[Guideline for the Diagnosis and Treatment of Asthma - Addendum 2020 - Guideline of the German Respiratory Society and the German Atemwegsliga in Cooperation with the Paediatric Respiratory Society and the Austrian Society of Pneumology]. / S2k-Leitlinie zur Diagnostik und Therapie von Patienten mit Asthma ­ Addendum 2020.

The present addendum of the guideline for the diagnosis and treatment of asthma (2017) complements new insights into the diagnosis and management of asthma as well as for the newly approved drugs for the treatment of asthma. Current, evidence-based recommendations on diagnostic and therapeutic approaches are presented for children and adolescents as well as for adults with asthma.

[Guideline for the Diagnosis and Treatment of Asthma - Guideline of the German Respiratory Society and the German Atemwegsliga in Cooperation with the Paediatric Respiratory Society and the Austrian Society of Pneumology]. / S2k-Leitlinie zur Diagnostik und Therapie von Patienten mit Asthma.

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.

Clinical characteristics and risk profile of patients with elevated baseline serum tryptase.

BACKGROUND: The clinical relevance of elevated basal serum tryptase (eBST ≥ 11.4 ng/ml) often remains unclear. METHODS: BST was assessed in 15,298 patients attending our outpatient clinic. Frequency and severity of anaphylaxis was compared in 900 patients with eBST and 900 patients with normal BST. The prevalence of eBST was evaluated in patients with drug reactions, urticaria, gastrointestinal symptoms or venom allergy. Mast cell-associated symptoms were recorded prospectively in 100 patients with eBST and 100 controls using a standardised questionnaire. RESULTS: 5.9% (n=900) of 15,298 patients had eBST ≥11.4 ng/ml (mean 20 ± 21 ng/ml, 11.4-390 ng/ml). In 47% of them BST was <15.0 and in 78% <20.0 ng/ml. In patients with normal BST (4.5 ± 2.1 ng/ml), mean levels increased continuously with age (0.28 ng/ml per decade; p<0.001). Fatigue, meteorism, muscle/bone ache, vertigo, tachycardia, flush, palpitations, diarrhoea and oedema were associated with eBST (p<0.05 to <0.0001) without significant differences between slightly (11.4-20 ng/ml) or strongly (>20 ng/ml) eBST. eBST was significantly associated with adverse reactions to drugs (34%), radio contrast media (15%) and insect stings (24%) (p<0.05). Anaphylaxis was more common in patients with eBST (21% vs. 14%, p<0.001). The relative role of insect stings, drugs and food as the most important triggers was similar in patients with elevated and normal BST. Severe reactions (grade 3/4) occurred most often in subjects with BST >20 ng/ml (BST <11.4 mg/ml: 2.8%; 11.5-20 ng/ml: 5.9%; >20 ng/ml: 12.4%). CONCLUSIONS: In clinical practice it appears reasonable to assess BST, besides after anaphylactic reactions also in patients suffering repeatedly from vertigo, flush, tachycardia, palpitations, oedema and nausea. Even patients with slightly eBST have a higher risk of anaphylaxis and experience more severe reactions.

Wine and headache.

Headache can be induced by histamine in wine in patients suffering from histamine intolerance, a disease characterized by impaired histamine degradation based on reduced diamine oxidase activity or a lack of the enzyme. Diamine oxidase is localized in the jejunal mucosa and is the most important enzyme metabolising histamine. It is competitively inhibited by alcohol and numerous drugs. In preliminary investigations, assessment of diamine oxidase levels gave decreased activity (0.03 nKat/l) in patients with histamine intolerance compared to healthy controls (0.07 nKat/l). In pregnancy, diamine oxidase levels are known to be about 500-fold elevated, giving mean levels of 25.0 nKat/l. Other biogenic amines such as phenylethylamine or serotonin may be causative for wine/food-induced headache. In experimental models, headache has been induced by histamine infusion as well as red wine provocation. Histamine-induced headache is a vascular headache likely to be caused by nitric oxide which probably represents a key molecule in vascular headaches. A histamine-free diet is the treatment of choice for patients with histamine intolerance and chronic headache. To start treatment, an antihistamine (H1 blocker) for 14 days as well as a histamine-free diet for at least 4 weeks are recommended. Clinical improvement to the diet as well as in vitro tests for plasma histamine and diamine oxidase in the serum as well as vitamin B6 levels have to confirm the diagnosis. As supportive treatment, a vitamin B6 (pyridoxal phosphate) substitution appears useful in histamine-intolerant patients as pyridoxal phosphate seems to be crucial for diamine oxidase activity. Histamine intolerance, based on reduced diamine oxidase activity or a lack in the enzyme is causative for wine/food-induced chronic headache. According to the localization of diamine oxidase in the jejunal mucosa, histamine intolerance is primarily a disease of intestinal origin. A histamine-free diet is the treatment of choice in histamine-intolerant patients suffering from chronic headache. In addition, it is also important to avoid diamine-oxidase-blocking drugs and alcohol which act as inhibitors of diamine oxidase. As avoidance of histamine-rich food is simple, inexpensive and harmless treatment, histamine-containing food such as cheese and alcoholic beverages should be labeled.

