Tag: long covid pathophysiology

Amino acids, post-translational modifications, nitric oxide, and oxidative stress in serum and urine of long COVID and ex COVID human subjects

Abstract:

In this study, we investigated the status of amino acids, their post-translational modifications (PTM), major nitric oxide (NO) metabolites and of malondialdehyde (MDA) as a biomarker of oxidative stress in serum and urine samples of long COVID (LoCo, n = 124) and ex COVID (ExCo, n = 24) human subjects collected in 2022.

Amino acids and metabolites were measured by gas chromatography–mass spectrometry (GC–MS) methods using stable-isotope labelled analogs as internal standards. There were no differences with respect to circulating and excretory arginine and asymmetric dimethylarginine (ADMA). LoCo participants excreted higher amounts of guanidino acetate than ExCo participants (17.8 ± 10.4 µM/mM vs. 12.6 ± 8.86 µM/mM, P = 0.005). By contrast, LoCo participants excreted lower amounts of the advanced glycation end-product (AGE) NG-carboxyethylarginine (CEA) than ExCo participants did (0.675 ± 0.781 µM/mM vs. 1.16 ± 2.04 µM/mM, P = 0.0326).

The serum concentrations of MDA did not differ between the groups, indicating no elevated oxidative stress in LoCo or ExCo. The serum concentration of nitrite was lower in LoCo compared to ExCo (1.96 ± 0.92 µM vs. 2.56 ± 1.08 µM; AUC, 0.718), suggesting altered NO synthesis in the endothelium. The serum concentration of nitrite correlated inversely with the symptom anxiety (r = − 0.293, P = 0.0003). The creatinine-corrected urinary excretion of Lys and its metabolite L-5-hydroxy-Lys correlated positively with COVID toes (r = 0.306, P = 0.00027) and sore throat (r = 0.302, P = 0.0003).

Our results suggest that amino acid metabolism, PTM and oxidative stress are not severely affected in long COVID. LoCo participants may have a lower circulating NO reservoir than ExCo.

Source: Mikuteit, M., Baskal, S., Klawitter, S. et al. Amino acids, post-translational modifications, nitric oxide, and oxidative stress in serum and urine of long COVID and ex COVID human subjects. Amino Acids (2023). https://doi.org/10.1007/s00726-023-03305-1 https://link.springer.com/article/10.1007/s00726-023-03305-1 (Full text)

Vagus nerve inflammation contributes to dysautonomia in COVID-19

Abstract:

Dysautonomia has substantially impacted acute COVID-19 severity as well as symptom burden after recovery from COVID-19 (long COVID), yet the underlying causes remain unknown. Here, we hypothesized that vagus nerves are affected in COVID-19 which might contribute to autonomic dysfunction.

We performed a histopathological characterization of postmortem vagus nerves from COVID-19 patients and controls, and detected SARS-CoV-2 RNA together with inflammatory cell infiltration composed primarily of monocytes. Furthermore, we performed RNA sequencing which revealed a strong inflammatory response of neurons, endothelial cells, and Schwann cells which correlated with SARS-CoV-2 RNA load. Lastly, we screened a clinical cohort of 323 patients to detect a clinical phenotype of vagus nerve affection and found a decreased respiratory rate in non-survivors of critical COVID-19.

Our data suggest that SARS-CoV-2 induces vagus nerve inflammation followed by autonomic dysfunction which contributes to critical disease courses and might contribute to dysautonomia observed in long COVID.

Source:Woo MS, Shafiq M, Fitzek A, Dottermusch M, Altmeppen H, Mohammadi B, Mayer C, Bal LC, Raich L, Matschke J, Krasemann S, Pfefferle S, Brehm TT, Lütgehetmann M, Schädler J, Addo MM, Schulze Zur Wiesch J, Ondruschka B, Friese MA, Glatzel M. Vagus nerve inflammation contributes to dysautonomia in COVID-19. Acta Neuropathol. 2023 Jul 15. doi: 10.1007/s00401-023-02612-x. Epub ahead of print. PMID: 37452829. https://link.springer.com/article/10.1007/s00401-023-02612-x (Full text)

Persistent post-COVID-19 neuromuscular symptoms

Abstract:

Neuromuscular symptoms may develop or persist after resolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Besides residual sensorimotor symptoms associated with acute neuromuscular complications of coronavirus disease-2019 (COVID-19), such as Guillain-Barré syndrome, critical illness neuromyopathy, and rhabdomyolysis, patients may report persistent autonomic symptoms, sensory symptoms, and muscle symptoms in the absence of these acute complications, including palpitations, orthostatic dizziness and intolerance, paresthesia, myalgia, and fatigue.

These symptoms may be associated with long COVID, also known as post-COVID-19 conditions or postacute sequelae of SARS-CoV-2 infection, which may significantly impact quality of life. Managing these symptoms represents a challenge for health-care providers.

Recent advances have identified small-fiber neuropathy as a potential etiology that may underlie autonomic dysfunction and paresthesia in some long COVID patients. The pathogenic mechanisms underlying myalgia and fatigue remain elusive and need to be investigated. Herein we review the current state of knowledge regarding the evaluation and management of patients with persistent post-COVID-19 neuromuscular symptoms.

