Tag: long covid pathomechanism

An Exercise Immune Fitness test to unravel mechanisms of post-acute sequelae of COVID-19

Abstract:

The Post-Acute Sequelae of COVID-19 (PASC) Syndrome is a debilitating syndrome with onset three months post COVID-19 infection, marked by the presence of fatigue, headache, cognitive dysfunction, post-exertional malaise, orthostatic intolerance, and dyspnea that is clinically relevant and is at least as severe as fatigue in several other clinical conditions, including cancer. The onset, progression, and symptom profile of PASC patients have considerable overlap with Myalgic-Encephalopathy/Chronic Fatigue Syndrome (ME/CFS).

In people with ME/CFS, exercise (and other types of exertion) can cause serious setbacks and deterioration in function. Post-exertional malaise (PEM) appears to be a common and a significant challenge for the majority of this patient group. Of the nearly 24 million adults in the U.S. who currently have long COVID, more than 80% are having some trouble carrying out daily activities. Mechanisms of PACS remain poorly understood.

While multi-omic information gathered at the time of acute COVID-19 onset may help predict long COVID outcomes, we here propose to test the hypothesis that additional molecular immunological information collected during standardized exercise-testing for cardio-respiratory fitness after recovery from acute COVID-19 can be used to improve the understanding of mechanisms of PASC.

Source: Deng MC. An Exercise Immune Fitness test to unravel mechanisms of post-acute sequelae of COVID-19. Expert Rev Clin Immunol. 2023 May 16. doi: 10.1080/1744666X.2023.2214364. Epub ahead of print. PMID: 37190994. https://www.tandfonline.com/doi/full/10.1080/1744666X.2023.2214364 (Full text)

Proteomic profiling demonstrates inflammatory and endotheliopathy signatures associated with impaired cardiopulmonary exercise hemodynamic profile in Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome

Abstract:

Approximately 50% of patients who recover from the acute SARS-CoV-2 experience Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome. The pathophysiological hallmark of PASC is characterized by impaired system oxygen extraction (EO2) on invasive cardiopulmonary exercise test (iCPET). However, the mechanistic insights into impaired EO2 remain unclear.

We studied 21 consecutive iCPET in PASC patients with unexplained exertional intolerance. PASC patients were dichotomized into mildly reduced (EO2peak-mild) and severely reduced (EO2peak-severe) EO2 groups according to the median peak EO2 value. Proteomic profiling was performed on mixed venous blood plasma obtained at peak exercise during iCPET.

PASC patients as a group exhibited depressed peak exercise aerobic capacity (peak VO2; 85 ± 18 vs. 131 ± 45% predicted; p = 0.0002) with normal systemic oxygen delivery, DO2 (37 ± 9 vs. 42 ± 15 mL/kg/min; p = 0.43) and reduced EO2 (0.4 ± 0.1 vs. 0.8 ± 0.1; p < 0.0001). PASC patients with EO2peak-mild exhibited greater DO2 compared to those with EO2peak-severe [42.9 (34.2-41.2) vs. 32.1 (26.8-38.0) mL/kg/min; p = 0.01]. The proteins with increased expression in the EO2peak-severe group were involved in inflammatory and fibrotic processes. In the EO2peak-mild group, proteins associated with oxidative phosphorylation and glycogen metabolism were elevated.

In PASC patients with impaired EO2, there exist a spectrum of PASC phenotype related to differential aberrant protein expression and cardio-pulmonary physiologic response. PASC patients with EO2peak-severe exhibit a maladaptive physiologic and proteomic signature consistent with persistent inflammatory state and endothelial dysfunction, while in the EO2peak-mild group, there is enhanced expression of proteins involved in oxidative phosphorylation-mediated ATP synthesis along with an enhanced cardiopulmonary physiological response.

Source: Singh I, Leitner BP, Wang Y, Zhang H, Joseph P, Lutchmansingh DD, Gulati M, Possick JD, Damsky W, Hwa J, Heerdt PM, Chun HJ. Proteomic profiling demonstrates inflammatory and endotheliopathy signatures associated with impaired cardiopulmonary exercise hemodynamic profile in Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome. Pulm Circ. 2023 Apr 1;13(2):e12220. doi: 10.1002/pul2.12220. PMID: 37091121; PMCID: PMC10113513. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10113513/ (Full text)

Changes in the State of Vital Systems with Long COVID-19

Abstract:

Long COVID-19 is a chronic disease that continues to be studied. Data on epidemiology and the main symptoms typical for long COVID-19 are presented. Issues related to the pathogenesis of the disease are discussed. At the same time, special attention is paid to the inflammation process (including of the vascular wall endothelium), the state of the immune system (cytokine storm), the hemostasis system (the mechanism for the development of microangiopathy and thrombosis), and oxidative stress. During the analysis, a special place is given to central nervous system disorders (including organic brain damage) and disorders of cognitive functions. In addition, currently known complications from the cardiovascular system and respiratory organs are described. The treatment and rehabilitation of patients with long COVID-19 is not only a medical, but also a significant social problem.

