Lars Lange

Congenital Heart Disease and Other Heterotaxic Defects in a Large Cohort of Patients With Primary Ciliary Dyskinesia

Background— Primary ciliary dyskinesia (PCD) is a recessive genetic disorder that is characterized by sinopulmonary disease and reflects abnormal ciliary structure and function. Situs inversus totalis occurs in ≈50% of PCD patients (Kartagener’s syndrome in PCD), and there are a few reports of PCD with heterotaxy (situs ambiguus), such as cardiovascular anomalies. Advances in diagnosis of PCD, such as genetic testing, allow the systematic investigation of this association. Methods and Results— The prevalence of heterotaxic defects was determined in 337 PCD patients by retrospective review of radiographic and ultrasound data. Situs solitus (normal situs) and situs inversus totalis were identified in 46.0% and 47.7% of patients, respectively, and 6.3% (21 patients) had heterotaxy. As compared with patients with situs solitus, those with situs abnormalities had more ciliary outer dynein arm defects, fewer inner dynein arm and central apparatus defects (P<0.001), and more mutations in ciliary outer dynein arm genes (DNAI1 and DNAH5; P=0.022). Seven of 12 patients with heterotaxy who were genotyped had mutations in DNAI1 or DNAH5. Twelve patients with heterotaxy had cardiac and/or vascular abnormalities, and most (8 of 12 patients) had complex congenital heart disease. Conclusions— At least 6.3% of patients with PCD have heterotaxy, and most of those have cardiovascular abnormalities. The prevalence of congenital heart disease with heterotaxy is 200-fold higher in PCD than in the general population (1:50 versus 1:10 000); thus, patients with PCD should have cardiac evaluation. Conversely, mutations in genes that adversely affect both respiratory and embryological nodal cilia are a significant cause of heterotaxy and congenital heart disease, and screening for PCD is indicated in those patients.

Provoking allergens and treatment of anaphylaxis in children and adolescents--data from the anaphylaxis registry of German-speaking countries.

To cite this article: Hompes S, Köhli A, Nemat K, Scherer K, Lange L, Rueff F, Rietschel E, Reese T, Szepfalusi Z, Schwerk N, Beyer K, Hawranek T, Niggemann B, Worm M. Provoking allergens and treatment of anaphylaxis in children and adolescents – data from the anaphylaxis registry of German‐speaking countries. Pediatr Allergy Immunol 2011; 22: 568–574.

Anaphylaxis in children and adolescents: The European Anaphylaxis Registry.

BACKGROUND Anaphylaxis in children and adolescents is a potentially life-threatening condition. Its heterogeneous clinical presentation and sudden occurrence in virtually any setting without warning have impeded a comprehensive description. OBJECTIVE We sought to characterize severe allergic reactions in terms of elicitors, symptoms, emergency treatment, and long-term management in European children and adolescents. METHODS The European Anaphylaxis Registry recorded details of anaphylaxis after referral for in-depth diagnosis and counseling to 1 of 90 tertiary allergy centers in 10 European countries, aiming to oversample the most severe reactions. Data were retrieved from medical records by using a multilanguage online form. RESULTS Between July 2007 and March 2015, anaphylaxis was identified in 1970 patients younger than 18 years. Most incidents occurred in private homes (46%) and outdoors (19%). One third of the patients had experienced anaphylaxis previously. Food items were the most frequent trigger (66%), followed by insect venom (19%). Cows milk and hens egg were prevalent elicitors in the first 2 years, hazelnut and cashew in preschool-aged children, and peanut at all ages. There was a continuous shift from food- to insect venom- and drug-induced anaphylaxis up to age 10 years, and there were few changes thereafter. Vomiting and cough were prevalent symptoms in the first decade of life, and subjective symptoms (nausea, throat tightness, and dizziness) were prevalent later in life. Thirty percent of cases were lay treated, of which 10% were treated with an epinephrine autoinjector. The fraction of intramuscular epinephrine in professional emergency treatment increased from 12% in 2011 to 25% in 2014. Twenty-six (1.3%) patients were either admitted to the intensive care unit or had grade IV/fatal reactions. CONCLUSIONS The European Anaphylaxis Registry confirmed food as the major elicitor of anaphylaxis in children, specifically hens egg, cows milk, and nuts. Reactions to insect venom were seen more in young adulthood. Intensive care unit admissions and grade IV/fatal reactions were rare. The registry will serve as a systematic foundation for a continuous description of this multiform condition.

