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1.
Sci Rep ; 12(1): 8991, 2022 05 30.
Article in English | MEDLINE | ID: covidwho-1947470

ABSTRACT

Knowledge about contagiousness is key to accurate management of hospitalized COVID-19 patients. Epidemiological studies suggest that in addition to transmission through droplets, aerogenic SARS-CoV-2 transmission contributes to the spread of infection. However, the presence of virus in exhaled air has not yet been sufficiently demonstrated. In pandemic situations low tech disposable and user-friendly bedside devices are required, while commercially available samplers are unsuitable for application in patients with respiratory distress. We included 49 hospitalized COVID-19 patients and used a disposable modular breath sampler to measure SARS-CoV-2 RNA load in exhaled air samples and compared these to SARS-CoV-2 RNA load of combined nasopharyngeal throat swabs and saliva. Exhaled air sampling using the modular breath sampler has proven feasible in a clinical COVID-19 setting and demonstrated viral detection in 25% of the patients.


Subject(s)
COVID-19 , RNA, Viral , COVID-19/diagnosis , Humans , Nasopharynx , Pharynx , RNA, Viral/genetics , SARS-CoV-2/genetics
2.
Front Immunol ; 13: 859387, 2022.
Article in English | MEDLINE | ID: covidwho-1924095

ABSTRACT

Recent genome-wide association studies (GWASs) of COVID-19 patients of European ancestry have identified genetic loci significantly associated with disease severity. Here, we employed the detailed clinical, immunological and multi-omics dataset of the Human Functional Genomics Project (HFGP) to explore the physiological significance of the host genetic variants that influence susceptibility to severe COVID-19. A genomics investigation intersected with functional characterization of individuals with high genetic risk for severe COVID-19 susceptibility identified several major patterns: i. a large impact of genetically determined innate immune responses in COVID-19, with ii. increased susceptibility for severe disease in individuals with defective cytokine production; iii. genetic susceptibility related to ABO blood groups is probably mediated through the von Willebrand factor (VWF) and endothelial dysfunction. We further validated these identified associations at transcript and protein levels by using independent disease cohorts. These insights allow a physiological understanding of genetic susceptibility to severe COVID-19, and indicate pathways that could be targeted for prevention and therapy.


Subject(s)
COVID-19 , Genome-Wide Association Study , COVID-19/genetics , Genetic Predisposition to Disease , Humans , Immunity , von Willebrand Factor/genetics , von Willebrand Factor/metabolism
3.
Clin Infect Dis ; 2022 Mar 05.
Article in English | MEDLINE | ID: covidwho-1831053

ABSTRACT

BACKGROUND: Older age is associated with increased severity and death from respiratory infections, including coronavirus disease 2019 (Covid-19). The tuberculosis vaccine Bacille Calmette-Guérin (BCG) may provide heterologous protection against non-tuberculous infections, and has been proposed as a potential preventive strategy against Covid-19. METHODS: In this multicenter, placebo-controlled trial, we randomly assigned elderly individuals (60 years or older, n=2014) to intracutaneous vaccination with BCG (n=1008) or placebo (n=1006). The primary endpoint was the cumulative incidence of respiratory tract infections that required medical intervention, during 12 months of follow-up. Secondary endpoints included the incidence of Covid-19, and the effect of BCG vaccination on the cellular and humoral immune responses. RESULTS: The cumulative incidence of respiratory tract infection requiring medical intervention was 0.029 in the BCG-vaccinated group and 0.024 in the control group (subdistribution hazard ratio [SHR], 1.26; 98.2% confidence interval [CI], 0.65 to 2.44). 51 and 48 individuals tested positive for SARS-CoV-2 by PCR in the BCG and placebo group, respectively (SHR, 1.053; 95% CI, 0.71 to 1.56). No difference was observed in the frequency of adverse events. BCG vaccination was associated with enhanced cytokines responses after influenza, and partially also after SARS-CoV-2 stimulation. In patients diagnosed with Covid-19, antibody responses after infection were significantly stronger if the volunteers had previously received BCG. CONCLUSIONS: BCG-vaccination had no effect on the incidence of respiratory tract infections, including SARS-CoV-2 infection, in elderly volunteers. However, BCG vaccination improved cytokine responses stimulated by influenza and SARS-CoV-2, and induced stronger antibody titers after Covid-19 infection.

