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1.
Annals of Intensive Care ; 12(1), 2022.
Article in English | ProQuest Central | ID: covidwho-1837129

ABSTRACT

BackgroundLymphopenia is a hallmark of severe coronavirus disease 19 (COVID-19). Similar alterations have been described in bacterial sepsis and therapeutic strategies targeting T cell function such as recombinant human interleukin 7 (rhIL-7) have been proposed in this clinical context. As COVID-19 is a viral sepsis, the objectives of this study were to characterize T lymphocyte response over time in severe COVID-19 patients and to assess the effect of ex vivo administration of rhIL-7.ResultsPeripheral blood mononuclear cells from COVID-19 patients hospitalized in intensive care unit (ICU) were collected at admission and after 20 days. Transcriptomic profile was evaluated through NanoString technology. Inhibitory immune checkpoints expressions were determined by flow cytometry. T lymphocyte proliferation and IFN-γ production were evaluated after ex vivo stimulation in the presence or not of rhIL-7. COVID-19 ICU patients were markedly lymphopenic at admission. Mononuclear cells presented with inhibited transcriptomic profile prevalently with impaired T cell activation pathways. CD4 + and CD8 + T cells presented with over-expression of co-inhibitory molecules PD-1, PD-L1, CTLA-4 and TIM-3. CD4 + and CD8 + T cell proliferation and IFN-γ production were markedly altered in samples collected at ICU admission. These alterations, characteristic of a T cell exhaustion state, were more pronounced at ICU admission and alleviated over time. Treatment with rhIL-7 ex vivo significantly improved both T cell proliferation and IFN-γ production in cells from COVID-19 patients.ConclusionsSevere COVID-19 patients present with features of profound T cell exhaustion upon ICU admission which can be reversed ex vivo by rhIL-7. These results reinforce our understanding of severe COVID-19 pathophysiology and opens novel therapeutic avenues to treat such critically ill patients based of immunomodulation approaches. Defining the appropriate timing for initiating such immune-adjuvant therapy in clinical setting and the pertinent markers for a careful selection of patients are now warranted to confirm the ex vivo results described so far.Trial registration ClinicalTrials.gov identifier: NCT04392401 Registered 18 May 2020, http:// clinicaltrials.gov/ct2/show/NCT04392401.

3.
EBioMedicine ; 78: 103967, 2022 Mar 26.
Article in English | MEDLINE | ID: covidwho-1757276

ABSTRACT

BACKGROUND: In critically ill COVID-19 patients, the initial response to SARS-CoV-2 infection is characterized by major immune dysfunctions. The capacity of these severe patients to mount a robust and persistent SARS-CoV-2 specific T cell response despite the presence of severe immune alterations during the ICU stay is unknown. METHODS: Critically ill COVID-19 patients were sampled five times during the ICU stay and 9 and 13 months afterwards. Immune monitoring included counts of lymphocyte subpopulations, HLA-DR expression on monocytes, plasma IL-6 and IL-10 concentrations, anti-SARS-CoV-2 IgG levels and T cell proliferation in response to three SARS-CoV-2 antigens. FINDINGS: Despite the presence of major lymphopenia and decreased monocyte HLA-DR expression during the ICU stay, convalescent critically ill COVID-19 patients consistently generated adaptive and humoral immune responses against SARS-CoV-2 maintained for more than one year after hospital discharge. Patients with long hospital stays presented with stronger anti-SARS-CoV-2 specific T cell response but no difference in anti-SARS-CoV2 IgG levels. INTERPRETATION: Convalescent critically ill COVID-19 patients consistently generated a memory immune response against SARS-CoV-2 maintained for more than one year after hospital discharge. In recovered individuals, the intensity of SARS-CoV-2 specific T cell response was dependent on length of hospital stay. FUNDING: This observational study was supported by funds from the Hospices Civils de Lyon, Fondation HCL, Claude Bernard Lyon 1 University and Région Auvergne Rhône-Alpes and by partial funding by REACTing (Research and ACTion targeting emerging infectious diseases) INSERM, France and a donation from Fondation AnBer (http://fondationanber.fr/).

