Antibiotic use during coronavirus disease 2019 intensive care unit shape multidrug resistance bacteriuria: A Swedish longitudinal prospective study.

Objectives: High frequency of antimicrobial prescription and the nature of prolonged illness in COVID-19 increases risk for complicated bacteriuria and antibiotic resistance. We investigated risk factors for bacteriuria in the ICU and the correlation between antibiotic treatment and persistent bacteria. Methods: We conducted a prospective longitudinal study with urine from indwelling catheters of 101 ICU patients from Uppsala University Hospital, Sweden. Samples were screened and isolates confirmed with MALDI-TOF and whole genome sequencing. Isolates were analyzed for AMR using broth microdilution. Clinical data were assessed for correlation with bacteriuria. Results: Length of stay linearly correlated with bacteriuria (R2 = 0.99, p ≤ 0.0001). 90% of patients received antibiotics, primarily the beta-lactams (76%) cefotaxime, piperacillin-tazobactam, and meropenem. We found high prevalence of Enterococcus (42%) being associated with increased cefotaxime prescription. Antibiotic-susceptible E. coli were found to cause bacteriuria despite concurrent antibiotic treatment when found in co-culture with Enterococcus. Conclusion: Longer stays in ICUs increase the risk for bacteriuria in a predictable manner. Likely, high use of cefotaxime drives Enterococcus prevalence, which in turn permit co-colonizing Gram-negative bacteria. Our results suggest biofilms in urinary catheters as a reservoir of pathogenic bacteria with the potential to develop and disseminate AMR.

In Vivo Visualization and Quantification of Neutrophil Elastase in Lungs of COVID-19 Patients - A First-In-Human Positron Emission Tomography Study with 11C-GW457427.

COVID-19 can cause life-threatening lung-inflammation that is suggested to be mediated by neutrophils, whose effector mechanisms in COVID-19 is inexplicit. The aim of the present work is to evaluate a novel PET tracer for neutrophil elastase in COVID-19 patients and healthy controls. METHODS: In this open-label, First-In-Man study, four patients with hypoxia due to COVID-19 and two healthy controls were investigated with positron emission tomography (PET) using the new selective and specific neutrophil elastase PET-tracer [11C]GW457427 and [15O]water for the visualization and quantification of NE and perfusion in the lungs, respectively. RESULTS: [11C]GW457427 accumulated selectively in lung areas with ground-glass opacities on computed tomography characteristic of COVID-19 suggesting high levels on NE in these areas. In the same areas perfusion was severely reduced in comparison to healthy lung tissue as measured with [15O]water. CONCLUSION: The data suggests that NE may be responsible for the severe lung inflammation in COVID-19 patients and that inhibition of NE could potentially reduce the acute inflammatory process and improve the condition.

Poor long-term recovery after critical COVID-19 during 12 months longitudinal follow-up.

OBJECTIVES: This study aimed to describe the burden of illness and impact on health and working situation among former intensive care patients treated for COVID-19. METHODS: A prospective cohort study was performed at one intensive care unit of a university hospital in Sweden during the first wave of COVID-19 in spring 2020. The burden of illness in health status, cognitive, physical, and psychological outcomes, and working situation were assessed at four and 12 months after discharge from intensive care, using nine validated instruments. RESULTS: Forty-six participants treated for COVID-19 participated in both follow-ups and were included in this study. General fatigue was reported by 37 of 46 participants (82%) at both follow-ups (p = 1.000). For overall health status 28 (61%) participants at the first follow-up and 26 (57%) (p = 0.414) at the second reported lower values than the general population. Cognitive impairment was seen in 22 (52%) participants at four months and in 13 (31%) at 12 months (p = 0.029). The proportion of participants on sick-leave decreased between the first and second follow-up (24% vs 13%, p = 0.025), but the proportion of participants working full-time was almost the same at both follow-ups (35% vs 37%, p = 0.317). CONCLUSIONS: The burden of illness of patients treated in intensive care due to COVID-19 included cognitive, physical, and psychological impacts. Cognitive functions were improved after 12 months, but no clear improvements could be distinguished in the physical or psychological outcome. Higher burden of illness was associated with inability to return to work.

