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1.
Panminerva Med ; 2022 Mar 11.
Article in English | MEDLINE | ID: covidwho-1743139

ABSTRACT

BACKGROUND: To assess the clinical effectiveness of Tocilizumab (TCZ) in moderate-to-severe hospitalized COVID-19 patients and factors associated with clinical response. METHODS: 508 inpatients with moderate-to-severe SARS-CoV-2 infection were enrolled. TCZ effect in addition to standard medical therapy was evaluated in terms of death during hospital stay. Unadjusted and adjusted risk of mortality for TCZ treated patients versus TCZ untreated ones was estimated using robust Cox regression model. We considered the combination of TCZ and ICU as time-dependent exposure and created a model using duplication method to assess the TCZ effect in very severe COVID-19 patients. RESULTS: TCZ REDUCED DEATH DURING HOSPITAL STAY IN THE UNADJUSTED MODEL (HR 0.54, 95%CI 0.33- 0.88) and also in the adjusted model, although with loss of statistical significance (HR 0.72, 0.43- 1.20). Better effectiveness was observed in patients with low SpO2/FiO2 ratio (HR 0.35, 0.21-0.61 vs 1.61, 0.54-4.82, p<0.05), and, without statistical significance, in patients with high CRP (HR 0.51, 0.30-0.87 vs 0.41, 0.12-1.37, p =NS) and high IL-6 (HR 0.49, 0.29-0.82 vs 1.00, 0.28-3.55, p=NS). TCZ was effective in patients not admitted to ICU, both in the unadjusted (HR 0.33, 0.14-0.74) and in the adjusted (HR 0.39, 0.17-0.91) model but no benefit was observed in critical ICU-admitted patients both in the unadjusted (HR 0.66, 0.37-1.15) and in the adjusted model (HR 0.95, 0.54-1.68). CONCLUSIONS: our real-life study suggests clinical efficacy of TCZ in moderate-to-severe COVID-19 patients but not in end-stage disease. Thus, to enhance TCZ effectiveness, patients should be selected before grave compromise of clinical conditions.

2.
J Clin Invest ; 131(12)2021 06 15.
Article in English | MEDLINE | ID: covidwho-1731387

ABSTRACT

The characterization of the adaptive immune response to COVID-19 vaccination in individuals who recovered from SARS-CoV-2 infection may define current and future clinical practice. To determine the effect of the 2-dose BNT162b2 mRNA COVID-19 vaccination schedule in individuals who recovered from COVID-19 (COVID-19-recovered subjects) compared with naive subjects, we evaluated SARS-CoV-2 Spike-specific T and B cell responses, as well as specific IgA, IgG, IgM, and neutralizing antibodies titers in 22 individuals who received the BNT162b2 mRNA COVID-19 vaccine, 11 of whom had a previous history of SARS-CoV-2 infection. Evaluations were performed before vaccination and then weekly until 7 days after second injection. Data obtained clearly showed that one vaccine dose is sufficient to increase both cellular and humoral immune response in COVID-19-recovered subjects without any additional improvement after the second dose. On the contrary, the second dose proved mandatory in naive subjects to further enhance the immune response. These findings were further confirmed at the serological level in a larger cohort of naive (n = 68) and COVID-19-recovered (n = 29) subjects, tested up to 50 days after vaccination. These results question whether a second vaccine injection in COVID-19-recovered subjects is required, and indicate that millions of vaccine doses may be redirected to naive individuals, thus shortening the time to reach herd immunity.


