Age-related changes in plasma biomarkers and their association with mortality in COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19)-induced mortality occurs predominantly in older patients. Several immunomodulating therapies seem less beneficial in these patients. The biological substrate behind these observations is unknown. The aim of this study was to obtain insight into the association between ageing, the host response and mortality in patients with COVID-19. METHODS: We determined 43 biomarkers reflective of alterations in four pathophysiological domains: endothelial cell and coagulation activation, inflammation and organ damage, and cytokine and chemokine release. We used mediation analysis to associate ageing-driven alterations in the host response with 30-day mortality. Biomarkers associated with both ageing and mortality were validated in an intensive care unit and external cohort. RESULTS: 464 general ward patients with COVID-19 were stratified according to age decades. Increasing age was an independent risk factor for 30-day mortality. Ageing was associated with alterations in each of the host response domains, characterised by greater activation of the endothelium and coagulation system and stronger elevation of inflammation and organ damage markers, which was independent of an increase in age-related comorbidities. Soluble tumour necrosis factor receptor 1, soluble triggering receptor expressed on myeloid cells 1 and soluble thrombomodulin showed the strongest correlation with ageing and explained part of the ageing-driven increase in 30-day mortality (proportion mediated: 13.0%, 12.9% and 12.6%, respectively). CONCLUSIONS: Ageing is associated with a strong and broad modification of the host response to COVID-19, and specific immune changes likely contribute to increased mortality in older patients. These results may provide insight into potential age-specific immunomodulatory targets in COVID-19.

Prophylactic and early outpatient treatment of COVID-19 in patients with kidney disease: considerations from the Immunonephrology Working Group of the European Renal Association (ERA-IWG).

The SARS-CoV-2 pandemic led to rapid vaccine development and large global vaccination schemes. However, patients with immune-mediated kidney disease, chronic kidney diseases and kidney transplant recipients show high non-response rates to vaccination despite more than 3 vaccinations and, consequently, reduced viral clearance capacity when infected while receiving certain immunosuppressants, carrying an elevated risk for COVID-19 related morbidity and mortality. SARS-CoV-2 evolution has been characterized by the emergence of novel variants and spike mutations contributing to waning efficacy of neutralizing antibodies. To this end, the therapeutic field expands from vaccination towards a combined approach of immunization, pre-exposure prophylaxis and early post-exposure treatment using direct-acting antivirals and neutralizing monoclonal antibodies to treat early in the disease course and avoid hospitalization. This expert opinion paper from the Immunonephrology Working Group (IWG) of the European Renal Association (ERA) summarizes available prophylactic and/or early treatment options (i.e. neutralizing monoclonal antibodies and direct-acting antivirals) of SARS-CoV-2 infected patients with immune-mediated kidney disease, chronic kidney disease and kidney transplant recipients.

ImmunoSep (Personalised Immunotherapy in Sepsis) international double-blind, double-dummy, placebo-controlled randomised clinical trial: study protocol.

INTRODUCTION: Sepsis is a major cause of death among hospitalised patients. Accumulating evidence suggests that immune response during sepsis cascade lies within a spectrum of dysregulated host responses. On the one side of the spectrum there are patients whose response is characterised by fulminant hyperinflammation or macrophage activation-like syndrome (MALS), and on the other side patients whose immune response is characterised by immunoparalysis. A sizeable group of patients are situated between the two extremes. Recognising immune endotype is very important in order to choose the appropriate immunotherapeutic approach for each patient resulting in the best chance to improve the outcome. METHODS AND ANALYSIS: ImmunoSep is a randomised placebo-controlled phase 2 clinical trial with a double-dummy design in which the effect of precision immunotherapy on sepsis phenotypes with MALS and immunoparalysis is studied. Patients are stratified using biomarkers. Specifically, 280 patients will be 1:1 randomly assigned to placebo or active immunotherapy as adjunct to standard-of-care treatment. In the active immunotherapy arm, patients with MALS will receive anakinra (recombinant interleukin-1 receptor antagonist) intravenously, and patients with immunoparalysis will receive subcutaneous recombinant human interferon-gamma. Τhe primary endpoint is the comparative decrease of the mean total Sequential Organ Failure Assessment score by at least 1.4 points by day 9 from randomisation. ETHICS AND DISSEMINATION: The protocol is approved by the German Federal Institute for Drugs and Medical Devices; the National Ethics Committee of Greece and by the National Organization for Medicines of Greece; the Central Committee on Research Involving Human Subjects and METC Oost Netherland for the Netherlands; the National Agency for Medicine and Medical Products of Romania; and the Commission Cantonale d'éthique de la recherche sur l'être human of Switzerland. The results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04990232.

