"Physiologische" versus "prä-atopische" IgG-Antworten gegenüber Nahrungsmittelallergenen und Aeroallergenen der PR-10 Gruppe in birkenpollen- sensibilisierten und nicht-atopischen Kindern

BACKGROUND: The route and dose of exposure are believed to be relevant factors in the sensitization process. Pathogenesis-related group 10 protein (PR-10) molecules are a family of allergenic proteins shared by many pollens (eg, birch and alder) and foods (eg, apple, peach, and soy). Children are exposed to both pollen-derived (inhaled) and food-derived (ingested) PR-10 molecules. OBJECTIVE: We sought to investigate the role of route and dose of exposure in the evolution of IgG and IgE responses to recombinant PR-10 molecules. METHODS: The German Multicentre Allergy Study examined a birth cohort born in 1990. Blood samples were collected at the ages of 1, 2, 3, 5, 6, 7, 10, and 13 years. Participants were included in the present analysis if they had (1) at least 1 serum sample at each of the 4 age periods or time points (1-3 years, 5-7 years, 10 years, and 13 years) and (2) IgE responses to birch (children with birch atopy) or no IgE response at all to 9 common aeroallergens and food allergens (non-atopic children). Therefore serum IgE antibodies to a panel of 4 airborne and 5 foodborne extracts, as well as to Bet v 1, were measured in singleplex assays, whereas IgG and IgE antibodies to a panel of 3 airborne PR-10 molecules (rBet v 1, rAln g 1, and rCor a 1.0101) and 7 foodborne PR-10 molecules (rCor a 1.0401, rMal d 1, rPru p 1, rGly m 4, rAra h 8, rApi g 1, and rDau c 1) were tested by using a multiplex microarray. RESULTS: In the present analyses we included 28 children with birch atopy and randomly selected 28 non-atopic children from the 190 children fulfilling the inclusion criteria. Two different patterns of IgG responses to PR-10 molecules were identified. Among non-atopic subjects, a ‘‘default’’ IgG response was directed mostly against foodborne PR-10, started often before age 2 years, stayed weak, and was mostly transient. Among all atopic subjects, the default IgG response at age 1 year was overwhelmed after age 2 years by an ‘‘pre-atopic’’ IgG response, which started with or shortly before the IgE response and was intense and persistent. This atopic IgG response, as well as the IgE response, involved progressively more foodborne PR-10 proteins with frequencies and levels related to their homology with Bet v 1. CONCLUSIONS: The results suggest that children have a default antibody response to PR-10 molecules, which is early, weak, and transient; does not involve IgE; and is initiated by foodborne PR-10. By contrast, an atopic antibody response to PR-10 molecules is delayed, strong, and persistent; involves both IgG and IgE; and is initiated by airborne PR-10.HINTERGRUND: Es wird angenommen, dass Route und Dosis der Allergenexposition eine besondere Rolle im allergischen Sensibilisierungsprozess einnehmen. Pathogenese-bezogene Proteinmoleküle der Gruppe 10 (PR-10) sind eine Familie allergener Proteine, die in vielen Pollen (z.B. Birke und Erle), sowie Nahrungsmitteln (z.B. Apfel, Pfirsich und Soja) enthalten sind. Kinder kommen so regelmäßig mit Allergenen beider PR-10 Gruppen in Kontakt, sei es durch Polleninhalation (Kontakt über die Atemwege) oder den Verzehr von Nahrungsmitteln (Kontakt über den Gastrointestinaltrakt). ZIELSETZUNG: Das Ziel dieser Studie ist es, die Rolle des Expositionsweges, sowie der Allergendosis in der Entwicklung von IgG und IgE Antworten gegen rekombinante PR-10 Moleküle zu untersuchen. METHODEN: Die deutsche Multizentrischen Allergie Studie (MAS) untersucht eine Geburtenkohorte des Jahrgangs 1990. In ihrem Rahmen fanden Blutentnahmen im Alter von 1, 2, 3, 5, 6, 7, 10 und 13 Jahren statt. Probanden wurden in die Analyse eingeschlossen wenn (1) mindestens eine Serumprobe für je einen der 4 festgelegten Zeiträume (1-3 Jahre, 5-7 Jahre, 10 Jahre, 13 Jahre) vorhanden war und (2) sie eine IgE Antwort auf Birkenpollen (Kinder mit Birkensensibilisierung) oder keinerlei IgE-Antwort auf die 9 gängigen aerogenen und nahrungsmittelassoziierten Allergene (nicht allergische Kinder) zeigten. Hierfür wurden IgE Antikörper gegen 4 inhalative und 5 nahrungsmittelassoziierte Allergenextrakte, sowie gegen Bet v 1 in einer singleplex Untersuchung bestimmt, während die IgG und IgE Antikörper gegen ein Set von 3 aerogenen (rBet v 1, rAln g 1, and rCor a 1.0101) und 7 nahrungsmittelassoziierten (rCor a 1.0401, rMal d 1, rPru p 1, rGly m 4, rAra h 8, rApi g 1, and rDau c 1) PR-10 Molekülen mittels einer Multiplex Microarray Methode getestet wurden. ERGEBNISSE: Die vorliegende Analyse umfasst 28 auf Birkenpollen sensibilisierte Kinder, sowie 28 stichprobenartig ausgewählte, nicht-allergische Kinder aus den 190 Kindern, welche die Einschlusskriterien für diese Gruppe erfüllten. Es wurden zwei unterschiedliche Verläufe der IgG-Antwort auf PR-10 Moleküle identifiziert. Unter den nicht-atopischen Kindern zeigte sich eine “standardmäßige” IgG- Antwort, welche sich hauptsächlich gegen nahrungsmittelassoziierte PR-10 Moleküle richtet, meist vor dem Erreichen des zweiten Lebensjahres begann, niedrige Konzentrationen aufwies und sich oft nur flüchtig zeigte. Unter allen atopischen Kindern wurde diese im ersten Lebensjahr beobachtete, “Standard- IgG-Antwort” im Alter von 2 Jahren von einer “prä-atopischen” IgG-Antwort überdeckt, welche sich zeitgleich mit oder kurz vor der IgE-Antwort zeigte, hohe Konzentrationen zeigte und persistierte. Diese atopische IgG-Antwort, wie auch die IgE-Antwort, bezog mit der Zeit eine zunehmende Anzahl nahrungsmittelassoziierter PR-10 Proteine mit ein, wobei die Häufigkeit der Antworten und deren Konzentration in Bezug zur Homologie der Proteine mit Bet v 1 stand. SCHLUSSFOLGERUNG: Die Ergebnisse weisen darauf hin, dass Kinder eine standardmäßige Antikörperantwort auf PR-10 Moleküle entwickeln, die früh, schwach und flüchtig ist. Sie beinhaltet nicht die Bildung von IgE-Antikörpern und ist durch nahrungsmittelassoziierte Allergene der PR-10 Gruppe initiiert. Im Gegensatz hierzu existiert eine atopische Antikörperantwort auf PR-10 Moleküle, welche später, stark und beständig ist, wobei sie die Bildung von IgG- und IgE-Antikörpern einschließt und durch aerogene PR-10 Proteine initiiert wird

