Publications by authors named "Alessandra Vultaggio"

80 Publications

Mechanisms of Drug Desensitization: Not Only Mast Cells.

Front Pharmacol 2020 23;11:590991. Epub 2020 Dec 23.

Translational Immunology Unit, Immunology Area, Pediatric Hospital Bambino Gesù, IRCCS, Rome, Italy.

Drug desensitization (DD) allows transient clinical tolerance to the drug in reactive patients and it is frequently and successfully used in the management of both IgE and non IgE-mediated hypersensitivity reactions (HRs). The underlying mechanisms behind this process is not well understood. The desensitization procedure is associated with the inhibition of mast cells degranulation and cytokine production, that, is attributable, at least partially, to the abrogation of Ca2+ mobilization; findings and mouse models of rapid desensitization show that the organization and spatial distribution of actin is critical for Ca2+ mobilization. Some clinical observations may suggest the induction of a longer memory of tolerance by DD and they raise the suspicion that other cells and mechanisms are involved in DD. Some data are emerging about the modifications of immune responses during DD in patients with previous immediate HRs. In particular, an increase of regulatory cytokines, mainly represented by IL-10, has been shown, and more importantly, the appearance of IL-35 producing T regulatory cells has been described during DD. The release of controlled cellular mediators by mast cells over time and the development of the antigen-specific regulation of adaptive response allow to safely and successfully reach the target dose of a first line drug during DD.
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http://dx.doi.org/10.3389/fphar.2020.590991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793680PMC
December 2020

Seasonal Allergic Rhinitis Symptoms in Relation to COVID-19.

Allergy Rhinol (Providence) 2020 Jan-Dec;11:2152656720968804. Epub 2020 Nov 19.

Department of Otorhinolaryngology, Careggi University Hospital, Florence, Italy.

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http://dx.doi.org/10.1177/2152656720968804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683838PMC
November 2020

COVID-19: general overview, pharmacological options and ventilatory support strategies.

Multidiscip Respir Med 2020 Jan 9;15(1):708. Epub 2020 Nov 9.

Department of Medical Specialties, Pneumology Unit, Arcispedale Santa Maria Nuova, Azienda USL di Reggio Emilia- IRCCS, Reggio Emilia.

The novel coronavirus called "Severe Acute Respiratory Syndrome Coronavirus 2" (SARS-CoV-2) caused an outbreak in December 2019, starting from the Chinese city of Wuhan, in the Hubei province, and rapidly spreading to the rest of the world. Consequently, the World Health Organization (WHO) declared that the coronavirus disease of 2019 (COVID-19) can be characterized as a pandemic. During COVID-19 several immunological alterations have been observed: in plasma of severe patients, inflammatory cytokines are at a much higher concentration ("cytokine storm"). These aspects are associated with pulmonary inflammation and parenchymal infiltrates with an extensive lung tissue damage in COVID-19 patients. To date, clinical evidence and guidelines based on reliable data and randomized clinical trials (RCTs) for the treatment of COVID-19 are lacking. In the absence of definitive management protocols, many treatments are currently being evaluated worldwide. Some of these options were soon abandoned due to ineffectiveness, while others showed promising results. As for ventilatory strategies, at the moment there are still no consistent data published about the different approaches and how they may influence disease progression. What will probably represent the real solution to this pandemic is the identification of a safe and effective vaccine, for which enormous efforts and investments are being put in place. This review will summarize the state-of-the-art of COVID-19 current treatment options and those potentially available in the future, as well as high flow oxygen therapy and non-invasive mechanical ventilation approaches.
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http://dx.doi.org/10.4081/mrm.2020.708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662457PMC
January 2020

The emerging role of type 2 inflammation in asthma.

Expert Rev Clin Immunol 2021 Jan 17;17(1):63-71. Epub 2020 Dec 17.

Immunoallergology Unit, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy.

: Bronchial asthma (BA) is a chronic airways inflammatory disease. Based on the biological mechanisms that underline the disease, asthma has been classified as type 2 or non-type 2 phenotype.: An emerging role has been identified for group 2 innate lymphoid cells (ILC2s) able to produce the classical type 2 cytokines. The role of Th2 cells and IL-4 is crucial in the pathogenesis of allergic BA as supported by asthma models. IL-13, shares many biological functions with IL-4 such as induction of IgE synthesis and regulation of eosinophil trafficking. However, IL-13 does not induce Th2 cell differentiation. The Authors reviewed evidence on the new concept of type 2 inflammation and the cellular and molecular network behind this process. Literature data in the PubMed were analyzed for peer-reviewed articles published until September 2020.: The current trend is to consider Th2- and ILC2-driven pathways as two separate pathogenic mechanisms, recent data underscore that adaptive Th2- and innate cell responses represent two integrated systems in the production of IL-4, IL-5, and IL-13 leading to the current 'concept' of type 2 inflammation. This review highlights the role of Th2 cells and ILC2 in the recent new concept of type 2 inflammation.
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http://dx.doi.org/10.1080/1744666X.2020.1860755DOI Listing
January 2021

Asthma in a large COVID-19 cohort: Prevalence, features, and determinants of COVID-19 disease severity.

Respir Med 2021 01 26;176:106261. Epub 2020 Nov 26.

Department of Medicine, University of Verona, Verona, Italy.

Background: Asthma prevalence among COVID-19 patients seems to be surprisingly low. However the clinical profile of COVID-19 asthmatic patients and potential determinants of higher susceptibility/worse outcome have been scarcely investigated. We aimed to describe the prevalence and features of asthmatic patients hospitalized for COVID-19 and to explore the association between their clinical asthma profile and COVID-19 severity.

Methods: Medical records of patients admitted to COVID-Units of six Italian cities major hospitals were reviewed. Demographic and clinical data were analyzed and compared according to the COVID-19 outcome (death/need for ventilation vs discharge at home without requiring invasive procedures).

