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Haploinsufficiency of A20 (HA20) is an inflammatory disease caused by mutations in the TNFAIP3 gene classically presenting with Behcet’s-like disease. A20 acts as an inhibitor of inflammation through its effect on NF-kB pathway. Here we describe four consanguineous patients (three sisters and their mother) with a predominantly autoimmune phenotype, including thyroiditis, type I diabetes, hemolytic anemia and chronic polyarthritis. All patients had recurrent oral ulcers, with only 1 patient presenting also recurrent fever episodes, as a classical autoinflammatory feature. Next generation sequencing identified a novel heterozygous frameshift mutation (p.His577Alafs*95) that causes a premature stop codon in the zinc finger domain of A20, leading to a putative haploinsufficiency of the protein. Functional analyses confirmed the pathogenicity of the mutation. The variant was associated with decreased levels of A20 in blood cells. Accordingly, ex-vivo lipopolysaccharide (LPS)-stimulated patients’ peripheral blood mononuclear cells (PBMCs) showed higher levels of p65 NF-kB phosphorylation, as well as increased production of the proinflammatory cytokines IL-1β, IL-6 and TNF-α. Moreover, in agreement with recent observations, demonstrating a role for A20 in inhibiting STAT1 and IFNγ pathways, markedly higher circulating levels of the two IFNγ-inducible chemokines CXCL9 and CXCL10 were detected in all patients. Supporting the findings of a hyperactivation of IFNγ signaling pathway in HA20 patients, patients’ monocytes showed higher levels of STAT1 without stimulation, as well as higher phosphorylated (active) STAT1 levels following IFNγ stimulation. In conclusion, our study show that in the clinical spectrum of HA20 autoimmune features may predominate over autoinflammatory features and demonstrate, from a molecular point of view, the involvement of A20 in modulating not only the NF-kB, but also the IFNγ pathway.

Familial Mediterranean fever (FMF) is characterized by self limited episodes of fever and polyserositis.1 MEFV gene en codes for a protein named Pyrin, which plays a pivotal role in the activation and secretion of IL-1.2 Daily colchicine is highly effective in preventing attacks in this disorder in a dose-related fashion.3 Many definitions of colchicine resistance are available in the literature. The European League Against Rheumatism (EULAR) guidelines defined resistance as one or more attacks per month in compliant patients who had been receiving the maxi mally tolerated dose for at least 6 months.4 A similar definition was confirmed by a recent consensus among experts.5 In the present national multicentric longitudinal study, we analyze the impact of colchicine treatment on disease activity and quality of life in real life in pediatric and adult patients with FMF.

To investigate the role of some variables, including allergy and autoimmunity, in the pathogenesis of vernal keratoconjunctivitis (VKC). The VKC is a chronic and often severe form of bilateral keratoconjunctivitis. Usually, it begins during the first decade and disappears during the end of the second decade of life.26 patients with VKC were selected. The diagnosis was performed by the ophthalmologist through a score based on ocular signs and subjective symptoms before and after administration of 1% cyclosporine A (Cy) eyedrops. Each variable was graded: 0 = absent; 1 = mild; 2 = moderate; 3 = severe. Patients with a total score ≥7 were included in the study. Blood samples were collected at the initial time for the determination of autoimmunity by total IgE and antinuclear antibodies (ANA). A Skin Prick Test (SPT) was performed on each patient to common inhalants and food allergens.53.8% of the children resulted atopic. The most important allergens were house dust mites and grasses. 46.1% of the patients showed total IgE100 UI/ml and 30.8% had ANA positivity at the first determination. The photophobia occurred in 42.3% of children, most frequently with respect to other symptoms like secretion or tearing (30.8%), foreign body sensation (15.4%), itching and conjunctival hyperemia (11.5%).Fortunately all children improved their symptoms after Cy eyedrop therapy. Moreover, there was an elevated percentage (30.8%) of children with ANA positivity compared with the values in the general pediatric population. Despite the fact that it is a non-specific autoantibody, its high presence in a population of children with VKC may have an important role in clarifying etiopathogenesis and chronic inflammation.

