Follow-up and outcome of symptomatic partial or absolute IgA deficiency in children.

Selective IgA deficiency is defined as absolute or partial when serum IgA level is < 7 mg/dl or 2 SD below normal for age, respectively. Few data are available on partial selective IgA deficiency, as probably most children with low serum IgA are seldom referred to a specialist clinic in common pediatric practice. The aim of our study was to better define the profile of both symptomatic forms and their clinical outcome in a pediatric immunology setting. Thus, clinical and immunological data from 103 symptomatic patients with selective IgA deficiency (53 absolute and 50 partial), 4-18 years of age, were collected at diagnosis and 80 patients (44 absolute and 36 partial) were monitored for a mean period of 5 years. Also, the prevalence of TNFRSF13B mutations has been assessed in 56 patients. The most common clinical features were infections (86/103; 83%), allergy (39/103; 38%), and autoimmunity (13/103; 13%). No significative differences were observed between absolute and partial selective IgA deficiency patients. However, a significative difference in the rate of IgA normalization between partial and absolute selective IgA deficiency patients (33 vs 9%, p = 0.01) was detected. Furthermore, a lower incidence of infections was associated to a normalization reversal compared to a final absolute or partial defect status (12 vs 53 and 64% respectively, p < 0.01).Conclusions: Regardless of a diagnosis of absolute or partial defect, monitoring of symptomatic patients with selective IgA deficiency is recommended overtime for prompt identification and treatment of associated diseases. Further, diagnostic workup protocols should be revisited in children with IgA deficiency. What is Known: ● Selective IgA Deficiency is the most common primary immunodeficiency and is usually asymptomatic. ● Symptomatic pediatric patients with selective IgA deficiency mostly suffer with respiratory and gastrointestinal infections. What is New: ● Symptomatic children with partial IgA defect may have similar clinical, immunological, and genetic features than symptomatic children with absolute IgA deficiency. ● Symptomatic children with partial IgA deficiency deserve accurate monitoring for associated diseases as per children with absolute IgA deficiency.

Biweekly Hizentra® in Primary Immunodeficiency: a Multicenter, Observational Cohort Study (IBIS).

Immunoglobulin G (IgG) replacement therapy is a standard treatment for patients with primary immunodeficiency diseases (PIDs). Hizentra®, a 20% human subcutaneous IgG (SCIG), is approved for biweekly administration for PIDs. The aim of the multicenter IBIS study was to prospectively investigate the efficacy of biweekly Hizentra® compared with previous IVIG or SCIG treatment regimens in patients with PIDs. The study consisted of a 12-month retrospective period followed by 12-month prospective observational period. The main endpoints included pre-infusion IgG concentrations, proportion of patients with serious bacterial infections (SBIs), other infections, hospitalizations due to PID-related illnesses, and days with antibiotics during the study periods. Of the 36 patients enrolled in the study, 35 patients continued the study (mean age 26.1 ± 14.4 years; 68.6% male). The mean pre-infusion IgG levels for prior immunoglobulin regimens during the retrospective period (7.84 ± 2.09 g/L) and the prospective period (8.55 ± 1.76 g/L) did not show any significant variations (p = 0.4964). The mean annual rate of SBIs/patient was 0.063 ± 0.246 for both prospective and retrospective periods. No hospitalizations related to PIDs were reported during the prospective period versus one in the retrospective period. All patients were either very (76.5%) or quite (23.5%) satisfied with biweekly Hizentra® at the end of the study. In conclusion, the IBIS study provided real-world evidence on the efficacy of biweekly Hizentra® in patients with PIDs, thus verifying the data generated by the pharmacometric modeling and simulation study in a normal clinical setting.

IPINeT Ped-unPAD Study: Goals, Design, and Preliminary Results.

