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Liebe Kolleginnen und Kollegen, Liebe Freundinnen und Freunde der GPP,nach einem ungewöhnlich kurzen Abstand zur vergangenen Jahrestagung, welcher durch eine Pandemie-bedingte Verschiebung der Jahrestagung 2022 in Bern begründet ist, erhalten Sie hiermit das GPP-Heft für die 44. Jahrestagung der Gesellschaft für Pädiatrische Pneumologie in Frankfurt.

Almost 2 years into the pandemic and with vaccination of children significantly lagging behind adults, long-term pediatric humoral immune responses to SARS-CoV-2 are understudied. The C19.CHILD Hamburg (COVID-19 Child Health Investigation of Latent Disease) Study is a prospective cohort study designed to identify and follow up children and their household contacts infected in the early 2020 first wave of SARS-CoV-2. We screened 6113 children P = 0.047). Most importantly, children showed sustained seroconversion up to 9 months PSO, and serum antibody concentrations persistently surpassed adult levels (ratio serum IgG spike children vs. adults 90 days PSO 1.75, P P = 0.01; 270 days 1.54, P = 0.001). In a low-incidence setting, SARS-CoV-2 infection and humoral immune response present distinct patterns in children including higher antibody levels, and lower seroprevalence in families with pediatric index cases. Children show long-term SARS-CoV-2 antibody responses. These findings are relevant to novel variants with increased disease burden in children, as well as for the planning of age-appropriate vaccination strategies.

Zusammenfassung Hintergrund Das Erkennen von Kindesmisshandlungen und der Umgang damit sind Herausforderungen im ärztlichen Alltag. Die Dunkelziffer bei Misshandlungen und Vernachlässigungen ist hoch. Ziel der Arbeit Das Ziel der Arbeit war, die Effektivität des neu strukturierten Kinderschutzprogrammes einer großen deutschen Kinderklinik zu untersuchen und durch die Präsentation der Vorteile der neuen Struktur die Verbesserung von Programmen für Kinder und Mediziner in anderen Kliniken anzuregen. Methode Es wurden retrospektiv alle Kinderschutzfälle im Altonaer Kinderkrankenhaus vor und nach Neukonzeption der Kinderschutzarbeit über einen Zeitraum von jeweils 2 Jahren untersucht und miteinander verglichen. Die Kinderschutzgruppe war neu strukturiert worden und wurde nachfolgend von einer hauptamtlichen Kinderschutzkoordinatorin geleitet. Ergebnis Die Prävalenz der Verdachtsfälle und der erhärteten Fälle von Kindeswohlgefährdung ist im Untersuchungszeitraum nach Neukonzeption hoch signifikant erhöht. Im Zeitraum vor der Neukonzeption wurden 24 Fälle mit dem Verdacht auf Kindswohlgefährdung untersucht, 23 erhärtet, danach 124 Fälle untersucht, 89 erhärtet. Eine Stigmatisierung der Familien bei der Abklärung wurde trotz des signifikanten Anstiegs falsch-positiver Verdachtsfälle durch sensibles Vorgehen und eine Konfrontation erst bei Erhärtung des Verdachtes vermieden. Schlussfolgerung Das vorgestellte Konzept zum medizinischen Kinderschutz in Kinderkliniken scheint das Hellfeld bei Kindeswohlgefährdung effektiv auszuweiten. Sowohl die Reduktion nichtdetektierter Fälle mit der Verhinderung potenzieller Eskalation mit prolongiertem Leidensweg als auch die Verminderung der immensen gesellschaftlichen Folgekosten rechtfertigen die personellen Investitionen.

Background Healthcare workers are considered a particularly high-risk group during the coronavirus disease 2019 (COVID-19) pandemic. Healthcare workers in paediatrics are a unique subgroup: they come into frequent contact with children, who often experience few or no symptoms when infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and, therefore, may transmit the disease to unprotected staff. In Germany, no studies exist evaluating the risk of COVID-19 to healthcare workers in paediatric institutions. Methods We tested the staff at a large children’s hospital in Germany for immunoglobulin (Ig) G antibodies against the nucleocapsid protein of SARS-CoV-2 in a period between the first and second epidemic wave in Germany. We used a questionnaire to assess each individual’s exposure risk and his/her own perception of having already been infected with SARS-CoV-2. Results We recruited 619 participants from all sectors, clinical and non-clinical, constituting 70% of the entire staff. The seroprevalence of SARS-CoV-2 antibodies was 0.325% (95% confidence interval 0.039–1.168). Self-perceived risk of a previous SARS-CoV-2 infection decreased with age (odds ratio, 0.81; 95% confidence interval, 0.70–0.93). Having experienced symptoms more than doubled the odds of a high self-perceived risk (odds ratio, 2.18; 95% confidence interval, 1.59–3.00). There was no significant difference in self-perceived risk between men and women. Conclusions Seroprevalence was low among healthcare workers at a large children’s hospital in Germany before the second epidemic wave, and it was far from a level that confers herd immunity. Self-perceived risk of infection is often overestimated.