Real-world Evidence of the Effects of Novel Treatments for COVID-19 on Mortality: A Nationwide Comparative Cohort Study of Hospitalized Patients in the First, Second, Third, and Fourth Waves in the Netherlands.

Background: Large clinical trials on drugs for hospitalized coronavirus disease 2019 (COVID-19) patients have shown significant effects on mortality. There may be a discrepancy with the observed real-world effect. We describe the clinical characteristics and outcomes of hospitalized COVID-19 patients in the Netherlands during 4 pandemic waves and analyze the association of the newly introduced treatments with mortality, intensive care unit (ICU) admission, and discharge alive. Methods: We conducted a nationwide retrospective analysis of hospitalized COVID-19 patients between February 27, 2020, and December 31, 2021. Patients were categorized into waves and into treatment groups (hydroxychloroquine, remdesivir, neutralizing severe acute respiratory syndrome coronavirus 2 monoclonal antibodies, corticosteroids, and interleukin [IL]-6 antagonists). Four types of Cox regression analyses were used: unadjusted, adjusted, propensity matched, and propensity weighted. Results: Among 5643 patients from 11 hospitals, we observed a changing epidemiology during 4 pandemic waves, with a decrease in median age (67-64 years; P < .001), in in-hospital mortality on the ward (21%-15%; P < .001), and a trend in the ICU (24%-16%; P = .148). In ward patients, hydroxychloroquine was associated with increased mortality (1.54; 95% CI, 1.22-1.96), and remdesivir was associated with a higher rate of discharge alive within 29 days (1.16; 95% CI, 1.03-1.31). Corticosteroids were associated with a decrease in mortality (0.82; 95% CI, 0.69-0.96); the results of IL-6 antagonists were inconclusive. In patients directly admitted to the ICU, hydroxychloroquine, corticosteroids, and IL-6 antagonists were not associated with decreased mortality. Conclusions: Both remdesivir and corticosteroids were associated with better outcomes in ward patients with COVID-19. Continuous evaluation of real-world treatment effects is needed.

Lung Microbiota of Critically Ill Patients with COVID-19 Are Associated with Nonresolving Acute Respiratory Distress Syndrome.

Rationale: Bacterial lung microbiota are correlated with lung inflammation and acute respiratory distress syndrome (ARDS) and altered in severe coronavirus disease (COVID-19). However, the association between lung microbiota (including fungi) and resolution of ARDS in COVID-19 remains unclear. We hypothesized that increased lung bacterial and fungal burdens are related to nonresolving ARDS and mortality in COVID-19. Objectives: To determine the relation between lung microbiota and clinical outcomes of COVID-19-related ARDS. Methods: This observational cohort study enrolled mechanically ventilated patients with COVID-19. All patients had ARDS and underwent bronchoscopy with BAL. Lung microbiota were profiled using 16S rRNA gene sequencing and quantitative PCR targeting the 16S and 18S rRNA genes. Key features of lung microbiota (bacterial and fungal burden, α-diversity, and community composition) served as predictors. Our primary outcome was successful extubation adjudicated 60 days after intubation, analyzed using a competing risk regression model with mortality as competing risk. Measurements and Main Results: BAL samples of 114 unique patients with COVID-19 were analyzed. Patients with increased lung bacterial and fungal burden were less likely to be extubated (subdistribution hazard ratio, 0.64 [95% confidence interval, 0.42-0.97]; P = 0.034 and 0.59 [95% confidence interval, 0.42-0.83]; P = 0.0027 per log10 increase in bacterial and fungal burden, respectively) and had higher mortality (bacterial burden, P = 0.012; fungal burden, P = 0.0498). Lung microbiota composition was associated with successful extubation (P = 0.0045). Proinflammatory cytokines (e.g., tumor necrosis factor-α) were associated with the microbial burdens. Conclusions: Bacterial and fungal lung microbiota are related to nonresolving ARDS in COVID-19 and represent an important contributor to heterogeneity in COVID-19-related ARDS.

Association between dexamethasone treatment and the host response in COVID-19 patients admitted to the general ward.

