Biomarkers and outcomes in critically ill COVID-19 patients

This thesis investigates the survival and long-term outcomes of critically ill COVID-19 patients admitted to intensive care units (ICUs) in the Skåne region of Sweden between May 2020 and May 2021. We aimed to address knowledge gaps by conducting a prospective, multicentre cohort study following 498 ICU patients over three years, evaluating mortality, functional, physical, and mental outcomes, as well as Health-Related Quality of Life (HRQoL) and disease severity biomarkers

Plasma bioactive adrenomedullin predicts mortality and need for dialysis in critical COVID-19

COVID-19 is a severe respiratory disease affecting millions worldwide, causing significant morbidity and mortality. Adrenomedullin (bio-ADM) is a vasoactive hormone regulating the endothelial barrier and has been associated with COVID-19 mortality and other adverse events. This prospective cohort pilot study included 119 consecutive patients with verified SARS-CoV-2 infection admitted to two intensive care units (ICUs) in Southern Sweden. Bio-ADM was retrospectively analysed from plasma on ICU admission, and days 2 and 7. Information on comorbidities, adverse events and mortality was collected. The primary outcome was 90-day mortality, and secondary outcomes were markers of disease severity. The association between bio-ADM and outcomes was analysed using survival analysis and logistic regression. Bio-ADM on admission, day 2, and day 7 only moderately predicted 90-day mortality in univariate and multivariate Cox regression. The relative change in bio-ADM between sample times predicted 90-day mortality better even when adjusting for the SAPS3 score, with an HR of 1.09 (95% CI 1.04–1.15) and a C-index of 0.82 (95% CI 0.72–0.92) for relative change between day 2 and day 7. Bio-ADM had a good prediction of the need for renal replacement therapy in multivariate Cox regression adjusting for creatinine, where day 2 bio-ADM had an HR of 3.18 (95% CI 1.21–8.36) and C-index of 0.91 (95% CI 0.87–0.96). Relative changes did not perform better, possibly due to a small sample size. Admission and day 2 bio-ADM was associated with early acute kidney injury (AKI). Bio-ADM on ICU admission, day 2 and day 7 predicted 90-day mortality and dialysis needs, highlighting bio-ADM’s importance in COVID-19 pathophysiology. Bio-ADM could be used to triage patients with a risk of adverse outcomes and as a potential target for clinical interventions

Plasma neutrophil gelatinase-associated lipocalin independently predicts dialysis need and mortality in critical COVID-19

Neutrophil gelatinase-associated lipocalin (NGAL) is a novel kidney injury and inflammation biomarker. We investigated whether NGAL could be used to predict continuous renal replacement therapy (CRRT) and mortality in critical coronavirus disease 2019 (COVID-19). This prospective multicenter cohort study included adult COVID-19 patients in six intensive care units (ICUs) in Sweden between May 11, 2020 and May 10, 2021. Blood was sampled at admission, days two and seven in the ICU. The samples were batch analyzed for NGAL, creatinine, and cystatin c after the end of the study period. Initiation of CRRT and 90-day survival were used as dependent variables in regression models. Of 498 included patients, 494 were analyzed regarding CRRT and 399 were analyzed regarding survival. Seventy patients received CRRT and 154 patients did not survive past 90 days. NGAL, in combination with creatinine and cystatin c, predicted the subsequent initiation of CRRT with an area under the curve (AUC) of 0.95. For mortality, NGAL, in combination with age and sex, had an AUC of 0.83. In conclusion, NGAL is a valuable biomarker for predicting subsequent initiation of CRRT and 90-day mortality in critical COVID-19. NGAL should be considered when developing future clinical scoring systems

Neurofilament light chain on intensive care admission is an independent predictor of mortality in COVID-19: a prospective multicenter study

