Tag: long covid pathophysiology

Persistent endothelial dysfunction in post-COVID-19 syndrome and its associations with symptom severity and chronic inflammation

Abstract:

Background: Post-COVID-19 syndrome (PCS) is a lingering disease with ongoing symptoms such as fatigue and cognitive impairment resulting in a high impact on the daily life of patients. Understanding the pathophysiology of PCS is a public health priority, as it still poses a diagnostic and treatment challenge for physicians.

Methods: In this prospective observational cohort study, we analyzed the retinal microcirculation using Retinal Vessel Analysis (RVA) in a cohort of patients with PCS and compared it to an age- and gender-matched healthy cohort (n=41, matched out of n = 204).

Measurements and main results: PCS patients exhibit persistent endothelial dysfunction (ED), as indicated by significantly lower venular flicker-induced dilation (vmax; 3.42% ± 1.77% vs. 4.64 % ± 2.59%; p = 0.02), narrower central retinal artery equivalent (CRAE; 178.1 [167.5 – 190.2] vs. 189.1 [179.4 – 197.2], p = 0.01) and lower arteriolar-venular ratio (AVR; (0.84 [0.8 – 0.9] vs. 0.88 [0.8 – 0.9], p = 0.007). When combining AVR and vmax, predicted scores reached good ability to discriminate groups (area under the curve: 0.75). Higher PCS severity scores correlated with lower AVR (R= -0.37 p = 0.017). The association of microvascular changes with PCS severity were amplified in PCS patients exhibiting higher levels of inflammatory parameters.

Conclusion: Our results demonstrate that prolonged endothelial dysfunction is a hallmark of PCS, and impairments of the microcirculation seem to explain ongoing symptoms in patients. As potential therapies for PCS emerge, RVA parameters may become relevant as clinical biomarkers for diagnosis and therapy management.

Source: Timon Kuchler, Roman Günthner, Andrea Ribeiro et al. Persistent endothelial dysfunction in post-COVID-19 syndrome and its associations with symptom severity and chronic inflammation, 22 May 2023, PREPRINT (Version 1) available at Research Square https://doi.org/10.21203/rs.3.rs-2952588/v1 (Full text)

The Renin-Angiotensin-System in COVID-19: Can Long COVID Be Predicted?

Abstract:

(1) Background: Co-morbidities such as hypertension and cardiovascular disease are major risk factors for severe COVID-19. The renin-angiotensin-system (RAS) is critically involved in their pathophysiology and is counterbalanced by both angiotensin-converting enzyme 2 (ACE2), the functional receptor of SARS-CoV-2, and the kallikrein-kinin-system (KKS). Considerable research interest with respect to COVID-19 treatment is, thus, currently directed towards the components of these systems. In an earlier study, we noticed significantly reduced carboxypeptidase N (CPN, KKS member) activity and partially excessive angiotensin-converting enzyme (ACE, RAS member) activity in the sera of both hospitalized (HoP) COVID-19 patients and a sub-group of covalescent patients, while in the majority of the probands recovering from the disease these values had returned to normal. The data had been obtained using bradykinin (BK) as a reporter peptide, which is a target of both CPN and ACE, and they were supplemented by serum proteomics of the same patient cohort. We hypothesized that the data could be indicative of Long COVID, which had not been fully appreciated at the time of our study.;

(2) Methods: The data were re-evaluated in the light of Long COVID. The recent literature on the RAS in COVID-19, antihypertensiva, and Long COVID was briefly reviewed.;

(3) Results: While the levels of the BK serum degradation products should return to normal concentrations during convalescence, this was not true for some patients. This could be due to persisting liver problems, because CPN is synthesized there, but also to a dysregulated RAS. This was not reflected in the levels of selected RAS/KKS serum proteins like angiotensinogen (AGT), although AGT correlated with disease severity in HoP. However, standard tests in routine patient care in Long COVID often come back normal, and it may be that BK degradation is specific in some pathophysiologies. Moreover, the HoP group was sub-divided based on the serum protein profiles and COVID-19 severity.;

(4) Conclusions: We point out two insights: 1) Sensitive technology such as omics methods might provide unexpected significant differences within the pre-defined patient groups of a clinical study. Those can only be explored, if the cohorts are large enough and properly matched with respect to the parameters known beforehand (e.g., age, gender, co-morbidities). 2) Results of the BK-reporter serum protease activity assay could be indicative of persisting liver problems and/or potentially of Long COVID. Clinical studies are required to test this hypothesis.

