Article

Nose and lung cross‐talk in allergic airways disease

Authors:
  • Franciscus Gasthuis en Vlietland
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

Allergic rhinitis and asthma are two manifestations of the atopic syndrome. Allergic rhinitis often coexists with, and may even precede, allergic asthma. Both diseases are characterized by a similar inflammatory process in which mast cells and eosinophils are major effector cells. To date, however, interaction between the upper and lower airways' inflammatory processes has not been demonstrated. Allergen provocation studies provide a good model to analyse the aspects of naso-bronchial cross-talk. We performed segmental bronchial provocation (SBP) and nasal provocation (NP) in seasonal allergic rhinitis patients without asthma. In allergic rhinitis patients, SBP as well as NP induced allergic inflammation in both nasal and bronchial mucosa. Furthermore, allergen provocation resulted in an increase in circulating inflammatory cells and mediators. Although the clinical response was more severe after SBP, allergic rhinitis patients developed pulmonary symptoms and decreased airway function after NP as well. These studies demonstrate that allergic rhinitis is not a local disease, but that the entire respiratory tract is involved even in the absence of clinical asthma. The systemic pathway, involving bloodstream and bone marrow, contributes to the cross-talk between upper and lower airways.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... In Spain, rhinitis affects 22% of the population (3) , while asthma is found in 7% (4) . Approximately 70-80% of all asthmatics have concomitant rhinitis, and recent studies point out that rhinitis is a predisposing factor for the development of asthma (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) . Chronic inflammation of the respiratory mucosa in rhinitis and asthma is characterized by the participation of a similar network of inflammatory cells and mediators (6,15) , and with similar triggering factors (16) . ...
... Both disorders share the same pathophysiological mechanisms mainly characterized by the presence of chronic inflammation of the respiratory mucosa, with participation of a similar network of inflammatory cells and mediators (17) . Nasal provocation, as well as segmental bronchial provocation in non-asthmatic seasonal rhinitis patients induces eosinophilic inflammation in both bronchial and nasal mucosa, with the consequence of respiratory symptoms (18) . It therefore, makes sense that treatment of one respiratory tract segment may influence the other, and that rhinitis treatment may influence the course of asthma. ...
Article
Full-text available
Rhinitis and asthma are linked by common epidemiological, clinical and inflammatory features. The objective of the AIR study was to understand the prevalence and characteristics of rhinitis in adult asthmatic patients who were seen in either primary or secondary care (Allergy or Pulmonology) in Spain. This was a prospective epidemiological study with the participation of 1,369 randomly selected physicians. Five thousand six hundred sixteen asthmatic patients older than 18 years of age were selected and the study was carried out between February-September 2006. Demographic data, rhinitis prevalence, pulmonary function, allergy tests and treatments were analyzed. Some 75% (N=4,212) of the asthmatic patients presented with additional rhinitis and these were characterised as being both younger (41.3 vs 50.4 years; p<0.0001) and with less severe asthma (FEV(1)=86.6 vs 79.3%, p<0.0001) than asthmatic patients without rhinitis. A positive correlation was found between asthma and rhinitis severity (p<0.0001) whilst atopy was significantly associated with the presence of rhinitis (81 vs 48%; OR: 4.80; CI 95%: 4.2-5.5). The presence of co-morbid rhinitis was associated with a higher number of asthma exacerbations (p<0.001). Some 75% of our asthmatic patients had associated rhinitis and this association was more frequent in atopic subjects. There is a positive correlation between the severity of rhinitis and asthma and between the number of asthma exacerbations and the presence of rhinitis. These results support the main message of ARIA and GEMA recommendations regarding the integral management of airways to improve the control of asthma.
... In Spain, rhinitis affects 22% of the population (3) , while asthma is found in 7% (4) . Approximately 70-80% of all asthmatics have concomitant rhinitis, and recent studies point out that rhinitis is a predisposing factor for the development of asthma (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) . Chronic inflammation of the respiratory mucosa in rhinitis and asthma is characterized by the participation of a similar network of inflammatory cells and mediators (6,15) , and with similar triggering factors (16) . ...
... Both disorders share the same pathophysiological mechanisms mainly characterized by the presence of chronic inflammation of the respiratory mucosa, with participation of a similar network of inflammatory cells and mediators (17) . Nasal provocation, as well as segmental bronchial provocation in non-asthmatic seasonal rhinitis patients induces eosinophilic inflammation in both bronchial and nasal mucosa, with the consequence of respiratory symptoms (18) . It therefore, makes sense that treatment of one respiratory tract segment may influence the other, and that rhinitis treatment may influence the course of asthma. ...
Article
Full-text available
Rhinitis and asthma share epidemiological, pathophysiological, and clinical features. The aim of the RINOASMAIR study was to examine the prevalence and characteristics of rhinitis in asthmatics in a Primary Care setting in Spain. A prospective epidemiological study was conducted with the participation of 1,027 Primary Care Physicians (PCP). A total of 4,174 asthmatics were included and demographic data, rhinitis prevalence, lung function, atopy, and rhinitis treatment were analysed. 71% of asthmatics suffered from rhinitis, these being younger (42.8 vs 50.2 yr; p<0.0001) and having milder asthma (FEV1=80.2% vs 76.1%, p<0.002) than those with-out rhinitis. A significant correlation (Rho=0.35, p<0.0001) between asthma and rhinitis severities was found. Atopy was associated to rhinitis, 77.8% of atopic compared to 47.6% of non atopic having rhinitis. Most asthmatics (71%) visited by Spanish PCP suffer from rhinitis, and these patients are younger and have milder asthma than asthmatics without rhinitis.
... Están ligadas por una epidemiología, clínica y mecanismo inflamatorio común e interrelacionados de la vía respiratoria alta y baja 1 . La rinitis afecta a un 22% de la población española y el asma a un 7%. ...
... Nasal surgeries and air pollutions nowadays are modern life sequels that invoke irritant stress on the nasal mucosa due to altered energy dissipation and direct chemical contaminations (1)(2)(3)(4). A wide-variety of sensory innervations inside nasal cavities and coexistence of different receptors in the nasal mucosa are well documented. ...