Results: Within the COVID-Units population (n = 2000) asthma prevalence was 2.1%. Among the asthmatics the mean age was 61.1 years and 60% were females. Around half of patients were atopic, blood eosinophilia was normal in most of patients. An asthma exacerbation in the 6 months before the Covid-Unit admittance was reported by 18% of patients. 24% suffered from GINA step 4-5 asthma, and 5% were under biologic treatment. 31% of patients were not on regular treatment and a negligible use of oral steroid was recorded. Within the worse outcome group, a prevalence of males was detected (64 vs 29%, p = 0.026); they suffered from more severe asthma (43 vs 14%, p = 0.040) and were more frequently current or former smokers (62 vs 25%, p = 0.038).

Conclusions: Our report, the first including a large COVID-19 hospitalized Italian population, confirms the low prevalence of asthma. On the other side patients with GINA 4/5 asthma, and those not adequately treated, should be considered at higher risk.
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http://dx.doi.org/10.1016/j.rmed.2020.106261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688414PMC
January 2021

Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: A prospective multicohort study of the ABIRISK consortium.

PLoS Med 2020 10 30;17(10):e1003348. Epub 2020 Oct 30.

CESP, INSERM UMR 1018, Faculty of Medicine, Paris-Sud University, UVSQ, Paris-Saclay University, Villejuif, France.

Background: Biopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related factors influencing the occurrence of antidrug antibodies (ADAs) is still limited.

Methods And Findings: The European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn's disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon [IFN]-beta-1a intramuscularly [IM], n = 38; IFN-beta-1a subcutaneously [SC], n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio [aHR] = 0.408 [95% confidence interval (CI) 0.253-0.657], p < 0.001) and antibiotics (aHR = 0.121 [0.0437-0.333], p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 [1.616-4.704], p < 0.001) and tobacco smoking (aHR = 2.150 [1.319-3.503], p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 [1.923-5.976], p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 [2.139-6.764], p < 1 × 10-5 for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum were more prone to develop ADAs (aHR = 2.329 [1.106-4.90], p = 0.026). A limitation of the study is the lack of replication; therefore, other studies are required to confirm our findings.

Conclusion: In our study, we found that immunosuppressants and antibiotics were associated with decreased risk of ADA development, whereas tobacco smoking and infections during the study were associated with increased risk. We found that the HLA-DQA1*05 allele was associated with an increased rate of immunogenicity. Moreover, our results suggest a relationship between CXCL12 production and ADA development independent of the disease, which is consistent with its known function in affinity maturation of antibodies and plasma cell survival. Our findings may help physicians in the management of patients receiving biotherapies.
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http://dx.doi.org/10.1371/journal.pmed.1003348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598520PMC
October 2020

Use of biologicals in allergic and type-2 inflammatory diseases during the current COVID-19 pandemic: Position paper of Ärzteverband Deutscher Allergologen (AeDA), Deutsche Gesellschaft für Allergologie und Klinische Immunologie (DGAKI), Gesellschaft für Pädiatrische Allergologie und Umweltmedizin (GPA), Österreichische Gesellschaft für Allergologie und Immunologie (ÖGAI), Luxemburgische Gesellschaft für Allergologie und Immunologie (LGAI), Österreichische Gesellschaft für Pneumologie (ÖGP) in co-operation with the German, Austrian, and Swiss ARIA groups, and the European Academy of Allergy and Clinical Immunology (EAACI).

Authors:
Ludger Klimek Oliver Pfaar Margitta Worm Thomas Eiwegger Jan Hagemann Markus Ollert Eva Untersmayr Karin Hoffmann-Sommergruber Alessandra Vultaggio Ioana Agache Sevim Bavbek Apostolos Bossios Ingrid Casper Susan Chan Alexia Chatzipetrou Christian Vogelberg Davide Firinu Paula Kauppi Antonios Kolios Akash Kothari Andrea Matucci Oscar Palomares Zsolt Szépfalusi Wolfgang Pohl Wolfram Hötzenecker Alexander R Rosenkranz Karl-Christian Bergmann Thomas Bieber Roland Buhl Jeroen Buters Ulf Darsow Thomas Keil Jörg Kleine-Tebbe Susanne Lau Marcus Maurer Hans Merk Ralph Mösges Joachim Saloga Petra Staubach Uta Jappe Klaus F Rabe Uta Rabe Claus Vogelmeier Tilo Biedermann Kirsten Jung Wolfgang Schlenter Johannes Ring Adam Chaker Wolfgang Wehrmann Sven Becker Laura Freudelsperger Norbert Mülleneisen Katja Nemat Wolfgang Czech Holger Wrede Randolf Brehler Thomas Fuchs Peter-Valentin Tomazic Werner Aberer Antje-Henriette Fink-Wagner Fritz Horak Stefan Wöhrl Verena Niederberger-Leppin Isabella Pali-Schöll Wolfgang Pohl Regina Roller-Wirnsberger Otto Spranger Rudolf Valenta Mübecell Akdis Paolo M Matricardi François Spertini Nicolai Khaltaev Jean-Pierre Michel Larent Nicod Peter Schmid-Grendelmeier Marco Idzko Eckard Hamelmann Thilo Jakob Thomas Werfel Martin Wagenmann Christian Taube Erika Jensen-Jarolim Stephanie Korn Francois Hentges Jürgen Schwarze Liam O Mahony Edward F Knol Stefano Del Giacco Tomás Chivato Pérez Jean Bousquet Anna Bedbrook Torsten Zuberbier Cezmi Akdis Marek Jutel

Allergol Select 2020 7;4:53-68. Epub 2020 Sep 7.

European Academy of Allergy and Clinical Immunology (EAACI).

Background: Since the beginning of the COVID-19 pandemic, the treatment of patients with allergic and atopy-associated diseases has faced major challenges. Recommendations for "social distancing" and the fear of patients becoming infected during a visit to a medical facility have led to a drastic decrease in personal doctor-patient contacts. This affects both acute care and treatment of the chronically ill. The immune response after SARS-CoV-2 infection is so far only insufficiently understood and could be altered in a favorable or unfavorable way by therapy with monoclonal antibodies. There is currently no evidence for an increased risk of a severe COVID-19 course in allergic patients. Many patients are under ongoing therapy with biologicals that inhibit type 2 immune responses via various mechanisms. There is uncertainty about possible immunological interactions and potential risks of these biologicals in the case of an infection with SARS-CoV-2.

