Publications by authors named "Isabella Quinti"

104 Publications

Editorial: Trained Immunity-Based Vaccines.

Front Immunol 2021 24;12:716296. Epub 2021 Jun 24.

Department of Clinical Immunology, San Carlos University Clinical Hospital, Madrid, Spain.

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http://dx.doi.org/10.3389/fimmu.2021.716296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264451PMC
June 2021

Medical algorithm: Diagnosis and management of antibody immunodeficiencies.

Allergy 2021 May 26. Epub 2021 May 26.

Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, UK.

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http://dx.doi.org/10.1111/all.14961DOI Listing
May 2021

Editorial: The Complexity of Primary Antibody Deficiencies.

Front Immunol 2021 21;12:635482. Epub 2021 Apr 21.

Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.

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http://dx.doi.org/10.3389/fimmu.2021.635482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097173PMC
April 2021

IgA Antibodies and IgA Deficiency in SARS-CoV-2 Infection.

Front Cell Infect Microbiol 2021 6;11:655896. Epub 2021 Apr 6.

Department of Laboratory Medicine, Research Area Multimodal Medicine, Diagnostic Immunology and Research Unit, Bambino Gesù Children's Hospital IRCCS, Rome, Italy.

A large repertoire of IgA is produced by B lymphocytes with T-independent and T-dependent mechanisms useful in defense against pathogenic microorganisms and to reduce immune activation. IgA is active against several pathogens, including rotavirus, poliovirus, influenza virus, and SARS-CoV-2. It protects the epithelial barriers from pathogens and modulates excessive immune responses in inflammatory diseases. An early SARS-CoV-2 specific humoral response is dominated by IgA antibodies responses greatly contributing to virus neutralization. The lack of anti-SARS-Cov-2 IgA and secretory IgA (sIgA) might represent a possible cause of COVID-19 severity, vaccine failure, and possible cause of prolonged viral shedding in patients with Primary Antibody Deficiencies, including patients with Selective IgA Deficiency. Differently from other primary antibody deficiency entities, Selective IgA Deficiency occurs in the vast majority of patients as an asymptomatic condition, and it is often an unrecognized, Studies are needed to clarify the open questions raised by possible consequences of a lack of an IgA response to SARS-CoV-2.
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http://dx.doi.org/10.3389/fcimb.2021.655896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057809PMC
May 2021

Granulomatous Lymphocytic Interstitial Lung Disease (GLILD) in Common Variable Immunodeficiency (CVID): A Multicenter Retrospective Study of Patients From Italian PID Referral Centers.

Front Immunol 2021 10;12:627423. Epub 2021 Mar 10.

Department of Molecular Medicine, "Sapienza" University of Rome, Rome, Italy.

Granulomatous and Lymphocytic Interstitial Lung Diseases (GLILD) is a severe non-infectious complication of Common Variable Immunodeficiency (CVID), often associated with extrapulmonary involvement. Due to a poorly understood pathogenesis, GLILD diagnosis and management criteria still lack consensus. Accordingly, it is a relevant cause of long-term loss of respiratory function and is closely associated with a markedly reduced survival. The aim of this study was to describe clinical, immunological, laboratory and functional features of GLILD, whose combination in a predictive model might allow a timely diagnosis. In a multicenter retrospective cross-sectional study we enrolled 73 CVID patients with radiologic features of interstitial lung disease (ILD) associated to CVID (CVID-ILD) and 125 CVID patients without ILD (controls). Of the 73 CVID-ILD patients, 47 received a definite GLILD diagnosis while 26 received a clinical-radiologic diagnosis of CVID related ILD defined as uILD. In GLILD group we found a higher prevalence of splenomegaly (84.8 vs. 39.2%), autoimmune cytopenia (59.6 vs. 6.4%) and bronchiectasis (72.3 vs. 28%), and lower IgA and IgG serum levels at CVID diagnosis. GLILD patients presented lower percentage of switched-memory B cells and marginal zone B cells, and a marked increase in the percentage of circulating CD21lo B cells (14.2 vs. 2.9%). GLILD patients also showed lower total lung capacity (TLC 87.5 vs. 5.0%) and gas transfer (DLCO 61.5 vs. 5.0%) percent of predicted. By univariate logistic regression analysis, we found IgG and IgA levels at CVID diagnosis, presence of splenomegaly and autoimmune cytopenia, CD21lo B cells percentage, TLC and DCLO percent of predicted to be associated to GLILD. The joint analysis of four variables (CD21lo B cells percentage, autoimmune cytopenia, splenomegaly and DLCO percent of predicted), together in a multiple logistic regression model, yielded an area under the ROC curve (AUC) of 0.98 (95% CI: 0.95-1.0). The AUC was only slightly modified when pooling together GLILD and uILD patients (0.92, 95% CI: 0.87-0.97). we propose the combination of two clinical parameters (splenomegaly and autoimmune cytopenia), one lung function index (DLCO%) and one immunologic variable (CD21lo%) as a promising tool for early identification of CVID patients with interstitial lung disease, limiting the use of aggressive diagnostic procedures.
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http://dx.doi.org/10.3389/fimmu.2021.627423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987811PMC
March 2021