Estimated glomerular filtration rates are higher when creatinine-based equations are compared with a cystatin C-based equation in coronavirus disease 2019.

OBJECTIVES: Estimations of glomerular filtration rate (eGFR) are based on analyses of creatinine and cystatin C, respectively. Coronavirus disease 2019 (COVID-19) patients in the intensive care unit (ICU) often have acute kidney injury (AKI) and are at increased risk of drug-induced kidney injury. The aim of this study was to compare creatinine-based eGFR equations to cystatin C-based eGFR in ICU patients with COVID-19. METHODS: After informed consent, we included 370 adult ICU patients with COVID-19. Creatinine and cystatin C were analyzed at admission to the ICU as part of the routine care. Creatinine-based eGFR (ml/min) was calculated using the following equations, developed in chronological order; the Cockcroft-Gault (C-G), Modified Diet in Renal Disease (MDRD)1999, MDRD 2006, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), and Lund-Malmö revised (LMR) equations, which were compared with eGFR calculated using the cystatin C-based Caucasian Asian Pediatric Adult (CAPA) equation. RESULTS: The median eGFR when determined by C-G was 99 ml/min and interquartile range (IQR: 67 ml/min). Corresponding estimations for MDRD1999 were 90 ml/min (IQR: 54); MDRD2006: 85 ml/min (IQR: 51); CKD-EPI: 91 ml/min (IQR: 47); and for LMR 83 ml/min (IQR: 41). eGFR was calculated using cystatin C and the CAPA equation value was 70 ml/min (IQR: 38). All differences between creatinine-based eGFR versus cystatin C-based eGFR were significant (p < .00001). CONCLUSIONS: Estimation of GFR based on various analyses of creatinine are higher when compared with a cystatin C-based equation. The C-G equation had the worst performance and should not be used in combination with modern creatinine analysis methods for determination of drug dosage in COVID-19 patients.

Immuno-Modulatory Effects of Dexamethasone in Severe COVID-19-A Swedish Cohort Study.

Dexamethasone (Dex) has been shown to decrease mortality in severe coronavirus disease 2019 (COVID-19), but the mechanism is not fully elucidated. We aimed to investigate the physiological and immunological effects associated with Dex administration in patients admitted to intensive care with severe COVID-19. A total of 216 adult COVID-19 patients were included-102 (47%) received Dex, 6 mg/day for 10 days, and 114 (53%) did not. Standard laboratory parameters, plasma expression of cytokines, endothelial markers, immunoglobulin (Ig) IgA, IgM, and IgG against SARS-CoV-2 were analyzed post-admission to intensive care. Patients treated with Dex had higher blood glucose but lower blood lactate, plasma cortisol, IgA, IgM, IgG, D-dimer, cytokines, syndecan-1, and E-selectin and received less organ support than those who did not receive Dex (Without-Dex). There was an association between Dex treatment and IL-17A, macrophage inflammatory protein 1 alpha, syndecan-1 as well as E-selectin in predicting 30-day mortality. Among a subgroup of patients who received Dex early, within 14 days of COVID-19 debut, the adjusted mortality risk was 0.4 (95% CI 0.2-0.8), i.e., 40% compared with Without-Dex. Dex administration in a cohort of critically ill COVID-19 patients resulted in altered immunological and physiologic responses, some of which were associated with mortality.

Loss of Y in leukocytes as a risk factor for critical COVID-19 in men.

