Tag: long covid pathophysiology

Vascular “Long COVID”: A New Vessel Disease?

Abstract:

Vascular sequelae following (SARS-CoV-2 coronavirus disease) (COVID)-19 infection are considered as “Long Covid (LC)” disease, when occurring 12 weeks after the original infection. The paucity of specific data can be obviated by translating pathophysiological elements from the original Severe Acute Respiratory Syndrome-Corona Virus (SARS-CoV-2) infection (In a microcirculatory system, a first “endotheliitis,” is often followed by production of “Neutrophil Extracellular Trap,” and can evolve into a more complex leukocytoklastic-like and hyperimmune vasculitis. In medium/large-sized vessels, this corresponds to endothelial dysfunction, leading to an accelerated progression of pre-existing atherosclerotic plaques through an increased deposition of platelets, circulating inflammatory cells and proteins. Associated dysregulated immune and pro-coagulant conditions can directly cause thrombo-embolic arterial or venous complications. In order to implement appropriate treatment, physicians need to consider vascular pathologies observed after SARS-Cov-2 infections as possible “LC” disease.

Source: Zanini G, Selleri V, Roncati L, Coppi F, Nasi M, Farinetti A, Manenti A, Pinti M, Mattioli AV. Vascular “Long COVID”: A New Vessel Disease? Angiology. 2023 Jan 18:33197231153204. doi: 10.1177/00033197231153204. Epub ahead of print. PMID: 36652923. https://pubmed.ncbi.nlm.nih.gov/36652923/

Investigating the possible mechanisms of autonomic dysfunction post-COVID-19

Abstract:

Patients with long COVID suffer from many neurological manifestations that persist for 3 months following infection by SARS-CoV-2. Autonomic dysfunction (AD) or dysautonomia is one complication of long COVID that causes patients to experience fatigue, dizziness, syncope, dyspnea, orthostatic intolerance, nausea, vomiting, and heart palpitations. The pathophysiology behind AD onset post-COVID is largely unknown. As such, this review aims to highlight the potential mechanisms by which AD occurs in patients with long COVID.

The first proposed mechanism includes the direct invasion of the hypothalamus or the medulla by SARS-CoV-2. Entry to these autonomic centers may occur through the neuronal or hematogenous routes. However, evidence so far indicates that neurological manifestations such as AD are caused indirectly.

Another mechanism is autoimmunity whereby autoantibodies against different receptors and glycoproteins expressed on cellular membranes are produced. Additionally, persistent inflammation and hypoxia can work separately or together to promote sympathetic overactivation in a bidirectional interaction. Renin-angiotensin system imbalance can also drive AD in long COVID through the downregulation of relevant receptors and formation of autoantibodies. Understanding the pathophysiology of AD post-COVID-19 may help provide early diagnosis and better therapy for patients.

Source: Jammoul M, Naddour J, Madi A, Reslan MA, Hatoum F, Zeineddine J, Abou-Kheir W, Lawand N. Investigating the possible mechanisms of autonomic dysfunction post-COVID-19. Auton Neurosci. 2022 Dec 24;245:103071. doi: 10.1016/j.autneu.2022.103071. Epub ahead of print. PMID: 36580747; PMCID: PMC9789535. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9789535/ (Full text)

Long Covid: Untangling the Complex Syndrome and the Search for Therapeutics

Abstract:

Long Covid can affect anyone who has previously had acute COVID-19. The root causes of this syndrome are still unknown, and no effective therapeutics are available. This complex syndrome, with a wide array of symptoms, is still evolving. Given the dire situation, it is important to identify the causes of Long Covid and the changes occurring within the immune system of affected patients to figure out how to treat it.
The immune system intersects with the persistent viral fragments and blood clots that are implicated in this syndrome; understanding how these complex systems interact may help in untangling the puzzling physiopathology of Long Covid and identifying mitigation measures to provide patients some relief. In this paper, we discuss evidence-based findings and formulate hypotheses on the mechanisms underlying Long Covid’s physiopathology and propose potential therapeutic options.
Source: Haque A, Pant AB. Long Covid: Untangling the Complex Syndrome and the Search for Therapeutics. Viruses. 2023; 15(1):42. https://doi.org/10.3390/v15010042 https://www.mdpi.com/1999-4915/15/1/42 (Full text)