The pathogenesis of rhinosinusitis (RS) is related to inflammation, caused by infections in the acute form of the disease but also by other agents in the chronic forms. Cytology allows to evaluate the defensive components, such as hair cells and muciparous cells, while the presence in the nasal mucosa of eosinophils, mast cells, bacteria and/or fungal hyphae, or spores indicates the nasal pathology. The anatomic and physiologic characteristics of the otorhinosinusal system account for the frequent concomitant involvement of the different components. The pivotal pathophysiologic sites are the ostiomeatal complex, the spheno-ethmoidal recess, and the Eustachian tube. The latter is the link with acute otitis media (AOM), which is the most common disease in infants and children and has major medical, social, and economic effects. Moreover, because of the strict relationship between upper and lower airways, nasal sinus disease may contribute to asthma and sinusitis may be considered as an independent factor associated with frequent severe asthma exacerbations. Concerning the role of allergy, the available data do not permit to attribute a central role to atopy in sinusitis and thus allergy testing should not be a routine procedure, while an allergologic evaluation may be indicated in children with OM, especially when they have concomitant rhinitis.

Allergies are multifactorial diseases the onset of which depends also on genetic and environmental factors in early life. Thus, environmental factors can affect the immune response and modify lung development, thereby leading to asthma. The role of the factors used to date to predict asthma development is modest, and clinical criteria should always be considered in association with familiarity for atopy. The aim of this study is to evaluate the risk of asthma in a population with positive Skin Prick Test (SPT) (which is a reliable marker of atopy) to food allergens, regardless of clinical manifestations in the early years of life. The cohort of children enrolled in our study who had a positive SPT to food in the first three years of life had a prevalence of asthma after 7–14 years, double that of the general pediatric population. This prevalence increased significantly in patients with SPT positivity for food and inhalant allergens. We identified a correlation between the sensitization profile in children under the age of 36 months and the development of asthma during a period of 7–14 years. This study confirms that early sensitization is an important risk factor for the development of asthma, particularly in association with sensitization to inhalants, and that the persistence of food sensitization in school-age children and adolescents is associated to more severe asthma.

OBJECTIVE: Allergic rhinitis (AR) is a disease with high and increasing prevalence. The management of AR includes allergen avoidance, anti-allergic drugs, and allergen specific immunotherapy (AIT), but only the latter works on the causes of allergy and, due to its mechanisms of action, modifies the natural history of the disease. Sublingual immunotherapy (SLIT) was proposed in the 1990s as an option to traditional, subcutaneous immunotherapy. MATERIAL AND METHODS: We reviewed all the available controlled trials on the efficacy and safety of SLIT. RESULTS AND CONCLUSION: Thus far, more than 60 trials, globally evaluated in 6 meta-analyses, showed that SLIT is an effective and safe treatment for AR. However, it must be noted that to expect clinical efficacy in the current practice SLIT has to be performed following the indications from controlled trials, that is, sufficiently high doses to be regularly administered for at least 3 consecutive years.

"Probiotics Usage in Childhood Helicobacter pylori Infection": chapter 51 of the volume "Probiotics,prebiotics,and synbiotics . Bioactive foods in health promotion" . Probiotics may represent a novel approach to the management of H. pylori infection. Although the majority of the studies in children have reported estimated odds ratios greater than 1.0, implying an estimated benefit for the addition of probiotics to triple H. pylori eradication therapy, only few reached statistical significance. Moreover, the very few trials performed in children on the effect of probiotics alone suggest only a temporary inhibition of H. pylori that disappears once the administration of the inhibiting factors is interrupted. Nonetheless, the majority of these studies were based on the relatively small samples, and therefore, they may lack the statistical power necessary to detect an important effect of the probiotics. Finally, in most studies, the effect of probiotic treatment on H. pylori infection in children has been estimated indirectly by 13C-UBT. Probiotic treatment seems to be able to reduce H. pylori therapy-associated side effects and indirectly may help to improve the eradication rate. However, its beneficial effects appear to be strain-specific. We conclude that standardized multicenter, placebo-controlled studies in larger series of children are needed to confirm benefits of probiotics in the management of H. pylori infection in children, including its effect on the severity of H. pylori gastritis. Additional work is necessary to determine the strain, dose and administration to be used. Long-term studies are also needed in children to prove whether the persistent-suppressive effect of probiotics on H. pylori and its associated gastritis could prevent diseases such as gastric cancer or peptic ulcer.