4.
Eur Stroke J ; 7(2): 180-187, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1785138

ABSTRACT

Background: COVID-19 is often complicated by thrombo-embolic events including ischemic stroke. The underlying mechanisms of COVID-19-associated ischemic stroke, the incidence and risk factors of silent cerebral ischemia, and the long-term functional outcome in these patients are currently unknown. Patients and methods: CORONavirus and Ischemic Stroke (CORONIS) is a multicentre prospective cohort study investigating the prevalence, risk factors and long-term incidence of (silent) cerebral ischemia, and the long-term functional outcome among patients with COVID-19. We aim to include 200 adult patients hospitalized with COVID-19 without symptomatic ischemic stroke to investigate the prevalence of silent cerebral ischemia compared with 60 (matched) controls with MRI. In addition, we will identify potential risk factors and/or causes of cerebral ischemia in COVID-19 patients with (n = 70) or without symptomatic stroke (n = 200) by means of blood sampling, cardiac workup and brain MRI. We will measure functional outcome and cognitive function after 3 and 12 months with standardized questionnaires in all patients with COVID-19. Finally, the long-term incidence of (new) silent cerebral ischemia in patients with COVID-19 will be assessed with follow up MRI (n = 120). Summary: The CORONIS study is designed to add further insight into the prevalence, long-term incidence and risk factors of cerebral ischemia, and the long-term functional outcome in hospitalized adult patients with COVID-19.

5.
Lancet Respir Med ; 10(2): 127-128, 2022 02.
Article in English | MEDLINE | ID: covidwho-1751528
6.
Nat Med ; 28(1): 39-50, 2022 01.
Article in English | MEDLINE | ID: covidwho-1641982

ABSTRACT

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.


Subject(s)
Anticoagulants/therapeutic use , COVID-19/therapy , Complement Inactivating Agents/therapeutic use , Glucocorticoids/therapeutic use , Immunologic Factors/therapeutic use , Immunomodulation , Protein Kinase Inhibitors/therapeutic use , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Neutralizing/therapeutic use , Azetidines/therapeutic use , Bradykinin/analogs & derivatives , Bradykinin/therapeutic use , Bradykinin B2 Receptor Antagonists/therapeutic use , COVID-19/immunology , Dexamethasone/therapeutic use , Drug Combinations , Factor Xa Inhibitors/therapeutic use , Heparin/therapeutic use , Humans , Hydrocortisone/therapeutic use , Imatinib Mesylate/therapeutic use , Immunization, Passive , Interferon beta-1a/therapeutic use , Interferon beta-1b/therapeutic use , Interferon-gamma/therapeutic use , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Kallikrein-Kinin System , Piperidines/therapeutic use , Purines/therapeutic use , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , SARS-CoV-2 , Sulfonamides/therapeutic use
7.
Trends Immunol ; 43(2): 106-116, 2022 02.
Article in English | MEDLINE | ID: covidwho-1560364

ABSTRACT

Not all individuals exposed to a pathogen develop illness: some are naturally resistant whereas others develop an asymptomatic infection. Epidemiological studies suggest that there is similar variability in susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. We propose that natural resistance is part of the disease history in some individuals exposed to this new coronavirus. Epidemiological arguments for natural resistance to SARS-CoV-2 are the lower seropositivity of children compared to adults, studies on closed environments of ships with outbreaks, and prevalence studies in some developing countries. Potential mechanisms of natural resistance include host genetic variants, viral interference, cross-protective natural antibodies, T cell immunity, and highly effective innate immune responses. Better understanding of natural resistance can help to advance preventive and therapeutic measures against infections for improved preparedness against potential future pandemics.


