Evaluation of Plasma Biomarkers to Predict Major Adverse Kidney Events in Hospitalized Patients With COVID-19.

RATIONALE & OBJECTIVE: Patients hospitalized with COVID-19 are at increased risk for major adverse kidney events (MAKE). We sought to identify plasma biomarkers predictive of MAKE in patients hospitalized with COVID-19. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: A total of 576 patients hospitalized with COVID-19 between March 2020 and January 2021 across 3 academic medical centers. EXPOSURE: Twenty-six plasma biomarkers of injury, inflammation, and repair from first available blood samples collected during hospitalization. OUTCOME: MAKE, defined as KDIGO stage 3 acute kidney injury (AKI), dialysis-requiring AKI, or mortality up to 60 days. ANALYTICAL APPROACH: Cox proportional hazards regression to associate biomarker level with MAKE. We additionally applied the least absolute shrinkage and selection operator (LASSO) and random forest regression for prediction modeling and estimated model discrimination with time-varying C index. RESULTS: The median length of stay for COVID-19 hospitalization was 9 (IQR, 5-16) days. In total, 95 patients (16%) experienced MAKE. Each 1 SD increase in soluble tumor necrosis factor receptor 1 (sTNFR1) and sTNFR2 was significantly associated with an increased risk of MAKE (adjusted HR [AHR], 2.30 [95% CI, 1.86-2.85], and AHR, 2.26 [95% CI, 1.73-2.95], respectively). The C index of sTNFR1 alone was 0.80 (95% CI, 0.78-0.84), and the C index of sTNFR2 was 0.81 (95% CI, 0.77-0.84). LASSO and random forest regression modeling using all biomarkers yielded C indexes of 0.86 (95% CI, 0.83-0.89) and 0.84 (95% CI, 0.78-0.91), respectively. LIMITATIONS: No control group of hospitalized patients without COVID-19. CONCLUSIONS: We found that sTNFR1 and sTNFR2 are independently associated with MAKE in patients hospitalized with COVID-19 and can both also serve as predictors for adverse kidney outcomes. PLAIN-LANGUAGE SUMMARY: Patients hospitalized with COVID-19 are at increased risk for long-term adverse health outcomes, but not all patients suffer long-term kidney dysfunction. Identification of patients with COVID-19 who are at high risk for adverse kidney events may have important implications in terms of nephrology follow-up and patient counseling. In this study, we found that the plasma biomarkers soluble tumor necrosis factor receptor 1 (sTNFR1) and sTNFR2 measured in hospitalized patients with COVID-19 were associated with a greater risk of adverse kidney outcomes. Along with clinical variables previously shown to predict adverse kidney events in patients with COVID-19, both sTNFR1 and sTNFR2 are also strong predictors of adverse kidney outcomes.

Longitudinal lung function assessment of patients hospitalised with COVID-19 using 1H and 129Xe lung MRI

Introduction: The progression of pathophysiological pulmonary changes in patients following acute COVID-19 is not well established. Method(s): Patients hospitalised with COVID-19 pneumonia without signs of ILD, had MRI exams at a median of 6 (n=9), 12 (n=9), 25 (n=7), and 52 (n=3) weeks. MRI sequences included: dynamic contrast enhanced (DCE) lung perfusion,129 Xe diffusion weighted (DW-MRI), 129Xe ventilation and 129Xe 3D dissolved phase imaging. Result(s): 9 patients (age 56+/-9 years;7 male;1 required treatment in an ICU) were recruited. Median RBC:TP was abnormally low at all visits compared to reference age and sex matched data. An individual's RBC:TP was significantly and positively associated with an increase in their pulmonary blood volume (p=0.026). For patients with 52 week data available, one showed a continued increase in RBC:TP, 2 patients maintained a low RBC:TP (Figure 1). Ventilation defect percentage, and ventilation heterogeneity significantly decreased at 25 weeks compared to 6 129 129 129 weeks (p=0.010 and p=0.048). DW-MRI was normal at all visits. Dissolved phase xenon imaging showed RBC:TP significantly increased at 12 and 25 weeks compared to 6 weeks (p=0.048). Conclusion(s): In patients recovering after COVID-19, poor gas transfer is reflected by impaired xenon transfer, which improves alongside pulmonary blood volume.

