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BackgroundThe respiratory tract microbiome is essential for human health and well-being and is determined by genetic, lifestyle, and environmental factors. Patients with Common Variable Immunodeficiency (CVID) suffer from respiratory and intestinal tract infections, leading to chronic diseases and increased mortality rates. While CVID patients’ gut microbiota have been analyzed, data on the respiratory microbiome ecosystem are limited.ObjectiveThis study aims to analyze the bacterial composition of the oropharynx of adults with CVID and its link with clinical and immunological features and risk for respiratory acute infections.MethodsOropharyngeal samples from 72 CVID adults and 26 controls were collected in a 12-month prospective study. The samples were analyzed by metagenomic bacterial 16S ribosomal RNA sequencing and processed using the Quantitative Insights Into Microbial Ecology (QIME) pipeline. Differentially abundant species were identified and used to build a dysbiosis index. A machine learning model trained on microbial abundance data was used to test the power of microbiome alterations to distinguish between healthy individuals and CVID patients.ResultsCompared to controls, the oropharyngeal microbiome of CVID patients showed lower alpha- and beta-diversity, with a relatively increased abundance of the order Lactobacillales, including the family Streptococcaceae. Intra-CVID analysis identified age >45 years, COPD, lack of IgA, and low residual IgM as associated with a reduced alpha diversity. Expansion of Haemophilus and Streptococcus genera was observed in patients with undetectable IgA and COPD, independent from recent antibiotic use. Patients receiving azithromycin as antibiotic prophylaxis had a higher dysbiosis score. Expansion of Haemophilus and Anoxybacillus was associated with acute respiratory infections within six months.ConclusionsCVID patients showed a perturbed oropharynx microbiota enriched with potentially pathogenic bacteria and decreased protective species. Low residual levels of IgA/IgM, chronic lung damage, anti antibiotic prophylaxis contributed to respiratory dysbiosis.

Sarcoidosis and Granulomatous and Lymphocytic Interstitial Lung Diseases (GLILD) are two rare entities primarily characterised by the development of Interstitial Lung Disease (ILD) in the context of systemic immune dysregulation. These two conditions partially share the immunological background and pathologic findings, with granuloma as the main common feature. In this narrative review, we performed a careful comparison between sarcoidosis and GLILD, with an overview of their main similarities and differences, starting from a clinical perspective and ending with a deeper look at the immunopathogenesis and possible target therapies. Sarcoidosis occurs in immunocompetent individuals, whereas GLILD occurs in patients affected by common variable immunodeficiency (CVID). Moreover, peculiar extrapulmonary manifestations and radiological and histological features may help distinguish the two diseases. Despite that, common pathogenetic pathways have been suggested and both these disorders can cause progressive impairment of lung function and variable systemic granulomatous and non-granulomatous complications, leading to significant morbidity, reduced quality of life, and survival. Due to the rarity of these conditions and the extreme clinical variability, there are still many open questions concerning their pathogenesis, natural history, and optimal management. However, if studied in parallel, these two entities might benefit from each other, leading to a better understanding of their pathogenesis and to more tailored treatment approaches.

Abstract Job’s syndrome, or autosomal dominant hyperimmunoglobulin E syndrome (AD-HIES, STAT3-Dominant Negative), is a rare inborn error of immunity (IEI) with multi-organ involvement and long-life post-infective damage. Longitudinal registries are of primary importance in improving our knowledge of the natural history and management of these rare disorders. This study aimed to describe the natural history of 30 Italian patients with AD-HIES recorded in the Italian network for primary immunodeficiency (IPINet) registry. This study shows the incidence of manifestations present at the time of diagnosis versus those that arose during follow up at a referral center for IEI. The mean time of diagnostic delay was 13.7 years, while the age of disease onset was