International multicenter experience of transjugular intrahepatic portosystemic shunt implantation in patients with common variable immunodeficiency.

J Allergy Clin Immunol Pract 2021 07 13;9(7):2931-2935.e1. Epub 2021 Mar 13.

Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Department of Rheumatology and Clinical Immunology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2021.02.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277733PMC
July 2021

COVID-19 - pathogenesis and immunological findings across the clinical manifestation spectrum.

Curr Opin Pulm Med 2021 05;27(3):193-198

Department of Hematology/Oncology, Bambino Gesù Children Hospital, IRCCS.

Purpose Of Review: The wide spectrum of COVID-19 clinical manifestations demonstrates the determinant role played by the individual immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the course of the disease. Thanks to the large number of published data, we are beginning to understand the logic of the human response to a virus adapted to bat immunity.

Recent Findings: Impairment of types I and III interferon responses may facilitate the occurrence of severe COVID-19 with reduced antiviral activity associated to potent inflammation. The human T and B-cell germline repertoire contain the specificities able to react against SARS-CoV-2 antigens. Although inflammation disrupts the structure of germinal centers, memory T and B cells can be found in the blood of patients after mild and severe COVID 19.

Summary: Further studies are indispensable to better understand the human immune response to SARS-CoV-2. The diversity of the individual reaction may contribute to explain the clinical manifestation spectrum. Immunological memory can be demonstrated in patients, convalescent from mild, moderate, or severe COVID-19, but we do not know whether asymptomatic individuals have memory of the virus. Tailored vaccination protocols may be needed for individuals with previous SAS-CoV-2 infection.
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http://dx.doi.org/10.1097/MCP.0000000000000775DOI Listing
May 2021

Clinical management of patients with primary immunodeficiencies during the COVID-19 pandemic.

Expert Rev Clin Immunol 2021 02 15;17(2):163-168. Epub 2021 Jan 15.

Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.

: Patients affected by Inborn Errors of Immunity (IEI) represent a potential group-at-risk in the current COVID-19 pandemic. Studies on large and small cohorts of IEI reported a huge variability clinical manifestations associated to SARS-Cov-2, ranging from asymptomatic, mild, moderate/severe to death. A great impulse to improve remote assistance programs and to switch to home-based treatment to reduce mobility and face to face contacts has been implemented.: The authors completed a comprehensive review of the literature by searching the PubMed database for studies on large and small cohorts and case reports of IEI patients with COVID-19, with the aim to provide useful information for their clinical management during the COVID-19 pandemic.: Surprisingly, a low number of IEI patients affected by SARS-Cov-2 were reported with a risk to die for COVID-19 overlapping that of the general population. The low number might be explained by the choice of most physicians to inform early in the pandemic about safety measures, to switch most of the IEI patients to home therapy and to remote assistance. The guidelines issued by the scientific societies and periodically updated, represent the best tool for the clinical management of IEI patients.
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http://dx.doi.org/10.1080/1744666X.2021.1873767DOI Listing
February 2021

Different Innate and Adaptive Immune Responses to SARS-CoV-2 Infection of Asymptomatic, Mild, and Severe Cases.

Front Immunol 2020 16;11:610300. Epub 2020 Dec 16.

