Narrative review on the management of moderate-severe atopic dermatitis in pediatric age of the Italian Society of Pediatric Allergology and Immunology (SIAIP), of the Italian Society of Pediatric Dermatology (SIDerP) and of the Italian Society of Pediatrics (SIP).

Currently, there are a few detailed guidelines on the overall management of children and adolescents with moderate-severe atopic dermatitis. AD ​​is a complex disease presenting with different clinical phenotypes, which require an individualized and multidisciplinary approach. Therefore, appropriate interaction between primary care pediatricians, pediatric allergists, and pediatric dermatologists is crucial to finding the best management strategy. In this manuscript, members of the Italian Society of Pediatric Allergology and Immunology (SIAIP), the Italian Society of Pediatric Dermatology (SIDerP), and the Italian Society of Pediatrics (SIP) with expertise in the management of moderate-severe atopic dermatitis have reviewed the latest scientific evidence in the field. This narrative review aims to define a pathway to appropriately managing children and adolescents with moderate-severe atopic dermatitis.

New Directions in Understanding Atopic March Starting from Atopic Dermatitis.

Recent evidence showed that the postulated linear progression of the atopic march, from atopic dermatitis to food and respiratory allergies, does not capture the heterogeneity of allergic phenotypes, which are influenced by complex interactions between environmental, genetic, and psychosocial factors. Indeed, multiple atopic trajectories are possible in addition to the classic atopic march. Nevertheless, atopic dermatitis is often the first manifestation of an atopic march. Improved understanding of atopic dermatitis pathogenesis is warranted as this could represent a turning point in the prevention of atopic march. In this review, we outline the recent findings on the pathogenetic mechanisms leading to atopic dermatitis that could be targeted by intervention strategies for the prevention of atopic march.

Atopic dermatitis and atopic march: which link?

There is a long standing debate on the atopic march in childhood. The natural progression of allergic manifestations may be considered as comorbidities, which occur more frequently in a specific evolutive age. On the other hand, the natural history of allergies in children may follow trajectories that may be heterogeneous. The effects of atopic march in clinical practice have also been reported.

Atopic dermatitis.

Atopic dermatitis (AD) is a common inflammatory skin disease, clinically characterized by recurrent eczematous lesions and intense itching, leading to excoriations and susceptibility to cutaneous infections. Although it is considered a pediatric disorder, mainly starting in infancy, it is also very common in adults. Etiology of AD is complex and multifactorial: interaction between genetic susceptibility and environment, but also cutaneous barrier impairment, change in microbiome composition and innate and adaptive immune dysregulation are the main factors involved in the pathogenesis of the disease. Originally, the disorder was considered mediated by an imbalance towards a T-helper 2 response and excessive IgE production to allergens, but now it is recognized as a lifelong disposition with variable clinical expressivity, where dysfunctions of the epidermal barrier, immune system and microbiome play a central role. AD leads to a substantial psycho-social burden on patients and their relatives and increases the risk of other allergic and non allergic disorders. The real economic impact of AD is difficult to measure due to the broad spectrum of disease severity and the multiple direct and indirect costs, but the overall medical expenses seem to be very high and similar to those of other diseases such as diabetes. Currently, a multiple therapeutic approach is aimed only at improving the skin state, reducing itching and keeping a stable condition. New safety and curative treatments may be developed only after enhancing our understanding on the pathogenesis of AD and the heterogeneity of its clinical manifestations.

Oral immunotherapy in children with IgE-mediated hen's egg allergy: Follow-ups at 2.5 and 7 years.

BACKGROUND: The present report was a follow-up investigation at 2.5- and 7-year intervals of a previous study of 20 children with moderate-to-severe immunoglobulin E (IgE) mediated hen's egg (HE) allergy who received oral immunotherapy (OIT) with raw HE. The study design of the previous study divided the 20 subjects into two groups of 10 each: (1) group 1, the OIT group (OIT-G), and, (2) group 2, an age-matched control group (C-G). In that study, 8 of 10 of the children in the OIT-G were successfully desensitized, one child was partially desensitized, and desensitization failed in one child. The aims of the present study were to evaluate the long-term effectiveness and safety profile of OIT with raw HE, and to assess the course and prognostic value of skin-prick tests (SPT) and serum-specific HE-IgEs in this study population. METHODS: Of the 20 children who were recalled, 2 dropped out, which left 18 to be evaluated. Information on their HE intake was recorded, and SPTs with HE allergen extracts and with raw and hard-boiled HE were performed. Ovomucoid- and ovalbumin-specific IgE levels were also measured. RESULTS: At the first (2.5-year) and second (7-year) follow-ups, 87.5% of the children in the OIT-G who tolerated raw HE were still tolerant, whereas the children in the C-G were significantly less tolerant. Overall, cutaneous sensitivity to HE significantly decreased after the 6-month desensitization period and at both follow-ups with regard to the OIT-G but not with regard to the C-G. A significant reduction in serum ovomucoid- and ovalbumin-specific IgE levels was seen in both the OIT-G and the C-G. CONCLUSION: Clinical raw HE tolerance induced by OIT persists over time. Negativization of SPTs could be considered a more reliable prognostic indicator of clinical tolerance to raw HE than the reduction in specific-HE IgE levels. Raw-HE OIT would seem to be a promising method to treat HE allergy.