Subject(s)
Antibodies, Neutralizing , Antibodies, Viral , COVID-19 Vaccines , COVID-19 , Immunity, Humoral/drug effects , Immunologic Memory/drug effects , SARS-CoV-2 , Adult , Aged , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , COVID-19/blood , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/immunology , Female , Humans , Male , Middle Aged , SARS-CoV-2/immunology , SARS-CoV-2/metabolism
3.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327684

ABSTRACT

Background: Waning immunity and the surge of SARS-CoV-2 variants are responsible for breakthrough infections, i.e. infections in fully vaccinated individuals. Although the majority of vaccinated infected subjects reports mild or no symptoms, some others require hospitalization. The clinical and immunological features of vaccinated hospitalized COVID-19 patients are currently unknown. Methods: 29 unvaccinated and 36 vaccinated hospitalized COVID-19 patients were prospectively enrolled and clinical and laboratory data. Immunophenotyping of leukocytes subsets, T and B cell SARS-CoV-2 specific responses were evaluated via flow cytometry. Anti-IFN-α autoantibodies were measured via ELISA. Results: Despite vaccinated patients were older and with more comorbidities, unvaccinated subjects showed higher levels of pro-inflammatory markers, more severe disease and increased mortality rate. Accordingly, they presented significant alterations in the circulating leukocyte composition, typical of severe COVID-19. Vaccinated patients displayed higher levels of anti-Spike IgGs and Spike-specific B cells. Of all participants, survivors showed higher levels of anti-Spike IgGs and S-specific CD4+ T cells than non-survivors. At hospital admission, 6 out of 65 patients (9.2%) displayed high serum concentrations of autoantibodies targeting IFN-α. Remarkably, 3 were unvaccinated and eventually died, while the other 3 were vaccinated and survived. Conclusion: Despite more severe pre-existing clinical conditions, vaccinated patients have good outcome. A rapid activation of anti-SARS-CoV-2-specific immunity is fundamental for the resolution of the infection. Therefore, prior immunization through vaccination provides a significant contribute to prevention of disease worsening and can even overcome the presence of high-risk factors (i.e. older age, comorbidities, anti-IFN-α autoantibodies positivity).

4.
J Clin Invest ; 132(6)2022 03 15.
Article in English | MEDLINE | ID: covidwho-1685792

ABSTRACT

BACKGROUNDImmunization against SARS-CoV-2, the causative agent of COVID-19, occurs via natural infection or vaccination. However, it is currently unknown how long infection- or vaccination-induced immunological memory will last.METHODSWe performed a longitudinal evaluation of immunological memory to SARS-CoV-2 up to 1 year after infection and following mRNA vaccination in naive individuals and individuals recovered from COVID-19 infection.RESULTSWe found that memory cells are still detectable 8 months after vaccination, while antibody levels decline significantly, especially in naive individuals. We also found that a booster injection is efficacious in reactivating immunological memory to spike protein in naive individuals, whereas it was ineffective in previously SARS-CoV-2-infected individuals. Finally, we observed a similar kinetics of decay of humoral and cellular immunity to SARS-CoV-2 up to 1 year following natural infection in a cohort of unvaccinated individuals.CONCLUSIONShort-term persistence of humoral immunity, together with the reduced neutralization capacity versus the currently prevailing SARS-CoV-2 variants, may account for reinfections and breakthrough infections. Long-lived memory B and CD4+ T cells may protect from severe disease development. In naive individuals, a booster dose restored optimal anti-spike immunity, whereas the needs for vaccinated individuals who have recovered from COVID-19 have yet to be defined.FUNDINGThis study was supported by funds to the Department of Experimental and Clinical Medicine, University of Florence (Project Excellence Departments 2018-2022), the University of Florence (project RICTD2122), the Italian Ministry of Health (COVID-2020-12371849), and the region of Tuscany (TagSARS CoV 2).