Materials And Methods: A selective literature search was carried out in PubMed, Livivo, and the internet to cover the past 10 years (May 2010 - April 2020). Additionally, the current German-language publications were analyzed. Based on these data, the present position paper provides recommendations for the biological treatment of patients with allergic and atopy-associated diseases during the COVID-19 pandemic.

Results: In order to maintain in-office consultation services, a safe treatment environment must be created that is adapted to the pandemic situation. To date, there is a lack of reliable study data on the care for patients with complex respiratory, atopic, and allergic diseases in times of an imminent infection risk from SARS-CoV-2. Type-2-dominant immune reactions, as they are frequently seen in allergic patients, could influence various phases of COVID-19, e.g., by slowing down the immune reactions. Theoretically, this could have an unfavorable effect in the early phase of a SARS-Cov-2 infection, but also a positive effect during a cytokine storm in the later phase of severe courses. However, since there is currently no evidence for this, all data from patients treated with a biological directed against type 2 immune reactions who develop COVID-19 should be collected in registries, and their disease courses documented in order to be able to provide experience-based instructions in the future.

Conclusion: The use of biologicals for the treatment of bronchial asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyps, and spontaneous urticaria should be continued as usual in patients without suspected infection or proven SARS-CoV-2 infection. If available, it is recommended to prefer a formulation for self-application and to offer telemedical monitoring. Treatment should aim at the best possible control of difficult-to-control allergic and atopic diseases using adequate rescue and add-on therapy and should avoid the need for systemic glucocorticosteroids. If SARS-CoV-2 infection is proven or reasonably suspected, the therapy should be determined by weighing the benefits and risks individually for the patient in question, and the patient should be involved in the decision-making. It should be kept in mind that the potential effects of biologicals on the immune response in COVID-19 are currently not known. Telemedical offers are particularly desirable for the acute consultation needs of suitable patients.
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http://dx.doi.org/10.5414/ALX02166EDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480069PMC
September 2020

Low-Dose Mepolizumab Effectiveness in Patients Suffering From Eosinophilic Granulomatosis With Polyangiitis.

Allergy Asthma Immunol Res 2020 Sep;12(5):885-893

Immunoallergology Unit, Careggi University Hospital, Florence, Italy.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by multisystemic manifestations including asthma. Mepolizumab (300 mg/4 weeks) has recently been approved for EGPA. However, real-life data are scarce and report experiences with high doses of mepolizumab intravenously administered (750 mg/4 weeks). The aim of our study was to investigate in a real-life setting whether mepolizumab in EGPA patients at low doses would enable us 1) to control asthma symptoms, 2) to obtain oral corticosteroids (OCS) and/or immunosuppressors tapering and 3) to maintain clinical remission and avoid disease relapses. Mepolizumab (100 mg/4 weeks) was subcutaneously administered for 12 months in 18 EGPA patients with uncontrolled severe asthma. Symptoms, annual asthma exacerbation rates, OCS-sparing effects, lung function and eosinophil activation markers were monitored. The proportion of patients with clinical remission or relapse was also evaluated in month 12. A significant decrease in the annual rate of asthma exacerbations in association with significant changes in asthma control were observed. Specifically, 66.6% of the patients experienced no exacerbations during the mepolizumab treatment. Most patients (77.7%) were able to reduce the daily OCS dose by at least 50%. Four patients also stopped cyclosporine A during the study period. No EGPA relapse was observed and a large majority of the patients achieved clinical remission (94.3%). Clinical benefits were paralleled by reduction in blood eosinophils and serum levels of eosinophil activation markers. Low-dose mepolizumab showed clinically relevant benefits in exacerbation rates, asthma symptoms, OCS and immunosuppressive use in EGPA patients. These effects occurred without any EGPA relapse for extrapulmonary manifestations.
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http://dx.doi.org/10.4168/aair.2020.12.5.885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346991PMC
September 2020

Anaphylactic reactions to biological drugs.

Curr Opin Allergy Clin Immunol 2020 08;20(4):346-351

Translational Immunology Unit, Immunology Area, Pediatric Hospital Bambino Gesù, IRCCS, Rome, Italy.

Purpose Of Review: This review summarizes the current knowledge of the pathogenic mechanisms of biologics-induced anaphylaxis, and the diagnostic and prophylactic strategies in the management of potentially reactive patients, to improve the safety profile of biologics.

Recent Findings: The recent knowledge on the topic highlights the involvement of both effector and regulatory mechanisms in the immune response to biological agents. In addition, the impact of biological's immunogenicity on hypersensitivity reactions has been confirmed in a wider number of studies, defining some details about the kinetics of antidrug antibodies development, specifically immunoglobulin G (IgG) and immunoglobulin E (IgE).

Summary: Biological agents may induce anaphylaxis, mainly through the induction of antidrug antibodies. Biologics-related infusion reactions are often clinically consistent with type I hypersensitivity, but IgG antidrug antibodies may also be involved. The immune response toward biologicals is orchestrated by both effector and regulatory T cells. In addition, nonantibody-dependent mechanisms may occur. Among clinicians persists today again a low awareness, not only of the possibility to understand the immunological mechanisms behind anaphylaxis to biologicals but also the opportunity to apply potential strategies for the management of reactive patients aimed to guarantee a safe retreatment.
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http://dx.doi.org/10.1097/ACI.0000000000000666DOI Listing
August 2020

Prompt Predicting of Early Clinical Deterioration of Moderate-to-Severe COVID-19 Patients: Usefulness of a Combined Score Using IL-6 in a Preliminary Study.

J Allergy Clin Immunol Pract 2020 Sep 19;8(8):2575-2581.e2. Epub 2020 Jun 19.

Immunoallergology Unit, Careggi University Hospital, Florence, Italy. Electronic address:

Background: The early identification of patients at risk of clinical deterioration is of interest considering the timeline of COVID-19 after the onset of symptoms.

Objective: The aim of our study was to evaluate the usefulness of testing serum IL-6 and other serological and clinical biomarkers, to predict a short-term negative clinical course of patients with noncritical COVID-19.

Methods: A total of 208 patients with noncritical COVID-19 pneumonia at admission were consecutively enrolled. Clinical and laboratory findings obtained on admission were analyzed by using survival analysis and stepwise logistic regression for variable selection. Three-day worsening as outcome in a logistic model to generate a prognostic score was used.