Visuelle Analogskalen (VAS) sind psychometrische Messinstrumente, welche zum Ziel haben, die Auspragung von patientenindividuellen Symptomstarken der jeweiligen Erkrankung zu erfassen und hierdurch eine rasche (statistische erfassbare und reproduzierbare) Kategorisierung der Symptomschwere zu erreichen. Auch bei der routinemasigen Anamaneseerhebung und Verlaufsbeurteilung der allergischen Rhinitis konnen VAS zur Anwendung kommen.

Introduction The aim of this study was to illustrate the pulmonary long term outcome of patients with repaired esophageal atresia and to further examine causes and correlations that might have led to this outcome. Methods Twenty-seven of 62 possible patients (43%) aged 5–20years, with repaired esophageal atresia were recruited. Body plethysmography and spirometry were performed to evaluate lung function, and the Bruce protocol treadmill exercise test to assess physical fitness. Results were correlated to conditions such as interpouch distance, gastroesophageal reflux or duration of post-operative mechanical ventilation. Results Seventeen participants (63%) showed abnormal lung function at rest or after exercise. Restrictive ventilatory defects (solely restrictive or combined) were found in 11 participants (41%), and obstructive ventilatory defects (solely obstructive or combined) in 13 subjects (48%). Twenty-two participants (81%) performed the Bruce protocol treadmill exercise test to standard. The treadmill exercise results were expressed in z-score and revealed to be significantly below the standard population mean (z-score=−1.40). Moreover, significant correlations between restrictive ventilatory defects and the interpouch distance; duration of post-operative ventilation; gastroesophageal reflux disease; plus recurrent aspiration pneumonia during infancy; were described. Conclusion It was shown that esophageal atresia and associated early complications have significant impact on pulmonary long term outcomes such as abnormal lung function and, in particular restrictive ventilatory defects. Long-running and regular follow-ups of patients with congenital esophageal atresia are necessary in order to detect and react to the development and progression of associated complications such as ventilation disorders or gastroesophageal reflux disease. Level of evidence Prognosis study, Level II.

Identification of child abuse is a daily challenge in medical work. The estimated number of unreported cases of child abuse and neglect is high.The aim of this study was to investigate the effectiveness of the redesigned clinical child protection program of a major German pediatric hospital and to improve programs in other hospitals for children and physicians through presentation of the advantages of the new structure.All cases of child protection at the Altona Children's Hospital were retrospectively analyzed before and after restructuring of the clinic's child protection program for a two-year period each, and a comparison was made. The child protection program was restructured and the new program subsequently managed by a fulltime coordinator.The prevalence of both suspected and substantiated cases of child abuse was significantly higher after restructuring of the child protection program. Before the change, 24 cases were investigated, of which 23 were substantiated; afterward, 124 cases were investigated and 89 were substantiated. Despite the high number of false-positive suspected cases, stigmatization of the families during the clarification progress was avoided by using a very sensitive approach, and the family was not confronted until the suspicion was affirmed.The presented concept of child protection in medical clinics seems to facilitate a higher detection rate of child abuse cases. The reduction in the number of undetected cases and thereby prevention of possible escalation of abuse, as well as the decline in the immense social follow-up costs, justifies the increased personnel costs.

Visual analogue scales (VAS) are psychometric measuring instruments designed to document the characteristics of disease-related symptom severity in individual patients and use this to achieve a rapid (statistically measurable and reproducible) classification of symptom severity and disease control. VAS can also be used in routine patient history taking and to monitor the course of a chronic disease such as allergic rhinitis (AR). More specifically, the VAS has been used to assess effectiveness of AR therapy in real life, both in intermittent and persistent disease. This position paper takes a detailed look at the historical development of VAS and its method-specific principles. Particular focus is put on aspects of practical application in daily routine and on a critical discussion of the advantages and disadvantages of the individual methods. VAS are well validated for the measurement of AR symptoms and correlate well with the ARIA (allergic rhinitis and its impact on asthma) severity classification and also correlated well with rTNSS and RQLQ. Moreover, several treatment studies on AR have used VAS as an evaluation parameter. Thanks to the use of new (real-life and real-time) communication technologies, such as smartphone apps, Discussion: VAS can be used relatively simply and highly effectively to assess disease control. The VAS lends itself very well to digitization and has now been incorporated into a smartphone app (called Allergy Diary) to assess AR control and direct treatment decisions as part of an AR clinical decision support system (CDSS). MASK Rhinitis has developed this app, which is currently available in 15 different languages