Article
Full-text available
Nasal mucosa has an extraordinary nerve supply with unique geometry that encompasses complex physiology. Among these, side-specific predilections to the respiratory and autonomic centers are the interesting issues that have been raised about the consequences of the nasal irritations. The aim of the study was an evaluation of how intranasal stimulation influences lung mechanics and determines whether unilateral stimulation produces side-specific partitioning responses. Tracheotomized-paralyzed rats received unilateral air-puff stimulation. Inspiratory pressure- volume (P-V) curve was obtained. Low frequency forced oscillation technique (FOT) was used to detect changes in central and peripheral airways. Mean airway pressure significantly increased to >10 cmH2O in the presence of 5cmH2O of positive end-expiratory pressure. Elastance was significantly changed, and significant higher airway resistance (Raw) and lower reactance (Xrs) were noticed in peripheral airways following different side of stimulation. Calculated inspiratory P-V curve showed significant deviations in transitional, rising and maximal pressures following stimulations. Transitional left-side shifting was observed following right side stimulation, whereas left side stimulation shifted the curve to the right. May be altered respiratory mechanics is the consequences of bimodal pressure-volume relationships observed in central and peripheral airways following nasal stimulation.
... Both conditions are characterized by inflammation of the respiratory mucosa and are associated with the same inflammatory cells and mediators [19,20]. Nasal provocation as well as segmental bronchial provocation in non-asthmatic, seasonal AR patients induced inflammation in both bronchial and nasal mucosa, and produced pulmonary symptoms and decreased airway function [21]. It is therefore meaningful to study health outcomes in patients with both conditions. ...
Article
Background Inadequately controlled allergic rhinitis (AR) in asthmatic patients can contribute towards increased asthma exacerbations and poorer symptom control, which may increase medical resource use. We assessed asthma-related medical resource use and attacks in asthmatic patients who did and did not have concomitant AR and were adding montelukast or salmeterol to baseline treatment with inhaled fluticasone.Methods A post hoc resource use analysis of a 52-week, double-blind multicentre clinical trial (IMPACT: IMProving Asthma Control Trial) including 1490 adults with chronic asthma, aged 15–72 years, with FEV1 50–90% of predicted and 12% increase in FEV1 after salbutamol administration, treated with either montelukast 10 mg daily or salmeterol 50 μg twice daily in addition to fluticasone 200 μg, was undertaken. Asthma-related medical resource use included medical visits (defined as either an unscheduled visit [to a general practitioner, a specialist or a non-medical provider] or a specialist visit), emergency room visits and hospitalizations during follow-up. Asthma attacks were defined as the worsening of asthma requiring unscheduled visit, emergency visit, hospitalization or oral/intravenous/intramuscular corticosteroids.Results A self-reported history of concomitant AR was identified in 60% of the patients (n=893). Univariate analysis suggests that significantly more patients with concomitant AR experienced emergency room visits (3.6% vs. 1.7%, P=0.029) and asthma attacks (21.3% vs. 17.1%, P=0.046). Multivariate analysis adjusting for treatment group, age and baseline asthma severity confirmed these results since the presence of concomitant AR in patients with asthma increases the likelihood of emergency room visit (odds ratio (OR)=2.35, 95% confidence interval (CI)=1.12–4.80) and asthma attack (OR=1.35, 95% CI=1.03–1.77). Patients with asthma alone compared with patients with both conditions did not differ in terms of unscheduled or specialist visits and hospitalizations.Conclusions Presence of self-reported concomitant AR in patients with asthma resulted in a higher rate of asthma attacks and more emergency room visits compared with asthma patients without concomitant AR.
... Están ligadas por una epidemiología, clínica y mecanismo inflamatorio común e interrelacionados de la vía respiratoria alta y baja 1 . La rinitis afecta a un 22% de la población española y el asma a un 7%. ...
... Comparten los mismos mecanismos fisiopatológicos que caracterizan la inflamación crónica de la mucosa respiratoria, en la que participan las mismas células inflamatorias y los mismos mediadores 16 . La provocación nasal y la provocación segmentaria bronquial en pacientes no asmáticos con rinitis estacional inducen la inflamación eosinofílica tanto en la mucosa bronquial como en la nasal, con síntomas respiratorios 17 . Por lo tanto, tiene sentido que el tratamiento sobre un tramo de la vía respiratoria influya sobre el otro y estudiar el efecto del tratamiento de la rinitis sobre la evolución del asma. ...
Article
Full-text available
Objective Rhinitis and asthma share an inflammatory mechanism, epidemiological patterns, and symptoms that affect both the nose and the bronchi. The RINAIR study examined the prevalence and characteristics of rhinitis in asthma patients in Spain. Patients and methods This prospective epidemiological study was carried out with the participation of 15% of Spanish respiratory medicine specialists sampled randomly from different geographic areas. The study population was composed of 703 asthmatic patients aged over 16 years who were enrolled between February and September 2005. Patient characteristics, prevalence of rhinitis, lung function, allergy test results, and treatment of rhinitis were analyzed. Results Seventy-one percent (n=499) of the asthmatic patients had rhinitis. These patients were younger (43.8 years vs 55.4 years; P<.0001) and had less severe asthma (forced expiratory volume in 1 second [FEV1], 85.7% vs 79.7% [P<.001]) than asthmatic patients who did not have rhinitis. A correlation was observed between the severity of asthma and the severity of rhinitis (P<.001). Atopy was significantly associated with rhinitis (odds ratio, 6.25; 95% confidence interval, 4.3-9.1): 84% of atopic patients and 51% of nonatopic patients had rhinitis. Treatment of rhinitis was associated with an increase in FEV1 (P=.057), irrespective of sex, age, severity of asthma, or smoking. Conclusions Seventy-one percent of asthmatic patients who attended respiratory medicine clinics had rhinitis. These patients were younger and had milder asthma than asthmatics who did not have rhinitis. Furthermore, atopy was correlated with asthma associated with rhinitis. Treatment of rhinitis led to improved lung function. These findings highlight the need to study and treat the upper and lower respiratory tract as a single airway.
... Allergy is a systemic disease with a local response following allergen exposure. Rhinitis, asthma and Bronchial Hyperresponsiveness (BHR) are closely related and a systemic pathway, involving the bloodstream and bone marrow, contributing to the cross-talk between the upper and lower airways [1]. The close relationship between allergic rhinitis and allergic asthma and the co-morbidity of upper and lower airway diseases has been carefully described elsewhere234. ...