The red wine provocation test: intolerance to histamine as a model for food intolerance.

Sneezing, flush, headache, diarrhea, skin itch, and shortness of breath are symptoms occurring in patients intolerant to wine after drinking one glass of red wine. The role of histamine in wine intolerance was evaluated by a red wine provocation test in 28 patients with a history of wine intolerance and in 10 controls with good tolerance of wine. Patients were challenged with 125 ml red wine (equivalent to 50 micrograms histamine); blood samples were drawn before and after 15 and 30 minutes. Plasma histamine was assessed by a radioimmunoassay. Lung function tests were performed before and after the wine test. Twenty-two of twenty-eight patients had symptoms showing significantly higher plasma histamine levels 30 minutes after wine challenge (p < .01) compared with asymptomatic controls. Basal histamine levels of patients were higher (p < .05) than in controls. A slight asthmatic attack as well as a 30% decrease of FEF 25 was seen in 2/22 patients. Terfenadine premedication significantly eliminated symptoms in 10/12 patients (p < .05) in a subsequent wine test. Histamine assessment was done in 52 wines (red, white, and champagne) and in 17 beers by radioimmunoassay. Histamine levels ranged from 3-120 micrograms/l in white wines; 15-670 micrograms/l in champagnes; 60-3800 micrograms/l in red wines; and 21-305 micrograms/l in beers. Histamine is causing wine intolerance. Patients intolerant to wine seem to have diminished histamine degradation probably based on a deficiency of diamine oxidase.

[The histamine-free diet]. / Die histaminfreie Diät.

Food intolerance is not IgE-mediated but caused by histamine. A diminished histamine degradation based on a deficiency of diaminoxidase is suspected to be the reason. The therapeutic efficacy of a histamine-free diet was evaluated in 100 patients with food intolerance and allergic diseases, who were required to avoid fish, cheese, hardcured sausage, pickled cabbage, wine and beer for 4 weeks. Considerable improvement was observed in 57 patients, 15 of whom had total remission. The most striking treatment results were obtained in food or wine intolerance (80% P < 0.05; treatment of choice), bronchial asthma (80%), headache (64%) and urticaria (58%). After ingestion of food rich in histamine clearcut recurrence of atopic eczema was seen in 50% of the patients affected. Histamine plays a major part in food and wine intolerance. Histamine in food causes worsening of symptoms in atopics and patients suffering from headache. The results obtained indicate a deficiency of diaminoxidase in patients with intolerance to food or wine. Histamine levels in alcoholic beverages should be displayed on the labels.

Histamine-free diet: treatment of choice for histamine-induced food intolerance and supporting treatment for chronic headaches.