Consensus Conference on Clinical Management of pediatric Atopic Dermatitis.

The Italian Consensus Conference on clinical management of atopic dermatitis in children reflects the best and most recent scientific evidence, with the aim to provide specialists with a useful tool for managing this common, but complex clinical condition. Thanks to the contribution of experts in the field and members of the Italian Society of Pediatric Allergology and Immunology (SIAIP) and the Italian Society of Pediatric Dermatology (SIDerP), this Consensus statement integrates the basic principles of the most recent guidelines for the management of atopic dermatitis to facilitate a practical approach to the disease. The therapeutical approach should be adapted to the clinical severity and requires a tailored strategy to ensure good compliance by children and their parents. In this Consensus, levels and models of intervention are also enriched by the Italian experience to facilitate a practical approach to the disease.

Modified expression of peripheral blood lymphocyte muscarinic cholinergic receptors in asthmatic children.

Lymphocytes possess an independent cholinergic system. We assessed the expression of muscarinic cholinergic receptors in lymphocytes from 49 asthmatic children and 10 age matched controls using Western blot. We demonstrated that CD4+ and CD8+ T cells expressed M2 and M4 muscarinic receptors which density were significantly increased in asthmatic children in comparison with controls. M2 and M4 receptor increase was strictly related with IgE and fraction of exhaled nitric oxide (FeNO) measurements and with impairment in objective measurements of airway obstruction. Increased lymphocyte muscarinic cholinergic receptor expression may concur with lung cholinergic dysfunction and with inflammatory molecular framework in asthma.

Streptococcus dysgalactiae subspecies equisimilis bacteraemia in an HIV-1 patient with HBV/HCV co-infections: case report and literature review.

Streptococcus dysgalactiae subspecies equisimilis (SDSE) is a common pathogen in animals and generally considered a rare cause of infection in humans. Recently, epidemiological studies demonstrated an increasing number of severe infections, including bacteraemia and endocarditis, caused by SDSE, mainly in predisposed hosts, immunocompromised by underlying conditions. Even though the immune status seems to play an important role in the appearance of SDSE infections, this microorganism has been rarely described as a pathogen in HIV-1 infected subjects. An extensive review of the literature on this pathogen is reported, with a description of a case of SDSE bacteraemia associated to septic arthritis with soft tissue infection in a patient with HIV-1 disease and chronic hepatitis due to HCV and HBV co-infections.

Oral food desensitization in children with IgE-mediated hen's egg allergy: a new protocol with raw hen's egg.

BACKGROUND: Hen's egg allergy affects young children and can cause severe allergic reactions. Avoidance results in dietary limitations and can affect the quality of life, especially in cases where potentially life-threatening reactions exist. Our objective was to desensitize children with moderate-severe IgE-mediated hen's egg allergy over a 6-month period, by introducing increasing and very gradual daily doses of raw hen's egg in order to enable the children to assume 25ml of this food, or to induce tolerance to the highest possible dose. The protocol foresaw the egg reintroduction in the home setting. METHODS: In this randomized, controlled open study, 20 hen's egg allergic children (10 in the active group) were admitted. A convincing history or a positive double-blind placebo-controlled food challenge confirmed the diagnosis. Oral desensitization was performed with increasing doses starting from 0.27 mg of hen's egg proteins (1 drop of raw hen's egg diluted 1:100). We adopted an original, mathematically calculated protocol in order to ensure a constant, daily increment of doses. RESULTS: 8/10 children (80%) in the active group achieved the daily intake of 25ml over a 6-month period. One child (10%) could tolerate up to 2ml/day while another child (10%) failed the desensitization. Six months after enrolment only 2 children in the control group (20%) could tolerate hen's egg. CONCLUSIONS: We successfully desensitized 8/10 children with IgE-mediated hen's egg allergy in a 6-month period. The partial outcome in the child who could tolerate 2ml/day reduced the risk of severe reactions after unnoticed introduction of egg. A regular protocol that ensures a daily constant increase of doses helps to reduce possible adverse events, thus improving safety and effectiveness.

