Diagnostic relevance of IgE sensitization profiles to eight recombinant Phleum pratense molecules.

BACKGROUND: 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. METHODS: We examined 1120 children (age 4-18 years) with SARg. Standardized questionnaires on atopy were acquired through informatics platform (AllergyCARD™). Skin prick tests were performed with pollen extracts. Serum IgE to airborne allergens and eight P. pratense molecules (rPhl p 1, rPhl p 2, rPhl p 4, rPhl p 5b, rPhl p 6, rPhl p 7, rPhl p 11, rPhl p 12) were tested by ImmunoCAP FEIA. RESULTS: The analysis of IgE responses against eight P. pratense molecules showed 87 profiles. According to the number of molecules recognized by IgE, the more complex profiles were characterized by higher serum total IgE, higher grass-specific serum IgE, and higher number and degree of sensitization to pollens. The most frequent IgE sensitization profile was the monomolecular Phl p 1. Sensitization to Phl p 7 was a reliable biomarker of asthma, whereas Phl p 12 of oral allergy syndrome. Sensitization to Phl p 7 was associated with a higher severity of SARg, and complex profiles were associated with longer disease duration. CONCLUSIONS: In a large pediatric population, the complexity of IgE sensitization profiles against P. pratense molecules is related to high atopic features although useless for predicting the clinical severity. The detection of serum IgE to Phl p 1, Phl p 7, and Phl p 12 can be used as clinical biomarkers of SARg and comorbidities. Further studies in different areas are required to test the impact of different IgE molecular profiles on AIT response.

Endotypes of pollen-food syndrome in children with seasonal allergic rhinoconjunctivitis: a molecular classification.

BACKGROUND: 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. METHODS: We examined 1271 Italian children (age 4-18 years) with seasonal allergic rhinoconjunctivitis (SAR). Foods triggering PFS were acquired by questionnaire. Skin prick tests were performed with commercial pollen extracts. IgE to panallergens Phl p 12 (profilin), Bet v 1 (PR-10), and Pru p 3 (nsLTP) were tested by ImmunoCAP FEIA. An unsupervised hierarchical agglomerative clustering method was applied within PFS population. RESULTS: PFS was observed in 300/1271 children (24%). Cluster analysis identified five PFS endotypes linked to panallergen IgE sensitization: (i) cosensitization to ≥2 panallergens ('multi-panallergen PFS'); (ii-iv) sensitization to either profilin, or nsLTP, or PR-10 ('mono-panallergen PFS'); (v) no sensitization to panallergens ('no-panallergen PFS'). These endotypes showed peculiar characteristics: (i) 'multi-panallergen PFS': severe disease with frequent allergic comorbidities and multiple offending foods; (ii) 'profilin PFS': oral allergy syndrome (OAS) triggered by Cucurbitaceae; (iii) 'LTP PFS': living in Southern Italy, OAS triggered by hazelnut and peanut; (iv) 'PR-10 PFS': OAS triggered by Rosaceae; and (v) 'no-panallergen PFS': mild disease and OAS triggered by kiwifruit. CONCLUSIONS: In a Mediterranean country characterized by multiple pollen exposures, PFS is a complex and frequent complication of childhood SAR, with five distinct endotypes marked by peculiar profiles of IgE sensitization to panallergens. Prospective studies in cohorts of patients with PFS are now required to test whether this novel classification may be useful for diagnostic and therapeutic purposes in the clinical practice.

Novel treatments of asthma and allergic diseases.

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.

Immune responses to tetanus vaccination in Italian healthy subjects and children with recurrent infections.

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.

Anti-infective prophylaxis for primary immunodeficiencies: what is done in Italian Primary Immunodeficiency Network centers (IPINet) and review of the literature.

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 impact of TACI mutations: from hypogammaglobulinemia in infancy to autoimmunity in adulthood.

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 hypogammaglobulinemic 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.

A prospective study on children with initial diagnosis of transient hypogammaglobulinemia of infancy: results from the Italian Primary Immunodeficiency Network.