Do not resuscitate orders in the time of COVID-19: Exploring media representations and implications for public and professional understandings

Context:: During the COVID-19 pandemic, the UK press featured headlines that heightened concerns around Do Not Attempt Cardiopulmonary Resuscitation (DNACPR) orders, particularly the use of 'blanket' DNACPR orders applied to older people in care settings. The portrayal of DNACPR may impact professional and public understandings with implications for end-of-life care. Objectives:: To explore the portrayal of DNACPR orders in the general and academic press and consider implications for public and professional understandings and practice. Method:: Academic papers and articles published in the general press during the first wave of the COVID-19 pandemic in the UK were retrieved. Those pertaining to the use of DNACPR orders were analysed thematically. Results:: Analysis of 179 media articles and 11 professional commentaries identified mixed understandings of DNACPR as indicated within three themes: rationing of acute services, championing autonomy in DNACPR decisions, and communication and trust. The call to 'protect the NHS' marginalised palliative and social care services with DNACPR constructed as a rationing tool. This led to ethical challenges around autonomy, DNACPR decisions, communication and trust. Conclusions:: Media coverage of DNACPR orders was contentious and raised questions around the value of life and quality of dying, particularly for vulnerable individuals. DNACPR orders were conflated with frailty, futility and rationing of acute services and the marginalisation of palliative care. Nevertheless, media outputs stimulated advocacy and support for human rights and autonomy. However, it is unclear what the legacy will be for public and professional understandings of advance care planning and the quality of dying.

Longitudinal 129xe and 1h Lung Mri Assessment of Lung Structure, Ventilation, Perfusion, and Gas Transfer Following Hospitalization with Covid-19

The long-term effects of coronavirus disease 2019 (COVID- 19) pneumonia on the lungs and pulmonary circulation require further characterization. We assessed progression of pathophysiological pulmonary changes during 1 year of follow-up of patients who had been hospitalized because of COVID-19. After discharge, recruited patients had up to four MRI examinations at a median of 6 (n=9), 12 (n=9), 25 (n=7) and 52 (n=3) weeks. Lung MRI examinations included: ultra-short echo time (UTE), dynamic contrastenhanced (DCE) lung perfusion, 129Xe diffusion weighted (DW-MRI), 129Xe ventilation and 129Xe 3D dissolved phase imaging. Nine patients (age 56 +/-9 years;six male) were recruited. Ventilation defect percentage and whole lung coefficient of variation of lung ventilation decreased significantly at 25 weeks (visit 3) compared with visit 1 at 6 weeks (p=0.010 and p=0.048). The UTE imaging indicated no evidence of lung scarring, and DW-MRI indicated normal lung microstructure across all visits. Dissolved phase xenon imaging showed that RBC:TP increased significantly at visits 2 and 3 compared with visit 1 (p=0.048). Median RBC:TP was abnormally low at all visits compared with reference age- and sex-matched data. An individual's RBC:TP was associated significantly and positively with an increase in their pulmonary blood volume (p=0.026). For patients with 52-week data available, one showed a continued improvement in RBC:TP;however, two of the patients maintained a low RBC:TP. In patients recovering from COVID-19, xenon gas transfer improves alongside pulmonary blood volume. Further work is needed to establish the proportion of post-COVID-19 patients who have longer-term impairment in xenon transfer and to correlate changes in lung MRI parameters with symptoms, lung function tests and other imaging modalities. Persistent impairment of xenon transfer might represent a physiological mechanism underlying ongoing symptoms in some patients and might indicate damage to the pulmonary microcirculation.

Long-term cognitive performance and its relation to anti-inflammatory therapy in a cohort of survivors of severe COVID-19.

