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1.
Respiratory research ; 23(1), 2022.
Article in English | EuropePMC | ID: covidwho-1876880

ABSTRACT

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. Supplementary Information The online version contains supplementary material available at 10.1186/s12931-022-02060-3.

2.
EBioMedicine ; 81: 104082, 2022 May 31.
Article in English | MEDLINE | ID: covidwho-1867077

ABSTRACT

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.

3.
Antibiotics (Basel) ; 11(2)2022 Feb 08.
Article in English | MEDLINE | ID: covidwho-1697083

ABSTRACT

The understanding of the gut microbiome in health and disease has shown tremendous progress in the last decade. Shaped and balanced throughout life, the gut microbiome is intricately related to the local and systemic immune system and a multitude of mechanisms through which the gut microbiome contributes to the host's defense against pathogens have been revealed. Similarly, a plethora of negative consequences, such as superinfections and an increased rate of hospital re-admissions, have been identified when the gut microbiome is disturbed by disease or by the iatrogenic effects of antibiotic treatment and other interventions. In this review, we describe the role that probiotics may play in the intensive care unit (ICU). We discuss what is known about the gut microbiome of the critically ill, and the concept of probiotic intervention to positively modulate the gut microbiome. We summarize the evidence derived from randomized clinical trials in this context, with a focus on the prevention of ventilator-associated pneumonia. Finally, we consider what lessons we can learn in terms of the current challenges, efficacy and safety of probiotics in the ICU and what we may expect from the future. Throughout the review, we highlight studies that have provided conceptual advances to the field or have revealed a specific mechanism; this narrative review is not intended as a comprehensive summary of the literature.

4.
Elife ; 102021 08 23.
Article in English | MEDLINE | ID: covidwho-1369909

ABSTRACT

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.


Subject(s)
COVID-19/immunology , Community-Acquired Infections/immunology , Influenza, Human/immunology , Single-Cell Analysis , Adult , Female , Humans , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/immunology , Male , Middle Aged
5.
JAMA Netw Open ; 4(7): e2118554, 2021 07 01.
Article in English | MEDLINE | ID: covidwho-1328587

ABSTRACT

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.


Subject(s)
Antibodies, Viral/blood , COVID-19/blood , COVID-19/genetics , Personnel, Hospital , Phylogeny , Population Surveillance , SARS-CoV-2/immunology , Adult , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19 Serological Testing , Cohort Studies , Female , Humans , Incidence , Male , Middle Aged
6.
Front Immunol ; 12: 664209, 2021.
Article in English | MEDLINE | ID: covidwho-1247863

ABSTRACT

Rationale: Systemic activation of procoagulant and inflammatory mechanisms has been implicated in the pathogenesis of COVID-19. Knowledge of activation of these host response pathways in the lung compartment of COVID-19 patients is limited. Objectives: To evaluate local and systemic activation of coagulation and interconnected inflammatory responses in critically ill COVID-19 patients with persistent acute respiratory distress syndrome. Methods: Paired bronchoalveolar lavage fluid and plasma samples were obtained from 17 patients with COVID-19 related persistent acute respiratory distress syndrome (mechanical ventilation > 7 days) 1 and 2 weeks after start mechanical ventilation and compared with 8 healthy controls. Thirty-four host response biomarkers stratified into five functional domains (coagulation, complement system, cytokines, chemokines and growth factors) were measured. Measurements and Main Results: In all patients, all functional domains were activated, especially in the bronchoalveolar compartment, with significantly increased levels of D-dimers, thrombin-antithrombin complexes, soluble tissue factor, C1-inhibitor antigen and activity levels, tissue type plasminogen activator, plasminogen activator inhibitor type I, soluble CD40 ligand and soluble P-selectin (coagulation), next to activation of C3bc and C4bc (complement) and multiple interrelated cytokines, chemokines and growth factors. In 10 patients in whom follow-up samples were obtained between 3 and 4 weeks after start mechanical ventilation many bronchoalveolar and plasma host response biomarkers had declined. Conclusions: Critically ill, ventilated patients with COVID-19 show strong responses relating to coagulation, the complement system, cytokines, chemokines and growth factors in the bronchoalveolar compartment. These results suggest a local pulmonary rather than a systemic procoagulant and inflammatory "storm" in severe COVID-19.


