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ZusammenfassungDas vorliegende Addendum zur Leitlinie zur Diagnostik und Therapie von Patienten mit Asthma (2017) ergänzt wichtige neue Erkenntnisse zur Diagnostik und Therapie von Asthma sowie zu neu für die Therapie des Asthmas zugelassenen Medikamenten. Es werden sowohl für Kinder und Jugendliche als auch für Erwachsene mit Asthma die aktuellen, Evidenz-basierten diagnostischen und therapeutischen Empfehlungen dargelegt.

ZusammenfassungDie vorliegende Fassung der deutschsprachigen AWMF-Leitlinie soll unter Berücksichtigung der vorliegenden Evidenz die medizinische Versorgung von Kindern und Jugendlichen mit ambulant erworbener Pneumonie (pediatric community acquired pneumonia, pCAP) verbessern. In Mitteleuropa steht einer Prävalenz von ca. 300 Fällen pro 100 000 Kinder/Jahr eine sehr geringe Mortalität gegenüber, die Prävention umfasst Hygiene-Maßnahmen und Impfung z. B. gegen Pneumokokken, Hämophilus, Masern und Influenza. Hauptsymptome der pCAP sind Fieber und Tachypnoe, die Diagnosestellung erfolgt primär klinisch durch Anamnese, körperliche Untersuchung und Pulsoxymetrie. Das zusätzliche Vorliegen von Warnsymptomen wie stark reduzierter Allgemeinzustand, Nahrungsverweigerung, Dehydratation, Bewusstseinsstörung oder Krampfanfälle definiert die schwere pCAP in Abgrenzung zur nicht-schweren pCAP. Das Erregerspektrum ist altersabhängig, zur Differenzierung zwischen viraler, bakterieller oder gemischt viral-bakterieller Infektion stehen jedoch keine zuverlässigen Biomarker zur Verfügung. Die meisten Kinder und Jugendlichen mit nicht-schwerer pCAP und O2-Sättigung > 92 % können ohne weitere Röntgen-, Labor- und Erreger-Diagnostik ambulant betreut werden. Der Einsatz von Antiinfektiva ist nicht grundsätzlich indiziert, vor allem bei jungen Kindern, bronchialer Obstruktion und anderen Hinweisen auf virale Genese kann darauf i. d. R. verzichtet werden. Zur kalkulierten Antibiotika-Therapie sind Aminopenicilline Mittel der Wahl, bei gewährleisteter Einnahme und Resorption sind die orale (Amoxicillin) und intravenöse Verabreichung (Ampicillin) von vergleichbarer Wirksamkeit. Nach 48 – 72 Stunden ist eine Verlaufsbeurteilung notwendig, um den Behandlungserfolg und mögliche Komplikationen wie z. B. parapneumonische Ergüsse oder Pleuraempyeme, die eine Erweiterung bzw. Änderung der Therapie erforderlich machen, rechtzeitig zu erfassen.

Ein chronisch feuchter Husten ist meist Ausdruck einer eitrigen Atemwegserkrankung. Dazu zahlen die protrahierte bakterielle Bronchitis (PBB), die chronisch eitrige Atemwegs‑/Lungenkrankheit („chronic suppurative lung disease“, CSLD) und die Bronchiektasie. Verschiedene Endotypen dieser Krankheiten sind bekannt. Die PBB ist definiert als mehrwochige bronchiale Infektion durch Bakterien, wodurch es zu taglichem feuchtem Husten uber mindestens 4 Wochen kommt. Virale Infekte gehen haufig voraus und andere chronische eitrige Atemwegserkrankungen mussen ausgeschlossen werden. Die Diagnose wird primar klinisch gestellt („PBB klinisch“) und eine 2‑ bis 4‑wochige orale Antibiotikagabe fuhrt bei der Halfte der Kinder zu einer deutlichen Besserung. Bei den restlichen Kindern soll eine genauere Abklarung mittels Thorax-Rontgenaufnahme, Lungenfunktionsmessung, flexibler Bronchoskopie und bronchoalveolarer Lavage und evtl. weiterer Untersuchungen erfolgen. Die haufigsten nachgewiesenen Bakterien sind Haemophilus influenzae, Moraxella catarrhalis und Streptococcus pneumoniae. Potenzielle weitere Therapieoptionen, die bisher noch nicht ausreichend in Studien fur diese Indikation untersucht wurden, sind tagliche Inhalationen mit hyperosmolarer Losung und verschiedene Formen thorakaler Physiotherapie.

The present guideline aims to improve the evidence-based management of children and adolescents with pediatric community-acquired pneumonia (pCAP). Despite a prevalence of approx. 300 cases per 100 000 children per year in Central Europe, mortality is very low. Prevention includes infection control measures and comprehensive immunization. The diagnosis can and should be established clinically by history, physical examination and pulse oximetry, with fever and tachypnea as cardinal features. Additional signs or symptoms such as severely compromised general condition, poor feeding, dehydration, altered consciousness or seizures discriminate subjects with severe pCAP from those with non-severe pCAP. Within an age-dependent spectrum of infectious agents, bacterial etiology cannot be reliably differentiated from viral or mixed infections by currently available biomarkers. Most children and adolescents with non-severe pCAP and oxygen saturation 92 % can be managed as outpatients without laboratory/microbiology workup or imaging. Anti-infective agents are not generally indicated and can be safely withheld especially in children of young age, with wheeze or other indices suggesting a viral origin. For calculated antibiotic therapy, aminopenicillins are the preferred drug class with comparable efficacy of oral (amoxicillin) and intravenous administration (ampicillin). Follow-up evaluation after 48 - 72 hours is mandatory for the assessment of clinical course, treatment success and potential complications such as parapneumonic pleural effusion or empyema, which may necessitate alternative or add-on therapy.Die vorliegende Fassung der deutschsprachigen AWMF-Leitlinie soll unter Berücksichtigung der vorliegenden Evidenz die medizinische Versorgung von Kindern und Jugendlichen mit ambulant erworbener Pneumonie (pediatric community acquired pneumonia, pCAP) verbessern. In Mitteleuropa steht einer Prävalenz von ca. 300 Fällen pro 100 000 Kinder/Jahr eine sehr geringe Mortalität gegenüber, die Prävention umfasst Hygiene-Maßnahmen und Impfung z. B. gegen Pneumokokken, Hämophilus, Masern und Influenza. Hauptsymptome der pCAP sind Fieber und Tachypnoe, die Diagnosestellung erfolgt primär klinisch durch Anamnese, körperliche Untersuchung und Pulsoxymetrie. Das zusätzliche Vorliegen von Warnsymptomen wie stark reduzierter Allgemeinzustand, Nahrungsverweigerung, Dehydratation, Bewusstseinsstörung oder Krampfanfälle definiert die schwere pCAP in Abgrenzung zur nicht-schweren pCAP. Das Erregerspektrum ist altersabhängig, zur Differenzierung zwischen viraler, bakterieller oder gemischt viral-bakterieller Infektion stehen jedoch keine zuverlässigen Biomarker zur Verfügung. Die meisten Kinder und Jugendlichen mit nicht-schwerer pCAP und O

