Deep Phenotyping of Neurologic Postacute Sequelae of SARS-CoV-2 Infection.

BACKGROUND AND OBJECTIVES: SARS-CoV-2 infection has been associated with a syndrome of long-term neurologic sequelae that is poorly characterized. We aimed to describe and characterize in-depth features of neurologic postacute sequelae of SARS-CoV-2 infection (neuro-PASC). METHODS: Between October 2020 and April 2021, 12 participants were seen at the NIH Clinical Center under an observational study to characterize ongoing neurologic abnormalities after SARS-CoV-2 infection. Autonomic function and CSF immunophenotypic analysis were compared with healthy volunteers (HVs) without prior SARS-CoV-2 infection tested using the same methodology. RESULTS: Participants were mostly female (83%), with a mean age of 45 ± 11 years. The median time of evaluation was 9 months after COVID-19 (range 3-12 months), and most (11/12, 92%) had a history of only a mild infection. The most common neuro-PASC symptoms were cognitive difficulties and fatigue, and there was evidence for mild cognitive impairment in half of the patients (MoCA score <26). The majority (83%) had a very disabling disease, with Karnofsky Performance Status ≤80. Smell testing demonstrated different degrees of microsmia in 8 participants (66%). Brain MRI scans were normal, except 1 patient with bilateral olfactory bulb hypoplasia that was likely congenital. CSF analysis showed evidence of unique intrathecal oligoclonal bands in 3 cases (25%). Immunophenotyping of CSF compared with HVs showed that patients with neuro-PASC had lower frequencies of effector memory phenotype both for CD4+ T cells (p < 0.0001) and for CD8+ T cells (p = 0.002), an increased frequency of antibody-secreting B cells (p = 0.009), and increased frequency of cells expressing immune checkpoint molecules. On autonomic testing, there was evidence for decreased baroreflex-cardiovagal gain (p = 0.009) and an increased peripheral resistance during tilt-table testing (p < 0.0001) compared with HVs, without excessive plasma catecholamine responses. DISCUSSION: CSF immune dysregulation and neurocirculatory abnormalities after SARS-CoV-2 infection in the setting of disabling neuro-PASC call for further evaluation to confirm these changes and explore immunomodulatory treatments in the context of clinical trials.

Advanced Nanomaterials-Based Electrochemical Biosensors for Catecholamines Detection: Challenges and Trends.

Catecholamines, including dopamine, epinephrine, and norepinephrine, are considered one of the most crucial subgroups of neurotransmitters in the central nervous system (CNS), in which they act at the brain's highest levels of mental function and play key roles in neurological disorders. Accordingly, the analysis of such catecholamines in biological samples has shown a great interest in clinical and pharmaceutical importance toward the early diagnosis of neurological diseases such as Epilepsy, Parkinson, and Alzheimer diseases. As promising routes for the real-time monitoring of catecholamine neurotransmitters, optical and electrochemical biosensors have been widely adopted and perceived as a dramatically accelerating development in the last decade. Therefore, this review aims to provide a comprehensive overview on the recent advances and main challenges in catecholamines biosensors. Particular emphasis is given to electrochemical biosensors, reviewing their sensing mechanism and the unique characteristics brought by the emergence of nanotechnology. Based on specific biosensors' performance metrics, multiple perspectives on the therapeutic use of nanomaterial for catecholamines analysis and future development trends are also summarized.

Significance of Catecholamine Biosynthetic/Metabolic Pathway in SARS-CoV-2 Infection and COVID-19 Severity.

