Expert consensus on practical aspects in the treatment of chronic urticaria

Background: Chronic urticaria (CU) is a common disease which represents a considerable burden for many patients. The current urticaria guideline describes the evidence-based diagnosis and treatment of CU. In addition, however, questions often arise in everyday practice that are not addressed by the guideline. Methods: In May 2020, a digital meeting with German urticaria experts was held, in which practical aspects of CU treatment were discussed and supporting aids for everyday clinical treatment formulated. The resulting advice in this document focus on practical questions and the available literature and experiences of the participants. Results: The diagnosis of CU can be made in a short time by means of a thorough anamnesis, a physical examination, and a basic laboratory chemical diagnosis. For this purpose, practical recommendations for everyday practice are given in this paper. An extended diagnosis is only indicated in a few cases and should always be carried out in parallel with an effective therapy. In general, CU should always be treated in the same way, regardless of whether wheals, angioedema or both occur. Symptomatic therapy should be carried out according to the treatment steps recommended by the guidelines. This publication provides practical advice on issues in everyday practice, such as the procedure in the current coronavirus disease 2019 (COVID-19) pandemic, the cardiac risk under higher dosed H1 antihistamines, the self-administration of omalizumab as well as vaccination under omalizumab therapy. In addition to treatment recommendations, topics such as documentation in the practice and family planning with urticaria will be discussed. Discussion: These supporting treatment recommendations serve as an addendum to the current CU guideline and provide support in dealing with CU patients in everyday practice. The aim is to ensure that patients suffering from CU achieve complete freedom of symptoms with the help of an optimal therapy

Oxytocin und Vasopressin als potentielle Verhaltensmodulatoren im Gehirn von Ratte und Graumull, Cryptomys anselli : eine experimentelle immunhistochemische Untersuchung

