A disturbed balance between blood complement protective factors (FH, ApoE) and common pathway effectors (C5a, TCC) in acute COVID-19 and during convalesce.

A complement effect on homeostasis during infection is determined by both cytotoxic (activate complement component 5 (C5a) terminal cytotoxic complex (TCC)), and cytoprotective elements (complement factor H (FH), as well as apolipoprotein E (ApoE)). Here, we investigated the gap in knowledge in their blood milieu during SARS-CoV-2 infection with respect to the viral burden, level of tissue necrosis, and immunological response. 101 patients hospitalized with a PCR-confirmed diagnosis of COVID-19 had blood collected at H1 (48 h), H2 (3-4 Days), H3 (5-7 days), H4 (more than 7 days up to 93 days). Pre-existing conditions, treatment, the incidence of cerebrovascular events (CVA), a history of deep venous thrombosis (DVT) and pulmonary embolism (PE), and mortality was collected using electronic medical records. Plasma C5a, TCC, FH, and ApoE were considered as a complement milieu. Tissue necrosis (HMGB1, RAGE), non-specific inflammatory responses (IL-6, C-reactive protein), overall viral burden (SARS-CoV-2 spike protein), and specific immune responses (IgG, IgA, IgM directed αS- & N-proteins) were assessed simultaneously. C5a remained elevated across all time points, with the peak at 5-7 days. Studied elements of complement coalesced around three clusters: #0 (↑↑↑C5a, ↑↑TCC, ↓↓ApoE), #1 ↑C5a, ↑TCC, ↑↑↑FH); #2 (↑C5a, ↑TCC, ↑FH, ↑↑↑ApoE). The decline in FH and ApoE was a predictor of death, while TCC and C5a correlated with patient length of stay, APACHE, and CRP. Increased levels of C5a (Δ = 122.64; p = 0.0294; data not shown) and diminished levels of FH (Δ = 836,969; p = 0.0285; data not shown) co-existed with CVA incidence. C5a correlated storngly with blood RAGE and HMGB1, but not with viral load and immunological responsiveness. Remdesivir positively affected FH preservation, while convalescent plasma treatment elevated C5a levels. Three clusters of complement activation demonstrated a various milieu of ApoE & FH vs C5a & TCC in COVID-19 patients. Complement activation is linked to increased necrosis markers but not to viral burden or immune system response.

A Survey of Tele-Critical Care State and Needs in 2019 and 2020 Conducted among the Members of the Society of Critical Care Medicine.

The study's objective was to assess facilitators and barriers of Tele-Critical Care (TCC) perceived by SCCM members. By utilizing a survey distributed to SCCM members, a cross-sectional study was developed to analyze survey results from December 2019 and July 2020. SCCM members responded to the survey (n = 15,502) with a 1.9% response rate for the first distribution and a 2.54% response rate for the second survey (n = 9985). Participants (n = 286 and n = 254) were almost equally distributed between non-users, providers, users, and potential users of TCC services. The care delivery models for TCC were similar across most participants. Some consumers of TCC services preferred algorithmic coverage and scheduled rounds, while reactive and on-demand models were less utilized. The surveys revealed that outcome-driven measures were the principal form of TCC performance evaluation. A 1:100 (provider: patients) ratio was reported to be optimal. Factors related to costs, perceived lack of need for services, and workflow challenges were described by those who terminated TCC services. Barriers to implementation revolved around lack of reimbursement and adequate training. Interpersonal communication was identified as an essential TCC provider skill. The second survey introduced after the onset pandemic demonstrated more frequent use of advanced practice providers and focus on performance measures. Priorities for effective TCC deployment include communication, knowledge, optimal operationalization, and outcomes measurement at the organizational level. The potential effect of COVID-19 during the early stages of the pandemic on survey responses was limited and focused on the need to demonstrate TCC value.

Decrease in Angiotensin-Converting Enzyme activity but not concentration in plasma/lungs in COVID-19 patients offers clues for diagnosis/treatment.

