Morgan Andersson

Albumin, bradykinins, and eosinophil cationic protein on the nasal mucosal surface in patients with hay fever during natural allergen exposure

This study examined plasma- and eosinophil-derived products in nasal lavage fluids obtained from patients with hay fever during natural allergen exposure. Nine patients with strictly seasonal allergic rhinitis and five normal, nonallergic subjects (control group) were studied. Nasal lavages were performed twice weekly, starting 1 week before the expected birch-pollen season and continuing for 6 weeks, thereby covering the entire birch-pollen season. Nasal symptoms and pollen counts were recorded daily. The lavage fluid was analyzed for it content of albumin, bradykinins, and eosinophil cationic protein (ECP). During the pollen season, each of these solutes was significantly increased in the nasal lavage fluid from the allergic patients (p less than 0.05) but not from the control subjects. Albumin, bradykinins, and ECP generally correlated better between themselves than with symptoms and pollen counts. We conclude that natural exposure to allergens induces plasma exudation and increased levels of ECP on the human nasal mucosa.

Prevalence of nasal symptoms and their relation to self-reported asthma and chronic bronchitis/emphysema

Little information is available on associations between rhinitis and chronic bronchitis/emphysema (CBE). Self-reported upper airway symptoms, asthma, and CBE were examined in 12,079 adults living in southern Sweden. The response rate was 70% (n=8,469), of whom 33% reported significant nasal symptoms: a blocked nose was reported by 21%; sneezing by 18%; nasal discharge by 17%; and thick yellow nasal discharge by 5.7%. Nasal symptoms and combined nasal and self-reported bronchial disease were generally more common among smokers than nonsmokers. There was little overlap between asthma and CBE, but 46% of those with asthma and 40% of those with CBE had significant nasal symptoms. Best predicting factors (odds ratios >3) for asthma and CBE were nasal symptoms due to exposure to animals and damp/cold air, respectively. One-third of an adult, southern Swedish population, had significant allergic and/or nonallergic nasal symptoms. Nasal symptoms were frequently found to coexist with both asthma and chronic bronchitis/emphysema, suggesting that pan-airway engagement is common in both diseases. Differing associations between types of nasal symptoms and allergic and irritant triggers of nasal symptoms, with regard to asthma and chronic bronchitis/emphysema, emphasize the different natures of these bronchial diseases.

Cytolysis and piecemeal degranulation as distinct modes of activation of airway mucosal eosinophils

BACKGROUND Cytotoxic eosinophil granule proteins are considered important in the pathogenesis of inflammatory airway diseases, including asthma, rhinitis, and polyposis. However, little is known about the mechanisms involved in the deposition of these tissue-damaging granular products in vivo. OBJECTIVE We sought to determine the occurrence of degranulating eosinophils, those with morphologic evidence of cytolysis with associated clusters of free eosinophil granules (Cfegs), and to identify the frequency of apoptotic eosinophils in inflamed upper airway tissue. METHODS Eosinophil-rich nasal polyps were processed for transmission electron microscopy and for light microscopic evaluation of whole-mount preparations subjected to deep tissue staining for eosinophil peroxidase. RESULTS The mean proportion of eosinophil subtypes were intact and resting (6.8%), intact but degranulating (83%), cytolytic or Cfegs (9.9%), and apoptotic (0.0%). All degranulating eosinophils exhibited piecemeal degranulation. The occurrence of Cfegs was confirmed in nonsectioned whole-mount preparations. Depending on the appearance of their core and matrix, the specific granules were divided into four subtypes, and a degranulation index (altered per total granules) was calculated for each eosinophil. Cytolytic eosinophils had a much lower degranulation index than intact eosinophils present in the same tissue (P < .001). CONCLUSIONS These data indicate that eosinophil cytolysis is present in human airway mucosa, that its occurrence is not an artifact of the means of tissue handling, and that cytolysis of eosinophils may occur without prior extensive degranulation. We suggest that eosinophil cytolysis is a major activation mechanism, which occurs along with, but is distinct from, other types of degranulation.

Contribution of Plasma-Derived Molecules to Mucosal Immune Defence, Disease and Repair in the Airways

This review discusses recent observations, in health and disease, on the release and distribution of plasma‐derived molecules in the airway mucosa. Briefly, the new data on airway mucosal exudation mechanisms suggest that the protein systems of plasma contribute significantly to the mucosal biology, not only in injured airways but also in such mildly inflamed airways that lack oedema and exhibit no sign of epithelial derangement. Plasma as a source of pluripotent growth factor, adhesive, leucocyte‐activating, etc., molecules may deserve a prominent position in schemes that claim to illustrate immunological and inflammatory mechanisms of the airway mucosa in vivo.