Guideline for acute therapy and management of anaphylaxis

S2 Guideline of the German Society for Allergology and Clinical Immunology (DGAKI), the Association of German Allergologists (AeDA), the Society of Pediatric Allergy and Environmental Medicine (GPA), the German Academy of Allergology and Environmental Medicine (DAAU), the German Professional Association of Pediatricians (BVKJ), the Austrian Society for Allergology and Immunology (ÖGAI), the Swiss Society for Allergy and Immunology (SGAI), the German Society of Anaesthesiology and Intensive Care Medicine (DGAI), the German Society of Pharmacology (DGP), the German Society for Psychosomatic Medicine (DGPM), the German Working Group of Anaphylaxis Training and Education (AGATE) and the patient organization German Allergy and Asthma Association (DAAB)

Predictive values of component-specific IgE for the outcome of peanut and hazelnut food challenges in children.

Oral challenges are the gold standard in food allergy diagnostic, but time‐consuming. Aim of the study was to investigate the role of peanut‐ and hazelnut‐component‐specific IgE in the diagnostics of peanut and hazelnut allergy and to identify cutoff levels to make some challenges superfluous.

Questionnaire-based survey of lifetime-prevalence and character of allergic drug reactions in German children.

Data on the epidemiology of adverse drug reactions (ADR), especially allergic drug reactions, in children are rare. The reported prevalence of ADR in pediatric populations varies a lot, depending on type of the study and the country where the data were collected. In order to assess the prevalence of ADR and allergic drug reactions in a population of German children, we conducted a study in a German pediatric university hospital. A questionnaire concerning occurrence and character of ADR was distributed to all parents presenting their children in the hospital for planned admissions or in the emergency department from May 2004 to November 2004. Additional telephone interviews were conducted to specify the reported symptoms in ambiguous cases. One thousand four hundred forty‐seven questionnaires were collected. The reported life‐time prevalence of ADR according to the information given by the parents was 7.5% (108/1447). Six of the reactions were severe, three children had experienced anaphylactic reactions. In 4.2% (61/1447), the history was suspicious for a potential allergic mechanism because of an immediate or late phase cutaneous drug reaction. In this group, the suspected drugs were antibiotics in 85% (32.7% aminopenicillins, 29.5% other penicillins, 11.5% cefaclor, 8.2% macrolides and 18% others), antiphlogistic and respiratory drugs in 4.9% each and vaccines and contrast media in 3.3% each. There was a higher percentage of children under the age of four suffering from ADR. This trend was not significant when analyzing only the allergic reactions. Forty‐four percent of the parents stated, their children suffer from drug allergy, although a clear non‐allergic reaction was described. Both, ADR and allergic drug reactions are frequent phenomena in children. It is important to monitor drug therapy for any adverse reaction in order to inform the parents about the character of the adverse reaction, the necessary consequences and to initiate further diagnostic procedures.

Guidelines on the management of IgE-mediated food allergies

S2k-Guidelines of the German Society for Allergology and Clinical Immunology (DGAKI) in collaboration with the German Medical Association of Allergologists (AeDA), the German Professional Association of Pediatricians (BVKJ), the German Allergy and Asthma Association (DAAB), German Dermatological Society (DDG), the German Society for Nutrition (DGE), the German Society for Gastroenterology, Digestive and Metabolic Diseases (DGVS), the German Society for Oto-Rhino-Laryngology, Head and Neck Surgery, the German Society for Pediatric and Adolescent Medicine (DGKJ), the German Society for Pediatric Allergology and Environmental Medicine (GPA), the German Society for Pneumology (DGP), the German Society for Pediatric Gastroenterology and Nutrition (GPGE), German Contact Allergy Group (DKG), the Austrian Society for Allergology and Immunology (OGAI), German Professional Association of Nutritional Sciences (VDOE) and the Association of the Scienti‰c Medical Societies Germany (AWMF)