An early IgE response to grass or birch pollen can anticipate seasonal allergic rhinitis to pollen later in life or remain clinically silent.To identify risk factors early in life that allow discriminating pathogenic from non-pathogenic IgE responses and contribute to the development of seasonal allergic rhinitis to grass pollen.The German Multicentre Allergy Study examined a birth cohort born in 1990. A questionnaire was yearly administered and blood samples collected at age 1,2,3,5,6,7,10,13 yr. The definition of the primary outcome grass- and birch-pollen-related seasonal allergic rhinitis (SARg, SARb) was based on nasal symptoms in June/July and April, respectively. Serum IgE antibodies to Phleum pratense and Betula verrucosae extracts were monitored with immune-enzymatic singleplex assays.Of the 820 examined children, 177 and 148 developed SARg and SARb, respectively. Among healthy children aged 3 or more years, IgE to grass pollen was the strongest risk factor of SARg (OR 10.39, 95%CI 6.1-17.6, p< 0.001), while parental hay fever was the only risk factor in early childhood independently associated with future SARg (1 parent: OR 2.56, 95%CI 1.4-4.5, p< 0.001; 2 parents: OR 4.17, 95%CI 1.7-10.1) and SARb (1 parent OR: 5.21, 95%CI 2.20-12.4, p< 0.001; 2 parents: OR 8.02, 95%CI 2.0-32.9, p< 0.001). Parental hay fever was associated with an increase of the concentration of pollen-specific IgE in seropositive subjects, after the age of 6 and was also a hallmark of molecularly more complex specific IgE responses to grass or birch pollen at age 6 or older.Parental hay fever and specific IgE to grass and/or birch pollen are strong pre-clinical determinants and potentially good predictors of seasonal allergic rhinitis.

Background Hypersensitivity reactions to parenterally administered antibiotics (HRPA) are a substantial problem in managing CF. We conducted this observational study to assess their nature and frequency as well as risk factors. Methods By reviewing medical records and conducting interviews, age, sex, FEV1, ∆F508-genotype, pseudomonal colonisation, allergy history, antibiotic exposure and HRPA were recorded. Results Of 100 patients included in the study, 60 had ≥1 HRPA. Overall, 3205 antibiotic courses with 185 HRPA were ascertained. Changes in therapy followed 65% of HRPA. Eighty-four percent of severe HRPA occurred during days 1–4. Approximately 10% of treatment courses with cefepime and piperacillin/tazobactam caused HRPA. Years of pseudomonal colonisation and cumulative annual exposure were significant risk factors. Conclusions During days 1–4 of antibiotic treatment patients are at elevated risk for HRPA. HRPA are drug-specific and dependent on cumulative annual exposure. Elucidation of HRPA's immunological mechanisms and development of diagnostic algorithms for clinical use are required.

An effective treatment strategy for chronic pruritus in children with dermatologic disorders should consider the multidimensional aspects of pruritus, the unique challenges associated with treating pruritic skin disorders in the pediatric population, and evidence-based therapies with demonstrated antipruritic benefits and clinically relevant effects on patient/family quality of life (QoL). The Course of Advanced Learning for the Management of ITch (CALM-IT) Task Force is an interdisciplinary group of experts specializing in core aspects of pruritus treatment, integrating pediatrics, dermatology, psychotherapy, pruritus management, and sleep. CALM-IT recently convened to provide updated guidance on managing chronic pruritus associated with dermatologic diseases in pediatric patients, with a special focus on atopic dermatitis (AD) and chronic spontaneous urticaria (csU). This review highlights the updated concepts and best practices, which were built upon international PRACTALL consensus and modified for children and infants with AD and csU. CALM-IT supports the routine use of basic skin therapy and the escalation of topical medications, according to severity and focused on rapid itch control. Anti-inflammatory agents should be appropriate for infants and children (i.e., with an optimized therapeutic index) and have proven antipruritic properties, such as those demonstrated by methylprednisolone aceponate. New experimental findings do not support the use of non-sedating oral antihistamines as adjuvant antipruritic therapy for AD. In csU, oral H1 -antihistamine use is justified, consistent with the distinct pathophysiologic mechanisms of itch underlying AD and csU. All encompassing QoL assessments should consider the burden of both patient and caregiver and should address outstanding unmet clinical needs of pediatric patients. Future research areas include integrated QoL assessments and multidisciplinary treatment programs with pediatric-targeted pruritic therapies providing rapid itch control.

In the online-first version of the article the following part of the main title was given as subtitle: “Measur-ing instruments for the documentation of symptoms and therapy monitoring in cases of allergic rhinitis in everyday health care”. Additionally, the subtitle was mistakenly set next to the author affiliations: “Position Paper of the German Society of Allergology (AeDA) and the German Society of Allergy and Clinical Immunology (DGAKI), ENT Section, in collaboration with the working group on Clinical Immunology, Allergology and Environmental Medicine of the German Society of Otorhinolaryngology, Head and Neck Surgery (DGHNOKHC)”. The original article was corrected.