The SARS-CoV-2 infection was previously associated with the expression of the dopamine biosynthetic enzyme L-Dopa decarboxylase (DDC). Specifically, a negative correlation was detected between DDC mRNA and SARS-CoV-2 RNA levels in in vitro infected epithelial cells and the nasopharyngeal tissue of COVID-19 patients with mild/no symptoms. However, DDC, among other genes related to both DDC expression and SARS-CoV-2-infection (ACE2, dACE2, EPO), was upregulated in these patients, possibly attributed to an orchestrated host antiviral response. Herein, by comparing DDC expression in the nasopharyngeal swab samples of severe/critical to mild COVID-19 cases, we showed a 20 mean-fold reduction, highlighting the importance of the expression of this gene as a potential marker of COVID-19 severity. Moreover, we identified an association of SARS-CoV-2 infection with the expression of key catecholamine biosynthesis/metabolism-related genes, in whole blood samples from hospitalized patients and in cultured cells. Specifically, viral infection downregulated the biosynthetic part of the dopamine pathway (reduction in DDC expression up to 7.5 mean-fold), while enhanced the catabolizing part (increase in monoamine oxidases A and B expression up to 15 and 10 mean-fold, respectively) in vivo, irrespectively of the presence of comorbidities. In accordance, dopamine levels in the sera of severe cases were reduced (up to 3.8 mean-fold). Additionally, a moderate positive correlation between DDC and MAOA mRNA levels (r = 0.527, p < 00001) in the blood was identified upon SARS-CoV-2-infection. These observations were consistent to the gene expression data from SARS-CoV-2-infected Vero E6 and A549 epithelial cells. Furthermore, L-Dopa or dopamine treatment of infected cells attenuated the virus-derived cytopathic effect by 55% and 59%, respectively. The SARS-CoV-2 mediated suppression of dopamine biosynthesis in cell culture was, at least in part, attributed to hypoxia-like conditions triggered by viral infection. These findings suggest that L-Dopa/dopamine intake may have a preventive or therapeutic value for COVID-19 patients.

Individualised flow-controlled versus pressure-controlled ventilation in a porcine oleic acid-induced acute respiratory distress syndrome model.

BACKGROUND: A continuous gas flow provided by flow-controlled ventilation (FCV) facilitates accurate dynamic compliance measurement and allows the clinician to individually optimise positive end-expiratory and peak pressure settings accordingly. OBJECTIVE: The aim of this study was to compare the efficiency of gas exchange and impact on haemodynamics between individualised FCV and pressure-controlled ventilation (PCV) in a porcine model of oleic acid-induced acute respiratory distress syndrome (ARDS). DESIGN: Randomised controlled interventional trial conducted on 16 pigs. SETTING: Animal operating facility at the Medical University Innsbruck. INTERVENTIONS: ARDS was induced in lung healthy pigs by intravenous infusion of oleic acid until moderate-to-severe ARDS at a stable Horowitz quotient (PaO 2 FiO 2-1 ) of 80 to 120 over a period of 30 min was obtained. Ventilation was then either performed with individualised FCV ( n  = 8) established by compliance-guided pressure titration or PCV ( n  = 8) with compliance-guided titration of the positive end-expiratory pressure and peak pressure set to achieve a tidal volume of 6 ml kg -1 over a period of 2 h. MAIN OUTCOME MEASURES: Gas exchange parameters were assessed by the PaO 2 FiO 2-1 quotient and CO 2 removal by the PaCO 2 value in relation to required respiratory minute volume. Required catecholamine support for haemodynamic stabilisation was measured. RESULTS: The FCV group showed significantly improved oxygenation [149.2 vs. 110.4, median difference (MD) 38.7 (8.0 to 69.5) PaO 2 FiO 2-1 ; P  = 0.027] and CO 2 removal [PaCO 2 7.25 vs. 9.05, MD -1.8 (-2.87 to -0.72) kPa; P  = 0.006] at a significantly lower respiratory minute volume [8.4 vs. 11.9, MD -3.6 (-5.6 to -1.5) l min -1 ; P  = 0.005] compared with PCV. In addition, in FCV-pigs, haemodynamic stabilisation occurred with a significant reduction of required catecholamine support [norepinephrine 0.26 vs. 0.86, MD -0.61 (-1.12 to -0.09) µg kg -1  min -1 ; P  = 0.037] during 2 ventilation hours. CONCLUSION: In this oleic acid-induced porcine ARDS model, individualised FCV significantly improved gas exchange and haemodynamic stability compared with PCV. TRIAL REGISTRATION: Protocol no.: BMBWF-66.011/0105-V/3b/2019).