In der vorliegenden Arbeit wird die Expression der Nonapetide Oxytocin und Vasopressin im Zentralnervensystem der Ratte, Rattus rattus und des afrikanischen Graumulls, Cryptomys anselli, mit immunhistochemischen Methoden untersucht. Bei Säugetieren allgemein werden Oxytocin (OX) und Vasopressin (VP) in separaten Populationen magnozellulärer Neuronen des Hycleus supraopticus und die weitverstreuten akzessorischen magnozellulären neurosekretorischen Zellen). Über axonalen Transport gelangen die Hormone hauptsächlich in die Neurohypophyse und werden von dort in das Blutgefäßsystem ausgeschüttet. Neben allgemein bekannten peripheren Wirkungen wie beispielsweise der Uteruskontraktion (Oxytocin), der Milchejektion (Oxytocin) und der Homöostase des Wasserhaushalts (Vasopressin) werden den beiden Hormonen auch wichtige zentrale Effekte wie die Beeinflussung von Sozialverhalten, Partnerwahl, Aggression etc. zugeschrieben, wobei sie als hypothalamische Neurotransmitter fungieren. Als ein subterranes, eusoziales Säugetier zeigt der Graumull eine ungewöhnliche (eusoziale) Familienstruktur: Die Tiere leben in großen Familien, wobei ein einziges Weibchen mit seinem Partner für die gesamte Nachkommenschaft sorgt. Die Jungtiere verweilen ihr gesamtes Leben bei den Eltern, meist ohne selbst zur Reproduktion zu kommen, und kümmern sich u.a. um ihre jüngeren Geschwister. Verhaltensbiologische Analysen konnten zeigen, daß im Gegensatz zum Nacktmull (Heterocephalus glaber) bei Cryptomys anselli weder Pheromone noch dominant-aggressives Verhalten der „Königin“ zu einer sexuellen Suppression der Nachkommen führen. Parallel zum Graumull wird die Ratte als ein in der Neurobiologie und Verhaltensphysiologie gut erforschter „Standardorganismus“ immunhistochemisch untersucht. Die vorliegende Arbeit beschäftigt sich zuerst mit der Frage, ob und inwieweit bei Ratten und Graumullen die jeweilige soziale Organisation mit dem Muster der Transmitterexpression von Oxytocin und Vasopressin korreliert. Desweiteren ist von besonderem Interesse, ob sich die einzelnen Angehörigen der Graumull-Familien mit ihrem jeweiligen individuellen sozialen Status auch bezüglich der Verteilung und Quantität der beiden Transmitter unterscheiden. Auf dieser Grundlage wurden insgesamt vierzehn Graumulle und vier Ratten auf die Oxytocin- und Vasopressin-Expression im Zentralnervensystem hin untersucht. Die vorgestellten immunhistochemischen Befunde an der Ratte und am Graumull entsprechen prinzipiell der in der Literatur beschriebenen Expression von Oxytocin und Vasopressin im Nucleus paraventricularis hypothalami, im Nucleus supraopticus sowie in den weit verbreiteten akzessorischen magnozellulären neurosekretorischen Neuronen im Hypothalamus anderer Säugetiere. Bei Cryptomys ergab weder die qualitative noch die quantitative intraspezifische Analyse der immunreaktiven OX- und VP- Neuronen signifikante Unterschiede zwischen Individuen unterschiedlicher sozialer Stellung. Dagegen weist der Graumull im Vergleich mit der Ratte und anderen daraufhin bearbeiteten Säugern bisher nicht bekannte qualitative Unterschiede im oxytocinergen System auf, wobei unsere Befunde an der Ratte weitgehend mit der vorhandenen Literatur übereinstimmen: Eine magnozelluläre Neuronen-population im Corpus mamillare, welche auch in der Routinefärbung (Kresylechtviolett) erkennbar ist, zeigt bei den Graumullen eine Oxytocin-Expression, nicht aber bei den Ratten. In der Literatur ist für diese Neuronenpopulation bis dato nur die Expression von ABA beschrieben worden, nicht aber ihr oxytocinerger Charakter. Darüber hinaus ist eine bei der Ratte auffällige Gruppe akzessorischer magnozellulärer und oxytocinerger Neuronen, der Nucleus commissuralis anterior der Ratte, beim Graumull weder in der Routinefärbung noch immunhistochemisch nachweisbar. Als ein weiterer Unterschied ist die Expression von Oxytocin in der Area hypothalamica lateralis bei der Ratte sehr viel dichter als beim Graumull, ein Merkmal von potentiell qualitativem Charakter. Der interspezifische Vergleich (Ratte-Graumull) ergab also eine potentiell neue Population Oxytocin-exprimierender Neuronen für den Graumull, nicht aber für die Ratte. Es wäre denkbar, daß über diese neu entdeckte oxytocinerge, aber nicht vasopressinerge Expression/Population mamillärer Neuronen innerhalb des limbischen Systems Projektionen in den Neokortex das Sozialverhalten der Graumulle beeinflussen können. In der Zukunft gilt es zu prüfen, ob diese Neuronenpopulation mit ihrer Oxytocin-Expression auch in anderen Säugetieren inklusive anderen eusozialen Spezies vorkommt. Das Fehlen des Nucleus commissuralis anterior (CoA) beim Graumull beruht hingegen wahrscheinlich nur auf strukturellen Unterschieden zwischen den Gehirnen von Ratten und Graumullen.This thesis analyses the expression of oxytocin (OX) and vasopressin (VP) nonapeptide hormones in the brains of rats (Rattus rattus) and African or common mole-rats (Ansell’s mole-rat, Cryptomys anselli) using immunohistochemical methods. In mammals, generally, oxytocin and vasopressin are synthesized in different populations of magnocellular hypothalamic neurosecretory cells, the perikarya of which are located in the paraventricular nucleus, the supraoptic