Subject(s)
COVID-19 , Humans , Immunity, Innate , Pandemics , SARS-CoV-2 , T-Lymphocytes
8.
Emerg Infect Dis ; 27(11): 2892-2898, 2021 11.
Article in English | MEDLINE | ID: covidwho-1551452

ABSTRACT

We performed an observational study to investigate intensive care unit incidence, risk factors, and outcomes of coronavirus disease-associated pulmonary aspergillosis (CAPA). We found 10%-15% CAPA incidence among 823 patients in 2 cohorts. Several factors were independently associated with CAPA in 1 cohort and mortality rates were 43%-52%.


Subject(s)
COVID-19 , Invasive Pulmonary Aspergillosis , Pulmonary Aspergillosis , Cohort Studies , Humans , SARS-CoV-2
10.
J Clin Microbiol ; 59(12): e0122921, 2021 11 18.
Article in English | MEDLINE | ID: covidwho-1522903

ABSTRACT

The literature regarding COVID-19-associated pulmonary aspergillosis (CAPA) has shown conflicting observations, including survival of CAPA patients not receiving antifungal therapy and discrepancy between CAPA diagnosis and autopsy findings. To gain insight into the pathophysiology of CAPA, we performed a case-control study in which we compared Aspergillus test profiles in CAPA patients and controls in relation to intensive care unit (ICU) mortality. This was a multinational case-control study in which Aspergillus test results, use of antifungal therapy, and mortality were collected from critically ill COVID-19 patients. Patients were classified using the 2020 European Confederation for Medical Mycology and the International Society for Human and Animal Mycology (ECMM/ISHAM) consensus case definitions. We analyzed 219 critically ill COVID-19 cases, including 1 proven, 38 probable, 19 possible CAPA cases, 21 Aspergillus-colonized patients, 7 patients only positive for serum (1,3)-ß-d-glucan (BDG), and 133 cases with no evidence of CAPA. Mortality was 53.8% in CAPA patients compared to 24.1% in patients without CAPA (P = 0.001). Positive serum galactomannan (GM) and BDG were associated with increased mortality compared to serum biomarker-negative CAPA patients (87.5% versus 41.7%, P = 0.046; 90.0% versus 42.1%, P = 0.029, respectively). For each point increase in GM or 10-point BDG serum concentration, the odds of death increased (GM, odds ratio [OR] 10.208, 95% confidence interval [CI], 1.621 to 64.291, P = 0.013; BDG, OR, 1.247, 95% CI, 1.029 to 1.511, P = 0.024). CAPA is a complex disease, probably involving a continuum of respiratory colonization, tissue invasion, and angioinvasion. Serum biomarkers are useful for staging CAPA disease progression and, if positive, indicate angioinvasion and a high probability of mortality. There is need for a biomarker that distinguishes between respiratory tract colonization and tissue-invasive CAPA disease.


Subject(s)
COVID-19 , Invasive Pulmonary Aspergillosis , Animals , Aspergillus , Case-Control Studies , Critical Illness , Humans , Invasive Pulmonary Aspergillosis/diagnosis , Mannans , SARS-CoV-2
12.
Med (N Y) ; 2(10): 1163-1170.e2, 2021 10 08.
Article in English | MEDLINE | ID: covidwho-1433668

ABSTRACT

BACKGROUND: Prolonged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shedding has been described in immunocompromised coronavirus disease 2019 (COVID-19) patients, resulting in protracted disease and poor outcome. Specific therapy to improve viral clearance and outcome for this group of patients is currently unavailable. METHODS: Five critically ill COVID-19 patients with severe defects in cellular immune responses, high SARS-CoV-2 viral RNA loads, and no respiratory improvement were treated with interferon gamma, 100 µg subcutaneously, thrice weekly. Bronchial secretion was collected every 48 h for routine diagnostic SARS-CoV-2 RT-PCR and viral culture. FINDINGS: Interferon gamma administration was followed by a rapid decline in SARS-CoV-2 load and a positive-to-negative viral culture conversion. Four patients recovered, and no signs of hyperinflammation were observed. CONCLUSIONS: Interferon gamma may be considered as adjuvant immunotherapy in a subset of immunocompromised COVID-19 patients. FUNDING: A.v.L. and R.v.C. are supported by National Institutes of Health (R01AI145781). G.J.O. and R.P.v.R. are supported by a VICI grant (016.VICI.170.090) from the Dutch Research Council (NWO). W.F.A. is supported by a clinical fellowship grant (9071561) of Netherlands Organization for Health Research and Development. M.G.N. is supported by an ERC advanced grant (833247) and a Spinoza grant of the Netherlands Organization for Scientific Research.