Source: Abrams RMC, Zhou L, Shin SC. Persistent post-COVID-19 neuromuscular symptoms. Muscle Nerve. 2023 Jul 19. doi: 10.1002/mus.27940. Epub ahead of print. PMID: 37466117. https://onlinelibrary.wiley.com/doi/10.1002/mus.27940 (Full text)

Post-acute sequelae of COVID-19: understanding and addressing the burden of multisystem manifestations

Abstract:

Individuals with SARS-CoV-2 infection can develop symptoms that persist well beyond the acute phase of COVID-19 or emerge after the acute phase, lasting for weeks or months after the initial acute illness. The post-acute sequelae of COVID-19, which include physical, cognitive, and mental health impairments, are known collectively as long COVID or post-COVID-19 condition.

The substantial burden of this multisystem condition is felt at individual, health-care system, and socioeconomic levels, on an unprecedented scale. Survivors of COVID-19-related critical illness are at risk of the well known sequelae of acute respiratory distress syndrome, sepsis, and chronic critical illness, and these multidimensional morbidities might be difficult to differentiate from the specific effects of SARS-CoV-2 and COVID-19.

We provide an overview of the manifestations of post-COVID-19 condition after critical illness in adults. We explore the effects on various organ systems, describe potential pathophysiological mechanisms, and consider the challenges of providing clinical care and support for survivors of critical illness with multisystem manifestations.

Research is needed to reduce the incidence of post-acute sequelae of COVID-19-related critical illness and to optimise therapeutic and rehabilitative care and support for patients.

Source: Parotto M, Gyöngyösi M, Howe K, Myatra SN, Ranzani O, Shankar-Hari M, Herridge MS. Post-acute sequelae of COVID-19: understanding and addressing the burden of multisystem manifestations. Lancet Respir Med. 2023 Jul 17:S2213-2600(23)00239-4. doi: 10.1016/S2213-2600(23)00239-4. Epub ahead of print. PMID: 37475125. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(23)00239-4/fulltext (Full text)

Mitigating neurological, cognitive, and psychiatric sequelae of COVID-19-related critical illness

Abstract:

Despite advances in the treatment and mitigation of critical illness caused by infection with SARS-CoV-2, millions of survivors have a devastating, post-acute infection syndrome known as long COVID. A large proportion of patients with long COVID have nervous system dysfunction, which is also seen in the distinct but overlapping condition of post-intensive care syndrome (PICS), putting survivors of COVID-19-related critical illness at high risk of long-lasting morbidity affecting multiple organ systems and, as a result, engendering measurable deficits in quality of life and productivity.

In this Series paper, we discuss neurological, cognitive, and psychiatric sequelae in patients who have survived critical illness due to COVID-19. We review current knowledge of the epidemiology and pathophysiology of persistent neuropsychological impairments, and outline potential preventive strategies based on safe, evidence-based approaches to the management of pain, agitation, delirium, anticoagulation, and ventilator weaning during critical illness. We highlight priorities for current and future research, including possible therapeutic approaches, and offer considerations for health services to address the escalating health burden of long COVID.

Source: Pandharipande P, Williams Roberson S, Harrison FE, Wilson JE, Bastarache JA, Ely EW. Mitigating neurological, cognitive, and psychiatric sequelae of COVID-19-related critical illness. Lancet Respir Med. 2023 Jul 17:S2213-2600(23)00238-2. doi: 10.1016/S2213-2600(23)00238-2. Epub ahead of print. PMID: 37475124. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(23)00238-2/fulltext (Full text)

Understanding the neurological implications of acute and long COVID using brain organoids

Abstract:

As early as in the acute phase of the coronavirus disease 2019 (COVID-19) pandemic, the research community voiced concerns about the long-term implications of infection. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), like many other viruses, can trigger chronic disorders that last months or even years.

Long COVID, the chronic and persistent disorder lasting more than 12 weeks after the primary infection with SARS-CoV-2, involves a variable number of neurological manifestations, ranging from mild to severe and even fatal. In vitro and in vivo modeling suggest that SARS-CoV-2 infection drives changes within neurons, glia and the brain vasculature.

In this Review, we summarize the current understanding of the neuropathology of acute and long COVID, with particular emphasis on the knowledge derived from brain organoid models. We highlight the advantages and main limitations of brain organoids, leveraging their human-derived origin, their similarity in cellular and tissue architecture to human tissues, and their potential to decipher the pathophysiology of long COVID.

Source: García-González L, Martí-Sarrias A, Puertas MC, Bayón-Gil Á, Resa-Infante P, Martinez-Picado J, Navarro A, Acosta S. Understanding the neurological implications of acute and long COVID using brain organoids. Dis Model Mech. 2023 Jul 1;16(7):dmm050049. doi: 10.1242/dmm.050049. Epub 2023 Jul 17. PMID: 37458167. https://journals.biologists.com/dmm/article/16/7/dmm050049/323961/Understanding-the-neurological-implications-of  (Full text)

Long COVID, linking etiopathogenic theories

Abstract:

In this letter we discuss the various theories involved in the pathogenesis of Long COVID and how they are closely interrelated, conditioning the full range of symptoms and signs presented by patients affected by this condition, as well as calling for the recognition of the disease by the health authorities that must begin to streamline their health processes to limit the burden of this disease, which tends to be chronic and degenerative.

