Hospitalization for bronchiolitis in children aged ≤ 1year, Southern Italy, year 2021: need for new preventive strategies?

BACKGROUND: Bronchiolitis is a major cause of hospitalization in infants, particularly in the first six months of life, with approximately 60-80% of admissions due to respiratory syncytial virus (RSV) infection. Currently, no prophylactic options are available for healthy infants. The present study aimed at describing the demographic, clinical, and epidemiological characteristics of infants hospitalized for bronchiolitis in the Apulia region of Italy in 2021. METHODS: From January to December 2021, data on children aged 0-12 months admitted for bronchiolitis in nine neonatal or pediatric units covering 61% of pediatric beds of hospitals in the Apulia region of Italy were analyzed. Demographic data, comorbidities, need for oxygen support, length of hospital stay, palivizumab administration, and outcomes were collected. For the purpose of the analysis, patients were divided into those aged 0-3 months and > 3 months. A multivariate logistic regression model was used to explore associations between the need for oxygen support and sex, age, comorbidities, history of prematurity, length of hospital stay, and palivizumab administration. RESULTS: This study included 349 children aged 0-12 months admitted for bronchiolitis, with a peak of hospitalization in November (7.4 cases/1,000 children). Of these patients, 70.5% were RSV positive, 80.2% were aged 0-3 months, and 73.1% required oxygen support. Moreover, 34.9% required observation in the sub-intensive care unit, and 12.9% in the intensive care unit. Of the infants who required intensive care, 96.9% were aged 0-3 months and 78.8% were born at term. Three patients required mechanical ventilation and one, who required Extra Corporeal Membrane Oxygenation, died. Children aged 0-3 months were more likely to show dyspnea, need oxygen support, and have a longer hospital stay. CONCLUSIONS: The present study showed that almost all of the children who required intensive care support were aged ≤ 3 months and most were born at term. Therefore, this age group remains the highest risk group for severe bronchiolitis. Preventive measures such as single-dose monoclonal antibody immunoprophylaxis, and maternal and childhood vaccination against RSV, may reduce the high public health burden of bronchiolitis.

Diagnosis and management of neutropenia in children: The approach of the Study Group on Neutropenia and Marrow Failure Syndromes of the Pediatric Italian Hemato-Oncology Association (Associazione Italiana Emato-Oncologia Pediatrica - AIEOP).

Neutropenia refers to a group of diseases characterized by a reduction in neutrophil levels below the recommended age threshold. The present study aimed to review the diagnosis and management of neutropenia, including a diagnostic toolkit and candidate underlying genes. This study also aimed to review the progress toward the definition of autoimmune and idiopathic neutropenia rising in infancy or in late childhood but without remission, and provide suggestions for efficient diagnostics, including indications for the bone marrow and genetic testing. The management and treatment protocols for common and unique presentations are also reviewed, providing evidence tailored to a single patient.

Vaccinations in Children and Adolescents Treated With Immune-Modifying Biologics: Update and Current Developments.

Treatment with immune-modifying biologics has positively impacted disease control and quality of life in many patients with immune-mediated disorders. However, the higher susceptibility to common and opportunistic pathogens is of concern. Thus, immunization strategies to control vaccine-preventable diseases represent a critical issue in this population. However, limited data exist on the safety, immunogenicity, and efficacy of available vaccines in patients on biologics, particularly in children. Here, according to published literature and real-life experience and practice, we report the interim indications of the Italian Society of Pediatric Allergology and Immunology (SIAIP) Vaccine Committee and of the Italian Primary Immunodeficiency Network (IPINet) Centers on immunization of children and adolescents receiving biologics. Our aim is to provide a practical guidance for the clinician to ensure optimal protection for patients and the community.

Novel artful applications of vaccines at the horizon.

Some live vaccines, particularly Bacillus Calmette-Guérin (BCG), oral polio vaccine (OPV), and measles vaccine, can reduce the incidence of all-cause mortality by outreaching the mere control of specific infections and exerting off-target effects. Asides from the prevention of viral infection, some other vaccines, such as those against flu or rotavirus, could reduce the risk of developing autoimmunity. The nonspecific effects of vaccines are mediated by the innate immune system, mainly through the so-called trained innate immunity. These observations paved the way for developing tolerogenic and trained immunity-based vaccines with substantial implications for more effective use of vaccines and combat vaccine hesitancy.

Pathobiologic Mechanisms of Neurodegeneration in Osteopetrosis Derived From Structural and Functional Analysis of 14 ClC-7 Mutants.

