Development and preliminary validation of a new screening questionnaire for identifying atopic children

Background: Allergic diseases represent a frequent and increasing condition affecting children. A screening questionnaire allowing an easy identification of children with symptoms of allergic diseases may improve management and clinical outcome. The aim of this study was to develop and validate an easy-to-use screening questionnaire to detect children requiring further allergological evaluations. Methods: A 10-item questionnaire, evaluating the presence and the history of the most frequent allergic conditions affecting children, including allergic asthma, allergic rhinitis and conjunctivitis, food allergy, and atopic dermatitis, was developed and administered to 214 parents of children from 5 to 10 years of age (163 with allergic disease and 51 healthy, nonallergic children). Validation was performed by Pearson's correlation between the clinical diagnosis and the responses to the questionnaire. Internal consistency was computed by Cronbach's alpha correlation coefficient. Sensitivity and specificity of the novel questionnaire were assessed by the receiver operating characteristic (ROC) curve. Results: Validation analysis of the new children atopy (ChAt) questionnaire showed good internal consistency with a Cronbach's alpha of 0.757. Responses to the items evaluating the presence of individual allergic conditions significantly correlated with the clinical diagnosis (p<0.001). The ROC curve showed an area of 0.956 and identified a cutoff value >2 of the ChAt questionnaire total score for detection of allergy (sensitivity =0.92 and specificity =0.902). Conclusion: The novel ChAt questionnaire represents a simple tool able to detect the presence of all major allergic diseases in a pediatric population allowing an early identification of allergic multimorbidity and potentially facilitating clinical management

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

Case Report: Altered NK Cell Compartment and Reduced CXCR4 Chemotactic Response of B Lymphocytes in an Immunodeficient Patient With HPV-Related Disease

the study of inborn errors of immunity (IEI) provides unique opportunities to elucidate the microbiome and pathogenic mechanisms related to severe viral infection. several immunological and genetic anomalies may contribute to the susceptibility to develop human papillomavirus (HPV) pathogenesis. they include different acquired immunodeficiencies, EVER1-2 or CIB1 mutations underlying epidermodysplasia verruciformis (EV) syndrome and multiple IEI. whereas EV syndrome patients are specifically unable to control infections with beta HPV, individuals with IEI show broader infectious and immune phenotypes. the WHIM (warts, hypogammaglobulinemia, infection, and myelokathexis) syndrome caused by gain-of-CXCR4-function mutation manifests by HPV-induced extensive cutaneous warts but also anogenital lesions that eventually progress to dysplasia. Here we report alterations of B and NK cells in a female patient suffering from cutaneous and mucosal HPV-induced lesions due to an as-yet unidentified genetic defect. despite no detected mutations in CXCR4, B but not NK cells displayed a defective CXCR4-dependent chemotactic response toward CXCL12. In addition, NK cells showed an abnormal distribution with an expanded CD56(bright) cell subset and defective cytotoxicity of CD56(dim) cells. our observations extend the clinical and immunological spectrum of IEI associated with selective susceptibility toward HPV pathogenesis, thus providing new insight on the immune control of HPV infection and potential host susceptibility factors

Novel artful applications of vaccines at the horizon

Some live vaccines, particularly Bacillus Calmette-Guerin (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

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. hh 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 I kappa B alpha 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

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

The Inborn Errors of Immunity-Virtual Consultation System Platform in Service for the Italian Primary Immunodeficiency Network: Results from the Validation Phase

Purpose: Inborn errors of immunity (IEI) represent a heterogeneous group of rare genetically determined diseases. In some cases, patients present with complex or atypical phenotypes, not fulfilling the accepted diagnostic criteria for IEI and, thus, at high risk of misdiagnosis or diagnostic delay. This study aimed to validate a platform that, through the opinion of immunologist experts, improves the diagnostic process and the level of care of patients with atypical/complex IEI. Methods: Here, we describe the functioning of the IEI-Virtual Consultation System (VCS), an innovative platform created by the Italian Immunodeficiency Network (IPINet). Results: In the validation phase, from January 2020 to June 2021, 68 cases were entered on the IEI-VCS platform. A final diagnosis was achieved in 35/68 cases (51%, 95% CI 38.7 to 64.2). In 22 out of 35 solved cases, the diagnosis was confirmed by genetic analysis. In 3/35 cases, a diagnosis of secondary immunodeficiency was made. In the remaining 10 cases, an unequivocal clinical and immunological diagnosis was obtained, even though not substantiated by genetic analysis. Conclusion: From our preliminary study, the VCS represents an innovative and useful system to improve the diagnostic process of patients with complex unsolved IEI disorders, with benefits both in terms of reduction of time of diagnosis and access to the required therapies. These results may help the functioning of other international platforms for the management of complex cases

Vaccinations in children of non-European origin: The Vax4globe survey

Background: An equitable immunization coverage to “leave no one behind” is one of the World Health Organization Sustainable Development Goals. However, disparities in vaccination coverage exist. The present study aims to investigate vaccine attitude of non-European parents living in Italy and those factors affecting vaccine uptake and equity. Methods: A cross sectional survey, named Vax4globe, on knowledge and immunization compliance in childhood and pregnancy of non-European (non-EU) parents was carried out among general pediatrician and Vaccine Centers located in Lazio Region, between February and July 2023. Logistic regression models were used in univariate and multivariate analyses to examine the socio-demographic parameters mainly associated with the vaccination status. Results: A total of 310 parent/child pair were included in the study. Most children were born in Italy (262/310; 86.5 %), while while 40/310 (13.2 %) migrated from country of origin and 1/310 (0.3 %) was adopted. Mandatory vaccines were perfomed by 270/306 (88 %) children, however flu, papillomavirus and meningococcal group B were vaccines most commonly refused by 208/289 (72 %), 11/36 (31 %) and 9/36 (25 %) parents, respectively. A lower educational degree of parents (p = 0.040) and the migration status of children (p < 0.001) were associated to incomplete or missed immunization. As to maternal immunization 164/310 (53 %) non-EU women decided not to vaccinate and received less information (155/297;52 %) compared to childhood immunization (268/305; 88 %) (p < 0.0001). The educational degree (p = 0.017), the origin from non-EU European countries (p = 0.008) and the age 25–40 years (p = 0.036) and > 40 years (p = 0.007) were associated to lack of immunization during pregnancy. Finally, while 279/310 (90 %) parents were vaccinated against Sars-CoV-2, only 60/199 (30 %) children had been immunized with this vaccine mainly due to the non-mandatory vaccine request at pediatric age and to the doubts about its value according to 39/127 (31 %) and 29/127 (23 %) parents, respectively. Conclusion: Our study highlights the need for targeted strategies to improve vaccine uptake both in childhood and in pregnancy among non-EU individuals living in Italy. Further, to achieve vaccination equity the role of institutions and healthcare personnel is pivotal to overcome vaccine hesitancy

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