Article
Full-text available
Allergen Specific Immunotherapy (SIT) for respiratory allergic diseases is able to significantly improve symptoms as well as reduce the need for symptomatic medication, but SIT also has the capacity for long-term clinical effects and plays a protective role against the development of further allergies and symptoms. The treatment acts on basic immunological mechanisms, and has the potential to change the pathological allergic immune response. In this paper we discuss some of the most important achievements in the documentation of the benefits of immunotherapy, over the last 2 decades, which have marked a period of extensive research on the clinical effects and immunological background of the mechanisms involved. The outcome of immunotherapy is described as different levels of benefit from early reduction in symptoms over progressive clinical effects during treatment to long-term effects after discontinuation of the treatment and prevention of asthma. The efficacy of SIT increases the longer it is continued and immunological changes lead to potential long-term benefits. SIT alone and not the symptomatic treatment nor other avoidance measures has so far been documented as the therapy with long-term or preventive potential. The allergic condition is driven by a subset of T-helper lymphocytes (Th2), which are characterised by the production of cytokines like IL-4, and IL-5. Immunological changes following SIT lead to potential curative effects. One mechanism whereby immunotherapy suppresses the allergic response is through increased production of IgG4 antibodies. Induction of specific IgG4 is able to influence the allergic response in different ways and is related to immunological effector mechanisms, also responsible for the reduced late phase hyperreactivity and ongoing allergic inflammation. SIT is the only treatment which interferes with the basic pathophysiological mechanisms of the allergic disease, thereby creating the potential for changes in the long-term prognosis of respiratory allergy. SIT should not only be recognised as first-line therapeutic treatment for allergic rhinoconjunctivitis but also as secondary preventive treatment for respiratory allergic diseases.
... Comparten los mismos mecanismos fisiopatológicos que caracterizan la inflamación crónica de la mucosa respiratoria, en la que participan las mismas células inflamatorias y los mismos mediadores 16 . La provocación nasal y la provocación segmentaria bronquial en pacientes no asmáticos con rinitis estacional inducen la inflamación eosinofílica tanto en la mucosa bronquial como en la nasal, con síntomas respiratorios 17 . Por lo tanto, tiene sentido que el tratamiento sobre un tramo de la vía respiratoria influya sobre el otro y estudiar el efecto del tratamiento de la rinitis sobre la evolución del asma. ...
Article
Full-text available
Rhinitis and asthma share an inflammatory mechanism, epidemiological patterns, and symptoms that affect both the nose and the bronchi. The RINAIR study examined the prevalence and characteristics of rhinitis in asthma patients in Spain. This prospective epidemiological study was carried out with the participation of 15% of Spanish respiratory medicine specialists sampled randomly from different geographic areas. The study population was composed of 703 asthmatic patients aged over 16 years who were enrolled between February and September 2005. Patient characteristics, prevalence of rhinitis, lung function, allergy test results, and treatment of rhinitis were analyzed. Seventy-one percent (n=499) of the asthmatic patients had rhinitis. These patients were younger (43.8 years vs 55.4 years; P< .0001) and had less severe asthma (forced expiratory volume in 1 second [FEV1], 85.7% vs 79.7% [P< .001]) than asthmatic patients who did not have rhinitis. A correlation was observed between the severity of asthma and the severity of rhinitis (P< .001). Atopy was significantly associated with rhinitis (odds ratio, 6.25; 95% confidence interval, 4.3-9.1): 84% of atopic patients and 51% of nonatopic patients had rhinitis. Treatment of rhinitis was associated with an increase in FEV1 (P=.057), irrespective of sex, age, severity of asthma, or smoking. Seventy-one percent of asthmatic patients who attended respiratory medicine clinics had rhinitis. These patients were younger and had milder asthma than asthmatics who did not have rhinitis. Furthermore, atopy was correlated with asthma associated with rhinitis. Treatment of rhinitis led to improved lung function. These findings highlight the need to study and treat the upper and lower respiratory tract as a single airway.
... 23 Hay fever, asthma and BHR are closely related and a systemic pathway, involving bloodstream and bone marrow, contributes to the cross-talk between upper and lower airways. 24 This is important for the diagnosis of the allergic patient and the choice between the various combinations of treatments available. 25 How closely these different symptoms interrelate remains to be described, although it seems that the more knowledge obtained from epidemiological surveys, the closer the connection between upper and lower airway diseases appears to be. ...
Article
Inadequately controlled allergic rhinitis (AR) in asthmatic patients can contribute towards increased asthma exacerbations and poorer symptom control, which may increase medical resource use. We assessed asthma-related medical resource use and attacks in asthmatic patients who did and did not have concomitant AR and were adding montelukast or salmeterol to baseline treatment with inhaled fluticasone. A post hoc resource use analysis of a 52-week, double-blind multicentre clinical trial (Investigation of Montelukast as a Partner Agent for Complementary Therapy) [corrected] including 1490 adults with chronic asthma, aged 15-72 years, with FEV(1) 50-90% of predicted and > or =12% increase in FEV(1) after salbutamol administration, treated with either montelukast 10 mg daily or salmeterol 50 microg twice daily in addition to fluticasone 200 microg, was undertaken. Asthma-related medical resource use included medical visits (defined as either an unscheduled visit [to a general practitioner, a specialist or a non-medical provider] or a specialist visit), emergency room visits and hospitalizations during follow-up. Asthma attacks were defined as the worsening of asthma requiring unscheduled visit, emergency visit, hospitalization or oral/intravenous/intramuscular corticosteroids. A self-reported history of concomitant AR was identified in 60% of the patients (n=893). Univariate analysis suggests that significantly more patients with concomitant AR experienced emergency room visits (3.6% vs. 1.7%, P=0.029) and asthma attacks (21.3% vs. 17.1%, P=0.046). Multivariate analysis adjusting for treatment group, age and baseline asthma severity confirmed these results since the presence of concomitant AR in patients with asthma increases the likelihood of emergency room visit (odds ratio (OR)=2.35, 95% confidence interval (CI)=1.12-4.80) and asthma attack (OR=1.35, 95% CI=1.03-1.77). Patients with asthma alone compared with patients with both conditions did not differ in terms of unscheduled or specialist visits and hospitalizations. Presence of self-reported concomitant AR in patients with asthma resulted in a higher rate of asthma attacks and more emergency room visits compared with asthma patients without concomitant AR.
Article
Asthma (A) and allergic rhinitis (AR) are common conditions with evidence of shared epidemiological and patho-physiological backgrounds. A systematic review of the literature in the last three decades was performed to summarize both the prevalence and the economic burden of concomitant AR in adult patients with asthma. The reported prevalence estimates of concomitant AR in patients with asthma in the United States and in Europe studies is in excess of 50%, with up to 100% prevalence reported in patients with allergic asthma. In these populations, asthma-related medical resource use, including asthma attacks, emergency room visits, physician visits, and prescription medication use, is higher among asthmatic patients with concomitant AR compared to those without AR. These patients also experience more frequent absence from work and decreased productivity. A low prevalence (6.2%) of comorbid AR in people with asthma has been reported in a single study from Asia. A combined treatment strategy as recommended by international guidelines may improve asthma outcomes in asthmatic patients with concomitant AR.