Zusammenfassung Zu den häufig vorkommenden Symptomen respiratorischer Notfälle bei Kindern und Jugendlichen zählen Dyspnoe, inspiratorischer Stridor, Pfeifen und Giemen, Zyanose und Thoraxschmerz. Die Atemwege von Säuglingen und Kleinkindern sind eng und weich, und die Sauerstoffreserve ist gering. Durch Erschöpfung der Atemmuskulatur kann es bedrohlich schnell zur respiratorischen Insuffizienz kommen. Symptome, Diagnose, Differenzialdiagnose und Therapie einer Fremdkörperaspiration, des Krupp-Syndroms, der Epiglottitis, der bakteriellen Tracheitis, der Bronchiolitis und des akuten Asthmaanfalls werden im Detail erläutert.

ZusammenfassungDie vorliegende Leitlinie ist eine Neufassung und Aktualisierung der Leitlinie zur Diagnostik und Therapie von Patienten mit Asthma, welche die bisher für den deutschen Sprachraum gültige Version aus dem Jahr 2006 ablöst. Die Fülle an neuen Erkenntnissen zur Pathophysiologie und zu den Phänotypen von Asthma und das erweiterte Spektrum an diagnostischen und therapeutischen Möglichkeiten bei dieser Erkrankung machte eine Neufassung und Aktualisierung notwendig. Es werden sowohl für Kinder und Jugendliche als auch für Erwachsene mit Asthma die aktuellen, Evidenz-basierten diagnostischen und therapeutischen Empfehlungen dargelegt.

The present guideline is a new version and an update of the guideline for the diagnosis and treatment of asthma, which replaces the previous version for german speaking countries from the year 2006. The wealth of new data on the pathophysiology and the phenotypes of asthma, and the expanded spectrum of diagnostic and therapeutic options necessitated a new version and an update. This guideline presents the current, evidence-based recommendations for the diagnosis and treatment of asthma, for children and adolescents as well as for adults with asthma.Die vorliegende Leitlinie ist eine Neufassung und Aktualisierung der Leitlinie zur Diagnostik und Therapie von Patienten mit Asthma, welche die bisher für den deutschen Sprachraum gültige Version aus dem Jahr 2006 ablöst. Die Fülle an neuen Erkenntnissen zur Pathophysiologie und zu den Phänotypen von Asthma und das erweiterte Spektrum an diagnostischen und therapeutischen Möglichkeiten bei dieser Erkrankung machte eine Neufassung und Aktualisierung notwendig. Es werden sowohl für Kinder und Jugendliche als auch für Erwachsene mit Asthma die aktuellen, Evidenz-basierten diagnostischen und therapeutischen Empfehlungen dargelegt.

Die protrahiert-bakterielle Bronchitis ist definiert als mehrwochige bronchiale Infektion durch Bakterien, wodurch es zu taglichem feuchtem Husten uber mindestens 4 Wochen kommt. Virale Infektionen gehen haufig voraus, und andere chronische Atemwegserkrankungen mussen ausgeschlossen werden. Die Diagnose wird primar klinisch gestellt. Eine mindestens 2-wochige Antibiotikagabe wird bei der Halfte der Kinder zu einer deutlichen Besserung fuhren. Bei den restlichen Kindern soll eine genauere Abklarung mithilfe der flexiblen Bronchoskopie, bronchoalveolarer Lavage und evtl. weiterer Untersuchungen erfolgen. Die am haufigsten nachgewiesenen Bakterien sind Haemophilus influenzae, Moraxella catarrhalis und Streptococcus pneumoniae. Potenzielle weitere Therapieoptionen, die bisher noch nicht ausreichend in Studien fur diese Indikation untersucht wurden, sind tagliche Inhalationen mit β-Mimetika und/oder hypertoner NaCl-Losung, verschiedene Thoraxphysiotherapieformen und die mehrwochige bis mehrmonatige Gabe von Azithromycin.

Asthma bronchiale ist eine der haufigsten chronischen Erkrankungen bei Kindern und Jugendlichen mit einer Pravalenz von rund 10 % in den deutschsprachigen Landern. Typische Symptome sind pfeifende Atemgerausche, Enge im Brustkorb und Atemnot. Die Diagnose wird klinisch gestellt; der wichtigste objektive Parameter ist der Nachweis der reversiblen Atemwegsobstruktion. Verschiedene Leitlinien stehen national und international fur die Therapie zur Verfugung. Neben der medikamentosen Therapie ist das nichtmedikamentose Management mit Allergenkarenz, Compliance-Uberprufung, Vermittlung der richtigen Inhalationstechnik und umfassender strukturierter Patientenschulung von groser Bedeutung.

