Grass pollen‐related seasonal allergic rhinoconjunctivitis (SARg) is clinically heterogeneous in severity, comorbidities, and response to treatment. The component‐resolved diagnostics disclosed also a high heterogeneity at molecular level. Our study aimed at analyzing the characteristics of the IgE sensitization to Phleum pratense molecules and investigating the diagnostic relevance of such molecules in childhood.

Transient hypogammaglobulinemia of infancy (THI) is a primary antibody deficiency occurring in the first years of life and is characterized by a delay in the immunoglobulin production that spontaneously recovers in early infancy. In the young symptomatic child with low IgG levels and more than 2% B cells, there are no peculiar clinical and immunologic features that allow discrimination between self-limiting THI, common variable immunodeficiency, or other dysgammaglobulinemias. Only those patients whose IgG levels have normalized after age 4 years have a definitive THI diagnosis made a posteriori.1Bonilla F.A. Bernstein I.L. Khan D.A. Ballas Z.K. Chinen J. Frank M.M. et al.Practice parameter for the diagnosis and management of primary immunodeficiency.Ann Allergy Asthma Immunol. 2005; 94: S1-S63Abstract Full Text PDF PubMed Scopus (442) Google Scholar, 2Moschese V. Graziani S. Avanzini M.A. Carsetti R. Marconi M. La Rocca M. et al.A prospective study on children with initial diagnosis of transient hypogammaglobulinemia of infancy: results from the Italian Primary Immunodeficiency Network.Int J Immunopathol Pharmacol. 2008; 21: 343-352Crossref PubMed Scopus (59) Google Scholar In a previous study, we demonstrated that a subgroup of children with putative THI shares abnormalities of B-cell memory subsets with other defined immune deficiencies, and cautiously suggested the term “hypogammaglobulinemia during infancy” to define conditions in which it is not yet possible to discriminate THI from other primary antibody defects.3Moschese V. Carsetti R. Graziani S. Chini L. Soresina A.R. La Rocca M. et al.Memory B-cell subsets as a predictive marker of outcome in hypogammaglobulinemia during infancy.J Allergy Clin Immunol. 2007; 120: 474-476Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar Recently, according to the new European Society for Immunodeficiencies diagnostic criteria, a working definition of “unclassified hypogammaglobulinemia” (UH) has been introduced to register patients with IgG values below age-related normal values detected in the first 3 years of life that will be moved to THI diagnosis if there is spontaneous resolution before age 4 years (http://esid.org/Working-Parties/Registry/Diagnosis-criteria). Measurement of pneumococcal antibodies is an important tool in the immunologic assessment of patients with suspected immune deficiencies.4Conley M.E. Notarangelo L.D. Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies).Clin Immunol. 1999; 93: 190-197Crossref PubMed Scopus (893) Google Scholar The aim of this study was to analyze prospectively IgM-, IgA-, and IgG-antibody responses to pneumococcus vaccine (PV) in children with UH until THI or other immune deficiencies criteria were met. In the context of the Italian Primary Immunodeficiency Network, we enrolled 21 patients (age range, 12-36 months) with a history of recurrent infections who had an initial diagnosis of UH in accordance with our national protocol for THI (http://www.aieop.org/stdoc/prot/rec_thi_en_06.pdf) and monitored them until age 4 years with regular clinical and immunologic evaluations. Eighteen healthy age-matched children (HC) (age range, 15-40 months) were used as controls. Informed consent was obtained from the patient's parents. The Institutional Ethical Committee approved the study. All patients and HC received 3 doses of 7-valent conjugated pneumococcus vaccine (PCV 7, Prevnar, Pfizer), with the exception of 5 children with UH and 6 HC who received the third PV dose with unconjugated pneumococcus polyvalent vaccine (Pneumo23; Aventis, Milan, Italy) because they were older than 2 years. Serum samples were collected from children with UH and HC before and 4 weeks after each dose of vaccine (post-I, post-II, and post-III). We measured anti–pneumococcal capsular polysaccharide (PCP) antibodies, anti–polyribosyl-ribitol phosphate antibodies (specific to Hib), and anti–tetanus toxoid by ELISA (The Binding Site, Birmingham, United Kingdom: VaccZyme Anti-PCP IgG Enzyme Immunoassay; Anti-PCP IgA and Anti-PCP IgM EIA kit; VaccZyme Human Anti-Hib Enzyme Immunoassay; VaccZyme Tetanus toxoid IgG).5Cavaliere F.M. Milito C. Martini H. Schlesier M. Dräger R. Schütz K. et al.Quantification of IgM and IgA anti-pneumococcal capsular polysaccharides by a new ELISA assay: a valuable diagnostic and prognostic tool for common variable immunodeficiency.J Clin Immunol. 