House Dust Mite Subcutaneous Immunotherapy and Lung Function Trajectory in Children and Adolescents with Asthma.

Background: Allergen-specific immunotherapy is currently the only disease-modifying treatment for allergic asthma, and it has been shown to improve control of asthma while reducing both drug use and asthma exacerbations. However, its effects on lung function­especially its long-term effects­remain controversial. We aimed to identify factors associated with a possible beneficial effect of allergen-specific immunotherapy on lung function in asthma by retrospectively evaluating the long-term changes in lung function in children with asthma who received house dust mite subcutaneous immunotherapy (HDM-SCIT). Methods: We enrolled children with asthma who had undergone HDM-SCIT for more than 1 year. Clinical information and lung function measurements were retrieved from the electronic chart system. To characterize the trajectory of lung function change, we performed linear regression analysis to evaluate the maximal expiratory flow at 50% of the forced vital capacity during two periods: before and during HDM-SCIT. Slopes from a least-squares regression line for the two periods, i.e., S1 before HDM-SCIT and S2 during HDM-SCIT, were compared. The subjects were then classified into two groups: an improving group (Group I) defined as S2 − S1 > 0, and a declining group (Group D) defined as S2 − S1 < 0. The clinical factors at the start of HDM-SCIT were compared between the two groups. Results: A total of 16 patients were analyzed. Eight patients were classified into each of Group I and Group D. The mean ages were 10.5 and 11.8 years, and the mean treatment periods were 4.1 and 3.9 years. Group I had a significantly lower blood eosinophil count and a significantly higher HDM-specific IgE level than Group D. Logistic regression showed a strong relationship between those two markers and the lung function trajectory. Conclusion: Control of the blood eosinophil count in highly HDM-sensitized patients may increase the beneficial effect of HDM-SCIT on lung function.

Is oral food challenge test useful for avoiding complete elimination of cow's milk in Japanese patients with or suspected of having IgE-dependent cow's milk allergy?

BACKGROUND: Cow's milk, along with hen's egg, are common causes of food allergies in children worldwide. Accidental ingestion of milk is common and often induces severe allergic reactions. Oral food challenge test (OFC) is usually performed in patients with or suspected of having a food allergy. However, the evidence of whether cow's milk OFC is useful in IgE-dependent cow's milk allergy patients to avoid total elimination is not known. METHODS: After setting the clinical question and outcomes, we performed a systematic review for relevant articles published from January 1, 2000 to August 31, 2019 using PubMed® and Ichushi-Web databases. Each article was then evaluated for the level of evidence. All positive results of the OFC were defined as adverse events. RESULTS: Forty articles were selected in this study. Our review revealed that cow's milk OFC was able to avoid the complete elimination of cow's milk in 66% of the patients with cow's milk allergy. We also found that adverse events occurred frequently (50.5%). CONCLUSIONS: This analysis supports the recommendation of conducting cow's milk OFC to avoid complete elimination of cow's milk, however the test should be conducted with careful consideration of the patient's safety. As the methods of OFC and subjects varied among the articles selected in this study, further studies are needed to obtain higher quality evidence.

Squamous cell carcinoma antigens are sensitive biomarkers for atopic dermatitis in children and adolescents: a cross-sectional study.