BACKGROUND: The COVID-19 pandemic, which has a prominent social and economic impact worldwide, shows a largely unexplained male bias for the severity and mortality of the disease. Loss of chromosome Y (LOY) is a risk factor candidate in COVID-19 due to its prior association with many chronic age-related diseases, and its impact on immune gene transcription. METHODS: Publicly available scRNA-seq data of PBMC samples derived from male patients critically ill with COVID-19 were reanalyzed, and LOY status was added to the annotated cells. We further studied LOY in whole blood for 211 COVID-19 patients treated at intensive care units (ICU) from the first and second waves of the pandemic. Of these, 139 patients were subject to cell sorting for LOY analysis in granulocytes, low-density neutrophils (LDNs), monocytes, and PBMCs. RESULTS: Reanalysis of available scRNA-seq data revealed LDNs and monocytes as the cell types most affected by LOY. Subsequently, DNA analysis indicated that 46%, 32%, and 29% of critically ill patients showed LOY above 5% cut-off in LDNs, granulocytes, and monocytes, respectively. Hence, the myeloid lineage that is crucial for the development of severe COVID-19 phenotype is affected by LOY. Moreover, LOY correlated with increasing WHO score (median difference 1.59%, 95% HDI 0.46% to 2.71%, p=0.025), death during ICU treatment (median difference 1.46%, 95% HDI 0.47% to 2.43%, p=0.0036), and history of vessel disease (median difference 2.16%, 95% HDI 0.74% to 3.7%, p=0.004), among other variables. In 16 recovered patients, sampled during ICU stay and 93-143 days later, LOY decreased significantly in whole blood and PBMCs. Furthermore, the number of LDNs at the recovery stage decreased dramatically (median difference 76.4 per 10,000 cell sorting events, 95% HDI 55.5 to 104, p=6e-11). CONCLUSIONS: We present a link between LOY and an acute, life-threatening infectious disease. Furthermore, this study highlights LOY as the most prominent clonal mutation affecting the myeloid cell lineage during emergency myelopoiesis. The correlation between LOY level and COVID-19 severity might suggest that this mutation affects the functions of monocytes and neutrophils, which could have consequences for male innate immunity.

Strain on the ICU resources and patient outcomes in the COVID-19 pandemic: A Swedish national registry cohort study.

BACKGROUND: The Coronavirus 2019 (COVID-19) pandemic has led to an unprecedented strain on the ICU resources. It is not known how the ICU resources employed in treating COVID-19 patients are related to inpatient characteristics, use of organ support or mortality. OBJECTIVES: To investigate how the use of ICU resources relate to use of organ support and mortality in COVID-19 patients. DESIGN: A national register-based cohort study. SETTING: All Swedish ICUs from March 2020 to November 2021. PATIENTS: All patients admitted to Swedish ICUs with a primary diagnosis of COVID-19 reported to the national Swedish Intensive Care Register (SIR). MAIN OUTCOME MEASURES: Organ support (mechanical ventilation, noninvasive ventilation, high-flow oxygen therapy, prone positioning, surgical and percutaneous tracheostomy, central venous catheterisation, continuous renal replacement therapy and intermittent haemodialysis), discharge at night, re-admission, transfer and ICU and 30-day mortality. RESULTS: Seven thousand nine hundred and sixty-nine patients had a median age of 63 years, and 70% were men. Median daily census was 167% of habitual census, daily new admissions were 20% of habitual census and the median occupancy was 82%. Census and new admissions were associated with mechanical ventilation, OR 1.37 (95% CI 1.28 to 1.48) and OR 1.44 (95% CI 1.13 to 1.84), respectively, but negatively associated with noninvasive ventilation, OR 0.83 (95% CI 0.77 to 0.89) and OR 0.40 (95% CI 0.30 to 52) and high-flow oxygen therapy, OR 0.72 (95% CI 0.67 to 0.77) and OR 0.77 (95% CI 0.61 to 0.97). Occupancy above 90% of available beds was not associated with mechanical ventilation or noninvasive ventilation, but with high-flow oxygen therapy, OR 1.36 (95% CI 1.21 to 1.53). All measures of pressure on resources were associated with transfer to other hospitals, but none were associated with discharge at night, ICU mortality or 30-day mortality. CONCLUSIONS: Pressure on ICU resources was associated with more invasive respiratory support, indicating that during these times, ICU resources were reserved for sicker patients.