Mukoviszidose (zystische Fibrose, CF) ist eine der haufigsten autosomal-rezessiv vererbten Erkrankungen der kaukasischen Bevolkerung. Der genetische Defekt im CFTR-Gen fuhrt zu einer Verringerung des Chloridionentransports an der Zellmembran. Die resultierende Dehydrierung des epithelialen Flussigkeitsfilms bedingt ihrerseits eine Reduktion der Sekret-Clearance. Die Folge ist eine Multiorganerkrankung. Die pulmonale Manifestation mit chronischen Infektionen und der Inflammation ist hierbei die dominierende Todesursache. Akute und chronische Infektion mit Pseudomonas aeruginosa (PA) konnen zu einem Abfall in der Lungenfunktion fuhren und sich direkt negativ auf die Uberlebenswahrscheinlichkeit auswirken. Die Entwicklung der ersten klinischen S3-Leitlinie fur die Mukoviszidose hat das Ziel, die Diagnostik und Therapie bei einem ersten Nachweis von PA in Deutschland, Osterreich und der Schweiz zu vereinheitlichen und zu optimieren. Zugleich sollen Impulse fur weitere Forschungsaktivitaten und Leitlinienentwicklungen gegeben werden. Auf der Grundlage eines Cochrane-Reviews wurde eine systematische Literaturrecherche im Zeitraum von 1995 bis November 2011 (Update September 2014) durchgefuhrt. Von den 286 resultierenden Originalarbeiten wurden 6 randomisierte klinische Studien und 8 weitere Eradikationsstudien niedrigerer Evidenz als relevant identifiziert und ausgewertet. Experten aus 13 wissenschaftlich-medizinischen Fachgesellschaften und Verbanden pruften anhand dieser Originalarbeiten und unter Zuhilfenahme von nationalen und internationalen Leitlinien und Konsensuspapieren die Evidenz als Grundlage fur die Formulierung von 36 Empfehlungen in einem nominalen Gruppenprozess. Die Auswertung der Eradikationsstudien zeigt, dass eine fruhe antibiotische Eradikationstherapie fur Patienten mit CF effektiv ist. Welches Therapieregime am erfolgversprechendsten ist, kann aufgrund von zu wenigen Daten aus vergleichenden Untersuchungen nicht entschieden werden. Nach Auswertung aller Hinweise konnten jedoch die folgenden Kernempfehlungen getroffen werden: Die fruhe Eradikation sollte mittels Tobramycin inhalativ fur 4 Wochen oder mittels Ciprofloxacin p.o., kombiniert mit Colistin inhalativ uber 3 Wochen, durchgefuhrt werden. Fur den Fall, dass eine Inhalation nicht moglich ist, sollte eine i.v.-Kombinationstherapie als Moglichkeit in Betracht gezogen werden. Falls eine Therapie mit inhalativen und oralen Antibiotika nicht zur Eradikation fuhrt, sollte eine Kombinationstherapie aus i.v.-Antibiotika und inhalativem Colistin durchgefuhrt werden. Bei einer pulmonalen Exazerbation und erstem Nachweis von PA wird eine sequenzielle Kombination aus i.v.- und inhalativem Antibiotikum empfohlen. Die fruhe Eradikationstherapie von PA bei Mukoviszidose ist effektiv und kann nach der vorliegenden Leitlinie durchgefuhrt werden. Es konnte in den vorliegenden Studien keine Uberlegenheit eines Therapieregimes gezeigt werden. Weitere vergleichende sowie Studien zur Beteiligung der oberen Atemwege sollten in Zukunft durchgefuhrt werden.

Kinder und Jugendliche werden haufig mit respiratorischen Symptomen oder einer auffalligen Atmung vorstellig. Eine organische Ursache ist nicht immer bestimmbar. Der Begriff „dysfunktionelle respiratorische Symptome“ beschreibt diese funktionellen oder psychogenen Storungen der Atemwege bei Kindern. In manchen Fallen uberlappen organische, funktionelle und psychische Zustande. In dieser Ubersicht werden das Erscheinungsbild und die Behandlung von Kindern und Jugendlichen mit habituellem Husten, Funktionsstorungen der Stimmbander („vocal cord dysfunction“), Seufzerdyspnoe, Hyperventilation und funktionellem Thoraxschmerz diskutiert. Von Bedeutung fur das Management und die Prognose dieser Storungen ist es, dem Patienten und seinen Eltern die klare Diagnose einer funktionellen Erkrankung zu vermitteln, unnotige diagnostische Verfahren zu vermeiden, unwirksame Medikationen abzusetzen und Behandlungsoptionen wie Physiotherapie oder psychologische Interventionen zu verschreiben.

Background Accurate assessment of atopic sensitization is pivotal to clinical practice and research. Skin prick test (SPT) and specific IgE (sIgE) are often used interchangeably. Some studies have suggested a disagreement between these two methods, and little is known about their association with allergic diseases. The aims of our study were to evaluate agreement between SPT and sIgE, and to compare their association with allergic diseases in 10-year-old children. Methods Skin prick test, sIgE measurements, and assessment of allergic diseases were performed in children aged 10 years in the Protection against Allergy: STUdy in Rural Environments (PASTURE) cohort. The agreement between SPT and sIgE was assessed by Cohen's kappa coefficient with different cutoff values. Results Skin prick tests and sIgE were performed in 529 children. The highest agreement (κ=.44) was found with a cutoff value of 3 and 5 mm for SPT, and 3.5 IU/mL for sIgE. The area under the curve (AUC) obtained with SPT was not significantly different from that obtained with sIgE. For asthma and hay fever, SPT (cutoff value at 3 mm) had a significantly higher specificity (P

Background Genomewide association and epigenetic studies found a region within the RAD50 gene on chromosome 5q31 to be associated with total serum IgE levels and asthma. In mice, this region harbors a locus control region for nearby TH2 cytokines, which is characterized by four Rad50 DNase I hypersensitive sites (RHS4–7). Among these, RHS7 seems to have the strongest impact on TH2 differentiation. We investigated whether within the human homolog of RHS7, functional polymorphisms exist, which could affect DNA methylation or gene expression in the 5q31 locus and might have an influence on asthma status or IgE regulation. Methods The human RHS7 region was fine mapped using 1000 genomes database information. In silico analysis and electrophoretic mobility shift assays were used to assess SNP function. Allele-specific effects on DNA methylation were evaluated in cord blood (n = 73) and at age of 4.5 years (n = 61) by pyrosequencing. Allele-specific effects on RAD50, IL4, and IL13 expression were analyzed in 100 subjects. Associations with asthma and IgE levels were investigated in the MAGICS/ISAAC II population (n = 1145). Results Polymorphism rs2240032 in the RHS7 region is suggestive of allele-specific transcription factor binding, affects methylation of the IL13 promoter region and influences RAD50 and IL4 expression (lowest P = 0.0027). It is also associated with total serum IgE levels (P = 0.0227). Conclusion A functional relevant polymorphism in the TH2 locus control region, equivalent to RHS7 in mice, affects DNA methylation and gene expression within 5q31 and influences total serum IgE on the population level.