Background and objectives: Long-term cognitive performance data in former critically ill COVID-19 patients are sparse. Current evidence suggests that cognitive decline is related to neuroinflammation, which might be attenuated by COVID-19 related anti-inflammatory therapies. The objective of this prospective cohort study was to study long term cognitive outcomes following severe COVID-19 and the relation to anti-inflammatory therapies. Methods: Prospective observational cohort of patients that survived an intensive care unit (ICU) admission due to severe COVID-19. Six months after hospital discharge, we extensively assessed both objective cognitive functioning and subjective cognitive complaints. Furthermore, patients were stratified in cohorts according to their anti-inflammatory treatment (i.e. no immunomodulatory therapy, dexamethasone, or both dexamethasone and interleukin-6 receptor antagonist tocilizumab). Results: 96 patients were included (March 2020-June 2021, median [IQR] age 61 [55-69] years). 91% received invasive mechanical ventilation, and mean ± SD severity-of-disease APACHE-II-score at admission was 15.8 ± 4.1. After 6.5 ± 1.3 months, 27% of patients scored cognitively impaired. Patients that did or did not develop cognitive impairments were similar in ICU-admission parameters, clinical course and delirium incidence. Patients with subjective cognitive complaints (20%) were more likely women (61% vs 26%), and had a shorter ICU stay (median [IQR] 8 [5-15] vs 18 [9-31], p = 0.002). Objective cognitive dysfunction did not correlate with subjective cognitive dysfunction. 27% of the participants received dexamethasone during intensive care admission, 44% received additional tocilizumab and 29% received neither. Overall occurrence and severity of cognitive dysfunction were not affected by anti-inflammatory therapy, although patients treated with both dexamethasone and tocilizumab had worse executive functioning scores (Trail Making Test interference) than patients without anti-inflammatory treatment (T-score 40.3 ± 13.5 vs 49.1 ± 9.3, p = 0.007). Discussion: A relevant proportion of critically ill COVID-19 patients shows deficits in long-term cognitive functioning. Apart from more pronounced executive dysfunction, overall, anti-inflammatory therapy appeared not to affect long-term cognitive performance. Our findings provide insight in long-term cognitive outcomes in patients who survived COVID-19, that may facilitate health-care providers counseling patients and their caregivers.

Impact of School Opening Model on Cases of SARS-CoV-2 in Surrounding Communities: A Nationwide, Retrospective Cohort Study

Background. Early in the COVID-19 pandemic, elementary and secondary schools were closed. There was variation in school opening mode (traditional, hybrid, remote) in fall 2020.The aim of this national, retrospective cohort study is to evaluate the impact of in-person learning on community incidence of SARS-CoV-2 and COVID-19-related deaths. Methods. Data were extracted from several data sources. School opening mode was collected from the Burbio school tracker, which tracks school openings in a sample of school districts across the US. Incidence of SARS-CoV-2 and COVID-19 related deaths were obtained from the CDC. Data on community-level SARS-CoV-2 mitigation measures were obtained from the Oxford University COVID-19 Government Response Tracker. The effect of school mode on SARS-CoV-2 cases and deaths/100,000 during the 12-weeks following the start of school was estimated using a log-linear model with state, week, and state-week fixed effects. Models were stratified by 9 US Census divisions and adjusted for variables determined a priori to be potentially associated with the outcome. Results. 519 US counties were included (Figure 1);mean cases of COVID-19 were increasing across all regions during the weeks following the start of school, regardless of school mode. Adjusted absolute differences in COVID-19 cases in counties with hybrid and traditional school opening modes relative to fully remote learning models are presented in Figure 2. In the Northeast and Midwest regions of the country, COVID-19 case rates were not statistically different between different school modes. However, in the South and West regions, there was a statistically significant increase in cases per week among counties that opened in an in-person relative to remote learning model, ranging from 17.1 (95% CI: 0.3-33.8) to 24.4 (95% CI: 7.3-41.5) in the South and from 19.0 (95% CI: 8.8-29.3) to 109.2 (95% CI: 50.4-168.0) in the West. There was no impact of school opening mode on COVID-19-related deaths. Conclusion. Impact of school mode on community case-rates of SARS-CoV-2 varied across the US. In some areas of the country, traditional school mode was associated with increases in case rates relative to virtual while there were no differences in other regions.

Multiscale PHATE identifies multimodal signatures of COVID-19.

As the biomedical community produces datasets that are increasingly complex and high dimensional, there is a need for more sophisticated computational tools to extract biological insights. We present Multiscale PHATE, a method that sweeps through all levels of data granularity to learn abstracted biological features directly predictive of disease outcome. Built on a coarse-graining process called diffusion condensation, Multiscale PHATE learns a data topology that can be analyzed at coarse resolutions for high-level summarizations of data and at fine resolutions for detailed representations of subsets. We apply Multiscale PHATE to a coronavirus disease 2019 (COVID-19) dataset with 54 million cells from 168 hospitalized patients and find that patients who die show CD16hiCD66blo neutrophil and IFN-γ+ granzyme B+ Th17 cell responses. We also show that population groupings from Multiscale PHATE directly fed into a classifier predict disease outcome more accurately than naive featurizations of the data. Multiscale PHATE is broadly generalizable to different data types, including flow cytometry, single-cell RNA sequencing (scRNA-seq), single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq), and clinical variables.