Background: An unclassified primary antibody deficiency (unPAD) is a widely heterogeneous clinical entity, recently identified within the spectrum of Inborn Errors of Immunity (IEIs). Since unPAD has been traditionally considered as a mild condition, it has incorrectly received little attention, resulting in the paucity of extensive and comparable studies describing its natural history. To address the gaps in characterizing, understanding, and managing pediatric unPAD patients, the Italian Primary Immunodeficiency Network (IPINet) Ped-unPAD study has recently been launched. Methods: Seventeen IPINeT Centers have expressed interest to participate, and data collection is still on-going. Hereby, we anticipate preliminary key issues emerging from the first 110 enrolled patients, attending three IPINet Centers. Results: A proportion of unPAD patients have experienced a severe infectious phenotype, which required hospitalization in a quarter of patients and antibiotic prophylaxis or Immunoglobulin Replacement Therapy in approximately 10% of patients. In this partial cohort, a mean follow-up (FU) of 5 years confirmed unPAD diagnosis in fifty percent of cases, with the remaining being reclassified as the Transient Hypogammaglobulinemia of Infancy (25%) and other IEIs (25%), such as a Common Variable Immunodeficiency, Selective IgA deficiency, Selective IgM deficiency, and IgG3 subclass deficiency. Conclusions: Despite a phenotype overlap at diagnosis, clinicians should be aware that unPAD is a mutable condition that deserves comprehensive evaluation and long-term monitoring to dissect the final diagnosis for optimal treatment.

The Evolutionary Scenario of Pediatric Unclassified Primary Antibody Deficiency to Adulthood.

BACKGROUND: Unclassified primary antibody deficiency (unPAD) is a relatively novel inborn error of immunity (IEI) condition that can vary with time to more defined entities. Since long-term follow-up (FU) studies are scarce, we aimed to provide insight into the evolutionary clinical and immunological scenario of unPAD children to adulthood and identification of biomarkers of primary immune deficiency (PID) persistence. METHODS: A total of 23 pediatric unPAD patients underwent clinical and immunological FU for a mean time of 14 years (range 3-32 years, median 16 years). RESULTS: UnPAD diagnosis may change over time. At the last FU, 10/23 (44%) children matched the diagnosis of transient hypogammaglobulinemia of infancy and 13/23 (56%) suffered from a persistent PID. In detail, an unPAD condition was confirmed in 7/23 (30%) patients, whereas 3/23 (13%), 2/23 (9%), and 1/23 (4%) were reclassified as common variable immunodeficiency, selective IgA deficiency, and isolated IgM deficiency, respectively. Low IgA, low specific antibody response to pneumococcus, and lower respiratory tract infections at diagnosis were independently associated with IEI persistence. CONCLUSIONS: Long-term monitoring of unPAD patients is required to define their outcome and possible evolution towards a definitive IEI diagnosis.

Vaccine hesitancy and knowledge regarding maternal immunization among reproductive age women in central Italy: a cross sectional study.

Background: Vaccination in pregnancy offers protection to the mother and the newborn. In Italy, influenza, pertussis, and COVID-19 vaccinations are recommended in pregnancy, but vaccination coverage is still far from the National Immunization Plan goals. We aimed to assess knowledge and attitude on maternal immunization in two groups of Italian women, in pregnancy and in reproductive age (non pregnant). Methods: A cross sectional study on Italian childbearing age women gathering information on their knowledge on maternal immunization and attitudes to receiving influenza and pertussis vaccines in pregnancy was carried out at the University of Rome Tor Vergata, between September 2019 and February 2020. Logistic and multinomial regressions were chosen as statistical tests for our analysis. Results: 1,031 women participated in the survey by answering the questionnaire. Out of these, 553 (53.6%) women were pregnant, and 478 (46.4%) were in the reproductive age. 37% (204/553) of pregnant women and 41% (198/476) of non pregnant women are aware of the existence of an immunization plan for pregnant women in Italy. The group with age between 20 and 30, for both pregnant women and women in the reproductive age, has a better knowledge of vaccination in pregnancy. Working status is a variable associated with more awareness about vaccination during pregnancy only for pregnant women (OR = 2.34, p < 0.00001). Educational status, trimester of pregnancy and knowledge on the topic are associated with vaccine hesitancy in our multivariate analysis for pregnant women. In the reproductive age group women who had a previous pregnancy are more likely to be hesitant towards vaccination in pregnancy, on the other hand the one with a higher knowledge and educational status are more likely to get vaccinated. Conclusions: The study highlights the persistent vaccine hesitancy among Italian women of reproductive age and pregnant women. Despite healthcare providers being identified as a reliable source of information, their recommendations alone are insufficient to overcome vaccine hesitancy. Factors such as employment status, educational level, pregnancy trimester, and knowledge about vaccinations during pregnancy influence vaccine hesitancy. Tailored educational interventions and communication campaigns targeting these areas can help reduce vaccine hesitancy and promote maternal immunization.