Article
This article reviews recent findings concerning occupational upper airway diseases, which, although very frequent, are usually not considered serious. However, the concept of the 'united airway', evoked during recent years, should change our attitude regarding these diseases. Moreover, new agents in the occupational environment must be characterized. Furthermore, exposure to carcinogens has changed over the years, and in most cases risk should be reassessed. Recent findings concerning work-related upper airway diseases caused by allergens and irritants, and their relationship to lower airway diseases, are reviewed. Findings of studies aimed at characterizing occupational allergens of plant and animal origin are presented. Recognition of work-related upper airway diseases both in clinic and in epidemiological studies is discussed. Current evidence on occupational cancer of the upper airways, its risk factors and changes in them over the years resulting from preventative measures are also described. There is significant evidence that occupational allergic diseases of the upper airways can pose important health problems because they represent an early stage of allergy throughout the respiratory system. However, how to detect those rhinitic patients who will develop asthma remains unresolved. New occupational health problems due to irritants were recently reported, and both follow-up studies and evaluations of their implications for the lower airways are warranted. Although preventative measures have been effective to some extent, risk for occupational cancer of the upper airways persists and more targeted epidemiological studies in this area are needed.
Article
Several studies have provided evidence of a strong association between asthma and rhinitis, with consequences in terms of therapy and disease management. The aims of our study were to evaluate physicians' knowledge about rhinitis/asthma comorbidity, to note the patients' management behaviour and to assess the patients' experience about symptoms and expectations, and to investigate the clinical and psychological meaning of general practitioners' and patients' awareness. One hundred and one general practitioners and 504 asthmatic patients participated in the study. General practitioners and patients filled in two different multiple choice questionnaires concerning asthma-rhinitis link and impact. 34.7% of general practitioners are aware of the link between asthma and rhinitis, and 43.6% of them hypothesize the comorbidity on the basis of their clinical experience. 21.8% of physicians make the diagnosis autonomously. 27.8% of asthmatic patients experience three or less rhinitic symptoms, 41% from four to six symptoms and 31.2 more than six symptoms. These symptoms deeply interfere with daily life, causing sleep problems (87.3%), lack of concentration (78.9%), difficulties in spare time (71.8%) and sport (71.7%). Rhinitis symptoms are responsible for the worsening of asthma, with an increase in dyspnoea (86.3%), cough (73.9%), and wheezing (59%). Ninety-three percent of patients expressed an interest in a combination therapy approach. Asthma and rhinitis interact in the development of clinical burden and impact on quality of life. The survey results showed different perspectives when evaluated from clinical and psychological points of view.
Article
The purpose of this review is to describe the scientific evidence that specific immunotherapy can prevent the development of asthma in patients suffering from rhinoconjunctivitis as well as reduce the number of new allergies developing. Proposed strategies for the prevention of the development of allergic rhinoconjunctivitis and asthma include allergen avoidance, pharmacological treatment (antihistamines and steroids) and specific immunotherapy. Long-term follow-up on immunotherapy studies demonstrates that specific immunotherapy for 3 years shows persistent long-term effects on clinical symptoms after termination of treatment and long-term, preventive effects on later development of asthma in children with seasonal rhinoconjunctivitis. It is so far the only treatment for allergic diseases that has been shown to be able to prevent worsening of disease and development of asthma. Also, specific immunotherapy seems to reduce the development of new allergic sensitivities as measured by the skin prick test as well as specific IgE measurements. Specific immunotherapy is the only treatment that interferes with the basic pathophysiological mechanisms of the allergic disease and thereby carries the potential for changes in the long-term prognosis of respiratory allergy. Specific immunotherapy should be recognized not only as first-line therapeutic treatment for allergic rhinoconjunctivitis, but also as secondary preventive treatment for respiratory allergic diseases.
Article
Full-text available
The CC-chemokine eotaxin is a potent eosinophil chemoattractant that stimulates recruitment of eosinophils from the blood to sites of allergic inflammation. Mobilization from the bone marrow is an important early step in eosinophil trafficking during the allergic inflammatory response. In this paper we examine the potential of eotaxin to mobilize eosinophils and their progenitors from bone marrow. Eotaxin stimulated selective, dose-dependent chemotaxis of guinea pig bone marrow eosinophils in vitro. Intravenous injection of eotaxin (1 nmol/kg) into guinea pigs in vivo stimulated a rapid blood eosinophilia (from 3.9 ± 1.2 to 28 ± 9.9 × 104eosinophils/mL at 30 minutes) and a corresponding decrease in the number of eosinophils retained in the femoral marrow (from 9.0 ± 0.8 to 4.8 ± 0.8 × 106 eosinophils per femur). To show a direct release of eosinophils from the bone marrow an in situ perfusion system of the guinea pig femoral bone marrow was developed. Infusion of eotaxin into the arterial supply of the perfused femoral marrow stimulated a rapid and selective release of eosinophils into the draining vein. In addition, eotaxin stimulated the release of colony-forming progenitor cells. The cytokine interleukin-5 was chemokinetic for bone marrow eosinophils and exhibited a marked synergism with eotaxin with respect to mobilization of mature eosinophils from the femoral marrow. Thus, eotaxin may be involved in both the mobilization of eosinophils and their progenitors from the bone marrow into the blood and in their subsequent recruitment into sites of allergic inflammation.
Article
Full-text available
Objective: To estimate trends between 1972-6 and 1996 in the prevalences of asthma and hay fever in adults. Design: Two epidemiological surveys 20 years apart. Identical questions were asked about asthma, hay fever, and respiratory symptoms at each survey. Setting: Renfrew and Paisley, two towns in the west of Scotland. Subjects: 1477 married couples aged 45-64 participated in a general population survey in 1972-6; and 2338 offspring aged 30-59 participated in a 1996 survey. Prevalences were compared in 1708 parents and 1124 offspring aged 45-54. Main outcome measures: Prevalences of asthma, hay fever, and respiratory symptoms. Results: In never smokers, age and sex standardised prevalences of asthma and hay fever were 3.0% and 5.8% respectively in 1972-6, and 8.2% and 19.9% in 1996. In ever smokers, the corresponding values were 1.6% and 5.4% in 1972-6 and 5.3% and 15.5% in 1996. In both generations, the prevalence of asthma was higher in those who reported hay fever (atopic asthma). In never smokers, reports of wheeze not labelled as asthma were about 10 times more common in 1972-6 than in 1996. With a broader definition of asthma (asthma and/or wheeze), to minimise diagnostic bias, the overall prevalence of asthma changed little. However, diagnostic bias mainly affected non-atopic asthma. Atopic asthma increased more than twofold (prevalence ratio 2.52 (95% confidence interval 1.01 to 6.28)) whereas the prevalence of non-atopic asthma did not change (1.00 (0.53 to 1.90)). Conclusion: The prevalence of asthma in adults has increased more than twofold in 20 years, largely in association with trends in atopy, as measured indirectly by the prevalence of hay fever. No evidence was found for an increase in diagnostic awareness being responsible for the trend in atopic asthma, but increased awareness may account for trends in non-atopic asthma.