ICATS Spine Mini-Mega Clinic making a big impact

Keywords: Orthopaedic ICATS;Mini-Mega Clinic;Spine Purpose: Orthopaedic ICATS clinicians work as part of the wider spinal team in Northern Ireland. In June 2020 Orthopaedic ICATS in The Belfast Trust in collaboration with Spinal Surgeon Mr. Darwish established a monthly Spine Mini-Mega Clinic. The main triggers for the clinic were the extensive spinal waiting list in Northern Ireland and improving the spinal orthopaedic journey for patients. The Mini-Mega Clinic model is in line with the Department of Health Rebuilding, Transition and Transformation of Elective Orthopaedic Care in Northern Ireland (DOH, July 2020). While the clinic is successful in assessing a large number of patients in a short time, patient centered care remains paramount with clinicians mindful that many of the patients have been waiting years for an appointment. The clinic also provides an educational opportunity for ICATS clinicians and increases clinician's confidence. The establishment of the Spine Mini-Mega Clinic builds on the previously successful Northern Ireland Regional Spine Mega Clinics, Co-located ICATS Clinics and the Virtual Consultant Spinal Opinion. The Mini-Mega Clinic is now built into the ICATS job plan and also affords Mr. Darwish protected time to manage the monthly ICATS spinal surgical queries. Methods: Due to the Covid-19 pandemic, patients on the Spinal Surgical Waiting List had a virtual consultation with an ICATS clinician. Potential surgical candidates with clinical symptoms concordant with MRI findings are discussed with Mr. Darwish who makes a decision on the most appropriate management. The ICATS team also refer new patients to the clinic who they deem to be potential surgical candidates following appropriate orthopaedic work-up. Results: Seven clinics were delivered between June 2020 and February 2021 with 493 patients seen. 329 patients (67%) were from the Regional Spinal Waiting List and 164 patients (33%) were referred by ICATS. Results show that 74% of waiting list patients were discharged with no further orthopaedic follow-up. Conversely 65% of ICATS referrals were boarded for surgery and only 15% were discharged. This supports the Single Point of Referral via Orthopaedic ICATS advocated in The Regional Spinal Pathway (2016) and demonstrates the high level at which ICATS clinicians are working to support consultants. Conclusion(s): The Spinal Mini-Mega Clinic has proven to be a highly effective model in assessing a large number of patients in a short time and therefore significantly impacting on waiting lists. There is a high discharge rate of Spinal Waiting List Patients. The clinic is cost effective and optimises the use of consultant time, it improves the patient journey for new patients and it provides education and upskilling of ICATS clinicians. The clinic also highlights the value and skills of the ICATS Advanced Practice Physiotherapists and how their skills can be utilised to reduce the demand on consultant clinics and streamline waiting lists. Impact: Other Trusts are now utilising a similar model with designated spinal consultant support for a virtual consultant opinion therefore reducing unnecessary referrals being added to the waiting list. The Mini-Mega Clinic model has potential to be utilised for other body parts to impact the ever increasing orthopaedic waiting lists. Funding acknowledgements: N/A.

Prognostic Significance of Urinary Biomarkers in Patients Hospitalized With COVID-19.

