Monogenic forms of common variable immunodeficiency and implications on target therapeutic approaches.

PURPOSE OF REVIEW: Common variable immunodeficiency (CVID) is the most common symptomatic inborn error of immunity. The disorder is characterized by variable clinical and immunological manifestations, and, in a small minority of patients, a monogenic cause may be identified. In this review, we focalized on three different monogenic forms of CVID-like disease. RECENT FINDINGS: Activated phosphoinositide 3-kinase delta syndrome (APDS) is a rare disorder characterized by hyperactivated class I phosphatidylinositol-3 kinase (PI3K) pathway. Affected patients present with respiratory infectious episodes, impaired viral clearance and lymphoproliferation. Recently, a direct PI3K inhibitor has been approved and it showed encouraging results both in controlling clinical and immunological manifestations of the disease. On the other hand, patients with defects in CTLA-4 or LRBA gene present with life-threatening immune dysregulation, autoimmunity and lymphocytic infiltration of multiple organs. Abatacept, a soluble cytotoxic T lymphocyte antigen 4 (CTLA-4) fusion protein that acts as a costimulation modulator, has been widely implemented for affected patients with good results as bridge treatment. SUMMARY: Understanding the biological basis of CVID is important not only for enriching our knowledge of the human immune system, but also for setting the basis for potential targeted treatments in this disorder.

Rituximab Monotherapy Is Effective as First-Line Treatment for Granulomatous Lymphocytic Interstitial Lung Disease (GLILD) in CVID Patients.

Granulomatous lymphocytic interstitial lung disease (GLILD) represents a fatal immune dysregulatory complication in common variable immunodeficiency (CVID). Evidence-based diagnostic guidelines are lacking, and GLILD treatment consists in immunosuppressive drugs; nonetheless, therapeutical strategies are heterogeneous and essentially based on experts' opinions and data from small case series or case reports.We aimed to evaluate the efficacy and safety of first-line Rituximab monotherapy for CVID-related GLILD, by assessing symptoms and quality of life alterations, immunological parameters, pulmonary function tests, and lung computed tomography.All six GLILD patients received Rituximab infusions as a first-line treatment. Rituximab was administered at 375 mg/m2 monthly for six infusions followed by maintenance every 3 months; none of the patients experienced severe adverse events. Symptom burden and quality of life significantly improved in treated patients compared to a control group of CVID patients without GLILD. Rituximab treatment indirectly caused a trend toward reduced T-cell activation and exhaustion markers sCD25 and sTIM-3. Lung function improved in treated patients, with statistically significant increases in TLC and DLCO. Lung CT scan findings expressed by means of Baumann scoring system displayed a reduction in the entire cohort.In conclusion, first-line monotherapy with Rituximab displayed high efficacy in disease remission in all treated patients, with improvement of symptoms and amelioration of quality of life, as well as restoration of PFTs and lung CT scan findings.

CARD11 dominant negative mutation leads to altered human Natural Killer cell homeostasis.

Dominant negative mutations in CARD11 have been reported in patients with immune dysregulation, severe atopic features, and variable T cell alterations. Data on Natural killer (NK) cells from affected patients are lacking. We report on a 12-year-old boy with severe atopic dermatitis, food induced anaphylaxis and hypogammaglobulinemia harbouring a novel de novo heterozygous variant c.169G > A; p.Glu57Lys in CARD11. The dominant negative effect of this mutation was confirmed on both CD4+ and CD8+. CTLA4+Foxp3+CD4+ Tregs were severely reduced. Patient's NK cells showed reduced expression of NKp46, NKG2D and CD69. Patient's CD56bright NK cells showed in vitro impaired production of IFN-γ. Steady state pS6 levels on patient's NK cells were increased and remained elevated upon IL2 + IL12 + IL18 overnight stimulation. Overall, the effect of CARD11 mutation on mTORC1 differs between T and NK cells. These findings may explain the increased susceptibility to viral infections and the reduced immune surveillance in affected patients.

Lymphocyte alterations in patients with Common Variable Immunodeficiency (CVID) and autoimmune manifestations.

