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1.
Front Immunol ; 13: 985433, 2022.
Article in English | MEDLINE | ID: covidwho-2080149

ABSTRACT

Multisystem inflammatory syndrome in children (MIS-C) is a rare, severe complication of COVID-19. A better knowledge of immunological, cellular, and genetic characteristics of MIS-C could help better understand the pathogenesis of the disease and contribute to identifying specific diagnostic biomarkers and develop targeted therapies. We studied 37 MIS-C children at hospital admission and 24 healthy controls analyzing serum cytokines (IFN-α, IFN-ß, IFN-γ, IL-6, IL-10, IL-17A, IL-12p70 and TNF), lymphocyte populations by flow cytometry and 386 genes related to autoimmune diseases, autoinflammation and primary immunodeficiencies by NGS. MIS-C patients showed a significant increase of serum IFNγ (despite a significant reduction of activated Th1) and ILs, even if with a great heterogeneity among patients, revealing different pathways involved in MIS-C pathogenesis and suggesting that serum cytokines at admission may help to select the inflammatory pathways to target in each patient. Flow cytometry demonstrated a relevant reduction of T populations while the percentage of B cell was increased in agreement with an autoimmune pathogenesis of MIS-C. Genetic analysis identified variants in 34 genes and 83.3% of patients had at least one gene variant. Among these, 9 were mutated in more patients. Most genes are related to autoimmune diseases like ATM, NCF1, MCM4, FCN3, and DOCK8 or to autoinflammatory diseases associated to the release of IFNγ like PRF1, NOD2, and MEF. Thus, an incomplete clearance of the Sars-CoV2 during the acute phase may induce tissue damage and self-antigen exposure and genetic variants can predispose to hyper-reactive immune dysregulation events of MIS-C-syndrome. Type II IFN activation and cytokine responses (mainly IL-6 and IL-10) may cause a cytokine storm in some patients with a more severe acute phase of the disease, lymphopenia and multisystemic organ involvement. The timely identification of such patients with an immunocytometric panel might be critical for targeted therapeutic management.


Subject(s)
Autoimmune Diseases , COVID-19 , Immunologic Deficiency Syndromes , Child , Humans , Interleukin-10 , SARS-CoV-2 , Interleukin-17 , Interleukin-6 , RNA, Viral , Cytokines/metabolism , Biomarkers , Autoantigens , Guanine Nucleotide Exchange Factors
2.
Transl Med Commun ; 7(1): 22, 2022.
Article in English | MEDLINE | ID: covidwho-2009492

ABSTRACT

Background: The pathogenesis of the novel described multisystem inflammatory syndrome in children (MIS-C) and Kawasaki disease (KD) is still debated as it is not clear if they are the same or different nosological entities. However, for both the diseases a rapid and unequivocal diagnosis is mandatory to start the therapy before the onset of severe complications. In this study, we aimed to evaluate the white cell populations in MIS-C and KD as potential markers to discriminate between the two diseases. Methods: We studied white cell populations by flow cytometry in 46 MIS-C and 28 KD patients in comparison to 70 age-matched healthy children. Results: MIS-C patients had a significant lymphopenia that involved both B and T populations while KD patients showed a significant neutrophilia and thrombocythemia. Granulocyte/lymphocyte ratio helped to diagnose both MIS-C and KD with a high diagnostic sensitivity, while a multivariate analysis of granulocyte and T lymphocyte number contributed to discriminate between the two diseases. Conclusions: The relevant lymphopenia observed in MIS-C patients suggests that the disease would be a post-infectious sequel of COVID-19 immunologically amplified by a massive cytokine release, while the significant neutrophilia and thrombocythemia observed in KD confirmed that the disorder has the genesis of a systemic vasculitis. The analysis of a panel of circulating cells may help to early diagnose and to discriminate between the two diseases. Supplementary Information: The online version contains supplementary material available at 10.1186/s41231-022-00128-2.

3.
J Clin Med ; 11(15)2022 Jul 25.
Article in English | MEDLINE | ID: covidwho-1957365

ABSTRACT

We previously observed an increase of serum interleukins (IL) and a reduction of most lymphocyte subpopulations in hospitalized COVID-19 patients. Herein, we aimed to evaluate the changes in serum IL-6, IL-10, and IL-17A levels and cytometric lymphocyte profiles in 144 COVID-19 patients at admission and after one week, also in relation to steroid treatment before hospitalization. After one week of hospitalization, we found that: (i) total lymphocytes were increased in all patients; (ii) neutrophils and IL-6 were reduced in mild/moderate patients; (iii) B lymphocytes were increased in severe patients; (iv) T lymphocyte populations increased in mild/moderate patients. In the eight patients that died during hospitalization, total leukocytes increased while T, T helper, T cytotoxic, T regulatory, and NK lymphocytes showed a reducing trend in five of the eight patients. Even if seven days are too few to evaluate the adaptive immunity of patients, we found that the steroid therapy was associated with a reduced COVID-19 inflammation and cytokine activation only in patients with severe disease, while in patients with less severe disease, the steroid therapy seems to have immunosuppressive effects on lymphocyte populations, and this could hamper the antiviral response. A better knowledge of cytokine and lymphocyte alterations in each COVID-19 patient could be useful to plan better treatment with steroids or cytokine targeting.