2013; 33: 838-846Crossref PubMed Scopus (34) Google Scholar Group comparisons were performed using the Mann-Whitney test. Data are presented as median. P values of less than .05 were considered statistically significant. Statistical analysis was performed using Statistical Analysis Software. Data of IgM, IgA, and IgG anti-PCP in HC are reported in Fig 1, A-C. The median level of IgM anti-PCP increased from 85 U/mL before vaccination to 366 U/mL (P = .028) after the first dose. This 4-fold increase was followed by a titer decline to prevaccination values after the second and third doses (87 and 69 U/mL, respectively). The median level of IgA anti-PCP prevaccination titer reached a more than 10-fold increase after the first dose (from 10 U/mL to 115 U/mL; P = .018) and then decreased to 50 and 27 U/mL after the second (P = .015) and third dose, respectively. The median level of IgG anti-PCP showed a more than 10-fold increase after the first dose (from 14 mg/L to 154 mg/L; P = .018). The post-I titer was stable at the post-II evaluation (164 mg/L; P = .008) and approximately halved at the post-III evaluation (78 mg/L in children who received 3 doses of PCV 7 and 111 mg/L in children who received the third PV dose with unconjugated PV vaccine because they were older than 2 years). The post-III titer maintained a more than 4-fold concentration in comparison to prevaccination titers independently of the type of vaccine used for the third immunization (pre vs post-III: P = .01 for PCV7; P = .006 for unconjugated PV). Thus, HC showed a transient IgM response and a persistent IgG response. Of interest was the finding of a strong initial specific IgA response followed by a rapid decline, suggesting an impaired capacity in the first years of life to maintain IgA-mediated memory responses. IgM, IgA, and IgG anti-PCP in children with UH showed a completely different pattern. As shown in Fig 1, A-C, poor specific anti-PCP responses were generally observed. The median IgM anti-PCP levels after each PV dose did not show any significant increase in children with UH (from a prevaccination titer of 35 U/mL to 41 U/mL [post-I], 67 U/mL [post-II], and 54 U/mL [post-III]). The IgA anti-PCP response was generally very low (from a prevaccination median titer of 2 U/mL to 7 U/mL [post-I], 3 U/mL [post-II], and 4 U/mL [post-III]). The IgG anti-PCP response was low (from a median prevaccination titer of 4 mg/L to 19 mg/L [post-I], 28 mg/L [post-II], and 21 mg/L in children who received 3 doses of PCV 7 and 46 mg/L in children who received unconjugated pneumococcus polyvalent as the third dose because they were older than 3 years [post-III]). All except 1 child with UH responded to tetanus toxoid vaccination (median, 1 IU/mL). All children with UH responded to Hib vaccine (median, 1.75 mg/L). B-cell subsets were similar to those already reported in THI children3Moschese V. Carsetti R. Graziani S. Chini L. Soresina A.R. La Rocca M. et al.Memory B-cell subsets as a predictive marker of outcome in hypogammaglobulinemia during infancy.J Allergy Clin Immunol. 2007; 120: 474-476Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar—CD27−IgM+IgD+: 84.6% ± 5.7%; CD27+IgM+IgD+: 8.8% ± 3%; CD27+IgM−IgD−: 4.8% ± 3.1%; CD38++IgM++: 11.5% ± 5.3%. About 90% (19 of 21) of the children with UH normalized their serum total IgG values, within age 22 months, allowing the diagnosis of THI. Conversely, 2 of 21 continued to suffer from recurrent respiratory infections and showed a persistent condition of hypogammaglobulinemia after the fourth year of life. One patient (no. 1) maintained the diagnosis of UH, owing to a marked decrease in IgG level with normal antibody responses. One patient (no. 2) met the criteria for common variable immunodeficiency diagnosis, owing to a marked decrease in IgG (495 mg/dL; age-matched healthy donors, 528-1312 mg/dL) and IgA (23 mg/dL) levels, poor antibody response to vaccines, and low switched memory B cells (2.7%). In this patient, we identified a heterozygous C104R variant in the TNFRSF13B gene encoding the transmembrane activator and calcium modulator and cyclophilin ligand interactor. In the 2 patients who did not normalize total IgG levels at age more than 4 years, we prospectively monitored IgM, IgA, and IgG anti-PCP after the completion of the primary vaccination series for a period of 54 months in patient 1 and for a period of 24 months in patient 2. As shown in Fig 2, A, in patient 1, anti-PCP IgM, IgA, and IgG levels declined over time from the completion of the cycle of immunization and then increased, with a peak at 46 months, when an acute infection, caused by Streptococcus pneumoniae, occurred. In patient 2, anti-PCP IgG and IgA responses were almost undetectable over time whereas only specific IgM antibodies were evident (Fig 2, B). According to a recent Jeffrey Modell Foundation survey, THI is generally listed within the top 10 more prevalent primary immunodeficiency disorders worldwide and as the most frequently reported in Eastern Europe.6Modell V. Knaus M. Modell F. Roifman C. Orange J. Notarangelo L.D. Global overview of primary immunodeficiencies: a report from Jeffrey Modell Centers worldwide focused on diagnosis, treatment, and discovery.Immunol Res. 2014; 60: 132-144Crossref PubMed Scopus (76) Google Scholar Although its outcome is considered benign, the psychological impact of this condition, due to patient's age and frustrating uncertainty on the long-term outlook, is greater than expected.7Titman P. Allwood Z. Gilmour C. Malcolmson C. Duran-Persson C. Cale C. et al.Quality of life in children with primary antibody deficiency.J Clin Immunol. 2014; 34: 844-852Crossref PubMed Scopus (27) Google Scholar In this study, although preliminary for the cohort size and the potential bias of age and vaccination schedule, we demonstrated that children with THI showed an abnormal anti-PCP response. Consistent with our previous report, a further tile is added to B-cell memory defect and immunoglobulin defect.