BackgroundPreventive strategies against severe COVID-19 in Inborn Errors of Immunity (IEI) include bivalent vaccines, treatment with SARS-CoV-2 monoclonal antibodies (mAbs), early antiviral therapies, and pre-exposure prophylaxis (PrEP).ObjectiveTo assess the effectiveness of the PrEP with tixagevimab/cilgavimab (AZD7442) in IEI with primary antibody defects during the COVID-19 Omicron wave.MethodsA six-month prospective study evaluated the SARS-CoV-2 infection rate and the COVID-19 severity in the AZD7442 group, in the no-AZD7442 group, and in a group of patients with a recent SARS-CoV-2 infection (< three months). Spike-specific IgG levels were measured at regular intervals.ResultsSix out of thirty-three patients (18%) and 54/170 patients (32%) became infected in the AZD7442 group and in the no-AZD7442 group, respectively. Within 90 days post-administration, the AZD7442 group was 85% less likely to be infected and 82% less likely to have a symptomatic disease than the no-AZD7442 group. This effect was lost thereafter. In the entire cohort, no mortality/hospitalisation was observed. The control group of 35 recently infected patients was 88% and 92% less likely to be infected than the AZD7442 and no-AZD7442 groups. Serum anti-Spike IgG reached the highest peak seven days post-AZD7442 PrEP then decreased, remaining over 1000 BAU/mL 180 days thereafter.ConclusionIn patients with IEI and antibody defects, AZD7442 prophylaxis had a transient protective effect, possibly lost possibly because of the appearance of new variants. However, PrEP with newer mAbs might still represent a feasible preventive strategy in the future in this population.

IntroductionIn patients with Common Variable Immunodeficiency, malignancy has been reported as the leading cause of death in adults, with a high risk of B-cell lymphomas and gastric cancer.MethodsWe conducted a five-year prospective study aiming to update the incidence and mortality of gastric cancer and the incidence of gastric precancerous lesions in 512 CVID patients who underwent a total of 400 upper gastrointestinal endoscopies.ResultsIn the pre-pandemic period, 0.58 endoscopies were performed per patient/year and in the COVID-19 period, 0.39 endoscopies were performed per patient/year. Histology revealed areas with precancerous lesions in about a third of patients. Patients who had more than one gastroscopy during the study period were more likely to have precancerous lesions. Two patients received a diagnosis of gastric cancer in the absence of Helicobacter pylori infection. The overall prevalence of Helicobacter pylori infection in biopsy specimens was 19.8% and related only to active gastritis. Among patients who had repeated gastroscopies, about 20% progressed to precancerous lesions, mostly independent of Helicobacter pylori.DiscussionWhile gastric cancer accounted for one in five deaths from CVID in our previous survey, no gastric cancer deaths were recorded in the past five years, likely consistent with the decline in stomach cancer mortality observed in the general population. However, during the COVID-19 pandemic, cancer screening has been delayed. Whether such a delay or true decline could be the reason for the lack of gastric cancer detection seen in CVID may become clear in the coming years. Due to the high incidence of precancerous lesions, we cannot rely on observed and predicted trends in gastric cancer mortality and strongly recommend tailored surveillance programs.

Ustekinumab is a monoclonal antibody targeting the p40 subunit of IL-12 and IL-23, approved for treating psoriasis, psoriatic arthritis, and inflammatory bowel disease. Despite a remarkable success in treating chronic inflammatory conditions and a generally favorable safety profile, its role in inducing rare adverse events, such as interstitial pneumonia and acute respiratory distress syndrome (ARDS), remains largely uncharted. We report a case of a 66-year-old male patient treated with Ustekinumab for severe psoriasis who, after almost two years of treatment, developed dyspnea, asthenia, and fever progressing to non-infectious pneumonia and ARDS leading to ICU admission. Moreover, we conducted a literature review on Ustekinumab-associated pulmonary complications. Our case underscores the importance of appropriate and long-term clinical monitoring in patients on Ustekinumab treatment, particularly considering the potential lung complications. The possibility of non-infectious pneumonitis should be considered alongside infectious causes, facilitating prompt management in the case of negative infectious screening. Additionally, the severity of ARDS underscores the importance of timely recognition and proper management. Further investigations are recommended to investigate the immunological basis of Ustekinumab-induced ARDS for designing appropriate monitoring strategies.