Histamine-induced food intolerance is not IgE-mediated. Skin-prick testing and specific IgE to food allergens are typically negative. Food rich in histamine or red wine may cause allergy-like symptoms such as sneezing, flush, skin itching, diarrhoea and even shortness of breath. The suspected reason is a diminished histamine degradation based on a deficiency of diamine oxidase. As diamine oxidase cannot be supplemented, a histamine-free diet was implemented to reduce histamine intake. Forty-five patients with a history of suffering from intolerance to food or wine (n = 17) and chronic headache (n = 28) were put on the diet over months to years. Fish, cheese, hard cured sausages, pickled cabbage and alcoholic beverages had to be avoided. Complaint intensity and drug-use per week prior to and 4 weeks after a histamine-free diet were compared. After 4 weeks on the diet 33/45 patients improved considerably (P < 0.01), eight of them had total remission. In 12/45 patients, however, no changes in symptoms were observed. Symptoms of food or wine intolerance significantly decreased (P < 0.02; treatment of choice), headaches decreased in frequency (P < 0.001), duration and intensity. After eating histamine-rich food symptoms were reproducible and could be eliminated by anti-histamines in most patients. These data indicate the role of histamine in food and wine intolerance and that histamine-rich food causes a worsening of symptoms in patients suffering from chronic headaches. Results obtained support the hypothesis of a deficiency of diamine oxidase in patients with intolerance to food or wine.

Spontaneous histamine release in whole blood in patients before and after 4 months of specific immunotherapy.

Spontaneous histamine release (SHR) in whole blood was assessed before and after 4 months of specific immunotherapy (SIT) for allergic rhinoconjunctivitis in 32 patients. Spontaneous histamine release was significantly enhanced (P < 0.05) in patients prior to immunotherapy compared with 20 controls. Spontaneous histamine release decreased significantly in patients after 4 months of specific immunotherapy (P < 0.04) and almost reached the same values as spontaneous histamine release in controls. Clinical success of treatment after 4 months was seen in 15 patients (improvement > or =50%), 10 of whom showed a significant decrease in spontaneous histamine release. Decrease of spontaneous histamine release after 4 months indicates the efficacy of specific immunotherapy already at an early stage of treatment. Assessment of spontaneous histamine release appears to be a useful and easily performable method for monitoring success of treatment of patients during specific immunotherapy.

Patch test reactions in children, adults and the elderly. A comparative study in patients with suspected allergic contact dermatitis.

The age- and sex-related distribution of positive patch test reactions was investigated in 234 children (0-7 years, n = 72 and 8-14 years, n = 162), 1200 adults (20 to 50 years) and 295 elderly patients (> or = 70 years) with suspected allergic contact dermatitis using a European standard series. In girls from 0 to 7 years, the most frequent contact allergens were thimerosal (37.5%) and nickel (27.5%), in girls from 8 to 14 years, nickel (28.7%) and thimerosal (26.6%), in women, thimerosal (25.3%) and nickel (25.2%), and in elderly women, nickel (12.6%) and balsam of Peru (9.7%). The most frequent contact allergens in boys from 0 to 7 years were ethylmercuric chloride (28.1%) and thimerosal (25.0%), in boys from 8 to 14 years, thimerosal (30.9%) and ethylmercuric chloride (14.7%), in men, thimerosal (21.1%) and ethylmercuric chloride (13.7%) and in elderly men, nickel (11.2%) and balsam of Peru (6.7%). Females showed more positive reactions than males. Whilst 0 to 7 year-old girls and boys showed relatively more frequent reactions, the elderly of both sexes were clearly less affected. Nickel is the most frequent contact allergen in females of 8 years and more. In men, thimerosal is most frequent and reactions to balsam of Peru show a peak incidence in the elderly. Results indicate that patch testing should be considered in children and elderly patients with appropriate indications.

Daily variations of serum diamine oxidase and the influence of H1 and H2 blockers: a critical approach to routine diamine oxidase assessment.