Subject(s)
COVID-19 , Critical Illness/therapy , Humans , Immunity, Cellular , Immunotherapy , Interferon-gamma , Research , SARS-CoV-2 , United States
13.
Emerg Infect Dis ; 27(11): 2892-2898, 2021 11.
Article in English | MEDLINE | ID: covidwho-1406813

ABSTRACT

We performed an observational study to investigate intensive care unit incidence, risk factors, and outcomes of coronavirus disease-associated pulmonary aspergillosis (CAPA). We found 10%-15% CAPA incidence among 823 patients in 2 cohorts. Several factors were independently associated with CAPA in 1 cohort and mortality rates were 43%-52%.


Subject(s)
COVID-19 , Invasive Pulmonary Aspergillosis , Pulmonary Aspergillosis , Cohort Studies , Humans , SARS-CoV-2
14.
Cell ; 181(5): 969-977, 2020 05 28.
Article in English | MEDLINE | ID: covidwho-1385208

ABSTRACT

SARS-CoV-2 infection is mild in the majority of individuals but progresses into severe pneumonia in a small proportion of patients. The increased susceptibility to severe disease in the elderly and individuals with co-morbidities argues for an initial defect in anti-viral host defense mechanisms. Long-term boosting of innate immune responses, also termed "trained immunity," by certain live vaccines (BCG, oral polio vaccine, measles) induces heterologous protection against infections through epigenetic, transcriptional, and functional reprogramming of innate immune cells. We propose that induction of trained immunity by whole-microorganism vaccines may represent an important tool for reducing susceptibility to and severity of SARS-CoV-2.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/immunology , Immunity, Innate , Immunomodulation , Pneumonia, Viral/immunology , SARS Virus/physiology , Animals , BCG Vaccine/immunology , COVID-19 , Clinical Trials as Topic , Coronavirus Infections/pathology , Coronavirus Infections/physiopathology , Coronavirus Infections/transmission , Humans , Immunity, Innate/drug effects , Lung/immunology , Lung/pathology , Lymphopenia/pathology , Middle East Respiratory Syndrome Coronavirus/physiology , Pandemics , Pneumonia, Viral/pathology , Pneumonia, Viral/physiopathology , Pneumonia, Viral/transmission , SARS-CoV-2 , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/pathology , Virus Replication
15.
SN Compr Clin Med ; 3(8): 1773-1779, 2021.
Article in English | MEDLINE | ID: covidwho-1384769

ABSTRACT

We describe a case of a previous healthy 20-year-old male athlete who presented with an atypical clinical profile with multiorgan involvement within five weeks after confirmed SARS-CoV-2 infection, suggestive for multisystem inflammatory syndrome (MIS); MIS is a rare, potentially life-threatening complication associated with SARS-CoV-2. MIS shares similar clinical features compatible with several overlapping lifethreatening hyperinflammatory syndromes, such as incomplete Kawasaki Disease (KD) and toxic shock syndrome (TSS) associated to a cytokine storm suggestive of a macrophage activation syndrome (MAS) without fulfilling the criteria for hemophagocytic lymphohistiocytosis (HLH), that may create a great challenge to distinguish between them. MIS should promptly be considered and treated, as uncontrolled MIS has a high mortality. In MIS cardiac involvement, heart failure may present as an additional problem, especially because volume loading is advised in accordance with proposed therapy. Carefully monitoring of the respiratory and cardiac status in response of resuscitation is therefore warranted.