While there is increasing information about the pathogenesis and treatment of chronic spontaneous urticaria (csU) in adults, there is little published information about csU in children. Consequently, most of the recommendations contained in current guidelines for the prevention and treatment of csU in infants and children is based on extrapolation of data obtained in adults. To rectify this, this review points out critical gaps in our knowledge and suggests strategies which may help us to improve our understanding of this condition. How common is csU in children? What do we know about its clinical presentation and the presence of useful biomarkers? What are its common underlying causes? What is the course of csU in children? How does csU affect the everyday life of children? What treatment options are available for children? To answer these questions, two separate types of information are required. The first is information about the prevalence of the condition in the community at large and how csU affects the everyday life of both the child-patient and the parent or carer. Because most csU cases in infants and children do not come to specialists but are treated by general practitioners or by parents using over-the-counter medications, these questions may be answered only by general population surveys or schools programmes. The second is clinical information including family history and disease presentation, the presence of biomarkers and comorbidities, objective measures of severity, frequency and duration of exacerbations, the response to therapy and the time to remission. Targeted questionnaires need to be developed and validated for these investigations. This has already begun in Germany with the establishment of the CU-KID Netzwerk (Email address: cu-kid@charite.de), the aim of which is to identify clinical centres and colleagues who treat children with urticaria and to initiate the information gathering described above.

Das TH1/TH2-Paradigma dominiert seit Mitte der 80er-Jahre unser Verstandnis immunologischer Erkrankungen wie Allergien und Asthma bronchiale. Wie wir heute wissen, werden allergische Erkrankungen durch sehr komplexe immunologische Vorgange reguliert.

Asthma is the result of chronic airway inflammation associated predominantly with CD4+ cells, eosinophils, mast cells, and basophils. Several T cells subsets, including NKT cells, play a critical role in orchestrating the inflammation in the airways predominantly, by secreting interleukin-4 and interleukin-13. Recently, Programmed death-1 (PD-1) with its ligands, programmed death ligand B7H1 (PD-L1) and B7DC (PD-L2), was shown to regulate T-cell activation and tolerance. PD-1 has been characterized as a negative regulator of conventional CD4+T cells. In addition, the relative roles of PD-L1 and PD-L2 in regulating the activation and function of T cells have recently been characterized. Recent studies have demonstrated that PD-L1 and PD-L2 have important but opposing roles in modulating and polarizing T cell functions in airway hyperreactivity. Whereas the severity of asthma is greatly enhanced in absence of PD-L2, PD-L1 deficiency resulted in reduced airway hyperresponsiveness (AHR) and only minimal inflammation. This observation is partially due to the polarization of NKT cells in PD-L1 and PD-L2 deficient mice. This review will discuss the recent literature regarding the role of PD-L1 and PD-L2 in allergic disease and asthma. Current understanding of the role of PD ligands in allergic asthma gives impetus to the development of novel therapeutic approaches.

The prevalence of asthma continues to increase in westernized countries, and optimal treatment remains a significant therapeutic challenge. Recently, CD1d-restricted invariant NKT (iNKT) cells were found to play a critical role in the induction of airway hyperreactivity (AHR) in animal models and are associated with asthma in humans. To test whether iNKT cell-targeted therapy could be used to treat allergen-induced airway disease, mice were sensitized with OVA and treated with di-palmitoyl-phosphatidyl-ethanolamine polyethylene glycol (DPPE-PEG), a CD1d-binding lipid antagonist. A single dose of DPPE-PEG prevented the development of AHR and pulmonary infiltration of lymphocytes upon OVA challenge, but had no effect on the development of OVA-specific Th2 responses. In addition, DPPE-PEG completely prevented the development of AHR after administration of α-galactosylceramide (α-GalCer) intranasally. Furthermore, we demonstrate that DPPE-PEG acts as antagonist to α-GalCer and competes with α-GalCer for binding to CD1d. Finally, we show that DPPE-PEG completely inhibits the α-GalCer–induced phosphorylation of ERK tyrosine kinase in iNKT cells, suggesting that DPPE-PEG specifically blocks TCR signaling and thus activation of iNKT cells. Because iNKT cells play a critical role in the development of AHR, the inhibition of iNKT activation by DPPE-PEG suggests a novel approach to treat iNKT cell-mediated diseases such as asthma.

