Kidney Outcomes in Critically Ill Patients With and Without COVID-19

Background: Case series have described high rates of AKI in critically ill persons with covid-19. However, no study has directly compared kidney outcomes in similarly ill persons with and without covid-19 that are contemporaneously enrolled. Method(s): We assessed 346 participants from a study of covid-19 in critical illness enrolled from University of Washington from April 2020 to May 2021. Patients in the ICU were recruited if symptoms of lower respiratory tract infection prompted covid testing. 2/3 of the cohort were covid positive;the remaining 1/3 had another cause of respiratory illness and served as controls. We defined major adverse kidney events (MAKE) as doubling of serum creatinine, dialysis, or death during hospitalization. Among 186 patients with available urine samples, we also assessed kidney injury molecule-1 (KIM-1), epidermal growth factor (EGF), and Cr. We used inverse probability of treatment weighting with propensity scores to increase similarity between the comparison groups. Result(s): Mean age was 55 years;64% were male, and mean admission serum Cr was 1.3 +/- 1.0 mg/dL. Baseline characteristics, including APACHE III and SOFA scores, were similar between groups after propensity weighting. Among Covid-19 patients the incidence of MAKE was 45% and in non-covid-19 patients was 26%. Covid-19 positivity was associated with a 55% greater incidence of MAKE and each component of MAKE was numerically higher in the covid-19 positive group (figure). The covid positive group had lower urine EGF levels (indexed to urine Cr) over time. Urine KIM-1 levels were similar. Conclusion(s): The incidences of clinical kidney outcomes are numerically higher in critically ill patients with covid-19 compared with similarly ill control patients without covid-19. Urinary concentrations of EGF are lower in covid positive patients.

In ICU Patients With COVID-19, Estimating Glomerular Filtration Rate From Creatinine and Cystatin C

Background: Accurate estimation of the glomerular filtration rate (eGFR) in critical illness is essential for judging the severity of kidney injury and informing medication dosing. Many drugs used to treat COVID-19 require dose adjustment (baricitinib) or are withheld (remdesivir) based on kidney function. Cystatin C provides more accurate and precise estimation of GFR than serum creatinine in outpatient settings, but the relationship of creatinine and cystatin C in critically ill patients with and without COVID-19 is less known. Method(s): We prospectively enrolled 253 ICU patients, including 176 (70%) patients with COVID-19 and 77 (30%) patients without COVID-19. We collected plasma on days 1, 3, 7, 10 and 14 leading to a total of 643 samples. Plasma creatinine was measured using the modified Jaffe method and plasma cystatin C was measured using an immunoturbidimetric assay (Gentian AS) on a Beckman DXC Unicell clinical analyzer. Result(s): Among 486 plasma samples in 176 unique COVID-19 patients, plasma cystatin C and creatinine were correlated (r=0.79) but calculated eGFR differed. Values of eGFRcr were, on average, 16-41 ml/min/1.73m2 higher than those of eGFRcys during hospitalization (p <0.001) (Figure 1). Each 15 ml/min/1.73m2 lower eGFRcys was associated with an estimated 11% greater risk of hospital mortality (RR =1.11, 95% CI, 1.03 to 1.21) compared to an estimated 6% greater risk of hospital mortality with eGFRcr (RR = 1.06;95% CI: 0.97 to 1.16). Among non-COVID-19 patients there was a similar trend with higher eGFRcr than eGFRcys but the difference on ICU admission was nonsignificant. Conclusion(s): In COVID-19 ICU patients eGFRcr was consistently higher than eGFRcys, and eGFRcys may more strongly associate with clinical outcomes. Our findings suggest that in COVID-19, calculating eGFR using creatinine or cystatin C could have implications on which treatments are available to patients.