Immune control of HIV-1 infection after therapy interruption: immediate versus deferred antiretroviral therapy.

BACKGROUND: The optimal stage for initiating antiretroviral therapies in HIV-1 bearing patients is still a matter of debate. METHODS: We present computer simulations of HIV-1 infection aimed at identifying the pro et contra of immediate as compared to deferred Highly Active Antiretroviral Therapy (HAART). RESULTS: Our simulations highlight that a prompt specific CD8+ cytotoxic T lymphocytes response is detected when therapy is delayed. Compared to very early initiation of HAART, in deferred treated patients CD8+ T cells manage to mediate the decline of viremia in a shorter time and, at interruption of therapy, the virus experiences a stronger immune pressure. We also observe, however, that the immunological effects of the therapy fade with time in both therapeutic regimens. Thus, within one year from discontinuation, viral burden recovers to the value at which it would level off in the absence of therapy.In summary, simulations show that immediate therapy does not prolong the disease-free period and does not confer a survival benefit when compared to treatment started during the chronic infection phase. CONCLUSION: Our conclusion is that, since there is no therapy to date that guarantees life-long protection, deferral of therapy should be preferred in order to minimize the risk of adverse effects, the occurrence of drug resistances and the costs of treatment.

Unravelling the complexity of T cell abnormalities in common variable immunodeficiency.

We investigated several phenotypic and functional parameters of T cell-mediated immunity in a large series of common variable immunodeficiency (CVID) patients. We demonstrated that the vast majority of CVID patients presented multiple T cell abnormalities intimately related among them, the severity of which was reflected in a parallel loss of CD4+ naive T cells. A strong correlation between the number of CD4+ naive T cells and clinical features was observed, supporting the subgrouping of patients according to their number of naive CD4+ T lymphocytes. A reduced thymic output and disrupted CD4+ and CD8+ TCR repertoires paralleled the contraction of CD4+ naive T cell pools. The evaluation of activation markers and cytokine production indicated a strong T cell activation that was significantly related to the increased levels of T cell turnover and apoptosis. Finally, discrete genetic profiles could be demonstrated in groups of patients showing extremely diverse T cell subset composition and function. Naive CD4+ T cell levels were significantly associated with the switched memory B cell-based classification, although the concordance between the respective subgroups did not exceed 58.8%. In conclusion, our data highlight the key role played by the T cell compartment in the pathogenesis of CVID, pointing to the need to consider this aspect for classification of this disease.

T-cell homeostasis alteration in HIV-1 infected subjects with low CD4 T-cell count despite undetectable virus load during HAART.

OBJECTIVE: To investigate the pathogenesis of low CD4 T-cell count in subjects who are immunological non responders (InR) to HAART. DESIGN: Thirty-five HIV-positive subjects on HAART for at least 1 year, all with undetectable HIV-1 RNA, were studied. Patients were defined as InR according to a CD4 cell increase < 20% from CD4 cell baseline or CD4 cell count < 200/microl; subjects with a CD4 T-cell increase > 20% from baseline and a CD4 cell count > 200/microl were defined as immunological responders (IR). We performed a comprehensive study to characterize the immune response of InR. METHODS: The immunological phenotype of peripheral blood mononuclear cells, thymic naive T cells, T-cell receptor Vbeta repertoire, serum concentration of interleukin (IL)-7, the expression of IL-7Ralpha on naive and memory CD4 and CD8 T cells, and regulatory T cells (Treg) were studied. RESULTS: In InR a significant reduction (P < 0.0001) of naive and thymic naive CD4 T cells was associated with a reduced expression of IL-7Ralpha in both cell subsets, with an increased serum concentration of IL-7 was observed. Furthermore, an increased immune activation with a reduced Treg frequency and increased number of expansions of Vbeta families was observed. CONCLUSIONS: The reduced expression of IL-7Ralpha associated with the persistent immune activation and the alteration of Treg frequencies in part explains the low level of CD4 T cells observed in InR.