IL-25 has been shown to induce Th2 responses and airway hyperreactivity (AHR) in mice, but the mechanism of action is not understood and it is unclear which cells mediate this disease. In this study we show that the receptor for IL-25, IL-17RB, is highly expressed on a subset of naive and activated CD4+ invariant NKT (iNKT) cells, but not on activated T cells. IL-17RB+ iNKT cells produced large amounts of Th2 cytokines that were substantially increased by IL-25 stimulation. Furthermore, IL-17RB+ iNKT cells were capable of restoring AHR in iNKT cell-deficient mice, whereas IL-17RB− iNKT cells failed to reconstitute AHR and lung inflammation. Finally, IL-17RB+ iNKT cells were detected in the lungs of wild-type mice, and induction of AHR by intranasal administration of IL-25 was significantly impaired in iNKT cell-deficient mice. Overall, our data suggest a critical role for iNKT cells in IL-25-mediated AHR. These results may lead to novel therapeutic approaches to target IL-17RB+ iNKT cells for the treatment of allergic asthma.

The development of airway hyperreactivity (AHR), a cardinal feature of asthma, requires the presence of invariant NKT (iNKT) cells. In a mouse model of asthma, we demonstrated that the induction of AHR required ICOS costimulation of iNKT cells. ICOS was highly expressed on both naive and activated iNKT cells, and expression of ICOS was greater on the CD4+ iNKT than on CD4− iNKT cells. Furthermore, the number of CD4+ iNKT cells was significantly lower in spleens and livers of ICOS−/− and ICOSL−/− mice, and the remaining iNKT cells in ICOS−/− mice were dysfunctional and failed to reconstitute AHR when adoptively transferred into iNKT cell-deficient Jα18−/− mice. In addition, direct activation of iNKT cells with α-GalCer, which induced AHR in wild-type mice, failed to induce AHR in ICOS−/− mice. The failure of ICOS−/− iNKT cells to induce AHR was due in part to an inability of the ICOS−/− iNKT cells to produce IL-4 and IL-13 on activation. Moreover, survival of wild-type iNKT cells transferred into ICOSL−/− mice was greatly reduced due to the induction of apoptosis. These results indicate that ICOS costimulation plays a major role in induction of AHR by iNKT cells and is required for CD4+ iNKT cell function, homeostasis, and survival in the periphery.

Wir wissen heute, dass allergische Erkrankungen und Asthma bronchiale durch eine inadaquate Aktivierung von TH2-Zellen verursacht werden. Unser Verstandnis daruber, wie gesunde Individuen vor allergischen Erkrankungen geschutzt sind, ist allerdings noch sehr begrenzt. Es ist kaum denkbar, dass TH1-polarisierte Immunantworten, welche ihrerseits proinflammatorisch sind, einen Primarmechanismus fur den Schutz vor TH2-polarisierten allergischen Erkrankungen bieten. Viel wahrscheinlicher ist, dass die grose Vielzahl an unterschiedlichen regulatorischen T-Zellen antiinflammatorische Immunantworten und somit eine protektive Immunitat induziert, welche die Entstehung allergischer Erkrankungen verhindert. Zukunftige Therapieformen sollten zum Ziel haben, regulatorische T-Zellen zu induzieren, um Patienten mit allergischen Erkrankungen und Asthma bronchiale kurativ zu behandeln sowie die Entstehung dieser Krankheiten zu verhindern.

Die Unterteilung der T-Helferzellen basiert im Wesentlichen auf der Analyse ihrer Zytokinprofile. Neben den zwei klassischen Effektortypen, denen die Mehrzahl der antigenstimulierten T-Helferzellen zugeordnet werden kann (TH1- und TH2-Typ), haben die regulatorischen T-Zellen (Treg) eine entscheidende Bedeutung fur die Regulation entzundlicher Reaktionen. Treg produzieren IL-10 und „transforming growth factor“-(TGF-)β und haben damit ausgepragte immunsuppressive Eigenschaften. Daruber hinaus konnen sich naive T-Helferzellen in Anwesenheit von TGF-β und IL-6 in TH17-Zellen differenzieren, die sich durch die Produktion von IL-17, IL-6 und Tumor-Nekrose-Faktor-(TNF-)α auszeichnen. IL-23 ist fur die Expansion und das Uberleben der TH17-Zellen wichtig.

Novel therapies that interfere specifically with immunologic mechanisms underlying allergen-induced pathology are currently in clinical evaluation. Among these is anti-IgE, which directly targets IgE serum antibodies, thus inhibiting the central mechanism of immediate-type hypersensitivity reactions. Application of anti-IgE antibodies effectively reduces IgE serum levels regardless of allergen specificity. Anti-IgE therapy has been successfully tested in patients with allergic rhinitis, asthma, and food allergy, showing significant efficacy in reducing symptom scores and the use of rescue medications. However, such therapy is limited by high costs and the requirements for permanent or every-season treatment. The advantage of specific immunotherapy (SIT) is the potential to alter the course of the disease, which has been demonstrated in patients with allergic rhinitis, insect venom allergy and, to a lesser degree, asthma. The broader application of SIT is restricted by sometimes life-threatening adverse effects. The combination of anti-IgE with SIT was suggested to be superior to each single treatment protocol in children and adolescents with allergic rhinitis. In a randomized, double-blind trial to assess the efficacy and safety of anti-IgE (omalizumab) or placebo in combination with SIT (birch pollen or grass pollen), the combination therapy reduced symptom load, the sum of daily symptom severity score plus rescue medication use, over the birch and grass pollen seasons by nearly 50% over SIT alone. These data show that the combination of anti-IgE plus SIT may be beneficial for the treatment of allergic diseases, offering improved efficacy, limited adverse effects, and potential immune-modifying effects.