Background: Farm exposure protects against development of allergies early in life. At 4.5 years, protection against asthma by farm-milk exposure was partially mediated by regulatory T cells (Tregs). The aim of this study was to investigate the critical time window of the ‘asthma-protective’ farm effect via Tregs during childhood immune maturation. Methods: Tregs were assessed longitudinally at 4.5 and 6 years in 111 children (56 farm and 55 reference children) from the PASTURE/EFRAIM birth cohort (flow cytometry). Peripheral blood mononuclear cells were cultured unstimulated (U), with phorbol 12-myristate 13-acetate/ionomycin (PI) or lipopolysaccharide (LPS), and stained for Tregs (CD4+CD25highFOXP3upper20%). mRNA expression of Treg/Th1/Th2/Th17-associated cell markers was measured ex vivo. Suppressive capacity of Tregs on effector cells and cytokines was assessed. Detailed questionnaires assessing farm exposures and clinical phenotypes from birth until age 6 years were answered by the parents. Results: Treg percentage before and after stimulation and FOXP3mRNA expression ex vivo decreased from age 4.5 to 6 years (P(U,LPS) < 0.001; P(PI) = 0.051; P(FOXP3) < 0.001). High vs low farm-milk and animal-stable exposure was associated with decreased LPS-stimulated Treg percentage at age 6 years (P(LPS) = 0.045). Elevated LPS-stimulated-Treg percentage at age 6 was associated with increased risk of asthma (aOR = 11.29, CI: 0.96–132.28, P = 0.053). Tregs from asthmatics vs nonasthmatics suppressed IFN-γ (P = 0.015) and IL-9 (P = 0.023) less efficiently. mRNA expression of Th1/Th2/Th17-associated cell markers decreased between 4.5 and 6 years (P < 0.001). Conclusions: Tregs at the age of 6 years were decreased with farm exposure and increased within asthmatics, opposite to age 4.5 years. This immunological switch defines a critical ‘time window’ for Treg-mediated asthma protection via environmental exposure before age 6 years.

Zu den haufig vorkommenden Symptomen respiratorischer Notfalle bei Kindern und Jugendlichen zahlen Dyspnoe, inspiratorischer Stridor, Pfeifen und Giemen, Zyanose und Thoraxschmerz. Die Atemwege von Sauglingen und Kleinkindern sind eng und weich, und die Sauerstoffreserve ist gering. Durch Erschopfung der Atemmuskulatur kann es bedrohlich schnell zur respiratorischen Insuffizienz kommen. Symptome, Diagnose, Differenzialdiagnose und Therapie einer Fremdkorperaspiration, des Krupp-Syndroms, der Epiglottitis, der bakteriellen Tracheitis, der Bronchiolitis und des akuten Asthmaanfalls werden im Detail erlautert.

Summary Background Recent studies indicate that prenatal vitamin D intake may protect against the development of atopic diseases in young children. Vitamin D has been shown to induce tolerogenic antigen-presenting cells such as dendritic cells. Whether the allergy-protective potential of prenatal vitamin D is mediated through such mechanisms is, however, unknown. Objective To evaluate the association between prenatal vitamin D supplementation and tolerogenic antigen-presenting cells in cord blood (CB) as determined by mRNA measurement of immunoglobulin-like transcripts (ILT)3 and ILT4. Methods A prospective multi-centre birth cohort was established in rural areas of five European countries. Information on maternal exposures including vitamin D intake was collected by questionnaires during pregnancy. The gene expression of ILT3 and ILT4 was analysed by real-time PCR in the CB of 927 children. Maternal vitamin D supplementation was assessed in Finland and France (n=349). Results Maternal vitamin D supplementation during pregnancy was associated with an increase in the gene expression of ILT3 (P=0.012) and ILT4 (P

Eczema is often associated with development of allergic asthma. The Neuropeptide S Receptor 1 (NPSR1) gene has previously been associated with asthma and elevated serum IgE levels. The aim of this study was to investigate a potential association between the NPSR1 gene and eczema in patients and healthy individuals from five different populations in Western Europe, in total 6275 individuals. Seven single nucleotide polymorphisms previously associated with allergic asthma were genotyped. The protein expression of NPSR1 in the skin was studied using immunohistochemistry in six eczema patients and eight healthy individuals. No association was found be tween eczema and the seven single nucleotide polymor phisms in NPSR1 in any of the populations, either independently or in combinations. In addition, no difference was detected in epidermal NPSR1 expression between eczema patients and healthy individuals. These results strongly suggest that NPSR1 is not involved in the pathogenesis of eczema.

Summary Background Dietary interventions as a means for atopy prevention attract great interest. Some studies in rural environments claimed an inverse association between consumption of farm-produced dairy products and the prevalence of allergic diseases, but current evidence is controversial. Objective To investigate whether consumption of farm-produced products is associated with a lower prevalence of asthma and allergy when compared with shop-purchased products. Methods Cross sectional multi-centre study (PARSIFAL) including 14 893 children aged 5–13 years from five European countries (2823 from farm families and 4606 attending Steiner Schools as well as 5440 farm reference and 2024 Steiner reference children). A detailed questionnaire including a dietary component was completed and allergen-specific IgE was measured in serum. Results Farm milk consumption ever in life showed a statistically significant inverse association with asthma: covariate adjusted odds ratio (aOR) 0.74 [95% confidence interval (CI) 0.61–0.88], rhinoconjunctivitis: aOR 0.56 (0.43–0.73) and sensitization to pollen and the food mix fx5 (cut-off level of 3.5 kU/L): aOR 0.67 (0.47–0.96) and aOR 0.42 (0.19–0.92), respectively, and sensitization to horse dander: aOR 0.50 (95% CI 0.28–0.87). The associations were observed in all four subpopulations and independent of farm-related co-exposures. Other farm-produced products were not independently related to any allergy-related health outcome. Conclusion Our results indicate that consumption of farm milk may offer protection against asthma and allergy. A deepened understanding of the relevant protective components of farm milk and a better insight into the biological mechanisms underlying this association are warranted as a basis for the development of a safe product for prevention.