Transient hypogammaglobulinemia of infancy (THI) is a heterogeneous disorder characterized by reduced serum IgG levels in early infancy. A putative diagnosis is initially made after exclusion of other causes of hypogammaglobulinemia while a definitive diagnosis of THI can only be made a posteriori in patients with normalization of IgG levels. The aim of this study is to characterize clinical and immunological features of children with an initial diagnosis of THI in correlation to natural outcome, and to assess predictive laboratory parameters of clinical evolution for this disorder. We prospectively analysed clinical and immunological characteristics of 77 THI children at initial diagnosis and of 57 patients at follow-up. Memory B cell subsets and in vitro immunoglobulin production were evaluated. Seventy patients (91 percent) showed clinical symptoms. Patients suffered from infections (91 percent), allergies (47 percent) and autoimmune disease (4 percent). During follow-up 41/57 children (72 percent) normalized IgG values, mostly within 24 months of age (p less than 0.001), allowing the diagnosis of THI. The 16 children who did not normalize their IgG levels showed a higher frequency of severe infections and autoimmune disease (p less than 0.01). Moreover, they expressed a reduced frequency of IgM and switched memory B cells (p less than 0.01) and an inability to produce IgG in vitro (p less than 0.02). We conclude that most patients with an initial diagnosis of THI spontaneously recover within 24 months of age and have a benign clinical course, while a subgroup of children with undefined hypogammaglobulinemia share a clinical and immunological profile with other primary immunodeficiencies. Early recognition of children with hypogammaglobulinemia during infancy who are likely to suffer from permanent immunodeficiencies later in life would allow prompt and appropriate laboratory and clinical interventions.

Happy Air: a school-based educational program to maximize detection of asthma in children.

OBJECTIVE: To investigate whether an active partnership among school, parents, and pediatricians allows early identification and treatment of asthmatic children. METHODS: An asthma educational program (Happy Air), based on a strong family-physician-school interrelationship, was performed in six primary schools (2,765 children) before administering a screening questionnaire to the parents. RESULTS: A high response rate (96%) demonstrated 2,649 responders available for the asthma screening: 135 children (5%) received a diagnosis of asthma, of which 37 (27%) were recognized de novo. CONCLUSION: The active participation of school and parents is the determining factor for the success of an asthma screening program.

Necrotizing enterocolitis in a 850 gram infant receiving sorbitol-free sodium polystyrene sulfonate (Kayexalate): clinical and histopathologic findings.

We report a 27-week, 850 g infant with severe Streptococcus group B sepsis and life-threatening hyperkalemia due to progressive anuria. On the fourth day of life, after he failed treatment with diuretics, salbutamol, insulin, calcium gluconate and sodium bicarbonate, he was treated with sorbitol-free Kayexalate enemas. Potassium level slowly decreased from 9.2 mmol/l to normal level along with a recovery of normal urine output. On the 11th day of life, clinical and radiological signs of a perforated necrotizing enterocolitis (NEC) occurred and the patient required surgical intestinal resection. Histologic examination of the ileum specimen revealed areas of necrosis with fibrosis and giant cell reaction to a nonpolarizable material consistent with sodium polystyrene sulfonate. Usually, Kayexalate is suspended in hyperosmolar sorbitol solutions and the elevated osmolarity seems to be responsible for hemorrhagic colitis, transmural necrosis and definitely NEC. Our case report shows that Kayexalate per se, and not necessarily suspended in sorbitol, can lead to gastrointestinal tract complications and NEC in preterm infants.

Relationship between uric acid levels and risk of chronic kidney disease in a retrospective cohort of Brazilian workers.