Degranulation patterns of eosinophil granulocytes as determinants of eosinophil driven disease

BACKGROUND Degranulation of eosinophils in target tissues is considered a key pathogenic event in major chronic eosinophilic diseases. However, because of a lack of appropriate methods, little is known about degranulation of eosinophils in common eosinophilic diseases. METHODS Using transmission electron microscopic (TEM) analysis, a novel approach has been devised and validated to quantify eosinophil degranulation in human tissues (assessed in individual cells as percentage granules with structural signs of protein release). Biopsy specimens from patients with inflammatory bowel disease, allergic rhinitis, asthma, and nasal polyposis were evaluated. RESULTS All conditions displayed a similar degree of local tissue eosinophilia, with no differences being observed in eosinophil numbers in the airway mucosa of patients with airway diseases and the colonic mucosa of those with inflammatory bowel disease (IBD). In contrast, marked differences in the mean (SE) extent of eosinophil degranulation were observed between the patient groups; IBD 9.3 (1.4)% altered granules, artificial and natural allergen challenge induced allergic rhinitis 67.8 (6.8)% and 86.6 (3.0)%, respectively, asthma 18.1 (2)%, and nasal polyposis 46.6 (7.6)%. CONCLUSIONS This study provides the first quantitative data which show that different eosinophilic conditions, despite having similar numbers of tissue eosinophils, may exhibit markedly different degranulation patterns. The present assessment of piecemeal degranulation would thus make it possible to delineate the conditions under which eosinophils are likely to contribute to disease processes. This novel type of analysis may also guide and validate anti-eosinophilic treatment options.

Eosinophils, secretory responsiveness and glucocorticoid‐induced effects on the nasal mucosa during a weak pollen season

This study examined the seasonal effects on eosinophils and secretory responsiveness of the nasal mucosa in 22 patients with allergic rhinitis due to birch pollen (11 patients received placebo and 11 budesonide. 200 μg once daily in each nostril). The pollen counts during the study season were too low to produce a significant symptomatology. Hence, our findings demonstrate threshold alterations of the airway mucosa in allergic rhinitis and their inhibition by anti‐inflammatory drug intervention. The patients were monitored for 8 weeks with daily recordings of pollen counts and symptom scores. Once every week a series of laboratory tests was carried out: the local eosinophil influx was determined using a Rhinobrush technique; the levels of eosinophil cationic protein (ECP) were analysed in nasal lavage fluids: and the secretory response to intranasal methacholine was measured. Treatments started after a 2‐week run‐in period. The proportion of eosinophils increased markedly in the placebo group and was elevated also during the last two study weeks when the pollen counts were practically nil. The secretory responsiveness to methacholine increased during the pollen season and returned to baseline towards the end of the study period. The topical glucocorticoid treatment reduced the proportion of eosinophils. the ECP levels, and the secretory response to methacholine compared to placebo.

Circulating eosinophil/basophil progenitors and nasal mucosal cytokines in seasonal allergic rhinitis.

Accumulation of eosinophils in the airways is characteristic of allergic rhinitis and asthma. The tissue eosinophilia may involve both recruitment of mature eosinophils and proliferation of their progenitors. This study examines mature eosinophils (nasal and circulating), their circulating progenitors, and a potential role of granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) in stimulating these progenitors. Twelve subjects with a history of seasonal allergic rhinitis and positive skin prick test for birch pollen were studied during four periods: shortly before, in the early and intense phase, at the end, and well after the Swedish birch‐pollen season. Nasal mucosal and circulating eosinophils were examined in both nasal brushings and peripheral blood samples. Eosinophil/basophil progenitors were determined by counting colony‐forming units in nonadherent mononuclear blood‐cell cultures in methylcellulose at 14 days. The nasal mucosal cytokines GM‐CSF, interleukin (IL)‐1β, IL‐3, IL‐5, IL‐6, IL‐8, and RANTES were analyzed (ELISA) in nasal lavage (NAL) fluids. All patients developed severe symptoms of rhinitis at the height of the season, with increased numbers of eosinophils in the nasal mucosa (P<0.05) and in the circulation (P<0.05). At this time point, the number of circulating progenitors (P<0.05) and the NAL fluid level of GM‐CSF (P<0.05) were also increased. In contrast, there was no change in the NAL fluid levels of IL‐1β, IL‐3, IL‐6, or IL‐8. Neither IL‐5 nor RANTES could be detected in any of the NAL fluids. At the end of or after the season, there was no increase in nasal eosinophils or circulating eosinophils or progenitors (P>0.05). Ex vivo addition of GM‐CSF (10–100 U) increased the number of blood progenitors grown before (P<0.01) and after (P<0.05) the season, compared with during the season. The in vitro GM‐CSF responsiveness of progenitors may be related to whether or not these already have been stimulated endogenously by GM‐CSF. Taken together, our data thus suggest that GM‐CSF may play a role in vivo to increase production of eosinophilic progenitors in allergic airway disease.