BackgroundGut microbiota and intestinal inflammation regulate the development of immune-mediated diseases, such as allergies. Fecal calprotectin is a biomarker of intestinal inflammation.ObjectiveWe evaluated the association of early-age fecal calprotectin levels to the later development of allergic diseases in children from farming and non-farming environments and further studied the effect of gut microbiota on the fecal calprotectin levels.MethodsFecal calprotectin was measured from 758 infants participating in the PASTURE study at the age of 2months using the ELISA method. Serum-specific IgE levels were measured at 6years of age. Data of environmental factors, doctor-diagnosed atopic dermatitis (AD) and asthma were collected by questionnaire. Multivariate logistic regression models were used for analysis. The composition of fecal microbiota was analysed in a subgroup of 120 infants with 16S rRNA pyrosequencing. The effect of Escherichia coli lipopolysaccharide (LPS) on in vitro monocyte IL-10 secretion was studied by flow cytometry.ResultsThe infants with high fecal calprotectin levels at 2months, that is above the 90th percentile, had an increased risk of developing AD and asthma/asthmatic bronchitis by the age of 6years (aOR 2.02 (1.06-3.85) and 2.41 (1.25-4.64), respectively). High fecal calprotectin levels correlated negatively with fecal Escherichia. LPS from E.coli stimulated production of IL-10 in monocytes.Conclusion and Clinical RelevanceHigh degree intestinal inflammation at 2months of age, detected as high fecal calprotectin, predicted asthma and AD by the age of 6years and was linked to low abundance of fecal Escherichia. Impaired IL-10 activation due to the lack of colonization with E.coli could explain the intestinal inflammation associated high fecal calprotectin and later risk of asthma and AD. Our results have implications for the design of probiotic treatments and suggest that early intestinal colonization has long-term health effects.

Dust collection by study participants instead of fieldworkers would be a practical and cost-effective alternative in large-scale population studies estimating exposure to indoor allergens and microbial agents. We aimed to compare dust weights and biological agent levels in house dust samples taken by study participants with nylon socks, with those in samples taken by fieldworkers using the sampling nozzle of the Allergology Laboratory Copenhagen (ALK). In homes of 216 children, parents and fieldworkers collected house dust within the same year. Dust samples were analyzed for levels of allergens, endotoxin, (1-->3)-beta-D-glucans and fungal extracellular polysaccharides (EPS). Socks appeared to yield less dust from mattresses at relatively low dust amounts and more dust at high dust amounts than ALK samples. Correlations between the methods ranged from 0.47-0.64 for microbial agents and 0.64-0.87 for mite and pet allergens. Cat allergen levels were two-fold lower and endotoxin levels three-fold higher in socks than in ALK samples. Levels of allergens and microbial agents in sock samples taken by study participants are moderately to highly correlated to levels in ALK samples taken by fieldworkers. Absolute levels may differ, probably because of differences in the method rather than in the person who performed the sampling. Practical Implications Dust collection by participants is a reliable and practical option for allergen and microbial agent exposure assessment. Absolute levels of biological agents are not (always) comparable between studies using different dust collection methods, even when expressed per gram dust, because of potential differences in particle-size constitution of the collected dust.

Background: The prevalence of allergic diseases has increased rapidly in recent decades, particularly in children. For adequate prevention it is important not only to identify risk factors, but also possible protective factors. The aim of this study was to compare the prevalence of allergic diseases and sensitization between farm children, children in anthroposophic families, and reference children, with the aim to identify factors that may protect against allergic disease. Methods: The study was of cross-sectional design and included 14 893 children, aged 5–13 years, from farm families, anthroposophic families (recruited from Steiner schools) and reference children in Austria, Germany, the Netherlands, Sweden and Switzerland. A detailed questionnaire was completed and allergen-specific IgE was measured in blood. Results: Growing up on a farm was found to have a protective effect against all outcomes studied, both self-reported, such as rhinoconjunctivitis, wheezing, atopic eczema and asthma and sensitization (allergen specific IgE ≥0.35 kU/l). The adjusted odds ratio (OR) for current rhinoconjunctivitis symptoms was 0.50 (95% confidence interval (CI) 0.38–0.65) and for atopic sensitization 0.53 (95% CI 0.42–0.67) for the farm children compared to their references. The prevalence of allergic symptoms and sensitization was also lower among Steiner school children compared to reference children, but the difference was less pronounced and not as consistent between countries, adjusted OR for current rhinoconjunctivitis symptoms was 0.69 (95% CI 0.56–0.86) and for atopic sensitization 0.73 (95% CI 0.58–0.92). Conclusions: This study indicates that growing up on a farm, and to a lesser extent leading an anthroposophic life style may confer protection from both sensitization and allergic diseases in childhood.

BACKGROUND Growing up on a farm and an anthroposophic lifestyle are associated with a lower prevalence of allergic diseases in childhood. This might be related to increased inhalatory exposure to microbial agents. OBJECTIVE To assess the association between microbial agents in house dust and atopic wheeze in farm children, Steiner school children and reference children. METHODS Levels of bacterial endotoxin, fungal beta(1,3)-glucans and fungal extracellular polysaccharides (EPS) in mattress and living room floor dust were measured in a population of 270 atopic (=Phadiatop-positive) children with self-reported wheezing, including 168 current atopic wheezers, and 441 non-atopic, non-symptomatic controls. These children were selected from a cross-sectional study in five European countries. RESULTS In the study population as a whole, average levels of mattress dust endotoxin, EPS and glucans were slightly (1.1-1.2-fold; P

Background: An increasing number of studies report pet exposure to be associated with lower risk of asthma and allergies. This ‘protective pet effect’ has been suggested to result from a modified T-helper (Th)2-cell response, or because of increased microbial load in homes where pets are kept. We examined the associations between pet contact and the occurrence of asthma and allergies in children of the rural Allergy and Endotoxin (ALEX) population, taking farm animal contact, endotoxin and cat allergen levels in mattress dust into account. Methods: Information about contact with pets and farm animals, asthma and allergy were collected for 812 children by a standardized parents’ questionnaire and an interview. Mattress dust endotoxin and cat allergen levels as well as specific IgE and IgG4 antibodies to Fel d1 were determined. Results: Current contact with dogs was inversely associated with diagnosed hay fever (OR 0.26, 95% CI 0.11–0.57), diagnosed asthma (OR 0.29, 95% CI 0.12–0.71), sensitization to cat allergen (OR 0.48, 95% CI 0.23–0.99) and to grass pollen (OR 0.55, 95% CI 0.33–0.94), but not with increased IgG4 levels. Early and current contact with cats were associated with reduced risk of wheezing (OR 0.48, 95% CI 0.23–1.00, and OR 0.49, 95% CI 0.26–0.92, respectively) and grass pollen sensitization. Adjustment for farm animal contact but not for endotoxin and cat allergen exposure attenuated these associations and the effect of pet was stronger among farmers’ children. Conclusion: Although pet exposure was very frequent in this rural population, the inverse relation between current dog contact, asthma and allergy was mostly explained by simultaneously occurring exposure to stable animals or was restricted to farm children. In addition, a subtle form of pet avoidance may contribute to the protective effect of pet.