Pollen‐food syndrome (PFS) is heterogeneous with regard to triggers, severity, natural history, comorbidities, and response to treatment. Our study aimed to classify different endotypes of PFS based on IgE sensitization to panallergens.

Background Cow’s milk protein (CMP) allergy (CMPA) affects 2-6% of children. The most important allergens are a-casein (ACA), a-lactoalbumin (ALA) and b-lactoglobulin (BLG). BLG, absent in human milk, is considered to be the major allergen of CMP. Little is known about T cells response and cytokines profile in relation to CMPA and tolerance acquisition. Our aim was to characterize T cells response and cytokines production to CMP in children with CMPA and in children who outgrew CMPA.

Inhaled corticosteroids (ICS) are established as first-line therapy for persistent asthma in children. Fluticasone propionate (FP) has been used because it has equivalent efficacy when used at half-dose of older-generation ICS and has a comparable safety profile. However, concerns persist about the potential risk of adverse effects of long-term FP therapy on childhood growth, bone, adrenal function and immune system. To evaluate the potential adverse effects of FP, we analyzed growth, glucidic metabolism, hypothalamic-pituitary-adrenal axis, bone metabolism, bone mass density and immune system in a cohort of 19 children (average 102±18 months), with asthma who were in treatment with FP (average duration: 14 months, range: 11–17 months). Of these, 11 children homogenous for control of asthma symptoms, and compliance to therapy, were selected for a prospective study during which they were treated with FP250 mg/day for further 6 months (total period of treatment average duration: 22 months, range: 18–23 months). In all children, no alterations of growth, glucidic metabolism, hypothalamic-pituitary-adrenal axis, bone metabolism, bone mass density, immune system nor severe exacerbation of the disease were observed. Our study, showing that FP was able to control the symptoms of asthma and confirming the lack of systemic side effects at the recommended doses, supports its long-term use in children with asthma.