16.
Front Immunol ; 12: 719115, 2021.
Article in English | MEDLINE | ID: covidwho-1348490

ABSTRACT

Introduction: Loss-of-function TLR7 variants have been recently reported in a small number of males to underlie strong predisposition to severe COVID-19. We aimed to determine the presence of these rare variants in young men with severe COVID-19. Methods: We prospectively studied males between 18 and 50 years-old without predisposing comorbidities that required at least high-flow nasal oxygen to treat COVID-19. The coding region of TLR7 was sequenced to assess the presence of potentially deleterious variants. Results: TLR7 missense variants were identified in two out of 14 patients (14.3%). Overall, the median age was 38 (IQR 30-45) years. Both variants were not previously reported in population control databases and were predicted to be damaging by in silico predictors. In a 30-year-old patient a maternally inherited variant [c.644A>G; p.(Asn215Ser)] was identified, co-segregating in his 27-year-old brother who also contracted severe COVID-19. A second variant [c.2797T>C; p.(Trp933Arg)] was found in a 28-year-old patient, co-segregating in his 24-year-old brother who developed mild COVID-19. Functional testing of this variant revealed decreased type I and II interferon responses in peripheral mononuclear blood cells upon stimulation with the TLR7 agonist imiquimod, confirming a loss-of-function effect. Conclusions: This study supports a rationale for the genetic screening for TLR7 variants in young men with severe COVID-19 in the absence of other relevant risk factors. A diagnosis of TLR7 deficiency could not only inform on treatment options for the patient, but also enables pre-symptomatic testing of at-risk male relatives with the possibility of instituting early preventive and therapeutic interventions.


Subject(s)
COVID-19/genetics , Mutation, Missense , SARS-CoV-2 , Toll-Like Receptor 7/genetics , Adult , Amino Acid Substitution , COVID-19/immunology , COVID-19/pathology , Genetic Testing , Humans , Male , Middle Aged , Risk Factors , Severity of Illness Index , Toll-Like Receptor 7/immunology
17.
Elife ; 92020 04 27.
Article in English | MEDLINE | ID: covidwho-1344522

ABSTRACT

COVID-19 patients can present with pulmonary edema early in disease. We propose that this is due to a local vascular problem because of activation of bradykinin 1 receptor (B1R) and B2R on endothelial cells in the lungs. SARS-CoV-2 enters the cell via ACE2 that next to its role in RAAS is needed to inactivate des-Arg9 bradykinin, the potent ligand of the B1R. Without ACE2 acting as a guardian to inactivate the ligands of B1R, the lung environment is prone for local vascular leakage leading to angioedema. Here, we hypothesize that a kinin-dependent local lung angioedema via B1R and eventually B2R is an important feature of COVID-19. We propose that blocking the B2R and inhibiting plasma kallikrein activity might have an ameliorating effect on early disease caused by COVID-19 and might prevent acute respiratory distress syndrome (ARDS). In addition, this pathway might indirectly be responsive to anti-inflammatory agents.


The COVID-19 pandemic represents an unprecedented threat to global health. Millions of cases have been confirmed around the world, and hundreds of thousands of people have lost their lives. Common symptoms include a fever and persistent cough and COVID-19 patients also often experience an excess of fluid in the lungs, which makes it difficult to breathe. In some cases, this develops into a life-threatening condition whereby the lungs cannot provide the body's vital organs with enough oxygen. The SARS-CoV-2 virus, which causes COVID-19, enters the lining of the lungs via an enzyme called the ACE2 receptor, which is present on the outer surface of the lungs' cells. The related coronavirus that was responsible for the SARS outbreak in the early 2000s also needs the ACE2 receptor to enter the cells of the lungs. In SARS, the levels of ACE2 in the lung decline during the infection. Studies with mice have previously revealed that a shortage of ACE2 leads to increased levels of a hormone called angiotensin II, which regulates blood pressure. As a result, much attention has turned to the potential link between this hormone system in relation to COVID-19. However, other mouse studies have shown that ACE2 protects against a build-up of fluid in the lungs caused by a different molecule made by the body. This molecule, which is actually a small fragment of a protein, lowers blood pressure and causes fluid to leak out of blood vessels. It belongs to a family of molecules known as kinins, and ACE2 is known to inactivate certain kinins. This led van de Veerdonk et al. to propose that the excess of fluid in the lungs seen in COVID-19 patients may be because kinins are not being neutralized due to the shortage of the ACE2 receptor. This had not been hypothesized before, even though the mechanism could be the same in SARS which has been researched for the past 17 years. If this hypothesis is correct, it would mean that directly inhibiting the receptor for the kinins (or the proteins that they come from) may be the only way to stop fluid leaking into the lungs of COVID-19 patients in the early stage of disease. This hypothesis is unproven, and more work is needed to see if it is clinically relevant. If that work provides a proof of concept, it means that existing treatments and registered drugs could potentially help patients with COVID-19, by preventing the need for mechanical ventilation and saving many lives.