Department of Hematology/Oncology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

SARS-CoV-2 is a novel coronavirus, not encountered before by humans. The wide spectrum of clinical expression of SARS-CoV-2 illness suggests that individual immune responses to SARS-CoV-2 play a crucial role in determining the clinical course after first infection. Immunological studies have focused on patients with moderate to severe disease, demonstrating excessive inflammation in tissues and organ damage. In order to understand the basis of the protective immune response in COVID-19, we performed a longitudinal follow-up, flow-cytometric and serological analysis of innate and adaptive immunity in adults with a spectrum of clinical presentations: healthy SARS-CoV-2-negative contacts of COVID-19 cases; asymptomatic SARS-CoV-2-infected cases; patients with Mild COVID-19 disease and cases of Severe COVID-19 disease. Our data show that high frequency of NK cells and early and transient increase of specific IgA, IgM and, to a lower extent, IgG are associated with asymptomatic SARS-CoV-2 infection. By contrast, monocyte expansion and high and persistent levels of IgA and IgG, produced relatively late in the course of the infection, characterize severe disease. Modest increase of monocytes and different kinetics of antibodies are detected in mild COVID-19. The importance of innate NK cells and the short-lived antibody response of asymptomatic individuals and patients with mild disease suggest that only severe COVID-19 may result in protective memory established by the adaptive immune response.
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http://dx.doi.org/10.3389/fimmu.2020.610300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772470PMC
January 2021

Managing Granulomatous-Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency Disorders: e-GLILDnet International Clinicians Survey.

Front Immunol 2020 26;11:606333. Epub 2020 Nov 26.

UCL Respiratory, University College London, London, United Kingdom.

Background: Granulomatous-lymphocytic interstitial lung disease (GLILD) is a rare, potentially severe pulmonary complication of common variable immunodeficiency disorders (CVID). Informative clinical trials and consensus on management are lacking.

Aims: The European GLILD network (e-GLILDnet) aims to describe how GLILD is currently managed in clinical practice and to determine the main uncertainties and unmet needs regarding diagnosis, treatment and follow-up.

Methods: The e-GLILDnet collaborators developed and conducted an online survey facilitated by the European Society for Immunodeficiencies (ESID) and the European Respiratory Society (ERS) between February-April 2020. Results were analyzed using SPSS.

Results: One hundred and sixty-one responses from adult and pediatric pulmonologists and immunologists from 47 countries were analyzed. Respondents treated a median of 27 (interquartile range, IQR 82-maximum 500) CVID patients, of which a median of 5 (IQR 8-max 200) had GLILD. Most respondents experienced difficulties in establishing the diagnosis of GLILD and only 31 (19%) had access to a standardized protocol. There was little uniformity in diagnostic or therapeutic interventions. Fewer than 40% of respondents saw a definite need for biopsy in all cases or performed bronchoalveolar lavage for diagnostics. Sixty-six percent used glucocorticosteroids for remission-induction and 47% for maintenance therapy; azathioprine, rituximab and mycophenolate mofetil were the most frequently prescribed steroid-sparing agents. Pulmonary function tests were the preferred modality for monitoring patients during follow-up.

Conclusions: These data demonstrate an urgent need for clinical studies to provide more evidence for an international consensus regarding management of GLILD. These studies will need to address optimal procedures for definite diagnosis and a better understanding of the pathogenesis of GLILD in order to provide individualized treatment options. Non-availability of well-established standardized protocols risks endangering patients.
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http://dx.doi.org/10.3389/fimmu.2020.606333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726128PMC
June 2021

Coronavirus disease 2019 in patients with inborn errors of immunity: An international study.

J Allergy Clin Immunol 2021 Feb 24;147(2):520-531. Epub 2020 Sep 24.

Istituto Molecolare "A Nocivelli," Department of Experimental and Clinical Sciences, University of Brescia & Asst Spedali civili, Brescia, Italy.

Background: There is uncertainty about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with rare inborn errors of immunity (IEI), a population at risk of developing severe coronavirus disease 2019. This is relevant not only for these patients but also for the general population, because studies of IEIs can unveil key requirements for host defense.

Objective: We sought to describe the presentation, manifestations, and outcome of SARS-CoV-2 infection in IEI to inform physicians and enhance understanding of host defense against SARS-CoV-2.

Methods: An invitation to participate in a retrospective study was distributed globally to scientific, medical, and patient societies involved in the care and advocacy for patients with IEI.

Results: We gathered information on 94 patients with IEI with SARS-CoV-2 infection. Their median age was 25 to 34 years. Fifty-three patients (56%) suffered from primary antibody deficiency, 9 (9.6%) had immune dysregulation syndrome, 6 (6.4%) a phagocyte defect, 7 (7.4%) an autoinflammatory disorder, 14 (15%) a combined immunodeficiency, 3 (3%) an innate immune defect, and 2 (2%) bone marrow failure. Ten were asymptomatic, 25 were treated as outpatients, 28 required admission without intensive care or ventilation, 13 required noninvasive ventilation or oxygen administration, 18 were admitted to intensive care units, 12 required invasive ventilation, and 3 required extracorporeal membrane oxygenation. Nine patients (7 adults and 2 children) died.