nucleus and the widespread accessory magnocellular neurosecretory cells. Via axonal transport these neuropeptides are mainly transferred to the posterior lobe of the pituitary where they are released into the circulatory system. Apart from more “classical” peripheral functional implications (e.g., oxytocin facilitating child delivery and maternal breastfeeding behaviour vs. vasopressin regulating blood volume and salt concentration), these peptides play an important role as hypothalamic neurotransmitters by modulating social behaviour, partner preference, aggression etc.. Common mole-rats (Cryptomys) are subterranean and eusocial and thus show an exceptional family structure. These animals live in large families, each consisting of a single breeding pair and non-reproductive offspring. The young animals remain in the parental nest for their whole life and most of them never reproduce but, among other things, take care of their younger siblings. Behavioural studies show that, in contrast to the situation in the naked mole-rat (Heterocephalus glaber), neither pheromones nor aggressive behaviour of the “queen” are responsible in African mole-rats for the sexual suppression of their offspring. In parallel to common mole-rats, the laboratory rat (Sprague-Dawley) is investigated immunohistochemically as a well-known reference animal in neurobiological and behavioural research. This thesis primarily deals with the question whether and to what extent the mode of social organisation in rats and mole-rats correlates with the expression pattern/topography of OX and VP as transmitters in hypothalamic neuron populations. Special attention is given to the comparison of individuals among different Cryptomys families and to the question whether the single members of mole-rat families with their individual social rank also differ in the distribution and quantity of the two transmitters. As a whole, we analysed brains of fourteen common mole-rats (Cryptomys anselli) and four rats (Sprague-Dawley). The results of our immunohistochemical studies, in principle, correspond with the expression of oxytocin and vasopressin in the hypothalamic paraventricular nucleus, the supraoptic nucleus, and in the widespread accessory magnocellular neurosecretory neurons throughout the hypothalamus reported in the literature on other mammals. In Cryptomys neither the qualitative nor the quantitative intraspecific analysis of immunoreactive OX and VP neurons reveal any significant differences among individuals of different social rank. Comparison between mole-rats and rats (and other mammals investigated so far), however, demonstrate qualitative differences, with our findings in the rat being largely consistent with the extant literature: A population of magnocellular neurons located in the mammillary complex which were also detected in cresyl violet, shows oxytocin expression in Cryptomys but not in rat. In the literature, these neurons are known to synthesize GABA, but their oxytocinergic character has never been demonstrated before. Moreover, one prominent group of accessory magnocellular neurons, the anterior commissural nucleus in the rat, being composed of oxytocinergic neurons, is not present in Cryptomys (neither in cresyl violet nor in OX- or VP-labelled sections). As an additional difference between the two rodent species, the lateral hypothalamic area showed a much higher concentration of oxytocinergic neurons in rat than in mole-rats, a feature of potentially qualitative significance. Interspecific comparison (Rattus, Cryptomys) thus revealed a potentially new population of oxytocin-immunoreactive neurons in the mammillary complex exclusively for Cryptomys anselli. It seems possible that this “new” oxytocinergic (but not vasopressinergic) expression/population of mammillary neurons, being part of the limbic system, are able to modulate social behaviour in Cryptomys via projections into the neocortex. Further studies will have to prove the consistency of our results in other mammals including eusocial species. The absence of the anterior commissural nucleus (CoA) in Cryptomys is probably based on mere structural differences between the brains of rats and mole-rats. The analyses presented here suggest that in eusocial mole-rats (Cryptomys anselli) neither sex, reproductive state nor the age of an animal has a significant influence on the topographical distribution and number of oxytocinergic and vasopressinergic neurons. Our results seem to confirm the hypothesis that, in Cryptomys anselli, non-reproductive family members are neither suppressed by genetic factors nor by dominant, aggressive behaviour of the reproductive female or by pheromones. Incest avoidance in eusocial common mole-rats more likely is caused by individual recognition and by he fact that family members (with the exception of the special bond between the reproductive animals) are sexually unattractive for each other. Finally, this thesis presents some reflections on the functional and clinical significance of oxytocin and vasopressin with regard to neurobiological and behavioural disorders and the problem that only with great care data and interpretations can be transferred from the animal model to the human