Results: Clinical worsening occurred in 63 patients (16 = died; 39 = transferred to intensive care unit; 8 worsening of respiratory failure). Forty-five of them worsened within 3 days after admission. The risk of clinical worsening was progressively enhanced along with increasing quartiles of IL-6 levels. Multivariate analysis showed that IL-6 (P = .005), C-reactive protein (CRP) (P = .003), and SaO/FiO (P = .014) were the best predictors for clinical deterioration in the first 3 days after admission. The combined score yielded an area under the curve = 0.88 (95% confidence interval: 0.83-0.93). A nomogram predicting the probability of 3-day worsening was generated. The score also showed good performance for 7-day and 14- or 21-day worsening and in predicting death occurring during all the follow-up.

Conclusions: Combining IL-6, CRP, and SaO/FiO in a score may help clinicians to identify on admission those patients with COVID-19 who are at high risk for a further 3-day clinical deterioration.
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http://dx.doi.org/10.1016/j.jaip.2020.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303032PMC
September 2020

Anwendung von Biologika bei allergischen und Typ-2-entzündlichen Erkrankungen in der aktuellen Covid-19-Pandemie: Positionspapier des Ärzteverbands Deutscher Allergologen (AeDA)A, der Deutschen Gesellschaft für Allergologie und klinische Immunologie (DGAKI)B, der Gesellschaft für Pädiatrische Allergologie und Umweltmedizin (GPA)C, der Österreichischen Gesellschaft für Allergologie und Immunologie (ÖGAI)D, der Luxemburgischen Gesellschaft für Allergologie und Immunologie (LGAI)E, der Österreichischen Gesellschaft für Pneumologie (ÖGP)F in Kooperation mit der deutschen, österreichischen, und schweizerischen ARIA-GruppeG und der Europäischen Akademie für Allergologie und Klinische Immunologie (EAACI)H.

Allergo J 2020 24;29(4):14-27. Epub 2020 Jun 24.

Zentrum für Rhinologie & Allergologie, An den Quellen 10, 65183 Wiesbaden, Germany.

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http://dx.doi.org/10.1007/s15007-020-2553-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289636PMC
June 2020

Considerations on biologicals for patients with allergic disease in times of the COVID-19 pandemic: An EAACI statement.

Allergy 2020 11;75(11):2764-2774

Translational Medicine Program, Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, Toronto, ON, Canada.

The outbreak of the SARS-CoV-2-induced coronavirus disease 2019 (COVID-19) pandemic re-shaped doctor-patient interaction and challenged capacities of healthcare systems. It created many issues around the optimal and safest way to treat complex patients with severe allergic disease. A significant number of the patients are on treatment with biologicals, and clinicians face the challenge to provide optimal care during the pandemic. Uncertainty of the potential risks for these patients is related to the fact that the exact sequence of immunological events during SARS-CoV-2 is not known. Severe COVID-19 patients may experience a "cytokine storm" and associated organ damage characterized by an exaggerated release of pro-inflammatory type 1 and type 3 cytokines. These inflammatory responses are potentially counteracted by anti-inflammatory cytokines and type 2 responses. This expert-based EAACI statement aims to provide guidance on the application of biologicals targeting type 2 inflammation in patients with allergic disease. Currently, there is very little evidence for an enhanced risk of patients with allergic diseases to develop severe COVID-19. Studies focusing on severe allergic phenotypes are lacking. At present, noninfected patients on biologicals for the treatment of asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyps, or chronic spontaneous urticaria should continue their biologicals targeting type 2 inflammation via self-application. In case of an active SARS-CoV-2 infection, biological treatment needs to be stopped until clinical recovery and SARS-CoV-2 negativity is established and treatment with biologicals should be re-initiated. Maintenance of add-on therapy and a constant assessment of disease control, apart from acute management, are demanded.
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http://dx.doi.org/10.1111/all.14407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300800PMC
November 2020

Impaired immune cell cytotoxicity in severe COVID-19 is IL-6 dependent.

J Clin Invest 2020 09;130(9):4694-4703

Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.

BACKGROUNDCoronavirus disease 19 (COVID-19) is an emerging infectious disease caused by SARS-CoV-2. Antiviral immune response is crucial to achieve pathogen clearance; however, in some patients an excessive and aberrant host immune response can lead to an acute respiratory distress syndrome. The comprehension of the mechanisms that regulate pathogen elimination, immunity, and pathology is essential to better characterize disease progression and widen the spectrum of therapeutic options.METHODSWe performed a flow cytometric characterization of immune cell subsets from 30 patients with COVID-19 and correlated these data with clinical outcomes.RESULTSPatients with COVID-19 showed decreased numbers of circulating T, B, and NK cells and exhibited a skewing of CD8+ T cells toward a terminally differentiated/senescent phenotype. In agreement, CD4+ T and CD8+ T, but also NK cells, displayed reduced antiviral cytokine production capability. Moreover, a reduced cytotoxic potential was identified in patients with COVID-19, particularly in those who required intensive care. The latter group of patients also showed increased serum IL-6 levels that inversely correlated to the frequency of granzyme A-expressing NK cells. Off-label treatment with tocilizumab restored the cytotoxic potential of NK cells.CONCLUSIONThe association between IL-6 serum levels and the impairment of cytotoxic activity suggests the possibility that targeting this cytokine may restore antiviral mechanisms.FUNDINGThis study was supported by funds from the Department of Experimental and Clinical Medicine of University of Florence (the ex-60% fund and the "Excellence Departments 2018-2022 Project") derived from Ministero dell'Istruzione, dell'Università e della Ricerca (Italy).
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http://dx.doi.org/10.1172/JCI138554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456250PMC
September 2020

Immunogenicity-unwanted immune responses to biological drugs - can we predict them?

Expert Rev Clin Pharmacol 2021 Jan 8;14(1):47-53. Epub 2020 Jun 8.

Immunoallergology Unit, University Hospital Careggi , Florence, Italy.

Introduction: Biological agents (BAs) target molecules involved in disease mechanisms and have modified the natural history of several immune-mediated disorders. All BAs are immunogenic, resulting in the formation of antidrug antibodies (ADAs), which can neutralize drug activity leading to loss of response and potential relapse, or serious adverse events such as infusion hypersensitivity reactions. The production of ADAs is the result of a specific adaptive immune response in which T and B cells are involved.