Hyperbaric oxygen treatment for long coronavirus disease-19: a case report

Abstract:

Background: The coronavirus disease 2019 pandemic has resulted in a growing population of individuals who experience a wide range of persistent symptoms referred to as “long COVID.” Symptoms include neurocognitive impairment and fatigue. Two potential mechanisms could be responsible for these long-term unremitting symptoms: hypercoagulability, which increases the risk of blood vessel occlusion, and an uncontrolled continuous inflammatory response. Currently, no known treatment is available for long COVID. One of the options to reverse hypoxia, reduce neuroinflammation, and induce neuroplasticity is hyperbaric oxygen therapy. In this article, we present the first case report of a previously healthy athletic individual who suffered from long COVID syndrome treated successfully with hyperbaric oxygen therapy.

Case presentation: A previously healthy 55-year-old Caucasian man presented 3 months after severe coronavirus disease 2019 infection with long COVID syndrome. His symptoms included a decline in memory, multitasking abilities, energy, breathing, and physical fitness. After evaluation that included brain perfusion magnetic resonance imaging, diffusion tensor imaging, computerized cognitive tests, and cardiopulmonary test, he was treated with hyperbaric oxygen therapy. Each session included exposure to 90 minutes of 100% oxygen at 2 atmosphere absolute pressure with 5-minute air breaks every 20 minutes for 60 sessions, 5 days per week. Evaluation after completing the treatment showed significant improvements in brain perfusion and microstructure by magnetic resonance imaging and significant improvement in memory with the most dominant effect being on nonverbal memory, executive functions, attention, information procession speed, cognitive flexibility, and multitasking. The improved cognitive functions correlated with the increased cerebral blood flow in brain regions as measured by perfusion magnetic resonance imaging. With regard to physical capacity, there was a 34% increase in the maximum rate of oxygen consumed during exercise and a 44% improvement in forced vital capacity. The improved physical measurements correlated with the regain of his pre-COVID physical capacity.

Conclusions: We report the first case of successfully treated long COVID symptoms with hyperbaric oxygen therapy with improvements in cognition and cardiopulmonary function. The beneficial effects of hyperbaric oxygen shed additional light on the pathophysiology of long COVID. As this is a single case report, further prospective randomized control studies are needed.

Source: Bhaiyat AM, Sasson E, Wang Z, Khairy S, Ginzarly M, Qureshi U, Fikree M, Efrati S. Hyperbaric oxygen treatment for long coronavirus disease-19: a case report. J Med Case Rep. 2022 Feb 15;16(1):80. doi: 10.1186/s13256-022-03287-w. PMID: 35168680; PMCID: PMC8848789. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8848789/ (Full text)

Pathophysiological mechanisms of thrombosis in acute and long COVID-19

Abstract:

COVID-19 patients have a high incidence of thrombosis, and thromboembolic complications are associated with severe COVID-19 and high mortality. COVID-19 disease is associated with a hyper-inflammatory response (cytokine storm) mediated by the immune system. However, the role of the inflammatory response in thrombosis remains incompletely understood.

In this review, we investigate the crosstalk between inflammation and thrombosis in the context of COVID-19, focusing on the contributions of inflammation to the pathogenesis of thrombosis, and propose combined use of anti-inflammatory and anticoagulant therapeutics. Under inflammatory conditions, the interactions between neutrophils and platelets, platelet activation, monocyte tissue factor expression, microparticle release, and phosphatidylserine (PS) externalization as well as complement activation are collectively involved in immune-thrombosis. Inflammation results in the activation and apoptosis of blood cells, leading to microparticle release and PS externalization on blood cells and microparticles, which significantly enhances the catalytic efficiency of the tenase and prothrombinase complexes, and promotes thrombin-mediated fibrin generation and local blood clot formation.

Given the risk of thrombosis in the COVID-19, the importance of antithrombotic therapies has been generally recognized, but certain deficiencies and treatment gaps in remain. Antiplatelet drugs are not in combination with anticoagulant treatments, thus fail to dampen platelet procoagulant activity. Current treatments also do not propose an optimal time for anticoagulation. The efficacy of anticoagulant treatments depends on the time of therapy initiation. The best time for antithrombotic therapy is as early as possible after diagnosis, ideally in the early stage of the disease.