Efficacy and usability of a novel nebulizer targeting both upper and lower airways

Abstract Background Upper and lower airways diseases share in part their pathogenic mechanisms and frequently occur simultaneously as “United Airway Disease.” Local treatment with nebulizers delivers anti-symptomatic drugs in either the upper or the lower airways, according to the particle size generated by the nebulizer. To our knowledge, no nebulizer combines both application ways. The aim of this study is to test the efficacy and usability of a new nebulizer (OMRON A3 complete), generating aerosols with particles diameters of 2-4.5 μm, 4.5-7.5 μm or >7.5 μm, according to the user’s choice. Methods Seventy-seven patients between 5 and 17 years of age with a diagnosis of rhinitis or asthma were examined. Oxymetazoline or Salbutamol were prescribed according to best clinical practice guidelines. Both drugs were administered through the OMRON A3 Complete nebulizer, with a particle dimension of >7.5 μm to treat nasal obstruction and 2-4.5 μm for bronchial obstruction. The efficacy of treatment was assessed by total nasal inspiratory airflow and FEV-1, Tiffeneau index (FEV1/FVC) and MMEF 25/75 respectively, 10 min before and after treatment. Symptom improvement and usability were measured by patients’ and doctors’ questionnaires. Results Overall, 77 patients seeking care for acute respiratory symptoms were assigned to the upper (n = 39) or lower (n = 38) airways disease group. For symptoms of the upper airways, 92% (95% CI, 77-97%) of the patients reported subjective improvement, while 87% (95% CI, 73-94%) did so for the lower airways. The average total nasal inspiratory airflow improved significantly (p = 0.030) among the patients with upper airways symptoms, from 275 ml/s (95% CI, 207-342 ml/s) to 359 ml/s (95% CI, 300-419 ml/s) after Oxymetazoline administration. All selected lung function parameters (FEV1, Tiffeneau Index and MMEF25-75) significantly improved among the patients with lower airways symptoms after inhalation of Salbutamol (p < 0.001). The nebulizer was assessed as “easy to use” by over 95% of participants in both groups. Conclusions The OMRON A3 efficiently delivers anti-symptomatic drugs in both upper and lower airways in a user-friendly way. This device may be useful to facilitate adherence to a complete treatment of respiratory symptoms in patients with symptoms of the so-called United Airway Disease

The impact of nasal aspiration with an automatic device on upper and lower respiratory symptoms in wheezing children: a pilot case-control study