Jugular Paraganglioma Presenting with a Tumor Thrombus Extending from Posterior Fossa to Right Atrium and Multiple Skeletal Metastases.

INTRODUCTION: Paragangliomas are tumors of neuroendocrine origin, may appear in different localizations, and are related to the autonomic nervous system. Paragangliomas are generally asymptomatic and may rarely appear with adrenergic symptoms, and clinical findings depend on the catecholamines they secrete. Extra-adrenal paragangliomas are mostly benign, like all paragangliomas. Malignancy criteria consist of local recurrence, metastasis after total resection, and presence of distant metastasis during primary diagnosis. CASE PRESENTATION: This report presents the case of a 31-year-old man with jugular paraganglioma, multiple skeletal metastases, and a long-segment tumor thrombus. Imaging procedures showed a continuous tumor thrombus extending from the posterior fossa to the right atrium and metastases in C2, T1, T6, T8, L5, and right humerus. Histopathological assessment of the metastasis in C2 identified malignant paraganglioma. Curative surgery was not an option for this patient, hence combined chemotherapy was given. CONCLUSION: In cases of malignant paraganglioma with multiple distant metastases, chemotherapy and radiotherapy are feasible treatment methods.

Healthcare-associated infections in COVID-19 ICU patients - two-centre study.

OBJECTIVE: The aim of this retrospective study was to estimate the prevalence of healthcare-associated infections (HAI), microbiological data including resistance patterns and impact of HAI on patients' survival. METHODS: Two-centre study on 172 patients was performed. Medical records of patients hospitalized in the two COVID-19 intensive care units (ICU) localized in Bydgoszcz between 1 October 2020 and 30 March 2021 were analysed retrospectively. Data collection included demographics, microbiological, clinical variables, and patient outcome. All infections were defined according to the HAI-Net ICU protocol of the European Centre for Disease Prevention and Control (ECDC). Detailed data concerning bloodstream infection (BSI), pneumonia (PN) and urinary tract infection (UTI) were collected. RESULTS: In 97 patients (56.4%), 138 HAI cases were identified. Patients with HAI statistically more often had been administered antimicrobial therapy prior to the admission to ICU (59.8% vs. 34.7%, p < 0.05), and needed catecholamines during hospitalization (93.8% vs. 70.7%, p < 0.001). The risk of HAI increased by 50% if antimicrobial therapy had been applied before the admission to ICU, and was three times higher if during the hospitalization in ICU catecholamines infusion was needed. Mortality was higher in patients diagnosed with HAI (72.2% vs. 65.3%) but the difference was not statistically significant (p = 0.34). CONCLUSIONS: Further investigation of co-infections in critically ill patients with COVID-19 is required in order to identify HAI risk factors, define the role of empiric antimicrobial therapy and proper prevention strategies.

Reverse Takotsubo Cardiomyopathy After Casirivimab-Imdevimab Therapy in a Patient with COVID-19: A Case Report.

BACKGROUND Takotsubo cardiomyopathy, also referred to as apical ballooning syndrome (ABS), stress cardiomyopathy, or broken heart syndrome, initially described in Japan, is characterized by transient wall motion abnormalities involving the apical segment. Several variants have been described, including reverse type, mid-ventricular type, and the focal type. In the reverse type, there is basal hypokinesis and apical hyperkinesis. Stress cardiomyopathy is most likely to occur in middle-aged women and the underlying etiology is believed to be related to catecholamine release due to intense stress. CASE REPORT We report an extremely rare case of reverse takotsubo cardiomyopathy (rTTC) in a young woman with COVID-19 who was treated with Casirivimab-Imdevimab therapy. Our report is the second to reveal rTTC in a patient with COVID-19 in which obstructive coronary artery disease was definitively ruled out by coronary CT angiography. CONCLUSIONS Cardiovascular involvement in COVID-19 has been linked to increased morbidity and mortality rates. Recent reports have suggested the occasional occurrence of TTC and the rare occurrence of reverse takotsubo cardiomyopathy (rTTC) in patients with COVID-19. In fact, to the best of our knowledge, this is only the fifth reported case of rTTC in a patient with COVID-19; importantly, 3 out of the 4 of the previous reported cases lacked definitive ischemic work-up to rule out obstructive coronary artery disease due to the critical condition of the patients.