Source: Kuznik, B.I., Shapovalov, K.G. & Chalisova, N.I. Changes in the State of Vital Systems with Long COVID-19. Biol Bull Rev 13, 112–123 (2023). https://doi.org/10.1134/S2079086423020044 (Full text)

NETosis induction reflects COVID-19 severity and Long COVID: insights from a two-center patient cohort study in Israel

Abstract:

Background: COVID-19 severity and its late complications continue to be poorly understood. Neutrophil extracellular traps (NETs) form in acute COVID-19, likely contributing to morbidity and mortality. This study evaluated immunothrombosis markers in a comprehensive cohort of acute and recovered COVID-19 patients, including the association of NETs with LongCOVID.

Methods: One-hundred-seventy-seven patients were recruited from clinical cohorts at two Israeli centers: acute COVID-19 (mild/moderate, severe/critical), convalescent COVID-19 (recovered and Long COVID), along with 54 non-COVID controls. Plasma was examined for markers of platelet activation, coagulation, and NETs. Ex vivo NETosis induction capability was evaluated after neutrophil incubation with patient plasma.

Results: Soluble P-selectin, Factor VIII, von Willebrand factor, and platelet factor 4 were significantly elevated in COVID-19 patients versus controls. Myeloperoxidase (MPO)-DNA complex levels were increased only in severe COVID-19 and did not differentiate between COVID-19 severities or correlate with thrombotic markers. NETosis induction levels strongly correlated with illness severity/duration, platelet activation markers, and coagulation factors, and were significantly reduced upon dexamethasone treatment and recovery. Long COVID patients maintained higher NETosis induction, but not NET fragments, compared to recovered convalescent patients.

Conclusions: Increased NETosis induction can be detected in Long COVID patients. NETosis induction appears to be a more sensitive NET measurement than MPO-DNA levels in COVID-19, differentiating between disease severity and Long COVID patients. Ongoing NETosis induction capability in Long COVID may provide insights into pathogenesis and serve as a surrogate marker for persistent pathology. This study emphasizes the need to explore neutrophil-targeted therapies in acute and chronic COVID-19.

Source: Krinsky N, Sizikov S, Nissim S, Dror A, Sas A, Prinz H, Pri-Or E, Perek S, Raz-Pasteur A, Lejbkowicz I, Cohen-Matsliah SI, Almog R, Chen N, Kurd R, Jarjou’i A, Rokach A, Ben-Chetrit E, Schroeder A, Caulin AF, Yost CC, Schiffman JD, Goldfeder M, Martinod K. NETosis induction reflects COVID-19 severity and Long COVID: insights from a two-center patient cohort study in Israel. J Thromb Haemost. 2023 Apr 11:S1538-7836(23)00274-X. doi: 10.1016/j.jtha.2023.02.033. Epub ahead of print. PMID: 37054916; PMCID: PMC10088279. https://www.jthjournal.org/article/S1538-7836(23)00274-X/fulltext (Full text available as PDF file)

Long COVID: pathophysiological factors and abnormalities of coagulation

Abstract:

Acute COVID-19 infection is followed by prolonged symptoms in approximately one in ten cases: known as Long COVID. The disease affects ~65 million individuals worldwide. Many pathophysiological processes appear to underlie Long COVID, including viral factors (persistence, reactivation, and bacteriophagic action of SARS CoV-2); host factors (chronic inflammation, metabolic and endocrine dysregulation, immune dysregulation, and autoimmunity); and downstream impacts (tissue damage from the initial infection, tissue hypoxia, host dysbiosis, and autonomic nervous system dysfunction). These mechanisms culminate in the long-term persistence of the disorder characterized by a thrombotic endothelialitis, endothelial inflammation, hyperactivated platelets, and fibrinaloid microclots. These abnormalities of blood vessels and coagulation affect every organ system and represent a unifying pathway for the various symptoms of Long COVID.

Source: Simone Turner, Asad Khan, David Putrino, Ashley Woodcock, Douglas B. Kell, and Etheresia Pretorius.  Long COVID: pathophysiological factors and abnormalities of coagulation. Trends in Endocrinology & Metabolism. April 19, 2023. https://www.sciencedirect.com/science/article/pii/S1043276023000553 (Full text)

Long COVID symptoms, pathophysiology and possible mechanisms: Still, we are learning!