Identifying ARDS using the Hierarchical Attention Network with Sentence Objectives Framework

Acute respiratory distress syndrome (ARDS) is a life-threatening condition that is often undiagnosed or diagnosed late. ARDS is especially prominent in those infected with COVID-19. We explore the automatic identification of ARDS indicators and confounding factors in free-text chest radiograph reports. We present a new annotated corpus of chest radiograph reports and introduce the Hierarchical Attention Network with Sentence

Severe acute respiratory infection-preparedness (Sari-Prep): A multicenter prospective study

OBJECTIVES: We designed a prospective cohort study to systematically study patients with severe acute respiratory infection (SARI) and improve hospital preparedness (SARI-PREP). The goal of this project is to evaluate the natural history, prognostic biomarkers, and characteristics, including hospital stress, associated with SARI clinical outcomes and severity. METHODS: In collaboration with the Society of Critical Care Medicine Discovery Research Network and the National Emerging Special Pathogen Training and Education Center (NETEC), SARIPREP is an ongoing, prospective, observational, multi-center cohort study of hospitalized patients with respiratory viral infections. We collected patient demographics, signs, symptoms, and medications;microbiology, imaging, and other diagnostics;mechanical ventilation, hospital procedures, and other interventions;and clinical outcomes. Hospital leadership completed a weekly hospital stress survey. Respiratory, blood, and urine biospecimens were collected from patients on days 0, 3, 7-14 after study enrollment and at hospital discharge. MEASUREMENTS AND MAIN RESULTS: SARI-PREP enrollment began on April 4, 2020 and currently includes 674 patients. Here we report results from the first 400 patients: 216 are from the University of Washington Hospitals, Seattle WA, 142 from New York University, New York NY and 42 from University of Southern California, Los Angeles, CA. Almost all tested positive for SARS-CoV-2 infection (n=397), whereas 3 patients tested positive for an alternative viral pathogen. The mean (±SD) age of the patients was 57±16 years;72% were men, 62% were White, 14% were Asian, 12% were Black, and 31% were Hispanic. Most of the patients were admitted to the intensive care unit (96%). The median (interquartile range) hospital length of stay was 22 (9-46) days. Rates of invasive mechanical ventilation (72%) and renal replacement therapy (19%) were common and the rate of hospital mortality was 35%. CONCLUSIONS: Initial SARI-PREP analysis indicates enrollment of a diverse population of hospitalized patients primarily with SARSCoV-2 infection. The demographics and clinical outcomes of our cohort mirror other large critically ill cohorts of COVID-19 patients. Results of a concomitant, weekly, hospital stress assessment are reported separately.

Rates of aki in ICU patients admitted under suspicion for COVID-19 do not differ by SARS-CoV 2 status or SARS-CoV-2 genomic load

Rationale: Since the onset of coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), studies have suggested a high incidence of acute kidney injury (AKI) among patients with COVID-19. However, these studies lack contemporaneously enrolled critically ill patients to understand whether high rates of AKI are unique to COVID-19. It is also unknown whether the risk of AKI is related to SARS-CoV-2 genomic load. Methods: We prospectively enrolled a cohort of patients admitted to the ICU with suspicion of COVID-19 (persons under investigation) from April to September 2020. Of these patients, 78 (46%) tested positive for SARS-CoV-2 (COVID-19) and 91 (54%) tested negative (non-COVID-19). AKI was defined as an increase ≥ 0.3 mg/dL in 48 hours or ≥ 50% increase in serum creatinine (sCr) measured during hospitalization compared to a 'baseline' sCr measured at study enrollment. New dialysis was defined as initiation of dialysis during hospitalization. SARS-CoV-2 qRT-PCR was performed across four different platforms with comparable cycle threshold (Ct) values. Ct values were a semiquantitative measure of genomic load with an inverse relationship of Ct to genomic load. We used relative risk regression to determine if there was an increased risk of AKI in COVID-19 compared to non-COVID-19 and whether SARS-CoV-2 genomic load was associated with AKI. Analyses were adjusted for age, sex, body mass index, and APACHE III scores. Results: Rates of AKI and new dialysis were similar in COVID-19 compared to non-COVID-19 (AKI: n=23 (29%) vs n=24 (26%) and Dialysis: n=8 (10%) vs n=6 (6%). Unadjusted and adjusted analyses demonstrated a non-significant difference in risk of AKI (adjusted RR = 1.04 (95% CI: 0.65-1.66) or new dialysis (adjusted RR = 1.55 (95% CI 0.58-4.12) in COVID-19 compared to non-COVID-19. We had Ct values available prior to ICU admission in 47 patients. In unadjusted and adjusted analyses, a 10-unit decrement in Ct values was not associated with AKI (adjusted RR = 0.40 (95% CI: 0.14-1.14) or new dialysis (adjusted RR = 0.96 (95% CI: 0.23-2.69) (Figure 1). Conclusions: Our study demonstrates that rates of AKI and new dialysis in ICU patients with COVID-19 are similar to rates in non-COVID-19 ICU patients. Moreover, the lack of association between Ct values and AKI in COVID-19, suggests that immune and host response to SARS-CoV-2 may contribute more to risk of AKI in ICU patients rather than the pathogen itself.

