Immune mechanisms induced by sublingual immunotherapy in allergic respiratory diseases.

Allergic respiratory diseases (ARDs) are still a major burden on global public health. Sublingual immunotherapy (SLIT) is a mode of allergen immunotherapy (AIT) which involves administration of the allergen under the tongue, and benefits from tolerogenic properties of the oral mucosa. Studies revealed reduced levels of eosinophilia and eosinophil-dominated inflammation in airways of both animals and humans after SLIT. SLIT was also suggested to lower basophil responsiveness and innate lymphoid cell-2 function in blood samples collected from patients with ARD. Moreover, apart from shifting pathogenic type 2 (TH2) to a type 1 (TH1) and protective regulatory (Treg) polarization of helper T-cell immune response, antibody isotype switch from IgE to IgG1, IgG2, IgG4 and IgA was also reported in patients with ARD receiving SLIT. Today, the literature on SLIT-mediated activities is still scarce and more studies are required to further enlighten the mechanisms utilized by SLIT for the induction of tolerance. The aim of this review is to summarize the current knowledge about the immune-regulatory mechanisms induced by SLIT against ARDs.

Cutaneous Allergic reactions to pine processionary caterpillar (Thaumetopoea Pityocampa): a complicated cutaneous reaction in an infant and review of the literature.

BACKGROUND: Thaumetopoea Pityocampa (TP) are frequent in the Mediterranean region especially affecting forest workers in pinewood areas. The common symptoms include swelling, rash or burns like any form of dermatitis. The reactions can be triggered by mechanical, chemical or allergic factors and the `allergic` reaction is caused by sensitization to a hair protein named `thaumetopoein`. This protein triggers the IgE mediated reaction resulting in the mast cell degranulation causing urticaria. Different kinds of allergic reactions like urticaria or anaphylaxis have been reported previously commonly in adults, especially in forest workers while severe reactions without direct contact are rare in pediatric population. CASE: A 28 month old healthy boy was admitted to Near East University Pediatric Allergy and Immunology Outpatient Clinic in March with complaints of pain, hyperemia and swelling on the left hand. His complaints had started the day before his admission just after walking around in their garden which is surrounded by pine trees. On admission, his physical examination revealed serious edema and hyperemia on his left hand limiting his finger movements with a few bullae on the skin. His temperature was 38 C and the other vital parameters were normal. Based on hyperemia, swelling and high acute phase reactants he was hospitalized with the differential diagnosis of soft tissue inflammation and cellulitis. The case was treated with iv antihistamines, systemic steroids and antibiotics. CONCLUSIONS: Pine processionary (PP) is an important irritant and allergen especially in endemic areas like Cyprus which is a Mediterranean Country. It must be kept in mind in case of local or generalized urticaria, dermatitis, bullae and other allergic reactions even if there had been no direct contact with PP. Systemic involvement with fever and elevated acute phase reactants in infancy may necessitate hospitalization and intravenous treatment. Hereby, we reported an infant who presented with fever in addition to severe cutaneous lesions following the exposure to TP without direct contact. This is the first case reported from North Cyprus.

Association of cord blood bisphenol A (BPA) with cord blood adiponectin, leptin, fetal growth; adiposity and neoantal complications in a newborn cohort.

Objective: To evaluate the relation between cord blood bisphenol A (BPA), leptin, adiponectin, birth weight, height, skin thickness, and postnatal results.Method: This study was performed in near East University Medical Faculty, Nicosia, Cyprus with 150 healthy newborns. Cord blood leptin, adiponectin, BPA levels were measured by ELISA and birth weight, heights and back, waist, and arm skin thickness were measured and postnatal problems noted.Results: One hundred eighty-seven newborns were included in the study. Mean ± SD of BPA, adiponectin, leptin levels were 48.3 ± 2.22 ng/mL, 65.60 ± 15.29 µg/mL and 3.08 ± 2.08 ng/mL. Mean birth weight, height, head circumferences were 3156.76 ± 493.45 g, 48.28 ± 2.04 cm, 34.14 ± 1.74 cm. The association anthropometric measurements, BPA, leptin, and adiponectin levels were not statistically significant (p>.05). The relation between cord blood leptin, adiponectin, and BPA levels and small for gestation, large for gestation and average for gestation groups were not significant (p>.05). Moreover, relation between back, waist and arm skin thickness and BPA, leptin, and adiponectin were not statistically significant (p>.05). However, newborns who were hospitalized and had newborn jaundice had higher BPA levels (p<.05).Conclusion: In previous studies, higher BPA levels were associated with small for gestational age (SGA) birth, however, this relation was not noted in our study. Furthermore, there is no relation between skin thickness, BPA, leptin, and adiponectin. This difference may be as a result of higher cord BPA levels compared with previous studies.

Is celiac disease misdiagnosed in children with functional constipation?