Areas Covered: Factors conditioning the immunogenicity of BAs, including drug-, treatment- and patient-related factors are currently the subject of many studies. Among them, a lot of attention is dedicated to define the impact of BAs structure, the effect of targeting (soluble or membrane) molecules, the impact of interruption of therapy as well as the role of genetic (HLA and non-HLA) predisposing factors and disease activity.

Expert Opinion: Knowledge of factors capable of influencing the immunogenicity of BAs may help to understand, in a predictive manner and at the single patient level, the presence of risk factors influencing the production of ADAs and their impact on clinical outcomes.
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http://dx.doi.org/10.1080/17512433.2020.1772053DOI Listing
January 2021

Serum Free Light Chains in Common Variable Immunodeficiency Disorders: Role in Differential Diagnosis and Association With Clinical Phenotype.

Front Immunol 2020 31;11:319. Epub 2020 Mar 31.

Department of Medicine-DIMED, University of Padova, Padova, Italy.

We report on an observational, multicenter study of 345 adult CVID patients, designed to assess the diagnostic value and the clinical association of serum free light chain (sFLC) pattern in Common Variable Immunodeficiency disorders (CVID). Sixty CVID patients were tested twice in order to assess intraindividual variability of sFLC. As control groups we included 138 patients affected by undefined primary antibody defects (UAD), lymphoproliferative diseases (LPDs), and secondary antibody deficiencies not related to hematological malignancies (SID). CVID patients presented lower κ and λ chain concentration compared to controls, showing low intraindividual sFLC variability. On the basis of the sFLC pattern, patients were classified into four groups: κ-λ+, κ+λ-, κ-λ-, κ+λ+. The most common pattern in CVID patients was κ-λ- (51%), followed by κ-λ+, (25%), κ+λ+ (22%), and κ+λ- (3%). In UAD, LPD, and SID groups κ+λ+ was the most common pattern observed. By analyzing the possible association between sFLC patterns and disease-related complications of CVID, we observed that patients belonging to the κ-λ- group presented more commonly unexplained enteropathy compared to the κ+λ+ group and showed higher frequency of bronchiectasis and splenomegaly compared to both the κ-λ+ and κ+λ+ patients. When compared to the other groups, κ-λ- had also lower serum IgG, IgA, and IgM concentrations at diagnosis, lower frequency of CD27+IgD-IgM- switched memory B cells, and higher frequency of CD21 B cells, receiving earlier CVID diagnosis. Thus, lower levels of sFLC might be an epiphenomenon of impairment in B cell differentiation, possibly leading κ-λ- patients to a higher risk for bacterial infections and chronic lung damage. Based on these results, we suggest adding sFLC assay to the diagnostic work-up of hypogammaglobulinemia and during follow-up. The assay may be useful to differentiate CVID from other causes of hypogammaglobulinemia and to early detect monoclonal lymphoproliferation occurring over years. Moreover, since the sFLC pattern seems to be related to disease phenotypes and clinical manifestations of CVID and after confirmation by further studies, sFLC assay might be considered a promising prognostic tool for identifying patients at higher risk of developing enteropathy and chronic lung damage or splenomegaly. This will allow designing a tailored follow-up for CVID patients.
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http://dx.doi.org/10.3389/fimmu.2020.00319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136404PMC
March 2020

Biologicals in atopic disease in pregnancy: An EAACI position paper.

Allergy 2021 01;76(1):71-89

Division of Immunology and Allergy, Food Allergy and Anaphylaxis Program, The Hospital for Sick Children, Toronto, ON, Canada.

Biologicals have transformed the management of severe disease phenotypes in asthma, atopic dermatitis, and chronic spontaneous urticaria. As a result, the number of approved biologicals for the treatment of atopic diseases is continuously increasing. Although atopic diseases are among the most common diseases in the reproductive age, investigations, and information on half-life, pharmacokinetics defining the neonatal Fc receptors (FcRn) and most important safety of biologicals in pregnancy are lacking. Given the complex sequence of immunological events that regulate conception, fetal development, and the intrauterine and postnatal maturation of the immune system, this information is of utmost importance. We conducted a systematic review on biologicals in pregnancy for indications of atopic diseases. Evidence in this field is scarce and mainly reserved to reports on the usage of omalizumab. This lack of evidence demands the establishment of a multidisciplinary approach for the management of pregnant women who receive biologicals and multicenter registries for long-term follow-up, drug trial designs suitable for women in the reproductive age, and better experimental models that represent the human situation. Due to the very long half-life of biologicals, preconception counseling and healthcare provider education are crucial to offer the best care for mother and fetus. This position paper integrates available data on safety of biologicals during pregnancy in atopic diseases via a systematic review with a detailed review on immunological considerations how inhibition of different pathways may impact pregnancy.
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http://dx.doi.org/10.1111/all.14282DOI Listing
January 2021

Correlations Among Subcutaneous Immunoglobulin Dosage, Immunoglobulin G Serum Pre-infusional Levels and Body Mass Index in Primary Antibody Deficiency Patients: A Pooled Analysis from the SHIFT/IBIS Studies.

Clin Drug Investig 2020 Mar;40(3):279-286

Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Via S. Pansini 5, 80131, Naples, Italy.

BACKGROUND AND OBJECTIVE: In recent years, two Italian non-interventional studies evaluated subcutaneous immunoglobulin (SCIG) treatment in patients affected by primary antibody deficiency (PAD). The SHIFT study considered patients who were treated with intravenous immunoglobulin (IVIG) or SCIG 16% (Vivaglobin) and then replaced this therapy with weekly treatments of SCIG 20% (Hizentra). The IBIS study evaluated patients previously taking a weekly SCIG 20% regimen, who instead began therapy with biweekly SCIG 20% to assess the correlation between the dose of immunoglobulin G (IgG) administered and the body mass index (BMI) of patients, determine if there is a need for dosage adjustments on a BMI basis, and identify the predictors of serum IgG trough levels in our cohort.

Methods: In this study, we analyzed the pooled data of 109 PAD patients enrolled in the SHIFT and IBIS studies. Only prospective phases were considered.

