COVID-19: immunopathology, pathophysiological mechanisms, and treatment options.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to spread globally despite the worldwide implementation of preventive measures to combat the disease. Although most COVID-19 cases are characterised by a mild, self-limiting disease course, a considerable subset of patients develop a more severe condition, varying from pneumonia and acute respiratory distress syndrome (ARDS) to multi-organ failure (MOF). Progression of COVID-19 is thought to occur as a result of a complex interplay between multiple pathophysiological mechanisms, all of which may orchestrate SARS-CoV-2 infection and contribute to organ-specific tissue damage. In this respect, dissecting currently available knowledge of COVID-19 immunopathogenesis is crucially important, not only to improve our understanding of its pathophysiology but also to fuel the rationale of both novel and repurposed treatment modalities. Various immune-mediated pathways during SARS-CoV-2 infection are relevant in this context, which relate to innate immunity, adaptive immunity, and autoimmunity. Pathological findings in tissue specimens of patients with COVID-19 provide valuable information with regard to our understanding of pathophysiology as well as the development of evidence-based treatment regimens. This review provides an updated overview of the main pathological changes observed in COVID-19 within the most commonly affected organ systems, with special emphasis on immunopathology. Current management strategies for COVID-19 include supportive care and the use of repurposed or symptomatic drugs, such as dexamethasone, remdesivir, and anticoagulants. Ultimately, prevention is key to combat COVID-19, and this requires appropriate measures to attenuate its spread and, above all, the development and implementation of effective vaccines. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 and the pathophysiology of coronavirus disease 2019 (COVID-19).

Angiotensin-converting enzyme 2 (ACE2) has been established as the functional host receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the current devastating worldwide pandemic of coronavirus disease 2019 (COVID-19). ACE2 is abundantly expressed in a variety of cells residing in many different human organs. In human physiology, ACE2 is a pivotal counter-regulatory enzyme to ACE by the breakdown of angiotensin II, the central player in the renin-angiotensin-aldosterone system (RAAS) and the main substrate of ACE2. Many factors have been associated with both altered ACE2 expression and COVID-19 severity and progression, including age, sex, ethnicity, medication, and several co-morbidities, such as cardiovascular disease and metabolic syndrome. Although ACE2 is widely distributed in various human tissues and many of its determinants have been well recognised, ACE2-expressing organs do not equally participate in COVID-19 pathophysiology, implying that other mechanisms are involved in orchestrating cellular infection resulting in tissue damage. Reports of pathologic findings in tissue specimens of COVID-19 patients are rapidly emerging and confirm the established role of ACE2 expression and activity in disease pathogenesis. Identifying pathologic changes caused by SARS-CoV-2 infection is crucially important as it has major implications for understanding COVID-19 pathophysiology and the development of evidence-based treatment strategies. Currently, many interventional strategies are being explored in ongoing clinical trials, encompassing many drug classes and strategies, including antiviral drugs, biological response modifiers, and RAAS inhibitors. Ultimately, prevention is key to combat COVID-19 and appropriate measures are being taken accordingly, including development of effective vaccines. In this review, we describe the role of ACE2 in COVID-19 pathophysiology, including factors influencing ACE2 expression and activity in relation to COVID-19 severity. In addition, we discuss the relevant pathological changes resulting from SARS-CoV-2 infection. Finally, we highlight a selection of potential treatment modalities for COVID-19. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Insulin treatment guided by subcutaneous continuous glucose monitoring compared to frequent point-of-care measurement in critically ill patients: a randomized controlled trial.

INTRODUCTION: Glucose measurement in intensive care medicine is performed intermittently with the risk of undetected hypoglycemia. The workload for the ICU nursing staff is substantial. Subcutaneous continuous glucose monitoring (CGM) systems are available and may be able to solve some of these issues in critically ill patients. METHODS: In a randomized controlled design in a mixed ICU in a teaching hospital we compared the use of subcutaneous CGM with frequent point of care (POC) to guide insulin treatment. Adult critically ill patients with an expected stay of more than 24 hours and in need of insulin therapy were included. All patients received subcutaneous CGM. CGM data were blinded in the control group, whereas in the intervention group these data were used to feed a computerized glucose regulation algorithm. The same algorithm was used in the control group fed by intermittent POC glucose measurements. Safety was assessed with the incidence of severe hypoglycemia (<2.2 mmol/L), efficacy with the percentage time in target range (5.0 to 9.0 mmol/L). In addition, we assessed nursing workload and costs. RESULTS: In this study, 87 patients were randomized to the intervention and 90 to the control group. CGM device failure resulted in 78 and 78 patients for analysis. The incidence of severe glycemia and percentage of time within target range was similar in both groups. A significant reduction in daily nursing workload for glucose control was found in the intervention group (17 versus 36 minutes; P <0.001). Mean daily costs per patient were significantly reduced with EUR 12 (95% CI -32 to -18, P = 0.02) in the intervention group. CONCLUSIONS: Subcutaneous CGM to guide insulin treatment in critically ill patients is as safe and effective as intermittent point-of-care measurements and reduces nursing workload and daily costs. A new algorithm designed for frequent measurements may lead to improved performance and should precede clinical implementation. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01526044. Registered 1 February 2012.

