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1.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-316537

ABSTRACT

Treating COVID-19 remains challenging, in part due to limited understanding of severe immunopathology. We performed a holistic and unbiased analysis of 17 immune cell types using flow cytometry immunophenotyping in 802 blood samples from 513 COVID-19 patients obtained at presentation and follow-up, 44 cases with other infection and 36 healthy donors. After adjusting to the corresponding age-range, we found that most COVID-19 patients showed normal patterns of immune response to infection. However, 14% displayed an immune signature at presentation with skewing of all cell types except neutrophils and plasmablasts, which was significantly associated with severe outcome. Divergent immune trajectories were observed in 8 cell types of cases with favorable vs fatal outcome. B-cells had the strongest impact in patients’ survival and, together with non-classical monocytes, had independent prognostic value regardless of age and comorbidities. Collectively, these results shed light into the immunopathology of COVID-19 and provide new tools for risk-stratification.Funding: This study was supported by the Centro de Investigación Biomédica en Red – Área de Oncología - del Instituto de Salud Carlos III (CIBERONC;CB16/12/00369), Instituto de Salud Carlos III/Subdirección General de Investigación Sanitaria (FIS No. PI17/01243), Fondo Europeo de Desarrollo Regional (FEDER) and Asociación Española Contra el Cáncer (FCAECC, Predoctoral Grant Junta Provincial Navarra). This study was supported internationally by the Cancer Research UK, FCAECC and AIRC under the Accelerator Award Programme, and the European Research Council (ERC) 2015 Starting Grant (MYELOMANEXT). Conflict of Interest: The authors declare no competing conflict of interest.Ethical Approval: The Clinica Universidad de Navarra Ethics Committee approved the protocol and informed consent forms, required prior to patient enrollment. The study was conducted per the ethical principles of the Declaration of Helsinki.

2.
Blood Cancer J ; 11(12): 202, 2021 12 14.
Article in English | MEDLINE | ID: covidwho-1585877

ABSTRACT

There is evidence of reduced SARS-CoV-2 vaccine effectiveness in patients with hematological malignancies. We hypothesized that tumor and treatment-related immunosuppression can be depicted in peripheral blood, and that immune profiling prior to vaccination can help predict immunogenicity. We performed a comprehensive immunological characterization of 83 hematological patients before vaccination and measured IgM, IgG, and IgA antibody response to four viral antigens at day +7 after second-dose COVID-19 vaccination using multidimensional and computational flow cytometry. Health care practitioners of similar age were the control group (n = 102). Forty-four out of 59 immune cell types were significantly altered in patients; those with monoclonal gammopathies showed greater immunosuppression than patients with B-cell disorders and Hodgkin lymphoma. Immune dysregulation emerged before treatment, peaked while on-therapy, and did not return to normalcy after stopping treatment. We identified an immunotype that was significantly associated with poor antibody response and uncovered that the frequency of neutrophils, classical monocytes, CD4, and CD8 effector memory CD127low T cells, as well as naive CD21+ and IgM+D+ memory B cells, were independently associated with immunogenicity. Thus, we provide novel immune biomarkers to predict COVID-19 vaccine effectiveness in hematological patients, which are complementary to treatment-related factors and may help tailoring possible vaccine boosters.


Subject(s)
Biomarkers/blood , COVID-19 Vaccines , COVID-19/immunology , Hematologic Neoplasms/complications , Immunocompromised Host/immunology , Adult , Aged , Aged, 80 and over , COVID-19/prevention & control , Female , Humans , Male , Middle Aged , SARS-CoV-2
3.
Blood ; 136(Supplement 1):22-23, 2020.
Article in English | PMC | ID: covidwho-1338966