We also elaborate on the possible mechanisms of long COVID thromboembolic complications, including persistent inflammation, endothelial injury and dysfunction, and coagulation abnormalities. The above-mentioned contents provide therapeutic strategies for COVID-19 patients and further improve patient outcomes.

Source: Jing H, Wu X, Xiang M, Liu L, Novakovic VA, Shi J. Pathophysiological mechanisms of thrombosis in acute and long COVID-19. Front Immunol. 2022 Nov 16;13:992384. doi: 10.3389/fimmu.2022.992384. PMID: 36466841; PMCID: PMC9709252. https://www.frontiersin.org/articles/10.3389/fimmu.2022.992384/full (Full text)

Post-COVID-19 syndrome/condition or long COVID: Persistent illness after acute SARS CoV-2 infection

Abstract:

Background: Approximately 10 million Australians have had confirmed SARS-CoV-2 infection. The waves of infection in the population have been succeeded by smaller waves of people affected by persistent illness following acute infection. Post-COVID-19 symptoms may extend for months following infection. There is a range of symptoms causing mild to debilitating impairment.

Objective: This article summarises what is currently understood about the pathophysiology, risk factors, symptoms and how to approach both the assessment and care of people with post-COVID-19 sequelae.

Discussion: Currently recommended is a person-centred approach from a multidisciplinary team, with general practitioners centrally coordinating care. As the understanding of post-acute COVID-19 is evolving, regularly updated or ‘living guidelines’ will be crucial for those affected to be provided with best care within the health system.

Source: Allard N, Miller A, Morgan M, Chakraborty S. Post-COVID-19 syndrome/condition or long COVID: Persistent illness after acute SARS CoV-2 infection. Aust J Gen Pract. 2022 Dec;51(12):952-957. doi: 10.31128/AJGP-05-22-6429. PMID: 36451331. https://www1.racgp.org.au/ajgp/2022/december/post-covid-19-syndrome-condition-or-long-covid (Full text)

Reduced Muscle Strength in Patients with Long-COVID-19 Syndrome Is Mediated by Limb Muscle Mass

Abstract:

Understanding the impact of COVID-19 on muscle strength may help to elucidate the organ systems that contribute to acute and chronic COVID-19 sequelae. We questioned whether patients with postdischarge symptoms after COVID-19 had compromised muscle strength compared with a control group, and if this potential relationship was mediated by the lower appendicular lean mass index (ALMI).

A total of 99 patients with long-COVID-19 and 97 control participants were screened. Maximal grip strength was assessed with a TKK 5101 digital dynamometer, and leg extension 1RM was measured using EGYM Smart Strength machines. Body composition (fat mass percentage, lean mass, visceral fat and appendicular lean mass index) was determined using a whole-body dual-energy X-ray densitometer.

Results showed that grip strength and leg extension strength were significantly higher in controls than in COVID-19 survivors (mean [SD], 32.82 [10.01] vs. 26.94 [10.33] kg; difference, 5.87 kg; P < 0.001) and (mean [SD], 93.98 [33.73] vs. 71.59 [33.70] kg; difference, 22.38 kg; P < 0.001), respectively). The relationship between long-COVID syndrome and grip/leg strength levels was partly mediated by ALMI, which explained 52% of the association for grip strength and 39% for leg extension.

Our findings provide novel insights into the mechanisms underlying the relationship between long-COVID syndrome and grip/leg strength levels, supporting the negative effects of long-COVID syndrome on muscle function.

Source: Ramírez-Vélez R, Legarra-Gorgoñon G, Oscoz-Ochandorena S, García-Alonso Y, García-Alonso N, Oteiza J, Ernaga Lorea A, Correa-Rodríguez M, Izquierdo M. Reduced Muscle Strength in Patients with Long-COVID-19 Syndrome Is Mediated by Limb Muscle Mass. J Appl Physiol (1985). 2022 Nov 30. doi: 10.1152/japplphysiol.00599.2022. Epub ahead of print. PMID: 36448687. https://journals.physiology.org/doi/abs/10.1152/japplphysiol.00599.2022 (Full text available as PDF file)

Long COVID: mechanisms, risk factors and recovery

Abstract:

New findings: What is the topic of this review? The emerging condition of long COVID, its epidemiology, pathophysiological impacts on patients of different backgrounds, physiological mechanisms emerging as explanations of the condition, and treatment strategies being trialled. The review leads from a Physiological Society online conference on this topic. What advances does it highlight? Progress in understanding the pathophysiology and cellular mechanisms underlying Long COVID and potential therapeutic and management strategies.

