Tag: long covid pathophysiology

Long COVID: A Molecular, Cellular and Histopathology Overview

Abstract:

Long COVID has been studied as different sequelae that some individuals can develop after the acute phase of the disease. Persistent symptoms such as dry cough, fatigue, and dyspnea can remain after six months of COVID-19 cure. Others such as lung fibrosis, kidney injury, and thrombotic risk also are observed. Here, a deep review of each human organ and system infected by the virus was performed aiming to show how molecules expression and cell signaling can induce the organism cure or injuries and, subsequently sequelae. The review also suggests the importance of public health surveillance for these cases including a more comprehensive analysis of molecular biology tools that can clarify and assist in the prognosis, treatment, and preventive methods for potentially more serious disorders in post-COVID-19 patients.

Source: da Silva Barros, B. , de Oliveira Cruz, L. , de Sousa, G. , Souza-Silva, G. , de Lima, M. , Oliveira, E. , Silva, A. , Macêdo, L. , Leal, L. , Marcos, B. , Elsztein, C. , Invenção, M. , de Freitas, A. and Moutinho-Melo, C. (2023) Long COVID: A Molecular, Cellular and Histopathology Overview. Journal of Biosciences and Medicines, 11, 90-113. doi: 10.4236/jbm.2023.119009. https://www.scirp.org/journal/paperinformation.aspx?paperid=127523 (Full text)

Structural and functional impairments of skeletal muscle in patients with post-acute sequelae of SARS-CoV-2 infection

Abstract:

Background: Following acute COVID-19, a substantial proportion of patients showed symptoms and sequelae for several months, namely the post-acute sequelae of COVID-19 (PASC) syndrome. Major phenomena are exercise intolerance, muscle weakness and fatigue. We aimed to investigate the physiopathology of exercise intolerance in patients with PASC syndrome by structural and functional analyses of skeletal muscle.

Methods: At least 3 months after infection, non-hospitalized patients with PASC (n=11,ys:54±11; PASC) and patients without long-term symptoms (n=12,ys:49±9; CTRL) visited the laboratory on four non-consecutive days. Spirometry, lung diffusion capacity and quality of life were assessed at rest. Cardiopulmonary incremental exercise test was performed. Oxygen consumption (VO2) kinetics were determined by moderate-intensity exercises. Muscle oxidative capacity (k) was assessed by near-infrared spectroscopy. Histochemical analysis, O2 flux (JO2) by high-resolution respirometry, and quantification of key molecular markers of mitochondrial biogenesis and dynamics were performed in vastus lateralis biopsies.

Results: Pulmonary and cardiac functions were within normal range in all patients. VO2peak was lower in PASC than CTRL (24.7±5.0vs32.9±7.4mL*min-1*kg-1, respectively, P<.05). VO2 kinetics was slower in PASC than CTRL (41±12vs30±9s-1, P<.05). k was lower in PASC than CTRL (1.54±0.49vs2.07±0.51min-1, P<.05). Citrate synthase, PGC1alfa and JO2 for mitochondrial complex II were significantly lower in PASC vs CTRL (all P<.05).

Conclusion: In our cohort of patients with PASC, we showed limited exercise tolerance mainly due to “peripheral” determinants. Substantial reductions were observed for biomarkers of mitochondrial function, content, and biogenesis. PASC syndrome appears to negatively impact skeletal muscle function, although the disease is an heterogenous condition.

Source: Colosio M, Brocca L, Gatti M, Neri M, Crea E, Cadile F, Canepari M, Pellegrino MA, Polla B, Porcelli S, Bottinelli R. Structural and functional impairments of skeletal muscle in patients with post-acute sequelae of SARS-CoV-2 infection. J Appl Physiol (1985). 2023 Sep 7. doi: 10.1152/japplphysiol.00158.2023. Epub ahead of print. PMID: 37675472. https://journals.physiology.org/doi/abs/10.1152/japplphysiol.00158.2023 (Full text available as PDF file)

Unveiling the Mysteries of Long COVID Syndrome: Exploring the Distinct Tissue and Organ Pathologies Linked to Prolonged COVID-19 Symptoms

Abstract:

The ongoing battle against the coronavirus disease 2019 (COVID-19) pandemic has encountered a complex aspect with the emergence of long COVID syndrome. There has been a growing prevalence of COVID-19-affected individuals experiencing persistent and diverse symptoms that extend beyond the initial infection phase. The phenomenon known as long COVID syndrome raises significant questions about the underlying mechanisms driving these enduring symptoms.