OBJECTIVE AND DESIGN: Histamine in food has been shown to induce intolerance reactions mimicking food allergy. These reactions seem to be due to impaired histamine metabolism caused by reduced diamine oxidase activity. To validate routine serum diamine oxidase assessment, daily variations of diamine oxidase were evaluated. METHODS: Blood was drawn from each of 20 healthy volunteers (10 female, 10 male; mean age 32.5 years) every 2 h from 9 a.m. to 5 p.m., and diamine oxidase activity was measured using the C14 putrescine method. To assess possible influences of H1 and H2 blockers on diamine oxidase activity, diphenhydramine, ketotifen, cimetidine, and ranitidine were incubated at pharmacologic concentrations with human placental diamine oxidase (identical to neutrophilic and eosinophilic diamine oxidase). Inhibition of diamine oxidase activity was calculated as the percentage of inhibition versus control. In addition, the known diamine oxidase inhibitors, dihydralazine and aminoguanidine, were used as positive controls. RESULTS: Serum diamine oxidase levels showed no significant daily variations (0.041 +/- 0.025; 0.037 +/- 0.022; 0.041 +/- 0.023; 0.040 +/- 0.023; 0.038 +/- 0.025 nKat/l) and no significant sex differences (female 0.040 +/- 0.028 nKat/l versus male 0.039 +/- 0.019 nKat/l). Antihistamines had no influence on diamine oxidase activity except for cimetidine, which caused 25% inhibition at the highest dose tested ( p < 0.0002) (positive control: aminoguanidine 85% inhibition (p< 0.0001), dihydralazine 68% inhibition (p<0.0001)) and diphenhydramine, which caused 19% increase (p<0.0001) of enzyme activity. CONCLUSION: Serum diamine oxidase levels do not show daily variations allowing assessment anytime during office hours. However, diagnostic interpretation of serum diamine oxidase levels may be difficult.

Anaphylaxis after dental treatment with a formaldehyde-containing tooth-filling material.

A 67-year-old patient developed systemic reactions after application of a formaldehyde-containing tooth filling. She had a clearly positive RAST result for formaldehyde, whereas skin prick testing and patch tests were negative. Sensitization to formaldehyde appears to have occurred 1 year previously. Induction of formaldehyde allergy may represent a major complication during dental treatment, and assessment of specific IgE should be considered in patients at risk.

Ethylmercuric chloride: the responsible agent in thimerosal hypersensitivity.

The causative agent of thimerosal allergy (sodium ethylmercury thiosalicylate) has not previously been thoroughly investigated. To evaluate whether the organic mercury component or the thiosalicylic acid molecule induces thimerosal sensitization, 23 patients positive to thimerosal were patch tested with ethylmercuric chloride, thiosalicylic acid and 8 different derivatives of mercury. To date, ethylmercuric chloride has not been tested in thimerosal allergy. 19/23 patients (82%) showed positive patch test reactions to ethylmercuric chloride. 4/23 patients negative to ethylmercuric chloride reacted positively to thimerosal 0.1% but not to thimerosal 0.05%. 8/23 patients (35%) also reacted to other mercurials. 20 controls negative to thimerosal showed negative patch test reactions to ethylmercuric chloride. Neither patients nor controls reacted to thiosalicylic acid. These results indicate that testing with thimerosal 0.1% leads to false-positive reactions and that the ethyl mercury component is the responsible agent in thimerosal allergy.

Allergic contact dermatitis to artificial fingernails prepared from UV light-cured acrylates.

BACKGROUND: Contact dermatitis from artificial nails made from self-curing acrylic resins is occasionally reported. Recently, UV light-cured products introducing new acrylics have become available. OBJECTIVE: Our purpose was to identify relevant allergens in commercial light-curing products by patch tests and to evaluate the efficacy of "hypoallergenic" products by inclusion into the test series. METHODS: Patients wearing photobonded acrylic nails who had perionychial and subonychial eczema were patch tested with an acrylate battery and "hypoallergenic" commercial products. RESULTS: Triethyleneglycol dimethacrylate, hydroxyfunctional methacrylates, and (meth)-acrylated urethanes proved to be relevant allergens in photobonded nail preparations. Methacrylated epoxy resin sensitization was not observed. All "hypoallergenic" products provoked positive reactions. CONCLUSION: The omission of irritant methacrylic acid in UV-curable products does not reduce the high sensitizing potential of new acrylates. In contrast to the manufacturers' declarations, all "hypoallergenic" products continue to include acrylate functional monomers and therefore continue to cause allergic sensitization.

Histamine in wine. Bronchoconstriction after a double-blind placebo-controlled red wine provocation test.