RATIONALE & OBJECTIVE: Acute kidney injury (AKI) is common in patients with coronavirus disease 2019 (COVID-19) and associated with poor outcomes. Urinary biomarkers have been associated with adverse kidney outcomes in other settings and may provide additional prognostic information in patients with COVID-19. We investigated the association between urinary biomarkers and adverse kidney outcomes among patients hospitalized with COVID-19. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Patients hospitalized with COVID-19 (n=153) at 2 academic medical centers between April and June 2020. EXPOSURE: 19 urinary biomarkers of injury, inflammation, and repair. OUTCOME: Composite of KDIGO (Kidney Disease: Improving Global Outcomes) stage 3 AKI, requirement for dialysis, or death within 60 days of hospital admission. We also compared various kidney biomarker levels in the setting of COVID-19 versus other common AKI settings. ANALYTICAL APPROACH: Time-varying Cox proportional hazards regression to associate biomarker level with composite outcome. RESULTS: Out of 153 patients, 24 (15.7%) experienced the primary outcome. Twofold higher levels of neutrophil gelatinase-associated lipocalin (NGAL) (HR, 1.34 [95% CI, 1.14-1.57]), monocyte chemoattractant protein (MCP-1) (HR, 1.42 [95% CI, 1.09-1.84]), and kidney injury molecule 1 (KIM-1) (HR, 2.03 [95% CI, 1.38-2.99]) were associated with highest risk of sustaining primary composite outcome. Higher epidermal growth factor (EGF) levels were associated with a lower risk of the primary outcome (HR, 0.61 [95% CI, 0.47-0.79]). Individual biomarkers provided moderate discrimination and biomarker combinations improved discrimination for the primary outcome. The degree of kidney injury by biomarker level in COVID-19 was comparable to other settings of clinical AKI. There was evidence of subclinical AKI in COVID-19 patients based on elevated injury biomarker level in patients without clinical AKI defined by serum creatinine. LIMITATIONS: Small sample size with low number of composite outcome events. CONCLUSIONS: Urinary biomarkers are associated with adverse kidney outcomes in patients hospitalized with COVID-19 and may provide valuable information to monitor kidney disease progression and recovery.

Prognostic significance of urinary biomarkers in patients hospitalized with COVID-19

Background: Acute kidney injury (AKI) is common in patients with COVID-19 and associated with poor outcomes. Urinary biomarkers have been associated with adverse kidney outcomes in other settings and may provide additional prognostic information in patients with COVID-19. Methods: We evaluated 19 urinary biomarkers of injury, inflammation, and repair in patients hospitalized with COVID-19 at 2 academic medical centers between April and June 2020. We associated biomarkers with a primary composite outcome of KDIGO stage 3 AKI, requirement for dialysis, or death within 60 days of admission. We also compared various kidney biomarker levels in the setting of COVID-19 versus other common AKI settings. Results: Out of 157 patients, 24 (15.3%) experienced the primary outcome. Twofold higher levels of neutrophil gelatinase-associated lipocalin (NGAL) (HR: 1.53;95% CI: 1.33-1.76), monocyte chemoattractant protein (MCP-1) (HR: 1.86;95% CI: 1.48-2.33), and kidney injury molecule-1 (KIM-1) (HR: 2.32;95% CI: 1.69-3.18) were associated with highest risk of the primary outcome. Higher epidermal growth factor (EGF) levels were associated with a lower risk of the primary outcome (HR 0.52;95% CI: 0.40-0.69). Individual biomarkers provided moderate discrimination and biomarker combinations improved discrimination for the primary outcome. Conclusions: Urinary biomarkers are associated with severe kidney complications in patients with COVID-19 and provide valuable information to monitor kidney disease recovery and progression.

Plasma TNFR1 predicts major adverse kidney events in hospitalized patients with COVID-19

Background: Patients hospitalized with COVID-19 are at risk for major adverse kidney events (MAKE). Predicting which patients will experience progression of disease and poor outcomes remains elusive. We sought to develop a biomarker-based risk model for predicting MAKE in patients hospitalized with COVID-19. Methods: We applied least absolute shrinkage and regression methodology (LASSO) to a prospectively enrolled cohort of 432 patients admitted with COVID-19 who had blood specimens collected (median 2 days [IQR 2-4 days] from admission) from March 2020-January 2021, at three large academic medical centers. Clinical variables and 26 plasma biomarkers were used as candidate features in the prediction models for the outcome of MAKE, defined as KDIGO stage 3 AKI, dialysis-requiring AKI, or in hospital mortality. Cross-validation was used for optimal shrinkage parameter selection and model AUCs were optimism-corrected using bootstrapping. Results: MAKE occurred in 85 (20%) patients within 60 days of admission. Application of LASSO to the 26 biomarkers selected IL-12, IL-13, IL-6, Tie2, FLT1, NGAL, MCP1, YKL40, Ang1, Ang2, and TNFR1, which yielded an AUC of 0.88 (95% CI 0.85-0.91). Plasma TNFR-1 alone had an AUC of 0.88 (0.84,0.91). When LASSO was applied on the clinical variables and TNFR1, 4 clinical variables (age, black race, obesity, WHO COVID severity score) and TNFR1 were selected with an AUC was 0.88 (95% CI 0.87-0.89). Random Forest models of biomarkers and clinical variables had similar prediction performance. A cutoff of TNFR1 at 3005 pg/ml had a sensitivity of 69%, specificity of 89%, PPV of 60% and NPV of 92% for occurrence of MAKE over 60 days. Conclusions: In this multi-center cohort study, plasma TNFR1 by itself produced a robust prediction for MAKE in patients hospitalized with COVID-19 that did not improve when combined with multiple clinical variables and was equivalent to combined inputs of 10 other plasma biomarkers.