BACKGROUND: We recently reported that squamous cell carcinoma antigen 2 (SCCA2) is a reliable biomarker for atopic dermatitis (AD). OBJECTIVE: To further clarify its utility, we investigated for effects of comorbid allergies and AD treatment on serum SCCA levels. METHODS: Volunteers <18 years old were recruited through our website. Their allergic status was elucidated using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. We also recruited pediatric patients who were hospitalized because of severe AD. The serum levels of SCCA1 and SCCA2 were measured by enzyme-linked immunosorbent assays. In the severe AD patients, the levels of thymus and activation-regulated chemokine (TARC), SCCA1, and SCCA2 were measured before and after hospitalization. The severity of AD was assessed using the severity scoring of atopic dermatitis (SCORAD). RESULTS: A total of 576 participants (547 volunteers and 29 patients) were enrolled in the study. The levels of SCCA1 and SCCA2 were significantly higher in volunteers with mild AD and patients with severe AD than in healthy volunteers without allergic diseases. The levels were not elevated in those who had mild bronchial asthma or allergic rhinitis without AD. TARC, SCCA1, and SCCA2 were decreased during the treatment in severe AD patients, reflecting clinical improvement in response to treatment. Linear regression analysis for predicting a decrease in the SCORAD index showed R2 values of 0.16, 0.38, and 0.48 for TARC, SCCA1, and SCCA2, respectively. CONCLUSION: SCCAs, especially SCCA2, are sensitive biomarkers for detecting AD in children and adolescents and for assessing the severity and response to treatment of severe AD.

Season of birth is associated with increased risk of atopic dermatitis in Japanese infants: a retrospective cohort study.

BACKGROUND: Several epidemiological studies have examined the possibility of a relationship between season of birth and atopic dermatitis (AD) and food allergy (FA), yet their results are contradictory. We investigated the association between season of birth and risk of AD and FA in Japanese infants. METHODS: Study subjects were 612 newborn infants born at a single obstetric/pediatric clinic without perinatal diseases. Season of birth was classified as spring (March-May), summer (June-August), autumn (September-November) or winter (December-February). AD was diagnosed according to the United Kingdom Working Party's criteria. FA was defined as present if there was a history of immediate allergic symptoms within 2 h after ingestion of a food. Specific IgE to the corresponding food was also assessed to support the diagnosis. We assessed the association between season of birth and risk of AD and FA using Cox proportional hazard models. RESULTS: We identified a total of 365 cases of AD occurring during 3659 person-months of follow-up. Compared with summer birth, autumn, winter, and spring birth were significantly positively associated with the risk of AD: adjusted HRs (95% CIs) were 2.67 (1.96-3.63), 1.42 (1.03-1.95), and 1.43 (1.04-1.98), respectively. We identified a total of 23 cases of physician-diagnosed FA occurring during 6815 person-months of follow-up. CONCLUSIONS: Being born in the summer is associated with a lower risk of AD compared to other seasons of birth. The low incidence of FA in our cohort group made it difficult to establish a valid association between FA and season of birth as the statistical power was low.

Immunogenicity of Milk Protein-Containing Hydrophilic Gel Patch for Epicutaneous Immunotherapy for Milk Allergy.

PURPOSE: Epicutaneous immunotherapy (EPIT) involving the skin's immune system is easy to use, painless and has a low risk of systemic side effects; it can be applied to food allergies that have a high morbidity rate in children. In this study, we evaluated the safety and efficacy of hydrophilic gel patch (HG) for EPIT. METHODS: Milk protein concentrate (MPC)-containing HG was applied to the skin that maintained a barrier function or formed puncture holes with microneedle, and MPC-specific antibodies were measured. The clinical study was conducted involving patients with severe milk allergy. RESULTS: No specific immune response was induced when immunizing to intact skin, and antibody production was observed by forming puncture holes. It was suggested that MPC contained in HG has immunogenicity and a very small amount of MPC was delivered to intact skin. In the clinical study, the symptom induction threshold increased in four of eight subjects, allowing them to consume milk and switch to oral immunotherapy. Although local skin reactions and temporary elevation of specific IgE antibodies were observed, no systemic side effects appeared throughout the study. CONCLUSIONS: EPIT using HG is a safe method to enable oral administration even in patients with severe milk allergies.

Role of Matrix Metalloproteinase-2 in Eosinophil-Mediated Airway Remodeling.