Article
Full-text available
We do not have an estimate of how much tissue is needed for a reliable measure of bronchial epithelial reticular basement membrane (RBM) thickness or for counts of inflammatory cells. An assessment of the frequency distribution and variance of data from repeat measurements of RBM thickness and biopsy section inflammatory cell counts in cases with asthma (n=6), chronic obstructive pulmonary disease (COPD; n=5), and normal healthy subjects (n=7) was made. Tissue sections were stained with haematoxylin and eosin or by immunohistochemistry for EG2, mast cell tryptase and CD3-positive cells. Measurements of RBM thickness in individuals followed a log-normal distribution. For a precision of approximately +/-15%, 31-45 measurements were required. In contrast, inflammatory cell counts for each individual did not follow a normal distribution. There was high variance such that the cumulative weighted mean did not become stable until at least 5-10 mm of tissue underlying the RBM had been included. In conclusion multiple measurements of reticular basement membrane thickness or tissue section cell counts should be made for each individual in studies of bronchial biopsies. It is recommended that reticular basement membrane thickness should be measured at 20 mm intervals over a 1 mm reticular basement membrane length and that a zone beneath it of at least 5-10 mm of reticular basement membrane should be included for counts of inflammatory cells.
Article
Full-text available
Increases in bone-marrow (BM) inflammatory cell progenitors are associated with allergen-induced airway hyperresponsiveness and inflammation in asthmatics and dogs. Here, for the first time, we compare the time course of airway hyperresponsiveness, inflammation, and marrow progenitor responses in a mouse model of airway allergen challenge. Sensitized BALB/c mice were studied at 2, 12, 24, 48, and 72 h after intranasal ovalbumin or saline challenges. Outcome measurements included airway responsiveness, airway inflammation as assessed via bronchoalveolar lavage (BAL) and lung tissue sections, and BM eosinophil colony-forming units (Eo-CFU) as enumerated using a semisolid culture assay with optimal concentrations of interleukin-5. We observed significant increases in BAL fluid eosinophils, neutrophils, lymphocytes, and macrophages by 2 h after the second of two intranasal allergen challenges (P < 0.05). Significant increases in airway responsiveness or BM Eo-CFU were observed at 24 h and persisted until 48 h after the second challenge (P < 0.05). Airway inflammation, including eosinophils, persisted until at least 72 h (P < 0.05). We observed that allergen-induced airway eosinophilia is accompanied by increases in BM eosinophil progenitors, indicating that in this model, increased eosinophil production involves an expansion of the relevant stem-cell population. These findings support the use of this model to explore the mechanisms of increased eosinopoiesis observed in human asthma.
Article
Full-text available
In order to investigate the relationship between airways inflammation and disease severity, and improve the understanding of persistent asthma, 74 asthmatics, with disease severity ranging from intermittent, to mild to moderate and severe persistent (classified according to the Global Initiative for Asthma [GINA] guidelines), and 22 nonatopic control subjects were studied using the method of induced sputum. Sputum was analyzed for total and differential cell counts concentrations of albumin, and levels of eosinophil cationic protein (ECP), myeloperoxidase (MPO), and tryptase, inflammatory mediators reflecting eosinophil, neutrophil, and mast cell activation. Asthma severity (assessed by FEV(1), peak expiratory flow [PEF] variability, and daily symptom scores) and methacholine airways responsiveness were related to sputum eosinophilia and ECP. In addition, sputum neutrophilia and MPO levels correlated, albeit weakly, with PEF variability and symptom scores, respectively. Tryptase concentrations were raised in mild to moderate asthmatics. Albumin concentrations were significantly raised across the spectrum of asthma severity and correlated with those of tryptase and ECP. Despite treatment with either high doses of inhaled corticosteroids or oral corticosteroids, prominent eosinophilic inflammation with raised ECP was noted. This study points to persistent, disease severity-related airways inflammation in asthma, involving eosinophils, mast cells, and neutrophils, which is evident despite treatment with corticosteroids.
Article
Full-text available
Allergic rhinitis and asthma often coexist and share a genetic background. Pathophysiologic connections between the nose and lungs are still not entirely understood. This study was undertaken to compare allergic inflammation and clinical findings in the upper and lower airways after segmental bronchial provocation (SBP) in nonasthmatic allergic rhinitis patients. Eight nonasthmatic, grass pollen-sensitive patients with allergic rhinitis and eight healthy controls were included. Bronchial biopsies and blood samples were taken before (T(0)) and 24 h (T(24)) after SBP. Nasal biopsies were obtained at T(0), 1 h after SBP (T(1)), and T(24). Immunohistochemical staining was performed for eosinophils (BMK13), interleukin (IL)-5, and eotaxin. The number of eosinophils increased in the challenged and unchallenged bronchial mucosa (p < 0.05) and in the blood (p = 0.03) of atopic subjects at T(24). We detected an increase of BMK13-positive and eotaxin-positive cells in the nasal lamina propria and enhanced expression of IL-5 in the nasal epithelium of atopic subjects only at T(24) (p < 0.05). SBP induced nasal and bronchial symptoms as well as reductions in pulmonary and nasal function in the allergic group. No significant changes could be observed in healthy controls. The study shows that SBP in nonasthmatic allergic rhinitis patients results in peripheral blood eosinophilia, and that SBP can induce allergic inflammation in the nose.