Uric acid (UA) levels are increased in patients with kidney dysfunction. We analyzed the association between asymptomatic hyperuricemia and new-onset chronic kidney disease (CKD). A retrospective cohort study was designed to collect data from employees of an energy generation and distribution company in the city of Rio de Janeiro, Brazil, who had undergone the company's annual medical checkup from 2008 to 2014. People with ≤2 years of follow-up, with baseline estimated glomerular filtration rate (eGFR) <60 mL·min-1·(1.73 m2)-1 or with incomplete data were excluded. The endpoint was defined as eGFR <60 mL·min-1·(1.73 m2)-1 estimated through the chronic kidney disease epidemiology collaboration equation (CKD-EPI). The study included 1094 participants. The mean follow-up period was 5.05±1.05 years and 44 participants exhibited new-onset CKD. The prevalence of hyperuricemia was 4.2%. There was a significant inverse correlation between baseline serum levels of UA and baseline eGFR (R=-0.21, P<0.001). Female gender (OR=4.00; 95%CI=1.92-8.29, P<0.001) and age (OR=1.06; 95%CI=1.02-1.11, P=0.004) but not UA levels (OR=1.12; 95%CI=0.83-1.50; P=0.465) were associated with new-onset CKD. Diabetes mellitus and body mass index were independent factors for fast progression (OR=2.17; 95%CI=1.24-3.80, P=0.007 and OR=1.04; 95%CI=1.01-1.07; P=0.020). These results did not support UA as an independent predictor for CKD progression in the studied population.

Fragilidade em idosos que vivem na comunidade: prevalência e fatores associados / Frailty in community-dwelling older people: prevalence and associated factors

Fundamentos: Idosos que vivem na comunidade são propensos a desenvolver fragilidade, considerada como um estado clinicamente identificável que aumenta a vulnerabilidade a resultados adversos e prediz incapacidade e mortalidade na população idosa. Objetivo: Identificar a prevalência e fatores associados à fragilidade em idosos que vivem em uma comunidade. Método: Trata-se de um inquérito domiciliar transversal e analítico, de abordagem quantitativa realizado com 854 idosos que vivem na comunidade. A fragilidade foi mensurada pela Edmonton Frail Scale (EFS). A associação entre fragilidade e variáveis sociodemográficas e de condições clínicas foi mensurada pela análise múltipla por regressão logística. Resultados: A prevalência de fragilidade encontrada neste estudo foi de 12,3% (IC95%: 10,1 a 14,5). O modelo de regressão logística mostrou que as variáveis estatisticamente associadas à fragilidade foram: queda recorrente, uso de dispositivo para auxílio à marcha, polifarmácia, autopercepção ruim de saúde, dependência nas atividades básicas e instrumentais de vida diária. Conclusão: A prevalência de fragilidade em idosos foi baixa em comparação a outros estudos nacionais que empregaram a EFS. Os resultados indicaram múltiplos fatores associados à fragilidade modificáveis. Assim, a investigação da síndrome da fragilidade bem como dos seus fatores relacionados passíveis de prevenção são ações a serem incluídas na prática clínica. (AU)

Foundations: Elderly people living in the community are prone to developing frailty, considered as a clinically identifiable state that increases vulnerability to adverse events and predicts disability and mortality in the elderly population. Objective: To identify the prevalence and factors associated with frailty in the elderly living in the community. Materials and method: This is a cross-sectional and analytical household survey with a quantitative approach conducted with 854 elderly people living in the community. Frailty was measured by Edmonton Frail Scale (EFS). The association between frailty and sociodemographic and clinical condition variables was measured by multiple analysis using logistic regression. Results: The prevalence of frailty found in this study was 12.3% (95% CI: 10.1 to 14.5). The logistic regression model showed that the variables statistically associated with frailty were: recurrent fall, use of walking aids, polypharmacy, poor self-rated health, dependence on basic and instrumental activities of daily living. Conclusion: The prevalence of frailty in the elderly was low compared to other national studies that employed the SAI. Results indicated potentially modifiable factors associated with frailty. Thus, the investigation of frailty syndrome and its related preventable factors are actions to be included in clinical practice. (AU)

Erythema nodosum: a presenting sign of early onset sarcoidosis.

