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1.
Trials ; 22(1): 692, 2021 Oct 11.
Article in English | MEDLINE | ID: covidwho-1463262

ABSTRACT

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a severe complication of COVID-19 pneumonia, with a mortality rate amounting to 34-50% in moderate and severe ARDS, and is associated with prolonged duration of invasive mechanical ventilation. Such as in non-COVID ARDS, harmful mechanical ventilation settings might be associated with worse outcomes. Reducing the tidal volume down to 4 mL kg-1 of predicted body weight (PBW) to provide ultra-low tidal volume ventilation (ULTV) is an appealing technique to minimize ventilator-inducted lung injury. Furthermore, in the context of a worldwide pandemic, it does not require any additional material and consumables and may be applied in low- to middle-income countries. We hypothesized that ULTV without extracorporeal circulation is a credible option to reduce COVID-19-related ARDS mortality and duration of mechanical ventilation. METHODS: The VT4COVID study is a randomized, multi-centric prospective open-labeled, controlled superiority trial. Adult patients admitted in the intensive care unit with COVID-19-related mild to severe ARDS defined by a PaO2/FiO2 ratio ≤ 150 mmHg under invasive mechanical ventilation for less than 48 h, and consent to participate to the study will be eligible. Patients will be randomized into two balanced parallels groups, at a 1:1 ratio. The control group will be ventilated with protective ventilation settings (tidal volume 6 mL kg-1 PBW), and the intervention group will be ventilated with ULTV (tidal volume 4 mL kg-1 PBW). The primary outcome is a composite score based on 90-day all-cause mortality as a prioritized criterion and the number of ventilator-free days at day 60 after inclusion. The randomization list will be stratified by site of recruitment and generated using random blocks of sizes 4 and 6. Data will be analyzed using intention-to-treat principles. DISCUSSION: The purpose of this manuscript is to provide primary publication of study protocol to prevent selective reporting of outcomes, data-driven analysis, and to increase transparency. Enrollment of patients in the study is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov NCT04349618 . Registered on April 16, 2020.


Subject(s)
COVID-19 , Respiratory Distress Syndrome , Adult , Extracorporeal Circulation , Humans , Prospective Studies , Randomized Controlled Trials as Topic , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/therapy , SARS-CoV-2
3.
Clin Transl Immunology ; 10(8): e1327, 2021.
Article in English | MEDLINE | ID: covidwho-1359783

ABSTRACT

OBJECTIVES: Impairment of type I interferon (IFN-I) immunity has been reported in critically ill COVID-19 patients. This defect can be explained in a subset of patients by the presence of circulating autoantibodies (auto-Abs) against IFN-I. We set out to improve the detection and the quantification of IFN-I auto-Abs in a cohort of critically ill COVID-19 patients, in order to better evaluate the prevalence of these Abs as the pandemic progresses, and how they correlate with the clinical course of the disease. METHODS: The concentration of anti-IFN-α2 Abs was determined in the serum of 84 critically ill COVID-19 patients who were admitted to ICU in Hospices Civils de Lyon, France, using a commercially available kit (Thermo Fisher, Catalog #BMS217). RESULTS: A total of 21 of 84 (25%) critically ill COVID-19 patients had circulating anti-IFN-α2 Abs above cut-off (> 34 ng mL-1). Among them, 15 of 21 had Abs with neutralising activity against IFN-α2, that is 15 of 84 (18%) critically ill patients. In addition, we noticed an impairment of the IFN-I response in the majority of patients with neutralising anti-IFN-α2 Abs. There was no significant difference in the clinical characteristics or outcome of with or without neutralising anti-IFN-α2 auto-Abs. We detected anti-IFN-α2 auto-Abs in COVID-19 patients' sera throughout their ICU stay. Finally, we also found auto-Abs against multiple subtypes of IFN-I including IFN-ω. CONCLUSIONS: We reported that 18% of critically ill COVID-19 patients were positive for IFN-I auto-Abs, whereas all mild COVID-19 patients were negative, confirming that the presence of these antibodies is associated with a higher risk of developing a critical COVID-19 form.