Shrunken Pore Syndrome Is Frequently Occurring in Severe COVID-19.

A selective decrease in the renal filtration of larger molecules is attributed to the shrinkage of glomerular pores, a condition termed Shrunken Pore Syndrome (SPS). SPS is associated with poor long-term prognosis. We studied SPS as a risk marker in a cohort of patients with COVID-19 treated in an intensive care unit. SPS was defined as a ratio < 0.7 when the estimated glomerular filtration rate (eGFR), determined by cystatin C, calculated by the Cystatin C Caucasian-Asian-Pediatric-Adult equation (CAPA), was divided by the eGFR determined by creatinine, calculated by the revised Lund−Malmö creatinine equation (LMR). Clinical data were prospectively collected. In total, SPS was present in 86 (24%) of 352 patients with COVID-19 on ICU admission. Patients with SPS had a higher BMI, Simplified Physiology Score (SAPS3), and had diabetes and/or hypertension more frequently than patients without SPS. Ninety-nine patients in the total cohort were women, 50 of whom had SPS. In dexamethasone-naïve patients, C-reactive protein (CRP ), TNF-alpha, and interleukin-6 did not differ between SPS and non-SPS patients. Demographic factors (gender, BMI) and illness severity (SAPS3) were independent predictors of SPS. Age and dexamethasone treatment did not affect the frequency of SPS after adjustments for age, sex, BMI, and acute severity. SPS is frequent in severely ill COVID-19 patients. Female gender was associated with a higher proportion of SPS. Demographic factors and illness severity were independent predictors of SPS.

Differential Bias for Creatinine- and Cystatin C- Derived Estimated Glomerular Filtration Rate in Critical COVID-19.

COVID-19 is a systemic disease, frequently affecting kidney function. Dexamethasone is standard treatment in severe COVID-19 cases, and is considered to increase plasma levels of cystatin C. However, this has not been studied in COVID-19. Glomerular filtration rate (GFR) is a clinically important indicator of renal function, but often estimated using equations (eGFR) based on filtered metabolites. This study focuses on sources of bias for eGFRs (mL/min) using a creatinine-based equation (eGFRLMR) and a cystatin C-based equation (eGFRCAPA) in intensive-care-treated patients with COVID-19. This study was performed on 351 patients aged 18 years old or above with severe COVID-19 infections, admitted to the intensive care unit (ICU) in Uppsala University Hospital, a tertiary care hospital in Uppsala, Sweden, between 14 March 2020 and 10 March 2021. Dexamethasone treatment (6 mg for up to 10 days) was introduced 22 June 2020 (n = 232). Values are presented as medians (IQR). eGFRCAPA in dexamethasone-treated patients was 69 (37), and 74 (46) in patients not given dexamethasone (p = 0.01). eGFRLMR was not affected by dexamethasone. eGFRLMR in females was 94 (20), and 75 (38) in males (p = 0.00001). Age and maximal CRP correlated negatively to eGFRCAPA and eGFRLMR, whereas both eGFR equations correlated positively to BMI. In ICU patients with COVID-19, dexamethasone treatment was associated with reduced eGFRCAPA. This finding may be explained by corticosteroid-induced increases in plasma cystatin C. This observation is important from a clinical perspective since adequate interpretation of laboratory results is crucial.

Dehydration is associated with production of organic osmolytes and predicts physical long-term symptoms after COVID-19: a multicenter cohort study.

