Management Of Atopic Diseases Research Articles

Allergen-specific immunotherapy, novel drugs and biologicals: hopes from the difficult-to-treat allergic child

In the last decades, significant progresses have been reached in the management of atopic diseases in childhood. Several approaches have been proposed in patients affected by moderate-to-severe atopic diseases. Severe asthma and atopic dermatitis are poorly known with different underlying phenotypes and endotypes, and they may require further cares with biological therapies. Omalizumab, anti-IgE monoclonal antibody, is effective and safe in patients with atopic diseases, especially uncontrolled asthma and chronic urticaria. Anti-IL-5 drugs including mepolizumab, reslizumab and benralizumab are effective in resistant eosinophilic asthma. In patients with uncontrolled atopic dermatitis, dupilumab is of benefit. Allergen-specific immunotherapy (AIT) represents the only treatment attaining immunologic tolerance and sustaining improvement in symptoms. Both subcutaneous and sublingual immunotherapies are characterized by a short-term and a long-term efficacy, as demonstrated by a reduced immunologic reactivity after discontinuation. Component-resolved diagnosis has been found an essential diagnostic tool potentially able to increase the efficacy of AIT in polysensitized children, establishing a precise AIT prescription for patient genuinely sensitized to allergens. The future care of allergic diseases in childhood requires an individualized approach to achieve a patient-tailored therapy for difficult-to-treat atopic diseases.

Interleukin-4 and immunoglobulin E levels in newborns at risk of atopic diseases

Background The clinical syndrome of atopy is associated v.ith the production of immunoglobulin E (lgE) in response to antigenic stimulation as part of a type I hypersensitivity reaction. Since early prevention is regarded as an important cornerstone in the management of atopic diseases, the identification of reliable markers such as IgE and interleukin 4 (IL-4) in detecting individuals at risk are of major interest.Objective To determine whether cord blood IgE and IL-4 levels can be used as an predictor of atopy in newborns with a family history of atopic diseases.Methods We conducted a cross-sectional study on healthy-term newborns in the neonatal ward at R.D. Kandou Hospital from June to August 2010. A total of 50 healthy newborns in atopic and non-atopic groups were examined for cord blood IgE and IIA levels.Result The mean cord blood ILA levels in the atopic and non-atopic groups were 0.1 μg/mL (SD 0.08) and 0.1 μg/mL (SD 0.16) (P=0.359), respectively. The mean cord blood IgE levels in the atopic and non-atopic groups were 2.2 IU/mL (SD 1.98) and 0.5 IU/mL (SD 0.29) (P<0.00l), respectively. A point-biserial correlation coefficient analysis showed no significant correlation between ILA levels and family history of atopic disease (rpb=0.098), and a weak correlation between IgE levels and family history of atopic disease (rpb=0.54).Conclusions Cord blood IgE and IL-4 levels should not be used to distinguish newborns with a family history of atopic diseases from those without.

In search for predictive factors for atopy in human cord blood

Since early prevention is regarded as an important corner stone in the management of atopic diseases, the identification of reliable markers detecting individuals at risk are of major interest. Therefore, many efforts have been made to unravel reliable predictors for atopy which might identify children at risk and allow the initiation of preventive strategies at an early stage. In the past, much scientific energy has been forced in particular on the development of as noninvasive methods as possible to reach this goal. It is obvious that the identification of markers for atopy at the earliest time of life - namely immediately after birth - represents one of the most attractive attempts. In consequence various studies have been initiated to address this issue investigating markers for atopy in cord blood. Most of them have been geared to our current knowledge about cellular and soluble factors which are dysregulated in adolescent atopic individuals. Although the findings of these studies will improve our knowledge about the initial evolution of atopy, several parameters evaluated did not show any association or have led to almost conflicting results. In order to provide an up-date about the current developments in this field, recent research findings on predictive factors for atopy in cord blood are summarized in the following synopsis.