Purpose of review Allergic diseases are caused by the overdevelopment of T-helper type 2 biased immune responses in susceptible individuals. A number of recent studies indicate that regulatory T cells play an important role in controlling such T-helper type 2 biased responses not only in animal models, but in humans as well, and these will be reviewed in this article. Recent findings A family of regulatory cells appears to be involved in regulating allergies. Both naturally occurring CD4+CD25+ regulatory T cells and inducible forms of antigen-specific regulatory T cells, both expressing the transcription factor foxp3, have been shown to inhibit the inappropriate immune responses involved in allergic diseases. Impaired expansion of natural or adaptive regulatory T cells is hypothesized to lead to the development of allergy, and treatment to induce allergen-specific regulatory T cells could provide curative therapies for allergy and asthma. Summary Allergen-specific regulatory T cells play an important role in controlling the development of allergy and asthma.

The range of regulatory T cell (T(R) cell) types that control immune responses is poorly understood. We describe here a population of T(R) cells that developed in vivo from naive CD4(+)CD25(-) T cells during a T helper type 1 (T(H)1)-polarized response, distinct from CD25(+) T(R) cells. These antigen-specific T(R) cells were induced by CD8alpha(+) DCs, produced both interleukin 10 and interferon-gamma, and potently inhibited the development of airway hyper-reactivity. These T(R) cells expressed the transcription factors Foxp3 and T-bet, indicating that these T(R) cells are related to T(H)1 cells. Thus, adaptive T(R) cells are heterogeneous and comprise T(H)1-like T(R) cells as well as previously described T(H)2-like T(R) cells, which express Foxp3 and are induced during the development of respiratory tolerance by CD8alpha(-) DCs.

Th2 cells play a critical role in the pathogenesis of allergy and asthma. However, the immunological mechanisms that downmodulate and protect against the development of these disorders are poorly understood. A spectrum of CD4(+) T cells, including Th3 cells, T(R) cells, CD4(+)CD25(+) cells and NKT cells play a critical role in regulating these diseases. A better understanding of the role of regulatory cells in allergic diseases may lead to the identification of novel therapeutic targets.

Background: Exposure to endotoxins, allergens, or both in early life might regulate the development of tolerance to allergens later in life. Objective: We investigated whether continuous exposure of infant mice to aerosolized endotoxin, allergen, or both inhibits subsequent allergen-induced immune and inflammatory responses. Methods: Infant BALB/c mice were pre-exposed to aerosolized endotoxin, ovalbumin (OVA), or both (3 times a week for the first 4 weeks of life) before systemic sensitization (days 1-14) and repeated airway challenge (days 28-30) with OVA. Results: Compared with that seen in negative control animals, systemic sensitization and airway allergen challenges induced high serum levels of allergen-specific IgE (0.7 ± 0.09 vs 0.02 ± 0.01 OD units), predominant T H 2-type cytokine production (IL-5 by splenic mononuclear cells in vitro, 1.2 ± 0.2 vs 0.04 ± 0.06 ng/mL), airway inflammation (bronchoalveolar lavage fluid leukocytes, 125 ± 15 vs 64 ± 7/μL; eosinophils, 28 ± 5 vs 1 ± 0/μL) and development of in vivo airway hyperreactivity (maximal enhanced pause, 11 ± 1.9 vs 4 ± 0.2). Pre-exposure with LPS before sensitization increased production of specific IgG2a (67 ± 10 vs 32 ± 5 U/mL) but failed to prevent T H 2-mediated immune responses. Pre-exposure with OVA or with OVA plus LPS completely suppressed allergen sensitization, airway inflammation, and development of in vivo airway hyperreactivity; values were similar to those of negative control animals. Inhibition was due to allergen-specific T-cell anergy indicated by omitted allergen-specific T H 2 and T H 1 immune responses. In addition, combined exposure to endotoxin and allergen induced a general shift toward an unspecific T H 1 immune response. Conclusion: Exposure with endotoxins before allergen sensitization is not able to induce unresponsiveness but might decrease the susceptibility for sensitization to a variety of common allergens. (J Allergy Clin Immunol 2003;112:389-96.)

