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1.
Diabetes ; 2022 May 12.
Article in English | MEDLINE | ID: covidwho-1847103

ABSTRACT

Patients with type 1 diabetes (T1D) may develop severe outcomes during COVID-19 disease, but their ability to generate an immune response against the SARS-CoV-2 messenger RNA (mRNA) vaccines remains to be established. Here we evaluated the safety, immunogenicity and glycometabolic effects of the SARS-CoV-2 mRNA vaccines in patients with T1D. A total of 375 patients, 326 with T1D and 49 non-diabetics, who received two doses of the SARS-CoV-2 mRNA vaccines (mRNA-1273, BNT162b2) between March and April 2021 at the ASST FBF-Sacco Milan, Italy, were included in this monocentric observational study (NCT04905823). Local and systemic adverse events were reported in both groups after SARS-CoV-2 mRNA vaccination without statistical differences between them. While both T1D patients and non-diabetic subjects exhibited a parallel increase in anti-SARS-CoV-2S titers after vaccination, the vast majority of T1D patients (70% and 78% respectively) did not show any increase in the SARS-CoV-2-specific cytotoxic response as compared to the robust increased observed in all non-diabetic subjects. A reduced secretion of the T cell-related cytokines IL-2 and TNF-alpha in vaccinated patients with T1D was also observed. No glycometabolic alterations were evident in patients with T1D using continuous glucose monitoring during follow-up. Administration of the SARS-CoV-2 mRNA vaccine is associated with an impaired cellular SARS-CoV-2-specific cytotoxic immune response in T1D patients.

2.
Diabetes ; 71(7): 1579-1590, 2022 07 01.
Article in English | MEDLINE | ID: covidwho-1834217

ABSTRACT

Recent studies have shown that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may induce metabolic distress, leading to hyperglycemia in patients affected by coronavirus disease 19 (COVID-19). We investigated the potential indirect and direct effects of SARS-CoV-2 on human pancreatic islets in 10 patients who became hyperglycemic after COVID-19. Although there was no evidence of peripheral anti-islet autoimmunity, the serum of these patients displayed toxicity on human pancreatic islets, which could be abrogated by the use of anti-interleukin-1ß (IL-1ß), anti-IL-6, and anti-tumor necrosis factor α, cytokines known to be highly upregulated during COVID-19. Interestingly, the receptors of those aforementioned cytokines were highly expressed on human pancreatic islets. An increase in peripheral unmethylated INS DNA, a marker of cell death, was evident in several patients with COVID-19. Pathology of the pancreas from deceased hyperglycemic patients who had COVID-19 revealed mild lymphocytic infiltration of pancreatic islets and pancreatic lymph nodes. Moreover, SARS-CoV-2-specific viral RNA, along with the presence of several immature insulin granules or proinsulin, was detected in postmortem pancreatic tissues, suggestive of ß-cell-altered proinsulin processing, as well as ß-cell degeneration and hyperstimulation. These data demonstrate that SARS-CoV-2 may negatively affect human pancreatic islet function and survival by creating inflammatory conditions, possibly with a direct tropism, which may in turn lead to metabolic abnormalities observed in patients with COVID-19.


Subject(s)
COVID-19 , Islets of Langerhans , COVID-19/complications , Cytokines/metabolism , Humans , Hyperglycemia/virology , Islets of Langerhans/metabolism , Islets of Langerhans/virology , Proinsulin/metabolism , SARS-CoV-2
4.
JCI Insight ; 6(24)2021 12 22.
Article in English | MEDLINE | ID: covidwho-1518198

ABSTRACT

A substantial proportion of patients who have recovered from coronavirus disease-2019 (COVID-19) experience COVID-19-related symptoms even months after hospital discharge. We extensively immunologically characterized patients who recovered from COVID-19. In these patients, T cells were exhausted, with increased PD-1+ T cells, as compared with healthy controls. Plasma levels of IL-1ß, IL-1RA, and IL-8, among others, were also increased in patients who recovered from COVID-19. This altered immunophenotype was mirrored by a reduced ex vivo T cell response to both nonspecific and specific stimulation, revealing a dysfunctional status of T cells, including a poor response to SARS-CoV-2 antigens. Altered levels of plasma soluble PD-L1, as well as of PD1 promoter methylation and PD1-targeting miR-15-5p, in CD8+ T cells were also observed, suggesting abnormal function of the PD-1/PD-L1 immune checkpoint axis. Notably, ex vivo blockade of PD-1 nearly normalized the aforementioned immunophenotype and restored T cell function, reverting the observed post-COVID-19 immune abnormalities; indeed, we also noted an increased T cell-mediated response to SARS-CoV-2 peptides. Finally, in a neutralization assay, PD-1 blockade did not alter the ability of T cells to neutralize SARS-CoV-2 spike pseudotyped lentivirus infection. Immune checkpoint blockade ameliorates post-COVID-19 immune abnormalities and stimulates an anti-SARS-CoV-2 immune response.