4.
J Transl Med ; 19(1): 403, 2021 09 23.
Article in English | MEDLINE | ID: covidwho-1438276

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) pandemic had a 1st wave in Europe from March to May 2020 and a 2nd wave since September 2020. We previously studied 35 hospitalized COVID-19 patients of the 1st wave demonstrating a cytokine storm and the exhaustion of most lymphocyte subpopulations. Herein, we describe the results obtained from COVID-19 patients of the 2nd wave. METHODS: We analyzed interleukin (IL)-6 by human-specific enzyme-linked immunosorbent assay and a large set of lymphocyte subpopulations by flow cytometry in 274 COVID-19 patients hospitalized from September 2020 to May 2021. RESULTS: Patients of 2nd wave compared with those of 1st wave showed lower serum IL-6 levels and a higher number of B and most T lymphocyte subpopulations in advanced stages, in relation with the age and the gender. On the other hand, we observed in 2nd wave patients: (i) a reduction of most lymphocyte subpopulations at mild and moderate stages; (ii) a reduction of natural killer cells and T regulatory cells together with a higher number of activated T helper (TH) 17 lymphocytes in all stages, which were mainly related to steroid and azithromycin therapies before hospitalization. CONCLUSIONS: COVID-19 had a less severe impact in patients of the 2nd wave in advanced stages, while the impact appeared more severe in patients of mild and moderate stages, as compared with 1st wave patients. This finding suggests that in COVID-19 patients with milder expression at diagnosis, steroid and azithromycin therapies appear to worsen the immune response against the virus. Furthermore, the cytometric profile may help to drive targeted therapies by monoclonal antibodies to modulate specific IL/lymphocyte inhibition or activation in COVID-19 patients.


Subject(s)
COVID-19 , Humans , Killer Cells, Natural , Lymphocyte Count , Pandemics , SARS-CoV-2
5.
Life Sci ; 261: 118355, 2020 Nov 15.
Article in English | MEDLINE | ID: covidwho-733713

ABSTRACT

AIMS: This study aims to cast light on immunocytometric alterations in COVID-19, a potentially fatal viral infection with heterogeneous clinical expression and a not completely defined pathophysiology. METHODS: We studied 35 COVID patients at hospital admission testing by cytofluorimetry a large panel of lymphocyte subpopulations and serum tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-17A and the soluble receptor of IL-17A (IL-17RA). KEY FINDINGS: At hospital admission, total lymphocytes and most T and B subpopulations were reduced in 50-80% of patients, with close relationship to disease severity. While activated T helper 1 (TH1) and TH17 cells resulted normal or higher. Serum IL-6 was increased in all patients, while TNF-α and IL-17A were higher in advanced stages. A patient subset with low severity had very high IL-17RA levels. Tocilizumab treatment caused an increase of IL-17A in 3/6 patients and a reduction in 3 others, while the lymphocyte number increased in 3 patients and did not change in the others. SIGNIFICANCE: Cytofluorimetry revealed a functional exhaustion of most lymphocyte populations in COVID patients not involving activated TH1 and TH17. Consequently, there was a relevant cytokines production that contributes to impair the respiratory inflammation. The increase of TH17 and IL-17 in a subset of cases and the evidence of a significant increase of IL-17RA (that prevents the interaction of IL-17 with the cell receptor) in patients with low severity suggest that some patients could benefit from monoclonal antibodies treatment targeting IL-17 pathway. Immunocytofluorimetric markers may contribute to a personalized therapy in COVID patients.


Subject(s)
Coronavirus Infections/immunology , Cytokines/blood , Flow Cytometry/methods , Lymphocyte Subsets/immunology , Pneumonia, Viral/immunology , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/pharmacology , COVID-19 , Coronavirus Infections/physiopathology , Coronavirus Infections/virology , Female , Humans , Inflammation/immunology , Inflammation/virology , Lymphocyte Count , Male , Middle Aged , Pandemics , Patient Admission , Pneumonia, Viral/physiopathology , Pneumonia, Viral/virology , Precision Medicine , Prospective Studies , Severity of Illness Index
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