Source: König, S.; Vollenberg, R.; Tepasse, P. The Renin-Angiotensin-System in COVID-19: Can Long COVID Be Predicted?. Preprints.org 2023, 2023051298. https://doi.org/10.20944/preprints202305.1298.v1 (Full text available as PDF file)

Long COVID is primarily a Spike protein Induced Thrombotic Vasculitis

Abstract:

Long COVID describes an array of often debilitating symptoms in the aftermath of SARS-CoV-2 infection, with similar symptomatology affecting some people post-vaccination. With an estimated > 200 million Long COVID patients worldwide and cases still rising, the effects on quality of life and the economy are significant, thus warranting urgent attention to understand the pathophysiology. Herein we describe our perspective that Long COVID is a continuation of acute COVID-19 pathology, whereby coagulopathy is the main driver of disease and can cause or exacerbate other pathologies common in Long COVID, such as mast cell activation syndrome and dysautonomia.
Considering the SARS-CoV-2 spike protein can independently induce fibrinaloid microclots, platelet activation, and endotheliitis, we predict that persistent spike protein will be a key mechanism driving the continued coagulopathy in Long COVID. We discuss several treatment targets to address the coagulopathy, and predict that (particularly early) treatment with combination anticoagulant and antiplatelet drugs will bring significant relief to many patients, supported by a case study. To help focus attention on such treatment targets, we propose Long COVID should be referred to as Spike protein Induced Thrombotic Vasculitis (SITV). These ideas require urgent testing, especially as the world tries to co-exist with COVID-19.

Source: Kerr R, Carroll HA. Long COVID is primarily a Spike protein Induced Thrombotic Vasculitis. Research Square; 2023. DOI: 10.21203/rs.3.rs-2939263/v1. https://assets.researchsquare.com/files/rs-2939263/v1_covered_7190a867-1475-4b57-b220-716a953649f1.pdf?c=1684433225 (Full text)

Sonographic Diaphragm Abnormalities are an Unexpectedly Frequent Feature of Long COVID Outpatients with Unexplained Dyspnea and Fatigue

Abstract:

Purpose: The primary aim of this study is to define the sonographic diaphragm phenotype of Long COVID rehabilitation outpatients with non-specific dyspnea and fatigue. We analyzed patients referred from a pulmonary post-COVID clinic that were lacking a specific cardiopulmonary diagnosis for their symptoms. Additionally, we report the functional outcomes of subset of patients who completed an outpatient cardiopulmonary physical therapy program.

Methods: This was a retrospective cohort study (n = 58) of consecutive patients referred for neuromuscular ultrasound assessment of diaphragm muscle using B-mode technique. Patients were recruited from a single academic hospital between February 25, 2021 and November 22, 2022.

Results: Sonographic abnormalities were identified in 57% (33/58) of patients, and in the vast majority of cases (33/33) was defined by a low diaphragm muscle thickness. Thinner diaphragm muscles are correlated with lower serum creatinine and creatine kinase values, but there was no association with markers of systemic inflammation. Thirty three patients participated in outpatient cardiopulmonary physical therapy that included respiratory muscle training, and 75.8% (25/33) had documented improvement.

Conclusion: In the outpatient rehabilitation setting, patients with Long COVID display low diaphragm muscle thickness, but intact muscle contractility, with surprising frequency on neuromuscular ultrasound. We speculate this represents a form of disuse atrophy. Also, these patients appear to have a favorable response to cardiopulmonary physical therapy that includes respiratory muscle training.

Source: Prabhav P. Deo, Joseph I. Bailey, Alexandra S. Jensen, Ellen Farr, Meghan Fahey, Matthew Isherwood, Keerthana Chakka, Lisa F. Wolfe, Ishan Roy, Marc A. Sala, Colin K. Franz. Sonographic Diaphragm Abnormalities are an Unexpectedly Frequent Feature of Long COVID Outpatients with Unexplained Dyspnea and Fatigue. medRxiv 2022.06.29.22277054; doi: https://doi.org/10.1101/2022.06.29.22277054 (Full text)

Thromboembolism in the Complications of Long COVID-19

Abstract:

SARS-CoV-2 is a +ssRNA helical coronavirus responsible for the global pandemic caused by coronavirus disease 19 (COVID-19). Classical clinical symptoms from primary COVID-19 when symptomatic include cough, fever, pneumonia or even ARDS; however, they are limited primarily to the respiratory system. Long-COVID-19 sequalae is responsible for many pathologies in almost every organ system and may be present in up to 30% of patients who have developed COVID-19.

Our review focuses on how long-COVID-19 (3 -24 weeks after primary symptoms) may lead to an increased risk for stroke and thromboembolism. Patients who were found to be primarily at risk for thrombotic events included critically ill and immunocompromised patients. Additional risk factors for thromboembolism and stroke included diabetes, hypertension, respiratory and cardiovascular disease, and obesity.