This comprehensive analysis explores the complex domain of long COVID syndrome with a view to shed light on the specific tissue and organ pathologies contributing to its intricate nature. This review aims to analyze the various clinical manifestations of this condition across different bodily systems and explore potential mechanisms such as viral persistence, immune dysregulation, autoimmunity, and molecular mimicry. The goal is to gain a better understanding of the intricate network of pathologies contributing to long COVID syndrome.

Understanding these distinct pathological indicators provides valuable insights into comprehending the complexities of long COVID and presents opportunities for developing more accurate diagnostic and therapeutic strategies, thereby improving the quality of patient care by effectively  addressing the ever-changing medical challenge in a more focused manner.

Source: Sapna F, Deepa F, Sakshi F, et al. (September 02, 2023) Unveiling the Mysteries of Long COVID Syndrome: Exploring the Distinct Tissue and Organ Pathologies Linked to Prolonged COVID-19 Symptoms. Cureus 15(9): e44588. DOI 10.7759/cureus.44588. https://assets.cureus.com/uploads/review_article/pdf/182615/20230903-23556-1g56qsl.pdf (Full text)

Severity of neurological long-COVID symptoms correlates with increased level of autoantibodies targeting vasoregulatory and autonomic nervous system receptors

Abstract:

Background: The Long-COVID syndrome constitutes a plethora of persisting symptoms with neurological disorders being the most disabling ones. The pathogenesis of Long-COVID is currently under heavy scrutiny and existing data on the role of auto-immune reaction to G-protein coupled receptors (GPCR) are conflicting.

Methods: This monocentric, cross-sectional study included patients who suffered a mild to moderate SARS-CoV-2 infection up to 12 months prior to enrollment with (n = 72) or without (n = 58) Long-COVID diagnosis according to the German S1 guideline or with no known history of SARS-CoV-2 infection (n = 70). While autoantibodies towards the vasoregulation associated Adrenergic Receptor (ADR) B1 and B2 and the CNS and vasoregulation associated muscarinic acetylcholine receptor (CHR) M3 and M4 were measured by ELISA, neurological disorders were quantified by internationally standardized questionnaires.

Results: The prevalence and concentrations of evaluated autoantibodes were significantly higher in Long-COVID compared to the 2 other groups (p = 2.1*10−9) with a significantly higher number of patients with simultaneous detection of more than one autoantibody in Long-COVID group (p = 0.0419). Importantly, the overall inflammatory state was low in all 3 groups. ARB1 and ARB2 correlated negatively CERAD Trail Marking A and B (R ≤ −0.26, p ≤ 0.043), while CHRM3 correlated positively with Chadler Fatigue Scale (R = 0.37, p = 0.0087).

Conclusions: Concentrations of autoantibodies correlates to intensity of neurological disorders including psychomotor speed, visual search, attention, and fatigue.

Source: Felix S. Seibert, Ulrik Stervbo, Lea Wiemers, Sarah Skrzypczyk, Maximillian Hogeweg, Sebastian Bertram, Julia Kurek, Moritz Anft, Timm H. Westhoff, Nina Babel. Severity of neurological long-COVID symptoms correlates with increased level of autoantibodies targeting vasoregulatory and autonomic nervous system receptors. Autoimmunity Reviews,2023, 103445, ISSN 1568-9972. https://www.sciencedirect.com/science/article/abs/pii/S1568997223001799 (Full text)

L-Arginine in Restoring ‘Immune Dysregulation’ in Long COVID: It’s the Therapeutic Role Beyond the Routine Dietary Supplement!