Although several therapeutics are used to treat coronavirus disease 2019 (COVID-19) patients, there is still no definitive metabolic marker to evaluate disease severity and recovery or a quantitative test to end quarantine. Because severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infects human cells via the angiotensin-converting-enzyme 2 (ACE2) receptor and COVID-19 is associated with renin-angiotensin system dysregulation, we evaluated soluble ACE2 (sACE2) activity in the plasma/saliva of 80 hospitalized COVID-19 patients and 27 non-COVID-19 volunteers, and levels of ACE2/Ang (1-7) in plasma or membrane (mACE2) in lung autopsy samples. sACE2 activity was markedly reduced (p < 0.0001) in COVID-19 plasma (n = 59) compared with controls (n = 27). Nadir sACE2 activity in early hospitalization was restored during disease recovery, irrespective of patient age, demographic variations, or comorbidity; in convalescent plasma-administered patients (n = 45), restoration was statistically higher than matched controls (n = 22, p = 0.0021). ACE2 activity was also substantially reduced in the saliva of COVID-19 patients compared with controls (p = 0.0065). There is a strong inverse correlation between sACE2 concentration and sACE2 activity and Ang (1-7) levels in participant plasmas. However, there were no difference in membrane ACE2 levels in lungs of autopsy tissues of COVID-19 (n = 800) versus other conditions (n = 300). These clinical observations suggest sACE2 activity as a potential biomarker and therapeutic target for COVID-19.

The Rapid Implementation of Ad Hoc Tele-Critical Care Respiratory Therapy (eRT) Service in the Wake of the COVID-19 Surge.

A 24/7 telemedicine respiratory therapist (eRT) service was set up as part of the established University of Pennsylvania teleICU (PENN E-LERT®) service during the COVID-19 pandemic, serving five hospitals and 320 critical care beds to deliver effective remote care in lieu of a unit-based RT. The eRT interventions were components of an evidence-based care bundle and included ventilator liberation protocols, low tidal volume protocols, tube patency, and an extubation checklist. In addition, the proactive rounding of patients, including ventilator checks, was included. A standardized data collection sheet was used to facilitate the review of medical records, direct audio-visual inspection, or direct interactions with staff. In May 2020, a total of 1548 interventions took place, 93.86% of which were coded as "routine" based on established workflows, 4.71% as "urgent", 0.26% "emergent", and 1.17% were missing descriptors. Based on the number of coded interventions, we tracked the number of COVID-19 patients in the system. The average intervention took 6.1 ± 3.79 min. In 16% of all the interactions, no communication with the bedside team took place. The eRT connected with the in-house respiratory therapist (RT) in 66.6% of all the interventions, followed by house staff (9.8%), advanced practice providers (APP; 2.8%), and RN (2.6%). Most of the interaction took place over the telephone (88%), secure text message (16%), or audio-video telemedicine ICU platform (1.7%). A total of 5115 minutes were spent on tasks that a bedside clinician would have otherwise executed, reducing their exposure to COVID-19. The eRT service was instrumental in several emergent and urgent critical interventions. This study shows that an eRT service can support the bedside RT providers, effectively monitor best practice bundles, and carry out patient-ventilator assessments. It was effective in certain emergent situations and reduced the exposure of RTs to COVID-19. We plan to continue the service as part of an integrated RT service and hope to provide a framework for developing similar services in other facilities.

PATTERNS OF URINARY BIOMARKERS OF IMMUNOLOGIC ACTIVATION AND SEPSIS IN PATIENTS WITH COVID-19

B Background: b In the past, few studies have utilized urine to assess the state of the immune system. Here, we hypothesize that urine biomarkers can assess immune activation and the effect of antiviral treatment in patients infected with COVID-19. With regards to treatments, Remdesivir had a more profound impact on the urine biomarkers than steroids. [Extracted from the article] Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

APOL1 risk variants in individuals of African genetic ancestry drive endothelial cell defects that exacerbate sepsis.