4.
Ann Intensive Care ; 12(1): 21, 2022 Mar 05.
Article in English | MEDLINE | ID: covidwho-1731543

ABSTRACT

BACKGROUND: Lymphopenia is a hallmark of severe coronavirus disease 19 (COVID-19). Similar alterations have been described in bacterial sepsis and therapeutic strategies targeting T cell function such as recombinant human interleukin 7 (rhIL-7) have been proposed in this clinical context. As COVID-19 is a viral sepsis, the objectives of this study were to characterize T lymphocyte response over time in severe COVID-19 patients and to assess the effect of ex vivo administration of rhIL-7. RESULTS: Peripheral blood mononuclear cells from COVID-19 patients hospitalized in intensive care unit (ICU) were collected at admission and after 20 days. Transcriptomic profile was evaluated through NanoString technology. Inhibitory immune checkpoints expressions were determined by flow cytometry. T lymphocyte proliferation and IFN-γ production were evaluated after ex vivo stimulation in the presence or not of rhIL-7. COVID-19 ICU patients were markedly lymphopenic at admission. Mononuclear cells presented with inhibited transcriptomic profile prevalently with impaired T cell activation pathways. CD4 + and CD8 + T cells presented with over-expression of co-inhibitory molecules PD-1, PD-L1, CTLA-4 and TIM-3. CD4 + and CD8 + T cell proliferation and IFN-γ production were markedly altered in samples collected at ICU admission. These alterations, characteristic of a T cell exhaustion state, were more pronounced at ICU admission and alleviated over time. Treatment with rhIL-7 ex vivo significantly improved both T cell proliferation and IFN-γ production in cells from COVID-19 patients. CONCLUSIONS: Severe COVID-19 patients present with features of profound T cell exhaustion upon ICU admission which can be reversed ex vivo by rhIL-7. These results reinforce our understanding of severe COVID-19 pathophysiology and opens novel therapeutic avenues to treat such critically ill patients based of immunomodulation approaches. Defining the appropriate timing for initiating such immune-adjuvant therapy in clinical setting and the pertinent markers for a careful selection of patients are now warranted to confirm the ex vivo results described so far. Trial registration ClinicalTrials.gov identifier: NCT04392401 Registered 18 May 2020, http:// clinicaltrials.gov/ct2/show/NCT04392401.

6.
Arch Med Res ; 52(8): 850-857, 2021 11.
Article in English | MEDLINE | ID: covidwho-1631298

ABSTRACT

BACKGROUND: As COVID-19 pandemic and vaccination effects progress, research now focuses on adaptive immunological response to SARS-CoV-2. Few studies specifically investigated intensive care unit (ICU) patients, and little is known about kinetics of humoral response in such critically ill patients. In this context, the main objective of the present work was to perform a longitudinal analysis of the humoral response in critically ill COVID-19 patients with prolonged ICU stays in regard with initial inflammatory response, disease severity and mortality. METHODS: Over a 3 week period, circulating immunoglobulins (Ig) against SARS-CoV-2 along with several immunological and clinical parameters were measured in 64 ICU COVID-19 patients. RESULTS: Critically ill COVID-19 patients mounted a dynamic and sustained antibody response of both IgM and IgG as soon as the first day of ICU hospitalization. This serological response was not associated with any of the classical immunological parameters measured at ICU admission or with initial severity clinical scores. IgM and IgG levels and seroconversion trajectories were not associated with unfavourable outcome. CONCLUSION: Despite rapid seroconversion and elevated humoral response, COVID-19 patients are still characterized by elevated mortality. Additional studies, including cytotoxic T cell functions, are mandatory to understand the immunological mechanisms contributing to long stay of COVID-19 patients in ICU.


Subject(s)
COVID-19 , Critical Illness , Humans , Intensive Care Units , Pandemics , SARS-CoV-2 , Seroconversion
7.
J Intensive Care ; 9(1): 64, 2021 Oct 18.
Article in English | MEDLINE | ID: covidwho-1477471

ABSTRACT

Dexamethasone improves survival of patients with COVID-19 acute respiratory distress syndrome, but might shorten the delay between the start of invasive mechanical ventilation and the occurrence of ventilator-associated pneumonia, suggesting possible worsening of COVID-19-induced immune dysfunction with this treatment. In a prospective observational study, we found that mechanically ventilated patients with COVID-19 treated with dexamethasone presented earlier ventilator-associated pneumonia, had significantly lower monocyte Human Leukocyte Antigen-DR expression and number of circulating CD4 + cells after ICU admission, than those not treated with corticoids.