Abstract: Long COVID, the prolonged illness and fatigue suffered by a small proportion of those infected with SARS-CoV-2, is placing an increasing burden on individuals and society. A Physiological Society virtual meeting in February 2022 brought clinicians and researchers together to discuss the current understanding of long COVID mechanisms, risk factors and recovery.

This review highlights the themes arising from that meeting. It considers the nature of long COVID, exploring its links with other post-viral illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome, and highlights how long COVID research can help us better support those suffering from all post-viral syndromes. Long COVID research started particularly swiftly in populations routinely monitoring their physical performance – namely the military and elite athletes.

The review highlights how the high degree of diagnosis, intervention and monitoring of success in these active populations can suggest management strategies for the wider population. We then consider how a key component of performance monitoring in active populations, cardiopulmonary exercise training, has revealed long COVID-related changes in physiology – including alterations in peripheral muscle function, ventilatory inefficiency and autonomic dysfunction. The nature and impact of dysautonomia are further discussed in relation to postural orthostatic tachycardia syndrome, fatigue and treatment strategies that aim to combat sympathetic overactivation by stimulating the vagus nerve.

We then interrogate the mechanisms that underlie long COVID symptoms, with a focus on impaired oxygen delivery due to micro-clotting and disruption of cellular energy metabolism, before considering treatment strategies that indirectly or directly tackle these mechanisms. These include remote inspiratory muscle training and integrated care pathways that combine rehabilitation and drug interventions with research into long COVID healthcare access across different populations.

Overall, this review showcases how physiological research reveals the changes that occur in long COVID and how different therapeutic strategies are being developed and tested to combat this condition.

Source: Astin R, Banerjee A, Baker MR, Dani M, Ford E, Hull JH, Lim PB, McNarry M, Morten K, O’Sullivan O, Pretorius E, Raman B, Soteropoulos DS, Taquet M, Hall CN. Long COVID: mechanisms, risk factors and recovery. Exp Physiol. 2022 Nov 22. doi: 10.1113/EP090802. Epub ahead of print. PMID: 36412084. https://physoc.onlinelibrary.wiley.com/doi/10.1113/EP090802 (Full text)

Mild SARS-CoV-2 infection results in long-lasting microbiota instability

Abstract:

Viruses targeting mammalian cells can indirectly alter the gut microbiota, potentially compounding their phenotypic effects. Multiple studies have observed a disrupted gut microbiota in severe cases of SARS-CoV-2 infection that require hospitalization. Yet, despite demographic shifts in disease severity resulting in a large and continuing burden of non-hospitalized infections, we still know very little about the impact of mild SARS-CoV-2 infection on the gut microbiota in the outpatient setting. To address this knowledge gap, we longitudinally sampled 14 SARS-CoV-2 positive subjects who remained outpatient and 4 household controls. SARS-CoV-2 cases exhibited a significantly less stable gut microbiota relative to controls, as long as 154 days after their positive test. These results were confirmed and extended in the K18-hACE2 mouse model, which is susceptible to SARS-CoV-2 infection. All of the tested SARS-CoV-2 variants significantly disrupted the mouse gut microbiota, including USA-WA1/2020 (the original variant detected in the United States), Delta, and Omicron. Surprisingly, despite the fact that the Omicron variant caused the least severe symptoms in mice, it destabilized the gut microbiota and led to a significant depletion in Akkermansia muciniphila. Furthermore, exposure of wild-type C57BL/6J mice to SARS-CoV-2 disrupted the gut microbiota in the absence of severe lung pathology.