Interferon gamma immunotherapy in five critically ill COVID-19 patients with impaired cellular immunity: A case series.

BACKGROUND: Prolonged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shedding has been described in immunocompromised coronavirus disease 2019 (COVID-19) patients, resulting in protracted disease and poor outcome. Specific therapy to improve viral clearance and outcome for this group of patients is currently unavailable. METHODS: Five critically ill COVID-19 patients with severe defects in cellular immune responses, high SARS-CoV-2 viral RNA loads, and no respiratory improvement were treated with interferon gamma, 100 µg subcutaneously, thrice weekly. Bronchial secretion was collected every 48 h for routine diagnostic SARS-CoV-2 RT-PCR and viral culture. FINDINGS: Interferon gamma administration was followed by a rapid decline in SARS-CoV-2 load and a positive-to-negative viral culture conversion. Four patients recovered, and no signs of hyperinflammation were observed. CONCLUSIONS: Interferon gamma may be considered as adjuvant immunotherapy in a subset of immunocompromised COVID-19 patients. FUNDING: A.v.L. and R.v.C. are supported by National Institutes of Health (R01AI145781). G.J.O. and R.P.v.R. are supported by a VICI grant (016.VICI.170.090) from the Dutch Research Council (NWO). W.F.A. is supported by a clinical fellowship grant (9071561) of Netherlands Organization for Health Research and Development. M.G.N. is supported by an ERC advanced grant (833247) and a Spinoza grant of the Netherlands Organization for Scientific Research.

Predicting patients with false negative SARS-CoV-2 testing at hospital admission: A retrospective multi-center study.

IMPORTANCE: False negative SARS-CoV-2 tests can lead to spread of infection in the inpatient setting to other patients and healthcare workers. However, the population of patients with COVID who are admitted with false negative testing is unstudied. OBJECTIVE: To characterize and develop a model to predict true SARS-CoV-2 infection among patients who initially test negative for COVID by PCR. DESIGN: Retrospective cohort study. SETTING: Five hospitals within the Yale New Haven Health System between 3/10/2020 and 9/1/2020. PARTICIPANTS: Adult patients who received diagnostic testing for SARS-CoV-2 virus within the first 96 hours of hospitalization. EXPOSURE: We developed a logistic regression model from readily available electronic health record data to predict SARS-CoV-2 positivity in patients who were positive for COVID and those who were negative and never retested. MAIN OUTCOMES AND MEASURES: This model was applied to patients testing negative for SARS-CoV-2 who were retested within the first 96 hours of hospitalization. We evaluated the ability of the model to discriminate between patients who would subsequently retest negative and those who would subsequently retest positive. RESULTS: We included 31,459 hospitalized adult patients; 2,666 of these patients tested positive for COVID and 3,511 initially tested negative for COVID and were retested. Of the patients who were retested, 61 (1.7%) had a subsequent positive COVID test. The model showed that higher age, vital sign abnormalities, and lower white blood cell count served as strong predictors for COVID positivity in these patients. The model had moderate performance to predict which patients would retest positive with a test set area under the receiver-operator characteristic (ROC) of 0.76 (95% CI 0.70-0.83). Using a cutpoint for our risk prediction model at the 90th percentile for probability, we were able to capture 35/61 (57%) of the patients who would retest positive. This cutpoint amounts to a number-needed-to-retest range between 15 and 77 patients. CONCLUSION AND RELEVANCE: We show that a pragmatic model can predict which patients should be retested for COVID. Further research is required to determine if this risk model can be applied prospectively in hospitalized patients to prevent the spread of SARS-CoV-2 infections.

Kidney transplantation in the time of COVID-19: Dilemmas, experiences, and perspectives.