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Neutralizing , Antibodies, Viral , CD4-Positive T-Lymphocytes , COVID-19/prevention & control , Humans , Immunity, Humoral , Spike Glycoprotein, Coronavirus , Vaccination
5.
Frontiers in immunology ; 13, 2022.
Article in English | EuropePMC | ID: covidwho-1678999

ABSTRACT

Although accumulating data have investigated the effect of SARS-CoV-2 mutations on antibody neutralizing activity, less is known about T cell immunity. In this work, we found that the ancestral (Wuhan strain) Spike protein can efficaciously reactivate CD4+ T cell memory in subjects with previous Alpha variant infection. This finding has practical implications, as in many countries only one vaccine dose is currently administered to individuals with previous COVID-19, independently of which SARS-CoV-2 variant was responsible of the infection. We also found that only a minority of Spike-specific CD4+ T cells targets regions mutated in Alpha, Beta and Delta variants, both after natural infection and vaccination. Finally, we found that the vast majority of Spike-specific CD4+ T cell memory response induced by natural infection or mRNA vaccination is conserved also against Omicron variant. This is of importance, as this newly emerged strain is responsible for a sudden rise in COVID-19 cases worldwide due to its increased transmissibility and ability to evade antibody neutralization. Collectively, these observations suggest that most of the memory CD4+ T cell response is conserved against SARS-CoV-2 variants of concern, providing an efficacious line of defense that can protect from the development of severe forms of COVID-19.

6.
Andrology ; 2021 Dec 08.
Article in English | MEDLINE | ID: covidwho-1575098

ABSTRACT

BACKGROUND: There is evidence that, after severe acute respiratory syndrome coronavirus 2 infection, male reproductive function and semen quality may be damaged OBJECTIVES: To evaluate a panel of inflammatory mediators in semen in patients recovered from coronavirus disease 2019. MATERIAL AND METHODS: Sexually active men with previous severe acute respiratory syndrome coronavirus 2 infection and proven recovery from coronavirus disease 2019 were enrolled in a prospective cohort study. Clinical, uro-andrological data and semen specimens were prospectively collected. For previously hospitalized coronavirus disease 2019 patients, data on serum inflammatory markers were retrospectively collected. RESULTS: A total of 43 men were enrolled in the study. Of these, 32 men were normozoospermic, three were oligozoospermic, and eight were crypto-azoospermic. Serum inflammatory markers (procalcitonin and C-reactive protein) were analyzed in previously hospitalized patients both at admission and at peak of infection. Levels at admission were statistically significantly higher in patients resulting in crypto-azoospermic with respect to those resulting in normozoospermic (p = 0.05; p = 0.03 and p = 0.02, respectively) after healing. Seminal cytokine levels were similar among all groups. Interleukin-1ß and tumor necrosis factor-α levels were significantly negatively related to sperm total number and concentration, whereas interleukin-4 was correlated with sperm motility. DISCUSSION AND CONCLUSION: Negative correlations between interleukin-1ß and tumor necrosis factor-α and sperm number and the overall high levels of semen cytokines indicate a potential detrimental role of severe acute respiratory syndrome coronavirus 2 driven inflammation on spermatogenesis. Overall, our results indicate that male patients recovering from coronavirus disease 2019 deserve accurate follow-up for their fertility status.

7.
Eur J Immunol ; 51(12): 2708-3145, 2021 12.
Article in English | MEDLINE | ID: covidwho-1568038

ABSTRACT

The third edition of Flow Cytometry Guidelines provides the key aspects to consider when performing flow cytometry experiments and includes comprehensive sections describing phenotypes and functional assays of all major human and murine immune cell subsets. Notably, the Guidelines contain helpful tables highlighting phenotypes and key differences between human and murine cells. Another useful feature of this edition is the flow cytometry analysis of clinical samples with examples of flow cytometry applications in the context of autoimmune diseases, cancers as well as acute and chronic infectious diseases. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid. All sections are written and peer-reviewed by leading flow cytometry experts and immunologists, making this edition an essential and state-of-the-art handbook for basic and clinical researchers.