Using natural killer T (NKT) cell-deficient mice, we show here that allergen-induced airway hyperreactivity (AHR), a cardinal feature of asthma, does not develop in the absence of V(alpha)14i NKT cells. The failure of NKT cell-deficient mice to develop AHR is not due to an inability of these mice to produce type 2 T-helper (Th2) responses because NKT cell-deficient mice that are immunized subcutaneously at non-mucosal sites produce normal Th2-biased responses. The failure to develop AHR can be reversed by the adoptive transfer of tetramer-purified NKT cells producing interleukin (IL)-4 and IL-13 to Ja281(-/-) mice, which lack the invariant T-cell receptor (TCR) of NKT cells, or by the administration to Cd1d(-/-) mice of recombinant IL-13, which directly affects airway smooth muscle cells. Thus, pulmonary V(alpha)14i NKT cells crucially regulate the development of asthma and Th2-biased respiratory immunity against nominal exogenous antigens. Therapies that target V(alpha)14i NKT cells may be clinically effective in limiting the development of AHR and asthma.

Background Hypersensitivity reactions to parenteral administered antibiotics (HRPA) are a substantial problem in managing pulmonary disease in Cystic Fibrosis (CF), especially in advanced CF. This group of patients requires a life long antibiotic treatment with extremely high cumulative doses compared to other patients. In our daily routine we observed a growing number of hypersensitivities. Therefore we conducted this observational study to assess HRPA s impact on the daily clinical work with CF, as well as it’s nature, frequency and predisposing risk factors.

In its classical definition, the renin-angiotensin system (RAS) acts predominantly by endocrine mechanisms. This view has been modified since several components of the RAS and their mRNAs were found in peripheral tissues. These findings gave rise to the concept of local tissue renin-angiotensin systems. Although no cells of cardiovascular organs containing a complete RAS have been identified as of this writing, angiotensinogen and angiotensin-converting enzyme (ACE) are most likely synthesized within the vasculature for example. Local synthesis of renin may be limited to very small amounts, but uptake of renin from the circulation is very likely. The function of local RASs is shown by reduction of blood pressure by ACE inhibitors, which correlates better with the inhibition of ACE activity in certain tissues than with its activity in the plasma. Further studies have put forward the notion that the circulating RAS could mainly be important for acute hemodynamic stability, whereas the tissue RAS could be involved in more long term maintenance of hemodynamics. This review will try to summarize the findings leading to the concept of a local tissue renin-angiotensin system, and discuss interactions between the circulating and the local RAS in the light of recent experimental findings.

Respiratory exposure to allergen induces T cell tolerance and protection against the development of airway hyperactivity in animal models of asthma. Whereas systemic administration of dexamethasone during the delivery of respiratory Ag has been suggested to prevent the development of mucosal tolerance, the effects of local administration of corticosteroids, first-line treatment for patients with bronchial asthma, on mucosal tolerance remain unknown. To analyze the effects of systemic versus local administration of different types of corticosteroids on the development of mucosal tolerance, mice were exposed to respiratory allergen to induce mucosal tolerance with or without systemic or intranasal application of different doses of dexamethasone or prednisolone. After the induction of mucosal tolerance, proliferation of T cells was inhibited in tolerized mice, whereas systemic applications of corticosteroids restored T cell proliferation and secretion of Th2 cytokines. In contrast, inhaled corticosteroids showed no effect on both T cell proliferation and cytokine secretion. In addition, mice systemically treated with corticosteroids showed an increased airway hyperactivity with a significant lung inflammation, but also an increased T effector cells/regulatory T cells ratio in the second lymphoid organs when compared with mice that receive corticosteroids by inhalation. These results demonstrate that local administration of corticosteroids has no effect on the development of immune tolerance in contrast to systemically applied corticosteroids. Furthermore, although different concentrations of corticosteroids are administered to patients, our results demonstrated that the route of administration rather than the doses affects the effect of corticosteroids on respiratory tolerance induction. Considering the broad application of corticosteroids in patients with allergic disease and asthma, the route of administration of steroid substances seems crucial in terms of treatment and potential side effects. These findings may help elucidate the apparently contradicting results of corticosteroid treatment in allergic diseases.