8.
Arch Med Res ; 52(8): 850-857, 2021 11.
Article in English | MEDLINE | ID: covidwho-1427555

ABSTRACT

BACKGROUND: As COVID-19 pandemic and vaccination effects progress, research now focuses on adaptive immunological response to SARS-CoV-2. Few studies specifically investigated intensive care unit (ICU) patients, and little is known about kinetics of humoral response in such critically ill patients. In this context, the main objective of the present work was to perform a longitudinal analysis of the humoral response in critically ill COVID-19 patients with prolonged ICU stays in regard with initial inflammatory response, disease severity and mortality. METHODS: Over a 3 week period, circulating immunoglobulins (Ig) against SARS-CoV-2 along with several immunological and clinical parameters were measured in 64 ICU COVID-19 patients. RESULTS: Critically ill COVID-19 patients mounted a dynamic and sustained antibody response of both IgM and IgG as soon as the first day of ICU hospitalization. This serological response was not associated with any of the classical immunological parameters measured at ICU admission or with initial severity clinical scores. IgM and IgG levels and seroconversion trajectories were not associated with unfavourable outcome. CONCLUSION: Despite rapid seroconversion and elevated humoral response, COVID-19 patients are still characterized by elevated mortality. Additional studies, including cytotoxic T cell functions, are mandatory to understand the immunological mechanisms contributing to long stay of COVID-19 patients in ICU.


Subject(s)
COVID-19 , Critical Illness , Humans , Intensive Care Units , Pandemics , SARS-CoV-2 , Seroconversion
10.
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
11.
J Leukoc Biol ; 111(2): 489-496, 2022 02.
Article in English | MEDLINE | ID: covidwho-1293207

ABSTRACT

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells with immunosuppressive properties. In cancer patients, the expression of lectin-type oxidized LDL receptor 1 (LOX-1) on granulocytic MDSC identifies a subset of MDSC that retains the most potent immunosuppressive properties. The main objective of the present work was to explore the presence of LOX-1+ MDSC in bacterial and viral sepsis. To this end, whole blood LOX-1+ cells were phenotypically, morphologically, and functionally characterized. They were monitored in 39 coronavirus disease-19 (COVID-19, viral sepsis) and 48 septic shock (bacterial sepsis) patients longitudinally sampled five times over a 3 wk period in intensive care units (ICUs). The phenotype, morphology, and immunosuppressive functions of LOX-1+ cells demonstrated that they were polymorphonuclear MDSC. In patients, we observed the significant emergence of LOX-1+ MDSC in both groups. The peak of LOX-1+ MDSC was 1 wk delayed with respect to ICU admission. In COVID-19, their elevation was more pronounced in patients with acute respiratory distress syndrome. The persistence of these cells may contribute to long lasting immunosuppression leaving the patient unable to efficiently resolve infections.


Subject(s)
COVID-19/immunology , Leukocytes, Mononuclear/immunology , Myeloid-Derived Suppressor Cells/immunology , Respiratory Distress Syndrome/physiopathology , SARS-CoV-2/immunology , Scavenger Receptors, Class E/metabolism , Shock, Septic/immunology , Aged , COVID-19/metabolism , COVID-19/pathology , COVID-19/virology , Female , Humans , Male , Middle Aged , Shock, Septic/metabolism , Shock, Septic/microbiology , Shock, Septic/pathology
12.
Cytometry B Clin Cytom ; 2021 Jun 12.
Article in English | MEDLINE | ID: covidwho-1265376