Subject(s)
Autoimmune Diseases/immunology , Flow Cytometry , Infections/immunology , Neoplasms/immunology , Animals , Chronic Disease , Humans , Mice , Practice Guidelines as Topic
8.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-294747

ABSTRACT

Background: Recent reports evidenced an impairment of semen parameters in men affected by coronavirus disease 2019 (COVID-19). In particular, our group previously reported that 1 over 4 COVID-19 healed men were found to be crypto- / azoo-spermic. Moreover, most patients had elevated IL-8 semen levels at sperm analysis. The aim of our study was to assess semen parameters and inflammation by evaluating a panel of sperm cytokine levels (IL-1, IL-4, IL-6, IL-8, IL-17, INF gamma, TNF-alpha) on average 1 month after the second SARS-CoV-2 negative nasopharyngeal swab and 3 months later. Methods: : Ten men who showed normozoospermia (n=3), oligozoospermia (n=3) or crypto/azoospermia (n=4) 1 month after healing from COVID-19 in our previous study, were re-called and re-evaluated 3 months after the first semen analysis. Semen parameters were evaluated according to WHO manual and seminal plasma cytokine levels by an ELISA method. Results: : At 3-months follow-up, 8 men showed an overall increase of semen parameters compared to levels assessed after 1 month. In particular, of the 4 crypto-/azoo-spermic men 1 month after healing, 2 resulted oligozoospermic, 1 normozoospermic and only 1 remained azoospermic. Two of the 3 oligozoospermic men turned normozoozpermic. Semen cytokine levels were remarkably high one month after healing and remained elevated after 3 months, with the exception of IL-6. Conclusions: : This is the first longitudinal, prospective study comparing semen parameters and semen inflammatory markers one and three months after recovering from COVID-19. Our data indicate an overall tendency to an improvement of semen parameters although a genital tract inflammatory condition appears to persist at least 3 months after COVID-19 recovery. This condition could have an impact on male fertility requiring a careful follow up of these patients.

9.
Eur J Immunol ; 52(2): 352-355, 2022 02.
Article in English | MEDLINE | ID: covidwho-1530141

ABSTRACT

A late presenter AIDS patient with severe T cell depletion presented non-severe COVID-19 symptoms, with prolonged viral shedding. Our case report supports the hypothesis that an effective T cell response may be dispensable for the control of COVID-19 progression to severe forms, while it may be necessary for SARS-CoV-2 clearance.


Subject(s)
Acquired Immunodeficiency Syndrome/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Acquired Immunodeficiency Syndrome/blood , Adult , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/metabolism , COVID-19/blood , Female , Humans , SARS-CoV-2/metabolism
10.
Semin Immunol ; 55: 101508, 2021 06.
Article in English | MEDLINE | ID: covidwho-1482974

ABSTRACT

One and half year following the occurrence of COVID-19 pandemic, significant efforts from laboratories all over the world generated a huge amount of data describing the prototypical features of immunity in the course of SARS-CoV-2 infection. In this Review, we rationalize and organize the main observations, trying to define a "core" signature of immunity in COVID-19. We identified six hallmarks describing the main alterations occurring in the early infection phase and in the course of the disease, which predispose to severe illness. The six hallmarks are dysregulated type I IFN activity, hyperinflammation, lymphopenia, lymphocyte impairment, dysregulated myeloid response, and heterogeneous adaptive immunity to SARS-CoV-2. Dysregulation and exhaustion came out as the trait d'union, connecting abnormalities affecting both innate and adaptive immunity, humoral and cellular responses.


Subject(s)
COVID-19 , Adaptive Immunity , Humans , Pandemics , SARS-CoV-2
11.
Journal of Clinical Investigation ; 131(12):1-7, 2021.
Article in English | ProQuest Central | ID: covidwho-1334628

