COVID-19 and the renin-angiotensin system (RAS): A spark that sets the forest alight?

Wiese, Owen J.; Allwood, Brian; Zemlin, Annalise E

doi:10.1016/j.mehy.2020.110231

Cited by 74 publications

(98 citation statements)

References 42 publications

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“…(Curran et al, 2020) provide a model of pathology in COVID-19 involving a number of systems including the RAAS system and suggest that COVID-19 disrupts regulatory networks. (Wiese et al, 2020) hypothesise that pathology in COVID-19 arises from an upregulation of the classical arm of the RAS pathway and a downregulation of the ‘protective arm’ of the RAS pathway. (Czick et al, 2020) suggest a role for RAS imbalance in multiple aspects of COVID-19.…”

Section: Resultsmentioning

confidence: 99%

Characterising COVID-19 as a Viral Clotting Fever: A Mixed Methods Scoping Review

Marley

2020

Preprint

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BackgroundThe COVID-19 pandemic has claimed over 1 million lives globally and results from the SARS-COV2 virus. COVID-19 is associated with a coagulopathy. In this mixed-methods PRISMA-compliant scoping review, we set out to determine if ARDS, sepsis and DIC could account for the coagulopathy and if there were any other features of the coagulopathy we could determine so as to inform future research. Methods: We used a search strategy to identify papers with clinically relevant thromboembolic events in COVID-19. We then developed a technique referred to as an Abridged Thematic Analysis (ATA) to quickly identify themes in the papers so as to increase the yield of clinically relevant information. We further developed Validated Abridged Thematic Analysis (VATA) to validate the resulting taxonomy of themes. Finally we developed a number of methods that can be used by other researchers to take forwards this work. Results: We identified 56 studies with 10,523 patients, 456 patients with COVID-19 and thromboembolic events (TBE’s) and 586 thrombembolic events. There were an average of 1.3 TBE’s per patient. There were five main arterial territories with corresponding clinical sequelae: Acute limb ischaemia, myocardial infarcts, strokes, mesenteric ischaemia and pulmonary embolism. We also identified DVT’s. There were two further groups: medical-device-related coagulopathy and dermal lesions. In a subgroup of 119 patients we found mortality ranged from 26% in DVT to 79% in acute limb ischaemia although there was evidence of selection bias in the latter group. All patients were hospitalised and the average age of survivors was 63 versus 73 for those who died. 91/150 patients with TE’s had fever. From the ATA, we identified 16 characteristics of the clotting pathology in COVID-19. From the VATA, we identified 34 mechanisms leading to coagulopathy and grouped them according to Virchow’s triad of vascular damage, stasis and hypercoagulability. Coagulopathy occurred with and without each of ARDS, Sepsis and DIC. We conclude that COVID-19 leads to the syndrome of a viral clotting fever in a subgroup of patients and that the presentation of coagulopathy and fever should raise the possibility of COVID-19 as a differential. We make recommendations for future research studies.

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Section: Resultsmentioning

confidence: 99%

Characterising COVID-19 as a Viral Clotting Fever: A Mixed Methods Scoping Review

Marley

2020

Preprint

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“…While the mechanisms of pathophysiology remain unclear, the critical role of the immune system in advancing the disease has been well documented [ 5 , 6 ]. Assessment of these immunopathological features has revealed two key events – 1.…”

Section: Pathogenesis and Complications Of Covid-19mentioning

confidence: 99%

“…Several clinical trials have reported safety of MSC administration in patients with severe ADRS with very few or no infusion related-adverse effects. Of key note is the prospective, double-blind multi-center, randomized trial (START study) wherein 10x10 6 BM-MSCs/kg body weight were transplanted intravenously into 40 ARDS patients. A significant decrease in Ang-2 levels was observed and attributed to reduced inflammation (61).…”

Section: Mesenchymal Stromal Cells (Mscs) To Target Hyperinflammation In Covid-19mentioning

confidence: 99%

“…ACE2 is abundantly expressed on vascular smooth muscle cells, arterial and venous endothelial cells and pericytes, thus facilitating entry for the virus into vasculature (12). Once the virus gains entry, ACE2 is rendered unavailable to cleave Angiotensin I, thus activating the classical arm of the RAAS pathway resulting in vasoconstriction, fibrosis, oxidative stress and inflammation (6). Upon infection, endothelial cells undergo apoptosis, disrupt intercellular junctions, and lose contact with the basal membrane, resulting in the loss of integrity of the endothelium.…”

mentioning

confidence: 99%

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Mesenchymal stromal cell therapy for coronavirus disease 2019: which? when? and how much?

Shahani

2021

Cytotherapy

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Mesenchymal Stromal Cells (MSCs) are under active consideration as a treatment strategy to control the hyperinflammation and slow disease progression in COVID-19. The possible mechanism of protection through their immunoregulatory and paracrine action has been reviewed extensively. However, the importance of process control to achieve a consistent cell quality, maximum safety and efficacy - for which the three key questions are of ‘which’, ‘when’ and ‘how much’ - remain unaddressed. Any commonality, if exists, in the ongoing clinical trials is yet to be analysed and reviewed. In this review, we have therefore compiled and discussed study design data from ongoing clinical trials to address the key questions of ‘which’ tissue source, donor profile, isolation technique, culture conditions, long-term culture and cryopreservation for MSCs; the question of ‘when’ with regard to defining the transplantation window, by identifying and staging of patients based on their pro-inflammatory profile; and finally that of ‘how much’ with respect to the number of cells in a single administration, the number of doses and route of transplantation. To homogenize MSC therapy for COVID-19 on a global scale and to make it readily available in large numbers, a shared understanding and uniform agreement on these fundamental issues is essential.

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“…Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses angiotensin-converting enzyme-2 (ACE2) as a receptor for cell entry and, therefore, might have an effect on the renin–angiotensin system (RAS) in the body [1] , [2] . RAS imbalance has been implicated in the pathogenesis of hypertension, heart failure, and chronic kidney disorder, which are commonly treated with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs).…”

mentioning

confidence: 99%

The fight against COVID-19: Striking a balance in the renin–angiotensin system

Dean

Bozza

Twomey

et al. 2021

Drug Discovery Today

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The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells by interacting with membrane-bound angiotensin-converting enzyme 2 (ACE2), a vital element in the renin–angiotensin system (RAS), which regulates blood pressure, fluid balance, and cardiovascular functions. We herein evaluate existing evidence for the molecular alterations within the RAS pathway (e.g., ACE2 and angiotensin II) during SARS-CoV-2 infection and subsequent Coronavirus 2019 (COVID-19). This includes reports regarding potential effect of RAS blockade (e.g., ACE inhibitors and angiotensin II receptor blockers) on ACE2 expression and clinical outcomes in patients with co-morbidities commonly treated with these agents. The collective evidence suggests a dual role for ACE2 in COVID-19, depending on the stage of infection and the coexisting diseases in individual patients. This information is further discussed with respect to potential therapeutic strategies targeting RAS for COVID-19 treatment.

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COVID-19 and the renin-angiotensin system (RAS): A spark that sets the forest alight?

Cited by 74 publications

References 42 publications

Characterising COVID-19 as a Viral Clotting Fever: A Mixed Methods Scoping Review

Characterising COVID-19 as a Viral Clotting Fever: A Mixed Methods Scoping Review

Mesenchymal stromal cell therapy for coronavirus disease 2019: which? when? and how much?

The fight against COVID-19: Striking a balance in the renin–angiotensin system

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