The incidence and severity of sepsis is higher among individuals of African versus European ancestry. We found that genetic risk variants (RVs) in the trypanolytic factor apolipoprotein L1 (APOL1), present only in individuals of African ancestry, were associated with increased sepsis incidence and severity. Serum APOL1 levels correlated with sepsis and COVID-19 severity, and single-cell sequencing in human kidneys revealed high expression of APOL1 in endothelial cells. Analysis of mice with endothelial-specific expression of RV APOL1 and in vitro studies demonstrated that RV APOL1 interfered with mitophagy, leading to cytosolic release of mitochondrial DNA and activation of the inflammasome (NLRP3) and the cytosolic nucleotide sensing pathways (STING). Genetic deletion or pharmacological inhibition of NLRP3 and STING protected mice from RV APOL1-induced permeability defects and proinflammatory endothelial changes in sepsis. Our studies identify the inflammasome and STING pathways as potential targets to reduce APOL1-associated health disparities in sepsis and COVID-19.

Dynamic Changes in Central and Peripheral Neuro-Injury vs. Neuroprotective Serum Markers in COVID-19 Are Modulated by Different Types of Anti-Viral Treatments but Do Not Affect the Incidence of Late and Early Strokes.

The balance between neurodegeneration, neuroinflammation, neuroprotection, and COVID-19-directed therapy may underly the heterogeneity of SARS-CoV-2's neurological outcomes. A total of 105 patients hospitalized with a diagnosis of COVID-19 had serum collected over a 6 month period to assess neuroinflammatory (MIF, CCL23, MCP-1), neuro-injury (NFL, NCAM-1), neurodegenerative (KLK6, τ, phospho τ, amyloids, TDP43, YKL40), and neuroprotective (clusterin, fetuin, TREM-2) proteins. These were compared to markers of nonspecific inflammatory responses (IL-6, D-dimer, CRP) and of the overall viral burden (spike protein). Data regarding treatment (steroids, convalescent plasma, remdasavir), pre-existing conditions, and incidences of strokes were collected. Amyloid ß42, TDP43, NF-L, and KLK6 serum levels declined 2-3 days post-admission, yet recovered to admission baseline levels by 7 days. YKL-40 and NCAM-1 levels remained elevated over time, with clusters of differential responses identified among TREM-2, TDP43, and YKL40. Fetuin was elevated after the onset of COVID-19 while TREM-2 initially declined before significantly increasing over time. MIF serum level was increased 3-7 days after admission. Ferritin correlated with TDP-43 and KLK6. No treatment with remdesivir coincided with elevations in Amyloid-ß40. A lack of convalescent plasma resulted in increased NCAM-1 and total tau, and steroidal treatments did not significantly affect any markers. A total of 11 incidences of stroke were registered up to six months after initial admission for COVID-19. Elevated D-dimer, platelet counts, IL-6, and leukopenia were observed. Variable MIF serum levels differentiated patients with CVA from those who did not have a stroke during the acute phase of COVID-19. This study demonstrated concomitant and opposite changes in neurodegenerative and neuroprotective markers persisting well into recovery.

Persistence of Lipoproteins and Cholesterol Alterations after Sepsis: Implication for Atherosclerosis Progression.