Results: The total monthly SCIG dose showed comparable trends among weight categories, except for underweight patients. When we considered the monthly SCIG dosage per kilogram of body weight, a significant decreasing trend according to BMI was observed. Data on IgG trough levels were available for 88 patients, with a mean IgG serum level of 8.4 ± 1.6 g/L. A stepwise regression model revealed that the mean monthly dosage of SCIG 20% (p = 0.04248) and the mean monthly dosage of IgG per kilogram of body weight were the only two independent predictors associated with IgG trough levels. No association was found between BMI and IgG trough levels.

Conclusions: These findings support the concept that the cumulative monthly dose of SCIG and the dose of SCIG per kilogram of body weight affect IgG trough levels in PAD patients, irrespective of BMI.
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http://dx.doi.org/10.1007/s40261-020-00885-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035227PMC
March 2020

Systemic hypereosinophilic syndromes: when autoimmunity is Th2 mediated.

Curr Opin Allergy Clin Immunol 2020 04;20(2):175-180

Immunoallergology Unit, AOU Careggi, University of Florence, Florence.

Purpose Of Review: Clinical conditions associated with hypereosinophilia represent a field of particular interest, taking into account the epidemiological impact of the different primary and secondary forms. In addition to a classical Th1 response, also Th2 cells can be involved in the pathogenesis of autoimmune diseases, among them eosinophilic forms such as eosinophilic granulomatosis with polyangiitis.

Recent Findings: In patients with severe asthma, recent evidence highlights the role of pathogenic autoantibodies against autologous eosinophil proteins (e.g. eosinophil peroxidase) suggest the role of autoimmune mechanisms, particularly in patients in which asthma is included in eosinophilic vasculitis with antineutrophilic autoantibody positivity. Is now evident that in addition to Th2 cells, also type 2 innate lymphoid cells and Th1/Th17 cells play a central role in the pathogenesis of hypereosinophilic syndrome.

Summary: The definition of cellular and molecular mechanisms and the critical role of specific cytokines involved in the pathogenesis of hypereosinophilic syndrome open the way to new therapeutic strategies by using biological agents targeting these specific factors.
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http://dx.doi.org/10.1097/ACI.0000000000000614DOI Listing
April 2020

Desensitization modulates humoral and cellular immune response to infliximab in a patient with an immediate hypersensitivity reaction.

J Allergy Clin Immunol Pract 2020 05 13;8(5):1764-1767.e1. Epub 2020 Jan 13.

Immunoallergology Unit, Department of Medicine and Geriatrics, Careggi University Hospital, Florence, Italy.

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http://dx.doi.org/10.1016/j.jaip.2019.12.040DOI Listing
May 2020

Eosinophils, the IL-5/IL-5Rα axis, and the biologic effects of benralizumab in severe asthma.

Respir Med 2019 Nov - Dec;160:105819. Epub 2019 Nov 11.

Immunoallergology Unit, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy.

Bronchial asthma is a chronic inflammatory disease characterized, in a percentage of patients, as an eosinophilic inflammation of the airways. Eosinophils are recognized as a proinflammatory granulocyte playing a major role in the T2-high phenotype, which includes severe eosinophilic asthma. Eosinophilic asthma represents the majority of the phenotypic variants clinically characterized by severity and frequent exacerbations. For patients with severe uncontrolled asthma, monoclonal antibodies are used as add-on treatments. Among them, in addition to anti-immunoglobulin E therapy, biologic agents directed toward the interleukin (IL)-5/IL-5Rα axis and, thus, interfering with the pathologic functions of eosinophils, are now available. Unlike the other anti‒IL-5 monoclonal antibodies which exert an indirect effect on eosinophils, benralizumab, an afucosylated IgG kappa antibody directed against the α subunit of IL-5R, directly depletes eosinophils and their associated bone marrow progenitor cells through induction of antibody-dependent cell-mediated cytotoxicity, through recruitment of natural killer cells. This article reviews the role of eosinophils in the pathogenesis of bronchial asthma and discusses the potential advantageous biologic effects of benralizumab in comparison with other monoclonal antibodies targeting the IL-5 ligand.
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http://dx.doi.org/10.1016/j.rmed.2019.105819DOI Listing
August 2020

Hypersensitivity reactions to biologics used in rheumatology.

Expert Rev Clin Immunol 2019 12 30;15(12):1263-1271. Epub 2019 Oct 30.

Immunoallergology Unit, Department of Medicine and Geriatrics, Careggi University Hospital, Florence, Italy.

: Biological agents (BAs) target disease mechanisms and have modified the natural history of several immune-mediated disorders. All BAs are immunogenic, resulting in the formation of antidrug antibodies (ADAs), which can neutralize drug activity leading to loss of response and potential relapse. In addition, ADAs can also cause serious adverse events such as infusion hypersensitivity reactions (HRs).: This review discusses the recent knowledge on the effector and regulatory mechanisms involved in the immune response to BAs used in patients suffering from rheumatic diseases leading to the production of ADAs and the impact on clinical outcome. Specifically, the demonstration of the involvement of specific T cell responses underlines B cells activation, and ADAs production is discussed correlating them to the different possible clinical consequences.: Although the mechanisms of the immune response and specifically the ADAs production to BAs have been extensively clarified in the last years, as well as their capacity to impact on clinical outcomes, among clinicians today a low awareness and in some cases a rejection persists, not only of the analysis and understanding of the immunological mechanisms behind the immunogenicity of BAs, but also the possible clinical impact that this may have.
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http://dx.doi.org/10.1080/1744666X.2020.1684264DOI Listing
December 2019

Systematic Review of Safety and Efficacy of Rituximab in Treating Immune-Mediated Disorders.

Front Immunol 2019 6;10:1990. Epub 2019 Sep 6.

Department of Immunology, University Hospital Zurich, Zurich, Switzerland.