Subject(s)
COVID-19/immunology , Critical Illness , Lung/metabolism , Respiratory Distress Syndrome/immunology , SARS-CoV-2/physiology , Thromboplastin/metabolism , Aged , Blood Coagulation , Cohort Studies , Female , Fibrin Fibrinogen Degradation Products/metabolism , Follow-Up Studies , Humans , Immunity, Innate , Lung/pathology , Male , Middle Aged , Respiration, Artificial
7.
EBioMedicine ; 67: 103378, 2021 May.
Article in English | MEDLINE | ID: covidwho-1230442

ABSTRACT

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.


Subject(s)
Biomarkers/blood , COVID-19/mortality , Patient Admission/statistics & numerical data , Aged , COVID-19/blood , Chemotaxis , Female , Humans , Intensive Care Units , Interleukins/blood , Male , Middle Aged , Prognosis , Prospective Studies
8.
Thorax ; 76(10): 1010-1019, 2021 10.
Article in English | MEDLINE | ID: covidwho-1180971

ABSTRACT

BACKGROUND: Knowledge of the pathophysiology of COVID-19 is almost exclusively derived from studies that examined the immune response in blood. We here aimed to analyse the pulmonary immune response during severe COVID-19 and to compare this with blood responses. METHODS: This was an observational study in patients with COVID-19 admitted to the intensive care unit (ICU). Mononuclear cells were purified from bronchoalveolar lavage fluid (BALF) and blood, and analysed by spectral flow cytometry; inflammatory mediators were measured in BALF and plasma. FINDINGS: Paired blood and BALF samples were obtained from 17 patients, four of whom died in the ICU. Macrophages and T cells were the most abundant cells in BALF, with a high percentage of T cells expressing the ƴδ T cell receptor. In the lungs, both CD4 and CD8 T cells were predominantly effector memory cells (87·3% and 83·8%, respectively), and these cells expressed higher levels of the exhaustion marker programmad death-1 than in peripheral blood. Prolonged ICU stay (>14 days) was associated with a reduced proportion of activated T cells in peripheral blood and even more so in BALF. T cell activation in blood, but not in BALF, was higher in fatal COVID-19 cases. Increased levels of inflammatory mediators were more pronounced in BALF than in plasma. INTERPRETATION: The bronchoalveolar immune response in COVID-19 has a unique local profile that strongly differs from the immune profile in peripheral blood. Fully elucidating COVID-19 pathophysiology will require investigation of the pulmonary immune response.


Subject(s)
COVID-19/immunology , Immunity, Cellular/physiology , Inflammation Mediators/metabolism , Aged , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/cytology , COVID-19/blood , COVID-19/pathology , Critical Care , Critical Illness , Female , Flow Cytometry , Humans , Macrophages/physiology , Male , Middle Aged , T-Lymphocytes/physiology
9.
Eur J Immunol ; 51(6): 1535-1538, 2021 06.
Article in English | MEDLINE | ID: covidwho-1151896

ABSTRACT

Despite high levels of CXCR3 ligands in mechanically ventilated COVID-19 patients, BALF CD8 T cells were not enriched in CXCR3+ cells but rather CCR6+ , likely due to high CCL20 levels in BALF, and had very high PD-1 expression. In mechanically ventilated, but not ward, patients Th-1 immunity is impaired. ​.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Chemokine CCL20/immunology , Lung/immunology , Receptors, CCR6/immunology , Respiration, Artificial , SARS-CoV-2/immunology , Aged , Aged, 80 and over , CD8-Positive T-Lymphocytes/pathology , COVID-19/pathology , COVID-19/therapy , Female , Humans , Lung/pathology , Lymphocyte Count , Male , Middle Aged
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