INTRODUCTION: Autoimmunity is a common feature in CVID patients. To date the mechanisms leading to the development of such complications are not fully elucidated. MATERIALS AND METHODS: Data from 122 CVID patients subdivided in three groups based on the absence of autoimmunity (n-AI) or the presence of hematologic autoimmune phenomena (Cy-AI) or non-hematologic autoimmune phenomena (n-Cy-AI) were evaluated. RESULTS: We identified a total of 128 autoimmune manifestations in 55/122 patients (45.1%). 30/122 (24.6%) patients presented hematologic autoimmune phenomena while 29/122 (23.8%) presented gastrointestinal autoimmune involvement. Immune thrombocytopenia was the most common manifestation (27/122; 22.1%), followed by autoimmune hemolytic anemia (18/122; 14.8%) and autoimmune enteropathy (17/122; 13.9%). Cy-AI patients displayed higher CD4+ effector memory and terminally differentiated CD8+ cells with lower percentages of naïve and recent thymic emigrants (RTEs) CD4+ cells and a significant expansion of the CD19hiCD21low population. CONCLUSIONS: CVID patients developing autoimmune cytopenias display characteristic immune phenotypic features.

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

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.

Activated Phosphoinositide 3-Kinase Delta Syndrome 1: Clinical and Immunological Data from an Italian Cohort of Patients.

Activated phosphoinositide 3-kinase delta syndrome 1 (APDS-1) is a recently described inborn error of immunity caused by monoallelic gain-of-function mutations in the PIK3CD gene. We reviewed for the first time medical records and laboratory data of eight Italian APDS-1 patients. Recurrent sinopulmonary infections were the most common clinical feature at onset of disease. Seven patients presented lymphoproliferative disease, at onset or during follow-up, one of which resembled hemophagocytic lymphohistiocytosis (HLH). Genetic analysis of the PIK3CD gene revealed three novel mutations: functional testing confirmed their activating nature. In the remaining patients, the previously reported variants p.E1021K (n = 4) and p.E525A (n = 1) were identified. Six patients were started on immunoglobulin replacement treatment (IgRT). One patient successfully underwent hematopoietic stem cell transplantation (HSCT), with good chimerism and no GVHD at 21 months post-HSCT. APDS-1 is a combined immune deficiency with a wide variety of clinical manifestations and a complex immunological presentation. Besides IgRT, specific therapies targeting the PI3Kδ pathway will most likely become a valid aid for the amelioration of patients' clinical management and their quality of life.

Paediatric MAS/HLH caused by a novel monoallelic activating mutation in p110δ.

This study provides evidence for the first time for APDS-1 presenting as MAS/HLH, with evident clinical implications in patient's management and prognosis.

First-ever convulsive seizures in children presenting to the emergency department: risk factors for seizure recurrence and diagnosis of epilepsy.

AIM: Aetiologies of first-ever convulsive seizures may be diverse, not all leading to recurrence or epilepsy diagnosis. We aimed to describe the epidemiology of first-ever convulsive seizures in children, investigating risk factors for recurrence and epilepsy diagnosis. METHOD: This was a retrospective study of children presenting with a first-ever convulsive seizure to a tertiary-care paediatric emergency department (PED) in Italy, in a 12-month period (2011-2012). RESULTS: One hundred and eight children (57 males, 51 females) presented to the PED for a first-ever convulsive seizure; 90.7% were 6 months to 6 years old (median age 1y 10mo, mean 2y 7mo, range 0mo-14y 4mo). Seizure duration was less than 5 minutes in 76.8%. Seizures were 'unprovoked' in 19.4% and 'provoked' in 80.6%. At 4-year follow-up, 37.9% of patients experienced recurrence and 13.6% received a diagnosis of epilepsy. Factors significantly associated with recurrence were the 'unprovoked' nature of the first seizure, multiple seizures in the first 24 hours, positive family history of febrile seizures or epilepsy, and pre-existing neurological conditions/problems. Factors significantly associated with a diagnosis of epilepsy were the 'unprovoked' nature of the first seizure, age older than 6 years, pre-existing neurological conditions/problems, and focal onset of first seizure. INTERPRETATION: Children presenting to the PED with first-ever convulsive seizures represent a heterogeneous group. The identification of prognostic factors for recurrence and epilepsy diagnosis may help provide tailored counselling and follow-up. WHAT THIS PAPER ADDS: Seizures were 'unprovoked' in 19.4% and 'provoked' in 80.6% of children presenting to the emergency department. At 4-year follow-up, 37.9% relapsed, and 13.6% received a diagnosis of epilepsy. 'Unprovoked' first seizure, family history of febrile seizures, and pre-existing neurological conditions were associated with recurrence. 'Unprovoked' first seizure, age younger than 6 years, and pre-existing neurological conditions were associated with epilepsy diagnosis.