The etiology of how long-COVID-19 leads to a hypercoagulable state are yet to be definitively elucidated. However, anti-phospholipid antibodies and elevated D-dimer are present in many patients who develop thromboembolism. In addition, chronic upregulation and exhaustion of the immune system may lead to a pro-inflammatory and hypercoagulable state, increasing the likelihood for induction of thromboembolism or stroke. ‘

This article provides an up-to-date review on the proposed etiologies for thromboembolism and stroke in patients with long-COVID-19 and to assist health care providers in examining patients who may be at a higher risk for developing these pathologies.

Source: Leilani A Lopes, Devendra K Agrawal. Thromboembolism in the Complications of Long COVID-19. Cardiology and Cardiovascular
Medicine. 7 (2023): 123-128. https://fortunepublish.com/articles/10.26502.fccm.92920317.pdf (Full text)

Reduced exercise capacity, chronotropic incompetence, and early systemic inflammation in cardiopulmonary phenotype Long COVID

Abstract:

Background: Mechanisms underlying persistent cardiopulmonary symptoms following SARS-CoV-2 infection (post-acute sequelae of COVID-19 “PASC” or “Long COVID”) remain unclear. This study sought to elucidate mechanisms of cardiopulmonary symptoms and reduced exercise capacity.

Methods: We conducted cardiopulmonary exercise testing (CPET), cardiac magnetic resonance imaging (CMR) and ambulatory rhythm monitoring among adults > 1 year after confirmed SARS-CoV-2 infection in a post-COVID cohort, compared those with or without symptoms, and correlated findings with previously measured biomarkers.

Results: Sixty participants (median age 53, 42% female, 87% non-hospitalized) were studied at median 17.6 months following SARS-CoV-2 infection. On CPET, 18/37 (49%) with symptoms had reduced exercise capacity (<85% predicted) compared to 3/19 (16%) without symptoms (p = 0.02). Adjusted peak VO2 was 5.2 ml/kg/min lower (95%CI 2.1-8.3; p = 0.001) or 16.9% lower percent predicted (95%CI 4.3-29.6; p = 0.02) among those with symptoms. Chronotropic incompetence was common. Inflammatory markers and antibody levels early in PASC were negatively correlated with peak VO2 more than 1 year later. Late-gadolinium enhancement on CMR and arrhythmias were absent.

Conclusions: Cardiopulmonary symptoms >1 year following COVID-19 were associated with reduced exercise capacity, which was associated with elevated inflammatory markers early in PASC. Chronotropic incompetence may explain exercise intolerance among some with cardiopulmonary Long COVID.

Source: Durstenfeld MS, Peluso MJ, Kaveti P, Hill C, Li D, Sander E, Swaminathan S, Arechiga VM, Lu S, Goldberg SA, Hoh R, Chenna A, Yee BC, Winslow JW, Petropoulos CJ, Kelly JD, Glidden DV, Henrich TJ, Martin JN, Lee YJ, Aras MA, Long CS, Grandis DJ, Deeks SG, Hsue PY. Reduced exercise capacity, chronotropic incompetence, and early systemic inflammation in cardiopulmonary phenotype Long COVID. J Infect Dis. 2023 May 11:jiad131. doi: 10.1093/infdis/jiad131. Epub ahead of print. PMID: 37166076. https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiad131/7159960 (Full text available as PDF file)

Pulmonary circulation abnormalities in post-acute COVID-19 syndrome: dual-energy CT angiographic findings in 79 patients

Abstract:

Objectives: To evaluate the frequency and pattern of pulmonary vascular abnormalities in the year following COVID-19.

Methods: The study population included 79 patients remaining symptomatic more than 6 months after hospitalization for SARS-CoV-2 pneumonia who had been evaluated with dual-energy CT angiography.

Results: Morphologic images showed CT features of (a) acute (2/79; 2.5%) and focal chronic (4/79; 5%) PE; and (b) residual post COVID-19 lung infiltration (67/79; 85%). Lung perfusion was abnormal in 69 patients (87.4%). Perfusion abnormalities included (a) perfusion defects of 3 types: patchy defects (n = 60; 76%); areas of non-systematized hypoperfusion (n = 27; 34.2%); and/or PE-type defects (n = 14; 17.7%) seen with (2/14) and without (12/14) endoluminal filling defects; and (b) areas of increased perfusion in 59 patients (74.9%), superimposed on ground-glass opacities (58/59) and vascular tree-in-bud (5/59). PFTs were available in 10 patients with normal perfusion and in 55 patients with abnormal perfusion. The mean values of functional variables did not differ between the two subgroups with a trend toward lower DLCO in patients with abnormal perfusion (74.8 ± 16.7% vs 85.0 ± 8.1).

Conclusion: Delayed follow-up showed CT features of acute and chronic PE but also two types of perfusion abnormalities suggestive of persistent hypercoagulability as well as unresolved/sequelae of microangiopathy.