(1) Background: Sepsis is one of the most common critical care illnesses with increasing survivorship. The quality of life in sepsis survivors is adversely affected by several co-morbidities, including increased incidence of dementia, stroke, cardiac disease and at least temporary deterioration in cognitive dysfunction. One of the potential explanations for their progression is the persistence of lipid profile abnormalities induced during acute sepsis into recovery, resulting in acceleration of atherosclerosis. (2) Methods: This is a targeted review of the abnormalities in the long-term lipid profile abnormalities after sepsis; (3) Results: There is a well-established body of evidence demonstrating acute alteration in lipid profile (HDL-c ↓↓, LDL-C -c ↓↓). In contrast, a limited number of studies demonstrated depression of HDL-c levels with a concomitant increase in LDL-C -c in the wake of sepsis. VLDL-C -c and Lp(a) remained unaltered in few studies as well. Apolipoprotein A1 was altered in survivors suggesting abnormalities in lipoprotein metabolism concomitant to overall lipoprotein abnormalities. However, most of the studies were limited to a four-month follow-up and patient groups were relatively small. Only one study looked at the atherosclerosis progression in sepsis survivors using clinical correlates, demonstrating an acceleration of plaque formation in the aorta, and a large metanalysis suggested an increase in the risk of stroke or acute coronary event between 3% to 9% in sepsis survivors. (4) Conclusions: The limited evidence suggests an emergence and persistence of the proatherogenic lipid profile in sepsis survivors that potentially contributes, along with other factors, to the clinical sequel of atherosclerosis.

Longitudinal urinary biomarkers of immunological activation in covid-19 patients without clinically apparent kidney disease versus acute and chronic failure.

Kidney function is affected in COVID-19, while kidney itself modulates the immune response. Here, hypothesize if COVID-19 urine biomarkers level can assess immune activation vs. clinical trajectory. Considering the kidney's critical role in modulating the immune response, we sought to analyze activation markers in patients with pre-existing dysfunction. This was a cross-sectional study of 68 patients. Blood and urine were collected within 48 h of hospital admission (H1), followed by 96 h (H2), seven days (H3), and up to 25 days (H4) from admission. Serum level ferritin, procalcitonin, IL-6 assessed immune activation overall, while the response to viral burden was gauged with serum level of spike protein and αspike IgM and IgG. 39 markers correlated highly between urine and blood. Age and race, and to a lesser extend gender, differentiated several urine markers. The burden of pre-existing conditions correlated with urine DCN, CAIX and PTN, but inversely with IL-5 or MCP-4. Higher urinary IL-12 and lower CAIX, CCL23, IL-15, IL-18, MCP-1, MCP-3, MUC-16, PD-L1, TNFRS12A, and TNFRS21 signified non-survivors. APACHE correlated with urine TNFRS12, PGF, CAIX, DCN, CXCL6, and EGF. Admission urine LAG-3 and IL-2 predicted death. Pre-existing kidney disease had a unique pattern of urinary inflammatory markers. Acute kidney injury was associated, and to a certain degree, predicted by IFNg, TWEAK, MMP7, and MUC-16. Remdesavir had a more profound effect on the urine biomarkers than steroids. Urinary biomarkers correlated with clinical status, kidney function, markers of the immune system activation, and probability of demise in COVID-19.

Guillain–Barré Syndrome in COVID-19—The Potential Role of NCAM-1 and Immunotherapy

Coronavirus disease 2019 (COVID-19) interacts with the nervous system directly and indirectly by affecting the activation of the immune system. Guillain–Barré syndrome (GBS) is triggered by an inappropriate immune system activation that overlaps with the neurotoxic mechanism of an invading pathogen. Here, we discuss the complexity of an abnormal immune system response leading to the generation of autoimmunity in the setting of acute viral infection. A 67-year-old male patient with COVID-19 developed a sensory motor acute polyneuropathy with respiratory failure. Several serum inflammatory and neurodegeneration markers were collected during hospital days 1, 3, 8, and 67 and compared to healthy individuals. Neural cell adhesion molecule 1 (NCAM-1) and neurofilament light chain (NfL) values were highly variable when compared to healthy individuals, but not to the reference COVID-19 group. We focused our attention on NCAM-1 as a possible target for antibodies directed at COVID-19 in silico.