IntroductionAssessing the response to vaccinations is one of the diagnostic criteria for Common Variable Immune Deficiencies (CVIDs). Vaccination against SARS-CoV-2 offered the unique opportunity to analyze the immune response to a novel antigen. We identify four CVIDs phenotype clusters by the integration of immune parameters after BTN162b2 boosters.MethodsWe performed a longitudinal study on 47 CVIDs patients who received the 3rd and 4th vaccine dose of the BNT162b2 vaccine measuring the generation of immunological memory. We analyzed specific and neutralizing antibodies, spike-specific memory B cells, and functional T cells.ResultsWe found that, depending on the readout of vaccine efficacy, the frequency of responders changes. Although 63.8% of the patients have specific antibodies in the serum, only 30% have high-affinity specific memory B cells and generate recall responses.DiscussionThanks to the integration of our data, we identified four functional groups of CVIDs patients with different B cell phenotypes, T cell functions, and clinical diseases. The presence of antibodies alone is not sufficient to demonstrate the establishment of immune memory and the measurement of the in-vivo response to vaccination distinguishes patients with different immunological defects and clinical diseases.

IntroductionCommon variable immunodeficiency related interstitial lung disease (CVID-ILD, also referred to as GLILD) is generally considered a manifestation of systemic immune dysregulation occurring in up to 20% of people with CVID. There is a lack of evidence-based guidelines for the diagnosis and management of CVID-ILD.AimTo systematically review use of diagnostic tests for assessing patients with CVID for possible ILD, and to evaluate their utility and risks.MethodsEMBASE, MEDLINE, PubMed and Cochrane databases were searched. Papers reporting information on the diagnosis of ILD in patients with CVID were included.Results58 studies were included. Radiology was the investigation modality most commonly used. HRCT was the most reported test, as abnormal radiology often first raised suspicion of CVID-ILD. Lung biopsy was used in 42 (72%) of studies, and surgical lung biopsy had more conclusive results compared to trans-bronchial biopsy (TBB). Analysis of broncho-alveolar lavage was reported in 24 (41%) studies, primarily to exclude infection. Pulmonary function tests, most commonly gas transfer, were widely used. However, results varied from normal to severely impaired, typically with a restrictive pattern and reduced gas transfer.ConclusionConsensus diagnostic criteria are urgently required to support accurate assessment and monitoring in CVID-ILD. ESID and the ERS e-GLILDnet CRC have initiated a diagnostic and management guideline through international collaboration.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42022276337.

Summary: Common variable immune deficiency (CVID) is a heterogeneous disorder characterized by recurrent infections, low levels of serum immunoglobulins, and impaired vaccine responses. Autoimmune manifestations are common, but B cell central and peripheral selection mechanisms in CVID are incompletely understood. Here, we find that receptor editing, a measure of central tolerance, is increased in transitional B cells from CVID patients and that these cells have a higher immunoglobulin κ:λ ratio in CVID patients with autoimmune manifestations than in those with infection only. Contrariwise, the selection pressure in the germinal center on CD27bright memory B cells is decreased in CVID patients with autoimmune manifestations. Finally, functionally, T cell-dependent activation showed that naive B cells in CVID patients are badly equipped for activation and induction of mismatch repair genes. We conclude that central tolerance is functional whereas peripheral selection is defective in CVID patients with autoimmune manifestations, which could underpin the development of autoimmunity.

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BackgroundCVID patients present an increased risk of prolonged SARS-CoV-2 infection and re-infection and a higher COVID-19-related morbidity and mortality compared to the general population. Since 2021, different therapeutic and prophylactic strategies have been employed in vulnerable groups (vaccination, SARS-CoV-2 monoclonal antibodies and antivirals). The impact of treatments over the last 2 years has not been explored in international studies considering the emergence of viral variants and different management between countries.MethodsA multicenter retrospective/prospective real-life study comparing the prevalence and outcomes of SARS-CoV-2 infection between a CVID cohort from four Italian Centers (IT-C) and one cohort from the Netherlands (NL-C), recruiting 773 patients.Results329 of 773 CVID patients were found positive for SARS-CoV-2 infection between March 1st, 2020 and September 1st 2022. The proportion of CVID patients infected was comparable in both national sub-cohorts. During all waves, chronic lung disease, “complicated” phenotype, chronic immunosuppressive treatment and cardiovascular comorbidities impacted on hospitalization, whereas risk factors for mortality were older age, chronic lung disease, and bacterial superinfections. IT-C patients were significantly more often treated, both with antivirals and mAbs, than NL-C patients. Outpatient treatment, available only in Italy, started from the Delta wave. Despite this, no significant difference was found for COVID-19 severity between the two cohorts. However, pooling together specific SARS-CoV-2 outpatient treatments (mAbs and antivirals), we found a significant effect on the risk of hospitalization starting from Delta wave. Vaccination with ≥ 3 doses shortened RT-PCR positivity, with an additional effect only in patients receiving antivirals.ConclusionsThe two sub-cohorts had similar COVID-19 outcomes despite different treatment approaches. This points out that specific treatment should now be reserved for selected subgroups of CVID patients, based on pre-existing conditions.