ClC-7 is a chloride-proton antiporter of the CLC protein family. In complex with its accessory protein Ostm-1, ClC-7 localizes to lysosomes and to the osteoclasts' ruffled border, where it plays a critical role in acidifying the resorption lacuna during bone resorption. Gene inactivation in mice causes severe osteopetrosis, neurodegeneration, and lysosomal storage disease. Mutations in the human CLCN7 gene are associated with diverse forms of osteopetrosis. The functional evaluation of ClC-7 variants might be informative with respect to their pathogenicity, but the cellular localization of the protein hampers this analysis. Here we investigated the functional effects of 13 CLCN7 mutations identified in 13 new patients with severe or mild osteopetrosis and a known ADO2 mutation. We mapped the mutated amino acid residues in the homology model of ClC-7 protein, assessed the lysosomal colocalization of ClC-7 mutants and Ostm1 through confocal microscopy, and performed patch-clamp recordings on plasma-membrane-targeted mutant ClC-7. Finally, we analyzed these results together with the patients' clinical features and suggested a correlation between the lack of ClC-7/Ostm1 in lysosomes and severe neurodegeneration. © 2020 American Society for Bone and Mineral Research (ASBMR).

One step closer to influenza vaccine inclusiveness.

Flu virus infection is a common cause of acute respiratory illness, with the major incidence in pediatric age, high morbidity, and mortality. The flu vaccine is recommended for all people aged ≥6 months, unless specific contraindications are present. Younger and older age, pregnancy, chronic diseases like asthma, and immunodeficiency are risk factors for severe complications following flu infection. Thus, these categories represent the target for flu vaccine strategies in most countries. Inactivated influenza vaccine (IIV), recombinant influenza vaccine (RIV) or live-attenuated influenza virus (LAIV) are currently available, with specific precautions and contraindications. We aim to resume the current indications for vaccines in the vulnerable populations to support flu vaccination inclusiveness, in anticipation of a "universal vaccine" strategy.

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.

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.

Consensus of the Italian Primary Immunodeficiency Network on transition management from pediatric to adult care in patients affected with childhood-onset inborn errors of immunity.

Medical advances have dramatically improved the long-term prognosis of children and adolescents with inborn errors of immunity (IEIs). Transfer of the medical care of individuals with pediatric IEIs to adult facilities is also a complex task because of the large number of distinct disorders, which requires involvement of patients and both pediatric and adult care providers. To date, there is no consensus on the optimal pathway of the transitional care process and no specific data are available in the literature regarding patients with IEIs. We aimed to develop a consensus statement on the transition process to adult health care services for patients with IEIs. Physicians from major Italian Primary Immunodeficiency Network centers formulated and answered questions after examining the currently published literature on the transition from childhood to adulthood. The authors voted on each recommendation. The most frequent IEIs sharing common main clinical problems requiring full attention during the transitional phase were categorized into different groups of clinically related disorders. For each group of clinically related disorders, physicians from major Italian Primary Immunodeficiency Network institutions focused on selected clinical issues representing the clinical hallmark during early adulthood.

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).

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.

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.

Clinical, Immunological, and Molecular Features of Typical and Atypical Severe Combined Immunodeficiency: Report of the Italian Primary Immunodeficiency Network.

Severe combined immunodeficiencies (SCIDs) are a group of inborn errors of the immune system, usually associated with severe or life-threatening infections. Due to the variability of clinical phenotypes, the diagnostic complexity and the heterogeneity of the genetic basis, they are often difficult to recognize, leading to a significant diagnostic delay (DD). Aim of this study is to define presenting signs and natural history of SCID in a large cohort of patients, prior to hematopoietic stem cell or gene therapies. To this purpose, we conducted a 30-year retro-prospective multicenter study within the Italian Primary Immunodeficiency Network. One hundred eleven patients, diagnosed as typical or atypical SCID according to the European Society for Immune Deficiencies criteria, were included. Patients were subsequently classified based on the genetic alteration, pathogenic mechanism and immunological classification. A positive relationship between the age at onset and the DD was found. SCID patients with later onset were identified only in the last decade of observation. Syndromic SCIDs represented 28% of the cohort. Eight percent of the subjects were diagnosed in Intensive Care Units. Fifty-three percent had an atypical phenotype and most of them exhibited a discordant genotype-immunophenotype. Pre-treatment mortality was higher in atypical and syndromic patients. Our study broadens the knowledge of clinical and laboratory manifestations and genotype/phenotype correlation in patients with SCID and may facilitate the diagnosis of both typical and atypical forms of the disease in countries where newborn screening programs have not yet been implemented.

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

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.

Immunophenotype Anomalies Predict the Development of Autoimmune Cytopenia in 22q11.2 Deletion Syndrome.