Clinical relevance statement: Despite dramatic resolution of lung abnormalities seen during the acute phase of the disease, acute pulmonary embolism and alterations at the level of lung microcirculation can be identified in patients remaining symptomatic in the year following COVID-19.

Key points: • This study demonstrates newly developed proximal acute PE/thrombosis in the year following SARS-CoV-2 pneumonia. • Dual-energy CT lung perfusion identified perfusion defects and areas of increased iodine uptake abnormalities, suggestive of unresolved damage to lung microcirculation. • This study suggests a complementarity between HRCT and spectral imaging for proper understanding of post COVID-19 lung sequelae.

Source: Mohamed I, de Broucker V, Duhamel A, Giordano J, Ego A, Fonne N, Chenivesse C, Remy J, Remy-Jardin M. Pulmonary circulation abnormalities in post-acute COVID-19 syndrome: dual-energy CT angiographic findings in 79 patients. Eur Radiol. 2023 Apr 25:1–13. doi: 10.1007/s00330-023-09618-9. Epub ahead of print. PMID: 37145145; PMCID: PMC10129318. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10129318/ (Full text)

Post-acute Sequelae of SARS Co-V2 and Chronic Fatigue/Myalgic Encephalitis Share Similar Pathophysiologic Mechanisms of Exercise Limitation

Abstract:

Abstract available online: https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A6470

Source: S. Jothi, G. Claessen, M. Insel, S. Kubba, E. Howden, S.-R. Carmona, F.P. Rischard. Post-acute Sequelae of SARS Co-V2 and Chronic Fatigue/Myalgic Encephalitis Share Similar Pathophysiologic Mechanisms of Exercise Limitation. https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A6470

Netosis -A double-edged sword in the Pathogenesis of LONG COVID

Abstract:

The emergence of COVID-19 as a global pandemic has had far-reaching effects on the health of individuals worldwide. Although there has been a decrease in the severity of the disease, there is a growing concern about the long-term impact of COVID-19 on the health of individuals, particularly cardiovascular complications, known as Long-COVID, which can significantly increase morbidity and mortality rates in people recovering from COVID-19 in the recent past.
The severity of COVID-19 has been linked to various factors, including the role of neutrophils and neutrophil extracellular traps (NET). These extracellular webs, composed of chromatin, microbicidal proteins, and oxidant enzymes, are released by neutrophils to fight infections. However, if not properly regulated, NETs can lead to thrombo-inflammatory states and microangiopathy in the body, resulting in complications such as sepsis, thrombosis, and respiratory failure.
Understanding the detailed pathophysiology and association of NETs with the prognosis of COVID-19 infection is crucial for future implications and management. The purpose of this review is to analyze the potential contribution of NETosis in the pathophysiology of COVID-19 and its subsequent complications apart from its beneficial effect. This may provide insight into potential therapeutic interventions for COVID-19 patients.
Source: Durre Aden, vagisha sharma, sufian zaheer, et al. Netosis -A double-edged sword in the Pathogenesis of LONG COVID. Authorea. April 28, 2023. https://www.authorea.com/users/570888/articles/640398-netosis-a-double-edged-sword-in-the-pathogenesis-of-long-covid (Full text available as PDF file)

Damage to endothelial barriers and its contribution to long COVID

Abstract:

The world continues to contend with COVID-19, fueled by the emergence of viral variants. At the same time, a subset of convalescent individuals continues to experience persistent and prolonged sequelae, known as long COVID. Clinical, autopsy, animal and in vitro studies all reveal endothelial injury in acute COVID-19 and convalescent patients. Endothelial dysfunction is now recognized as a central factor in COVID-19 progression and long COVID development.

Different organs contain different types of endothelia, each with specific features, forming different endothelial barriers and executing different physiological functions. Endothelial injury results in contraction of cell margins (increased permeability), shedding of glycocalyx, extension of phosphatidylserine-rich filopods, and barrier damage.

During acute SARS-CoV-2 infection, damaged endothelial cells promote diffuse microthrombi and destroy the endothelial (including blood-air, blood-brain, glomerular filtration and intestinal-blood) barriers, leading to multiple organ dysfunction. During the convalescence period, a subset of patients is unable to fully recover due to persistent endothelial dysfunction, contributing to long COVID. There is still an important knowledge gap between endothelial barrier damage in different organs and COVID-19 sequelae. In this article, we mainly focus on these endothelial barriers and their contribution to long COVID.

Source: Wu X, Xiang M, Jing H, Wang C, Novakovic VA, Shi J. Damage to endothelial barriers and its contribution to long COVID. Angiogenesis. 2023 Apr 27:1–18. doi: 10.1007/s10456-023-09878-5. Epub ahead of print. PMID: 37103631; PMCID: PMC10134732. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10134732/ (Full text)