6. Atopic disease in childhood

A child with atopy produces IgE antibodies after exposure to common environmental allergens. The atopic diseases (eczema, asthma and rhinoconjunctivitis) are clinical syndromes each defined by a group of symptoms and signs. Not all children with atopy will have atopic disease or develop symptoms after exposure to an allergen. Both genetic and environmental factors determine the development of atopic disease. The presence of specific IgE antibodies to environmental allergens is determined with skin prick or radioallergosorbent testing in children with atopy. Test results should be interpreted in the context of the clinical history and further investigations (eg, allergen avoidance or challenge). Management of atopic disease is frequently symptomatic, but it is important to avoid identified allergen triggers. Immunotherapy may be considered in selected school-age children with severe rhinoconjunctivitis. Preventing atopic disease in high-risk infants and hindering progression of disease in children with established disease are the areas of active research.

Probiotic Bacteria in the Management of Atopic Disease: Underscoring the Importance of Viability

ABSTRACTObjectivesThe aim of this study was to assess the efficacy of oral supplementation of viable and heat‐inactivated probiotic bacteria in the management of atopic disease and to observe their effects on the composition of the gut microbiota.MethodsThe study population included 35 infants with atopic eczema and allergy to cow's milk. At a mean age of 5.5 months, they were assigned in a randomized double‐blind manner to receive either extensively hydrolyzed whey formula (placebo group) or the same formula supplemented with viable (viable LGG group) or heat‐inactivated Lactobacillus GG (heat‐inactivated LGG group), respectively. The changes in symptoms were assessed by the SCORAD method and the presence of some predominant bacterial genera in the feces detected with 16S rRNA‐specific probes.ResultsThe treatment with heat‐inactivated LGG was associated with adverse gastrointestinal symptoms and diarrhea. Consequently, the recruitment of patients was stopped after the pilot phase. Within the study population, atopic eczema and subjective symptoms were significantly alleviated in all the groups; the SCORAD scores (interquartile range) decreased from 13 (range, 4–29) to 8 (range, 0–29) units in the placebo group, from 19 (range, 4–47) to 5 (range, 0–18) units in the viable LGG group, and from 15 (range, 0–29) to 7 (range, 0–26) units in the heat‐inactivated LGG group. The decrease in the SCORAD scores within the viable LGG group tended to be greater than within the placebo group. The treatments did not appear to affect the bacterial numbers within the genera enumerated.ConclusionsSupplementation of infant formulas with viable but not heat‐inactivated LGG is a potential approach for the management of atopic eczema and cow's milk allergy.

Immune effector cells induced by complete Freund's adjuvant exert an inhibitory effect on antigen‐specific type 2 T helper responses

It has been well documented that environmental factors such as antigenpresenting cells and related cytokines could affect the development of T helper cells. The purpose of this study is to investigate the effect of different adjuvants on T cell development. Ovalbumin (OVA) combined with aluminum hydroxide (Alum) plus pertussis toxin (PT) or complete Freund's adjuvant (CFA) were used to sensitize mice; the production of IgG and IgE anti-OVA antibodies was then followed. In addition, OVA-specific proliferative responses and cytokine production by spleen cells were also investigated. The data showed that the adjuvants themselves could modify the pattern of immune response: (1) IgG2a anti-OVA antibody was higher in mice sensitized with OVA + CFA compared to that of mice sensitized with OVA + Alum + PT; (2) the ratio of IFN-gamma/IL-4 produced by OVA-stimulated spleen cells was higher in mice sensitized with OVA + CFA than that of mice sensitized with OVA + Alum + PT: (3) increased percentage of gamma delta T cells was noted in the peritoneal exudate cells of OVA + CFA immunized mice; and (4) the immune response of mice sensitized with OVA + Alum + PT was inhibited by the adoptively transferred ascitic cells from OVA + CFA immunized mice. In general, the data suggested higher IgG2a and the ratio of IFN-gamma/IL-4 was noted in mice sensitized with OVA + CFA. Further elucidation of the regulatory mechanism of allergen-specific T helper cells development and exploration of possible agents for immunotherapy might shed light on the management of atopic diseases.

Enhanced production and gene expression of IL-5 in bronchial asthma. Possible management of atopic diseases with IL-5 specific gene transcription inhibitor.