The Facilitated Immunoglobulin Administration Registry And Outcomes (FIGARO) Study was a European, multicenter, prospective, observational study conducted across Europe designed to provide insights on the clinical use and tolerability of facilitated subcutaneous immunoglobulin (fSCIG). Data herein are reported for the cohort of patients with secondary immunodeficiency (SID), with a subgroup analysis by age. The SID cohort included 31 patients: 1 pediatric, 15 adult, and 15 older adult patients. Over the 36-month observation period, the median monthly dose of fSCIG (30 g) and median monthly infusion volume per patient (300 mL) remained constant in both adult-age cohorts. Serum trough levels tended to increase over time. Most patients required only one infusion site and could receive the full dose every 3–4 weeks. There was a trend toward self-administration at home. In the adult group, infusion site inflammation and headache were reported at the inclusion visit (n = 1 each), with no adverse drug reactions reported at any of the follow-up visits. No acute severe bacterial infections were reported during the study follow-up. These results demonstrate the feasibility and tolerability of fSCIG use in patients with SID and the flexibility of administration settings including self-administration at home in patients aged ≥65 years.

Background: The SARS-CoV-2 infection is now a part of the everyday lives of immunocompromised patients, but the choice of treatment and the time of viral clearance can often be complex, exposing patients to possible complications. The role of the available antiviral and monoclonal therapies is a matter of debate, as are their effectiveness and potential related adverse effects. To date, in the literature, the amount of data on the use of combination therapies and on the multiple lines of anti-SARS-CoV-2 therapy available to the general population and especially to inborn error of immunity (IEI) patients is small. Methods: Here, we report a case series of five adult IEI patients managed as inpatients at three Italian IEI referral centers (Rome, Treviso, and Cagliari) treated with combination therapy or multiple therapeutic lines for SARS-CoV-2 infection, such as monoclonal antibodies (mAbs), antivirals, convalescent plasma (CP), mAbs plus antiviral, and CP combined with antiviral. Results: This study may support the use of combination therapy against SARS-CoV-2 in complicated IEI patients with predominant antibody deficiency and impaired vaccine response.

Natural Killer (NK) cells are key innate effectors of antiviral immune response, and their activity changes in ageing and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we investigated the age-related changes of NK cell phenotype and function during SARS-CoV-2 infection, by comparing adult and elderly patients both requiring mechanical ventilation. Adult patients had a reduced number of total NK cells, while elderly showed a peculiar skewing of NK cell subsets towards the CD56lowCD16high and CD56neg phenotypes, expressing activation markers and check-point inhibitory receptors. Although NK cell degranulation ability is significantly compromised in both cohorts, IFN-γ production is impaired only in adult patients in a TGF-β−dependent manner. This inhibitory effect was associated with a shorter hospitalization time of adult patients suggesting a role for TGF-β in preventing an excessive NK cell activation and systemic inflammation. Our data highlight an age-dependent role of NK cells in shaping SARS-CoV-2 infection toward a pathophysiological evolution.

BackgroundSince the beginning of the COVID-19 pandemic, patients with Inborn Errors of Immunity have been infected by SARS-CoV-2 virus showing a spectrum of disease ranging from asymptomatic to severe COVID-19. A fair number of patients did not respond adequately to SARS-CoV-2 vaccinations, thus early therapeutic or prophylactic measures were needed to prevent severe or fatal course or COVID-19 and to reduce the burden of hospitalizations.MethodsLongitudinal, multicentric study on patients with Inborn Errors of Immunity immunized with mRNA vaccines treated with monoclonal antibodies and/or antiviral agents at the first infection and at reinfection by SARS-CoV-2. Analyses of efficacy were performed according to the different circulating SARS-CoV-2 strains.ResultsThe analysis of the cohort of 192 SARS-CoV-2 infected patients, across 26 months, showed the efficacy of antivirals on the risk of hospitalization, while mabs offered a positive effect on hospitalization, and COVID-19 severity. This protection was consistent across the alpha, delta and early omicron waves, although the emergence of BA.2 reduced the effect of available mabs. Hospitalized patients treated with mabs and antivirals had a lower risk of ICU admission. We reported 16 re-infections with a length of SARS-CoV-2 positivity at second infection shorter among patients treated with mabs. Treatment with antivirals and mabs was safe.ConclusionsThe widespread use of specific therapy, vaccination and better access to care might have contributed to mitigate risk of mortality, hospital admission, and severe disease. However, the rapid spread of new viral strains underlines that mabs and antiviral beneficial effects should be re- evaluated over time.