Case Report: Crossing a rugged road in a primary immune regulatory disorder.

Over the last decades, Inborn Errors of Immunity (IEI) characterized by an immune dysregulatory picture, isolated or combined with infections, have been increasingly identified and referred as Primary Immune Regulatory Disorders (PIRD). PIRD diagnosis may be difficult due to heterogeneity of time onset, sequence of clinical manifestations and laboratory abnormalities. Moreover, the dissection of a PIRD vs. a secondary immunodeficiency (SID) might be a real challenge since the same indications for immunosuppressant treatments might represent per se a PIRD clinical expression. Here we report a female patient with a history of recurrent respiratory and urinary tract infections since early infancy and a diagnosis of Rheumatoid Arthritis in adulthood. After poor response to several biologicals she was treated with Rituximab and sent to immunology referral for a severe hypogammaglobulinemia. Clinical and immunological features matched a diagnosis of common variable immunodeficiency and when IgG replacement therapy and antibiotic prophylaxis were added a good infectious control was obtained. Next generation sequencing analysis has revealed a novel heterozygous VUS in the IKBKB gene (c.1465A > G; p.Ser489Gly). Functional analysis has shown a reduced capacity of B lymphocytes and CD4 positive T cells in inducing IκBα degradation, with negative impact on NF-kB pathway. Due to recurrent infections attributed to a common condition in childhood and to an exclusive autoimmunity-centered approach in adulthood, both diagnosis and suitable treatment strategies have suffered a significant delay. To reduce the diagnostic delay, pediatricians, general practitioners and specialists should be aware of IEI and the challenges to differentiate them from SID. Furthermore, genetic characterization and functional analysis may contribute to a personalized approach, in a perspective of targeted or semi-targeted therapy.

Happy air®, a successful school-based asthma educational and interventional program for primary school children.

BACKGROUND: To investigate whether an active partnership between schools, parents, and pediatricians can improve the management of asthma and quality of life of children with asthma. METHODS: A comprehensive asthma program (Happy Air®), based on a strong family-physician-school relationship, was carried out over a period of 3 years in six primary schools (2765 children). This program provides educational intervention to families, school staff, and students, as well as the administration of written questionnaires to identify children with asthma, asthma diagnosis and management, and, last but not least, extracurricular activities to improve respiratory and psychological conditions. Quality of life of children and parents, at the beginning and end of the program, was assessed using PedsQL™ 4.0 (Pediatric Quality of Life Inventory) measurement model. RESULT: Asthma was diagnosed in 135 children, of which 37 (27%) were diagnosed de novo. In all children, both single item and total clinical asthma scores showed a significant increase (p < .001) at the end of the Happy Air® program. The average scores of both the total PedsQL™ 4.0 and the four Scales were significantly increased (p < .001). CONCLUSION: Happy Air® is a model for a strategy of education- and school-based intervention for children with asthma and their families. This multi-action program for diagnosis, clinical follow-up, education, self-management, and quality-of-life control aims to minimize the socioeconomic burden of asthma disease.

Pediatric health care professionals' vaccine knowledge, awareness and attitude: a survey within the Italian Society of Pediatric Allergy and Immunology.