Article
There have been few studies of the population prevalence of allergic rhinitis and atopic eczema, and although hundreds of asthma-prevalence studies have been done in various parts of the world, they have seldom used standard approaches. An exception is the European Community Respiratory Health Survey (ECRHS), 1–3 which involved surveys of asthma and allergic-rhinitis prevalence in adults aged 20–44 years in 48 centres in 22 countries, although only nine centres in six countries were outside of western Europe. The ECRHS suggested that there were regional risk factors for asthma and allergic rhinitis in western Europe, but it did not comprehensively assess the global patterns. For children, the largest standard studies of the prevalences of asthma, allergic rhinitis, or atopic eczema have involved at most four countries. 4–6 Thus, in some respects, the epidemiology of asthma and other allergic disorders is currently similar to that of cancer epidemiology in the 1950s and 1960s, when the international patterns of the incidence of cancer were studied. 7 These studies revealed striking international differences that gave rise to many new hypotheses, tested in further epidemiological studies that identified previously unknown risk factors for cancer. These risk factors may not have been in the hypotheses investigated if the initial international comparisons had been confined to few western countries. More specifically, Rose 8,9 has noted that whole populations may be exposed to risk factors for disease (eg, high exposure to house-dust-mite allergen) and the patterns may be apparent only when comparisons are made between, rather than within, populations. Therefore, we carried out systematic, standardised, international comparisons of the prevalence of asthma and allergies to generate new hypotheses and to investigate existing hypotheses in the International Study of Asthma and Allergies in Childhood (ISAAC). The detailed findings for the prevalence and severity of the symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema in children aged 6–7 years and 13–14 years will be reported elsewhere. Here, we give an overview of the findings for children aged 13–14 years (the age-group that was studied by all participating centres), assess the relationship between the findings for the three disorders, and discuss the potential for future ecological and case-control studies. Methods Phase one of the ISAAC programme 10 used a simple standard approach at minimum cost in as wide a range of centres and countries as possible, based on school populations to ensure Summary Background Systematic international comparisons of the prevalences of asthma and other allergic disorders in children are needed for better understanding of their global epidemiology, to generate new hypotheses, and to assess existing hypotheses of possible causes. We investigated worldwide prevalence of asthma, allergic rhinoconjunctivitis, and atopic.
Article
The independent association of individual allergen reactivity with respiratory disease was evaluated with use of the second National Health and Nutrition Examination Survey, a sample of the U.S. white civilian population, ages 6 to 24 years (n = 4295). Eight, 1:20 wt/vol, 50% glycerol, unstandardized extracts were administered by prick puncture. Allergen reactivity was reported as the percent with a mean erythema diameter 10.5 mm or greater at 20 minutes. Only the prevalence of asthma and allergic rhinitis increased with the increasing number of positive allergen skin tests. The independent association of individual allergen reactivity with respiratory disease was quantified with logistic models that included other allergen reactivity, age, sex, smoking, and region. Asthma was associated with reactivity to house dust (odds ratio, 2.9; 95% confidence interval [CI] 1.7 to 5) and Alternaria (odds ratio, 5.1; 95% CI: 2.9 to 8.9). Allergic rhinitis was associated with reactivity to ragweed (odds ratio, 2.3; 95% CI: 1.5 to 3.3); ryegrass (odds ratio, 2.8; 95% CI: 1.8 to 4.3); house dust (odds ratio, 2.5; 95% CI: 1.6 to 3.9); Alternaria (odds ratio, 2.3; 95% CI: 1.5 to 3.4). Asthma only (without allergic rhinitis) was associated with dust and Alternaria. Allergic rhinitis only (without asthma) was associated with ryegrass, ragweed, and house dust. When both asthma and allergic rhinitis were present, only house dust and Alternaria remained associated. These findings highlight the association of specific allergens with upper and lower respiratory diseases and the interactions among coexisting respiratory diseases.
Article
Background Systematic international comparisons of the prevalences of asthma and other allergic disorders in children are needed for better understanding of their global epidemiology, to generate new hypotheses, and to assess existing hypotheses of possible causes. We investigated worldwide prevalence of asthma, allergic rhinoconjunctivitis, and atopic. Methods We studied 463 801 children aged 13–14 years in 155 collaborating centres in 56 countries. Children self-reported, through one-page questionnaires, symptoms of these three atopic disorders. In 99 centres in 42 countries, a video asthma questionnaire was also used for 304 796 children. Findings We found differences of between 20-fold and 60-fold between centres in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema, with four-fold to 12-fold variations between the 10th and 90th percentiles for the different disorders. For asthma symptoms, the highest 12-month prevalences were from centres in the UK, Australia, New Zealand, and Republic of Ireland, followed by most centres in North, Central, and South America; the lowest prevalences were from centres in several Eastern European countries, Indonesia, Greece, China, Taiwan, Uzbekistan, India, and Ethiopia. For allergic rhinoconjunctivitis, the centres with the highest prevalences were scattered across the world. The centres with the lowest prevalences were similar to those for asthma symptoms. For atopic eczema, the highest prevalences came from scattered centres, including some from Scandinavia and Africa that were not among centres with the highest asthma prevalences; the lowest prevalence rates of atopic eczema were similar in centres, as for asthma symptoms. Interpretation The variation in the prevalences of asthma, allergic rhinoconjunctivitis, and atopic-eczema symptoms is striking between different centres throughout the world. These findings will form the basis of further studies to investigate factors that potentially lead to these international patterns.
Article
The CC-chemokine eotaxin is a potent eosinophil chemoattractant that stimulates recruitment of eosinophils from the blood to sites of allergic inflammation. Mobilization from the bone marrow is an important early step in eosinophil trafficking during the allergic inflammatory response. In this paper we examine the potential of eotaxin to mobilize eosinophils and their progenitors from bone marrow. Eotaxin stimulated selective, dose-dependent chemotaxis of guinea pig bone marrow eosinophils in vitro. Intravenous injection of eotaxin (1 nmol/kg) into guinea pigs in vivo stimulated a rapid blood eosinophilia (from 3.9 +/- 1.2 to 28 +/- 9.9 x 10(4) eosinophils/mL at 30 minutes) and a corresponding decrease in the number of eosinophils retained in the femoral marrow (from 9.0 +/- 0. 8 to 4.8 +/- 0.8 x 10(6) eosinophils per femur). To show a direct release of eosinophils from the bone marrow an in situ perfusion system of the guinea pig femoral bone marrow was developed. Infusion of eotaxin into the arterial supply of the perfused femoral marrow stimulated a rapid and selective release of eosinophils into the draining vein. In addition, eotaxin stimulated the release of colony-forming progenitor cells. The cytokine interleukin-5 was chemokinetic for bone marrow eosinophils and exhibited a marked synergism with eotaxin with respect to mobilization of mature eosinophils from the femoral marrow. Thus, eotaxin may be involved in both the mobilization of eosinophils and their progenitors from the bone marrow into the blood and in their subsequent recruitment into sites of allergic inflammation.