Abstract:
Long COVID is an unpredicted sequel of COVID-19 disease documented nearly in half cases globally. 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. Most common long COVID symptoms (ten in number) as joint pain, fatigability, chest discomfort, shortness of breath, hair loss, chest pain, weight gain, anxiety/depression & memory impairment. 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. Long COVID symptoms cases are more health conscious and usually follows pattern of doctor shopping due to underestimation by family physicians either due to lack of suspicion or lack of knowledge regarding treatment protocol.
Source: Shital Patil, Sanika Narkar, Jayashree Dahiphale, Vipul Raka, Shubham Choudhari. and Gajanan Gondhali. Long COVID symptoms, pathophysiology and possible mechanisms: Still, we are learning! World Journal of Advanced Pharmaceutical and Medical Research, 2023, 04(01), 053–065. https://zealjournals.com/wjapmr/content/long-covid-symptoms-pathophysiology-and-possible-mechanisms-still-we-are-learning (Full text available as PDF file)

Long COVID and the cardiovascular system-elucidating causes and cellular mechanisms in order to develop targeted diagnostic and therapeutic strategies: a joint Scientific Statement of the ESC Working Groups on Cellular Biology of the Heart and Myocardial and Pericardial Diseases

Abstract:

Long COVID has become a world-wide, non-communicable epidemic, caused by long-lasting multiorgan symptoms that endure for weeks or months after SARS-CoV-2 infection has already subsided. This scientific document aims to provide insight into the possible causes and therapeutic options available for the cardiovascular manifestations of long COVID.

In addition to chronic fatigue, which is a common symptom of long COVID, patients may present with chest pain, ECG abnormalities, postural orthostatic tachycardia, or newly developed supraventricular or ventricular arrhythmias. Imaging of the heart and vessels has provided evidence of chronic, post-infectious perimyocarditis with consequent left or right ventricular failure, arterial wall inflammation, or microthrombosis in certain patient populations.

Better understanding of the underlying cellular and molecular mechanisms of long COVID will aid in the development of effective treatment strategies for its cardiovascular manifestations. A number of mechanisms have been proposed, including those involving direct effects on the myocardium, microthrombotic damage to vessels or endothelium, or persistent inflammation.

Unfortunately, existing circulating biomarkers, coagulation, and inflammatory markers, are not highly predictive for either the presence or outcome of long COVID when measured 3 months after SARS-CoV-2 infection. Further studies are needed to understand underlying mechanisms, identify specific biomarkers, and guide future preventive strategies or treatments to address long COVID and its cardiovascular sequelae.

Source: Selvakumar J, Havdal LB, Drevvatne M, Brodwall EM, Lund Berven L, Stiansen-Sonerud T, Einvik G, Leegaard TM, Tjade T, Michelsen AE, Mollnes TE, Lund-Johansen F, Holmøy T, Zetterberg H, Blennow K, Sandler CX, Cvejic E, Lloyd AR, Wyller VBB. Prevalence and Characteristics Associated With Post-COVID-19 Condition Among Nonhospitalized Adolescents and Young Adults. JAMA Netw Open. 2023 Mar 1;6(3):e235763. doi: 10.1001/jamanetworkopen.2023.5763. PMID: 36995712; PMCID: PMC10064252. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10064252/ (Full text)

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)

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)

What is really ‘Long COVID’?

Abstract:

The previous acute respiratory diseases caused by viruses originating from China or the middle east (e.g., SARS, MERS) remained fast developing short diseases without major sequalae or any long-lasting complications. The new COVID-19, on the other hand, not only that it rapidly spread over the world, but some patients never fully recovered or even if they did, a few weeks later started to complain not only of shortness of breath, if any, but general weakness, muscle pains and ‘brain fog’, i.e., fuzzy memories. Thus, these signs and symptoms were eventually labelled ‘long COVID’, for which the most widely used definition is ‘new signs and symptoms occurring 4-8 weeks after recovering from acute stage of COVID-19’.

The other most frequent manifestations associated with long COVID include headache, loss of memory, smell and of hair, nausea, and vomiting. Thus, long COVID is not a simple disease, but complex disorder of several organ systems malfunctioning; hence, it is probably more appropriate to call this a syndrome.

The pathogenesis of long COVID syndrome is poorly understood, but initial and persistent vascular endothelial injury that often triggers the formation of microthrombi that if dislodged as emboli, damage several organs, especially in the brain, heart and kidney, by creating microinfarcts.

The other major contributory mechanistic factor is the persistent cytokine storm that may last longer in long COVID patients than in others, probably triggered by aggregates of SARS-Co-2 discovered recently in the adrenal cortex, kidney and brain.

The prevalence of long COVID is relatively high, e.g., initially varied 3-30%, and recent data indicate that 2.5% of UK population suffers from this syndrome, while in the US 14.7% of acute COVID-19 patients continued to have symptoms longer than 2 months. Thus, the long COVID syndrome deserves to be further investigated, both from clinical and basic research perspectives.

Source: Szabo S, Zayachkivska O, Hussain A, Muller V. What is really ‘Long COVID’? Inflammopharmacology. 2023 Mar 25:1–7. doi: 10.1007/s10787-023-01194-0. Epub ahead of print. PMID: 36964860; PMCID: PMC10039447. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10039447/ (Full text)