During the past years biologic agents (also termed biologicals or biologics) have become a crucial treatment option in immunological diseases. Numerous articles have been published on biologicals, which complicates the decision making process on the use of the most appropriate biologic for a given immune-mediated disease. This systematic review is the first of a series of articles assessing the safety and efficacy of B cell-targeting biologics for the treatment of immune-mediated diseases. To evaluate rituximab's safety and efficacy for the treatment of immune-mediated disorders compared to placebo, conventional treatment, or other biologics. The PRISMA checklist guided the reporting of the data. We searched the PubMed database between 4 October 2016 and 26 July 2018 concentrating on immune-mediated disorders. The literature search identified 19,665 articles. After screening titles and abstracts against the inclusion and exclusion criteria and assessing full texts, 105 articles were finally included in a narrative synthesis. Rituximab is both safe and effective for the treatment of acquired angioedema with C1-inhibitor deficiency, ANCA-associated vasculitis, autoimmune hemolytic anemia, Behçet's disease, bullous pemphigoid, Castleman's disease, cryoglobulinemia, Goodpasture's disease, IgG4-related disease, immune thrombocytopenia, juvenile idiopathic arthritis, relapsing-remitting multiple sclerosis, myasthenia gravis, nephrotic syndrome, neuromyelitis optica, pemphigus, rheumatoid arthritis, spondyloarthropathy, and systemic sclerosis. Conversely, rituximab failed to show an effect for antiphospholipid syndrome, autoimmune hepatitis, IgA nephropathy, inflammatory myositis, primary-progressive multiple sclerosis, systemic lupus erythematosus, and ulcerative colitis. Finally, mixed results were reported for membranous nephropathy, primary Sjögren's syndrome and Graves' disease, therefore warranting better quality trials with larger patient numbers.
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http://dx.doi.org/10.3389/fimmu.2019.01990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743223PMC
October 2020

Subcutaneous Immunoglobulin Twenty Percent Every Two Weeks in Pediatric Patients with Primary Immunodeficiencies: Subcohort Analysis of the IBIS Study.

Pediatr Allergy Immunol Pulmonol 2019 Jun 17;32(2):70-75. Epub 2019 Jun 17.

Department of Pediatric Immunology, Jeffrey Modell Center for Primary Immunodeficiency, Anna Meyer's Hospital, University of Florence, Florence, Italy.

Subcutaneous immunoglobulin G (SCIG) may be a better option than intravenous immunoglobulin G (IVIG) for patients with primary immunodeficiencies (PID) due to reduced systemic and serious adverse reactions and easier administration. The Infusione Bimensile di Immunoglobuline Sottocute (IBIS) study investigated the effects of Hizentra, a 20%-concentrated SCIG, administered biweekly in patients with PID. This subanalysis aimed to evaluate clinical and laboratory outcomes in the IBIS pediatric subcohort. Thirteen children with PID were observed for 12 months retrospectively (with previous IVIG/SCIG) and prospectively with biweekly Hizentra. Mean ± standard deviation serum IG levels during the retrospective (833.8 ± 175.7 mg/dL) and the prospective (842.0 ± 188.0 mg/dL) phases were comparable; there were also no differences in the number of infections. Biweekly Hizentra is a noninferior option with respect to previous IVIG/SCIG-based treatment.
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http://dx.doi.org/10.1089/ped.2018.0967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733055PMC
June 2019

Rapid clinical improvement of atopic dermatitis in an Omalizumab treated patient.

Clin Mol Allergy 2019 12;17. Epub 2019 Mar 12.

2Immunoallergology Unit, Department of Biomedicine, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy.

Background: Atopic dermatitis is a chronic inflammatory skin disorder, whose symptoms and severity grossly depend on individual trigger factors. The majority of patients are satisfactorily treated with emollients together with topical and systemic therapies. However, treatment failure or long-term side effects with conventional treatment options can be a significant clinical problem. Recently, novel therapeutic approaches focus on targeting skewed immune responses providing a more effective, and less harmful approach. Among them, variable success has been reported using Omalizumab, when used in combination with classic therapies. This report describes an interesting case of severe adult onset difficult-to-treat atopic dermatitis dramatically improved in response to treatment with Omalizumab.

Case Presentation: We present a case of an adult male with severe allergic atopic dermatitis, with concomitant involvement of the face, neckline, trunk and forearms and systemic symptoms such as diarrhoea with important decrease of his daily quality of life. The patient had been prescribed oral steroids in addition to anti-histamines to no avail. Due to lack of response to classic therapies, strict diet, as well as to treatment with intravenous corticosteroids, an off-label treatment with Omalizumab based on patient weight and total IgE value was proposed. Clear clinical results were observed after only a few weeks with regards to systemic symptoms, and just after 2 months of treatment in regards to skin involvement.

Conclusions: In the majority of treated patients the clinical improvement of cutaneous manifestations is expected after several months of treatment, as skin manifestations are the consequence of a chronic inflammatory process. The outstanding rapid response observed in this case as well as the persistence of the clinical remission suggests that the block of the IgE pathways modulate functions of cells involved in the pathogenic mechanisms of chronic skin inflammation but also in the acute phases observed in the flare-ups of the disease.
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http://dx.doi.org/10.1186/s12948-019-0109-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413441PMC
March 2019

Double-blind, placebo-controlled, randomized trial on low-dose azithromycin prophylaxis in patients with primary antibody deficiencies.

J Allergy Clin Immunol 2019 08 22;144(2):584-593.e7. Epub 2019 Mar 22.

Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy. Electronic address:

Background: Lacking protective antibodies, patients with primary antibody deficiencies (PADs) experience frequent respiratory tract infections, leading to chronic pulmonary damage. Macrolide prophylaxis has proved effective in patients with chronic respiratory diseases.

Objective: We aimed to test the efficacy and safety of orally administered low-dose azithromycin prophylaxis in patients with PADs.

Methods: We designed a 3-year, double-blind, placebo-controlled, randomized clinical trial to test whether oral azithromycin (250 mg administered once daily 3 times a week for 2 years) would reduce respiratory exacerbations in patients with PADs and chronic infection-related pulmonary diseases. The primary end point was the number of annual respiratory exacerbations. Secondary end points included time to first exacerbation, additional antibiotic courses, number of hospitalizations, and safety.