BACKGROUND: Physicians play a key role in driving vaccine acceptance and their recommendations are crucial to address vaccine hesitancy. The aim of the study was to assess knowledge, awareness and attitude of Italian Pediatric Health Care Professionals (pHCPs) on vaccinations. METHODS: An anonymous on-line questionnaire was developed within the Vaccine Committee of Italian Society of Pediatric Allergy and Immunology (SIAIP) and spontaneously completed by 231 Pediatricians and Pediatric Nurses (PN). RESULTS: An accurate vaccine education was reported by 70% of pediatricians and 13% of PN but 11% of pediatricians versus 26% of PN consult social media instead of scientific sources for their vaccine update. The investigation on the pHCPs attitudes to vaccination in a personal and family setting highlights poor adherence to vaccinations. Only 63% of pediatricians versus 16% of PN (p < 0.0001) annually received the Flu vaccine. In their family setting 93% of pediatricians versus 51% of PN recommended all vaccinations (p < 0.0001). Anti-flu, anti-rotavirus, anti-zoster and anti-pneumococcal vaccines were not regularly recommended by all pHCPs due to doubts of uselessness (55% of pediatricians versus 40% of PN) and preference for "natural immunity" (44% of pediatricians versus 40% of PN). CONCLUSIONS: Our results indicate that pHCPs' attitude and confidence in regards to vaccines remain suboptimal. Current COVID-19 pandemic and the rapid development of vaccines could increase vaccine hesitancy. Due to the documented pHCPs' influence in the parental decision, educational interventions are needed to improve their level of knowledge and counselling skills in order to address parental vaccine hesitancy and to maintain continuity of immunization services.

Pediatric subset of primary immunodeficiency patients treated with SCIG: post hoc analysis of SHIFT and IBIS pooled data.

BACKGROUND: Primary immunodeficiencies (PID) constitute a heterogeneous group of more than 350 monogenetic diseases. PID patients with antibody impairment require lifelong administration of immunoglobulin G replacement therapy, administered either intravenously (IVIG) or subcutaneously (SCIG). Although the effectiveness of weekly and biweekly (every other week) SCIG administration has been shown in several trials, data on the viability of these two regimens in pediatric PID patients are sparse. METHODS: Data on the pediatric subsets of PID patients enrolled in SHIFT (weekly) and IBIS (biweekly) studies were pooled and analyzed to indirectly compare two different 20%-concentrated SCIG (Hizentra®) regimens. The primary endpoints were to evaluate trough IgG levels and cumulative monthly doses; the secondary endpoint was to analyze incidence of infections. RESULTS: Fifteen and 13 children from the SHIFT and IBIS studies were included, respectively. Cumulative 20%-concentrated SCIG monthly dose was slight lower for the biweekly regimen (Δ = - 2.04, 90% CI - 8.3 to 4.23). However, the trough IgG levels were similar between the two groups (Δ = 0.28, 90% CI - 0.51 to 1.07) and constantly above the threshold of 5 g/L. After adjusting for potential confounders, the annualized rate of infections was similar between SHIFT and IBIS patients (incidence rate ratio = 1.09, 90% CI 0.72-1.67); only 1 serious bacterial infection was experienced by a patient in the IBIS group. CONCLUSION: In pediatric PID patients, weekly and biweekly Hizentra® administrations appeared equally effective treatment options.

Rituximab Unveils Hypogammaglobulinemia and Immunodeficiency in Children with Autoimmune Cytopenia.