Occupational immediate-type reactions to locusts - a possible cross-reactivity between desert locusts (Schistocerca gregoria) and migratory locusts (Locusta migratoria)?

Exposure to locusts, which belong to the arthropod phylum, is an underestimated health problem, especially among workers in research facilities exposed to laboratory animals. We describe a rare case of an occupational immediate-type reaction to locusts with a possible cross-reactivity between desert locust (Schistocerca gregaria) and migratory locust (Locusta migratoria)

Functional histology of the skin in the subterranean African giant mole-rat: thermal windows are determined solely by pelage characteristics

Excavation of burrows is an extremely physically demanding activity producing a large amount of metabolic heat. Dissipation of its surplus is crucial to avoid the risk of overheating, but in subterranean mammals it is complicated due to the absence of notable body extremities and high humidity in their burrows. IR-thermography in a previous study on two species of African mole-rats revealed that body heat was dissipated mainly through the ventral body part, which is notably less furred. Here, we analyzed the dorsal and ventral skin morphology, to test if dermal characteristics could contribute to higher heat dissipation through the ventral body part. The thickness of the epidermis and dermis and the presence, extent and connectivity of fat tissue in the dermis were examined using routine histological methods, while vascular density was evaluated using fluorescent dye and confocal microscopy in the giant mole-rat Fukomys mechowii. As in other hitherto studied subterranean mammals, no subcutaneous adipose tissue was found. All examined skin characteristics were very similar for both dorsal and ventral regions: relative content of adipose tissue in the dermis (14.4 ± 3.7% dorsally and 11.0 ± 4.0% ventrally), connectivity of dermal fat (98.5 ± 2.8% and 95.5 ± 6.8%), vascular density (26.5 ± 3.3% and 22.7 ± 2.3%). Absence of large differences in measured characteristics between particular body regions indicates that the thermal windows are determined mainly by the pelage characteristics

Hypersensitivity reactions to non‐steroidal anti‐inflammatory drugs (NSAIDs) – a retrospective study

Background: The aim of this study was to verify the validity of clinical history and oral provocation challenges of patients with NSAID hypersensitivity and to identify safe alternatives. The COX‐2 inhibitor etoricoxib, in particular, was studied. Patients and methods: In all, 104 patients with confirmed diagnoses of NSAID hypersensitivity treated at the Department of Dermatology, Frankfurt University Hospital, Germany between 2004 and 2012 were retrospectively studied. Results: The medical history and hypersensitivity symptoms during oral provocation testing (OPT) largely coincided and were mostly mild to moderate. Acetylsalicylic acid (ASA) was the most frequent trigger both anamnestically (27.9 %) and during OPT (47.8 %). Etoricoxib caused the fewest reactions during OPT (4.2 %). Acetaminophen led to reactions in only 6.7 % of the cases studied although it was named more often in clinical histories (14 %). Conclusions: OPT should be the aim whenever possible as most symptoms are mild to moderate. To distinguish between selective and cross‐hypersensitivity reactions, ASA should be part of the test protocol. Furthermore, the findings of this study indicate that etoricoxib and acetaminophen are safe treatment alternatives in case of NSAID hypersensitivity. However, these drugs should not be administered without prior OPT in an inpatient setting, as severe symptoms can occur

Treatment of granulomas in patients with ataxia telangiectasia

Background: Ataxia telangiectasia (A-T) is a devastating multi-system disorder characterized by progressive cerebellar ataxia, growth retardation, immunodeficiency, chronic pulmonary disease and chromosomal instability. Cutaneous granulomas are a known phenomenon in A-T but extra-dermal manifestation of granulomas at bone and synovia has not been reported so far. The clinical presentation, immunological findings, the long-term course and treatment options of eight patients with severe granulomas will be reported. Methods: From our cohort of 44 classical A-T patients, eight patients aged 2–11 years (18.2%) presented with granulomas. Immunological features of patients with and without granulomas were compared. Five patients suffered from cutaneous manifestation, in two patients we detected a bone and in one a joint involvement. Patients with significant extra-dermal involvement as well as one patient with massive skin manifestation were treated with TNF inhibitors. The patient with granulomas at his finger joint and elbow was treated with hematopoietic stem cell transplantation (HSCT). Results: Interestingly, seven of eight patients with granulomas were total IgA deficient, but there were no differences in IgG and IgM levels. All lymphocytes subsets were equally distributed except patients with granuloma had significantly lower naïve CD8 cells. In patients without treatment, four of eight showed a slow but significant enlargement of the granuloma. Treatment success with TNF inhibitors was variable. In one patient, treatment with TNF inhibitors led to a total remission for 3 years up to now. In two patients, treatment with TNF inhibitors led to a partial regression of granulomas. Treatment interruptions caused deterioration again. Conclusions: Granulomas in A-T progress slowly over years and can lead to significant morbidity.Treatment with TNF inhibitors was safe and in part successful in our patients. Interestingly HSCT leads to complete remission, and indicates that aberrant immune function is responsible for granulomas in A-T patients. At a glance commentary: Scientific knowledge on the subject: Little is known about the clinical presentation, course and treatment of granulomas in ataxia telangiectasia (A-T). In addition, this is the first report of extra-dermal manifestation of granulomas at bone and synovia in patients with A-T. What This Study Adds to the Field: Granulomas in A-T progress slowly over years and can lead to significant morbidity. Treatment with TNF inhibitors was safe and in part successful in our patients