Abstract Background The impact of proper aspiration of nasal secretions during upper respiratory infection on the frequency and severity of symptoms of lower airways has never been investigated. The study was aimed at testing if cleaning the nasal cavities of children with recurrent wheezing using an automatic nasal aspirator improves the upper and lower respiratory symptoms during the cold season. Methods Parents of wheezing children (age 3-72 mo.) answered questionnaires and learned using a nebulizer equipped (cases) or not equipped (controls) with an automatic nasal aspirator (DuoBaby, OMRON, Japan). During a 90-days monitoring period parents filled an electronic diary (BreathMonitor, TPS, Rome, Italy) on their child’s symptoms of the upper and lower airways. Results Eighty-nine/91 patients (43 cases, 46 controls) completed the study. Less days with upper (25.0% vs 46.4%, p = 0.004) or lower (21.8% vs 32.8%, p = 0.022) airways symptoms and less days with salbutamol inhalation (12.2% vs 16.9%, p < 0.001) were reported by cases than by controls. The episodes of upper respiratory symptoms were shorter [4.3 days (95%CI:3.8–4.9) vs 5.7 days (95%CI:5.0–6.4), p = 0.007] but not less frequent [2.3 (95%CI: 1.8–2.8) vs 2.6 (95%CI:2.2–3.0), p = 0.122] among cases than among controls. Similarly, the episodes of lower respiratory symptoms tended to be shorter [3.8 days, (95%CI: 3.4–4.2) vs 4.4 days, (95%CI: 4.4–6.0), p = 0.067] but not less frequent [1.9 (95%CI:1.5–2.3) vs 2.1 (95%CI:1.7–2.4), p = 0.240] among the group using the nasal aspirator. Conclusions In our pilot study, the use of an automatic nasal aspirator in children with a history of recurrent wheezing was associated with an improved respiratory health during the cold season

Correction to: The impact of nasal aspiration with an automatic device on upper and lower respiratory symptoms in wheezing children: a pilot case-control study

The original article [1] contained a typesetting error in Table 5; this has now been corrected

Additional file 1: of The impact of nasal aspiration with an automatic device on upper and lower respiratory symptoms in wheezing children: a pilot case-control study

Figure S1. The DuoBaby nebulizer (a) and its functional scheme (b). Figure S2. Salbutamol consumption (expressed in percentage of days) among patients younger (cases n = 16, controls n = 16) or older (cases n = 27, controls n = 30) than 24 months and using a DuoBaby nebulizer equipped (cases) or not equipped (controls) with a nasal aspirator. Percentages are calculated considering the total days with symptoms over the total day of reported days (see method for definition). Chi-squared test was used to evaluate frequency differences between independent groups. Figure S3. Percentage of days with symptoms among patients using a DuoBaby nebulizer equipped (cases, n = 43) or not equipped (controls; n = 46) with an nasal aspirator. Percentage are calculated reporting the total days with symptoms on the total number of reported days. Chi-squared test was used to evaluate the association of categorical data between independent groups. Significant differences are highlighted as follows: *p < 0.05,** < 0.01, *** < 0.001. †Statistical significant differences after adjusting for multiple repeated measures through mixed-effects logistic regression. Table S1. List of the questions in the BreathMonitor APP (electronic Diary). Table S2. Questionnaire on the DuoBaby’s nebulizer unit. Table S3. Questionnaire on the use of the DuoBaby’s nasal aspirator. Table S4. Frequency of symptoms among patients using a DuoBaby nebulizer equipped (cases, n = 43) or not equipped (controls; n = 46) with a nasal aspirator stratified by age in months.* (DOCX 579 kb

IgG and IgG4 to 91 allergenic molecules in early childhood by route of exposure and current and future IgE sensitization: Results from the Multicentre Allergy Study birth cohort

Abstract BACKGROUND: Studies of a limited number of allergens suggested that nonsensitized children produce IgG responses mainly to foodborne allergens, whereas IgE-sensitized children also produce strong IgG responses to the respective airborne molecules. OBJECTIVE: We sought to systematically test the hypothesis that both the route of exposure and IgE sensitization affect IgG responses to a broad array of allergenic molecules in early childhood. METHODS: We examined sera of 148 children participating in the Multicentre Allergy Study, a birth cohort born in 1990. IgG to 91 molecules of 42 sources were tested with the ImmunoCAP Solid-Phase Allergen Chip (ISAC; TFS, Uppsala, Sweden). IgE sensitization at age 2 and 7 years was defined by IgE levels of 0.35 kUA/L or greater to 1 or more of 8 or 9 extracts from common allergenic sources, respectively. RESULTS: The prevalence and geometric mean levels of IgG to allergenic molecules in nonsensitized children were lower at age 2 years than in IgE-sensitized children, and they were extremely heterogeneous: highest for animal food (87% ± 13%; 61 ISAC Standardized Units [ISU], [95% CI, 52.5-71.5 ISU]), intermediate for vegetable food (48% ± 27%; 13 ISU [95% CI, 11.2-16.1 ISU]), and lowest for airborne allergens (24% ± 20%; 3 ISU [95% CI, 2.4-3.4 ISU]; P for trend < .001 [for percentages], P for trend < .001 [for levels]). IgG4 antibodies were infrequent (<5%) and contributed poorly (<3%) to overall IgG antibody levels. IgG responses at age 2 years were slightly more frequent and stronger among children with than in those without IgE sensitization at age 7 years. CONCLUSION: The children's repertoire of IgG antibodies at 2 years of age to a broad array of animal foodborne, vegetable foodborne, and airborne allergenic molecules is profoundly dependent on the route of allergen exposure and the child's IgE sensitization status and only marginally involves the IgG4 isotype