BACKGROUND: We have previously shown that iatrogenic dehydration is associated with a shift to organic osmolyte production in the general ICU population. The aim of the present investigation was to determine the validity of the physiological response to dehydration known as aestivation and its relevance for long-term disease outcome in COVID-19. METHODS: The study includes 374 COVID-19 patients from the Pronmed cohort admitted to the ICU at Uppsala University Hospital. Dehydration data was available for 165 of these patients and used for the primary analysis. Validation was performed in Biobanque Québécoise de la COVID-19 (BQC19) using 1052 patients with dehydration data. Dehydration was assessed through estimated osmolality (eOSM = 2Na + 2 K + glucose + urea), and correlated to important endpoints including death, invasive mechanical ventilation, acute kidney injury, and long COVID-19 symptom score grouped by physical or mental. RESULTS: Increasing eOSM was correlated with increasing role of organic osmolytes for eOSM, while the proportion of sodium and potassium of eOSM were inversely correlated to eOSM. Acute outcomes were associated with pronounced dehydration, and physical long-COVID was more strongly associated with dehydration than mental long-COVID after adjustment for age, sex, and disease severity. Metabolomic analysis showed enrichment of amino acids among metabolites that showed an aestivating pattern. CONCLUSIONS: Dehydration during acute COVID-19 infection causes an aestivation response that is associated with protein degradation and physical long-COVID. TRIAL REGISTRATION: The study was registered à priori (clinicaltrials.gov: NCT04316884 registered on 2020-03-13 and NCT04474249 registered on 2020-06-29).

Chest dual-energy CT to assess the effects of steroids on lung function in severe COVID-19 patients.

BACKGROUND: Steroids have been shown to reduce inflammation, hypoxic pulmonary vasoconstriction (HPV) and lung edema. Based on evidence from clinical trials, steroids are widely used in severe COVID-19. However, the effects of steroids on pulmonary gas volume and blood volume in this group of patients are unexplored. OBJECTIVE: Profiting by dual-energy computed tomography (DECT), we investigated the relationship between the use of steroids in COVID-19 and distribution of blood volume as an index of impaired HPV. We also investigated whether the use of steroids influences lung weight, as index of lung edema, and how it affects gas distribution. METHODS: Severe COVID-19 patients included in a single-center prospective observational study at the intensive care unit at Uppsala University Hospital who had undergone DECT were enrolled in the current study. Patients' cohort was divided into two groups depending on the administration of steroids. From each patient's DECT, 20 gas volume maps and the corresponding 20 blood volume maps, evenly distributed along the cranial-caudal axis, were analyzed. As a proxy for HPV, pulmonary blood volume distribution was analyzed in both the whole lung and the hypoinflated areas. Total lung weight, index of lung edema, was estimated. RESULTS: Sixty patients were analyzed, whereof 43 received steroids. Patients not exposed to steroids showed a more extensive non-perfused area (19% vs 13%, p < 0.01) and less homogeneous pulmonary blood volume of hypoinflated areas (kurtosis: 1.91 vs 2.69, p < 0.01), suggesting a preserved HPV compared to patients treated with steroids. Moreover, patients exposed to steroids showed a significantly lower lung weight (953 gr vs 1140 gr, p = 0.01). A reduction in alveolar-arterial difference of oxygen followed the treatment with steroids (322 ± 106 mmHg at admission vs 267 ± 99 mmHg at DECT, p = 0.04). CONCLUSIONS: The use of steroids might cause impaired HPV and might reduce lung edema in severe COVID-19. This is consistent with previous findings in other diseases. Moreover, a reduced lung weight, as index of decreased lung edema, and a more homogeneous distribution of gas within the lung were shown in patients treated with steroids. TRIAL REGISTRATION: Clinical Trials ID: NCT04316884, Registered March 13, 2020.

Estimated Global Proportions of Individuals With Persistent Fatigue, Cognitive, and Respiratory Symptom Clusters Following Symptomatic COVID-19 in 2020 and 2021.