BACKGROUND: Patients with 22q11.2 deletion syndrome (22q11.2DS) may develop severe thrombocytopenic purpura and hemolytic anemia. There are no reliable predictors for the development of hematologic autoimmunity (HA) in these patients. OBJECTIVE: To describe the peculiar B and T subpopulation defects in patients with 22q11DS who have developed HA and test if these defects precede the development of HA. METHODS: We performed a case-control multicenter study. Patients with HA were compared with a control population of 22q11.2DS without HA (non-HA). A complete immunological evaluation was performed at diagnosis and at the last follow-up including extensive T and B phenotypes. RESULTS: Immunophenotype at the last follow-up was available in 23 HA and 45 non-HA patients. HA patients had significantly decreased percentage of naïve CD4+ cells (26.8% vs 43.2%, P = .003) and recent thymic emigrants (48.6% vs 80.5%, P = .046); decreased class-switched B cells (2.0% vs 5.9%, P = .04) and increased naive B cells (83.5% vs 71.4%, P = .02); increased CD16+/56+ both in absolute number (312 vs 199, P = .009) and percentage (20.0% vs 13.0%, P = .03). Immunophenotype was performed in 36 patients (11 HA and 25 non-HA) at diagnosis. Odds ratio (OR) of immune cytopenia were estimated for both CD4 naïve ≤30% (OR 14.0, P = .002) and switched memory B cells ≤2% (OR 44.0, P = .01). The estimated survival curves reached statistical significance, respectively, P = .0001 and P = .002. CONCLUSIONS: Among patients with 22q11.2DS, those with HA have characteristic lymphocyte anomalies that appear considerably before HA onset. Systematic immunophenotyping of patients with 22q11.2DS at diagnosis is advisable for early identification of patients at risk for this severe complication.

A novel monoallelic gain of function mutation in p110δ causing atypical activated phosphoinositide 3-kinase δ syndrome (APDS-1).

This study reports on a novel activating p110δ mutation causing adult-onset hypogammaglobulinemia with lymphopenia without the classical presentation of atypical Activated phosphoinositide 3-kinase δ syndrome (ADPS-1), underlining thus the heterogeneous clinical and immunological presentation of p110δ mutated individuals and offers additional data on the role of p110δ in early and late B cell development in humans.

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.

Long term outcome of eight patients with type 1 Leukocyte Adhesion Deficiency (LAD-1): Not only infections, but high risk of autoimmune complications.

Leukocyte Adhesion Deficiency type 1 (LAD-1) is a rare primary immunodeficiency due to mutations in the gene encoding for the common ß-chain of the ß2 integrin family (CD18). Herein, we describe clinical manifestations and long-term complications of eight LAD-1 patients. Four LAD-1 patients were treated with hematopoietic stem cell transplantation (HSCT), while the remaining four, including two with moderate LAD-1 deficiency, received continuous antibiotic prophylaxis. Untreated patients presented numerous infections and autoimmune manifestations. In particular, two of them developed renal and intestinal autoimmune diseases, despite the expression of Beta-2 integrin was partially conserved. Other two LAD-1 patients developed type 1 diabetes and autoimmune cytopenia after HSCT, suggesting that HSCT is effective for preventing infections in LAD-1, but does not prevent the risk of the autoimmune complications.

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.

Diagnostic value of cell bound and circulating neutrophil antibody detection in pediatric neutropenia.

BACKGROUND: Chronic benign neutropenia of infancy includes primary autoimmune neutropenia (pAIN) and chronic idiopathic neutropenia (CIN). A diagnosis of CIN is supported by the absence of free and/or cell-bound neutrophil autoantibodies, which can be detected by flow cytometry with the indirect-granulocyte immunofluorescence test (I-GIFT) and direct-granulocyte immunofluorescence test (D-GIFT), respectively. Conclusive evidence is lacking on the diagnostic value of the D-GIFT, whose performance requires specific laboratory expertise, may be logistically difficult, and hampered by very low neutrophil count in patient samples. This study investigated whether the evaluation of D-GIFT improves the diagnostic accuracy of pediatric neutropenia. PROCEDURE: I-GIFT and D-GIFT were performed in 174 pAIN, 162 CIN, 81 secondary AIN, 51 postinfection neutropenic, and 65 nonautoimmune neutropenic children referred to this laboratory during 2002-2014. RESULTS: Using 90% specific median fluorescence intensity cut-off values calculated by receiver operating characteristic curves, D-GIFT was positive in 49% of CIN patients, who showed similar clinical features as those with pAIN. In 44 (27%) of 162 CIN patients, I-GIFT was repeated two to three times in a year, resulting positive in 12 and two patients at second and third screening, respectively. Interestingly, 10 of the latter 14 patients showed a positive D-GIFT at the first serological screening. False positive D-GIFT was shown by 12% and 22% of nonneutropenic and nonautoimmune neutropenic patients, respectively. CONCLUSIONS: D-GIFT evaluation improves the diagnostic accuracy of pediatric neutropenia, but improvement of cell-bound antibody detection is needed to decrease false positive results.