Conclusions: This study demonstrates that (1) more than 30% of patients with IEI had mild coronavirus disease 2019 (COVID-19) and (2) risk factors predisposing to severe disease/mortality in the general population also seemed to affect patients with IEI, including more younger patients. Further studies will identify pathways that are associated with increased risk of severe disease and are nonredundant or redundant for protection against SARS-CoV-2.
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http://dx.doi.org/10.1016/j.jaci.2020.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832563PMC
February 2021

The Italian Registry for Primary Immunodeficiencies (Italian Primary Immunodeficiency Network; IPINet): Twenty Years of Experience (1999-2019).

J Clin Immunol 2020 10 15;40(7):1026-1037. Epub 2020 Aug 15.

Department of Clinical and Molecular Medicine, Sapienza University, Rome, Italy.

Primary immunodeficiencies (PIDs) are heterogeneous disorders, characterized by variable clinical and immunological features. National PID registries offer useful insights on the epidemiology, diagnosis, and natural history of these disorders. In 1999, the Italian network for primary immunodeficiencies (IPINet) was established. We report on data collected from the IPINet registry after 20 years of activity. A total of 3352 pediatric and adult patients affected with PIDs are registered in the database. In Italy, a regional distribution trend of PID diagnosis was observed. Based on the updated IUIS classification of 2019, PID distribution in Italy showed that predominantly antibody deficiencies account for the majority of cases (63%), followed by combined immunodeficiencies with associated or syndromic features (22.5%). The overall age at diagnosis was younger for male patients. The minimal prevalence of PIDs in Italy resulted in 5.1 per 100.000 habitants. Mortality was similar to other European registries (4.2%). Immunoglobulin replacement treatment was prescribed to less than one third of the patient cohort. Collectively, this is the first comprehensive description of the PID epidemiology in Italy.
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http://dx.doi.org/10.1007/s10875-020-00844-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505879PMC
October 2020

IgM, IgA and IgG response to conjugate polysaccharides in children with recurrent respiratory infections.

Scand J Immunol 2021 Jan 27;93(1):e12955. Epub 2020 Aug 27.

Pediatric Immunopathology and Allergology Unit, Policlinico Tor Vergata, University of Rome Tor Vergata, Rome, Italy.

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http://dx.doi.org/10.1111/sji.12955DOI Listing
January 2021

IGA Antibody Induced by Immunization With Pneumococcal Polysaccharides Is a Prognostic Tool in Common Variable Immune Deficiencies.

Front Immunol 2020 24;11:1283. Epub 2020 Jun 24.

Department of Molecular Medicine, "Sapienza" University of Rome, Rome, Italy.

The evaluation of the response to vaccination in patients with inborn errors of immunity is a tool to evaluate T-dependent and T-independent antibody residual function of B lymphocytes and it is part of the diagnostic definition for Common Variable Immune Deficiencies. Currently used classifications for Common Variable Immune Deficiencies patients are based on the frequency of B cell subsets, and have been proven as a valid instrument for identification of patients at higher risk of infectious and non-infectious complications. This 6-years period observational study delineated the measurement of specific IgA antibodies induced by a 23-valent pneumococcal polysaccharides vaccine by a standardized ELISA for the quantification of IgA antibodies to all 23 pneumococcal serotypes as an additional prognostic marker in 74 CVID patients. The inability to mount an IgA-mediated response against the pneumococcal polysaccharide antigens or the inability to maintain the antibody response over time identified poor IgA CVID responders with severe immunological impairment, great risk of co-morbidities, and poor prognosis. The division of CVID patient into specific IgA-non responders and IgA-responders discriminated better than other CVID classifications for infectious risk, while it overlapped for non-infectious complications. Our study suggested to add the evaluation of the antibody response by the 23-valent IgA assay in the clinical monitoring of CVID patients.
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http://dx.doi.org/10.3389/fimmu.2020.01283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336165PMC
April 2021

The immune system of children: the key to understanding SARS-CoV-2 susceptibility?

Lancet Child Adolesc Health 2020 06 6;4(6):414-416. Epub 2020 May 6.