Importance: Some individuals experience persistent symptoms after initial symptomatic SARS-CoV-2 infection (often referred to as Long COVID). Objective: To estimate the proportion of males and females with COVID-19, younger or older than 20 years of age, who had Long COVID symptoms in 2020 and 2021 and their Long COVID symptom duration. Design, Setting, and Participants: Bayesian meta-regression and pooling of 54 studies and 2 medical record databases with data for 1.2 million individuals (from 22 countries) who had symptomatic SARS-CoV-2 infection. Of the 54 studies, 44 were published and 10 were collaborating cohorts (conducted in Austria, the Faroe Islands, Germany, Iran, Italy, the Netherlands, Russia, Sweden, Switzerland, and the US). The participant data were derived from the 44 published studies (10 501 hospitalized individuals and 42 891 nonhospitalized individuals), the 10 collaborating cohort studies (10 526 and 1906), and the 2 US electronic medical record databases (250 928 and 846 046). Data collection spanned March 2020 to January 2022. Exposures: Symptomatic SARS-CoV-2 infection. Main Outcomes and Measures: Proportion of individuals with at least 1 of the 3 self-reported Long COVID symptom clusters (persistent fatigue with bodily pain or mood swings; cognitive problems; or ongoing respiratory problems) 3 months after SARS-CoV-2 infection in 2020 and 2021, estimated separately for hospitalized and nonhospitalized individuals aged 20 years or older by sex and for both sexes of nonhospitalized individuals younger than 20 years of age. Results: A total of 1.2 million individuals who had symptomatic SARS-CoV-2 infection were included (mean age, 4-66 years; males, 26%-88%). In the modeled estimates, 6.2% (95% uncertainty interval [UI], 2.4%-13.3%) of individuals who had symptomatic SARS-CoV-2 infection experienced at least 1 of the 3 Long COVID symptom clusters in 2020 and 2021, including 3.2% (95% UI, 0.6%-10.0%) for persistent fatigue with bodily pain or mood swings, 3.7% (95% UI, 0.9%-9.6%) for ongoing respiratory problems, and 2.2% (95% UI, 0.3%-7.6%) for cognitive problems after adjusting for health status before COVID-19, comprising an estimated 51.0% (95% UI, 16.9%-92.4%), 60.4% (95% UI, 18.9%-89.1%), and 35.4% (95% UI, 9.4%-75.1%), respectively, of Long COVID cases. The Long COVID symptom clusters were more common in women aged 20 years or older (10.6% [95% UI, 4.3%-22.2%]) 3 months after symptomatic SARS-CoV-2 infection than in men aged 20 years or older (5.4% [95% UI, 2.2%-11.7%]). Both sexes younger than 20 years of age were estimated to be affected in 2.8% (95% UI, 0.9%-7.0%) of symptomatic SARS-CoV-2 infections. The estimated mean Long COVID symptom cluster duration was 9.0 months (95% UI, 7.0-12.0 months) among hospitalized individuals and 4.0 months (95% UI, 3.6-4.6 months) among nonhospitalized individuals. Among individuals with Long COVID symptoms 3 months after symptomatic SARS-CoV-2 infection, an estimated 15.1% (95% UI, 10.3%-21.1%) continued to experience symptoms at 12 months. Conclusions and Relevance: This study presents modeled estimates of the proportion of individuals with at least 1 of 3 self-reported Long COVID symptom clusters (persistent fatigue with bodily pain or mood swings; cognitive problems; or ongoing respiratory problems) 3 months after symptomatic SARS-CoV-2 infection.

A comparison of impact of comorbidities and demographics on 60-day mortality in ICU patients with COVID-19, sepsis and acute respiratory distress syndrome.

Severe Coronavirus disease 2019 (COVID-19) is associated with several pre-existing comorbidities and demographic factors. Similar factors are linked to critical sepsis and acute respiratory distress syndrome (ARDS). We hypothesized that age and comorbidities are more generically linked to critical illness mortality than a specific disease state. We used national databases to identify ICU patients and to retrieve comorbidities. The relative importance of risk factors for 60-day mortality was evaluated using the interaction with disease group (Sepsis, ARDS or COVID-19) in logistic regression models. We included 32,501 adult ICU patients. In the model on 60-day mortality in sepsis and COVID-19 there were significant interactions with disease group for age, sex and asthma. In the model on 60-day mortality in ARDS and COVID-19 significant interactions with cohort were found for acute disease severity, age and chronic renal failure. In conclusion, age and sex play particular roles in COVID-19 mortality during intensive care but the burden of comorbidity was similar between sepsis and COVID-19 and ARDS and COVID-19.