ABSTRACT

Background: The immune system reacts to viral infection with cellular and humoral responses. Thus, myelo- and lympho-suppression caused by cancer itself as well as cytotoxic treatment may pose a challenge to COVID-19 patients with solid and hematological tumors, but severe events from initial onset of COVID-19 appear to be more frequent in blood malignancies vs other cancer types. Preliminary data showed lower neutrophil and lymphocyte counts in COVID-19 patients bearing hematological cancer, but there are conflicting results supporting that both worsening of lymphopenia during COVID-19 and its depth prior to infection had a beneficial impact on survival. Thus, greater knowledge on the immune status of hematological patients may be useful to optimize prevention, risk stratification and treatment strategies.Aim: Analyze the immune status of COVID-19 patients with or without solid and hematological cancer.Methods: We use multidimensional flow cytometry (MFC) to analyze immune profiles in peripheral blood samples of 515 COVID-19 patients at presentation. Data was analyzed with a semi-automated pipeline that performs batch-analyses of MFC data to avoid variability intrinsic to manual analysis, and unveils full cellular diversity based on unbiased clustering. In 14 cases, deep immunophenotyping of B- and T-cells was performed and six myeloid- and dendritic-cell subsets were FACSorted for transcriptome analysis using RNAseq.Results: Of the 515 COVID-19 patients, 15 and 10 had solid and hematological tumors, respectively. Those with hematological cancer showed similar frequency of hospitalization than those with solid tumors (90% and 93%, respectively), which was modestly higher to that observed in persons without an active tumor (76%). By contrast, the frequency of hematological cases requiring intensive care (50%) and dying from COVID-19 (30%) was significantly higher to that observed in patients with no active tumor (5.5% and 4%, respectively), or with solid cancer (both 0%).Based on semi-automated analysis of MFC data, we systematically quantified a total of 19 cell types in PB that included 6 myeloid and 13 lymphoid subsets. Patients with hematological malignancies displayed altered immune profiles with significantly decreased absolute numbers of classical and intermediate monocytes, immunoregulatory and cytotoxic NK cells, double-negative, double-positive, CD4 and CD56- γδ T cells, as well as of mature B cells when compared to those with no tumor.Unsupervised hierarchical analysis of RNAseq data from basophils, myeloid and plasmacytoid dendritic cells, classical and non-classical monocytes and neutrophils showed considerable clustering of samples from hematological cases. Furthermore, a variable number of differentially expressed genes was found in all six cell types between COVID-19 patients with or without blood cancer. Genes related to NF-κB and STAT transcription factors as well as genes encoding toll-like receptors and proinflammatory interleukin receptors, all of which described to be implicated in the response and evasion of innate sensing by coronaviruses, were differentially expressed in many of these cell types. Deep phenotypic characterization of T- and B-cell compartments in PB of COVID-19 patients with (N = 4) or without (N = 10) hematological cancer showed that the relative distribution of antigen-dependent maturation stages within the T-cell compartment was generally similar between both groups. However, some hematological cases displayed profound alterations in virtually all of the 16 B-cell subsets analyzed, with a notorious reduction in memory B cells expressing IgG and IgA subclasses.We next compared immune responses from presentation to last follow-up in COVID-19 patients with hematological cancer and favorable (N = 3) vs fatal (N = 3) outcome. Interestingly, we found opposite kinetics in myeloid cell types such as eosinophils and neutrophils, decreasing numbers of various T cell subsets, as well as lower mature B cells and circulating PCs at presentation together with a decrease in B cell cou ts in deceased cases.Conclusions: Our study exposes for the first time that hematological patients show a constellation of immune alterations that could compromise the response to the infection caused by SARS-CoV-2, suggesting an association between impaired immune responses and poorer outcomes in COVID-19 patients with hematological malignancies.

4.
Front Immunol ; 12: 659018, 2021.
Article in English | MEDLINE | ID: covidwho-1236672

ABSTRACT

Information on the immunopathobiology of coronavirus disease 2019 (COVID-19) is rapidly increasing; however, there remains a need to identify immune features predictive of fatal outcome. This large-scale study characterized immune responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection using multidimensional flow cytometry, with the aim of identifying high-risk immune biomarkers. Holistic and unbiased analyses of 17 immune cell-types were conducted on 1,075 peripheral blood samples obtained from 868 COVID-19 patients and on samples from 24 patients presenting with non-SARS-CoV-2 infections and 36 healthy donors. Immune profiles of COVID-19 patients were significantly different from those of age-matched healthy donors but generally similar to those of patients with non-SARS-CoV-2 infections. Unsupervised clustering analysis revealed three immunotypes during SARS-CoV-2 infection; immunotype 1 (14% of patients) was characterized by significantly lower percentages of all immune cell-types except neutrophils and circulating plasma cells, and was significantly associated with severe disease. Reduced B-cell percentage was most strongly associated with risk of death. On multivariate analysis incorporating age and comorbidities, B-cell and non-classical monocyte percentages were independent prognostic factors for survival in training (n=513) and validation (n=355) cohorts. Therefore, reduced percentages of B-cells and non-classical monocytes are high-risk immune biomarkers for risk-stratification of COVID-19 patients.


Subject(s)
COVID-19/immunology , COVID-19/mortality , Adaptive Immunity , Adult , Aged , Aged, 80 and over , B-Lymphocytes/immunology , Biomarkers , COVID-19/pathology , Female , Humans , Immunity, Innate , Lymphopenia/immunology , Lymphopenia/mortality , Lymphopenia/pathology , Male , Middle Aged , Monocytes/immunology , Prognosis , SARS-CoV-2 , Survival Analysis , Young Adult
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