"Early onset sarcoidosis" is a chronic granulomatous disease occurring in children younger than 5 years of age, and characterized by a classic symptom triad consisting of skin, eye and joint lesions, with on rare occasion pulmonary involvement. The disorder often goes unrecognized because of its rarity and, since polyarthritis and uveitis are the predominant symptoms, most of these children are misdiagnosed as having juvenile chronic arthritis (JCA). A child with erythema nodosum at 7 months of age, later diagnosed as JCA and definitively recognized as "early onset sarcoidosis" is reported. This case shows that, whenever possible, a biopsy showing the typical picture of sarcoid granulomas is crucial to distinguish these clinical conditions.

Insight into B cell development and differentiation.

The main topic of this article is B cell development and differentiation, with a special focus on the mechanisms and molecules that regulate the expression of humoral immunity. Molecular epidemiological analysis was performed on the genes responsible for the X-linked agammaglobulinemia (XLA) phenotype of the majority of Italian patients and their distinct mutations were characterized. Mutations in Bruton's tyrosine kinase (BTK), a member of Tec Family of protein tyrosine kinases, have been found to be mainly responsible for XLA disease. The exact function of BTK in signal transduction is not yet known; thus, the specific role of BTK in receptor-dependent calcium signaling and the pro-antiapoptotic regulatory activity was addressed by transfecting RAMOS-1, a BTK-deficient human Burkitt's/B cell leukemia line with wild-type and mutant constructs. This work may provide clues about critical sites in the molecule and give support for gene therapy as a potential successful approach to XLA. Another aspect of this research is the identification and dissection of the molecular events that are likely to be directly related to the ability to express various isotypes of immunoglobulin with differing function and certain B cell immunodeficiency, mainly common variable disease and non-X-linked hyperIgM. B cell development and maturation steps in different compartments of the immune system are tracked by the analysis of cell-surface molecules and components of the signal transduction pathways, i.e. CD40, CD30, CD27, CD38, CD22 and CD24. A few components involved in B cell development, maturation and differentiation and their specific functional role are at least partially known, but these are far from fitting into an understandable pathway at present.

Neuroimaging is useful for monitoring disease activity in linear scleroderma "en coup de sabre".

Scleroderma is a group of rare chronic connective tissue disorders characterized by collagen accumulation that causes tissue hardening with consequent fibrosis. Skin involvement is mostly frequent, although several internal organs can be impaired (heart, lungs, liver, etc.). In childhood, juvenile localized scleroderma (JLS) is more frequently observed; in this subtype cutaneous lesions predominate frequently on the limbs but also on the face and scalp; in this case, it is referred to as scleroderma "en coup de sabre" (ECDS). Neurological abnormalities have been described in association with ECDS as an effect of progressive scalp and underlying tissues involvement. Up to now, no validated biomarkers exist to evaluate disease evolution and, in this way, frequently diagnosis of central nervous system (CNS) involvement occurs when patients are already symptomatic. We describe the case of a 5-year old girl, with a diagnosis of ECDS characterized by the typical scalp lesion, with slight subsidence of the underlying diploe. In this case, radiological examination has been essential to evaluate the degree of progression of skin and soft tissues lesions and to clarify the right therapeutic approach. In selected JLS children, both MRI and CT with 3D reconstruction images provide a useful tool to monitor disease evolution and to address therapeutic choices.

High-resolution global maps of 21st-century forest cover change.

Quantification of global forest change has been lacking despite the recognized importance of forest ecosystem services. In this study, Earth observation satellite data were used to map global forest loss (2.3 million square kilometers) and gain (0.8 million square kilometers) from 2000 to 2012 at a spatial resolution of 30 meters. The tropics were the only climate domain to exhibit a trend, with forest loss increasing by 2101 square kilometers per year. Brazil's well-documented reduction in deforestation was offset by increasing forest loss in Indonesia, Malaysia, Paraguay, Bolivia, Zambia, Angola, and elsewhere. Intensive forestry practiced within subtropical forests resulted in the highest rates of forest change globally. Boreal forest loss due largely to fire and forestry was second to that in the tropics in absolute and proportional terms. These results depict a globally consistent and locally relevant record of forest change.

Kinetics of in vitro response to Beta-lactoglobulin in children allergic to and tolerant of cow´s milk protein

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