BackgroundPrimary antibody deficiencies (PADs) without an identified monogenetic origin form the largest and most heterogeneous group of primary immunodeficiencies. These patients often remain undiagnosed for years and many present to medical attention in adulthood after several infections risking structural complications. Not much is known about their treatment, comorbidities, or prognosis, nor whether the various immunological forms (decreased total IgG, IgG subclass(es), IgM, IgA, specific antibody responses, alone or in combination(s)) should be considered as separate, clearly definable subgroups. The unclassified primary antibody deficiency (unPAD) study aims to describe in detail all PAD patients without an identified specific monogenetic defect regarding their demographical, clinical, and immunological characteristics at presentation and during follow-up. In constructing these patterns, the unPAD study aims to reduce the number of missed and unidentified PAD patients in the future. In addition, this study will focus on subclassifying unPAD to support the identification of patients at higher risk for infection or immune dysregulation related complications, enabling the development of personalized follow-up and treatment plans.Methods and analysisWe present a protocol for a multicenter observational cohort study using the ESID online Registry. Patients of all ages who have given informed consent for participation in the ESID online Registry and fulfill the ESID Clinical Working Definitions for 'unclassified antibody deficiency', 'deficiency of specific IgG', 'IgA with IgG subclass deficiency', 'isolated IgG subclass deficiency', 'selective IgM deficiency', 'selective IgA deficiency' or 'common variable immunodeficiency' will be included. For all patients, basic characteristics can be registered at first registration and yearly thereafter in level 1 forms. Detailed characteristics of the patients can be registered in level 2 forms. Consecutive follow-up forms can be added indefinitely. To ensure the quality of the collected data, all data will be fully monitored before they are exported from the ESID online Registry for analysis. Outcomes will be the clinical and immunological characteristics of unPAD at presentation and during follow-up. Subgroup analyses will be made based on demographical, clinical and immunological characteristics.

Activated PI3K-kinase Delta Syndrome (APDS) is an autosomal-dominant primary immunodeficiency (PID) caused by the constitutive activation of the PI3Kδ kinase. The consequent hyperactivation of the PI3K-Akt-mTOR pathway leads to an impaired T- and B-cells differentiation and function, causing progressive lymphopenia, hypogammaglobulinemia and hyper IgM. Patients with APDS show recurrent sinopulmonary and chronic herpes virus infections, immune dysregulation manifestations, including cytopenia, arthritis, inflammatory enteropathy, and a predisposition to persistent non-neoplastic splenomegaly/lymphoproliferation and lymphoma. The recurrence of the lymphoproliferative disorder and the difficulties in the proper definition of malignancy on histological examination represents the main challenge in the clinical management of APDS patients, since a prompt and correct diagnosis is needed to avoid major complications. Targeted therapies with PI3Kδ-Akt-mTOR pathway pharmacologic inhibitors (i.e., Rapamycin, Theophylline, PI3K inhibitors) represent a good therapeutic strategy. They can also be used as bridge therapies when HSCT is required in order to control refractory symptoms. Indeed, treated patients showed a good tolerance, improved immunologic phenotype and reduced incidence/severity of immune dysregulation manifestations. Here, we describe our experience in the management of four patients, one male affected with APDS1 (P1) and the other three, a male and two females, with APDS2 (P2, P3, P4) presenting with chronic EBV replication, recurrent episodes of immune dysregulation manifestations and lymphomas. These cases highlighted the importance of a tailored and close follow-up, including serial endoscopic and lymph nodes biopsies control to detect a prompt and correct diagnosis and offer the best therapeutic strategy.