ABSTRACT

The characterization of the adaptive immune response to COVID-19 vaccination in individuals who recovered from SARS-CoV-2 infection may define current and future clinical practice. To determine the effect of the 2-dose BNT162b2 mRNA COVID-19 vaccination schedule in individuals who recovered from COVID-19 (COVID-19-recovered subjects) compared with naive subjects, we evaluated SARS-CoV-2 Spike-specific T and B cell responses, as well as specific IgA, IgG, IgM, and neutralizing antibodies titers in 22 individuals who received the BNT162b2 mRNA COVID-19 vaccine, 11 of whom had a previous history of SARS-CoV-2 infection. Evaluations were performed before vaccination and then weekly until 7 days after second injection. Data obtained clearly showed that one vaccine dose is sufficient to increase both cellular and humoral immune response in COVID-19-recovered subjects without any additional improvement after the second dose. On the contrary, the second dose proved mandatory in naive subjects to further enhance the immune response. These findings were further confirmed at the serological level in a larger cohort of naive (n = 68) and COVID-19-recovered (n = 29) subjects, tested up to 50 days after vaccination. These results question whether a second vaccine injection in COVID-19-recovered subjects is required, and indicate that millions of vaccine doses may be redirected to naive individuals, thus shortening the time to reach herd immunity.

14.
Clin Transl Immunology ; 10(5): e1281, 2021.
Article in English | MEDLINE | ID: covidwho-1222609

ABSTRACT

OBJECTIVE: Although the adaptive immune response to SARS-CoV-2 has been characterised in the acute and early convalescent phase of the disease, few studies explore whether natural infection elicits long-lasting immunological memory in recovered individuals. In this work, we aimed to assess the maintenance of immunological memory to SARS-CoV-2. METHODS: We evaluated the long-term virus-specific cellular and humoral immune response in the members of an Italian Serie A football team, who experienced a cluster of COVID-19 in March 2020, which was strictly evaluated in the following months. RESULTS: Our results highlight a heterogeneous magnitude of immunological memory at 5 months after infection. Indeed, 20% of the subjects displayed a weak cellular and humoral memory to SARS-CoV-2, suggesting that they may be at higher risk of reinfection. In addition, a history of symptomatic COVID-19 was associated with higher levels of SARS-CoV-2-reactive CD4+ T cells and specific antibody levels than in asymptomatic individuals. CONCLUSION: Collectively, these data demonstrate that immunity to SARS-CoV-2 is maintained five months postinfection even if the magnitude of response is heterogeneous among individuals. This finding suggests that some COVID-19-recovered subjects may benefit from vaccination.

16.
PLoS Pathog ; 17(2): e1009243, 2021 02.
Article in English | MEDLINE | ID: covidwho-1058312

ABSTRACT

The current pandemic emergence of novel coronavirus disease (COVID-19) poses a relevant threat to global health. SARS-CoV-2 infection is characterized by a wide range of clinical manifestations, ranging from absence of symptoms to severe forms that need intensive care treatment. Here, plasma-EDTA samples of 30 patients compared with age- and sex-matched controls were analyzed via untargeted nuclear magnetic resonance (NMR)-based metabolomics and lipidomics. With the same approach, the effect of tocilizumab administration was evaluated in a subset of patients. Despite the heterogeneity of the clinical symptoms, COVID-19 patients are characterized by common plasma metabolomic and lipidomic signatures (91.7% and 87.5% accuracy, respectively, when compared to controls). Tocilizumab treatment resulted in at least partial reversion of the metabolic alterations due to SARS-CoV-2 infection. In conclusion, NMR-based metabolomic and lipidomic profiling provides novel insights into the pathophysiological mechanism of human response to SARS-CoV-2 infection and to monitor treatment outcomes.