A 38-year-old woman with a history of seasonal rhinoconjunctivitis reported repeated attacks of wheezing after drinking various alcoholic beverages. Two consecutive histamine provocations using two identical samples of red wine containing 200 micrograms histamine/l and 3,700 micrograms/l, respectively, were performed in a double-blind placebo-controlled fashion to assess a possible histamine-induced bronchoconstriction. Lung function, plasma histamine, skin temperature, pulse rate and symptoms were assessed. In 3 male controls, four consecutive wine tests were performed in a randomised double-blind placebo-controlled fashion. Drinking wine with 3,700 micrograms histamine/l caused coughing and wheezing with a decrease in lung function. Plasma histamine showed an increase at 10 and 20 min and decreased at 30 min both after histamine-rich as well as histamine-poor wine, reaching the peak increase after histamine-rich wine. Controls did not react and plasma histamine levels did not increase. Bronchoconstriction after wine or food rich in histamine seems to be caused by diminished histamine degradation on the basis of reduced activity of diamine oxidase. Histamine in wine may induce bronchoconstriction in patients suffering from histamine intolerance.

Ash (Fraxinus excelsior)-pollen allergy in central Europe: specific role of pollen panallergens and the major allergen of ash pollen, Fra e 1.

BACKGROUND: The role of ash (Fraxinus excelsior) pollen as a cause of spring pollinosis in central Europe has received little attention. It is not clear whether ash pollen is a primary cause of sensitization or whether it is implicated through cross-sensitization to other pollens. METHODS: Over a 22-month period, ash pollen was included in a screening series for inhalant allergies. Pollen data were documented from 1976 through 1999. The frequency of IgE-binding to the ash-specific allergen Fra e 1 and pollen panallergens, respectively, was compared by Western blot between mono- (n = 6), oligo- (n = 16), and polysensitized (n=25) patients. RESULTS: Of 5,416 consecutive patients sensitized to any pollen, 920 (17.6%) had a positive skin prick test to ash. Total pollen counts varied extensively between years (229-5,351) as did peak concentrations (23-837 grains/m3/24 h). Western blotting revealed Fra e 1 sensitization in 100% of monosensitized, 93% of oligosensitized, but only 44% of polysensitized patients. IgE against profilins (Fra e 2), Ca-binding proteins (Fra e 3), and carbohydrate epitopes in the three groups was found in 0/0/17%, 0/19/31%, and 32/72/60%, respectively. At least 50% of sera from patients with Fra e 1 sensitization did not bind with the protein in Western blots under reducing conditions. CONCLUSIONS: Ash pollen should be considered a relevant factor and distinct entity in spring pollinosis. In all, only 20% of positive skin tests to ash appear to result from cross-sensitization to pollen panallergens.

The human recombinant histamine releasing factor: functional evidence that it does not bind to the IgE molecule.

BACKGROUND: We have previously shown that the human recombinant histamine releasing factor (HrHRF) caused histamine release from a subset of basophils from donors with allergy, and this release seemed to be dependent on the presence of a certain type of IgE, termed IgE+. IgE molecules that did not support HrHRF-induced histamine release were termed IgE-. However, subsequently we demonstrated that HrHRF primes anti-IgE-antibody-induced histamine release from all basophils, irrespective of the type of IgE on the cell surface. OBJECTIVE: Because these data suggested that HrHRF does not exert its biologic effects by binding to IgE, but rather that it interacted with a surface receptor on the basophil, we wanted to obtain functional evidence that HrHRF did or did not bind to the IgE molecule. METHODS: The rat basophilic leukemia cell line (RBL-SX38), which has been transfected to express a functional human FcepsilonRI (alpha-, beta-, and gamma-chains of the receptor) in addition to the normal rat FcepsilonRI, was used. The presence of the human FcepsilonRI receptor enables these cells to be sensitized with human IgE. Cells were passively sensitized with 1000 ng/mL human IgE+ or 1000 ng/mL human IgE- for 60 minutes at 37 degrees C. Unsensitized cells served as a control. After the cells were washed, 1 x l0(5) cells were stimulated in the presence of 1 mmol/L Ca2+ with 0.1 microg/mL anti-IgE, 40 microg/mL HrHRF, or 40 microg/mL mouse recombinant HRF (MrHRF), which has 96% homology to HrHRF. RESULTS: Mean anti-IgE-induced histamine release was 33% +/- 15%, and there was no difference between IgE+ sensitization (32% +/- 12%) and IgE- sensitization (34% +/- 18%). However, in contrast to human basophil experiments, neither HrHRF (0% +/- 0%) nor MrHRF (3% +/- 5%) caused histamine release in RBL cells sensitized with IgE+. In addition, priming the transfected RBL-SX38 cells or the parental cell line, RBL-2H3 cells, with HrHRF or MrHRF did not increase anti-IgE-induced histamine release. CONCLUSION: The results indicate that HrHRF does not bind to IgE, either IgE+ or IgE-. Therefore it appears likely that rHRF signals through its own specific receptor, which is not expressed or functional on RBL-SX38 or RBL-2H3 cells, but which seems to be expressed on basophils of atopic and nonatopic donors.