Article
Experimental studies have demonstrated that induction of a nasal allergic reaction can lead to an increase in bronchial responsiveness (BR). To assess the clinical relevance of these experimental changes to chronic asthma, we sought to determine the effect of nasal beclomethasone dipropionate (Bdp) on BR in patients with seasonal allergic rhinitis and asthma. Eighteen subjects with histories of seasonal allergic rhinitis and asthma during the fall pollen season with positive skin tests to short ragweed and bronchial hyperresponsiveness to inhaled methacholine were assigned to receive either nasal Bdp (336 micrograms/day) or placebo for the entire ragweed season. Patients recorded daily nasal and chest symptoms, nasal blockage index, oral peak expiratory flow rates, and supplemental medication use. BR to methacholine was measured during the baseline period and 6 weeks into the ragweed season. Although the Bdp group did have a significant improvement in nasal blockage index, there was no improvement in daily asthma symptom scores, oral peak expiratory flow, or asthma medication use. However, subjects treated with Bdp were protected from the increase in BR seen in the placebo group (geometric mean PC20 placebo group: baseline = 0.70, week 6 = 0.29; Bdp group: baseline = 0.80, week 6 = 0.93; intergroup difference, p = 0.022). We conclude that nasal corticosteroid therapy can prevent the increase in BR associated with seasonal pollen exposure in patients with allergic rhinitis and asthma.
Article
Mast cell degranulation is thought to be an important component of the pathogenesis of allergic rhinitis. Quantitative studies on mast cells in nasal mucosa after allergen exposure have given widely divergent results, ranging from an overall decrease via redistribution to an overall increase. We investigated this problem by employing a combination of anti-IgE and toluidine blue staining of biopsy specimens. In allergic patients anti-IgE was found to identify all mast cells and toluidine blue to detect mast cells that were not (totally) degranulated.
Article
We studied the role of atopy, as defined by positive skin tests to common inhalant allergens, in allergic bronchial inflammation. Endobronchial biopsies were taken via the fibreoptic bronchoscope in 13 symptomatic atopic asthmatics, 10 atopic nonasthmatics, and 7 normals. The numbers of mast cells, identified in the submucosa by immunohistochemistry using the AA1 monoclonal antibody against tryptase, were no different between the three groups, but electron microscopy showed that mast cell degranulation, although less marked in atopic nonasthmatics, was a feature of atopy in general. The numbers of eosinophils, identified by immunohistochemical staining using the monoclonal anti-eosinophil cationic protein antibody, EG2, were greatest in the asthmatics, low or absent in the normals and intermediate in the atopic nonasthmatics. In both atopic groups eosinophils showed ultrastructural features of degranulation. Measurements of subepithelial basement membrane thickness on electron micrographs showed that the collagen layer was thickest in the asthmatics, intermediate in the atopic nonasthmatics and thinnest in the normals. The results suggest that airways eosinophilia and degranulation of eosinophils and mast cells, as well as increased subepithelial collagen deposition, are a feature of atopy in general and suggest that the degree of change may determine the clinical expression of this immune disorder.
Article
The relationship between upper airway inflammation and asthma is controversial. In the current study, we sought to investigate the relationship between allergic rhinitis and lower airway dysfunction by performing double-blind, randomized nasal challenges with allergen or placebo. Subjects were selected for a prior history of asthma exacerbations after the onset of seasonal allergic rhinitis symptoms. After the induction of a marked nasal-allergic reaction (with a technique of nasal provocation that limited allergen delivery to the nose), there were no changes in FEV1, specific conductance, or lung volumes either 30 minutes or 4 1/2 hours after nasal allergen challenge, nor any changes in peak flow rates followed hourly until the next day. However, nasal provocation with allergen resulted in a relative increase in bronchial responsiveness to methacholine compared with that to placebo (p = 0.011 at 30 minutes and p = 0.0009 at 4 1/2 hours after challenge). Our study suggests that, although a nasal-allergic response does not induce airflow limitation of the lower airways, it can alter bronchial responsiveness.
Segmental antigen bronchoprovocation was used to define the nature of the inflammatory process in allergic airway disease. Bronchoalveolar lavage fluid obtained from allergic rhinitis patients 12 min after segmental antigen instillation (immediate response) revealed a significant increase in histamine and tryptase, but no cellular response. Repeat segmental lavage 48 h later (late response) showed marked and significant increases in both low and normal density eosinophils as well as striking elevations of eosinophil granular protein levels (major basic protein, eosinophil-derived neurotoxin, eosinophil cationic protein, and eosinophil peroxidase). Leukotriene C4, but not tryptase, concentrations were also consistently elevated in late lavage samples. Further, the late lavage samples showed a significant increase in interleukin-5 concentrations that correlated with the presence of eosinophils and eosinophil granular proteins. Neither eosinophils nor soluble mediators of eosinophils increased when normal subjects were similarly challenged with antigen. These data suggest that eosinophils are attracted to the airway during the late-phase allergic reaction and that IL-5 may produce changes in airway eosinophil density and promote the release of granular proteins to cause airway injury.
Article
Bronchial biopsy specimens were obtained by fiberoptic bronchoscopy from 21 atopic subjects with asthma, 10 atopic subjects without asthma, and 12 normal healthy control subjects. With immunohistochemical techniques and a panel of monoclonal antibodies, inflammatory cells were identified and counted in the bronchial mucosa. The mean number of leukocytes (CD45+) and T-lymphocytes (CD3+, CD4+, and CD8+) at two airway levels in the subjects with asthma tended to be higher than in the other groups, but this difference did not achieve statistical significance. Similarly, there were no significant differences in the numbers of mucosal-type or connective tissue-type mast cells, elastase-positive neutrophils, or Leu-M3+ cells in the airway mucosa of subjects with asthma compared with atopic subjects without asthma and healthy control subjects. In contrast, significantly more interleukin-2 receptor-positive (CD25+) cells and "activated" (EG2+) eosinophils (EOSs) were present in the airways of subjects with asthma at both proximal and subsegmental biopsy sites. When the relationships between numbers of T-lymphocytes, activated (CD25+) cells, and EOSs were analyzed, there were positive correlations between CD3 and EG2, between CD3 and CD25, and between CD25 and EG2 positive cells in the airways of subjects with asthma. Furthermore, the ratio of EG2+ to CD45+ cells correlated with the provocative concentration of methacholine that caused a 20% decrease of FEV1 in hyperresponsive subjects. Although these associations do not prove a causal relationship, the results support the hypothesis that activated (CD25) T-lymphocytes release products which regulate recruitment of EOSs into the airway wall. In addition, our findings suggest that, in the large airways at least, asthma is not associated with hyperplasia of either mucosal-type or connective tissue-type mast cell.
Controversy exists on whether stimulation of the nasal mucosa results in reflex bronchoconstriction. To address shortcomings in previous experimental design, we performed double-blind randomized nasal challenges in asthmatic patients with allergic rhinitis and in controls. Using pledgets containing 10-microliters aliquots of 0.9% saline or increasing concentrations of methacholine or histamine, we were able to increase nasal resistance significantly in both groups. Only methacholine caused an increase in lower airway resistance, and this could be blunted by premedication of the nasal mucosa with phenylephrine. This suggests that the effect on lower airway resistance was due to systemic absorption. Our study does not support the existence of a nasobronchial reflex from mechanical alteration of the nasal mucosa.
