[Effects and side-effects of corticosteroids].
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Biomedical subjects
Publications and source records attributed to C Bachert.
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Although calcium has been used for several decades to treat allergic diseases of the skin and respiratory tract, controlled studies demonstrating the action of oral preparations in allergic rhinitis are lacking. This placebo-controlled, double-blind, crossover study shows that 1000 mg calcium administered orally significantly inhibits the allergen-induced swelling of the nasal mucosa in the allergen provocation test. Sneezing and secretion, which are allergic symptoms, were not reduced. This study is the first to confirm the positive effect of oral calcium on a symptom of allergic rhinitis.
Cytokines and cell adhesion receptors play a pivotal role in the recruitment of cells from the peripheral blood into inflamed tissue. Allergic rhinitis has previously been described as an inflammatory reaction characterised by the migration of granulocytes into the nasal mucosa. Using this model, we investigated the release of proinflammatory cytokines (interleukin IL-1 beta, IL-6, IL-8 and tumour necrosis factor-alpha TNF-alpha) and the expression of cell adhesion molecules (ELAM-1, ICAM-1 and LFA-1) in two studies involving biopsies as well as lavage and brush techniques. IL-1 beta and TNF-alpha can be found rapidly after allergen exposure and seem to initiate the cellular infiltration. The release of the chemokine IL-8 correlates with the continuously increasing number of granulocytes on the mucosal surface. Allergic rhinitis subjects showed significantly increased secretion levels of the proinflammatory cytokines IL-1 beta and IL-6 and of the chemokine IL-8. These findings correspond to a higher expression of the adhesion receptors ELAM-1, ICAM-1 and LFA-1 in allergic mucosa. We conclude that proinflammatory cytokines regulate the cell infiltration by the induction of adhesion receptor expression.
The neonate was born with the help of vacuum extraction because of difficult delivery of the shoulders. After birth respiratory distress developed and endotracheal intubation and artificial ventilation became necessary. When the tube was changed in the intensive care unit the infant's clinical status suddenly deteriorated. A rupture of the trachea was diagnosed immediately followed by surgery. The child survived without neurological sequelae. The chronological sequence of symptoms after birth suggests that the rupture of the trachea primarily developed during delivery and was secondarily enlarged by repeated endotracheal intubation.
Mononuclear phagocytes have been investigated in biopsies taken from the nasal mucosa and in epithelial cell samples from 22 grass-pollen-allergic subjects before season, after allergen challenge and during season by means of immunohistochemistry and electron microscopy. The cells were positive for CD68/EBM11 and HLA-DR, but failed to react with CD1 and CD23/BB10. The cells increased in number during season as well as after allergen challenge, especially in the upper part of the mucosa. Heteromorphy of macrophages, as seen by transmission electron microscopy, confirmed the presence of diverse macrophage subpopulations in the nasal mucosa of allergic subjects. Using brush sampling techniques, CD68-positive and HLA-DR-positive cells significantly increased in epithelial cell samples 4-8 h after allergen challenge, indicating a central role of these cells not only in antigen processing but also in late phase reactions of allergic rhinitis.
Macrophages are the most common cell type residing in the lumen of the lower airways. However, very little is known about the presence and putative pathogenic implications of macrophages in the upper airways. Using specific immunohistochemical techniques, the presence of and changes in macrophage density were studied before and after allergen exposure in the laboratory and during natural allergen exposure of subjects with seasonal allergic rhinitis. The monoclonal antibody EBM 11 combined with the alkaline phosphatase-anti-alkaline phosphatase-technique was applied on cytospin-prepared slides. In the challenge experiment, 0.5 +/- 0.2% (mean +/- SEM; n = 10) of the total cell number were positive for the EBM 11 marker before challenge, thereby not differing from the controls (0.2 +/- 0.2%; mean +/- SEM; n = 3). Local allergen challenge induced an increase of these cells to a peak of 1.3 +/- 0.4% after 4 h (p less than 0.05). During seasonal exposure there was also a similar increase, from 0.7 +/- 0.2 to 1.3 +/- 0.3% (p less than 0.05; n = 11) in placebo-treated patients and from 0.7 +/- 0.2 to 1.6 +/- 0.4% (p less than 0.05; n = 11) in patients treated with topical glucocorticoids. There was, however, no direct relationship between nasal symptoms and number of macrophages present on the mucosal surface. The study indicates that macrophages are involved in the inflammatory processes of allergic rhinitis.