BACKGROUND: Rituximab (RTX; anti-CD20 mAb) is a treatment option in children with refractory immune thrombocytopenia, autoimmune hemolytic anemia (AHA), and Evans syndrome (ES). Prevalence and clinical course of RTX-induced hypogammaglobulinemia in these patients are poorly known. OBJECTIVE: To evaluate the prevalence and risk factors for persistent hypogammaglobulinemia (PH) after RTX use. METHODS: Clinical and immunologic data from children treated with RTX for immune thrombocytopenia, AHA, and ES were collected from 16 Italian centers and 1 UK center at pre-RTX time point (0), +6 months, and yearly, up to 4 years post-RTX. Patients with previously diagnosed malignancy or primary immune deficiency (PID) were excluded. RESULTS: We analyzed 53 children treated with RTX for immune thrombocytopenia (n = 36), AHA (n = 13), and ES (n = 4). Median follow-up was 30 months (range, 12-48). Thirty-two percent of patients (17 of 53) experienced PH, defined as IgG levels less than 2 SD for age at last follow-up (>12 months after RTX). Significantly delayed B-cell recovery was observed in children experiencing PH (hazard ratio, 0.55; P < .05), and 6 of 17 (35%) patients had unresolved B-cell lymphopenia at last follow-up. PH was associated with IgA and IgM deficiency, younger age at RTX use (51 vs 116 months; P < .01), a diagnosis of AHA/ES, and better response to RTX. Nine patients with PH (9 of 17 [53%]) were eventually diagnosed with a PID. CONCLUSIONS: Post-RTX PH is a frequent condition in children with autoimmune cytopenia; a sizable proportion of patients with post-RTX PH were eventually diagnosed with a PID. In-depth investigation for PID is therefore recommended in these patients.

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

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

Identification of a Btk mutation in a dysgammaglobulinemic patient with reduced B cells: XLA diagnosis or not?

The identification of a Btk mutation in a male patient with <2% CD19(+) B cells warrants making the diagnosis of X-linked Agammaglobulinemia (XLA). Herein we report the case of a 31 year-old male with a gradual decline of peripheral B lymphocytes and low IgA and IgM but normal IgG levels. His clinical history revealed recurrent respiratory and skin infections, sclerosing cholangitis and chronic obstructive pancreatitis. Molecular studies revealed a novel aminoacidic substitution in Btk protein (T316A). His mother, maternal aunts and a maternal female cousin were heterozygotes for the same Btk mutation and were variably affected with pulmonary emphysema. This is a puzzling case where the patient's clinical history and laboratory findings divorce molecular genetics. Either this case confirms the variable expressivity of XLA disease or the T316A change in Btk SH2 domain is a novel non-pathogenic mutation and another unknown gene alteration is responsible for the disease.

Vaccination in immunocompromised host: Recommendations of Italian Primary Immunodeficiency Network Centers (IPINET).

Infectious complications are a major cause of morbidity and mortality in patients with primary or secondary immunodeficiency. Prevention of infectious diseases by vaccines is among the most effective healthcare measures mainly for these subjects. However immunocompromised people vary in their degree of immunosuppression and susceptibility to infection and, therefore, represent a heterogeneous population with regard to immunization. To date there is no well- established evidence for use of vaccines in immunodeficient patients, and indications are not clearly defined even in high-quality reviews and in most of the guidelines prepared to provide recommendations for the active vaccination of immunocompromised hosts. The aim of this document is to issue recommendations based on published literature and the collective experience of the Italian primary immunodeficiency centers, about how and when vaccines can be used in immunocompromised patients, in order to facilitate physician decisions and to ensure the best immune protection with the lowest risk to the health of the patient.

Temporary henna tattoo is unsafe in atopic children.

UNLABELLED: Temporary henna tattoos have become increasingly popular as a safe alternative to permanent tattoos among American and European children and teenagers during the summer holidays. Currently, temporary henna tattoos contain not only henna, but also other additives such as para-phemylenediamine (PPD), which is considered to be the chemical agent that most frequently causes skin reactions associated with the use of commercial black henna. In this report, we describe an 11-year-old boy who applied a temporary black henna tattoo on his right arm during the summer holidays in Greece and developed a severe contact dermatitis at the tattoo site with residual hypopigmentation. He had no previous history of contact dermatitis, however he did suffer from seasonal allergic rhinitis and atopic dermatitis. Patch testing revealed a strong reaction to PPD, a substance commonly contained in temporary henna tattoo preparations. CONCLUSION: Henna tattoos are an increasing problem worldwide since they carry an increased risk of severe skin reactions; therefore we suggest that the use of temporary henna tattoos in children be discouraged.