Abstract Background Neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and total-tau protein (tau) are novel blood biomarkers of neurological injury, and may be used to predict outcomes in critical COVID-19. Methods A prospective multicentre cohort study of 117 consecutive and critically ill COVID-19 patients in six intensive care units (ICUs) in southern Sweden between May and November 2020. Serial NfL, GFAP and tau were analysed in relation to mortality, the Glasgow Outcome Scale Extended (GOSE) and the physical (PCS) and mental (MCS) components of health-related quality of life at one year. Results NfL, GFAP and tau on ICU admission predicted one-year mortality with an area under the curve (AUC) of 0.82 (95% confidence interval [CI] 0.74 $$-$$ - 0.90), 0.72 (95% CI 0.62 $$-$$ - 0.82) and 0.66 (95% CI 0.54 $$-$$ - 0.77). NfL on admission was an independent predictor of one-year mortality (p = 0.039). Low NfL and GFAP values were associated with good PCS ( $$\ge$$ ≥ 45) at one year but not with good MCS ( $$\ge$$ ≥ 45) or GOSE ( $$\ge$$ ≥ 5). Conclusions NfL on ICU admission was an independent predictor of mortality. High levels of NfL, GFAP and tau were associated with mortality but not with poor GOSE in survivors at one year. Low levels of NfL and GFAP were associated with improved physical health-related quality of life. Graphical Abstrac

Plasma endostatin at intensive care admission is independently associated with acute kidney injury, dialysis, and mortality in COVID-19.

BACKGROUND: Critical COVID-19 is associated with high mortality, and acute kidney injury (AKI) is common. Endostatin has emerged as a promising prognostic biomarker for predicting AKI and mortality in intensive care. This study aimed to investigate plasma endostatin at intensive care unit (ICU) admission as a biomarker for AKI, renal replacement therapy (RRT), and 90-day mortality in COVID-19. METHODS: A pre-planned retrospective analysis of a prospectively collected cohort of admissions with a primary SARS-CoV-2 infection to six ICUs in southern Sweden between May 2020 and May 2021 was undertaken. Endostatin at ICU admission was evaluated with multivariable logistic regression analyses adjusted for age, sex, C-reactive protein, and creatinine. Net reclassification index analyses were also performed. RESULTS: Four hundred eighty-four patients were included. Endostatin showed a non-linear association with AKI, RRT, and 90-day mortality. Endostatin levels of 100-200 ng/mL were associated with AKI on ICU day 1 (OR 5.1, 95% CI 1.5-18, p = 0.0097), RRT during the ICU stay (OR 3.5, 95% CI 1.1-12, p = 0.039), and 90-day mortality (OR 4.2, 95% CI 1.6-11, p = 0.0037). Adding endostatin to creatinine improved prediction of AKI on ICU day 1, while adding it to a model containing age, sex, CRP, and creatinine improved prediction of both AKI on ICU day 1 and 90-day mortality, but not RRT. CONCLUSIONS: Endostatin at ICU admission was independently associated with AKI, RRT, and 90-day mortality in ICU patients with COVID-19. In addition, endostatin improved the prediction of AKI and 90-day mortality, highlighting its potential as a biomarker for early risk stratification in intensive care

Increasing plasma calprotectin (S100A8/A9) is associated with 12-month mortality and unfavourable functional outcome in critically ill COVID-19 patients

BACKGROUND: Calprotectin (S100A8/A9) is a pro-inflammatory mediator primarily released from neutrophils. Previous studies have revealed associations between plasma calprotectin, disease severity and in-hospital mortality in unselected COVID-19 patients.OBJECTIVE: We aimed to assess whether plasma calprotectin dynamics during the first week of intensive care are associated with mortality and functional outcome in critically ill COVID-19 patients.METHODS: This prospective study included 498 COVID-19 patients admitted to six intensive care units (ICUs) in Sweden between May 2020 and May 2021. Blood samples were collected on ICU admission and on day 7. The primary outcome was 12-month mortality. Secondary outcomes were functional outcome of survivors at 3 and 12 months, and the need for invasive mechanical ventilation (IMV) or continuous renal replacement therapy (CRRT) during the ICU stay. Functional outcome was assessed by the Glasgow Outcome Scale Extended (GOSE, range 1-8, with < 5 representing an unfavourable outcome). Associations between plasma calprotectin and outcomes were examined in binary logistic regression analyses adjusted for age, sex, BMI, hypertension, smoking, and creatinine.RESULTS: High plasma calprotectin on admission and day 7 was independently associated with increased 12-month mortality. Increasing calprotectin from admission to day 7 was independently associated with higher mortality at 12 months [OR 2.10 (95% CI 1.18-3.74), p = 0.012], unfavourable functional outcome at 3 months [OR 2.53 (95% CI 1.07-6.10), p = 0.036], and the use of IMV [OR 2.23 (95% CI 1.10-4.53), p = 0.027)] and CRRT [OR 2.07 (95% CI 1.07-4.00), p = 0.031)]. A receiver operator characteristic (ROC) model including day 7 calprotectin and age was a good predictor of 12-month mortality [AUC 0.79 (95% CI 0.74-0.84), p < 0.001]. Day 7 calprotectin alone predicted an unfavourable functional outcome at 3 months [AUC 0.67 (95% CI 0.58-0.76), p < 0.001].CONCLUSION: In critically ill COVID-19 patients, increasing calprotectin levels after admission to the ICU are associated with 12-month mortality and unfavourable functional outcome in survivors. Monitoring plasma calprotectin dynamics in the ICU may be considered to evaluate prognosis in critical COVID-19.STUDY REGISTRATION: ClinicalTrials.gov Identifier: NCT04974775, registered April 28, 2020