BACKGROUND/AIMS: Functional constipation is one of the common problems in childhood, and it comprises approximately 5% of the pediatric outpatient clinical applications. On the other hand, celiac disease (CD) is an immune enteropathy with the prevalence between 1/150 and 1/200. In addition to the classical symptoms of the disease such as diarrhea and weight loss, the incidence of atypical symptoms is increasing. This study aims to determine the prevalence of CD in patients with chronic constipation. MATERIALS AND METHODS: The study was conducted between 2010 and 2012 and included 1046 children (range, 2-18 y; median, 11.4 y) diagnosed with chronic constipation according to the Rome III criteria. Serum immunoglobulin A, tissue transglutaminase, and/or anti-endomysial antibodies were examined. The patients with serological positive results were subjected to upper gastrointestinal system endoscopy and duodenal biopsy to confirm the diagnosis of CD. RESULTS: Blood tests were positive in 36 patients (3.25%). One of the patients had Hashimoto's thyroiditis, and 4 patients had short stature. Endoscopic findings included nodularity in bulbus and duodenal mucosa (n=16), scalloping fold (n=13), and normal mucosa (n=5). Histopathologic findings revealed that 10 patients had total villous atrophy, 24 patients had subtotal and partial villous atrophy, and 34 patients had intraepithelial lymphocyte infiltration. All patients followed a gluten-free diet, resulting in a resolution of symptoms. CONCLUSION: In the present study, a CD ratio of 1:28 was diagnosed in chronically constipated children. The use of screening tests for CD should be considered in children with conventional treatment-resistant constipation.

Predictive risk factors for relapse after cessation of inhaled corticosteroids in well-controlled childhood asthma.

BACKGROUND: There is limited data for predicting the risk of exacerbations following the cessation of inhaled corticosteroids (ICS) in well controlled childhood asthma. In current study, clinical, functional and inflammatory parameters at the time of ICS withdrawal were investigated in that respect. METHODS: Forty children asymptomatic for at least 3 months on low dose ICS's were enrolled and ICS were discontinued in summer. At enrolment symptom/medication diary, pulmonary function parameters, methacholine provocation testing, peripheral blood eosinophilia, serum total and allergen-specific IgE levels and skin prick testing were performed. In a subgroup of patients, phytohemaglutinin induced secretion of IL-5, IL-13, IFN-γ and IL-10 from blood mononuclear cells were measured. Patients were assessed with symptom/medication diary and pulmonary function test every 2 months for 6 months. RESULTS: Eighteen of 37 patients experienced recurrence of acute asthma symptoms. In patients with acute attack (group I), changes in rhinitis symptom scores at 2nd month vs. baseline were statistically higher. In addition, group I had significantly higher rhinitis symptom scores compared to group II at fourth-month visit. Patients with acute exacerbation revealed a significant decrease in FEV1% at 2nd month compared to baseline. Moreover, group I showed significantly lower FEF 25-75% compared to group II at 2nd month. Baseline bronchial hyper-responsiveness with methacholine was found to be an independent risk factor for asthma exacerbation. CONCLUSIONS: The findings of this study identified baseline bronchial hyperreactivity, higher rhinitis symptom scores and gradual decrease in pulmonary function parameters during follow-up as risk factors for subsequent exacerbation of asthma.

Leptin, ghrelin and calprotectin: inflammatory markers in childhood asthma?

BACKGROUND: Appetite-modulating hormones ghrelin and leptin might be relevant to asthma with their pro-inflammatory effects, and calprotectin has been recognized as a promising marker of inflammation. The purpose of this study was to explore whether asthma, atopy and lung functions has a relation with serum levels of leptin, ghrelin and calprotectin as inflammatory markers in children. METHODS: A cross-sectional study was performed by searching the doctor diagnosed asthma through questionnaires filled in by parents who were phoned, and children were invited to supply fasting blood samples in order to measure serum levels of leptin, ghrelin and calprotectin, and to perform skin prick test and spirometry. Participants were divided into Group 1, children with previous diagnosis of asthma, and Group 2, children without previous diagnosis of asthma. RESULTS: One thousand and two hundred questionnaires were distributed and 589 of them were returned filled in. Out of 74 children whose parents accepted to participate in the study, 23 were in Group 1 and 51 were in Group 2. There was no statistical difference in serum levels of leptin, ghrelin, calprotectin, forced expiratory volume in one second (FEV1), forced vital capacity (FVC), peak expiratory flow (PEF) , forced expiratory flow between 25 and 75% of vital capacity (FEF25-75) values , and skin prick test results between the two groups (p values are 0.39, 0.72, 0.5, 0.17, 0.5, 0.27, 0.18, and 0.81 respectively). CONCLUSION: In this study the inflammation in asthmatic children could not be shown by using serum leptin, ghrelin and calprotectin levels and this is possibly due to the low number of children with ever asthma and equal skin prick test positivity in both groups. This study is the first study aimed to show the relation between serum calprotectin levels and inflammation in asthma. As this study was a cross-sectional study, further prospectively designed randomized controlled studies are necessary to show the association of these markers and inflammation in asthma.