Results: Eighty-nine patients received azithromycin (n = 44) or placebo (n = 45). The number of exacerbations was 3.6 (95% CI, 2.5-4.7) per patient-year in the azithromycin arm and 5.2 (95% CI, 4.1-6.4) per patient-year in the placebo arm (P = .02). In the azithromycin group the hazard risk for having an acute exacerbation was 0.5 (95% CI, 0.3-0.9; P = .03), and the hazard risk for hospitalization was 0.5 (95% CI, 0.2-1.1; P = .04). The rate of additional antibiotic treatment per patient-year was 2.3 (95% CI, 2.1-3.4) in the intervention group and 3.6 (95% CI, 2.9-4.3) in the placebo group (P = .004). Haemophilus influenzae and Streptococcus pneumoniae were the prevalent isolates, and they were not susceptible to macrolides in 25% of patients of both arms. Azithromycin's safety profile was comparable with that of placebo.

Conclusion: The study reached the main outcome centered on the reduction of exacerbation episodes per patient-year, with a consequent reduction in additional courses of antibiotics and risk of hospitalization.
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http://dx.doi.org/10.1016/j.jaci.2019.01.051DOI Listing
August 2019

T Cell Response to Infliximab in Exposed Patients: A Longitudinal Analysis.

Front Immunol 2018 11;9:3113. Epub 2019 Jan 11.

Immunoallergology Unit, Careggi University-Hospital, Florence, Italy.

This study aimed to evaluate the proportion of infliximab (IFX)-exposed patients exhibiting cellular response to the drug in a longitudinal way and to establish whether it is predictive for anti-drug antibodies (ADA) development. Seventeen patients suffering from immuno-mediated disorders were enrolled. Blood was sampled at baseline and before each of the first eight infusions of IFX. The proliferation of PBMCs to 15-mer peptides covering VH/VL frames of IFX was assessed as well as transcription factors and cytokines mRNA expression of memory T cells in IFX-stimulated PBMCs. The number of peptides recognized by T cells after four infusions was higher than those recognized by the same patients before treatment. IFX-stimulated PBMCs from more than 90% of patients were able to express the main regulators and adaptive cytokines of memory T cells. While IFN-γ mRNAs increased after the first infusion and declined during the subsequent ones, IL-10 mRNA was upregulated throughout the treatment. IL-10 was functionally active because its neutralization improved IFN-γ and IL-13 mRNA expression . The IL-10/IFN-γ ratio was shown to be lower in patients who developed ADAs solely at the early infusions. IL-10 production consistently preceded or paralleled the IFN-γ onset in ADA- patients, while it was not produced or followed IFN-γ onset in ADA+ patients. In conclusion, this study provides evidence that the majority of exposed patients undergo a cellular response to IFX with the upregulation of IL-10. The development of ADA is associated with the early impairment of IL-10 and low levels of the IL-10/IFN-γ ratio.
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http://dx.doi.org/10.3389/fimmu.2018.03113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336713PMC
October 2019

The percentage of patients achieving complete remission of urticaria increases with repeated courses of treatment.

J Allergy Clin Immunol Pract 2019 Jan 2;7(1):339-340. Epub 2018 Jul 2.

Immunoallergology Unit, Careggi University Hospital, Florence, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2018.06.011DOI Listing
January 2019

Omalizumab dampens type 2 inflammation in a group of long-term treated asthma patients and detaches IgE from FcεRI.

Eur J Immunol 2018 12 9;48(12):2005-2014. Epub 2018 Oct 9.

Department of Experimental and Clinical Medicine and DENOTHE Center, University of Florence, Florence, Italy.

Even if omalizumab is broadly used in the treatment of severe, allergic asthma, the immunological effects in long-term treated patients have not been fully elucidated. To this aim, a cohort of 15 allergic asthmatic patients treated with omalizumab for at least three years was compared with 12 allergic asthma patients treated with standard therapy. Omalizumab treated asthmatic patients showed lower frequencies of circulating plasmacytoid DCs, and lower CD154 expression on CD4 T-helper cells than the control group. Moreover, basophils and DCs from omalizumab-treated patients had lower surface expression of IgE compared to the control group. In a longitudinal evaluation of two patients that started omalizumab treatment, we show that FcεRI free of IgE were evident on basophils just after four weeks of drug administration. Finally, in vitro experiments with basophils obtained from healthy donors confirm that omalizumab is able to detach IgE from high affinity IgE receptors. Collectively these data indicate that long-term omalizumab treatment dampens type 2 inflammation acting on different cell types that play a pivotal role in the pathogenesis of allergic asthma. Moreover, we have identified a further mechanism of action of omalizumab, such as the ability to detach IgE from its receptor.
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http://dx.doi.org/10.1002/eji.201847668DOI Listing
December 2018

Direct and Indirect Costs of Immunoglobulin Replacement Therapy in Patients with Common Variable Immunodeficiency (CVID) and X-Linked Agammaglobulinemia (XLA) in Italy.

Clin Drug Investig 2018 Oct;38(10):955-965

Economic Evaluation and HTA (EEHTA), CEIS, Faculty of Economics, University of Rome "Tor Vergata", Rome, Italy.

Background: In Italy, there is scarce evidence on the epidemiological and economic burden induced by primary antibody deficiencies.

Objective: The aim of this study was to elaborate the available epidemiological and cost data in order to estimate the annual expenditure induced by the management of patients affected by the common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA) requiring immunoglobulin (Ig) replacement therapy.

Methods: A probabilistic cost-of-illness model was developed to estimate the number of patients with CVID and XLA, and the economic burden associated with their therapy in terms of direct or indirect costs. A systematic literature review was carried out to reveal both epidemiological and economic data. Furthermore, a probabilistic sensitivity analysis with 5000 Monte Carlo simulations was performed.

Results: The epidemiological model allowed us to estimate the number of prevalent patients affected by XLA and CVID in Italy in 2017, corresponding to 1885 (95% confidence interval [CI] 944-3145) and 133 (95% CI 115-152) patients, respectively. The estimated total expenditure for the treatment and management of patients with CVID and XLA requiring Ig replacement therapy amounts to €42.68 million (95% CI €14.38-€86.1 million).

Conclusions: This information provides a comprehensive perspective of the economic issues, and facilitates better-informed public health decision making, in the management of CVID and XLA in Italy.
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http://dx.doi.org/10.1007/s40261-018-0688-3DOI Listing
October 2018