Abstract:

COVID-19 pandemic is over now and we are in great peace of relief after three years. This pandemic has observed significant impact on quality of life globally and the put unforgettable imprints on history of mankind. Reason for more havoc in this pandemic was less studied virus by medical scientists regarding its pathophysiology, available treatment options and lack of effective vaccine to tackle this dragon. COVID-19 is the first observed and reported pandemic of corona virus related global disease apart from its previous SARS and MERS. Fast track developments in medical treatment options due to this ultrafast digital and artificial intelligence techniques have curtailed mortality on large scale globally.
Although mortality is significantly reduced, morbidity is documented on a large scale worldwide in this pandemic. Morbidity due to COVID-19 now called as ‘Long COVID’, which is underreported & half-heartedly evaluated globally. Long COVID is related to persistent immune dysregulation occurs during evolution of COVID-19 as natural trend of disease.
Immune dysregulation has documented during course of active viremia, during recovery of viral illness and after post viral phase. Immune dysregulation occurs in ‘selected group’ of cases irrespective of disease severity and vaccination status and observed in cases with negligible illness to advanced one mandates further research. Thus, Immune dysregulation in COVID-19 is predominant cause for long covid and leading to brainstorming effect on medical scientists and researchers as of today.
Globally, one third of recovered or affected cases of COVID-19 are facing long covid and needs prompt treatment options to tackle this dragon related long term effect on body. ‘Immunomodulatory’ or immunity modifying agents are the primary targets to curtail immune dysregulation and long covid. Some experts recommend ‘disease modifying agents’ to treat long covid cases. Still, many miles to go to reach to effective treatment options for long covid and we don’t have effective options for this ‘health issue of global concern’.
L-Arginine is amino acid with multiple beneficial effects such as immunomodulatory effects which will regulates immunological response in inhibit dysregulated immune system additional to its universally known antioxidant, vasodilatory and regenerative and cellular proliferation effects on immune cells. These Immunomodulatory and or diseases modifying effects of L-Arginine makes it the future candidate with ‘game changer’ role for management of Long covid resulting from immune dysregulation as a core pathophysiologic pathway of this Dragon Pandemic.
Source: Patil, Dr Shital, Patil, Swati, Gondhali, Gajanan. L-Arginine in Restoring ‘Immune Dysregulation’ in Long COVID: It’s the Therapeutic Role Beyond the Routine Dietary Supplement!  South Asian Journal of Life Sciences, 5(4):60-74. https://www.researchgate.net/publication/373217918_L-Arginine_in_Restoring_%27Immune_Dysregulation%27_in_Long_COVID_It%27s_the_Therapeutic_Role_Beyond_the_Routine_Dietary_Supplement (Full text)

Pathophysiology, diagnosis, and management of neuroinflammation in covid-19

Abstract:

Although neurological complications of SARS-CoV-2 infection are relatively rare, their potential long term morbidity and mortality have a significant impact, given the large numbers of infected patients. Covid-19 is now in the differential diagnosis of a number of common neurological syndromes including encephalopathy, encephalitis, acute demyelinating encephalomyelitis, stroke, and Guillain-Barré syndrome.

Physicians should be aware of the pathophysiology underlying these presentations to diagnose and treat patients rapidly and appropriately. Although good evidence has been found for neurovirulence, the neuroinvasive and neurotropic potential of SARS-CoV-2 is limited. The pathophysiology of most complications is immune mediated and vascular, or both. A significant proportion of patients have developed long covid, which can include neuropsychiatric presentations. The mechanisms of long covid remain unclear. The longer term consequences of infection with covid-19 on the brain, particularly in terms of neurodegeneration, will only become apparent with time and long term follow-up.