IMPORTANCE Taken together, our results demonstrate that even mild cases of SARS-CoV-2 can disrupt gut microbial ecology. Our findings in non-hospitalized individuals are consistent with studies of hospitalized patients, in that reproducible shifts in gut microbial taxonomic abundance in response to SARS-CoV-2 have been difficult to identify. Instead, we report a long-lasting instability in the gut microbiota. Surprisingly, our mouse experiments revealed an impact of the Omicron variant, despite producing the least severe symptoms in genetically susceptible mice, suggesting that despite the continued evolution of SARS-CoV-2 it has retained its ability to perturb the intestinal mucosa. These results will hopefully renew efforts to study the mechanisms through which Omicron and future SARS-CoV-2 variants alter gastrointestinal physiology, while also considering the potentially broad consequences of SARS-CoV-2-induced microbiota instability for host health and disease.

Source: Vaibhav Upadhyay, Rahul Suryawanshi, Preston Tasoff, Maria McCavitt-Malvido, G. Renuka Kumar, Victoria Wong Murray, Cecilia Noecker, Jordan E. Bisanz, Yulin Hswen, Connie Ha, Bharat Sreekumar, Irene P. Chen, Susan V Lynch, Melanie Ott, Sulggi Lee, Peter J. Turnbaugh. Mild SARS-CoV-2 infection results in long-lasting microbiota instability. bioRxiv 2022.12.07.519508; doi: https://doi.org/10.1101/2022.12.07.519508  https://www.biorxiv.org/content/10.1101/2022.12.07.519508v1.full (Full text)

Signatures of Mitochondrial Dysfunction and Impaired Fatty Acid Metabolism in Plasma of Patients with Post-Acute Sequelae of COVID-19 (PASC)

Abstract:

Exercise intolerance is a major manifestation of post-acute sequelae of severe acute respiratory syndrome coronavirus infection (PASC, or “long-COVID”). Exercise intolerance in PASC is associated with higher arterial blood lactate accumulation and lower fatty acid oxidation rates during graded exercise tests to volitional exertion, suggesting altered metabolism and mitochondrial dysfunction. It remains unclear whether the profound disturbances in metabolism that have been identified in plasma from patients suffering from acute coronavirus disease 2019 (COVID-19) are also present in PASC.

To bridge this gap, individuals with a history of previous acute COVID-19 infection that did not require hospitalization were enrolled at National Jewish Health (Denver, CO, USA) and were grouped into those that developed PASC (n = 29) and those that fully recovered (n = 16). Plasma samples from the two groups were analyzed via mass spectrometry-based untargeted metabolomics and compared against plasma metabolic profiles of healthy control individuals (n = 30). Observational demographic and clinical data were retrospectively abstracted from the medical record.

Compared to plasma of healthy controls or individuals who recovered from COVID-19, PASC plasma exhibited significantly higher free- and carnitine-conjugated mono-, poly-, and highly unsaturated fatty acids, accompanied by markedly lower levels of mono-, di- and tricarboxylates (pyruvate, lactate, citrate, succinate, and malate), polyamines (spermine) and taurine. Plasma from individuals who fully recovered from COVID-19 exhibited an intermediary metabolic phenotype, with milder disturbances in fatty acid metabolism and higher levels of spermine and taurine. Of note, depletion of tryptophan-a hallmark of disease severity in COVID-19-is not normalized in PASC patients, despite normalization of kynurenine levels-a tryptophan metabolite that predicts mortality in hospitalized COVID-19 patients.

In conclusion, PASC plasma metabolites are indicative of altered fatty acid metabolism and dysfunctional mitochondria-dependent lipid catabolism. These metabolic profiles obtained at rest are consistent with previously reported mitochondrial dysfunction during exercise, and may pave the way for therapeutic intervention focused on restoring mitochondrial fat-burning capacity.

Source: Guntur VP, Nemkov T, de Boer E, Mohning MP, Baraghoshi D, Cendali FI, San-Millán I, Petrache I, D’Alessandro A. Signatures of Mitochondrial Dysfunction and Impaired Fatty Acid Metabolism in Plasma of Patients with Post-Acute Sequelae of COVID-19 (PASC). Metabolites. 2022 Oct 26;12(11):1026. doi: 10.3390/metabo12111026. PMID: 36355108; PMCID: PMC9699059. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9699059/ (Full text)