Department of Haematology and Oncology, Bambino Gesù Children's Hospital, IRCCS, Rome; Department of Paediatrics, Sapienza University of Rome, Rome, Italy.

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http://dx.doi.org/10.1016/S2352-4642(20)30135-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202830PMC
June 2020

A possible role for B cells in COVID-19? Lesson from patients with agammaglobulinemia.

J Allergy Clin Immunol 2020 07 22;146(1):211-213.e4. Epub 2020 Apr 22.

Pediatrics Clinic and Institute for Molecular Medicine A. Nocivelli, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy; ASST-Spedali Civili di Brescia, Brescia, Italy.

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http://dx.doi.org/10.1016/j.jaci.2020.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175894PMC
July 2020

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 2021

Health-Related Quality of Life in Common Variable Immunodeficiency Italian Patients Switched to Remote Assistance During the COVID-19 Pandemic.

J Allergy Clin Immunol Pract 2020 06 9;8(6):1894-1899.e2. Epub 2020 Apr 9.

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

Background: A rapidly expanding pandemic of the new coronavirus has become the focus of global scientific attention. Data are lacking on the impact of the pandemic caused by the severe acute respiratory syndrome coronavirus 2 on health-related quality of life among patients affected by primary antibody deficiencies (PADs).

Objective: To identify factors impacting the health-related-quality of life (HRQOL) among Italian patients affected by PADs switched to remote assistance at the time of the coronavirus disease 2019 pandemic.

Methods: The quality of life was surveyed in 158 patients with PADs by the Common Variable Immune Deficiency Quality of Life questionnaire, a disease-specific tool, and by the 12-item General Health Questionnaire, a generic tool to assess the risk of anxiety/depression. Since the beginning of the coronavirus disease 2019 epidemic, we shifted all patients with PADs to home therapy, and activated remote visits. Questionnaires were sent by email 4 weeks later. Common Variable Immune Deficiency Quality of Life questionnaire and 12-item General Health Questionnaire data scores were compared with the same set of data from a survey done in 2017.

Results: Of 210 patients, 158 (75%) agreed to participate. The quality of life was worse in the group of patients who were at risk of anxiety/depression at the study time. HRQOL was similar in patients forced to shift from hospital-based to home-based immunoglobulin treatment and in patients who continued their usual home-based replacement. The risk of anxiety/depression is associated with pandemia caused by the severe acute respiratory syndrome coronavirus 2 and with patients' fragility, and not with related clinical conditions associated with common variable immune deficiencies. Anxiety about running out of medications is a major new issue.

Conclusions: The coronavirus disease 2019 epidemic impacted HRQOL and the risk of anxiety/depression of patients with PADs. The remote assistance program was a useful possibility to limit personal contacts without influencing the HRQOL.
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http://dx.doi.org/10.1016/j.jaip.2020.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195351PMC
June 2020

The Usefulness of Scintigraphic Studies in the Assessment of Asymptomatic Bowel Disease in Patients with Primary Antibody Diseases.

J Clin Med 2020 Mar 30;9(4). Epub 2020 Mar 30.

Department of Radiological, Oncological and Pathological Anatomy Sciences, Sapienza University of Rome, 00185 Rome, Italy.

Enteropathy may be the first presentation of immunodeficiency or it may occur during the course of the disease and in association with malabsorption in patients affected by primary antibody diseases. For these patients, immunoglobulin G (IgG) replacement therapy prevents infectious and non-infectious complications. Nonetheless some patients cannot achieve optimal IgG trough levels, even when treated with high Ig doses in absence of protein-losing syndromes. We investigated seven patients affected by common variable immunodeficiencies (CVIDs) and treated with high Ig doses (600-800 mg/kg/month) showing low IgG trough level. Patients underwent abdominal scintigraphy with human polyclonal immunoglobulin G labeled with 99mTc and with white blood cells labeled by 111 Indium-oxinate to investigate asymptomatic bowel inflammation. A concentration of labeled leukocytes in abdominal segments greater than that observed with human polyclonal immunoglobulin G was evident only in one patient. In five patients a slight concentration of both radiopharmaceuticals was reported, due to mild intestinal inflammatory response. These data might be related to mild increase of capillary permeability in the absence of inflammation leukocyte mediated. This study discloses a new cause of IgG-accelerated catabolism due to inflammatory bowel conditions without diarrhea in CVID patients.
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http://dx.doi.org/10.3390/jcm9040949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230964PMC
March 2020

Long-term follow-up of 168 patients with X-linked agammaglobulinemia reveals increased morbidity and mortality.