Source: Brown R L, Benjamin L, Lunn M P, Bharucha T, Zandi M S, Hoskote C et al. Pathophysiology, diagnosis, and management of neuroinflammation in covid-19 BMJ 2023; 382 :e073923 doi:10.1136/bmj-2022-073923 https://www.bmj.com/content/382/bmj-2022-073923.abstract (Full text available as PDF file)

Serum ferritin level during hospitalization is associated with Brain Fog after COVID-19

Abstract:

The coronavirus disease 2019 (COVID-19) remains an epidemic worldwide. Most patients suffer residual symptoms, the so-called “Long COVID,” which includes respiratory and neuropsychiatric symptoms. Brain Fog, one of the symptoms of Long COVID, is a major public health issue because it can impair patients’ quality of life even after recovery from the disease. However, neither the pathogenesis nor the treatment of this condition remains unknown.

We focused on serum ferritin levels in this study and collected information on the onset of Brain Fog through questionnaires and found that high ferritin levels during hospitalization were associated with the occurrence of Brain Fog. In addition, we excluded confounders as far as possible using propensity score analyses and found that ferritin was independently associated with Brain Fog in most of the models. We conducted phase analysis and evaluated the interaction of each phase with ferritin levels and Brain Fog.

We found a positive correlation between serum ferritin levels during hospitalization and Brain Fog after COVID-19. High ferritin levels in patients with Brain Fog may reflect the contribution of chronic inflammation in the development of Brain Fog. This study provides a novel insight into the pathogenic mechanism of Brain Fog after COVID-19.

Source: Ishikura T, Nakano T, Kitano T, Tokuda T, Sumi-Akamaru H, Naka T. Serum ferritin level during hospitalization is associated with Brain Fog after COVID-19. Sci Rep. 2023 Aug 11;13(1):13095. doi: 10.1038/s41598-023-40011-0. PMID: 37567939; PMCID: PMC10421912. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10421912/ (Full text)

Ivabradine effects on COVID-19-associated postural orthostatic tachycardia syndrome: a single center prospective study

Abstract:

Background: A wide range of cardiac arrhythmias were reported in the setting of active infection or as a complication of COVID-19. The main pathophysiology can be attributed to dysautonomia or autonomic nervous system dysfunction. Postural orthostatic tachycardia syndrome (POTS) is a complex, multisystemic disorder affecting usually younger age with tachycardia at rest or with minimal effort being the main symptom. Data regarding the safety and efficacy of ivabradine in POTS treatment is limited to small studies and case reports.

Methods: This prospective observational study included a total of 55 COVID-19-associated POTS patients after the exclusion of other causes of tachycardia. Ivabradine 5 mg twice daily was initiated. Re-assessment of patients’ symptoms, heart rate, and heart rate variability (HRV) parameters’ changes after 3 days of ivabradine therapy was done.

Results: The mean age of the included patients was 30.5±6.9 years with 32 patients being males (58.2%). 43 of 55 (78%) of the included patients reported significant improvement of the symptoms within 7 days of ivabradine therapy. 24-hour heart rate (minimum, average, and maximum) was significantly lower (p-value < 0.0001*, = 0.001*, < 0.0001* consecutively) with a significant difference in HRV time-domain parameters (SDNN, rMSSD) (p-value < 0.0001*) after ivabradine therapy.

Conclusion: In a prospective study that evaluated the effects of ivabradine in post-COVID-19 POTS, patients treated with ivabradine reported improvement of their symptoms within 7 days of ivabradine treatment with a significant reduction of 24-hour average, minimum, and maximum heart rate, and improvement of HRV time domains parameters. Ivabradine might be a useful option to relieve symptoms of tachycardia in COVID-19 POTS. Further research is required to confirm the safety and efficacy of ivabradine in POTS treatment.