Airway remodeling is responsible for the progressive decline of lung function in bronchial asthma. Matrix metalloproteinase-2 and fibroblast-to-myofibroblast transition are involved in tissue remodeling. Here we evaluated whether eosinophils play a role in fibroblasts-to-myofibroblasts transition and in the expression of matrix metalloproteinase-2. We co-cultured human eosinophils with human fetal lung fibroblast-1 cells, assessed the expression of remodeling-associated molecules by immunoassays and polymerase-chain reaction, and eosinophils-mediated migration of human fetal lung fibroblast-1 cells using a Boyden chamber. To clarify the participation of matrix metalloproteinase-2 in airway remodeling we administered bone marrow-derived eosinophils by intra-tracheal route to transgenic mice overexpressing the human matrix metalloproteinase-2. The expression of α-smooth muscle actin significantly increased in human fetal lung fibroblast-1 cells co-cultured with human eosinophils compared to controls. There was enhanced expression of matrix metalloproteinase-2 during fibroblast-to-myofibroblast transition. An inhibitor of matrix metalloproteinases blocked eosinophils-associated fibroblast-to-myofibroblast transition and increased migration of fibroblasts. The human matrix metalloproteinase-2 transgenic mice receiving adoptive transfer of mouse eosinophils exhibited increased inflammation and advanced airway remodeling compared to wild type mice. This study demonstrated that eosinophils induce fibroblast-to-myofibroblast transition, secretion of matrix metalloproteinase-2, accelerated migration of fibroblasts, and promote matrix metalloproteinase-2-related airway remodeling. These findings provide a novel mechanistic pathway for eosinophil-associated airway remodeling in bronchial asthma.

ß2 adrenergic agonist suppresses eosinophil-induced epithelial-to-mesenchymal transition of bronchial epithelial cells.

BACKGROUND: Epithelial-mesenchymal transition is currently recognized as an important mechanism for the increased number of myofibroblasts in cancer and fibrotic diseases. We have already reported that epithelial-mesenchymal transition is involved in airway remodeling induced by eosinophils. Procaterol is a selective and full ß2 adrenergic agonist that is used as a rescue of asthmatic attack inhaler form and orally as a controller. In this study, we evaluated whether procaterol can suppress epithelial-mesenchymal transition of airway epithelial cells induced by eosinophils. METHODS: Epithelial-mesenchymal transition was assessed using a co-culture system of human bronchial epithelial cells and primary human eosinophils or an eosinophilic leukemia cell line. RESULTS: Procaterol significantly inhibited co-culture associated morphological changes of bronchial epithelial cells, decreased the expression of vimentin, and increased the expression of E-cadherin compared to control. Butoxamine, a specific ß2-adrenergic antagonist, significantly blocked changes induced by procaterol. In addition, procaterol inhibited the expression of adhesion molecules induced during the interaction between eosinophils and bronchial epithelial cells, suggesting the involvement of adhesion molecules in the process of epithelial-mesenchymal transition. Forskolin, a cyclic adenosine monophosphate-promoting agent, exhibits similar inhibitory activity of procaterol. CONCLUSIONS: Overall, these observations support the beneficial effect of procaterol on airway remodeling frequently associated with chronic obstructive pulmonary diseases.

Sensitization to secretoglobin and lipocalins in a group of young children with risk of developing respiratory allergy.