Background: Selective IgA deficiency (SIgAD) is the most common inborn error of immunity. The exact prevalence and pathogenesis of allergy in SIgAD have not yet been defined. We aimed to describe the prevalence and the characteristics of allergy in pediatric SIgAD subjects, evaluate the association between allergy and other comorbidities, and define the immune phenotype of allergic and non-allergic patients. Methods: Clinical and immunological data from 67 SIgAD patients were collected over a 13-year period at a single center. Patients’ characteristics were analyzed according to the presence of allergy. Results: Allergy was diagnosed in 34% of SIgAD patients, with a median age at allergy diagnosis of 8 years. Allergy was the second-most-common clinical manifestation, following recurrent respiratory infections. Among the allergic group, 74% had rhinitis, 30% asthma, 30% atopic dermatitis, and 22% food allergy; one out of three had more than one allergic manifestation. SIgAD patients showed more frequent transitory lymphopenia and a lower count of CD19+ at diagnosis than at last FU. However, compared to non-allergic subjects, allergic patients did not differ in their immune phenotype, number and severity of infections, or increased autoimmunity. Conclusions: In our longitudinal study, compared to non-allergic SIgAD patients, those with allergies did not present a more severe immune defect or complex clinical phenotype. However, evaluation and early identification of allergy in the context of SIgAD assessment, both at diagnosis and during FU, and definition of a proper management are important to prevent complications and improve the patient’s quality of life.

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.

Following the third booster dose of the mRNA vaccine, Common Variable Immune Deficiencies (CVID) patients may not produce specific antibodies against the virus spike protein. The T-cell abnormalities associated with the absence of antibodies are still a matter of investigation. Spike-specific IgG and IgA, peripheral T cell subsets, CD40L and cytokine expression, and Spike-specific specific T-cells responses were evaluated in 47 CVID and 26 healthy donors after three doses of BNT162b2 vaccine. Testing was performed two weeks after the third vaccine dose. Thirty-six percent of the patients did not produce anti-SARS-CoV-2 IgG or IgA antibodies. Non responder patients had lower peripheral blood lymphocyte counts, circulating naïve and central memory T-cells, low CD40L expression on the CD4+CD45+RO+ and CD8+CD45+RO+ T-cells, high frequencies of TNFα and IFNγ expressing CD8+ T-cells, and defective release of IFNγ and TNFα following stimulation with Spike peptides. Non responders had a more complex disease phenotype, with higher frequencies of structural lung damage and autoimmunity, especially autoimmune cytopenia. Thirty-five percent of them developed a SARS-CoV-2 infection after immunization in comparison to twenty percent of CVID who responded to immunization with antibodies production. CVID-associated T cell abnormalities contributed to the absence of SARS-CoV-2 specific antibodies after full immunization.

Patients with severely impaired antibody responses represent a group at-risk in the SARS-CoV-2 pandemic due to the lack of Spike-specific neutralizing antibodies. The main objective of this paper was to assess, by a longitudinal prospective study, COVID-19 infection and mortality rates, and disease severity in the first two years of the pandemic in a cohort of 471 Primary Antibody Defects adult patients. As secondary endpoints, we compared SARS-CoV-2 annual mortality rate to that observed over a 10-year follow-up in the same cohort, and we assessed the impact of interventions done in the second year, vaccination and anti-SARS-CoV-2 monoclonal antibodies administration on the disease outcome. Forty-one and 84 patients were infected during the first and the second year, respectively. Despite a higher infection and reinfection rate, and a higher COVID-19-related mortality rate compared to the Italian population, the pandemic did not modify the annual mortality rate for any cause in our cohort compared to that registered over the last ten years in the same cohort. PADs patients who died from COVID-19 had an underlying end-stage lung disease. We showed a beneficial effect of MoAbs administration on the likelihood of hospitalization and development of severe disease. In conclusion, COVID-19 did not cause excess mortality in Severe Antibody Deficiencies.

Background: 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.Methods: 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.Results: 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).Conclusions: 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.

