V. Stephan

Safety and efficacy in children of an SQ-standardized grass allergen tablet for sublingual immunotherapy.

BACKGROUND Immunotherapy with the SQ-standardized grass tablet Grazax is efficacious and well-tolerated in adult patients with rhinoconjunctivitis. Allergic asthma and rhinoconjunctivitis are closely linked, and a strategy combining treatment of the upper and lower airways is recommended. OBJECTIVE To investigate the efficacy of treatment with the grass tablet on grass pollen-induced rhinoconjunctivitis and asthma as well as the immunologic response and the safety profile in children. METHODS A total of 253 children age 5 to 16 years, with grass pollen-induced rhinoconjunctivitis with/without asthma, were randomized 1:1 to active treatment or placebo. Treatment was initiated 8 to 23 weeks before the start of the grass pollen season 2007 and continued throughout the entire season. Symptomatic medication was provided as relief medication to both groups in a stepwise fashion. Primary endpoints were rhinoconjunctivitis symptom and medication scores. RESULTS The rhinoconjunctivitis symptom and medication scores and the asthma symptom score were all statistically significantly different between the 2 treatment groups. The differences in medians relative to placebo were 24%, 34%, and 64% in favor of active treatment. The immunologic response was similar to that observed in adults. The most common adverse reaction was oral pruritus, reported by 40 subjects (32%) in the active and 3 (2%) in the placebo group. Six subjects withdrew because of adverse events. No serious adverse events were assessed as treatment-related. CONCLUSION Immunotherapy with the grass tablet reduced grass pollen-induced rhinoconjunctivitis and asthma symptoms in a pediatric population and introduced an immunomodulatory response, consistent with treatment of the underlying allergic disease. The treatment was well tolerated.

Evaluation of a quantitative real-time PCR for the detection of respiratory syncytial virus in pulmonary diseases

Respiratory syncytial virus (RSV) is known to cause acute lower respiratory tract infections (ARI) in young children and is involved in exacerbation of chronic obstructive pulmonary disease (COPD) in adults. The role of RSV in stable COPD and the viral load in different respiratory diseases has not been investigated to date. The present authors established and evaluated a quantitative TaqMan® real-time polymerase chain reaction assay specific for RSV subgroup A. Absolute quantification for the determination of viral load input was achieved using a control plasmid. The assay allowed for a quantification over a >6-log range and a detection limit of <10 RSV copies per reaction mixture. The assay was 30 times more sensitive than conventional nested polymerase chain reaction assays. Interassay sd was 1.3 and coefficient of variation 4.7% on average. Clinical specimens from infants with ARI (n=62) and elderly adults with COPD (n=125) were compared for viral loads. A total of 47% RSV-positive samples were found in the ARI study group and 28% in the COPD study group. The viral load of both study groups was found to differ significantly. In the ARI study group the viral load was increased almost 2000-fold, suggesting acute infection in this group and former or latent infection in the COPD group. Respiratory syncytial virus-A specific TaqMan® real-time polymerase chain reaction assay is a sensitive and rapid method for the determination of viral load in clinical samples. It enables differential statements concerning the involvement of respiratory syncytial virus in acute lower respiratory tract infections and chronic obstructive pulmonary disease to be achieved.

Sensitization to four common inhalant allergens within 302 nuclear families

The coincidence of allergic sensitization was investigated in 302 school‐aged children and their parents. Specific sensitization to four common inhalant allergens (grass and birch pollens, cat dander, Dermatophagoides pteronyssinus) was ascertained by means of skin‐prick tests (SPT) carried out on the complete family unit at the beginning of a 22‐month follow‐up period. The same test procedure was then repeated on the children twice at 11‐month intervals to provide cumulative prevalences of sensitization. A clinical history of atopy in the children (hay fever or asthma; n= 47), which was derived from an interview, is associated with sensitization (positive SPT in 89%). For three allergens (grass and birch pollens, cat dander) sensitization occurs significantly more frequently in the children of mothers who are sensitized to the same allergen (odds‐ratios (ORs), 2.5–4.1). Additionally, in three of the four explanatory models related to a single antigen, maternal sensitization to one of the complementary allergens is of importance (ORs, 2.7–3.7). In contrast to this finding, none of the paternal sensitizations has statistical significance. Based on a reaction to at least one of the four allergens, the childs relative risk to be sensitized is increased in case of maternal (OR, 2.88; P= 0.001) but not of paternal (OR, 1.06; P= 0.83) sensitization. In conclusion, our data indicate that the maternal status is more predictive than that of the father with regard to the childs risk of sensitization.