Decreased renal perfusion during acute kidney injury in critical COVID-19 assessed by magnetic resonance imaging: a prospective case control study.

BACKGROUND: Renal hypoperfusion has been suggested to contribute to the development of acute kidney injury (AKI) in critical COVID-19. However, limited data exist to support this. We aim to investigate the differences in renal perfusion, oxygenation and water diffusion using multiparametric magnetic resonance imaging in critically ill COVID-19 patients with and without AKI. METHODS: A prospective case-control study where patients without prior kidney disease treated in intensive care for respiratory failure due to COVID-19 were examined. Kidney Disease: Improving Global Outcomes Creatinine criteria were used for group allocation. Main comparisons were tested using Mann-Whitney U test. RESULTS: Nineteen patients were examined, ten with AKI and nine without AKI. Patients with AKI were examined in median 1 [0-2] day after criteria fulfillment. Age and baseline Plasma-Creatinine were similar in both groups. Total renal blood flow was lower in patients with AKI compared with patients without (median 645 quartile range [423-753] vs. 859 [746-920] ml/min, p = 0.037). Regional perfusion was reduced in both cortex (76 [51-112] vs. 146 [123-169] ml/100 g/min, p = 0.015) and medulla (28 [18-47] vs. 47 [38-73] ml/100 g/min, p = 0.03). Renal venous saturation was similar in both groups (72% [64-75] vs. 72% [63-84], ns.), as was regional oxygenation (R2*) in cortex (17 [16-19] vs. 17 [16-18] 1/s, ns.) and medulla (29 [24-39] vs. 27 [23-29] 1/s, ns.). CONCLUSIONS: In critically ill COVID-19 patients with AKI, the total, cortical and medullary renal blood flows were reduced compared with similar patients without AKI, whereas no differences in renal oxygenation were demonstrable in this setting. Trial registration ClinicalTrials ID: NCT02765191 , registered May 6 2014 and updated May 7 2020.

Iatrogenic dehydration drives organic osmolyte production in critical COVID‐19

Fluid removal with concomitant dehydration is a common treatment strategy in acute respiratory distress syndrome (ARDS). We have previously shown that iatrogenic dehydration during treatment in the intensive care unit (ICU) is associated with a shift to organic osmolyte production in the general ICU population. In this study we investigate the development of estimated osmolality (eOSM = 2Na+2K+glucose+urea) over time in ICU, as well as the relationship between the major osmolytes and eOSM. The study includes 370 COVID‐19 patients admitted to the ICU at Uppsala University Hospital between March 13. 2020 and June 11. 2021. Complete data was available for 176 of these patients, which were used for the analysis. The results show that eOSM increases with time spent in ICU (R2 = 0.75, P<0.001), which indicates iatrogenic dehydration. Further, increasing eOSM is correlated with increasing role of urea as an osmolyte (R2 = 0.6, P<0.001), while the role of sodium and potassium are inversely correlated to eOSM. This is consistent with the aestivation response where dehydration with increased osmolality drives production of organic osmolytes through gluconeogenesis and urea synthesis. Interestingly, glucose shows a weak negative correlation to eOSM (R2 = 0.01, P<0.01), which we interpret as a sign of iatrogenic control using insulin treatment. Acute Kidney Injury with reduced kidney function is an alternative explanation for increasing urea concentration. However, although there is a correlation between urea and the GFR‐markers creatinine and cystatin‐C the effect size cannot explain more than part of the association. In conclusion, iatrogenic dehydration causes an aestivation response in critical COVID‐19 where urea plays an increasing role as an osmolyte with increasing total osmolality.