Multiallergen-specific immunotherapy in polysensitized patients: where are we?

Allergen-specific immunotherapy administered by the subcutaneous route was introduced a century ago and has been shown to be effective in the management of allergic rhinitis and asthma. More recently, the sublingual administration of allergen extracts has become popular, especially in European countries, and has also demonstrated efficacy in respiratory allergic diseases. Both modes of allergen administration during immunotherapy have been shown not only to reduce symptoms and the need for medication, but also to prevent the development of additional sensitivities in monosensitized patients, as well as asthma development in patients with allergic rhinitis, with a long-lasting effect after the completion of several years of treatment. Almost all of the well-designed and double-blinded, placebo-controlled studies evaluated treatment with single-allergen extracts. Therefore, most meta-analyses published to date evaluated immunotherapy with single allergen or extracts containing several cross-reactive allergens. As a result, in general, multiallergen immunotherapy in polysensitized patients (mixture of noncross-reactive allergens) is not recommended owing to lack of evidence. Although some guidelines have recommended against the use of multiallergen mixtures, allergists commonly use mixtures to which the patient is sensitive with the rationale that effective immunotherapy should include all major sensitivities. Literature on this subject is scarce in spite of the widespread use worldwide. Here, this issue will be extensively discussed based on currently available literature and future perspectives will also be explored.

Subcutaneous versus sublingual immunotherapy for allergic rhinitis and/or asthma.

Subcutaneous allergen-specific immunotherapy has long been used in allergic rhinitis and/or asthma and has been recognized to be efficacious. However, owing to the inconvenience of injection and the risk of serious side effects, alternative concepts inspiring the search for effective noninjective routes, namely sublingual administration of allergens, have emerged. Sublingual immunotherapy (SLIT) appears to be associated with a lower incidence of systemic reactions. The clinical efficacy of subcutaneous immunotherapy (SCIT) is well established for both rhinitis and asthma. Meta-analyses relating to its efficacy on asthma and rhinitis are available. SLIT has also been validated in this respect. Comparative clinical studies of SLIT versus SCIT are scarce demonstrating both routes to be clinically efficient. Knowledge of the exact mechanism of action of SLIT has been increasing in the last decade. In addition, recent studies have proved similarities of the immunological changes with the treatment of both routes. Further comparative clinical and immunological studies of SLIT versus SCIT are needed to confirm the long-term efficacy and to complete the knowledge of immunological mechanisms of both routes. Moreover, better understanding of the interaction of allergen and oral mucosal dendritic cells during SLIT may allow improved targeting of SLIT vaccines.

Outcome of hypogammaglobulinemia in children: immunoglobulin levels as predictors.

We evaluated 131 children (M=88, F=43) with hypogammaglobulinemia. Data was analyzed mainly for delineating predictor factors for outcome. The distance from the lower limit of normal (-2SD) for any single measurement of immunoglobulins (Ig) was calculated and transformed into Ig scores. Mean age and duration of follow-up were 5.06 ± 4.05 and 3.7 ± 3.03 years, respectively. The diagnoses were: 22 CVID, 16 IgA deficiency, 33 transient hypogammaglobulinemia of childhood (THC), 3 selective IgM deficiency and 57 unclassified hypogammaglobulinemia (UCH). Low IgA scores (<-0.124) at presentation were indicative of subsequent development of IgA deficiency or CVID, whereas low IgM score (<-0.038) pointed towards more severe and persistent phenotypes. Combination of low IgM score between 2 and 5 years, impaired antibody response and low B cell counts enabled us to predict persistence of hypogammaglobulinemia beyond 5 years (specificity=90.5% and PPV=94.9%) and chronic lung disease (sensitivity=90.4% and specificity=68.3%). The set of criteria including low IgM scores, impaired antibody response and low B cell counts provided a high predictive value in detecting those with persistent hypogammaglobulinemia.

Immunologic aspects of sublingual immunotherapy in the treatment of allergy and asthma.

Recently interest has been focused on the administration of allergen specific immunotherapy by the oral route particularly sublingually. The mechanism by which sublingual immunotherapy exerts its effects remain unclear. Most likely, allergen captured within the oral mucosa by Langerhan's-like dendritic cells play a role in subsequent T cell responses. There is a growing body of evidence to support the role of regulatory T cells in controlling the development of allergic diseases. Nevertheless, there remains a lack of firm evidence that sublingual immunotherapy induces regulatory T cells. New vaccine developments with the increasing understanding of the molecular engineering techniques are on the way to offer the opportunity to design recombinant allergens that are safe, effective and easy to administer. In addition, the idea of using adjuvants along with allergen within the oral cavity is another promising approach.