Dexamethasone improves clinical outcomes in COVID-19 patients requiring supplementary oxygen. We investigated possible mechanisms of action by comparing sixteen plasma host response biomarkers in general ward patients before and after implementation of dexamethasone as standard of care. 48 patients without and 126 patients with dexamethasone treatment were sampled within 48 h of admission. Endothelial cell and coagulation activation biomarkers were comparable. Dexamethasone treatment was associated with lower plasma interleukin (IL)-6 and IL-1 receptor antagonist levels, whilst other inflammation parameters were not affected. These data argue against modification of vascular-procoagulant responses as an early mechanism of action of dexamethasone in COVID-19.

Effect of intravenous clarithromycin in patients with sepsis, respiratory and multiple organ dysfunction syndrome: a randomized clinical trial.

BACKGROUND: Clarithromycin may act as immune-regulating treatment in sepsis and acute respiratory dysfunction syndrome. However, clinical evidence remains inconclusive. We aimed to evaluate whether clarithromycin improves 28-day mortality among patients with sepsis, respiratory and multiple organ dysfunction syndrome. METHODS: We conducted a multicenter, randomized, clinical trial in patients with sepsis. Participants with ratio of partial oxygen pressure to fraction of inspired oxygen less than 200 and more than 3 SOFA points from systems other than the respiratory function were enrolled between December 2017 and September 2019. Patients were randomized to receive 1 gr of clarithromycin or placebo intravenously once daily for 4 consecutive days. The primary endpoint was 28-day all-cause mortality. Secondary outcomes were 90-day mortality; sepsis response (defined as at least 25% decrease in SOFA score by day 7); sepsis recurrence; and differences in peripheral blood cell populations and leukocyte transcriptomics. RESULTS: Fifty-five patients were allocated to each arm. By day 28, 27 (49.1%) patients in the clarithromycin and 25 (45.5%) in the placebo group died (risk difference 3.6% [95% confidence interval (CI) - 15.7 to 22.7]; P = 0.703, adjusted OR 1.03 [95%CI 0.35-3.06]; P = 0.959). There were no statistical differences in 90-day mortality and sepsis response. Clarithromycin was associated with lower incidence of sepsis recurrence (OR 0.21 [95%CI 0.06-0.68]; P = 0.012); significant increase in monocyte HLA-DR expression; expansion of non-classical monocytes; and upregulation of genes involved in cholesterol homeostasis. Serious and non-serious adverse events were equally distributed. CONCLUSIONS: Clarithromycin did not reduce mortality among patients with sepsis with respiratory and multiple organ dysfunction. Clarithromycin was associated with lower sepsis recurrence, possibly through a mechanism of immune restoration. Clinical trial registration clinicaltrials.gov identifier NCT03345992 registered 17 November 2017; EudraCT 2017-001056-55.

The host response in different aetiologies of community-acquired pneumonia.

BACKGROUND: Community-acquired pneumonia (CAP) can be caused by a variety of pathogens, of which Streptococcus pneumoniae, Influenza and currently SARS-CoV-2 are the most common. We sought to identify shared and pathogen-specific host response features by directly comparing different aetiologies of CAP. METHODS: We measured 72 plasma biomarkers in a cohort of 265 patients hospitalized for CAP, all sampled within 48 hours of admission, and 28 age-and sex matched non-infectious controls. We stratified the biomarkers into several pathophysiological domains- antiviral response, vascular response and function, coagulation, systemic inflammation, and immune checkpoint markers. We directly compared CAP caused by SARS-CoV-2 (COVID-19, n=39), Streptococcus pneumoniae (CAP-strep, n=27), Influenza (CAP-flu, n=22) and other or unknown pathogens (CAP-other, n=177). We adjusted the comparisons for age, sex and disease severity scores. FINDINGS: Biomarkers reflective of a stronger cell-mediated antiviral response clearly separated COVID-19 from other CAPs (most notably granzyme B). Biomarkers reflecting activation and function of the vasculature showed endothelial barrier integrity was least affected in COVID-19, while glycocalyx degradation and angiogenesis were enhanced relative to other CAPs. Notably, markers of coagulation activation, including D-dimer, were not different between the CAP groups. Ferritin was most increased in COVID-19, while other systemic inflammation biomarkers such as IL-6 and procalcitonin were highest in CAP-strep. Immune checkpoint markers showed distinctive patterns in viral and non-viral CAP, with highly elevated levels of Galectin-9 in COVID-19. INTERPRETATION: Our investigation provides insight into shared and distinct pathophysiological mechanisms in different aetiologies of CAP, which may help guide new pathogen-specific therapeutic strategies. FUNDING: This study was financially supported by the Dutch Research Council, the European Commission and the Netherlands Organization for Health Research and Development.