Indirect challenges act by causing the release of endogenous mediators that cause the airway smooth muscle to contract. This is in contrast to the direct challenges where agonists such as methacholine or histamine cause airflow limitation predominantly via a direct effect on airway smooth muscle. Direct airway challenges have been used widely and are well standardised. They are highly sensitive, but not specific to asthma and can be used to exclude current asthma in a clinic population. Indirect bronchial stimuli, in particular exercise, hyperventilation, hypertonic aerosols, as well as adenosine, may reflect more directly the ongoing airway inflammation and are therefore more specific to identify active asthma. They are increasingly used to evaluate the prevalence of bronchial hyperresponsiveness and to assess specific problems in patients with known asthma, e.g. exercise-induced bronchoconstriction, evaluation before scuba diving. Direct bronchial responsiveness is only slowly and to a modest extent, influenced by repeated administration of inhaled steroids. Indirect challenges may reflect more closely acute changes in airway inflammation and a change in responsiveness to an indirect stimulus may be a clinically relevant marker to assess the clinical course of asthma. Moreover, some of the indirect challenges, e.g. hypertonic saline and mannitol, can be combined with the assessment of inflammatory cells by induction of sputum.

Introduction et but de l’étudeUne diversité alimentaire importante et précoce a été montrée protectrice contre des maladies allergiques (Roduit C. et al, JACI2012 Jul;130(1): 130-6). L’effet de la diversité de consommation de fromages, riches en microorganismes, n’a pas été étudié. Or l’exposition aux microorganismes est suspectée pour son rôle protecteur contre la survenue de maladies allergiques. Le but de notre étude était d’évaluer l’effet protecteur de la diversité de consommation de fromages contre des maladies allergiques (MA) : allergie alimentaire (AA), dermatite atopique (DA), asthme (AS), rhinite allergique (RA) et bronchite (BR).Matériel et méthodesL’étude a porté sur 941 enfants de la cohorte PATURE (Protection contre l’Allergie : étude du milieu Rural et de son Environnement) qui étudie l’influence de l’exposition à l’environnement fermier sur le développement des maladies allergiques dans 5 pays européens (France, Allemagne, Autriche, Suisse et Finlande). Les données concernant les habitudes alimentaires, l’atopie parentale et les facteurs environnementaux ont été colligées par questionnaire de la naissance à 6 ans. Les MA ont été définies par un diagnostic médical rapporté par les parents. Les fromages ont été classés en 6 catégories (à pâte dure pressée, semi-pressée, molle, bleu, frais, de la ferme). La diversité de consommation de fromages à 18 mois (DC18) a été définie par le nombre de différentes catégories de fromages consommées. L’effet de la diversité de consommation de fromages contre chaque MA à l’âge de 6 ans a été analysé par régressions logistiques linéaires multiples ajustées pour la diversité alimentaire à 6 mois, le pays, l’environnement fermier et les facteurs confondants d’atopie, comme l’atopie parentale.Résultats et Analyse statistiqueDC18 n’était pas corrélée à la diversité alimentaire à 6 ou 12 mois (P < 0,001). Une diversité élevée de fromages consommés avait un effet significativement protecteur contre la DA à 6 ans (P < 0,0007 ; OR = 0,60; IC[0,44;0,81]) et les AA à 6 ans (P < 0,041 ; OR = 0,57; IC[0,33;0,98]), mais pas contre les autres MA à 6 ans (AS, RA, BR).ConclusionLa consommation d’une diversité de fromages à 18 mois semble avoir un effet protecteur contre la DA et les A A à 6 ans, indépendamment de la diversité de consommation des autres groupes d’aliments.

We study an Ising spin system coupled to the fluctuating two-dimensional geometry of the discrete Regge model and compare with the results of the standard Regge calculus. Particular emphasis is placed on the phase transition of the spin system and the associated critical exponents. The results are obtained from finite-size scaling analyses of extensive Monte Carlo simulations.

Summary Background and objectives In some studies, the prevalence of hay fever and asthma has been found to be lower in children from rural areas than in children from an urban environment. We hypothesized that living on a farm might be protective against development of allergic sensitization and allergic diseases. Methods In a cross-sectional survey, parents of 2283 children aged 8‐10 years from a mostly rural area in Austria answered a standardized questionnaire on allergic diseases and environmental factors. 1137 children performed a skin prick test to seven local allergens. Results The prevalence of hay fever (3.1 vs 10.3%, Pa 0.0002), asthma (1.1 vs 3.9%, Pa 0.017) and a positive skin prick reactivity to at least one of the common local allergens (18.8 vs 32.7%, Pa 0.001) was significantly lower in children living on a farm than in children from a non-farming environment. In a multivariate logistic regression model, adjusting for genetic background, parent education, living and housing conditions and dietary factors did not change the odds ratio for the association of farming and allergic sensitization. Only after including ‘regular contact with livestock and poultry’ into the model did the odds ratio change significantly (cOR 0.48 95% CI 0.30‐0.75 to aOR 0.75 95% CI 0.37‐1.52) indicating an association between regular contact with farm animals and reduced risk of atopic sensitization. Conclusion Possible explanations for the lower prevalence of hay fever, asthma and allergic sensitization in children living on a farm might be the development of immunotolerance or the stimulation of TH1 cells and suppression of TH2 cells by increased exposure of farm children to microbial antigens in the stables or farmhouses.

Viral colds are an important cause of respiratory symptoms in normal children. Studies in adults suggest that inflammation in the lower respiratory tract is associated with viral colds, but there are no data regarding inflammation and viral infection in the lower airway of normal children with colds. We, therefore, studied the lower airway of two groups of children: Group I, those with active coryzal symptoms and a respiratory virus isolated from bronchoalveolar lavage fluid (BALF); and Group II: asymptomatic children who had had a clinical cold within the previous 2 weeks and no respiratory virus in BALF. Both groups were compared to age- and weight-matched normal noninfected controls, who had had no coryzal symptoms for at least 8 weeks. Viruses isolated from BALF of Group I (n = 7) were: respiratory syncytial virus (n = 2), rhinovirus (n = 3), parainfluenza I (n = 1), and echovirus 11 (n = 1). Compared to normal controls, Group I had an increased BALF lymphocyte and neutrophil differential count (P < 0.05), a concomitant depressed alveolar macrophage differential count (P < 0.05), and increased BALF concentrations of soluble intercellular adhesion molecule-1 (sICAM-1) (P < 0.05, n = 6), total protein (P < 0.05, n = 6) and albumin (P < 0.05, n = 7). Similar changes were seen in Group II (n = 22), with an increased BALF neutrophil (P < 0.05) and lymphocyte (P < 0.01) differential count, and increased concentrations of sICAM-1 (P < 0.01, n = 15), total protein (P < 0.0001, n = 9) and albumin (P = 0.05, n = 17). Our results suggest that inflammation and viral infection in the lower airway are present during active colds, and that inflammation is also present during the convalescent period.