Exposure to gaseous formaldehyde induces IgE-mediated sensitization to formaldehyde in school-children.

BACKGROUND: Children attending a primary school showed symptoms such as headache, cough, rhinitis and epistaxis. Assessment of specific IgE to formaldehyde gave positive results in some children. OBJECTIVE: Was IgE-mediated sensitization as well as symptoms in children associated with formaldehyde exposure at school? METHODS: Sixty-two 8-year-old children attending three forms at a primary school were investigated. Indoor formaldehyde concentrations were measured in classrooms of both schools (one frame construction with particleboard used extensively as panelling vs a brick building) which were consecutively attended. Assessment of specific IgE to formaldehyde was done in all children. Children were transferred to a brick building and 3 months later specific IgE to formaldehyde in pupils showing initially elevated radioallergosorbent test (RAST) values reassessed. In all children symptoms were evaluated by questionnaire before and 3 months after changing school. RESULTS: In the school panelled with particleboard the World Health Organization (WHO) threshold for formaldehyde of 0.050 ppm was crossed in two classrooms (0.075 ppm and 0.069 ppm) whereas in one classroom 0.043 ppm was found. RAST classes of > or = 2 were found in three children, two of them attending the classroom with 0.075 ppm formaldehyde. Elevated RAST classes of > or = 1.3 were found in another 21 pupils. Thirty-eight pupils as well as 19 control children showed RAST classes in the normal range of < or = 1.2. Headache, nose bleeding, rhinitis, fatigue, cough, dry nasal mucosa and burning eyes were found in the affected children. There was a good correlation between symptoms and the formaldehyde concentrations in the classrooms. However, elevated IgE levels to formaldehyde did not correlate with symptoms. Formaldehyde concentrations in the classrooms of the brick built school were 0.029 ppm, 0.023 ppm and 0.026 ppm. After transferral specific IgE to formaldehyde decreased significantly from 1.7 +/- 0.5 to 1.2 +/- 0.2 (P < 0.002) as did the incidence of symptoms. CONCLUSION: Gaseous formaldehyde, besides its irritant action, leads to IgE-mediated sensitization. As children are more sensitive to toxic substances than adults, threshold levels for indoor formaldehyde should be reduced for children.

Oilseed rape pollen is a potentially relevant allergen.

Oilseed rape (Brassica napus) (OSR) is a partly wind-pollinated crop which has been increasingly cultivated both in Europe and overseas. Allergological data about OSR is scarce and controversial. We evaluated the frequency of sensitization to OSR pollen by skin prick test and RAST over a period of 1 yr. Airborne OSR pollen load and the agricultural role of this crop were analysed. Furthermore, six patients were investigated by immunoblot. In 4468 patients with suspect inhalant allergy investigated between June 1994 and May 1995, routine skin prick testing revealed OSR sensitivity in 7.1% of pollen-allergic patients. In all, monovalent sensitization was detected in nine patients. Routine pollen counts showed daily maxima not exceeding 50 grains/m3/24 h, but airborne OSR pollen has continuously increased during the last decade correlating with the increasing acreage. Characterization of OSR allergens by immunoblot revealed major allergens of 6/8 kD, 12/14 kD and in the high molecular weight range at 33, 42, 51, 58/61 and 70 kD. Some OSR proteins may cross-react with birch pollen allergens. In summary, the results suggest that OSR pollen is a moderate but true source of allergy and may sensitize despite low pollen exposure.