BACKGROUND: Multiple sensitizations in early age have been reported to be a risk for development of asthma. This study evaluates the emergence and evolution of IgE to aeroallergens among a cohort of children with physician-diagnosed atopic dermatitis and/or showing food allergy symptoms and to examine the relation to asthma development. METHODS: Three-hundred and four children (median age 13.4 months at entry) with food allergy symptoms and/or atopic dermatitis without asthma at inclusion were analysed for IgE antibodies against food-, indoor- and outdoor-allergens and pet allergen components and correlated to the individuals' outcome on asthma inception. RESULTS: At 2 years of follow-up, physician-diagnosed asthma was 19.7% (n = 49) and asthma diagnosed any time was 24% (n = 67). History of persistent cough and asthma of father, combination of milk- and wheat-allergy symptoms and dual sensitization to house dust mite and Japanese cedar were independent risk factors for asthma. Sensitization to dog was the most prevalent inhalant allergen at entry. Asthma children had a higher proportion of sensitization to dog, cat and horse allergens at entry compared with non-asthma children. Being sensitized to both food, house dust mite and pet allergens was strongly associated with asthma (p = 0.0006). Component resolved diagnosis for dog and cat allergens showed that IgE antibodies to Can f 1 and Fel d 1 was common even at very young age. CONCLUSIONS: Early sensitization to inhalant allergens increases the risk of developing asthma as well as having milk and wheat allergy symptoms. Sensitization to dog, was common at an early age despite dog ownership. Sensitization to secretoglobin and lipocalins and less to serum albumins explained the pet sensitization.

Evaluation and application of the RD50 for determining acceptable exposure levels of airborne sensory irritants for the general public.

BACKGROUND: The RD(50) (exposure concentration producing a 50% respiratory rate decrease) test evaluates airborne chemicals for sensory irritation and has become an American Society for Testing and Materials (ASTM) standard method. Past studies reported good correlations (R(2)) between RD(50)s and the occupational exposure limits, particularly threshold limit values (TLVs). OBJECTIVE: The main purpose of this study was to examine the relationship between RD(50)s and human sensory irritation responses in a quantitative manner, particularly for chemicals that produce burning sensation of the eyes, nose, or throat, based on lowest observed adverse effect levels (LOAELs) reported for human subjects. METHODS: We compared RD(50)s with LOAELs and acute reference exposure levels (RELs). RELs, developed by the California Environmental Protection Agency's Office of Environmental Health Hazard Assessment, represent a level at which no adverse effects are anticipated after exposure. We collected RD(50)s from the published literature and evaluated them for consistency with ASTM procedures. We identified LOAELs for human irritation and found 25 chemicals with a corresponding RD(50) in mice. DISCUSSION: We found the relationship between RD(50)s and LOAELs as log RD(50) = 1.16 (log LOAEL) + 0.77 with an R(2) value of 0.80. This strong correlation supports the use of the RD(50) in establishing exposure limits for the public. We further identified 16 chemical irritants with both RD(50)s and corresponding acute RELs, and calculated the relationship as log RD(50) = 0.71 (log REL) + 2.55 with an R(2) value of 0.71. This relationship could be used to identify health protective values for the public to prevent respiratory or sensory irritation. CONCLUSION: Consequently, we believe that the RD(50) has benefits for use in setting protective levels for the health of both workers and the general population.

Merging models and biomonitoring data to characterize sources and pathways of human exposure to organophosphorus pesticides in the Salinas Valley of California.

We characterize cumulative intakes of organophosphorus (OP) pesticides in an agricultural region of California by drawing on human biomonitoring data, California pesticide use reporting (PUR) data, and limited environmental samples together with outputs from the CalTOX multimedia, multipathway, source-to-dose model. The study population is the CHAMACOS cohort of almost 600 pregnant Latina women in the Salinas Valley region. We use model estimates of OP intake and urinary dialkylphosphate (DAP) metabolite excretion to develop premises about relative contributions from different exposure sources and pathways. We evaluate these premises by comparing the magnitude and variation of DAPs in the CHAMACOS cohort with those of the whole U.S. population using data from the National Health and Nutrition Examination Survey (NHANES). This comparison supports the premise that diet is the common and dominant exposure pathway in both populations. Biomarker comparisons and model results support the observation that, relative to NHANES, the CHAMACOS population has a statistically significant (p < 0.001) added intake of OP pesticides with low inter-individual variability. We attribute the magnitude and small variance of this intake to residential nondietary exposures from local agricultural OP uses. These results show that mass-balance models can estimate exposures for OP pesticides within the range measured by biological monitoring.