Plasma SCD14-ST, but not SCD14, is inversely associated with risk for SARSCoV2 positivity and positively associated with COVID-19-related respiratory failure in critically ill patients admitted under suspicion for COVID-19

Intro: Early innate immune responses are hypothesized to impact inflammation and therefore severity of disease and organ injury in COVID-19. Prior work in sepsis has identified CD14 as a marker of innate immune responses to bacterial infection and emerging evidence has implicated CD14 in COVID-19. CD14 exists in membrane bound and soluble (sCD14) form. A soluble N-terminal fragment of sCD14, sCD14 subtype (sCD14-ST, “Presepsin”) has been shown to have utility in diagnosis of sepsis and prognosis of associated organ failure and death. Goal: To determine the relationship between plasma sCD14 and sCD14-ST levels, COVID-19 status, and COVID-19 related outcomes in a cohort of prospectively enrolled critically ill patients admitted under suspicion for COVID-19. Methods: Critically ill patients under investigation for COVID-19 were prospectively enrolled between April 2020 and November 2020 at three hospitals affiliated with University of Washington. We ascertained COVID-19 status by SARS-CoV-2 RT-PCR upon admission. We measured plasma sCD14 and sCD14-ST levels in samples collected within 24 hours of admission. We tested for associations between biomarker levels and COVID-19 status using logistic regression adjusting for age, sex and APACHE III. In patients with COVID-19, we tested for associations between biomarker levels and disease severity and clinical outcomes using regression analyses adjusting for age, sex and APACHE III. Results: The cohort (n=222) mean age was 55 years, it was predominantly male (66%), in hospital mortality was 26%, and 50% of patients were positive by SARS-CoV-2 RT-PCR. Patients with COVID-19 had lower APACHE III scores (p: 0.013) than non-COVID-19. SCD14-ST levels were inversely associated with risk of SARS-CoV-2 positivity in multivariate regression (OR: 0.70, 95% CI: 0.57-0.84). Among patients with COVID-19, sCD14-ST levels were associated with higher APACHE III scores (beta: 7.3, 95% CI: 4.1-11), lower ventilatorfree days (beta:-1.6, 95% CI:-3.2 to-0.05) and higher risk for AKI (OR: 1.6, 95% CI: 1.0 to 2.7). SCD14-ST levels were not associated with these clinical outcomes in non-COVID-19 controls. In contrast to sCD14-ST levels, sCD14 levels did not differ between COVID-19 and non-COVID-19 patients and were not associated with COVID-19 clinical outcomes. Conclusions: In critically ill patients, sCD14-ST levels are inversely associated with risk of COVID-19 and positively associated with severity of disease and clinical outcomes among patients with COVID-19 while sCD14 levels were not associated with COVID-19 status or related outcomes. Early measurements of sCD14-ST levels could have prognostic utility in COVID-19.

Interferon-inducible mediators are associated with sars-cov-2 and related severity amongst critically ill patients suspected of covid-19