While there is increasing information about the pathogenesis and treatment of chronic spontaneous urticaria (csU) in adults, there is little published information about csU in children. Consequently, most of the recommendations contained in current guidelines for the prevention and treatment of csU in infants and children is based on extrapolation of data obtained in adults. To rectify this, this review points out critical gaps in our knowledge and suggests strategies which may help us to improve our understanding of this condition. How common is csU in children? What do we know about its clinical presentation and the presence of useful biomarkers? What are its common underlying causes? What is the course of csU in children? How does csU affect the everyday life of children? What treatment options are available for children? To answer these questions, two separate types of information are required. The first is information about the prevalence of the condition in the community at large and how csU affects the everyday life of both the child-patient and the parent or carer. Because most csU cases in infants and children do not come to specialists but are treated by general practitioners or by parents using over-the-counter medications, these questions may be answered only by general population surveys or schools programmes. The second is clinical information including family history and disease presentation, the presence of biomarkers and comorbidities, objective measures of severity, frequency and duration of exacerbations, the response to therapy and the time to remission. Targeted questionnaires need to be developed and validated for these investigations. This has already begun in Germany with the establishment of the CU-KID Netzwerk (Email address: cu-kid@charite.de), the aim of which is to identify clinical centres and colleagues who treat children with urticaria and to initiate the information gathering described above.

Asthma is the result of chronic airway inflammation that is dominated by the presence of eosinophils and CD4(+) T lymphocytes. CD4(+) T cells include several subsets and play a critical role in orchestrating the inflammation, predominantly by secreting interleukin-4 and interleukin-13. Recently, research identified a new subset of T cells, natural killer T (NKT) cells, which also express the CD4 marker. In contrast to conventional CD4(+) T cells, NKT cells do not respond to peptide antigens, but rather to glycolipids. In animal models of asthma, direct activation of NKT cells by glycolipids results in the secretion of extensive amounts of cytokines and triggers the development of airway hyperreactivity. Moreover, in patients with chronic asthma, NKT cells can be found in bronchoalveolar lavage fluids in significant amounts. These data strongly suggest that NKT cells play an important role in asthma pathogenesis.

Numerous epidemiological studies have shown an inverse correlation between helminth infections and the manifestation of atopic diseases, yet the immunological mechanisms governing this phenomenon are indistinct. We therefore investigated the effects of infection with the filarial parasite Litomosoides sigmodontis on allergen-induced immune reactions and airway disease in a murine model of asthma. Infection with L. sigmodontis suppressed all aspects of the asthmatic phenotype: Ag-specific Ig production, airway reactivity to inhaled methacholine, and pulmonary eosinophilia. Similarly, Ag-specific recall proliferation and overall Th2 cytokine (IL-4, IL-5, and IL-3) production were significantly reduced after L. sigmodontis infection. Analysis of splenic mononuclear cells and mediastinal lymph nodes revealed a significant increase in the numbers of T cells with a regulatory phenotype in infected and sensitized mice compared with sensitized controls. Additionally, surface and intracellular staining for TGF-β on splenic CD4+ T cells as well as Ag-specific TGF-β secretion by splenic mononuclear cells was increased in infected and sensitized animals. Administration of Abs blocking TGF-β or depleting regulatory T cells in infected animals before allergen sensitization and challenges reversed the suppressive effect with regard to airway hyperreactivity, but did not affect airway inflammation. Despite the dissociate results of the blocking experiments, these data point toward an induction of regulatory T cells and enhanced secretion of the immunomodulatory cytokine TGF-β as one principle mechanism. In conclusion, our data support the epidemiological evidence and enhance the immunological understanding concerning the impact of helminth infections on atopic diseases thus providing new insights for the development of future studies.

Objectives Hypersensitivity reactions to parenteral antibiotics (HRPA) are a major problem in the management of patients with CF. These patients require lifelong treatment with antibiotics in high cumulative doses. Allergy testing methods such as specific IgE in serum are are not available for antipseudomonal antibiotics. Skin tests seem to have limited value. This pilot study was carried out to asses the diagnostic value of in-vitro cellular allergy tests for HRPA and the underlying immune reactions. Methods Patients with CF and a documented hypersensitivity to ≥1 parenteral antibiotic were recruited. The suggested antibiotic had never been prescibed after the initial reaction. For a total of 13 patients, basophil activation tests (BAT) and and lymphocyte transformation tests (LTT) for each suspected antibiotic were performed (piperacillin/tazobactam (pip/taz), ceftazidime, meropenem and others). BAT with an activation index (AI) of >2.5 and LTT with a stimulation index (SI) >2 were considered positive. Results Two positive BAT (each for pip/taz, AI = 2.7 and 3.1) and seven positive LTT in five patients were ascertained (pip/taz SI = 76.6 and 2.2; cefepime SI = 10.5, 3.0 & 2.4; sulbactam SI = 8.7; ceftazidime SI = 2.1). Conclusion The pilot study showed mostly for LTT positive results. This may indicate a T-cellular genesis of HRPA that is consistent with the lack of association to atopy. These results could be an argument for this method as a diagnostic tool for HRPA. The sample size was small though and clinical trials with reexponation of the negative tested patients are pending. Therefore, no clear recommendations can be applied for the routine clinical setting.

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 (nonatopic 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 nonatopic children from the 190 children fulfilling the inclusion criteria. Two different patterns of IgG responses to PR-10 molecules were identified. Among nonatopic 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.