Autopsy Histopathologic Cardiac Findings in 2 Adolescents Following the Second COVID-19 Vaccine Dose.

CONTEXT.­: Myocarditis in adolescents has been diagnosed clinically following the administration of the second dose of an mRNA vaccine for coronavirus disease 2019 (COVID-19). OBJECTIVE.­: To examine the autopsy microscopic cardiac findings in adolescent deaths that occurred shortly following administration of the second Pfizer-BioNTech COVID-19 dose to determine if the myocarditis described in these instances has the typical histopathology of myocarditis. DESIGN.­: Clinical and autopsy investigation of 2 teenage boys who died shortly following administration of the second Pfizer-BioNTech COVID-19 dose. RESULTS.­: The microscopic examination revealed features resembling a catecholamine-induced injury, not typical myocarditis pathology. CONCLUSIONS.­: The myocardial injury seen in these postvaccine hearts is different from typical myocarditis and has an appearance most closely resembling a catecholamine-mediated stress (toxic) cardiomyopathy. Understanding that these instances are different from typical myocarditis and that cytokine storm has a known feedback loop with catecholamines may help guide screening and therapy.

Covid-19 associated reduction in hypertension-related diagnostic and therapeutic procedures in Excellence Centers of the European Society of Hypertension.

BACKGROUND: The Covid-19 pandemic necessitated a decrease in non-Covid-19 related diagnostic and therapeutic procedures in many countries. We explored the impact on tertiary hypertension care. METHODS: We conducted an electronic survey regarding 6 key procedures in hypertension care within the Excellence Center network of the European Society of Hypertension. RESULTS: Overall, 54 Excellence Centers from 18 European and 3 non-European countries participated. From 2019 to 2020, there were significant decreases in the median number per centre of ambulatory blood pressure monitorings (ABPM: 544/289 for 2019/2020), duplex ultrasound of renal arteries (Duplex RA: 88.5/55), computed tomographic/magnetic resonance imaging angiography of renal arteries (CT/MRI RA: 66/19.5), percutaneous angioplasties of renal arteries (PTA RA: 5/1), laboratory tests for catecholamines (116/67.5) and for renin/aldosterone (146/83.5) (p < 0.001 for all comparisons, respectively). While reductions in all assessed diagnostic and therapeutic procedures were observed in all annual 3-months periods in the comparisons between 2019 and 2020, the most pronounced reduction occurred between April and June 2020, which was the period of the first wave and the first lockdown in most affected countries. In this period, the median reductions in 2020, as compared to 2019, were 50.7% (ABPM), 47.1% (Duplex RA), 50% (CT/MRI RA), 57.1% (PTA RA), 46.9% (catecholamines) and 41.0% (renin/aldosterone), respectively. Overall differences in reduction between 3-month time intervals were statistically highly significant. CONCLUSION: Diagnostic and therapeutic procedures related to hypertension were dramatically reduced during the first year of the Covid-19 pandemic, with the largest reduction during the first lockdown. The long-term consequences regarding blood pressure control and, ultimately, cardiovascular events remain to be investigated.