4.
J Exp Med ; 218(10)2021 10 04.
Article in English | MEDLINE | ID: covidwho-1345702

ABSTRACT

IFN-I and IFN-III immunity in the nasal mucosa is poorly characterized during SARS-CoV-2 infection. We analyze the nasal IFN-I/III signature, namely the expression of ISGF-3-dependent IFN-stimulated genes, in mildly symptomatic COVID-19 patients and show its correlation with serum IFN-α2 levels, which peak at symptom onset and return to baseline from day 10 onward. Moreover, the nasal IFN-I/III signature correlates with the nasopharyngeal viral load and is associated with the presence of infectious viruses. By contrast, we observe low nasal IFN-I/III scores despite high nasal viral loads in a subset of critically ill COVID-19 patients, which correlates with the presence of autoantibodies (auto-Abs) against IFN-I in both blood and nasopharyngeal mucosa. In addition, functional assays in a reconstituted human airway epithelium model of SARS-CoV-2 infection confirm the role of such auto-Abs in abrogating the antiviral effects of IFN-I, but not those of IFN-III. Thus, IFN-I auto-Abs may compromise not only systemic but also local antiviral IFN-I immunity at the early stages of SARS-CoV-2 infection.


Subject(s)
Autoantibodies/immunology , COVID-19/immunology , Interferon Type I/immunology , SARS-CoV-2/immunology , Adult , Aged , Animals , Antiviral Agents/immunology , Antiviral Agents/pharmacology , Autoantibodies/blood , COVID-19/blood , COVID-19/virology , Chlorocebus aethiops , Female , Humans , Interferon Type I/pharmacology , Longitudinal Studies , Male , Middle Aged , Nasal Cavity/immunology , Nasal Cavity/virology , Prospective Studies , SARS-CoV-2/physiology , Vero Cells , Viral Load/drug effects , Viral Load/immunology , Virus Replication/drug effects , Virus Replication/immunology
5.
Sci Immunol ; 6(59)2021 05 25.
Article in English | MEDLINE | ID: covidwho-1337429

ABSTRACT

Multiple Inflammatory Syndrome in Children (MIS-C) is a delayed and severe complication of SARS-CoV-2 infection that strikes previously healthy children. As MIS-C combines clinical features of Kawasaki disease and Toxic Shock Syndrome (TSS), we aimed to compare the immunological profile of pediatric patients with these different conditions. We analyzed blood cytokine expression, and the T cell repertoire and phenotype in 36 MIS-C cases, which were compared to 16 KD, 58 TSS, and 42 COVID-19 cases. We observed an increase of serum inflammatory cytokines (IL-6, IL-10, IL-18, TNF-α, IFNγ, CD25s, MCP1, IL-1RA) in MIS-C, TSS and KD, contrasting with low expression of HLA-DR in monocytes. We detected a specific expansion of activated T cells expressing the Vß21.3 T cell receptor ß chain variable region in both CD4 and CD8 subsets in 75% of MIS-C patients and not in any patient with TSS, KD, or acute COVID-19; this correlated with the cytokine storm detected. The T cell repertoire returned to baseline within weeks after MIS-C resolution. Vß21.3+ T cells from MIS-C patients expressed high levels of HLA-DR, CD38 and CX3CR1 but had weak responses to SARS-CoV-2 peptides in vitro. Consistently, the T cell expansion was not associated with specific classical HLA alleles. Thus, our data suggested that MIS-C is characterized by a polyclonal Vß21.3 T cell expansion not directed against SARS-CoV-2 antigenic peptides, which is not seen in KD, TSS and acute COVID-19.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , COVID-19/pathology , Receptors, Antigen, T-Cell, alpha-beta/immunology , Systemic Inflammatory Response Syndrome/immunology , Systemic Inflammatory Response Syndrome/pathology , Adult , Child , Child, Preschool , Cytokines/blood , HLA-DR Antigens/immunology , Humans , Lymphocyte Activation/immunology , SARS-CoV-2/immunology
6.
Eur J Immunol ; 51(4): 989-994, 2021 04.
Article in English | MEDLINE | ID: covidwho-1187983