Determination of N-methylhistamine in urine as an indicator of histamine release in immediate allergic reactions

The use of the urine histamine metabolite, N-methylhistamine (N-MH), as a parameter of histamine release in immediate allergic reactions was investigated. Baseline levels were determined in 34 normal control subjects and 29 atopic patients. Increases of urine N-MH values were measured during histamine infusions and in venom-allergic patients receiving bee-sting challenges. N-MH was determined by a newly developed radioimmunoassay. Baseline levels in control subjects and atopic patients demonstrated no significant differences. With regard to challenge tests, fluctuation of N-MH levels during a 6-hour period was measured. Random 6-hour increases in healthy and atopic subjects ranged from 5% to 41%. Before infusion of histamine (0.25 micrograms/kg/min for 30 minutes), baseline values were 137 +/- 11.4 micrograms N-MH per gram of creatinine and 9 +/- 1.1 micrograms N-MH per hour (n = 9). Levels peaked 1 hour after infusion at 275 +/- 45 micrograms/gm of creatinine and 44 +/- 5.6 micrograms/hr and decreased to resting levels after 2 hours. Metabolization by N-MH accounted for 9.5% +/- 4.9% (range, 2.4% to 18.4%) of infused histamine in the urine of the nine subjects. Bee-sting challenges were performed in 12 patients and three control subjects. Only in three patients experiencing generalized urticaria, nausea, dyspnea, and hypotension were significant increases of urine N-MH levels (138%, 144%, and 238%) observed. All other patients and three normal control subjects demonstrated normal local reactions without increase of N-MH values.(ABSTRACT TRUNCATED AT 250 WORDS)

Longitudinal variability of skin prick test results

The skin prick test (SPT) is a commonly used procedure for assessing a specific sensitization. The longitudinal variability of test results is of interest for clinical as well as epidemiological investigations. The sensitization to four common aeroallergens (grass pollen, birch pollen, Dermatophagoides pteronyssinus, cat dander) is investigated within the framework of three consecutive SPTs at 11‐month intervals for a population of 587 schoolchildren. The prevalence of sensitization based on a weal diameter of at least 2 mm was between 12.9% (cat dander) and 23.9% (grass pollen) in the initial testing. The positive predictive values of the initial SPT were between 75.3% (birch pollen) and 88.2% (cat dander) for the two subsequent SPTs. In the case of initially negative tests with positive second and third SPTs the incidence ranged between 3.2% (cat dander) and 4.3% (birch pollen) per year. A clear increase in the intensity of reaction in subsequent tests was observed in a number of probands testing positively in the initial SPT. In conclusion, our data indicate a high long‐term stability of a specific sensitization to aeroallergens in SPT.

Anti-ganglioside monoclonal antibody AA4 selectively inhibits IgE-induced signal transduction pathways in rat basophilic leukemia cells.

In rat basophilic leukemia 2H3 (RBL-2H3) cells, mAb AA4 binds to two derivatives of ganglioside GD1b that associate with the Src family kinase p53/56lyn and a serine kinase. Pre-incubation of cells with mAb AA4 blocks immunoglobulin E (IgE) mediated histamine release. In the present study we investigated the effect of incubation with mAb AA4 on signal transduction events. In addition to stimulation of the high affinity IgE receptor (Fc epsilonRI), cells were also activated by the calcium ionophore A23187 and the acetylcholine agonist carbachol in RBL-2H3 cells transfected with the G protein-coupled m3 muscarinic receptor. Incubation of cells with mAb AA4 in a dose-dependent manner inhibited the following Fc epsilonRI-induced signal transduction events: the increase of intracellular free calcium, phosphoinositol breakdown, tyrosine phosphorylation of proteins including the beta- of Fc epsilonRI and secretion. However, there was no inhibition of degranulation or of these biochemical events when cells were stimulated with calcium ionophore or activated via a G protein-coupled pathway. Our results demonstrate that mAb AA4 selectively blocks Fc epsilonRI-induced cell activation at a very early step upstream of receptor tyrosine phosphorylation. As mAb AA4 has previously been found to bind to gangliosides associated with Fc epsilonRI, inhibition of very early biochemical events may be due to interaction of mAb AA4 with the Fc epsilonRI induced signal transduction cascade at the receptor level.

Luftschadstoffbelastung und Asthma bronchiale bei Schulkindern

To examine the possibility of an effect of indoor and outdoor exposures on the prevalence of asthma in childhood we conducted a cross-sectional study in the area of Freiburg city and two communities in the Black Forest. The study group consists of 704 children aged 7 to 16 years. The children and their mothers took part in a standardized interview and a medical examination. Indoor exposures were assessed from information gathered in the interview by two different indices: (a) heating system and single room heating, and (b) the amount of indoor ventilation. The measurement of outdoor pollutants took into account weekly estimations of NO2 and combustion particles. The presence of asthma was recorded according to a previous medical diagnosis. Confounders were assessed during the interview (passive smoking, genetic predisposition to asthma etc.) or during the medical examination (cutaneous sensitization with a skin prick test). For the analysis of the data we applied logistic regression models and estimated odds-ratios. Only one of the four hypothesis variables displays a significant effect on the prevalence of asthma: Stoves as heating device carry a 4.8-fold relative risk for asthma compared to other types of heating. Among the confounding variables controlled for in the explanatory model, cutaneous reactions showed a relative risk of eight.