Effects of ß-Blockers on the Sympathetic and Cytokines Storms in Covid-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a causative virus in the development of coronavirus disease 2019 (Covid-19) pandemic. Respiratory manifestations of SARS-CoV-2 infection such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) leads to hypoxia, oxidative stress, and sympatho-activation and in severe cases leads to sympathetic storm (SS). On the other hand, an exaggerated immune response to the SARS-CoV-2 invasion may lead to uncontrolled release of pro-inflammatory cytokine development of cytokine storm (CS). In Covid-19, there are interactive interactions between CS and SS in the development of multi-organ failure (MOF). Interestingly, cutting the bridge between CS and SS by anti-inflammatory and anti-adrenergic agents may mitigate complications that are induced by SARS-CoV-2 infection in severely affected Covid-19 patients. The potential mechanisms of SS in Covid-19 are through different pathways such as hypoxia, which activate the central sympathetic center through carotid bodies chemosensory input and induced pro-inflammatory cytokines, which cross the blood-brain barrier and activation of the sympathetic center. ß2-receptors signaling pathway play a crucial role in the production of pro-inflammatory cytokines, macrophage activation, and B-cells for the production of antibodies with inflammation exacerbation. ß-blockers have anti-inflammatory effects through reduction release of pro-inflammatory cytokines with inhibition of NF-κB. In conclusion, ß-blockers interrupt this interaction through inhibition of several mediators of CS and SS with prevention development of neural-cytokine loop in SARS-CoV-2 infection. Evidence from this study triggers an idea for future prospective studies to confirm the potential role of ß-blockers in the management of Covid-19.

Pathophysiology of Takotsubo Cardiomyopathy: Reopened Debate.

Takotsubo cardiomyopathy (TTC), a persistently obscure dysfunctional condition of the left ventricle, is uniquely transient but nevertheless dangerous. It features variable ventricular patterns and is predominant in women. For 30 years, pathophysiologic investigations have progressed only slowly and with inadequate focus. It was initially proposed that sudden-onset spastic obliteration of coronary flow induced myocardial ischemia with residual stunning and thus TTC. Later, it was generally accepted without proof that, in the presence of pain or emotional stress, the dominant mechanism for TTC onset was a catecholamine surge that had a direct, toxic myocardial effect. We think that the manifestations of TTC are more dynamic and complex than can be assumed from catecholamine effects alone. In addition, after reviewing the recent medical literature and considering our own clinical observations, especially on spasm, we theorize that atherosclerotic coronary artery disease modulates and physically opposes obstruction during spasm. This phenomenon may explain the midventricular variant of TTC and the lower incidence of TTC in men. We continue to recommend and perform acetylcholine testing to reproduce TTC and to confirm our theory that coronary spasm is its initial pathophysiologic factor. An improved understanding of TTC is especially important because of the condition's markedly increased incidence during the ongoing COVID-19 pandemic.

Flight hormones as therapeutic target for novel Coronavirus infectious disease.

Coronavirus Disease 2019 (COVID-19) pandemic has made more awful effect on wellbeing and economy worldwide on an extraordinary scale. Angiotensin I Converting Enzyme 2 (ACE2), the principal receptor of SARS-CoV2, has been found to be communicated with Dopa decarboxylase in unwinding the connection of catecholamines with COVID-19 infection. Cardiovascular (CV) sickness, diabetes, hypertension, and related conditions cause significant risks during the current situation and the affected people are under basic observation around the world. The hypertension and diabetes are related with alterations in the degrees of catecholamines associated with renal gland. The naive form of renal dopaminergic framework is related with the expanded reabsorption of sodium resulting in downregulation of the ACE2 expression. Catecholamine biosynthesis is managed by counter-controlling angiotensin type 1R (AT1R) and angiotensin type 2R (AT2R), incitement of AT2 lessens catecholamine biosynthesis by means of a diminishing in cGMP levels likewise incitement of AT1 initiate catecholamine biosynthesis. This audit sums up the conceivable contribution of catecholamines in intense COVID-19 contamination and furthermore featured possible restorative adequacy of catecholamine flagging pathways against the incessant SARS-CoV-2.

Catecholamine physiology and its implications in patients with COVID-19.