INTRODUCTION: Hospital do Rim is a high-volume kidney transplant (KT) center located in São Paulo, a city with 12.2 million inhabitants. Over the last 18 years, we performed 11 436 KT, 70% of which from deceased donors. To mitigate the effects of reduction in the number of transplants on the waiting list, sequential measures were implemented when COVID-19 was declared pandemic. METHODS: The first step was to provide SARS-COV-2 RT-PCR testing for all symptomatic employees and patients and the compulsory use of personal protective equipment in the hospital facilities. Living donor KT were postponed, and all deceased donors and recipients were tested before the transplantation. The immunosuppressive protocols were maintained, and telehealth strategies were developed. RESULTS: Among the 1013 employees, there were 214 cases of COVID-19, nine required ward hospitalization, and no deaths occurred. In 26%, the probable source of contamination was occupational. From the first patient diagnosed with COVID-19 in 03/20/2020 till 10/21/2020, 523 deceased KT were performed, a 21% increase compared with 2019, with no confirmed donor-derived SARS-CoV-2 infection. Four patients were transplanted with a positive pretransplant SARS-CoV-2 test, but none of them developed the disease. Overall, of 11 875 KT followed in our center, 674 developed COVID-19. Among the hospitalized, 53% required mechanical ventilation, and 45% required hemodialysis. Their overall mortality rate was 27.5%. CONCLUSION: This experience shows the challenges that transplant centers faced as the pandemic unfolded and illustrates the effectiveness of the sequential measures implemented to provide a safe environment for transplantation.

Assessment of Acute Kidney Injury and Longitudinal Kidney Function After Hospital Discharge Among Patients With and Without COVID-19.

Importance: Acute kidney injury (AKI) occurs in up to half of patients hospitalized with coronavirus disease 2019 (COVID-19). The longitudinal effects of COVID-19-associated AKI on kidney function remain unknown. Objective: To compare the rate of change in estimated glomerular filtration rate (eGFR) after hospital discharge between patients with and without COVID-19 who experienced in-hospital AKI. Design, Setting, and Participants: A retrospective cohort study was conducted at 5 hospitals in Connecticut and Rhode Island from March 10 to August 31, 2020. Patients who were tested for COVID-19 and developed AKI were screened, and those who survived past discharge, did not require dialysis within 3 days of discharge, and had at least 1 outpatient creatinine level measurement following discharge were included. Exposures: Diagnosis of COVID-19. Main Outcomes and Measures: Mixed-effects models were used to assess the association between COVID-19-associated AKI and eGFR slope after discharge. The secondary outcome was the time to AKI recovery for the subgroup of patients whose kidney function had not returned to the baseline level by discharge. Results: A total of 182 patients with COVID-19-associated AKI and 1430 patients with AKI not associated with COVID-19 were included. The population included 813 women (50.4%); median age was 69.7 years (interquartile range, 58.9-78.9 years). Patients with COVID-19-associated AKI were more likely to be Black (73 [40.1%] vs 225 [15.7%]) or Hispanic (40 [22%] vs 126 [8.8%]) and had fewer comorbidities than those without COVID-19 but similar rates of preexisting chronic kidney disease and hypertension. Patients with COVID-19-associated AKI had a greater decrease in eGFR in the unadjusted model (-11.3; 95% CI, -22.1 to -0.4 mL/min/1.73 m2/y; P = .04) and after adjusting for baseline comorbidities (-12.4; 95% CI, -23.7 to -1.2 mL/min/1.73 m2/y; P = .03). In the fully adjusted model controlling for comorbidities, peak creatinine level, and in-hospital dialysis requirement, the eGFR slope difference persisted (-14.0; 95% CI, -25.1 to -2.9 mL/min/1.73 m2/y; P = .01). In the subgroup of patients who had not achieved AKI recovery by discharge (n = 319), COVID-19-associated AKI was associated with decreased kidney recovery during outpatient follow-up (adjusted hazard ratio, 0.57; 95% CI, 0.35-0.92). Conclusions and Relevance: In this cohort study of US patients who experienced in-hospital AKI, COVID-19-associated AKI was associated with a greater rate of eGFR decrease after discharge compared with AKI in patients without COVID-19, independent of underlying comorbidities or AKI severity. This eGFR trajectory may reinforce the importance of monitoring kidney function after AKI and studying interventions to limit kidney disease after COVID-19-associated AKI.

A neutrophil activation signature predicts critical illness and mortality in COVID-19.