Allergen-induced increase in nonspecific nasal reactivity is blocked by antihistamines without a clear-cut relationship to eosinophil influx

Antihistaminic compounds have been suggested to possess other properties besides H1-receptor antagonism. To evaluate whether two different antihistamines could inhibit local eosinophil infiltration and allergen-induced nonspecific nasal hyperreactivity, 15 subjects with seasonal allergic rhinitis participated in a double-blind, randomized, placebo-controlled study outside the pollen season. At steady-state levels of either 60 mg of terfenadine, twice daily, cetirizine, 10 mg once daily, or placebo, a nasal methacholine challenge was performed before and 24 hours after a nasal allergen challenge. The volume of the methacholine-induced nasal secretions was measured. The response to allergen was determined with a scoring technique. Cells from the nasal mucosal surface were harvested with the aid of a rhinobrush. Both antihistamines induced a similar (p less than 0.01) reduction in nasal symptoms after the allergen challenge compared with placebo. Both antihistamines inhibited the increased nonspecific nasal reactivity induced by methacholine 24 hours later (p less than 0.05). The allergen challenge induced an increase in surface eosinophils, which, however, appeared unaffected by any of the active treatments. Since histamine per se does not induce changes in nonspecific reactivity, we suggest that the antihistamines possess other properties besides being H1-receptor antagonists.

Natural exposure to Alternaria spores induces allergic rhinitis symptoms in sensitized children.

Allergic rhinitis is associated with exposure to inhaled allergens. Allergic sensitization to the fungus Alternaria is common, especially in warm climates, but the relevance of sensitization to Alternaria in the generation of rhinitis has not been elucidated. The aim of this study was to determine whether natural exposure to Alternaria induces rhinoconjuctivitis symptoms in Alternaria‐sensitized children. Symptoms of rhinoconjuctivitis in 132 atopic (measured by skin prick tests) children (aged 7–12 years) in inland New South Wales Australia were measured using parent‐completed questionnaires in summer and winter 1998. Airborne concentrations of Alternaria spores and grass pollen were measured throughout the study period using a Burkard volumetric trap. The relation between airborne concentrations of Alternaria spores and symptoms of rhinoconjunctivitis was examined using Wilcoxons matched pairs signed ranked test and generalized estimating equations. The proportion of children atopic to Alternaria reporting symptoms of rhinitis was significantly higher in the summer, when airborne concentrations of Alternaria were high, than in the winter, when airborne concentrations were low (66.2% vs. 38.2% for nasal symptoms at night, p = 0.0001, 70.6% vs. 51.52% for nasal symptoms during the day, p = 0.02). The proportion of children using anti‐allergic treatment was also higher in summer than in winter (anti‐allergic medication for the nose 39.7% vs. 17.7%, p = 0.0003). A strong correlation between airborne concentrations of grass pollen and Alternaria was found (R = 0.94, p < 0.001). However, when all children atopic to ryegrass were excluded from the analyses, significant associations between symptoms and season remained. We conclude that exposure to Alternaria spores may be an important cause of allergic rhinoconjunctivitis.

Effects of orally inhaled budesonide in seasonal allergic rhinitis

It has previously been demonstrated that topical nasal treatment with glucocorticosteroids has significant effects on the bronchial airways. Less is known about effects on nasal disease by topical bronchial treatment with these drugs. The present study examined effects on nasal allergic disease of inhaled budesonide (avoiding nasal deposition of the drug). Patients with seasonal allergic rhinitis, but without asthma, were thus given inhalations of budesonide (600 microg b.i.d.) or placebo. The aim of the design was to allow the study of eosinophilic airway disease in a part of the airway other than the directly treated locus. Moderate to high birch pollen levels were recorded during the study season, and nasal symptoms were significantly increased in both treatment groups, although they were milder in patients receiving budesonide than in the placebo group (p<0.05). Nasal brush eosinophils and nasal lavage fluid levels of eosinophil cationic protein as well as blood eosinophils were increased during the season (p<0.05), but these increases were prevented by the inhaled budesonide. Nasal lavage fluid levels of alpha2-macroglobulin were particularly elevated in the placebo group but did not differ between patients receiving placebo and budesonide. Budesonide prevented the seasonal development of increased bronchoconstrictor responses to methacholine challenge (p<0.05). In conclusion, budesonide reduced the seasonal eosinophilia both in the circulation and in the nose along with an attenuation of seasonal nasal symptoms. Hence, at a daily dose of 600 microg b.i.d., known to cause no, or minimal, adverse effects, inhaled budesonide produces clinically significant anti-inflammatory effects in the entire airways, including the nasal mucosa, which is not exposed topically to the drug. We suggest that nasal and systemic anti-eosinophil actions are produced at commonly employed dose levels of orally inhaled budesonide.