Secondary antibody deficiencies (SAD) may require immunoglobulin replacement therapy (IgRT). While the intravenous route (IVIG) is broadly considered effective in SAD, the use of subcutaneous immunoglobulins (SCIG) is mainly adopted from the experience in primary antibody deficiencies (PAD), where SCIG have been shown to perform as effective as IVIG. However, evidence-based data on SCIG administration in SAD patients are still insufficient. Herein we retrospectively evaluated the efficacy and safety profile of SCIG treatment in 131 SAD patients as compared to a group of 102 PAD patients. We found SCIG being equally effective in reducing annual infectious rate both in SAD and PAD patients. However, SAD patients required lower SCIG dosage and lower IgG through level to achieve similar biological effect in terms of infection burden, at the steady state. SAD patients also showed better correlation between SCIG dose and serum IgG achieved value. Furthermore, within SAD, SCIG were found to work irrespective of the underlying disease. Especially in Non-Hodgkin Lymphoma patients, whose indication to IgRT is still not included in all guidelines and for whom evidence-based data are still lacking, SCIG were as effective as in Chronic Lymphocytic Leukemia or Multiple Myeloma patients, and SCIG discontinuation, without evidence of B cell recovery, led to IgG decline and relapsed infections. Finally, treatment tolerance in SAD patients was comparable to the PAD cohort. Globally, our data suggest that SCIG, as already appreciated in PAD, represent a valuable option in SAD patients, independent on the disease leading to antibody deficiency.

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 64 adults with a spectrum of clinical presentations: 28 healthy SARS-CoV-2-negative contacts of COVID-19 cases; 20 asymptomatic SARS-CoV-2-infected cases; eight patients with Mild COVID-19 disease and eight 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.

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.

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 CD21low 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.

Background: 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.Objective: To demonstrate whether IgM memory B cells are necessary for generating IgA-secreting plasma cells in the human gut.Methods: We studied intestinal SIgA in two disorders sharing the IgM memory B cell defect, namely asplenia, and common variable immune deficiency (CVID).Results: 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 vitro. 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.Conclusions: 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.

Background: Patients with primary antibody deficiencies are at risk in the current COVID-19 pandemic due to their impaired response to infection and vaccination. Specifically, patients with common variable immunodeficiency (CVID) generated poor spike-specific antibody and T cell responses after immunization. Methods: Thirty-four CVID convalescent patients after SARS-CoV-2 infection, 38 CVID patients immunized with two doses of the BNT162b2 vaccine, and 20 SARS-CoV-2 CVID convalescents later and immunized with BNT162b2 were analyzed for the anti-spike IgG production and the generation of spike-specific memory B cells and T cells. Results: Spike-specific IgG was induced more frequently after infection than after vaccination (82% vs. 34%). The antibody response was boosted in convalescents by vaccination. Although immunized patients generated atypical memory B cells possibly by extra-follicular or incomplete germinal center reactions, convalescents responded to infection by generating spike-specific memory B cells that were improved by the subsequent immunization. Poor spike-specific T cell responses were measured independently from the immunological challenge. Conclusions: SARS-CoV-2 infection primed a more efficient classical memory B cell response, whereas the BNT162b2 vaccine induced non-canonical B cell responses in CVID. Natural infection responses were boosted by subsequent immunization, suggesting the possibility to further stimulate the immune response by additional vaccine doses in CVID.

Primary antibody deficiencies (PADs) are the most common primary immunodeficiencies (PIDs). They can be divided into the following groups, depending on their immunological features: agammaglobulinemia; common variable immunodeficiency (CVID) isotype; hyper IgM isotype; light chain or functional deficiencies with normal B cell count; specific antibody deficiency with normal Ig concentrations and normal numbers of B cells and transient hypogammaglobulinemia of infancy. The role of vaccination in PADs is recognized as therapeutic, diagnostic and prognostic and may be used in patients with residual B-cell function to provide humoral immunity to specific infective agents. According to their content and mechanisms, vaccines are grouped as live attenuated, inactivated (conjugated, polysaccharide), mRNA or replication-deficient vector vaccines. Vaccination may be unsafe or less effective when using certain vaccines and in specific types of immunodeficiency. Inactivated vaccines can be administered in PAD patients even if they could not generate a protective response; live attenuated vaccines are not recommended in major antibody deficiencies. From December 2020, European Medicines Agency (EMA) approved vaccines against COVID-19 infection: according to ESID advises, those vaccinations are recommended in patients with PADs. No specific data are available on safety and efficacy in PAD patients.