ABSTRACT

Low concentrations of type-I interferon (IFN) in blood seem to be associated with more severe forms of Coronavirus disease 2019 (COVID-19). However, following the type-I interferon response (IR) in early stage disease is a major challenge. We evaluated detection of a molecular interferon signature on a FilmArray® system, which includes PCR assays for four interferon stimulated genes. We analyzed three types of patient populations: (i) children admitted to a pediatric emergency unit for fever and suspected infection, (ii) ICU-admitted patients with severe COVID-19, and (iii) healthcare workers with mild COVID-19. The results were compared to the reference tools, that is, molecular signature assessed with Nanostring® and IFN-α2 quantification by SIMOA® (Single MOlecule Array). A strong correlation was observed between the IR measured by the FilmArray®, Nanostring®, and SIMOA® platforms (r-Spearman 0.996 and 0.838, respectively). The FilmArray® panel could be used in the COVID-19 pandemic to evaluate the IR in 45-min with 2 min hand-on-time at hospitalization and to monitor the IR in future clinical trials.


Subject(s)
COVID-19/blood , Interferon-alpha/blood , Polymerase Chain Reaction/methods , SARS-CoV-2/immunology , Adult , Aged , COVID-19/immunology , Child , Female , Health Personnel , Humans , Interferon Type I/blood , Interferon Type I/genetics , Interferon-alpha/genetics , Male
7.
Ann Intensive Care ; 10(1): 129, 2020 Oct 01.
Article in English | MEDLINE | ID: covidwho-810354

ABSTRACT

BACKGROUND: Data on respiratory mechanics of COVID-19 ARDS patients are scarce. Respiratory mechanics and response to positive expiratory pressure (PEEP) may be different in obese and non-obese patients. METHODS: We investigated esophageal pressure allowing determination of transpulmonary pressures (PL ) and elastances (EL) during a decremental PEEP trial from 20 to 6 cm H2O in a cohort of COVID-19 ARDS patients. RESULTS: Fifteen patients were investigated, 8 obese and 7 non-obese patients. PEEP ≥ 16 cm H2O for obese patients and PEEP ≥10 cm H2O for non-obese patients were necessary to obtain positive expiratory PL. Change of PEEP did not alter significantly ΔPL or elastances in obese patients. However, in non-obese patients lung EL  and ΔPL increased significantly with PEEP increase. Chest wall EL was not affected by PEEP variations in both groups.

8.
J Crit Care ; 60: 169-176, 2020 12.
Article in English | MEDLINE | ID: covidwho-710098

ABSTRACT

PURPOSE: The aim of this study was to assess whether the computed tomography (CT) features of COVID-19 (COVID+) ARDS differ from those of non-COVID-19 (COVID-) ARDS patients. MATERIALS AND METHODS: The study is a single-center prospective observational study performed on adults with ARDS onset ≤72 h and a PaO2/FiO2 ≤ 200 mmHg. CT scans were acquired at PEEP set using a PEEP-FiO2 table with VT adjusted to 6 ml/kg predicted body weight. RESULTS: 22 patients were included, of whom 13 presented with COVID-19 ARDS. Lung weight was significantly higher in COVID- patients, but all COVID+ patients presented supranormal lung weight values. Noninflated lung tissue was significantly higher in COVID- patients (36 ± 14% vs. 26 ± 15% of total lung weight at end-expiration, p < 0.01). Tidal recruitment was significantly higher in COVID- patients (20 ± 12 vs. 9 ± 11% of VT, p < 0.05). Lung density histograms of 5 COVID+ patients with high elastance (type H) were similar to those of COVID- patients, while those of the 8 COVID+ patients with normal elastance (type L) displayed higher aerated lung fraction.


Subject(s)
COVID-19/diagnostic imaging , Image Processing, Computer-Assisted/methods , Respiratory Distress Syndrome/diagnostic imaging , Tomography, X-Ray Computed , Adult , Aged , Case-Control Studies , Female , Humans , Lung , Lung Compliance , Male , Middle Aged , Positive-Pressure Respiration , Prospective Studies
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