The pathogenesis of acute and chronic diseases of the nasal mucosa is multivariate. Cytological examination of nasal cells by conventional and immunocytochemical techniques helps to clarify the diagnosis. We present the morphology and functions of cell populations of interest, as well as typical cytological findings and their interpretation. Allergic and pseudoallergic disease can be recognised and differentiated from other forms of rhinitis. The demonstration of IgE-positive cells represents a new diagnostic feature of high sensitivity and specificity. In addition to the pathogenesis of the disease, cytology also indicates the degree and appropriate therapy of rhinitis.
One of the most effective defense mechanisms of the nasal mucosa is its immune response leading to the synthesis of antibodies directed against inhaled antigens. In order to understand the immunology of the upper respiratory tract it is essential to know whether this response takes place within the mucosa itself or within regional lymphoid organs. The authors investigated cell populations involved in immune processes within the mucosa and as a model of a lymphoid organ, in the tonsil. Using a range of monoclonal cell surface markers, the authors concentrated on antigen-presenting cells, the B-cell differentiation, and T-cell subpopulations and their corresponding activation markers. The findings demonstrate that the normal mucosa has no organized lymphoid structures and few or no early, maturing, or activated B-lymphocyte stages. The antibody-producing plasma cells found within the mucosa can therefore not be regarded as locally formed. On the contrary, the palatine tonsils demonstrate a typical lymphoid structure and contain all activation and differentiation stages of B-lymphocytes from premature to plasma cells. This would suggest that the human nasal mucosa is not capable of providing a local immune response, but is dependent on lymphoid organs like the tonsil, as the regional "mucosa-associated lymphoid tissue" (MALT).
Allergen-specific IgE antibodies have not only been demonstrated in the serum, but also in the nasal secretions of allergic patients by means of the radio-allergosorbent test (RAST). In this preliminary study we adapted the technique of crossed radio-immunoelectrophoresis (CRIE) to nasal secretions in order to obtain further insight into the specificity of locally collected antibodies. Based on RAST results we compared CRIE patterns in serum, nasal secretions in 13 out of 23 grass pollen allergic subjects and two out of three house dust mite allergic subjects. In the nasal secretions the same IgE specificities were found as in the corresponding serum of the individual subject and as in a reference serum pool. These data indicate that the same specificity of IgE antibody can be found in the serum and the target organ. From these data there is no evidence for a local mucosal immune response that differs in specificity from the serum response.
The mode of action of different groups of anti-allergic drugs is described in relation to our current knowledge of the pathomechanism of allergic immediate and late-phase reactions. Recent developments in the therapy of allergic rhinitis are discussed. Knowledge of the principal effects and the clinical properties of the drugs represents the basis for the use of the different compounds.
The antiallergic activity of calcium was investigated in 25 patients with allergic rhinitis by nasal provocation with increasing doses of phleum pratense during a symptom free interval. Prior to that provocation, the patients received 9 mmol calcium (Calcium-Sandoz) i.v. or placebo respectively (double blind cross-over design). The concentration of serum calcium increased after calcium injection by 0.45 +/- 0.055 mmol/l. Calcium exerted a significant protective effect as compared to placebo: higher allergen doses, (p = 0.021) i.e. 20433 biological units/ml vs. 7494 biological units/ml, were required in order to induce a defined allergic reaction (50% decrease of nasal air flow). The data thus furnish evidence that intravenous calcium reduces the allergic response in type I allergy.