J Allergy Clin Immunol 2020 08 10;146(2):429-437. Epub 2020 Mar 10.

University Department of Pediatrics, Unit of Immune and Infectious Diseases, Bambino Gesù Children's Hospital, University of Rome Tor Vergata, and the Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.

Background: X-linked agammaglobulinemia (XLA) is the prototype of primary humoral immunodeficiencies. Long-term follow-up studies regarding disease-related complications and outcome are scarce.

Objective: Our aim was to describe the natural history of XLA.

Methods: A nationwide multicenter study based on the Italian Primary Immunodeficiency Network registry was established in 2000 in Italy. Affected patients were enrolled by documenting centers, and the patients' laboratory, clinical, and imaging data were recorded on an annual base.

Results: Data on the patients (N = 168) were derived from a cumulative follow-up of 1370 patient-years, with a mean follow-up of 8.35 years per patient. The mean age at diagnosis decreased after establishment of the Italian Primary Immunodeficiency Network registry (84 months before vs 23 months after). Respiratory, skin, and gastrointestinal manifestations were the most frequent clinical symptoms at diagnosis and during long-term follow-up. Regular immunoglobulin replacement treatment reduced the incidence of invasive infections. Affected patients developed chronic lung disease over time (47% after 40 years of follow-up) in the presence of chronic sinusitis (84%). Malignancies were documented in a minority of cases (3.7%). Overall survival for affected patients was significantly reduced when compared with that for the healthy male Italian population, and it further deteriorated in the presence of chronic lung disease.

Conclusions: This is the first detailed long-term follow-up study for patients with XLA, revealing that although immunoglobulin replacement treatment reduces the incidence of invasive infections, it does not appear to influence the development of chronic lung disease. The overall survival of affected patients is reduced. Further studies are warranted to improve patients' clinical management and increase awareness among physicians.
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http://dx.doi.org/10.1016/j.jaci.2020.03.001DOI Listing
August 2020

Lack of Gut Secretory Immunoglobulin A in Memory B-Cell Dysfunction-Associated Disorders: A Possible Gut-Spleen Axis.

Front Immunol 2019 8;10:2937. Epub 2020 Jan 8.

Department of Molecular Medicine, Sapienza University, Rome, Italy.

B-1a B cells and gut secretory IgA (SIgA) are absent in asplenic mice. Human immunoglobulin M (IgM) memory B cells, which are functionally equivalent to mouse B-1a B cells, are reduced after splenectomy. To demonstrate whether IgM memory B cells are necessary for generating IgA-secreting plasma cells in the human gut. We studied intestinal SIgA in two disorders sharing the IgM memory B cell defect, namely asplenia, and common variable immune deficiency (CVID). Splenectomy was associated with reduced circulating IgM memory B cells and disappearance of intestinal IgA-secreting plasma cells. CVID patients with reduced circulating IgM memory B cells had a reduced frequency of gut IgA plasma cells and a disrupted film of SIgA on epithelial cells. Toll-like receptor 9 (TLR9) and transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) induced IgM memory B cell differentiation into IgA plasma cells . In the human gut, TACI-expressing IgM memory B cells were localized under the epithelial cell layer where the TACI ligand a proliferation inducing ligand (APRIL) was extremely abundant. Circulating IgM memory B cell depletion was associated with a defect of intestinal IgA-secreting plasma cells in asplenia and CVID. The observation that IgM memory B cells have a distinctive role in mucosal protection suggests the existence of a functional gut-spleen axis.
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http://dx.doi.org/10.3389/fimmu.2019.02937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960143PMC
November 2020

Health-Related Quality of Life and Emotional Difficulties in Chronic Granulomatous Disease: Data on Adult and Pediatric Patients from Italian Network for Primary Immunodeficiency (IPINet).

J Clin Immunol 2020 02 20;40(2):289-298. Epub 2019 Dec 20.

Unit of Pediatric Haemato-Oncology, Policlinico Giovanni XXIII Hospital, University of Bari, Piazza Giulio Cesare, 11, 70124, Bari, Italy.