Nonsteroidal anti-inflammatory drugs and glucocorticoids in COVID-19.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is characterized by a wide spectrum of symptom severity, which is manifested at different phases of infection and demands different levels of care. Viral load, host innate-immune response to SARS-CoV-2, and comorbidities have a direct impact on the clinical outcomes of COVID-19 patients and determine the diverse disease trajectories. The initial SARS-CoV-2 penetrance and replication in the host causes death of infected cells, determining the viral response. SARS-CoV-2 replication in the host triggers the activation of host antiviral immune mechanisms, determining the inflammatory response. While a healthy immune response is essential to eliminate infected cells and prevent spread of the virus, a dysfunctional immune response can result in a cytokine storm and hyperinflammation, contributing to disease progression. Current therapies for COVID-19 target the virus and/or the host immune system and may be complicated in their efficacy by comorbidities. Here we review the evidence for use of two classes of anti-inflammatory drugs, glucocorticoids and nonsteroidal anti-inflammatory drugs (NSAIDs) for the treatment of COVID-19. We consider the clinical evidence regarding the timing and efficacy of their use, their potential limitations, current recommendations and the prospect of future studies by these and related therapies.

Unbiased Analysis of Temporal Changes in Immune Serum Markers in Acute COVID-19 Infection With Emphasis on Organ Failure, Anti-Viral Treatment, and Demographic Characteristics.

Identification of novel immune biomarkers to gauge the underlying pathology and severity of COVID-19 has been difficult due to the lack of longitudinal studies. Here, we analyzed serum collected upon COVID-19 admission (t1), 48 hours (t2), and seven days later (t3) using Olink proteomics and correlated to clinical, demographics, and therapeutic data. Older age positively correlated with decorin, pleiotrophin, and TNFRS21 but inversely correlated with chemokine (both C-C and C-X-C type) ligands, monocyte attractant proteins (MCP) and TNFRS14. The burden of pre-existing conditions was positively correlated with MCP-4, CAIX, TWEAK, TNFRS12A, and PD-L2 levels. Individuals with COVID-19 demonstrated increased expression of several chemokines, most notably from the C-C and C-X-C family, as well as MCP-1 and MCP-3 early in the course of the disease. Similarly, deceased individuals had elevated MCP-1 and MCP-3 as well as Gal-9 serum levels. LAMP3, GZMB, and LAG3 at admission correlated with mortality. Only CX3CL13 and MCP-4 correlated positively with APACHE score and length of stay, while decorin, MUC-16 and TNFRSF21 with being admitted to the ICU. We also identified several organ-failure-specific immunological markers, including those for respiratory (IL-18, IL-15, Gal-9) or kidney failure (CD28, VEGF). Treatment with hydroxychloroquine, remdesivir, convalescent plasma, and steroids had a very limited effect on the serum variation of biomarkers. Our study identified several potential targets related to COVID-19 heterogeneity (MCP-1, MCP-3, MCP-4, TNFR superfamily members, and programmed death-ligand), suggesting a potential role of these molecules in the pathology of COVID-19.

The Characterization of the Toll of Caring for Coronavirus Disease 2019 on ICU Nursing Staff.

OBJECTIVES: Coronavirus disease 2019 pandemic exercised a significant demand on healthcare workers. We aimed to characterize the toll of caring for coronavirus disease 2019 patients by registered nurses. DESIGN: An observational study of two registered nurses cohorts. SETTING: ICUs in a large academic center. SUBJECTS: Thirty-nine ICU registered nurses assigned to coronavirus disease 2019 versus noncoronavirus disease 2019 patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Skin temperature (t [°C]), galvanic skin stress response (GalvStress), blood pulse wave, energy expenditure (Energy [cal]), number of steps (hr-1), heart rate (min-1), and respiratory rate (min-1) were collected using biosensors during the shift. National Aeronautics and Space Administration Task Loading Index measured the subjective perception of an assignment load. Elevated skin temperatures during coronavirus disease 2019 shifts were recorded (ΔtCOVID vs tnon-COVID = +1.3 [°C]; 95% CI, 0.1-2.5). Registered nurses staffing coronavirus disease patients self-reported elevated effort (ΔEffortCOVID vs Effortnon-COVID = +28.6; 95% CI, 13.3-43.9) concomitant with higher energy expenditure (ΔEnergyCOVID vs Energynon-COVID = +21.5 [cal/s]; 95% CI, 4.2-38.7). Galvanic skin stress responses were more frequent among coronavirus disease registered nurse (ΔGalStressCOVID vs GalvStressnon-COVID = +10.7 [burst/hr]; 95% CI, 2.6-18.7) and correlated with self-reported increased mental burden (ΔTLXMentalCOVID vs ΔTLXMentalnon-COVID = +15.3; 95% CI, 1.0-29.6). CONCLUSIONS: There are indications that registered nurses providing care for coronavirus disease 2019 in the ICU reported increased thermal discomfort coinciding with elevated energy expenditure and a more pronounced self-perception of effort, stress, and mental demand.