Background Vernal keratoconjunctivitis (VKC) is a chronic disease affecting conjunctiva even though the immunopathogenetic mechanisms underlying this inflammation are unclear. The aim of our study is to investigate serum levels of HMGB1 and circulating sRAGE in children affected by VKC before and after treatment with cyclosporine A (CsA) eye drops and in a group of healthy children. Methods Twenty-four children affected by VKC aged between 5 and 12 yrs of life were enrolled at the Department of Pediatrics, Division of Allergy and Immunology, ‘Sapienza’ University of Rome. Twenty-four healthy children without atopy, ocular, and systemic disease, cross-matched for sex and age to patients affected by VKC, represented the controls. All children affected by VKC were treated with CsA 1% eye drops for 4 wks, and blood samples were collected before and 2 wks after the end of treatment while the controls underwent to a single blood sample at the time of enrollment. Results Serum basal levels of HMGB1 and sRAGE were higher in children with VKC when compared with controls while, in patients affected by VKC, no difference was detected between atopic and non-atopic, and between ANA-positive and ANA-negative children. A significant reduction in serum HMGB1 and sRAGE levels was detected after the therapy while CsA serum levels were negative. Conclusions Our study gives a support to the definition of VKC as a systemic inflammation in which HMGB1 and its soluble receptors could play a role.

We describe the case of a 10-year-old girl with a history of severe persistent asthma and exercise-induced-asthma, controlled using an appropriate treatment with inhaled corticosteroid-long-acting beta-2 adrenergic agonists (ICS+LABA) and leukotriene receptor antagonists. She was healthy until the age of 8 years, when she presented two episodes of radiologically diagnosed pneumonia. After that, she began to present persistent cough, also nocturnal, stridor, dyspnea and respiratory distress and she was sent by pediatrician to our hospital. She performed a global spirometry which shows an obstructive and restrictive phenotype (FEV1: 75,3% and MEF50: 57,6%), without a significantly dilatation after inhaled salbutamol (400 mcg). She underwent to a systemic therapy with oral corticosteroid, with not benefit. She had no fever neither upper respiratory tract infections. We excluded gastro-esophageal reflux disease, cystic fibrosis, mycoplasma and chlamydia pneumonia. Cardiological examination was negative. During hospitalization, she spontaneously expectorated a thick fibrinous mucoid formation. A chest X-ray and a computed tomography (CT) scan showed atelectasis of both lung, widespread hyperlucency, and occlusion of the right main bronchus, compatible with a diagnosis of plastic bronchitis. Plastic bronchitis is a rare disease characterized by the formation of large gelatinous or rigid branching airway casts. The prevalence and etiology of plastic bronchitis are still unknown and the symptoms may also overlap with those of other diseases such as severe asthma, in the severe mucus plugging sometimes seen in allergic bronchopulmonary aspergillosis (ABPA) or in middle lobe syndrome. In the pathogenesis of the disease the inflammation is usually present and initiates cast formation. Treatment includes bronchodilators, inhaled and oral corticosteroids, mucolytics, airway clearance therapy and antibiotics. Other therapies can include inhaled heparin, urokinase, tissue plasminogen activator (TPA), dornase alfa and oral macrolide antibiotics as mucoregulatory therapy 2.

Previous studies have reported a high prevalence of allergy in children with Habitual Snoring (HS), but the relationship between allergy in the early years of life and the subsequent development of this Sleep Disordered Breathing (SDB) is yet to be elucidated. The purpose of the present study was to determine the role of early, under 36 months of age, allergic sensitization to food (with or without sensitization to airborne allergens) in determining the development of HS 8–10 years after. One hundred and fortyeight children (10–14 years, mean age 12 years) with a history of food allergy were selected. Under the age of 36 months, atopic status was assessed by skin prick test for a panel of airborne and food allergens. Questionnaires filled in by parents were used to collect information on children's snoring and associated symptoms. HS was defined as snoring three or more times per week. At 1–3 years of age 54 (36.5%) children were positive to food allergens alone, and 94 (63.5%) were positive also to airborne allergens. After 8–10 years of life, when patients were aged between 10 and 14 years, habitual snoring was reported in 37 (25%) children. Furthermore, among the 54 children under three years of age sensitized only to food, 8 (14.8%) became HS while of the 94 children sensitized to both food and inhalants allergens 29 (30.9%) developed HS. The difference between those two groups was statistically significant (p=0.04). We reported a significant risk of developing HS in children with early allergic sensitization. Specifically this risk was higher when food allergy was associated with inhalant allergy. The onset of upper airway inflammation due to allergic triggers in subjects under three years of age may be related to the subsequent development of SDB after 8–10 years.