Source: Luis del Carpio-Orantes, Andrés Aguilar-Silva. Long COVID, linking etiopathogenic theories. Qeios, CC-BY 4.0. https://www.qeios.com/read/A7TYBN (Full text)

Hematological alterations associated with long COVID-19

Abstract:

Long COVID-19 is a condition characterized by persistent symptoms lasting beyond the acute phase of COVID-19. Long COVID-19 produces diverse symptomatology and can impact organs and systems, including the hematological system. Several studies have reported, in COVID-19 patients, hematological abnormalities. Most of these alterations are associated with a higher risk of severe disease and poor outcomes.

This literature review identified studies reporting hematological parameters in individuals with Long COVID-19. Findings suggest that Long COVID-19 is associated with a range of sustained hematological alterations, including alterations in red blood cells, anemia, lymphopenia, and elevated levels of inflammatory markers such as ferritin, D-dimer, and IL-6.

These alterations may contribute to a better understanding of the pathophysiology of Long COVID-19 and its associated symptoms. However, further research is needed to elucidate the underlying mechanisms and potential treatments for these hematological changes in individuals with Long COVID-19.

Source: Lechuga Guilherme C., Giovanni De-Simone Salvatore, Morel Carlos M. Hematological alterations associated with long COVID-19. Frontiers in Physiology, Vol 14, 2023. DOI: 10.3389/fphys.2023.1203472  ISSN: 1664-042X https://www.frontiersin.org/articles/10.3389/fphys.2023.1203472 https://www.frontiersin.org/articles/10.3389/fphys.2023.1203472/full (Full text)

Carotid body dysregulation contributes to the enigma of long COVID

Abstract:

The symptoms of long COVID, which include fatigue, breathlessness, dysregulated breathing, and exercise intolerance, have unknown mechanisms. These symptoms are also observed in heart failure and are partially driven by increased sensitivity of the carotid chemoreflex. As the carotid body has an abundance of ACE2 (the cell entry mechanism for SARS-CoV-2), we investigated whether carotid chemoreflex sensitivity was elevated in participants with long COVID. During cardiopulmonary exercise testing, the VE/VCO2 slope (a measure of breathing efficiency) was higher in the long COVID group than in the controls, indicating excessive hyperventilation.

The hypoxic ventilatory response, which measures carotid chemoreflex sensitivity, was increased in long COVID participants and correlated with the VE/VCO2 slope, suggesting that excessive hyperventilation may be related to carotid body hypersensitivity. Therefore, the carotid chemoreflex is sensitized in long COVID and may explain dysregulated breathing and exercise intolerance in these participants. Tempering carotid body excitability may be a viable treatment option for long COVID patients.

Source: Ahmed El-Medany, Zoe H Adams, Hazel C Blythe, Katrina A Hope, Adrian H Kendrick, Ana Paula Abdala Sheikh, Julian FR Paton, Angus K Nightingale, Emma C Hart. Carotid body dysregulation contributes to the enigma of long COVID. medRxiv 2023.05.25.23290513; doi: https://doi.org/10.1101/2023.05.25.23290513 https://www.medrxiv.org/content/10.1101/2023.05.25.23290513v1.full-text (Full text)

Correlation between Hepatocyte Growth Factor (HGF) with D-Dimer and Interleukin-6 as Prognostic Markers of Coagulation and Inflammation in Long COVID-19 Survivors

Abstract:

In general, an individual who experiences the symptoms of Severe Acute Respiratory Syndrome Coronavirus 2 or SARS-CoV-2 infection is declared as recovered after 2 weeks. However, approximately 10–20% of these survivors have been reported to encounter long-term health problems, defined as ‘long COVID-19’, e.g., blood coagulation which leads to stroke with an estimated incidence of 3%, and pulmonary embolism with 5% incidence.
At the time of infection, the immune response produces pro-inflammatory cytokines that stimulate stromal cells to produce pro-hepatocyte growth factor (pro-HGF) and eventually is activated into hepatocyte growth factor (HGF), which helps the coagulation process in endothelial and epithelial cells. HGF is a marker that appears as an inflammatory response that leads to coagulation.
Currently, there is no information on the effect of SARS-CoV-2 infection on serum HGF concentrations as a marker of the prognosis of coagulation in long COVID-19 survivors. This review discusses the pathophysiology between COVID-19 and HGF, IL-6, and D-dimer.
Source: Zaira B, Yulianti T, Levita J. Correlation between Hepatocyte Growth Factor (HGF) with D-Dimer and Interleukin-6 as Prognostic Markers of Coagulation and Inflammation in Long COVID-19 Survivors. Current Issues in Molecular Biology. 2023; 45(7):5725-5740. https://doi.org/10.3390/cimb45070361 https://www.mdpi.com/1467-3045/45/7/361 (Full text)