Long-term recovery in critically ill COVID-19 survivors : A prospective cohort study

Background: Long-term recovery following critical COVID-19 has not been sufficiently studied. Objective: The primary objective was to describe changes in functional outcome and Health-Related Quality of Life (HRQoL) between 3 and 12 months in critically ill COVID-19 survivors. The secondary objective was to investigate factors associated with good functional outcome and HRQoL at 12 months. Methods: Prospective multicentre cohort study including critically ill COVID-19 patients admitted to six intensive care units in Sweden between May 2020 and May 2021. Surviving patients were invited to face-to-face follow-ups at 3 and 12 months. Functional outcome was assessed using the Glasgow Outcome Scale Extended (GOSE), ranging from 1 to 8. Physical and mental HRQoL was assessed by the physical component summary (PCS) and mental component summary (MCS) scores of the Short form health survey version 2 (SF-36v2®). Multivariable logistic regression models were used to identify factors associated with good functional outcome (GOSE ≥7) and good physical and mental HRQoL (PCS and MCS ≥45) at 12 months. Results: The percentage of participants with a good functional outcome increased from 35% to 64% between 3 and 12 months (p <.001). Mean PCS improved from 40 to 44 between 3 and 12 months (p <.001), while the mean MCS was within the normal range at 3 months, with no change at 12 months (46 vs. 48, p =.05). Increasing age was associated with a good functional outcome. Lower clinical frailty and absence of diabetes mellitus were associated with a good PCS. A shorter duration of mechanical ventilation was associated with a good outcome for all three outcome measures. Conclusion: Survivors of critical COVID-19 showed improved functional outcome and physical HRQoL from 3 to 12 months post-ICU. A shorter duration of mechanical ventilation is associated with good functional outcome and good HRQoL, while older age is associated with good functional outcome. Younger patients and those with comorbidities or higher frailty may require targeted follow-up and rehabilitation. Study registration ClinicalTrials.gov Identifier: NCT04974775, registered April 28, 2020

Prolonged Fatigue and Mental Health Challenges in Critical COVID-19 Survivors

Background: The aim of this study was to investigate the development of fatigue and mental illness between 3 and 12 months after critical COVID-19 and explore risk factors for long-lasting symptoms. Study Design and Methods: A prospective, multicenter COVID-19 study in southern Sweden, including adult patients (≥18 years) with rtPCR-confirmed COVID-19 requiring intensive care. Survivors were invited to a follow-up at 3 and 12 months, where patient-reported symptoms were assessed using the Modified Fatigue Impact Scale (MFIS), the Hospital Anxiety and Depression Scale (HADS) and the Posttraumatic Stress Disorder Checklist version 5 (PCL-5). The development between 3 and 12 months was described by changes in relation to statistical significance and suggested values for a minimally important difference (MID). Potential risk factors for long-lasting symptoms were analyzed by multivariable logistic regression. Results: At the 3-month follow-up, 262 survivors (87%) participated, 215 (72%) returned at 12 months. Fatigue was reported by 50% versus 40%, with a significant improvement at 12 months (MFIS; median 38 vs. 33, P < .001, MID ≥4). There were no significant differences in symptoms of mental illness between 3 and 12 months, with anxiety present in 33% versus 28%, depression in 30% versus 22%, and posttraumatic stress disorder in 17% versus 13%. A worse functional outcome and less sleep compared to before COVID-19 were risk factors for fatigue and mental illness at 12 months. Conclusions: Fatigue improved between 3 and 12 months but was still common. Symptoms of mental illness remained unchanged with anxiety being the most reported. A worse functional outcome and less sleep compared to before COVID-19 were identified as risk factors for reporting long-lasting symptoms