Subject(s)
COVID-19/complications , Cytokines/immunology , Immune Checkpoint Inhibitors/pharmacology , Programmed Cell Death 1 Receptor/immunology , SARS-CoV-2/immunology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , B7-H1 Antigen/immunology , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Case-Control Studies , Cytokines/drug effects , DNA Methylation , Female , Humans , Immunophenotyping , In Vitro Techniques , Interleukin 1 Receptor Antagonist Protein/drug effects , Interleukin 1 Receptor Antagonist Protein/immunology , Interleukin-1beta/drug effects , Interleukin-1beta/immunology , Interleukin-8/drug effects , Interleukin-8/immunology , Male , MicroRNAs/metabolism , Middle Aged , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Promoter Regions, Genetic
5.
Nat Metab ; 3(6): 774-785, 2021 06.
Article in English | MEDLINE | ID: covidwho-1243313

ABSTRACT

Patients with coronavirus disease 2019 (COVID-19) are reported to have a greater prevalence of hyperglycaemia. Cytokine release as a consequence of severe acute respiratory syndrome coronavirus 2 infection may precipitate the onset of metabolic alterations by affecting glucose homeostasis. Here we describe abnormalities in glycometabolic control, insulin resistance and beta cell function in patients with COVID-19 without any pre-existing history or diagnosis of diabetes, and document glycaemic abnormalities in recovered patients 2 months after onset of disease. In a cohort of 551 patients hospitalized for COVID-19 in Italy, we found that 46% of patients were hyperglycaemic, whereas 27% were normoglycaemic. Using clinical assays and continuous glucose monitoring in a subset of patients, we detected altered glycometabolic control, with insulin resistance and an abnormal cytokine profile, even in normoglycaemic patients. Glycaemic abnormalities can be detected for at least 2 months in patients who recovered from COVID-19. Our data demonstrate that COVID-19 is associated with aberrant glycometabolic control, which can persist even after recovery, suggesting that further investigation of metabolic abnormalities in the context of long COVID is warranted.


Subject(s)
Blood Glucose/metabolism , COVID-19/blood , Hyperglycemia/metabolism , COVID-19/complications , COVID-19/virology , Cohort Studies , Humans , Hyperglycemia/complications , Insulin Resistance , Insulin-Secreting Cells/pathology , SARS-CoV-2/isolation & purification
6.
Front Immunol ; 12: 656362, 2021.
Article in English | MEDLINE | ID: covidwho-1211814

ABSTRACT

Since March 2020, the outbreak of Sars-CoV-2 pandemic has changed medical practice and daily routine around the world. Huge efforts from pharmacological industries have led to the development of COVID-19 vaccines. In particular two mRNA vaccines, namely the BNT162b2 (Pfizer-BioNTech) and the mRNA-1273 (Moderna), and a viral-vectored vaccine, i.e. ChAdOx1 nCoV-19 (AstraZeneca), have recently been approved in Europe. Clinical trials on these vaccines have been published on the general population showing a high efficacy with minor adverse events. However, specific data about the efficacy and safety of these vaccines in patients with immune-mediated inflammatory diseases (IMIDs) are still lacking. Moreover, the limited availability of these vaccines requires prioritizing some vulnerable categories of patients compared to others. In this position paper, we propose the point of view about the management of COVID-19 vaccination from Italian experts on IMIDs and the identification of high-risk groups according to the different diseases and their chronic therapy.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/complications , COVID-19/prevention & control , Immune System Diseases/virology , Vaccination/methods , Diabetes Mellitus/immunology , Diabetes Mellitus/virology , Europe , Expert Testimony , Glomerulonephritis/complications , Glomerulonephritis/immunology , Glomerulonephritis/virology , Humans , Inflammation/immunology , Inflammation/virology , Inflammatory Bowel Diseases/complications , Inflammatory Bowel Diseases/immunology , Inflammatory Bowel Diseases/virology , Lung Diseases/complications , Lung Diseases/immunology , Lung Diseases/virology , Pandemics/prevention & control , Rheumatic Diseases/complications , Rheumatic Diseases/immunology , Rheumatic Diseases/virology , Skin Diseases/complications , Skin Diseases/immunology , Skin Diseases/virology , Uveitis/complications , Uveitis/immunology , Uveitis/virology
7.
8.
Diabetes Care ; 43(12): 2999-3006, 2020 12.
Article in English | MEDLINE | ID: covidwho-809048