RATIONALE: Several studies have identified host immune signatures that are associated with COVID-19. However, it is unclear whether these immune signatures are specific to COVID-19 or are merely reflective of illness severity. In vitro studies have demonstrated that human T-cell responses to SARS-CoV-2-specific antigens are mediated through interferon-gamma (IFN-γ). Methods: We prospectively enrolled a multi-site cohort of patients admitted to the ICU under suspicion for COVID-19 who were then determined to be SARS-CoV-2-positive (n = 82) or-negative (n = 97) by RT-PCR. We measured multiple molecular and cellular immune profiles from blood and endotracheal aspirates (ETAs) collected on ICU admission. Our primary analysis tested for associations between IFN-γ and interferon-inducible mediators (CXCL10 and soluble PD-L1 (sPD-L1)) in blood or ETAs and SARS-CoV-2 status. We then stratified our cohort into SARS-CoV-2-negative and-positive groups and tested for associations between interferon-inducible mediators and clinical outcomes and SARS-CoV-2-copy-number. We used cytometry time-of-flight (CyTOF) to simultaneously measure 39 cell surface and intracellular markers on peripheral blood mononuclear cells collected from a subset of patients with ARDS. We then compared immune cell signatures in subjects with vs. without SARS-CoV-2. Results: The mean APACHE III score was higher in SARS-CoV-2-negative vs.-positive subjects (80±30 vs. 69±29), but the groups were otherwise well-matched. SARS-CoV-2-positive subjects had higher plasma concentrations of IFN-γ, CXCL10, and sPD-L1 relative to SARSCoV-2-negative patients adjusting for age, sex, and severity of illness (all p ≤ 0.01). The levels of IL-6, TNF-α, IL-8, MCP-1, and IL-17A were not significantly different between the two groups. SARS-CoV-2-positive subjects also had higher CXCL10 concentrations in ETAs than SARS-CoV-2-negative subjects. Higher plasma concentrations of CXCL10 and sPD-L1 were associated with higher mortality (Table 1) and more severe respiratory disease (ventilator-free days (VFDs), ARDS) in SARS-CoV-2-positive, but not-negative, patients. In contrast, higher IL-6 was associated with a lower number of VFDs and ARDS in both groups. IFN-γ and CXCL10 (but not IL-6) were associated with SARS-CoV-2-copy-number. Using CyTOF, we found SARS-CoV-2-positive subjects had a lower proportion of CXCR3+ (CXCL10 receptor) T-cells, a higher proportion of PD-L1+ monocytes, and less T-cell and monocyte intracellular cytokine staining vs. SARS-CoV-2-negative patients. Conclusion: Our findings suggest interferon-inducible mediator responses and immune cell hypofunction are characteristic of critically ill subjects with SARS-CoV-2 compared with similar patients without SARS-CoV-2. Our identification of immune signatures that are associated with SARS-CoV-2 infection but are distinct from other forms of critical illness clarifies COVID-19 pathophysiology.

Comparison of host endothelial, epithelial and inflammatory response in ICU patients with and without COVID-19

Rationale: Analyses of blood biomarkers involved in the host response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection can reveal distinct biological pathways and inform development and testing of therapeutics for COVID-19. Objective: To evaluate host endothelial, epithelial and inflammatory biomarkers in COVID-19Methods: We prospectively enrolled 169 ICU patients with suspicion of COVID-19 infection, including 78 (46%) patients positive and 91 (54%) negative for SARS-CoV-2 infection from April to September, 2020. We compared 22 plasma biomarkers in blood collected within 24 hours and 3 days after ICU admission. Measurement and Main Results: ICU patients with and without COVID-19 had similar rates of severe acute kidney injury, shock, thromboembolism and in-hospital mortality. Rates of ARDS were higher in COVID-19 (aRR = 5.9, 95% CI: 3.2-11.0). While concentrations of interleukin 6 and 8 were not different between groups, markers of epithelial cell injury (soluble receptor for advanced glycation end products, sRAGE) and acute phase proteins (serum amyloid A, SAA) were significantly higher in COVID-19 compared to non-COVID-19, adjusting for demographics and APACHE III scores (Figure 1). In contrast, angiopoietin 2:1 (Ang-2:1 ratio) and soluble tumor necrosis factor receptor 1 (sTNFR-1), markers of endothelial dysfunction and inflammation, were significantly lower in COVID-19 (Bonferroni corrected p<0.002). Ang-2:1 ratio and SAA were associated with mortality only in non-COVID-19 patients.Conclusions: These studies demonstrate that, unlike other well-studied causes of critical illness, endothelial dysfunction is not characteristic of severe COVID-19 early after ICU admission. Pathways resulting in elaboration of acute phase proteins and inducing epithelial cell injury may be promising targets for therapeutics. 2 (Table Presented).