Plasma endostatin at intensive care admission is independently associated with acute kidney injury, dialysis, and mortality in COVID-19 [Elektronisk resurs]

Background Critical COVID-19 is associated with high mortality, and acute kidney injury (AKI) is common. Endostatin has emerged as a promising prognostic biomarker for predicting AKI and mortality in intensive care. This study aimed to investigate plasma endostatin at intensive care unit (ICU) admission as a biomarker for AKI, renal replacement therapy (RRT), and 90-day mortality in COVID-19. Methods A pre-planned retrospective analysis of a prospectively collected cohort of admissions with a primary SARS-CoV-2 infection to six ICUs in southern Sweden between May 2020 and May 2021 was undertaken. Endostatin at ICU admission was evaluated with multivariable logistic regression analyses adjusted for age, sex, C-reactive protein, and creatinine. Net reclassification index analyses were also performed. Results Four hundred eighty-four patients were included. Endostatin showed a non-linear association with AKI, RRT, and 90-day mortality. Endostatin levels of 100–200 ng/mL were associated with AKI on ICU day 1 (OR 5.1, 95% CI 1.5–18, p = 0.0097), RRT during the ICU stay (OR 3.5, 95% CI 1.1–12, p = 0.039), and 90-day mortality (OR 4.2, 95% CI 1.6–11, p = 0.0037). Adding endostatin to creatinine improved prediction of AKI on ICU day 1, while adding it to a model containing age, sex, CRP, and creatinine improved prediction of both AKI on ICU day 1 and 90-day mortality, but not RRT. Conclusions Endostatin at ICU admission was independently associated with AKI, RRT, and 90-day mortality in ICU patients with COVID-19. In addition, endostatin improved the prediction of AKI and 90-day mortality, highlighting its potential as a biomarker for early risk stratification in intensive care

Intensive care unit burden is associated with increased mortality in critically ill COVID-19 patients

BACKGROUND: Traditional models to predict intensive care outcomes do not perform well in COVID-19. We undertook a comprehensive study of factors affecting mortality and functional outcome after severe COVID-19.METHODS: In this prospective multicentre cohort study, we enrolled laboratory-confirmed, critically ill COVID-19 patients at six ICUs in the Skåne Region, Sweden, between May 11, 2020, and May 10, 2021. Demographics and clinical data were collected. ICU burden was defined as the total number of ICU-treated COVID-19 patients in the region on admission. Surviving patients had a follow-up at 90 days for assessment of functional outcome using the Glasgow Outcome Scale-Extended (GOSE), an ordinal scale (1-8) with GOSE ≥5 representing a favourable outcome. The primary outcome was 90-day mortality; the secondary outcome was functional outcome at 90 days.RESULTS: Among 498 included patients, 74% were male with a median age of 66 years and a median body mass index (BMI) of 30 kg/m 2 . Invasive mechanical ventilation was employed in 72%. Mortality in the ICU, in-hospital and at 90 days was 30%, 38% and 39%, respectively. Mortality increased markedly at age 60 and older. Increasing ICU burden was independently associated with a two-fold increase in mortality. Higher BMI was not associated with increased mortality. Besides age and ICU burden, smoking status, cortisone use, P a CO 2 >7 kPa, and inflammatory markers on admission were independent factors of 90-day mortality. Lower GOSE at 90 days was associated with a longer stay in the ICU. CONCLUSION: In critically ill COVID-19 patients, the 90-day mortality was 39% and increased considerably at age 60 or older. The ICU burden was associated with mortality, whereas a high BMI was not. A longer stay in the ICU was associated with unfavourable functional outcomes at 90 days