The prevalence of allergic diseases has considerably increased, mostly in industrialized countries (> 20%), and asthma affects approximately 300 million individuals worldwide. Current therapies are able to control symptoms although they do not modulate immunological dysregulation that characterizes allergic diseases. Over the last 30 years, only a few new drugs have been introduced on the market and they all act on Th2-type response which has a critical role in the pathogenesis of allergic diseases. Recently, a new scenario has been opened on Th17-cells, Th1-type cytokines and innate immune system components involved in the inflammatory pathogenesis of asthma and other allergic diseases. These findings suggest a promising therapeutic role of new agents that block the action of specific cytokines. Furthermore, the concept of an intrinsic structural defect in the bronchial epithelium paves the way to innovative therapeutic strategies. In this review we present an update on therapies for allergic diseases with special focus on asthma.

Primary immunodeficiencies (PIDs) are rare diseases characterized by an increased susceptibility to infections. Early diagnosis and appropriate treatment are critical for reducing morbidity and mortality. Based on available data, the efficacy of antibiotic administration for the prophylaxis of infections remains uncertain, and recommendations supporting this practice are poor. The use of antimicrobial prophylaxis is mainly based on single institution-specific experience without controlled measurements of patient safety and quality health outcomes. To address this issue an Italian Network on Primary Immunodeficiencies (IPINet) has been set up in 1999 within the Italian Association of Pediatric Hematology and Oncology (AIEOP) to increase the awareness of these disorders among physicians. Further, diagnostic and treatment guideline recommendations have been established to standardize the best clinical assistance to all patients, including antibiotic prophylaxis, and for a national epidemiologic monitoring of PIDs. The aim of this review is not only to give a scientific update on the use of antimicrobial prophylaxis in selected congenital immunological disorders but also to draw a picture of this practice in the context of the Italian Primary Immunodeficiency Network (IPINet). Controlled multicenter studies are necessary to establish if, when and how you should start an efficacious antimicrobial prophylaxis.

The ability of vaccine antigen to generate protection is a challenge that cannot be restricted to the antibody response; however, the contribution of T cell-mediated mechanisms has not been extensively analyzed. Age and administration to specific categories of patients, i.e. children with recurrent infections (RI), are some of the factors that might affect the vaccine immune response. We investigated the humoral and cellular response to tetanus toxoid (TT) vaccine in 104 healthy children (HC), 11 newborns and 22 healthy adults to characterize the status of immunity according to age and compared it to 118 RI children. Humoral and cellular responses varied in both groups according to age and doses of TT administered. The prevalence of antibody and cellular response was similar in both cohorts (HC 88 percent and 82 percent versus RI 86 percent and 85 percent), however, TT antibody values were significantly higher in 12-18 months old RI children compared to HC (median: 5 IU/ml vs 1.10 IU/ml) (p = 0.02). The lack of an efficient immune response was observed in 12-15 percent of children from both cohorts. Our data showed that specific antibodies were responsible for early protection, whereas cell-mediated mechanisms may contribute to the generation of long-term immunity after an appropriate vaccine recall. The occurrence of higher TT antibody values in 12-18 months old RI children deserves additional research to determine whether they are caused by different infectious agents and/or by other environmental factors. Clarification of this issue is important for categorizing patients into an optimal vaccine policy.

Common variable immunodeficiency (CVID) is considered the most common symptomatic antibody deficiency and, although mainly reported in adults, it may present from childhood. Few data on the impact of TACI defects on the clinical and immunological status of children are available. We screened 42 hypogammaglobulinemia children to investigate the frequency and mutational features of TACI defects. The genetic, clinical and immunological characterization was extended to 31 relatives of 11 children with TACI mutations. Of interest, our analysis showed a considerably higher mutation frequency in hypogammaglobulinemic children (13/42; 31%) than in other cohorts of adult patients. In seven out of nine families with the C104R variant, the prevalence of autoimmunity was significantly higher in C104R heterozygous relatives (8/15; 53%) than in those with no C104R mutation (1/11; 9%). Our data suggest a different impact of TACI mutations, from hypogammaglobulinemia in children to autoimmune disease in adulthood.