A call to action: time to recognise melioidosis as a neglected tropical disease.

Melioidosis is a tropical infection caused by the soil bacterium Burkholderia pseudomallei. Despite the substantial impact of this often overlooked pathogen on both the health-care systems and economies of numerous low-income and middle-income countries around the world, melioidosis is not officially classified as a neglected tropical disease (NTD) by WHO. Melioidosis causes a higher estimated disease burden and mortality than many other recognised NTDs, with deaths primarily occurring among rural poor populations in low-income and middle-income countries. Fortunately, the impact of melioidosis in a region can be reduced once awareness is established of its known or suspected endemicity. In this Personal View, we provide evidence in support of official recognition of melioidosis as an NTD. We urge member states to request that WHO revisit their NTD list and appeal to government and philanthropic organisations to establish programmes in endemic countries to control melioidosis in order to reduce its global health burden.

A guide to immunotherapy for COVID-19.

Immune dysregulation is an important component of the pathophysiology of COVID-19. A large body of literature has reported the effect of immune-based therapies in patients with COVID-19, with some remarkable successes such as the use of steroids or anti-cytokine therapies. However, challenges in clinical decision-making arise from the complexity of the disease phenotypes and patient heterogeneity, as well as the variable quality of evidence from immunotherapy studies. This Review aims to support clinical decision-making by providing an overview of the evidence generated by major clinical trials of host-directed therapy. We discuss patient stratification and propose an algorithm to guide the use of immunotherapy strategies in the clinic. This will not only help guide treatment decisions, but may also help to design future trials that investigate immunotherapy in other severe infections.

Skeletal muscle alterations in patients with acute Covid-19 and post-acute sequelae of Covid-19.

Skeletal muscle-related symptoms are common in both acute coronavirus disease (Covid)-19 and post-acute sequelae of Covid-19 (PASC). In this narrative review, we discuss cellular and molecular pathways that are affected and consider these in regard to skeletal muscle involvement in other conditions, such as acute respiratory distress syndrome, critical illness myopathy, and post-viral fatigue syndrome. Patients with severe Covid-19 and PASC suffer from skeletal muscle weakness and exercise intolerance. Histological sections present muscle fibre atrophy, metabolic alterations, and immune cell infiltration. Contributing factors to weakness and fatigue in patients with severe Covid-19 include systemic inflammation, disuse, hypoxaemia, and malnutrition. These factors also contribute to post-intensive care unit (ICU) syndrome and ICU-acquired weakness and likely explain a substantial part of Covid-19-acquired weakness. The skeletal muscle weakness and exercise intolerance associated with PASC are more obscure. Direct severe acute respiratory syndrome coronavirus (SARS-CoV)-2 viral infiltration into skeletal muscle or an aberrant immune system likely contribute. Similarities between skeletal muscle alterations in PASC and chronic fatigue syndrome deserve further study. Both SARS-CoV-2-specific factors and generic consequences of acute disease likely underlie the observed skeletal muscle alterations in both acute Covid-19 and PASC.

Time since SARS-CoV-2 infection and humoral immune response following BNT162b2 mRNA vaccination.

BACKGROUND: To optimise the use of available SARS-CoV-2 vaccines, some advocate delaying second vaccination for individuals infected within six months. We studied whether post-vaccination immune response is equally potent in individuals infected over six months prior to vaccination. METHODS: We tested serum IgG binding to SARS-CoV-2 spike protein and neutralising capacity in 110 healthcare workers, before and after both BNT162b2 messenger RNA (mRNA) vaccinations. We compared outcomes between participants with more recent infection (n = 18, median two months, IQR 2-3), with infection-vaccination interval over six months (n = 19, median nine months, IQR 9-10), and to those not previously infected (n = 73). FINDINGS: Both recently and earlier infected participants showed comparable humoral immune responses after a single mRNA vaccination, while exceeding those of previously uninfected persons after two vaccinations with 2.5 fold (p = 0.003) and 3.4 fold (p < 0.001) for binding antibody levels, and 6.4 and 7.2 fold for neutralisation titres, respectively (both p < 0.001). The second vaccine dose yielded no further substantial improvement of the humoral response in the previously infected participants (0.97 fold, p = 0.92), while it was associated with a 4 fold increase in antibody binding levels and 18 fold increase in neutralisation titres in previously uninfected participants (both p < 0.001). Adjustment for potential confounding of sex and age did not affect these findings. INTERPRETATION: Delaying the second vaccination in individuals infected up to ten months prior may constitute a more efficient use of limited vaccine supplies. FUNDING: Netherlands Organization for Health Research and Development ZonMw; Corona Research Fund Amsterdam UMC; Bill & Melinda Gates Foundation.