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , COVID-19/drug therapy , Lipidomics , Lipids/blood , SARS-CoV-2/metabolism , COVID-19/blood , COVID-19/epidemiology , Female , Humans , Male , Nuclear Magnetic Resonance, Biomolecular
17.
Mucosal Immunol ; 14(2): 305-316, 2021 03.
Article in English | MEDLINE | ID: covidwho-947522

ABSTRACT

The novel coronavirus SARS-CoV-2 enters into the human body mainly through the ACE2 + TMPRSS2+ nasal epithelial cells. The initial host response to this pathogen occurs in a peculiar immune microenvironment that, starting from the Nasopharynx-Associated Lymphoid Tissue (NALT) system, is the product of a long evolutionary process that is aimed to first recognize exogenous airborne agents. In the present work, we want to critically review the latest molecular and cellular findings on the mucosal response to SARS-CoV-2 in the nasal cavity and in NALT, and to analyze its impact in the subsequent course of COVID-19. Finally, we want to explore the possibility that the regulation of the systemic inflammatory network against the virus can be modulated starting from the initial phases of the nasal and nasopharyngeal response and this may have several clinical and epidemiological implications starting from a mucosal vaccine development.


Subject(s)
COVID-19/immunology , Nasopharynx/virology , SARS-CoV-2/physiology , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/pathology , COVID-19/transmission , COVID-19 Vaccines/immunology , Humans , Immune Evasion , Lymphoid Tissue/immunology , Nasopharynx/immunology , Serine Endopeptidases/metabolism , Virus Internalization
18.
Immunol Lett ; 228: 122-128, 2020 12.
Article in English | MEDLINE | ID: covidwho-909223

ABSTRACT

As of October 2020 management of Coronavirus disease 2019 (COVID-19) is based on supportive care and off-label or compassionate-use therapies. On March 2020 tocilizumab - an anti-IL-6 receptor monoclonal antibody - was suggested as immunomodulatory treatment in severe COVID-19 because hyperinflammatory syndrome occurs in many patients similarly to the cytokine release syndrome that develops after CAR-T cell therapy. In our retrospective observational study, 20 severe COVID-19 patients requiring intensive care were treated with tocilizumab in addition to standard-of-care therapy (SOC) and compared with 13 COVID-19 patients receiving only SOC. Clinical respiratory status, inflammatory markers and vascular radiologic score improved after one week from tocilizumab administration. On the contrary, these parameters were stable or worsened in patients receiving only SOC. Despite major study limitations, improvement of alveolar-arterial oxygen gradient as well as vascular radiologic score after one week may account for improved pulmonary vascular perfusion and could explain the more rapid recovery of COVID-19 patients receiving tocilizumab compared to controls.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/drug therapy , Respiration/drug effects , Aged , Aged, 80 and over , Biomarkers/blood , COVID-19/pathology , Combined Modality Therapy , Critical Care , Female , Humans , Male , Middle Aged , Receptors, Interleukin-6/antagonists & inhibitors , Retrospective Studies , SARS-CoV-2 , Time Factors , Treatment Outcome
19.
Eur J Immunol ; 50(12): 2013-2024, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-880266

ABSTRACT

The characterization of cell-mediated and humoral adaptive immune responses to SARS-CoV-2 is fundamental to understand COVID-19 progression and the development of immunological memory to the virus. In this study, we detected T-cells reactive to SARS-CoV-2 proteins M, S, and N, as well as serum virus-specific IgM, IgA, IgG, in nearly all SARS-CoV-2 infected individuals, but not in healthy donors. Virus-reactive T cells exhibited signs of in vivo activation, as suggested by the surface expression of immune-checkpoint molecules PD1 and TIGIT. Of note, we detected antigen-specific adaptive immune response both in asymptomatic and symptomatic SARS-CoV-2 infected subjects. More importantly, symptomatic patients displayed a significantly higher magnitude of both cell-mediated and humoral adaptive immune response to the virus, as compared to asymptomatic individuals. These findings suggest that an uncontrolled adaptive immune response contribute to the development of the life-threatening inflammatory phase of the disease. Finally, this study might open the way to develop effective vaccination strategies.


Subject(s)
Antibodies, Viral/immunology , COVID-19/immunology , Carrier State/immunology , Immunity, Humoral , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Adult , Carrier State/virology , Female , Humans , Programmed Cell Death 1 Receptor/immunology , Receptors, Immunologic/immunology , Viral Proteins/immunology
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