Subject(s)
Antiviral Agents/therapeutic use , Coronavirus Infections/drug therapy , Coronavirus Infections/pathology , Drug Development , Pneumonia, Viral/drug therapy , Pneumonia, Viral/pathology , Angioedema/drug therapy , Angioedema/metabolism , Angioedema/pathology , Anti-Inflammatory Agents/therapeutic use , Betacoronavirus/physiology , Bradykinin Receptor Antagonists/therapeutic use , COVID-19 , Coronavirus Infections/metabolism , Endothelial Cells/metabolism , Endothelial Cells/pathology , Humans , Inflammation/immunology , Inflammation/pathology , Kallikreins/metabolism , Kinins/metabolism , Lung/metabolism , Lung/pathology , Pandemics , Pneumonia, Viral/metabolism , Receptor, Bradykinin B1/metabolism , Receptor, Bradykinin B2/metabolism , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/prevention & control , SARS-CoV-2 , Signal Transduction
18.
Cell Host Microbe ; 29(8): 1277-1293.e6, 2021 Aug 11.
Article in English | MEDLINE | ID: covidwho-1293647

ABSTRACT

Immune deactivation of phagocytes is a central event in the pathogenesis of sepsis. Herein, we identify a master regulatory role of IL-6 signaling on LC3-associated phagocytosis (LAP) and reveal that uncoupling of these two processes during sepsis induces immunoparalysis in monocytes/macrophages. In particular, we demonstrate that activation of LAP by the human fungal pathogen Aspergillus fumigatus depends on ERK1/2-mediated phosphorylation of p47phox subunit of NADPH oxidase. Physiologically, autocrine IL-6/JAK2/Ninein axis orchestrates microtubule organization and dynamics regulating ERK recruitment to the phagosome and LC3+ phagosome (LAPosome) formation. In sepsis, loss of IL-6 signaling specifically abrogates microtubule-mediated trafficking of ERK, leading to defective activation of LAP and impaired killing of bacterial and fungal pathogens by monocytes/macrophages, which can be selectively restored by IL-6 supplementation. Our work uncovers a molecular pathway linking IL-6 signaling with LAP and provides insight into the mechanisms underlying immunoparalysis in sepsis.


Subject(s)
Interleukin-6/metabolism , Microtubule-Associated Proteins/metabolism , Phagocytosis/immunology , Signal Transduction , Aspergillus fumigatus/metabolism , Cytokines/metabolism , Cytoskeletal Proteins/metabolism , Humans , Janus Kinase 2/metabolism , Macrophages , Monocytes , Nuclear Proteins/metabolism , Phagocytes , Phagocytosis/physiology , Sepsis/metabolism
19.
Biosci Rep ; 41(7)2021 07 30.
Article in English | MEDLINE | ID: covidwho-1290282