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by life-threatening infections, inflammation, and autoimmunity with an impact on health-related quality of life (HRQoL). Few data are available for children, whereas no study has been conducted in adults. Here, we investigated HRQoL and emotional functioning of 19 children and 28 adults enrolled in Italian registry for CGD. PEDsQL and SDQ were used for children and their caregivers, and adults completed the SF-12 questionnaire. Mean scores were compared with norms and with patients affected by chronic diseases. Comparisons were made for CGD patients who underwent or not hematopoietic stem cell transplantation (HSCT). When compared with norms, CGD children exhibited higher difficulties in social/school areas, peer relationship, and conduct/emotional problems (< 5 years of age), as scored by proxies. Differently, CGD adults reported higher difficulties both in mental and physical area than norms. Only for children, clinical status had a damaging effect on psychosocial and school dimensions, whereas age had a negative impact on social areas. No significant difference was observed between patients treated or not with HSCT. When compared with patients affected by chronic diseases, CGD children and adults both displayed fewer physical disabilities. Differently, in mental scale adults scored lower than those with rheumatology diseases and had similar impairment in comparison with patients with diabetes mellitus and cancer. This study emphasized the impact of CGD on HRQoL since infancy and its decline in adulthood, with emotional difficulties occurring early. HRQoL impairment should be considered in clinical picture of CGD and pro-actively assessed and managed by clinicians.
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http://dx.doi.org/10.1007/s10875-019-00725-1DOI Listing
February 2020

The growing importance of achieving national self-sufficiency in immunoglobulin in Italy. The emergence of a national imperative.

Blood Transfus 2019 11 11;17(6):449-458. Epub 2019 Dec 11.

Italian National Blood Transfusion Centre, Rome, Italy.

Since the inception of industrial plasma fractionation during the Second World War, a succession of protein therapies isolated from plasma have determined the volume of plasma requiring collection, and have also shaped the economics of the industry. These so-called plasma drivers have successively included albumin, coagulation Factor VIII (FVIII) and, for the past thirty years, intravenously (IV) and subcutaneously (SC) administered immunoglobulin (IG) solutions. The sale of IG underpins the profitability of the industry and has experienced continuous growth over the past decades, as the result of growing clinical demand. Modelling this demand using decision analysis indicates that supplying the evidence-based indications for IG therapies will generate a need for IG which exceeds the current plasma collection capacity of most countries. A notable exception to this situation is the United States (US) of America, whose population of compensated plasma donors generates two thirds of the global supply of plasma for fractionation. The US is also the leading consumer of IG, and its health care providers pay the highest price for the product globally. Shortages of IG occur whenever the demand for the product outstrips the supply. Current shortages, following other historical periods of shortage, threaten the well-being of patients dependant on these products and incur heavy costs on health systems. In Italy, the national blood system, which is based on voluntary unpaid donors, reflects a policy of national self-sufficiency in blood-derived therapies (a strategic objective of the national blood system itself), based on solidarity as an ethical principle. This system has increased the collection of plasma for fractionation by 3.8% per annum over 2008-2017, in accordance to a plan for plasma procurement targeting a collection rate of 14.1 L of plasma per thousand (10) population by 2020. Over the same period, IG usage has increased by 8.5/per annum, to 89.2 g IG/10 population. In this paper, we review the factors which, increasingly, are causing an imbalance between the global supply and demand for IG, and we assess Italy's capacity to ensure that increasing this level of independence is no longer simply an ethical, but also an economic imperative, with implications for the security of Italy's health system.
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http://dx.doi.org/10.2450/2019.0265-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917530PMC
November 2019

Ibrutinib-based therapy impaired neutrophils microbicidal activity in patients with chronic lymphocytic leukemia during the early phases of treatment.

Leuk Res 2019 12 3;87:106233. Epub 2019 Oct 3.

Department of Molecular Medicine, Sapienza University, Viale Regina Elena, 291, 00161 Rome, Italy. Electronic address:

Ibrutinib is a tyrosine kinase inhibitor used in the treatment of a variety of lymphoid malignancies, including chronic lymphocytic leukemia (CLL). Drugs inhibiting B-cell-receptor (BCR)-associated kinases, including BTK inhibitors, act on B cells and on a wide spectrum of tissues and cells, including innate immunity cells. Thus, alterations in the Bruton's tyrosine kinase (BTK) kinase function could lead to an impairment of innate immune cells functions and to an increased infectious risk in patients receiving BTK inhibitors. We analyzed in vivo neutrophils oxidative burst, neutrophils granules release and cytokine production in relapsed/refractory CLL patients treated over time with ibrutinib as single-agent. We observed a dramatic reduction of neutrophils oxidative burst, Fc gamma receptors (FcγRs)-mediated degranulation and IL-8 plasma levels already after the first forty-eight hours of therapy with ibrutinib. However, ibrutinib treatment did not alter the surface expression of CD11b nor cytokine and proteinases release not mediated by FcγRs engagement. After three weeks, oxidative burst was still impaired, while degranulation and IL-8 levels were restored. In a group of CLL patients who survived for more than three years, all processes triggered by FcγRs completely recovered except the release of neutrophil elastase (NE) and IL-8. In conclusion, during the initial phases of ibrutinib therapy, the reduction of IL-8, NE, myeloperoxidase (MPO) levels and oxidative burst negatively impacted on mechanisms involved in neutrophils microbicidal activity.
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http://dx.doi.org/10.1016/j.leukres.2019.106233DOI Listing
December 2019

Appropriate lung management in patients with primary antibody deficiencies.

Expert Rev Respir Med 2019 09 30;13(9):823-838. Epub 2019 Jul 30.

Department of Molecular Medicine, "Sapienza" University of Roma , Roma , Italy.

: Human primary immunodeficiency diseases (PIDs) include a broad spectrum of more than 350 disorders, involving different branches of the immune system and classified as 'rare diseases.' Predominantly antibody deficiencies (PADs) represent more than half of the PIDs diagnosed in Europe and are often diagnosed in the adulthood. : Although PAD could first present with autoimmune or neoplastic features, respiratory infections are frequent and respiratory disease represents a relevant cause of morbidity and mortality. Pulmonary complications may be classified as infection-related (acute and chronic), immune-mediated, and neoplastic. : At present, no consensus guidelines are available on how to monitor and manage lung complications in PAD patients. In this review, we will discuss the available diagnostic, prognostic and therapeutic instruments and we will suggest an appropriate and evidence-based approach to lung diseases in primary antibody deficiencies. We will also highlight the possible role of promising new tools and strategies in the management of pulmonary complications. However, future studies are needed to reduce of diagnostic delay of PAD and to better understand lung diseases mechanisms, with the final aim to ameliorate therapeutic options that will have a strong impact on Quality of Life and long-term prognosis of PAD patients.
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http://dx.doi.org/10.1080/17476348.2019.1641085DOI Listing
September 2019

The high mortality of patients with common variable immunodeficiency and small bowel villous atrophy.

Scand J Gastroenterol 2019 Feb 21;54(2):164-168. Epub 2019 Apr 21.

a Coeliac Centre/First Department of Internal Medicine , Fondazione IRCCS Policlinico San Matteo University of Pavia , Pavia , Italy.

Objectives: Common variable immunodeficiency (CVID) is a primary humoral immunodeficiency characterised by reduced serum levels of immunoglobulins, recurrent infections, autoimmune phenomena and lymphoproliferative disorders. Gastrointestinal symptoms are very common in these patients and a coeliac-like villous atrophy was described in some of them. Since mortality in CVID is much higher than in the general population, our aim was to evaluate mortality rates and clinical predictors of survival in patients with both CVID and duodenal villous atrophy.

Patients And Methods: Sex, date of diagnosis of villous atrophy, HLA genomic typing, date of death/last follow-up, type of complication were retrospectively collected from medical files. Univariate analysis for each predictor was conducted and Kaplan-Meier curves were generated to evaluate survival.

Results: Twenty-three patients were enrolled (9 females, mean age at diagnosis of villous atrophy 38 ± 13 years) and 8 of them died after a median time of 96 months (25th-75th 60-120 months) corresponding to a mortality rate of 3.9 per 100 person-years (95% CI 1.9-7.7). Mortality was higher in men compared to women (60 vs. 11/1000 person-years), although not statistically significant. Causes of death included onco-haematological disorders and infections.

Conclusions: Although based on a small cohort, our results confirm that patients with CVID and villous atrophy are burdened by a very high mortality mainly due to onco-immunological disorders and infections. Strict follow-up is required in these patients.
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http://dx.doi.org/10.1080/00365521.2019.1568543DOI Listing
February 2019

Genetic stability of Campylobacter coli in patients with primary antibody deficiencies.

J Allergy Clin Immunol Pract 2019 May - Jun;7(5):1707. Epub 2019 Mar 27.

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

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http://dx.doi.org/10.1016/j.jaip.2019.02.033DOI Listing
May 2020

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
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