The risk factors for severe COVID-19 are diverse, yet closely resemble the clinical manifestations of catecholamine excess states (eg, hypertension, cardiovascular disease, immune dysregulation, and hyperglycaemia), suggesting a potentially common basis for disease. Unfortunately, severe illness (eg, respiratory failure, compromised cardiac function, and shock) incurred by COVID-19 hinders the direct study of catecholamines in these patients, especially among those on multiple medications or those on adrenaline or noradrenaline infusions, or both. Phaeochromocytoma and paraganglioma (PPGL) are tumours that secrete catecholamines, namely adrenaline and noradrenaline, often in excess. PPGL are well studied disease processes in which the effects of catecholamines are easily discernible and therefore their potential biochemical and physiological influences in patients with COVID-19 can be explored. Because catecholamines are expected to have a role in patients with critical illness, patients on vasopressor infusions, and patients who sustain some acute and chronic physical stresses, the challenges involved in the management of catecholamine excess states are directly relevant to the treatment of patients with COVID-19. In this Personal View, we discuss the complex interplay between catecholamines and COVID-19, and the management of catecholamine excess states, while referencing relevant insights derived from the study of PPGL.

Oxygen targets in the intensive care unit during mechanical ventilation for acute respiratory distress syndrome: a rapid review.

BACKGROUND: Supplemental oxygen is frequently administered to patients with acute respiratory distress syndrome (ARDS), including ARDS secondary to viral illness such as coronavirus disease 19 (COVID-19). An up-to-date understanding of how best to target this therapy (e.g. arterial partial pressure of oxygen (PaO2) or peripheral oxygen saturation (SpO2) aim) in these patients is urgently required. OBJECTIVES: To address how oxygen therapy should be targeted in adults with ARDS (particularly ARDS secondary to COVID-19 or other respiratory viruses) and requiring mechanical ventilation in an intensive care unit, and the impact oxygen therapy has on mortality, days ventilated, days of catecholamine use, requirement for renal replacement therapy, and quality of life. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register, CENTRAL, MEDLINE, and Embase from inception to 15 May 2020 for ongoing or completed randomized controlled trials (RCTs). SELECTION CRITERIA: Two review authors independently assessed all records in accordance with standard Cochrane methodology for study selection. We included RCTs comparing supplemental oxygen administration (i.e. different target PaO2 or SpO2 ranges) in adults with ARDS and receiving mechanical ventilation in an intensive care setting. We excluded studies exploring oxygen administration in patients with different underlying diagnoses or those receiving non-invasive ventilation, high-flow nasal oxygen, or oxygen via facemask. DATA COLLECTION AND ANALYSIS: One review author performed data extraction, which a second review author checked. We assessed risk of bias in included studies using the Cochrane 'Risk of bias' tool. We used the GRADE approach to judge the certainty of the evidence for the following outcomes; mortality at longest follow-up, days ventilated, days of catecholamine use, and requirement for renal replacement therapy. MAIN RESULTS: We identified one completed RCT evaluating oxygen targets in patients with ARDS receiving mechanical ventilation in an intensive care setting. The study randomized 205 mechanically ventilated patients with ARDS to either conservative (PaO2 55 to 70 mmHg, or SpO2 88% to 92%) or liberal (PaO2 90 to 105 mmHg, or SpO2 ≥ 96%) oxygen therapy for seven days. Overall risk of bias was high (due to lack of blinding, small numbers of participants, and the trial stopping prematurely), and we assessed the certainty of the evidence as very low. The available data suggested that mortality at 90 days may be higher in those participants receiving a lower oxygen target (odds ratio (OR) 1.83, 95% confidence interval (CI) 1.03 to 3.27). There was no evidence of a difference between the lower and higher target groups in mean number of days ventilated (14.0, 95% CI 10.0 to 18.0 versus 14.5, 95% CI 11.8 to 17.1); number of days of catecholamine use (8.0, 95% CI 5.5 to 10.5 versus 7.2, 95% CI 5.9 to 8.4); or participants receiving renal replacement therapy (13.7%, 95% CI 5.8% to 21.6% versus 12.0%, 95% CI 5.0% to 19.1%). Quality of life was not reported. AUTHORS' CONCLUSIONS: We are very uncertain as to whether a higher or lower oxygen target is more beneficial in patients with ARDS and receiving mechanical ventilation in an intensive care setting. We identified only one RCT with a total of 205 participants exploring this question, and rated the risk of bias as high and the certainty of the findings as very low. Further well-conducted studies are urgently needed to increase the certainty of the findings reported here. This review should be updated when more evidence is available.