Infiltration of various inflammatory cells into the bronchial mucosa and submucosa is a prominent pathological feature of bronchial asthma.1–3 Persistent mucosal inflammation, particularly epithelial damage caused by eosinophil-derived products, is believed to contribute to the pathogenesis of bronchial hypersensitivity.4–7 Inhalation of a relevant allergen results in an early asthmatic reaction (EAR) that subsides within 1 to 2 hours. In 40–60% of patients, this early reaction is followed after 6 to 10 hours by a late asthmatic reaction (LAR), which usually subsides during the next 1 to 2 days.8 Accumulating evidence suggests that LAR is a consequence of eosinophilic inflammation in the lung induced by a T cell cytokine, interleukin 5 (IL-5).9–15

Enhanced production and gene expression of interleukin-5 in patients with bronchial asthma: possible management of atopic diseases by down-regulation of interleukin-5 gene transcription.

Interleukin (IL)-5 was produced in vitro by peripheral blood mononuclear cells (PBMCs) of mite-sensitive atopic patients upon challenge with specific allergen, while PBMCs of healthy controls produced essentially no IL-5. Stimuli delivered by the combination of phorbol ester (PMA) and CA2+ ionophore (ionomycin) induced marked IL-5 production by PBMCs obtained from atopic as well as nonatopic asthmatics. CD2- or CD4-bearing-cell depletion almost completely removed IL-5 production and gene transcription while CD8 depletion did not. These findings indicated that CD4+ T cells are the principal source of IL-5 in asthmatic PBMCs. The capacity of PBMCs of atopic asthmatics, nonatopic asthmatics and healthy controls to produce IL-2, IL-3, IL-4, interferon-gamma and granulocyte/macrophage-colony-stimulating factor was comparable among the three groups. FK506 suppressed IL-5 production and gene expression in vitro in a dose-dependent manner.

IL-6 mediated isotype specific suppression of hapten specific IgE in serum of BPO-KLH sensitized mice: role of IFN alpha in maintainance of hapten specific IgE responses.

The ability of IL-6 or IFN alpha or antibodies to these cytokines to regulate serum levels of hapten specific immunoglobulins (IgM, IgG1, IgE, IgA) was studied in BPO-KLH (benzylpenicilloyl-keyhole limpet hemocyanin) sensitized BALB/c mice at the peak of a hapten specific IgE antibody forming cell (AFC) response. To induce peak IgE responses, mice were injected intraperitonealy (i.p.) with BPO-KLH (10 micrograms) in aluminum hydroxide gel (alum) on days 0, 21, and 42. On day 44, mice were injected s.c. with IL-6 (100-1000 U), IFN alpha (1000-10,000 U), anti-IL-6 (100-1000 neutralizing units [NU]), or anti-IFN alpha (1000-10,000 NU). On day 46, levels of BPO specific IgM, IgG1, IgE and IgA in serum were determined (ELISA). Data are expressed as micrograms/ml. IL-6 suppressed BPO specific IgE in serum in isotype specific fashion (to > 90%), increasing IgA (approximately 3 fold), and leaving IgM and IgG1 unchanged. Since removal of endogenous IL-6 with anti-IL-6 increased serum IgE, and suppressed IgG1 (approximately 50%), with IgM and IgA unchanged, this suggests that IL-6 is an isotype specific suppressor of peak IgE responses and as such may be useful in the therapeutic management of atopic disease. IFN alpha treatment increased serum IgE levels (60%), and potentiated IgA responses (> 30 fold), with IgM and IgG1 unchanged. Since removal of endogenous IFN alpha with anti-IFN alpha decreased IgE levels (approximately 50%), increasing IgA, with IgM and IgG1 unchanged, this suggests a role for IFN alpha as an isotype specific helper of peak IgE responses and in maintenance of IgA responses.

Regulation of IgE Biosynthesis

A biologic cell product that in an experimental system completely and and specifically suppresses the IgE response! This is one of the intriguing findings that give rise to optimism that the growing understanding of mechanisms that regulate normal IgE responses will, in the not-too-distant future, provide rational and effective therapy for the prevention and management of atopic diseases.