Impaired Antibody Response Is Associated with Histone-Release, Organ Dysfunction and Mortality in Critically Ill COVID-19 Patients.

PURPOSE: the pathophysiologic mechanisms explaining differences in clinical outcomes following COVID-19 are not completely described. This study aims to investigate antibody responses in critically ill patients with COVID-19 in relation to inflammation, organ failure and 30-day survival. METHODS: All patients with PCR-verified COVID-19 and gave consent, and who were admitted to a tertiary Intensive care unit (ICU) in Sweden during March-September 2020 were included. Demography, repeated blood samples and measures of organ function were collected. Analyses of anti-SARS-CoV-2 antibodies (IgM, IgA and IgG) in plasma were performed and correlated to patient outcome and biomarkers of inflammation and organ failure. RESULTS: A total of 115 patients (median age 62 years, 77% male) were included prospectively. All patients developed severe respiratory dysfunction, and 59% were treated with invasive ventilation. Thirty-day mortality was 22.6% for all included patients. Patients negative for any anti-SARS-CoV-2 antibody in plasma during ICU admission had higher 30-day mortality compared to patients positive for antibodies. Patients positive for IgM had more ICU-, ventilator-, renal replacement therapy- and vasoactive medication-free days. IgA antibody concentrations correlated negatively with both SAPS3 and maximal SOFA-score and IgM-levels correlated negatively with SAPS3. Patients with antibody levels below the detection limit had higher plasma levels of extracellular histones on day 1 and elevated levels of kidney and cardiac biomarkers, but showed no signs of increased inflammation, complement activation or cytokine release. After adjusting for age, positive IgM and IgG antibodies were still associated with increased 30-day survival, with odds ratio (OR) 7.1 (1.5-34.4) and 4.2 (1.1-15.7), respectively. CONCLUSION: In patients with severe COVID-19 requiring intensive care, a poor antibody response is associated with organ failure, systemic histone release and increased 30-day mortality.

Angiopoietin-2 Inhibition of Thrombomodulin-Mediated Anticoagulation-A Novel Mechanism That May Contribute to Hypercoagulation in Critically Ill COVID-19 Patients.

Hypercoagulation and endothelial dysfunction play central roles in severe forms of COVID-19 infections, but the molecular mechanisms involved are unclear. Increased plasma levels of the inflammatory cytokine and TIE2 receptor antagonist Angiopoietin-2 were reported in severely ill COVID-19 patients. In vitro experiments suggest that Angiopoietin-2 bind and inhibits thrombomodulin. Thrombomodulin is expressed on the luminal surface of endothelial cells where it is an important member of the intrinsic anticoagulant pathway through activation of protein C. Using clinical data, mouse models, and in vitro assays, we tested if Angiopoietin-2 plays a causal role in COVID-19-associated hypercoagulation through direct inhibition of thrombin/thrombomodulin-mediated physiological anticoagulation. Angiopoietin-2 was measured in 61 patients at admission, and after 10 days in the 40 patients remaining in the ICU. We found that Angiopoietin-2 levels were increased in COVID-19 patients in correlation with disease severity, hypercoagulation, and mortality. In support of a direct effect of Angiopoietin-2 on coagulation, we found that injected Angiopoietin-2 in mice associated to thrombomodulin and resulted in a shortened tail bleeding time, decreased circulating levels of activated protein C, and increased plasma thrombin/antithrombin complexes. Conversely, bleeding time was increased in endothelial-specific Angiopoietin-2 knockout mice, while knockout of Tie2 had no effect on tail bleeding. Using in vitro assays, we found that Angiopoietin-2 inhibited thrombomodulin-mediated anticoagulation and protein C activation in human donor plasma. Our data suggest a novel in vivo mechanism for Angiopoietin-2 in COVID-19-associated hypercoagulation, implicating that Angiopoietin-2 inhibitors may be effective in the treatment of hypercoagulation in severe COVID-19 infection.