ABSTRACT

BACKGROUND: Diminished expression of human leukocyte antigen DR on circulating monocytes (mHLA-DR), measured by standardized flow cytometry procedure, is a reliable indicator of immunosuppression in severely injured intensive care unit patients. As such, it is used as stratification criteria in clinical trials evaluating novel immunostimulating therapies. Preanalytical constraints relative to the short delay between blood sampling and flow cytometry staining have nevertheless limited its use in multicentric studies. The objective of the present work was to compare mHLA-DR expression between whole blood samples simultaneously drawn in EDTA or Cyto-Chex BCT tubes. METHODS: In two university hospitals, mHLA-DR was assessed in fresh whole blood from septic patients (n = 12) and healthy donors (n = 6) simultaneously sampled on EDTA and Cyto-Chex BCT tubes. Staining was performed immediately after sampling and after blood storage at room temperature. RESULTS: We confirmed that samples collected in Cyto-Chex tube had substantially enhanced stability for mHLA-DR results (48-72 h) over those collected in EDTA. On baseline values, despite good correlation between tubes (r = 0.98, p < 0.001), mHLA-DR expression was systematically lower with Cyto-Chex BCT. CONCLUSION: The present reports confirms the potential of Cyto-Chex BCT tubes to stabilize mHLA-DR expression before staining and extends the work of Quadrini et al. [Cytometry B 2021;100:103-114]. In centers without rapid access to flow cytometry facilities, it enables to tolerate delays in mHLA-DR staining. However, a 30% gap exists between results obtained with EDTA and Cyto-Chex BCT tubes. As current thresholds for clinical decisions were obtained with EDTA samples, further studies are needed to confirm clinical thresholds with Cyto-Chex BCT tubes.

13.
Lancet Respir Med ; 9(6): 622-642, 2021 06.
Article in English | MEDLINE | ID: covidwho-1219780

ABSTRACT

The zoonotic SARS-CoV-2 virus that causes COVID-19 continues to spread worldwide, with devastating consequences. While the medical community has gained insight into the epidemiology of COVID-19, important questions remain about the clinical complexities and underlying mechanisms of disease phenotypes. Severe COVID-19 most commonly involves respiratory manifestations, although other systems are also affected, and acute disease is often followed by protracted complications. Such complex manifestations suggest that SARS-CoV-2 dysregulates the host response, triggering wide-ranging immuno-inflammatory, thrombotic, and parenchymal derangements. We review the intricacies of COVID-19 pathophysiology, its various phenotypes, and the anti-SARS-CoV-2 host response at the humoral and cellular levels. Some similarities exist between COVID-19 and respiratory failure of other origins, but evidence for many distinctive mechanistic features indicates that COVID-19 constitutes a new disease entity, with emerging data suggesting involvement of an endotheliopathy-centred pathophysiology. Further research, combining basic and clinical studies, is needed to advance understanding of pathophysiological mechanisms and to characterise immuno-inflammatory derangements across the range of phenotypes to enable optimum care for patients with COVID-19.


Subject(s)
COVID-19 , Multiple Organ Failure , SARS-CoV-2/pathogenicity , COVID-19/immunology , COVID-19/physiopathology , Endothelium/physiopathology , Humans , Immunity , Multiple Organ Failure/etiology , Multiple Organ Failure/physiopathology , Patient Acuity , Severity of Illness Index
14.
Crit Care ; 25(1): 140, 2021 04 12.
Article in English | MEDLINE | ID: covidwho-1181117

ABSTRACT

BACKGROUND: Since the onset of the pandemic, only few studies focused on longitudinal immune monitoring in critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS) whereas their hospital stay may last for several weeks. Consequently, the question of whether immune parameters may drive or associate with delayed unfavorable outcome in these critically ill patients remains unsolved. METHODS: We present a dynamic description of immuno-inflammatory derangements in 64 critically ill COVID-19 patients including plasma IFNα2 levels and IFN-stimulated genes (ISG) score measurements. RESULTS: ARDS patients presented with persistently decreased lymphocyte count and mHLA-DR expression and increased cytokine levels. Type-I IFN response was initially induced with elevation of IFNα2 levels and ISG score followed by a rapid decrease over time. Survivors and non-survivors presented with apparent common immune responses over the first 3 weeks after ICU admission mixing gradual return to normal values of cellular markers and progressive decrease of cytokines levels including IFNα2. Only plasma TNF-α presented with a slow increase over time and higher values in non-survivors compared with survivors. This paralleled with an extremely high occurrence of secondary infections in COVID-19 patients with ARDS. CONCLUSIONS: Occurrence of ARDS in response to SARS-CoV2 infection appears to be strongly associated with the intensity of immune alterations upon ICU admission of COVID-19 patients. In these critically ill patients, immune profile presents with similarities with the delayed step of immunosuppression described in bacterial sepsis.