Changes in Attitudes and Actual Practice of Oxygen Therapy in ICUs after Implementation of a Conservative Oxygenation Guideline.

BACKGROUND: Little is known to what extent attitudes of ICU clinicians are influenced by new insights and recommendations to be more conservative with oxygen therapy. Our aim was to investigate whether implementation of a conservative oxygenation guideline structurally changed self-reported attitudes and actual clinical practice. METHODS: After the implementation of a conservative oxygen therapy guideline in 3 teaching hospitals in the Netherlands, ICU clinicians were surveyed regarding their attitudes toward oxygen therapy. The survey results were compared with survey results taken before the introduction of the new guideline. Arterial blood gas analysis data and ventilator settings were retrieved from all patients admitted to the participating ICUs in the studied period, and changes after implementing the guideline were assessed. RESULTS: In total, 180 ICU clinicians returned the survey. Compared to before implementation of a conservative oxygen guideline, more clinicians chose a preferred [Formula: see text] and an oxygen saturation measured from an arterial sample ([Formula: see text]) limit after implementation of the guideline. In general, clinicians reported a more conservative approach toward management of [Formula: see text] and less frequently increased the [Formula: see text]. In the period after the active implementation of the guideline, 5,840 subjects were admitted to the participating ICUs and 101,869 arterial blood gas analyses were retrieved. Actual practice changed with overall lower oxygenation levels (median [Formula: see text] 77.93 mm Hg, compared to 86.93 mm Hg before implementation) of arterial blood and a decrease of PEEP and [Formula: see text]. CONCLUSIONS: Implementing a conservative oxygenation guideline was an effective method that changed self-reported attitudes and actual clinical practice and improved adherence to conservative oxygenation targets in a short period of time.

Self-reported attitudes versus actual practice of oxygen therapy by ICU physicians and nurses.

BACKGROUND: High inspiratory oxygen concentrations are frequently administered in ventilated patients in the intensive care unit (ICU) but may induce lung injury and systemic toxicity. We compared beliefs and actual clinical practice regarding oxygen therapy in critically ill patients. METHODS: In three large teaching hospitals in the Netherlands, ICU physicians and nurses were invited to complete a questionnaire about oxygen therapy. Furthermore, arterial blood gas (ABG) analysis data and ventilator settings were retrieved to assess actual oxygen practice in the same hospitals 1 year prior to the survey. RESULTS: In total, 59% of the 215 respondents believed that oxygen-induced lung injury is a concern. The majority of physicians and nurses stated that minimal acceptable oxygen saturation and partial arterial oxygen pressure (PaO2) ranges were 85% to 95% and 7 to 10 kPa (52.5 to 75 mmHg), respectively. Analysis of 107,888 ABG results with concurrent ventilator settings, derived from 5,565 patient admissions, showed a median (interquartile range (IQR)) PaO2 of 11.7 kPa (9.9 to 14.3) [87.8 mmHg], median fractions of inspired oxygen (FiO2) of 0.4 (0.4 to 0.5), and median positive end-expiratory pressure (PEEP) of 5 (5 to 8) cm H2O. Of all PaO2 values, 73% were higher than the upper limit of the commonly self-reported acceptable range, and in 58% of these cases, neither FiO2 nor PEEP levels were lowered until the next ABG sample was taken. CONCLUSIONS: Most ICU clinicians acknowledge the potential adverse effects of prolonged exposure to hyperoxia and report a low tolerance for high oxygen levels. However, in actual clinical practice, a large proportion of their ICU patients was exposed to higher arterial oxygen levels than self-reported target ranges.

Implementing quality indicators in intensive care units: exploring barriers to and facilitators of behaviour change.

BACKGROUND: Quality indicators are increasingly used in healthcare but there are various barriers hindering their routine use. To promote the use of quality indicators, an exploration of the barriers to and facilitating factors for their implementation among healthcare professionals and managers of intensive care units (ICUs) is advocated. METHODS: All intensivists, ICU nurses, and managers (n = 142) working at 54 Dutch ICUs who participated in training sessions to support future implementation of quality indicators completed a questionnaire on perceived barriers and facilitators. Three types of barriers related to knowledge, attitude, and behaviour were assessed using a five-point Likert scale (1 = strongly disagree to 5 = strongly agree). RESULTS: Behaviour-related barriers such as time constraints were most prominent (Mean Score, MS = 3.21), followed by barriers related to knowledge and attitude (MS = 3.62; MS = 4.12, respectively). Type of profession, age, and type of hospital were related to knowledge and behaviour. The facilitating factor perceived as most important by intensivists was administrative support (MS = 4.3; p = 0.02); for nurses, it was education (MS = 4.0; p = 0.01), and for managers, it was receiving feedback (MS = 4.5; p = 0.001). CONCLUSIONS: Our results demonstrate that healthcare professionals and managers are familiar with using quality indicators to improve care, and that they have positive attitudes towards the implementation of quality indicators. Despite these facts, it is necessary to lower the barriers related to behavioural factors. In addition, as the barriers and facilitating factors differ among professions, age groups, and settings, tailored strategies are needed to implement quality indicators in daily practice.