Source: Abdelnabi M, Saleh Y, Ahmed A, Benjanuwattra J, Leelaviwat N, Almaghraby A. Ivabradine effects on COVID-19-associated postural orthostatic tachycardia syndrome: a single center prospective study. Am J Cardiovasc Dis. 2023 Jun 25;13(3):162-167. PMID: 37469536; PMCID: PMC10352820. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10352820/ (Full text)

Exercise Capacity and Vascular Function in Long-COVID Sufferers

Abstract:

Background: Exercise intolerance is a prominent aetiology of long-COVID syndrome, yet the mechanisms causing the debilitation remain unknown. Vascular dysfunction is thought to play a role, hence we sought to determine if there is a relationship between exercise capacity and vascular function in COVID survivors.

Methods: Forty-two COVID-19 survivors; 33 self-identified long-COVID sufferers and 9 recovered controls (40.7±11.8 vs 40.2±14.5 years, both 67% female) underwent extensive phenotyping >3 months post-infection. Blood pressure (BP) and heart rate were measured (automated BP device), before carotid, femoral, and radial tonometry (carotid–femoral pulse wave velocity; [cPWV], augmentation index; [AIx]) were performed to assess vascular stiffness. Endothelium-dependent and independent dilatation were assessed via brachial artery flow-mediated dilation ([FMD]; Doppler-ultrasound) in response to reactive hyperaemia and glyceryl trinitrate respectively. Cardiopulmonary exercise testing determined peak oxygen uptake (VO2).

Results: Long-COVID sufferers had reduced VO2 peak compared to controls (26.5±7.0 vs 32.8±11.3 ml/min/kg, p= 0.045). Haemodynamic and vascular function were similar between groups, though there was a medium effect size (ES) for between group differences in cPWV (6.6±1.2 vs 6.1±0.9 m/sec, p=0.20; ES 0.44) and AIx (14±15% vs 4±16%, p=0.11; ES 0.67). VO2 peak was inversely correlated with AIx (r = -0.60, p<0.001) and cPWV (r = -0.55, p<0.001). There was no significant association between endothelial function and exercise capacity parameters.

Conclusions: Lower VO2peak measures in long-COVID participants were strongly associated with increased AIx and cPWV. These findings indicate the need for further longitudinal investigations to determine if these manifestations persist and impact long-term cardiovascular health.

Source: I.Wallace, E. Howden, D. Green, G. Sesa-Ashton. Exercise Capacity and Vascular Function in Long-COVID Sufferers. Heart, Lung and Circulation. ABSTRACT| VOLUME 32, SUPPLEMENT 3, S114-S115, JULY 2023. https://www.heartlungcirc.org/article/S1443-9506(23)04000-3/fulltext 

Persistent immune and clotting dysfunction detected in saliva and blood plasma after COVID-19

Abstract:

A growing number of studies indicate that coronavirus disease 2019 (COVID-19) is associated with inflammatory sequelae, but molecular signatures governing the normal versus pathologic convalescence process have not been well-delineated. Here, we characterized global immune and proteome responses in matched plasma and saliva samples obtained from COVID-19 patients collected between 20 and 90 days after initial clinical symptoms resolved.

Convalescent subjects showed robust total IgA and IgG responses and positive antibody correlations in saliva and plasma samples. Shotgun proteomics revealed persistent inflammatory patterns in convalescent samples including dysfunction of salivary innate immune cells, such as neutrophil markers (e.g., myeloperoxidase), and clotting factors in plasma (e.g., fibrinogen), with positive correlations to acute COVID-19 disease severity. Saliva samples were characterized by higher concentrations of IgA, and proteomics showed altered myeloid-derived pathways that correlated positively with SARS-CoV-2 IgA levels.

Beyond plasma, our study positions saliva as a viable fluid to monitor normal and aberrant immune responses including vascular, inflammatory, and coagulation-related sequelae.

Source: Jang H, Choudhury S, Yu Y, Sievers BL, Gelbart T, Singh H, Rawlings SA, Proal A, Tan GS, Qian Y, Smith D, Freire M. Persistent immune and clotting dysfunction detected in saliva and blood plasma after COVID-19. Heliyon. 2023 Jul 4;9(7):e17958. doi: 10.1016/j.heliyon.2023.e17958. PMID: 37483779; PMCID: PMC10362241. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10362241/ (Full text)