Impact of different spa waters on inflammation parameters in human keratinocyte HaCaT cells

Background: The treatment of different skin conditions with spa waters is a long tradition dating back to at least late Hellenism. Interestingly, independent scientific examinations studying the effect of spa waters are scarce. Objective: In the present in vitro study, we compared the effect of culture media supplemented with (a) thermal spa waters (La Roche-Posay, Avène) and (b) two natural mineral drinking waters (Heppinger, Adelholzener) on physiological parameters in HaCaT keratinocytes. Methods: The different medium preparations were investigated with regard to cell proliferation and cell damage. Moreover, the impact on inflammation parameters with and without ultraviolet B (UVB) irradiation was examined. Results: Two popular thermal spring waters were found to suppress cell proliferation and cell damage. Moreover, these waters reversed the induction of interleukin-6, as measured using enzyme-linked immunosorbent assay and promoter transactivation, and the formation of reactive oxygen species after UVB stimulation. Of note, the two natural mineral waters, which are distributed as drinking waters, had some effect on the above-mentioned parameters but to a lesser extent. Conclusion: In summary, our results show that spa waters, and particularly those derived from thermal springs, reduce parameters associated with inflammation. It seems likely that trace elements such as selenium and zinc are critical for the observed effects

Safety and tolerability of venom immunotherapy: evaluation of 581 rush- and ultra-rush induction protocols (safety of rush and ultra-rush venom immunotherapy)

Background: Current literature is inconsistent regarding the risk of severe side effects using accelerated induction protocols in Hymenoptera venom immunotherapy (VIT). In addition, several data indicate the influence of purity grade of venom preparation on tolerability. We evaluated the safety and tolerability of ultra-rush and rush build-up protocols using purified and non-purified venom preparations. Methods: Retrospective single-center study of 581 VIT inductions (325 ultra-rush and 256 rush protocols) from 2005 to 2018 in 559 patients with bee and vespid venom allergy using aqueous purified (ALK SQ®) for ultra-rush protocol and aqueous non-purified (ALK Reless®) venom preparations for rush protocol. Results: Urticaria (8% vs. 3.1%, p = 0,013) and dose reductions (4.3% vs. 1.2%, p = 0,026) were significantly more frequent in the ultra-rush group. Overall rate of moderate-to-severe side effects (anaphylaxis ≥grade 2 according to Ring and Meβmer) was low and did not differ significantly between protocols (p = 0.105). Severe events (grade 4 anaphylaxis) were not reported. Discontinuation rate was very low in both cohorts (0.6% vs 1.2%). The higher purity grade of venom preparations in the ultra-rush cohort did not improve tolerability. The bee venom group showed a non-significant trend towards higher incidence of mild reactions (urticaria), resulting in more frequent dose reductions and antiallergic therapy. Conclusion: Rush and ultra-rush protocols show an excellent safety profile with only infrequent and mild anaphylactic reactions in bee and vespid venom allergy. Ultra-rush immunotherapy reduces the duration of the inpatient build-up phase setting and thus is viewed by the authors as preferred treatment in Hymenoptera venom allergic patients