Subject(s)
COVID-19/blood , Critical Illness , Intensive Care Units/trends , Interferon-alpha/blood , Respiratory Distress Syndrome/blood , Adult , Aged , Biomarkers/blood , COVID-19/epidemiology , COVID-19/immunology , Critical Illness/epidemiology , Female , Hospitalization/trends , Humans , Immunity/immunology , Longitudinal Studies , Male , Middle Aged , Respiratory Distress Syndrome/epidemiology , Respiratory Distress Syndrome/immunology
15.
EBioMedicine ; 66: 103291, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1163667

ABSTRACT

Many milestones in medical history rest on animal modeling of human diseases. The SARS-CoV-2 pandemic has evoked a tremendous investigative effort primarily centered on clinical studies. However, several animal SARS-CoV-2/COVID-19 models have been developed and pre-clinical findings aimed at supporting clinical evidence rapidly emerge. In this review, we characterize the existing animal models exposing their relevance and limitations as well as outline their utility in COVID-19 drug and vaccine development. Concurrently, we summarize the status of clinical trial research and discuss the novel tactics utilized in the largest multi-center trials aiming to accelerate generation of reliable results that may subsequently shape COVID-19 clinical treatment practices. We also highlight areas of improvement for animal studies in order to elevate their translational utility. In pandemics, to optimize the use of strained resources in a short time-frame, optimizing and strengthening the synergy between the preclinical and clinical domains is pivotal.


Subject(s)
COVID-19 Vaccines , COVID-19/drug therapy , COVID-19/etiology , Disease Models, Animal , SARS-CoV-2/genetics , Age Factors , Animals , Antiviral Agents/pharmacology , COVID-19/physiopathology , COVID-19/therapy , COVID-19 Vaccines/pharmacology , Clinical Trials as Topic , Cricetinae , Ferrets , Humans , Mice , Mutation , Primates
16.
Cytometry A ; 99(5): 466-471, 2021 05.
Article in English | MEDLINE | ID: covidwho-1064342

ABSTRACT

During the second surge of COVID-19 in France (fall 2020), we assessed the expression of monocyte CD169 (i.e., Siglec-1, one of the numerous IFN-stimulated genes) upon admission to intensive care units of 45 patients with RT-PCR-confirmed SARS-CoV2 pulmonary infection. Overall, CD169 expression was strongly induced on circulating monocytes of COVID-19 patients compared with healthy donors and patients with bacterial sepsis. Beyond its contribution at the emergency department, CD169 testing may be also helpful for patients' triage at the ICU to rapidly reinforce suspicion of COVID-19 etiology in patients with acute respiratory failure awaiting for PCR results for definitive diagnosis.


Subject(s)
COVID-19/blood , Intensive Care Units , Monocytes/metabolism , Patient Admission , SARS-CoV-2/pathogenicity , Sialic Acid Binding Ig-like Lectin 1/blood , Adult , Aged , Biomarkers/blood , COVID-19/diagnosis , COVID-19/immunology , COVID-19/virology , Female , Flow Cytometry , Host-Pathogen Interactions , Humans , Male , Middle Aged , Monocytes/immunology , Monocytes/virology , Predictive Value of Tests , Preliminary Data , Prognosis , Prospective Studies , SARS-CoV-2/immunology , Up-Regulation
17.
Cytometry A ; 97(12): 1217-1221, 2020 12.
Article in English | MEDLINE | ID: covidwho-893217

ABSTRACT

Several months after the sudden emergence of SARS-CoV-2 and COVID-19, the understanding of the appropriate host immune response to a virus totally unknown of human immune surveillance is still of major importance. By international definition, COVID-19 falls in the scope of septic syndromes (organ dysfunction due to dysregulated host response to an infection) in which immunosuppression is a significant driver of mortality. Sepsis-induced immunosuppression is mostly defined and monitored by the measurement of decreased expression of HLA-DR molecules on circulating monocytes (mHLA-DR). In this interim review, we summarize the first mHLA-DR results in COVID-19 patients. In critically ill patients, results homogenously indicate a decreased mHLA-DR expression, which, along with profound lymphopenia and other functional alterations, is indicative of a status of immunosuppression. © 2020 International Society for Advancement of Cytometry.


Subject(s)
COVID-19/immunology , HLA-DR Antigens/immunology , Monocytes/immunology , COVID-19/pathology , COVID-19/virology , Female , Flow Cytometry , HLA-DR Antigens/genetics , Humans , Immune Tolerance/genetics , Male , SARS-CoV-2/pathogenicity
18.
Cell Mol Immunol ; 17(9): 1001-1003, 2020 09.
Article in English | MEDLINE | ID: covidwho-690856
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