardiopulmonary disease were excluded from the analysis. A total of 63 patients who fulfilled our inclusion criteria were recruited into two groups according to the presence or absence of persistent dyspnoea and exercise intolerance. Clinical, laboratory & comprehensive echocardiographic examinations were done for all.

We observed that 31.7% of the previously healthy individuals developed dyspnoea & exercise intolerance post-COVID-19 infection. There were significantly impaired LAS parameters in the symptomatic group (LA reservoir, contraction & conduit strain, 22.7%, -6.6% & -16.1% versus 40%, -12%, and ? 27% in the asymptomatic group with P < 0.000).

Only LA reservoir strain and LA stiffness can independently predict the development of dyspnoea & exercise intolerance post-COVID-19 at cut-off values of 30% & 24.5% respectively with a sensitivity of 90% and a specificity of 91%, P < 0.001. These impaired LAS parameters could explain the developed symptoms post-COVID-19 recovery, even before disturbed conventional diastolic echocardiographic parameters. LAS parameters are significantly associated with the developed exertional dyspnoea & exercise intolerance post-COVID-19. LA reservoir strain & LA stiffness could provide a simple, easily available tool that points to early LV diastolic dysfunction and may direct the therapy in this subset of the population.

Source: ZeinElabdeen SG, Sherif A, Kandil NT, Altabib AMO, Abdelrashid MA. Left atrial longitudinal strain analysis in long Covid-19 syndrome. Int J Cardiovasc Imaging. 2023 Feb 14:1–6. doi: 10.1007/s10554-023-02801-5. Epub ahead of print. PMID: 36786877; PMCID: PMC9927057. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9927057/ (Full text)