Guideline for the diagnosis of drug hypersensitivity reactions

Drug hypersensitivity reactions are unpredictable adverse drug reactions. They manifest either within 1–6 h following drug intake (immediate reactions) with mild to life-threatening symptoms of anaphylaxis, or several hours to days later (delayed reactions), primarily as exanthematous eruptions. It is not always possible to detect involvement of the immune system (allergy). Waiving diagnostic tests can result in severe reactions on renewed exposure on the one hand, and to unjustified treatment restrictions on the other. With this guideline, experts from various specialist societies and institutions have formulated recommendations and an algorithm for the diagnosis of allergies. The key principles of diagnosing allergic/hypersensitivity drug reactions are presented. Where possible, the objective is to perform allergy diagnostics within 4 weeks–6 months following the reaction. A clinical classification of symptoms based on the morphology and time course of the reaction is required in order to plan a diagnostic work-up. In the case of typical symptoms of a drug hypersensitivity reaction and unequivocal findings from validated skin and/or laboratory tests, a reaction can be attributed to a trigger with sufficient confidence. However, skin and laboratory tests are often negative or insufficiently reliable. In such cases, controlled provocation testing is required to clarify drug reactions. This method is reliable and safe when attention is paid to indications and contraindications and performed under appropriate medical supervision. The results of the overall assessment are discussed with the patient and documented in an „allergy passport“ in order to ensure targeted avoidance in the future and allow the use of alternative drugs where possible.

Accurate oral food challenge requires a cumulative dose on a subsequent day

protease inhibitors expressed by keratinocytes, but their expression was not affected (Fig 1, E-G). Filaggrin and loricrin expression was significantly decreased by TH2 cytokines, as previously reported (Fig 1, H and I). Protease assays using specific substrates were performed to examine whether levels of serine protease activities increase in parallel to protein and mRNA levels (see the Methods section in this article’s Online Repository). As expected, KLK7 activity, namely chymotrypsin-like serine protease activity, was significantly enhanced by IL-4 (50 ng/mL) and IL-13 (50 ng/mL; Fig 2, A). Activities of trypsin-like serine proteases, such as KLK5, KLK8, and KLK14, were not changed (Fig 2, B). In addition to in vitro data, analyses using real-time PCR and immunohistochemistry showed an increase in KLK7 expression in AD lesions compared with that seen in normal skin (Fig 2, C and D, see the Methods section in this article’s Online Repository). Furthermore, the KLK7 protein level in the sera of patients with AD significantly correlated with IL-4 levels in sera (Fig 2, E, and see the Methods section in this article’s Online Repository). TH2 cytokines are generally expressed by TH2 lymphocytes, basophils, eosinophils, and mast cells and play roles in TH2 cell differentiation, IgE production, eosinophil recruitment, and so forth. These cytokines also affect epidermal barrier functions through signal transducer and activator of transcription 6 because IL-4 and IL-13 decrease the expression of filaggrin, loricrin, and involucrin in keratinocytes. Hatano et al reported that IL-4 suppresses the expression of ceramide and cutaneous permeability barrier functions induced by TNF-a and IFN-g and the recovery of cutaneous permeability barrier dysfunction in vivo. Desmoglein 3 expression is also inhibited by IL-4. IL-4 transgenic mice spontaneously have AD-like dermatitis, which supports the importance of TH2 cytokines in AD pathogenesis. 1 We here report how TH2 cytokines could further alter the skin barrier by showing that IL-4 and IL-13 increase KLK7 expression and function in keratinocytes. Excessive protease activity is known to induce epidermal barrier dysfunction, and thus the increase in KLK7 by IL-4 and IL-13 would count on the skin barrier disruption in patients with AD. Interestingly, among skinKLKs, onlyKLK7 is a chymotrypsinlike serine protease, and others are trypsin-like serine proteases. Chymotrypsin-like serine protease KLK7 degrades the human cathelicidin antimicrobial peptide LL-37, and a decrease in LL37 levels is documented in AD skin. Along with cathelicidin mRNA suppression by IL-4 and IL-13, the increase in KLK7 expression by IL-4 and IL-13 would further decrease the antimicrobial skin barrier in patients with AD. Taken together with previous reports suggesting an association between KLK7 and AD, the enhancement of protease activity through increased KLK7 expression by the TH2 cytokines IL-4 and IL-13 might be an important factor for mechanical and chemical epidermal barrier dysfunction in patients with AD. Shin Morizane, MD, PhD Kenshi Yamasaki, MD, PhD Ai Kajita, MD Kazuko Ikeda, MD Maosheng Zhan, MD Yumi Aoyama, MD, PhD Richard L. Gallo, MD, PhD Keiji Iwatsuki, MD, PhD

Effects of a structured educational intervention on knowledge and emergency management in patients at risk for anaphylaxis

Structured educational programmes for patients at risk for anaphylaxis have not yet been established. Patients and caregivers often lack adequate skills in managing the disease.