Remote Monitoring of Critically-Ill Post-Surgical Patients: Lessons from a Biosensor Implementation Trial.

Biosensors represent one of the numerous promising technologies envisioned to extend healthcare delivery. In perioperative care, the healthcare delivery system can use biosensors to remotely supervise patients who would otherwise be admitted to a hospital. This novel technology has gained a foothold in healthcare with significant acceleration due to the COVID-19 pandemic. However, few studies have attempted to narrate, or systematically analyze, the process of their implementation. We performed an observational study of biosensor implementation. The data accuracy provided by the commercially available biosensors was compared to those offered by standard clinical monitoring on patients admitted to the intensive care unit/perioperative unit. Surveys were also conducted to examine the acceptance of technology by patients and medical staff. We demonstrated a significant difference in vital signs between sensors and standard monitoring which was very dependent on the measured variables. Sensors seemed to integrate into the workflow relatively quickly, with almost no reported problems. The acceptance of the biosensors was high by patients and slightly less by nurses directly involved in the patients' care. The staff forecast a broad implementation of biosensors in approximately three to five years, yet are eager to learn more about them. Reliability considerations proved particularly troublesome in our implementation trial. Careful evaluation of sensor readiness is most likely necessary prior to system-wide implementation by each hospital to assess for data accuracy and acceptance by the staff.

Developing the eMedical Student (eMS)-A Pilot Project Integrating Medical Students into the Tele-ICU during the COVID-19 Pandemic and beyond.

The COVID-19 pandemic has accelerated the demand for virtual healthcare delivery and highlighted the scarcity of telehealth medical student curricula, particularly tele-critical care. In partnership with the Penn E-lert program and the Department of Anesthesiology and Critical Care, the Perelman School of Medicine (PSOM) established a tele-ICU rotation to support the care of patients diagnosed with COVID-19 in the Intensive Care Unit (ICU). The four-week course had seven elements: (1) 60 h of clinical engagement; (2) multiple-choice pretest; (3) faculty-supervised, student-led case and topic presentations; (4) faculty-led debriefing sessions; (5) evidence-based-medicine discussion forum; (6) multiple-choice post-test; and (7) final reflection. Five third- and fourth-year medical students completed 300 h of supervised clinical engagement, following 16 patients over three weeks and documenting 70 clinical interventions. Knowledge of critical care and telehealth was demonstrated through improvement between pre-test and post-test scores. Professional development was demonstrated through post-course preceptor and learner feedback. This tele-ICU rotation allowed students to gain telemedicine exposure and participate in the care of COVID patients in a safe environment.

What Can COVID-19 Teach Us about Using AI in Pandemics?

The COVID-19 pandemic put significant strain on societies and their resources, with the healthcare system and workers being particularly affected. Artificial Intelligence (AI) offers the unique possibility of improving the response to a pandemic as it emerges and evolves. Here, we utilize the WHO framework of a pandemic evolution to analyze the various AI applications. Specifically, we analyzed AI from the perspective of all five domains of the WHO pandemic response. To effectively review the current scattered literature, we organized a sample of relevant literature from various professional and popular resources. The article concludes with a consideration of AI's weaknesses as key factors affecting AI in future pandemic preparedness and response.