Integrated single-cell analysis unveils diverging immune features of COVID-19, influenza, and other community-acquired pneumonia.

The exact immunopathophysiology of community-acquired pneumonia (CAP) caused by SARS-CoV-2 (COVID-19) remains clouded by a general lack of relevant disease controls. The scarcity of single-cell investigations in the broader population of patients with CAP renders it difficult to distinguish immune features unique to COVID-19 from the common characteristics of a dysregulated host response to pneumonia. We performed integrated single-cell transcriptomic and proteomic analyses in peripheral blood mononuclear cells from a matched cohort of eight patients with COVID-19, eight patients with CAP caused by Influenza A or other pathogens, and four non-infectious control subjects. Using this balanced, multi-omics approach, we describe shared and diverging transcriptional and phenotypic patterns-including increased levels of type I interferon-stimulated natural killer cells in COVID-19, cytotoxic CD8 T EMRA cells in both COVID-19 and influenza, and distinctive monocyte compositions between all groups-and thereby expand our understanding of the peripheral immune response in different etiologies of pneumonia.

Serologic Surveillance and Phylogenetic Analysis of SARS-CoV-2 Infection Among Hospital Health Care Workers.

Importance: It is unclear when, where, and by whom health care workers (HCWs) working in hospitals are infected with SARS-CoV-2. Objective: To determine how often and in what manner nosocomial SARS-CoV-2 infection occurs in HCW groups with varying exposure to patients with COVID-19. Design, Setting, and Participants: This cohort study comprised 4 weekly measurements of SARS-CoV-2-specific antibodies and collection of questionnaires from March 23 to June 25, 2020, combined with phylogenetic and epidemiologic transmission analyses at 2 university hospitals in the Netherlands. Included individuals were HCWs working in patient care for those with COVID-19, HCWs working in patient care for those without COVID-19, and HCWs not working in patient care. Data were analyzed from August through December 2020. Exposures: Varying work-related exposure to patients infected with SARS-CoV-2. Main Outcomes and Measures: The cumulative incidence of and time to SARS-CoV-2 infection, defined as the presence of SARS-CoV-2-specific antibodies in blood samples, were measured. Results: Among 801 HCWs, there were 439 HCWs working in patient care for those with COVID-19, 164 HCWs working in patient care for those without COVID-19, and 198 HCWs not working in patient care. There were 580 (72.4%) women, and the median (interquartile range) age was 36 (29-50) years. The incidence of SARS-CoV-2 was increased among HCWs working in patient care for those with COVID-19 (54 HCWs [13.2%; 95% CI, 9.9%-16.4%]) compared with HCWs working in patient care for those without COVID-19 (11 HCWs [6.7%; 95% CI, 2.8%-10.5%]; hazard ratio [HR], 2.25; 95% CI, 1.17-4.30) and HCWs not working in patient care (7 HCWs [3.6%; 95% CI, 0.9%-6.1%]; HR, 3.92; 95% CI, 1.79-8.62). Among HCWs caring for patients with COVID-19, SARS-CoV-2 cumulative incidence was increased among HCWs working on COVID-19 wards (32 of 134 HCWs [25.7%; 95% CI, 17.6%-33.1%]) compared with HCWs working on intensive care units (13 of 186 HCWs [7.1%; 95% CI, 3.3%-10.7%]; HR, 3.64; 95% CI, 1.91-6.94), and HCWs working in emergency departments (7 of 102 HCWs [8.0%; 95% CI, 2.5%-13.1%]; HR, 3.29; 95% CI, 1.52-7.14). Epidemiologic data combined with phylogenetic analyses on COVID-19 wards identified 3 potential HCW-to-HCW transmission clusters. No patient-to-HCW transmission clusters could be identified in transmission analyses. Conclusions and Relevance: This study found that HCWs working on COVID-19 wards were at increased risk for nosocomial SARS-CoV-2 infection with an important role for HCW-to-HCW transmission. These findings suggest that infection among HCWs deserves more consideration in infection prevention practice.

Predicting mortality of individual patients with COVID-19: a multicentre Dutch cohort.