We examine the phase structure of standard Regge calculus in four dimensions and compare our Monte Carlo results with those of the -Regge model as well as with another formulation of lattice gravity derived from group-theoretical considerations. Within all of the three models of quantum gravity we find an extension of the well-defined phase to negative gravitational couplings and a new phase transition. In contrast to the well known transition at positive coupling there is evidence for a continuous phase transition which is essential for a continuum limit. We calculate two-point functions between geometrical quantities at the corresponding critical point and estimate the masses of the respective interaction particles.

SUMMARYThe occurrence ofBrachyspiraspecies andLawsonia intracellulariswas investigated by PCR analyses of faeces from 60 children living on European pig farms. In addition, 60 other children were included as controls. Two samples were positive forB. aalborgibutB. pilosicoliandL. intracellulariswere not demonstrated.

Introduction et but de l’etude Une diversite alimentaire importante et precoce a ete montree protectrice contre des maladies allergiques (Roduit C. et al, JACI2012 Jul;130(1): 130-6). L’effet de la diversite de consommation de fromages, riches en microorganismes, n’a pas ete etudie. Or l’exposition aux microorganismes est suspectee pour son role protecteur contre la survenue de maladies allergiques. Le but de notre etude etait d’evaluer l’effet protecteur de la diversite de consommation de fromages contre des maladies allergiques (MA) : allergie alimentaire (AA), dermatite atopique (DA), asthme (AS), rhinite allergique (RA) et bronchite (BR). Materiel et methodes L’etude a porte sur 941 enfants de la cohorte PATURE (Protection contre l’Allergie : etude du milieu Rural et de son Environnement) qui etudie l’influence de l’exposition a l’environnement fermier sur le developpement des maladies allergiques dans 5 pays europeens (France, Allemagne, Autriche, Suisse et Finlande). Les donnees concernant les habitudes alimentaires, l’atopie parentale et les facteurs environnementaux ont ete colligees par questionnaire de la naissance a 6 ans. Les MA ont ete definies par un diagnostic medical rapporte par les parents. Les fromages ont ete classes en 6 categories (a pâte dure pressee, semi-pressee, molle, bleu, frais, de la ferme). La diversite de consommation de fromages a 18 mois (DC18) a ete definie par le nombre de differentes categories de fromages consommees. L’effet de la diversite de consommation de fromages contre chaque MA a l’âge de 6 ans a ete analyse par regressions logistiques lineaires multiples ajustees pour la diversite alimentaire a 6 mois, le pays, l’environnement fermier et les facteurs confondants d’atopie, comme l’atopie parentale. Resultats et Analyse statistique DC18 n’etait pas correlee a la diversite alimentaire a 6 ou 12 mois (P Conclusion La consommation d’une diversite de fromages a 18 mois semble avoir un effet protecteur contre la DA et les A A a 6 ans, independamment de la diversite de consommation des autres groupes d’aliments.

We compare different models of a quantum theory of four-dimensional lattice gravity based on Regge's original proposal. From Monte Carlo simulations we calculate two-point functions between geometrical quantities and estimate the masses of the corresponding interaction particles., Comment: 4 pages, 9 figures, LaTeX uses espcrc2.sty, to be published in Nucl. Phys. B (Proc. Suppl.), Talk presented at LATTICE96(gravity)

Dyspnoe beschreibt eine erschwerte oder gestorte Atmung, entspricht also einer Kurzatmigkeit oder Atemnot; Tachypnoe beschreibt eine in der Frequenz erhohte Atmung. Die Dyspnoe kann verschiedene Ursachen haben und unter Umstanden auch rein subjektiv ohne objektivierbares Korrelat empfunden werden.

We analyze Regge quantum gravity coupled to SU(2) gauge theory on $4^3\times 2$, $6^{3}\times 4$ and $8^{3}\times 4$ simplicial lattices. It turns out that the window of the well-defined phase of the gravity sector where geometrical expectation values are stable extends to negative gravitational couplings as well as to gauge couplings across the deconfinement phase transition. We study the string tension from Polyakov loops, compare with the $\beta$-function of pure gauge theory and conclude that a physical limit through scaling is possible., Comment: RevTeX, 14 pages, 5 figures (2 eps, 3 tex), 2 tables

There is still controversy about the most suitable method to measure bronchial hyperresponsiveness in children. In epidemiological surveys, nonisotonic aerosols are being used increasingly for bronchial provocation testing. Our aim was to study the acceptability, safety and correlation between two published bronchial challenge tests. Two standardized protocols--the inhalation of hypertonic saline (HS) and ultrasonically-nebulized distilled water (UNDW)--were performed in 36 children: 19 patients with the clinical diagnosis of mild-to-moderate asthma (7-12 yrs of age), and 17 control subjects (8-18 yrs of age). HS challenge involved stepwise inhalation of 4.5% saline (for 0.5, 1, 2, 4 and 8 min), whereas challenge with UNDW was performed as a single step protocol with 10 min inhalation of cold UNDW. Asthma medication was withheld prior to challenge testing. Thirty five subjects completed both challenge tests (one asthmatic patient did not return after UNDW challenge) in random order within a 7 day time interval. For HS a > or = 15% reduction in forced expiratory volume in one second (FEV1) from baseline was considered a positive response, and for UNDW a > or = 10% decrease. In 13 of the 19 asthmatic patients, but in none of the controls, a positive response was observed for UNDW. Fifteen out of 18 patients and one control subject had a positive response to HS. Twelve out of 18 asthmatic children responded to both challenges, three responded only to HS and three had no response to either challenge. There was a negative correlation between log provocative dose causing a 15% reduction in FEV1 (PD15) after HS and the maximum fall in FEV1 after UNDW (rs = -0.63; p < 0.005). The HS challenge had a lower acceptability than challenge with UNDW due to the unpleasant salty taste of HS. However, this did not inhibit the completion of the tests in any subject. The results of this study suggest a good correlation between response to hypertonic saline and ultrasonically-nebulized distilled water in children with mild-to-moderate asthma. A multiple step protocol might be safer when applied in field studies involving children.