IgE-bearing mediator cells are suggested to be the effector cells in type I allergic rhinitis. These cells can be demonstrated by their granular constituents or by the surface-bound IgE antibodies. We developed immunohistochemical techniques in order to stain the cell-bound IgE using polyclonal or monoclonal anti-human IgE antibodies. These techniques can be applied to nasal biopsies as shown previously or to cytospin specimen harvested by a brush method. They deliver excellent staining results with well-preserved morphological details. Brush samples were taken from 24 grass pollen allergic subjects before season, after a nasal allergen provocation and two weeks after the onset of season. There was a statistically significant increase in toluidine blue positive and IgE-positive cells 24 hours after nasal provocation (app. 12-fold, p less than 0.05) and more pronounced within the season (app. 58-fold, p less than 0.001) compared to preseasonal values. These cells appeared to be mast cells rather than blood basophils judged by morphological criteria. There was a striking correlation between the number of toluidine blue cells and that of IgE-positive cells (r = 0.98). The number of eosinophils also increased due to the seasonal allergen exposure (p less than 0.001), but less pronouncedly compared to the mast cells. These data re-emphasize the migration of IgE-bearing mast cells and eosinophils into the epithelial lining of the nasal mucosa due to allergen interaction and point to a possible role of mast cells as a carrier for IgE-molecules.
The allergic reaction of the human nasal mucosa (Type I Coombs and Gell) can be divided in an immediate- and a late-phase reaction. The degranulation of IgE-bearing mast cells is crucial for the initiation of the immediate phase (app. 30 min). Mediators of these cells - especially histamine - cause the typical allergic symptoms. Some of the patients develop a late-phase reaction after a symptom-free interval. Eosinophils migrate into the epithelial lining and release mediators. Furthermore, mast cells increase in number in the epithelium. Other cells like macrophages and T lymphocytes may be involved as well. While the released mediators cause an unspecific mucosal hyperreactivity, the increased number of IgE-bearing mast cells leads to a specific immunological augmentation of the nasal reaction ("priming effect"). The allergic pathomechanism can be reduced by drugs at different points.
Findings in recent years have stressed the importance of research on the target organ in IgE-mediated allergies of the respiratory tract. In this review we have focussed on the nasal secretions (NS) as a contract medium between allergens and the respiratory mucosa. Our findings have demonstrated that NS show different allergen extraction activities in relation to different conditions. Whereas NS of allergic and inflamed noses extracted allergens very rapidly, NS of normal noses showed no extraction activity. Furthermore, it could be demonstrated that the IgE specificities in NS are comparable with those in the serum of individual patients not indicating a local IgE synthesis. The presence and function of basophilic cells and eosinophils and their mediators are discussed in the light of recent studies.
Besides mechanical or infectious factors in the genesis of secretory otitis media IgE-mediated hypersensitivity has often been discussed. In order to estimate the importance of an allergic reaction in the development of middle ear disease, we examined 27 children having adenoids and a secretory otitis media. We documented the patients' history of allergy and determined the IgE-levels in the serum, the middle ear effusions and the adenoid tissue. 5 out of 27 children suffered from an allergy of the upper respiratory tract, but only in one child we found an elevated level of IgE in middle ear effusion. On the basis of our investigations and recent literature, we suggest that an allergic rhinitis might cause an Eustachian tube dysfunction in a few patients. There is no evidence of a local allergic reaction of the middle ear mucosa.
The efficacy of picumast dihydrochloride (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarine++ + dihydrochloride) in a dosage of 2 mg o.d. (loading dose = 2 b.i.d. over the first three days) vs. placebo after nasal challenge was investigated in 20 patients with allergic rhinitis in a double-blind, controlled crossover study. The primary objective was the decrease in determinable nasal flow as a result of obstruction caused by swelling of the mucous membrane of the nose following nasal challenge with grass pollen. In addition, picumast dihydrochloride's effect on subjective symptoms elicited by nasal challenge, such as "runny nose" and "irritation", was also assessed. Picumast dihydrochloride's ability to inhibit nasal obstruction after challenge was significantly better than that of placebo in statistical terms. Nasal secretion after challenge with grass pollen was far less pronounced with picumast dihydrochloride than placebo. A positive effect on irritation was not seen after nasal challenge. The results of this study show that picumast dihydrochloride inhibits nasal obstruction and secretion in patients allergic to grass pollens following allergen challenge. It is also expected that picumast dihydrochloride will be able to clearly reduce allergic nasal reactions during times of natural, seasonally-high pollen counts.
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