OBJECTIVE: Develop and validate models that predict mortality of patients diagnosed with COVID-19 admitted to the hospital. DESIGN: Retrospective cohort study. SETTING: A multicentre cohort across 10 Dutch hospitals including patients from 27 February to 8 June 2020. PARTICIPANTS: SARS-CoV-2 positive patients (age ≥18) admitted to the hospital. MAIN OUTCOME MEASURES: 21-day all-cause mortality evaluated by the area under the receiver operator curve (AUC), sensitivity, specificity, positive predictive value and negative predictive value. The predictive value of age was explored by comparison with age-based rules used in practice and by excluding age from the analysis. RESULTS: 2273 patients were included, of whom 516 had died or discharged to palliative care within 21 days after admission. Five feature sets, including premorbid, clinical presentation and laboratory and radiology values, were derived from 80 features. Additionally, an Analysis of Variance (ANOVA)-based data-driven feature selection selected the 10 features with the highest F values: age, number of home medications, urea nitrogen, lactate dehydrogenase, albumin, oxygen saturation (%), oxygen saturation is measured on room air, oxygen saturation is measured on oxygen therapy, blood gas pH and history of chronic cardiac disease. A linear logistic regression and non-linear tree-based gradient boosting algorithm fitted the data with an AUC of 0.81 (95% CI 0.77 to 0.85) and 0.82 (0.79 to 0.85), respectively, using the 10 selected features. Both models outperformed age-based decision rules used in practice (AUC of 0.69, 0.65 to 0.74 for age >70). Furthermore, performance remained stable when excluding age as predictor (AUC of 0.78, 0.75 to 0.81). CONCLUSION: Both models showed good performance and had better test characteristics than age-based decision rules, using 10 admission features readily available in Dutch hospitals. The models hold promise to aid decision-making during a hospital bed shortage.

Clinical features and prognostic factors in Covid-19: A prospective cohort study.

BACKGROUND: Mortality rates are high among hospitalized patients with COVID-19, especially in those intubated on the ICU. Insight in pathways associated with unfavourable outcome may lead to new treatment strategies. METHODS: We performed a prospective cohort study of patients with COVID-19 admitted to general ward or ICU who underwent serial blood sampling. To provide insight in the pathways involved in disease progression, associations were estimated between outcome risk and serial measurements of 64 biomarkers in potential important pathways of COVID-19 infection (inflammation, tissue damage, complement system, coagulation and fibrinolysis) using joint models combining Cox regression and linear mixed-effects models. For patients admitted to the general ward, the primary outcome was admission to the ICU or mortality (unfavourable outcome). For patients admitted to the ICU, the primary outcome was 12-week mortality. FINDINGS: A total of 219 patients were included: 136 (62%) on the ward and 119 patients (54%) on the ICU; 36 patients (26%) were included in both cohorts because they were transferred from general ward to ICU. On the general ward, 54 of 136 patients (40%) had an unfavourable outcome and 31 (23%) patients died. On the ICU, 54 out of 119 patients (45%) died. Unfavourable outcome on the general ward was associated with changes in concentrations of IL-6, IL-8, IL-10, soluble Receptor for Advanced Glycation End Products (sRAGE), vascular cell adhesion molecule 1 (VCAM-1) and Pentraxin-3. Death on the ICU was associated with changes in IL-6, IL-8, IL-10, sRAGE, VCAM-1, Pentraxin-3, urokinase-type plasminogen activator receptor, IL-1-receptor antagonist, CD14, procalcitonin, tumor necrosis factor alfa, tissue factor, complement component 5a, Growth arrest-specific 6, angiopoietin 2, and lactoferrin. Pathway analysis showed that unfavourable outcome on the ward was mainly driven by chemotaxis and interleukin production, whereas death on ICU was associated with a variety of pathways including chemotaxis, cell-cell adhesion, innate host response mechanisms, including the complement system, viral life cycle regulation, angiogenesis, wound healing and response to corticosteroids. INTERPRETATION: Clinical deterioration in patients with severe COVID-19 involves multiple pathways, including chemotaxis and interleukin production, but also endothelial dysfunction, the complement system, and immunothrombosis. Prognostic markers showed considerable overlap between general ward and ICU patients, but we identified distinct differences between groups that should be considered in the development and timing of interventional therapies in COVID-19. FUNDING: Amsterdam UMC, Amsterdam UMC Corona Fund, and Dr. C.J. Vaillant Fonds.