Progressive lung disease in patients with cystic fibrosis (CF) is caused by thick secretions, which cause airway obstruction and subsequent colonization and infection by inhaled pathogenic microorganisms. Recently, recombinant human DNase has been shown to reduce the viscoelasticity of sputum in patients with cystic fibrosis and to improve lung function. Ultrasonically nebulized hypertonic saline (HS) has been demonstrated to enhance mucociliary clearance and sputum expectoration by rehydrating airway secretions, and may therefore provide a low cost alternative. We studied the changes in pulmonary function and symptoms in a group of patients with CF who have moderate to severe lung disease. The patients were evaluated following 2 weeks of treatment with HS in an open-label study. Subjects were randomly allocated to receive 10 ml of either 0.9% NaCl (IS) or 6% NaCl (HS). Twice daily, prior to physiotherapy, treatments were delivered by a portable ultrasonic nebulizer. To prevent bronchoconstriction, 600 mg of salbutamol was administered prior to the nebulized solutions. A symptom score was recorded and spirometry was performed on day 0 before therapy was started, on day 14 (the last day of therapy), and on day 28 (14 days after the last treatment with either IS or HS). Fifty-two patients (32 males), with a mean age of 16.2 (range 7-36) years completed the study. There was no difference in baseline characteristics between the two groups. Following 2 weeks of treatment, there was a significant improvement from baseline in FEV1 of 15.0 +/- 16.0% (mean +/- SD) in patients treated with HS, compared with a change of 2.8 +/- 13% in those on IS therapy (P = 0.004). Furthermore, there was a subjective improvement in the effectiveness of chest physiotherapy as reported by those using HS (P = 0.02). The treatment was well tolerated. We conclude that in patients with CF, ultrasonically nebulized hypertonic saline improves lung function in a way similar to that reported for human recombinant DNase when inhaled over a 2 week period. Nebulized saline also enhances the perception of effectiveness of chest physiotherapy.

The role of bronchoalveolar lavage (BAL) in children remains to be defined, and to date there has been no standardization of acquisition and processing of the BAL fluid. The aim of the present study was to evaluate a standardized protocol for obtaining, processing, and analyzing BAL fluid and to establish reference values for healthy children. Eighteen children 3 mo to 10 yr of age were lavaged with three 1-ml/kg aliquots of normal saline, using a flexible bronchoscope into the right middle lobe. The first aliquot was processed separately; the second and the third were pooled. There was a higher percentage of neutrophils and epithelial cells in the first aliquot. The number of total cells per milliliter (median, Q1 to Q3) in the first aliquot was 60 (45 to 90) x 10(3)/ml; in the pooled sample it was 155 (75 to 257) x 10(3)/ml. Percentages (median, Q1 to Q3) of different cell types in the pooled sample were: macrophages, 91% (84 to 94); lymphocytes, 7.5% (4.7 to 12.8); neutrophils, 1.7% (0.6 to 3.5); eosinophils, 0.15% (0.0 to 0.3). The ratio of helper/cytotoxic T-cells was 0.58 (0.4 to 1). The results of this study demonstrate that BAL, using a standardized protocol adjusting instilled fluid volume by weight, appears to be appropriate in children and that cellular and protein values from healthy children are, apart from differences in lymphocyte subsets, similar to those found in healthy adults.

To evaluate sensitivity and specificity of a 4.5% hypertonic saline challenge for a diagnosis of asthma, we studied 393 schoolchildren (13 to 15 yr of age) with "current wheeze," "former wheeze," and without history of wheeze in a community-based, cross-sectional survey. These children were selected from 2.836 schoolchildren in 26 schools in greater Melbourne, Australia who completed a self-administered questionnaire on respiratory symptoms, allergic rhinitis, and eczema. Three hundred eighty-two of 393 children successfully completed a 4.5% hypertonic saline challenge with increasing inhalation periods, and 365 of 393 performed a 6-min standardized, free running exercise challenge. The prevalence of bronchial hyperresponsiveness to hypertonic saline was 20.4%. Sensitivity and specificity for the hypertonic saline challenge to identify children with "current wheeze" were 47% and 92% respectively and for the exercise challenge, 46% and 88%. The agreement of response to hypertonic saline and to exercise was only moderate (kappa = 0.43). Factors associated with increased response to hypertonic saline in a multivariate logistic regression model were a history of "current wheeze," hay fever, response to the exercise challenge, female sex, and a lower baseline predicted FEV1. These results suggest that a 4.5% hypertonic saline challenge shows sensitivity and specificity similar to a standardized exercise challenge and pharmacologic challenges and a higher sensitivity than cold air hyperventilation and distilled water to identify asthma in children in a field study. Measurement of responsiveness to hypertonic saline may be of value as an objective marker of asthma to compare prevalence studies of bronchial hyperresponsiveness and of asthma over time and between countries.

Non-isotonic aerosols are being used more commonly to perform bronchial provocation tests. In contrast to histamine and methacholine challenge tests they appear to have higher specificity and a higher predictive value. The aim of the present study was to assess the reproducibility of the response to challenge with 4.5% hypertonic saline administered via an ultrasonic nebulizer in children with mild to severe asthma. Seventeen children with asthma aged 10 to 14 years completed two or three challenge tests at the same time of day within a 10 day period. Of these 17 children 9 had mild, 4 moderate, and 4 severe asthma. Children inhaled 4.5% hypertonic NaCl from an ultrasonic nebulizer with an output of 1.9 to 2.5 mL/min (Timeter) using the protocol developed by Anderson with modifications. A fall in forced expiratory volume in 1 second (FEV1) from baseline of 15% or more was considered a positive response and PD15, was calculated. In 16/17 subjects a greater than 15% fall in FEV1 occurred consistently on all study days. One subject with moderate asthma had a less than 15% fall in FEV1 on both study days. The coefficient of repeatability for PD15 was 1.8. This equals 0.85 of a doubling dose difference between the two or three measurements of PD15. The cumulative time of aerosol inhalation causing a fall in FEV1 2 15%) (PT15) showed a coefficient of repeatability of 1.59, similar to 0.67 doubling dose difference. The PD15 and PT15 were highly significantly correlated. The 4.5% NaCl challenge test yields good reproducibility in children with mild to severe asthma under laboratory conditions.Pediatr Pulmonol. 1994;18:330–336 © Wiley-Liss, Inc.