ABSTRACT

Patients with sepsis display increased concentrations of sTREM-1 (soluble Triggering Receptor Expressed on Myeloid cells 1), and a phase II clinical trial focusing on TREM-1 modulation is ongoing. We investigated whether sTREM-1 circulating concentrations are associated with the outcome of patients with coronavirus disease 2019 (COVID-19) to assess the role of this pathway in COVID-19. This observational study was performed in two independent cohorts of patients with COVID-19. Plasma concentrations of sTREM-1 were assessed after ICU admission (pilot cohort) or after COVID-19 diagnosis (validation cohort). Routine laboratory and clinical parameters were collected from electronic patient files. Results showed sTREM-1 plasma concentrations were significantly elevated in patients with COVID-19 (161 [129-196] pg/ml) compared to healthy controls (104 [75-124] pg/ml; P<0.001). Patients with severe COVID-19 needing ICU admission displayed even higher sTREM-1 concentrations compared to less severely ill COVID-19 patients receiving clinical ward-based care (235 [176-319] pg/ml and 195 [139-283] pg/ml, respectively, P = 0.017). In addition, higher sTREM-1 plasma concentrations were observed in patients who did not survive the infection (326 [207-445] pg/ml) compared to survivors (199 [142-278] pg/ml, P<0.001). Survival analyses indicated that patients with higher sTREM-1 concentrations are at higher risk for death (hazard ratio = 3.3, 95%CI: 1.4-7.8). In conclusion, plasma sTREM-1 concentrations are elevated in patients with COVID-19, relate to disease severity, and discriminate between survivors and non-survivors. This suggests that the TREM-1 pathway is involved in the inflammatory reaction and the disease course of COVID-19, and therefore may be considered as a therapeutic target in severely ill patients with COVID-19.


Subject(s)
COVID-19/diagnosis , Triggering Receptor Expressed on Myeloid Cells-1/blood , Aged , Biomarkers/blood , COVID-19/blood , COVID-19/mortality , COVID-19/virology , Case-Control Studies , Female , Healthy Volunteers , Hospital Mortality , Humans , Intensive Care Units/statistics & numerical data , Male , Middle Aged , Retrospective Studies , Risk Assessment/methods , SARS-CoV-2/isolation & purification , Severity of Illness Index , Survival Analysis
20.
Intensive Care Med ; 47(8): 819-834, 2021 08.
Article in English | MEDLINE | ID: covidwho-1279405

ABSTRACT

PURPOSE: Invasive pulmonary aspergillosis (IPA) is increasingly reported in patients with severe coronavirus disease 2019 (COVID-19) admitted to the intensive care unit (ICU). Diagnosis and management of COVID-19 associated pulmonary aspergillosis (CAPA) are challenging and our aim was to develop practical guidance. METHODS: A group of 28 international experts reviewed current insights in the epidemiology, diagnosis and management of CAPA and developed recommendations using GRADE methodology. RESULTS: The prevalence of CAPA varied between 0 and 33%, which may be partly due to variable case definitions, but likely represents true variation. Bronchoscopy and bronchoalveolar lavage (BAL) remain the cornerstone of CAPA diagnosis, allowing for diagnosis of invasive Aspergillus tracheobronchitis and collection of the best validated specimen for Aspergillus diagnostics. Most patients diagnosed with CAPA lack traditional host factors, but pre-existing structural lung disease and immunomodulating therapy may predispose to CAPA risk. Computed tomography seems to be of limited value to rule CAPA in or out, and serum biomarkers are negative in 85% of patients. As the mortality of CAPA is around 50%, antifungal therapy is recommended for BAL positive patients, but the decision to treat depends on the patients' clinical condition and the institutional incidence of CAPA. We recommend against routinely stopping concomitant corticosteroid or IL-6 blocking therapy in CAPA patients. CONCLUSION: CAPA is a complex disease involving a continuum of respiratory colonization, tissue invasion and angioinvasive disease. Knowledge gaps including true epidemiology, optimal diagnostic work-up, management strategies and role of host-directed therapy require further study.


Subject(s)
COVID-19 , Invasive Pulmonary Aspergillosis , Pulmonary Aspergillosis , Humans , Intensive Care Units , Invasive Pulmonary Aspergillosis/diagnosis , Pulmonary Aspergillosis/diagnosis , Pulmonary Aspergillosis/drug therapy , Pulmonary Aspergillosis/epidemiology , SARS-CoV-2
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