An increased prevalence of malignant lymphoma and of gastric cancer has been observed in large cohorts of patients with common variable immunodeficiency (CVID), the most frequently symptomatic primary immunodeficiency. Surveillance strategies for cancers in CVID should be defined based on epidemiological data. Risks and mortality for cancers among 455 Italian patients with CVID were compared to cancer incidence data from the Italian Cancer Registry database. CVID patients showed an increased cancer incidence for all sites combined (Obs = 133, SIR = 2.4; 95%CI = 1.7–3.5), due to an excess of non-Hodgkin lymphoma (Obs = 33, SIR = 14.3; 95%CI = 8.4–22.6) and of gastric cancer (Obs = 25; SIR = 6.4; 95%CI = 3.2–12.5). CVID patients with gastric cancer and lymphoma had a worse survival in comparison to cancer-free CVID (HR: 4.8, 95%CI: 4.2–44.4 and HR: 4.2, 95%CI: 2.8–44.4). Similar to what observed in other series, CVID-associated lymphomas were more likely to be of B cell origin and often occurred at extra-nodal sites. We collected the largest case-series of gastric cancers in CVID subjects. In contrast to other reports, gastric cancer was the leading cause of death in CVID. Standardized mortality ratio indicated a 10.1-fold excess mortality among CVID patients with gastric cancer. CVID developed gastric cancer 15 years earlier than the normative population, but they had a similar overall survival. Only CVID diagnosed at early stage gastric cancer survived >24 months. Stomach histology from upper endoscopy performed before cancer onset showed areas of atrophic gastritis, intestinal metaplasia or dysplasia. CVID patients might progress rapidly to an advanced cancer stage as shown by patients developing a III-IV stage gastric cancer within 1 year from an endoscopy without signs of dysplasia. Based on high rate of mortality due to gastric cancer in Italian CVID patients, we hereby suggest a strategy aimed at early diagnosis, based on regular upper endoscopy and on Helicobacter pylori infection treatment, recommending an implementation of national guidelines.

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.

We assessed the prevalence of TNFRSF13B mutations and the clinical correlates in an Italian cohort of 189 CVID, 67 IgAD patients, and 330 healthy controls to substantiate the role of TACI genetic testing in diagnostic workup. We found that 11% of CVID and 13% of IgAD carried at least one mutated TNFRSF13B allele. Seven per cent of CVID had monoallelic-mutations and 4% had biallelic-mutations. The frequency of C104R monoallelic-mutations was not higher than that found in healthy controls. Biallelic-mutations were exclusively found in CVID. CVID patients carrying monoallelic-mutations had an increased prevalence of lymphadenopathy, granulomata, and autoimmune cytopenias. CVID carrying biallelic-mutations had a low prevalence of autoimmunity in comparison with TACI wild-type CVID. Moreover, biallelic-mutated CVID had higher frequency of switched memory B-cells and higher IgM and IgA antibodies to polysaccharide antigens than TACI wild-type and monoallelic-mutated CVID. TACI-mutated IgAD patients had only monoallelic-mutations and did not display clinical difference from IgAD wild-type patients. In conclusion, TNFRSF13B genetic screening of antibody deficiencies may allow the identification of mutational patterns. However, as with counseling for risk assessment, geneticists should be aware that the interpretation of genetic testing for TACI mutations is difficult and the potential impact on clinical management is still limited.

Background and Aim. Portal hypertension has been reported in association with acquired and primary immune deficiencies without a comprehensive description of associated spleno-portal axis abnormalities. Pathological mechanisms are poorly defined. Methods. Observational, single centre study with the aim of assessing the prevalence of spleno-portal axis abnormalities in an unselected cohort of 123 patients with primary antibody deficiencies and without known causes of liver diseases regularly followed up for a mean time of 18 ± 14 years. A cumulative period of 1867 patients-year was analysed. Clinical and immunological data, abdominal ultrasounds, CT scans, and endoscopy features were included in the analysis. Results. Twenty-five percent of patients with primary antibody deficiencies had signs of portal vein enlargement but only 4% of them had portal hypertension, with portal systemic collaterals. Liver biopsies showed liver sinusoids congestive dilatation, endothelization, and micronodularity fulfilling the criteria for noncirrhotic portal hypertension. Patients with portal vein enlargement had severe clinical and immunological phenotypes. Conclusions. In primary antibody deficient patients, infections, inflammations, splenomegaly, increased blood venous flow, and lymphocyte abnormalities contribute to establishment of liver damage possibly leading to noncirrhotic portal hypertension. Patients with primary antibody deficiency should be considered a good model to give insight into the pathological mechanisms underlying noncirrhotic portal hypertension.