Pathologic immune hyperactivation is emerging as a key feature of critical illness in COVID-19, but the mechanisms involved remain poorly understood. We carried out proteomic profiling of plasma from cross-sectional and longitudinal cohorts of hospitalized patients with COVID-19 and analyzed clinical data from our health system database of more than 3300 patients. Using a machine learning algorithm, we identified a prominent signature of neutrophil activation, including resistin, lipocalin-2, hepatocyte growth factor, interleukin-8, and granulocyte colony-stimulating factor, which were the strongest predictors of critical illness. Evidence of neutrophil activation was present on the first day of hospitalization in patients who would only later require transfer to the intensive care unit, thus preceding the onset of critical illness and predicting increased mortality. In the health system database, early elevations in developing and mature neutrophil counts also predicted higher mortality rates. Altogether, these data suggest a central role for neutrophil activation in the pathogenesis of severe COVID-19 and identify molecular markers that distinguish patients at risk of future clinical decompensation.

Prolonged Unconsciousness Following Severe COVID-19.

OBJECTIVE: We report a case series of patients with prolonged but reversible unconsciousness after coronavirus disease 2019 (COVID-19)-related severe respiratory failure. METHODS: A case series of patients who were admitted to the intensive care unit due to COVID-19-related acute respiratory failure is described. RESULTS: After cessation of sedatives, the described cases all showed a prolonged comatose state. Diagnostic neurologic workup did not show signs of devastating brain injury. The clinical pattern of awakening started with early eye opening without obeying commands and persistent flaccid weakness in all cases. Time between cessation of sedatives to the first moment of being fully responsive with obeying commands ranged from 8 to 31 days. CONCLUSION: Prolonged unconsciousness in patients with severe respiratory failure due to COVID-19 can be fully reversible, warranting a cautious approach for prognostication based on a prolonged state of unconsciousness.

The Association of COVID-19 With Acute Kidney Injury Independent of Severity of Illness: A Multicenter Cohort Study.

RATIONALE & OBJECTIVE: Although coronavirus disease 2019 (COVID-19) has been associated with acute kidney injury (AKI), it is unclear whether this association is independent of traditional risk factors such as hypotension, nephrotoxin exposure, and inflammation. We tested the independent association of COVID-19 with AKI. STUDY DESIGN: Multicenter, observational, cohort study. SETTING & PARTICIPANTS: Patients admitted to 1 of 6 hospitals within the Yale New Haven Health System between March 10, 2020, and August 31, 2020, with results for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing via polymerase chain reaction of a nasopharyngeal sample. EXPOSURE: Positive test for SARS-CoV-2. OUTCOME: AKI by KDIGO (Kidney Disease: Improving Global Outcomes) criteria. ANALYTICAL APPROACH: Evaluated the association of COVID-19 with AKI after controlling for time-invariant factors at admission (eg, demographic characteristics, comorbidities) and time-varying factors updated continuously during hospitalization (eg, vital signs, medications, laboratory results, respiratory failure) using time-updated Cox proportional hazard models. RESULTS: Of the 22,122 patients hospitalized, 2,600 tested positive and 19,522 tested negative for SARS-CoV-2. Compared with patients who tested negative, patients with COVID-19 had more AKI (30.6% vs 18.2%; absolute risk difference, 12.5% [95% CI, 10.6%-14.3%]) and dialysis-requiring AKI (8.5% vs 3.6%) and lower rates of recovery from AKI (58% vs 69.8%). Compared with patients without COVID-19, patients with COVID-19 had higher inflammatory marker levels (C-reactive protein, ferritin) and greater use of vasopressors and diuretic agents. Compared with patients without COVID-19, patients with COVID-19 had a higher rate of AKI in univariable analysis (hazard ratio, 1.84 [95% CI, 1.73-1.95]). In a fully adjusted model controlling for demographic variables, comorbidities, vital signs, medications, and laboratory results, COVID-19 remained associated with a high rate of AKI (adjusted hazard ratio, 1.40 [95% CI, 1.29-1.53]). LIMITATIONS: Possibility of residual confounding. CONCLUSIONS: COVID-19 is associated with high rates of AKI not fully explained by adjustment for known risk factors. This suggests the presence of mechanisms of AKI not accounted for in this analysis, which may include a direct effect of COVID-19 on the kidney or other unmeasured mediators. Future studies should evaluate the possible unique pathways by which COVID-19 may cause AKI.