Pathophysiology of critically ill covid-19 patients

Abstract

With the onset of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, a new disease, COVID-19, challenged health care professionals and scientists. The angiotensin-converting enzyme type 2 (ACE2) was identified early in the pandemic as being the receptor used by SARS-CoV-2 for cell entrance. Since this discovery, a disruption of the renin-angiotensin-aldosterone system (RAAS) has been established as one of the main pathophysiological pathways for developing severe COVID-19. The RAAS is closely linked to cardiovascular health and a strict balance within the system is therefore crucial. The ACE2 is key to upholding this balance by keeping angiotensin II (ANG II) levels appropriate for the physiological demand. Any interference with ACE2-activity may result in increased unwanted ANG II effects such as hypertension, insulin resistance, thrombosis, and organ failure, all frequently seen during severe COVID-19. The overall aim of this thesis was to investigate the pathophysiological consequences of the viral interference with ACE2 and thus the RAAS, and its association with the clinical presentation of severe COVID-19.

Study I: In this translational study, we induced a pharmacological RAAS imbalance in swine, either by infusing ANG II or/and blocking ACE2. This causes a pathophysiological state (including impaired lung perfusion, increased pulmonary artery pressure, decreased oxygenation, alveolar damage, and acute kidney injury) which shared several clinical and radiological features observed in severe COVID-19. Study II: In a retrospective observational study of 385 hospitalised SARS-CoV-2 positive patients, we investigated the association between chronic dysglycemia, diagnosed by analysis of available HbA1c, and SARS-CoV-2 associated respiratory failure. We found that prediabetes (OR 14.41 [95% CI 5.27-39.43]), unknown diabetes (OR 15.86 [95% CI 4.55-55.36]) and uncontrolled diabetes (OR 17.61 [95% CI 5.77-53.74]) were associated with an increased risk of respiratory failure, independent of age, sex, and BMI. Study III: In this retrospective observational study of 406 hospitalised patients, we investigated the dynamics of common plasma electrolytes and acid-base biomarkers in patients with severe COVID-19 and its association with the requirement for invasive ventilation and mortality. We found hyponatremia on admission in 53% of the studied population followed by the development of hypernatremia in 42% the patients within the first 2 weeks of hospitalisation. The development of hypernatremia was associated with a more severe course of COVID-19 and increased 30-day mortality (OR 3,94 [95% CI 2,27-6.85) Study IV: In this prospective observational study, we compared circulating concentrations of three main biomarkers of the RAAS (ANG II, ANG 1-7 and ACE2) and arginine vasopressin (copeptin) in 56 COVID-19 patients admitted to the intensive care unit. We found plasma concentration of ACE2 and copeptin to be low compared to healthy controls. These findings were not combined with low concentrations of ANG 1-7 or hypotension.

We conclude that the interaction of SARS-CoV-2 with the RAAS may explain several of the clinical findings observed in COVID-19 patients. Patients with a pre-existing RAAS- imbalance may suffer from acute on chronic RAAS-activation with acceleration of several metabolic manifestations when infected with SARS-CoV-2. The complexity of RAAS and its impact on health and sickness needs to be further investigated, expanding the arsenal of tools for earlier identification of any developing imbalance within the system as well as intensifying treatment options to prevent disease progression. In summary, there are several findings in these studies indicating an association between an imbalanced RAAS and the development of severe COVID-19.