ABSTRACT

OBJECTIVE: Poor outcomes have been reported in patients with type 2 diabetes and coronavirus disease 2019 (COVID-19); thus, it is mandatory to explore novel therapeutic approaches for this population. RESEARCH DESIGN AND METHODS: In a multicenter, case-control, retrospective, observational study, sitagliptin, an oral and highly selective dipeptidyl peptidase 4 inhibitor, was added to standard of care (e.g., insulin administration) at the time of hospitalization in patients with type 2 diabetes who were hospitalized with COVID-19. Every center also recruited at a 1:1 ratio untreated control subjects matched for age and sex. All patients had pneumonia and exhibited oxygen saturation <95% when breathing ambient air or when receiving oxygen support. The primary end points were discharge from the hospital/death and improvement of clinical outcomes, defined as an increase in at least two points on a seven-category modified ordinal scale. Data were collected retrospectively from patients receiving sitagliptin from 1 March through 30 April 2020. RESULTS: Of the 338 consecutive patients with type 2 diabetes and COVID-19 admitted in Northern Italy hospitals included in this study, 169 were on sitagliptin, while 169 were on standard of care. Treatment with sitagliptin at the time of hospitalization was associated with reduced mortality (18% vs. 37% of deceased patients; hazard ratio 0.44 [95% CI 0.29-0.66]; P = 0.0001), with an improvement in clinical outcomes (60% vs. 38% of improved patients; P = 0.0001) and with a greater number of hospital discharges (120 vs. 89 of discharged patients; P = 0.0008) compared with patients receiving standard of care, respectively. CONCLUSIONS: In this multicenter, case-control, retrospective, observational study of patients with type 2 diabetes admitted to the hospital for COVID-19, sitagliptin treatment at the time of hospitalization was associated with reduced mortality and improved clinical outcomes as compared with standard-of-care treatment. The effects of sitagliptin in patients with type 2 diabetes and COVID-19 should be confirmed in an ongoing randomized, placebo-controlled trial.


Subject(s)
Coronavirus Infections , Coronavirus , Diabetes Mellitus, Type 2 , Pandemics , Pneumonia, Viral , Betacoronavirus , COVID-19 , Diabetes Mellitus, Type 2/drug therapy , Hospitalization , Humans , Italy , Retrospective Studies , SARS-CoV-2 , Sitagliptin Phosphate/therapeutic use
9.
Acta Diabetol ; 57(7): 779-783, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-549301

ABSTRACT

AIMS: SARS-CoV-2 causes severe respiratory syndrome (COVID-19) with high mortality due to a direct cytotoxic viral effect and a severe systemic inflammation. We are herein discussing a possible novel therapeutic tool for COVID-19. METHODS: Virus binds to the cell surface receptor ACE2; indeed, recent evidences suggested that SARS-CoV-2 may be using as co-receptor, when entering the cells, the same one used by MERS-Co-V, namely the DPP4/CD26 receptor. The aforementioned observation underlined that mechanism of cell entry is supposedly similar among different coronavirus, that the co-expression of ACE2 and DPP4/CD26 could identify those cells targeted by different human coronaviruses and that clinical complications may be similar. RESULTS: The DPP4 family/system was implicated in various physiological processes and diseases of the immune system, and DPP4/CD26 is variously expressed on epithelia and endothelia of the systemic vasculature, lung, kidney, small intestine and heart. In particular, DPP4 distribution in the human respiratory tract may facilitate the entrance of the virus into the airway tract itself and could contribute to the development of cytokine storm and immunopathology in causing fatal COVID-19 pneumonia. CONCLUSIONS: The use of DPP4 inhibitors, such as gliptins, in patients with COVID-19 with, or even without, type 2 diabetes, may offer a simple way to reduce the virus entry and replication into the airways and to hamper the sustained cytokine storm and inflammation within the lung in patients diagnosed with COVID-19 infection.


Subject(s)
Betacoronavirus , Coronavirus Infections/drug therapy , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Lung/metabolism , Pneumonia, Viral/drug therapy , COVID-19 , Coronavirus Infections/enzymology , Dipeptidyl Peptidase 4/drug effects , Humans , Pandemics , Pneumonia, Viral/enzymology , SARS-CoV-2
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