Over the past decade, it has become increasingly recognized that airways inflammation is one of the major components of asthma. Until recently, measurements of bronchial responsiveness and mediators of allergic reactions were the only methods of studying pathogenetic mechanisms in asthma. With improved diagnostic procedures such as fiberoptic bronchoscopy, it has become possible to investigate these mechanisms and the resulting inflammatory changes in situ. BAL has highlighted the presence of mast cells and eosinophils and has given proof of their mediator participation in airways inflammation and hyperresponsiveness. Endobronchial biopsies have so far yielded results that are similar to those obtained from postmortem studies, although it appears that there are varying degrees of inflammation in living asthmatics. Even in mild disease, the histopathologic features of bronchial asthma are consistent with chronic inflammation. Indirect evidence obtained from allergen challenge leading to increased bronchial hyperresponsiveness during LAR, and direct evidence of inflammatory cells and their mediators in the airway mucosa and lumen after allergen challenge argue for an active role of cells in bringing about inflammatory changes. At present, however, it is not possible to relate precisely the findings obtained by bronchoscopy to the clinical presentation and progression of asthma. Cell activation with production of potent mediators of inflammation may be more relevant to inflammation than the simple presence of these cells in the airways. Almost all the inflammatory cells present in the bronchial wall and lumen have been implicated in the pathogenesis of mucosal inflammation in asthma, but with our current state of knowledge, none can be singled out as the most important contributor. The mast cell was the first to be investigated in depth, and despite the accumulation of large amounts of data concerning its ultrastructure and function, it remains uncertain to what extent this cell is involved in inflammatory responses. Thus, while its main role appears to be that of initiator of allergen-induced responses, the eosinophil has attracted more attention as a proinflammatory cell rather than as an antiinflammatory cell with a capacity to be selectively recruited from the circulation in response to IgE-dependent signals. The eosinophil secretes potent mediators that cause damage to the bronchial epithelium and lead to bronchoconstriction. The role of other cells is at present not as well defined.(ABSTRACT TRUNCATED AT 400 WORDS)
Article
The importance of eosinophils in the pathogenesis of bronchial asthma is not established. In an attempt to evaluate the role of eosinophilic inflammation in asthma, we compared 10 normal subjects with 43 patients with chronic asthma, 19 of whom had severe disease as assessed by a clinical scoring method described by Aas and by pulmonary-function tests. Eosinophils were counted in peripheral blood and bronchoalveolar-lavage fluid, and in biopsy specimens obtained from the patients and post mortem from 8 subjects without asthma, but not from the 10 normal controls. Eosinophil cationic protein was titrated by radioimmunoassay in the bronchoalveolar-lavage fluid from all subjects and studied by immunohistochemistry in the biopsy specimens. There was a significant increase in the number of peripheral-blood eosinophils in the patients that was correlated with the clinical severity of asthma (P less than 0.001) and pulmonary function (P less than 0.03). Levels of eosinophils and eosinophil cationic protein were increased in the bronchoalveolar-lavage fluid from the patients and were also correlated with the severity of asthma (P less than 0.001 and P less than 0.002, respectively). Hematoxylin-eosin staining of bronchial-biopsy specimens showed that intraepithelial eosinophils were present only in patients with asthma. Immunohistochemical analysis of eosinophil cationic protein revealed that normal subjects had only a few nondegranulated eosinophils deep in the submucosa, whereas all the patients had degranulated eosinophils beneath the basement membrane and among epithelial cells. In some patients there was a relation between the presence of degranulated eosinophils and epithelial damage. Eosinophilic inflammation of the airways is correlated with the severity of asthma. These cells are likely to play a part in the epithelial damage seen in this disease.
Article
The frequent association of asthma and paranasal sinusitis has been ascribed to a nasobronchial reflex, aspiration of sinus secretions, or enhanced beta-adrenergic blockade. We investigated possible pulmonary aspiration in a pilot study (eight patients) and follow-up study (13 patients) by means of a radionuclide technique. In the pilot study, the aim was to demonstrate aspiration as well as visibility of the radionuclide in the thorax during a period of 24 hours. The radionuclide was initially placed bronchoscopically in the bronchial tree in four patients and was still clearly visible in the same position after 24 hours in three patients. Aspiration from the nasopharynx was unequivocally demonstrated in two of four patients with depressed consciousness. The follow-up study population consisted of four patients with maxillary sinusitis only and nine patients with sinusitis and asthma. The radionuclide was placed in a maxillary sinus during therapeutic puncture. In the patients with only sinusitis as well as patients with asthma and sinusitis the radionuclide could be demonstrated in the maxillary sinus, nasopharynx, esophagus, and lower gastrointestinal tract during a 24-hour period. However, no pulmonary aspiration of radionuclide could be demonstrated in any patient. We conclude that seeding of the lower airways by mucopurulent secretions is unlikely to account for coexistent pulmonary disease. The association is probably related to generalized mucosal disease affecting both upper and lower airways.
Article
Although three effective topical treatments for allergic rhinitis are available, little information to assist the clinician in choosing among them has been reported. Therefore, we conducted a randomized clinical trial to compare beclomethasone nasal solution, flunisolide, and cromolyn with placebo in 120 patients with hay fever during the ragweed season of 1984. We found that all three agents were superior to placebo (P less than 0.001) and that the glucocorticoids were more effective than cromolyn (P less than 0.001). Surprisingly, we also found that these intranasal treatments considerably reduced the symptoms of seasonal asthma. Further study of this therapeutic advantage is needed.
Article
Nasal deposition of allergen or histamine could cause bronchoconstriction in subjects with asthma by a reflex mechanism. To investigate this possibility, six atopic subjects with stable asthma and five normal control subjects were studied by nasal-challenge testing with saline, Bermuda grass-pollen allergen, and histamine on paper disks. Challenges were done on 3 separate days by use of a double-blind, randomized trial design. Fivefold serial dilutions were used to determine threshold doses for provocation of at least a twofold increase in the postsaline nasal airway resistance. No patient developed cough or wheezing or required treatment at the end of the nasal-challenge tests, even when persistent sneezing was provoked or in the subject who had a dual nasal response to nasal challenge. In spite of changes in nasal airway resistance that generally conformed to expectations, there were no significant effects of nasal challenge on lung function, including forced expiratory flow rates, vital capacity, residual volume, and partial expiratory flow-volume curves.
Article
In 27 asthmatic patients a single cold stimulus into the nose resulted in a sudden increase of airway resistance, measured continuously by a forced-oscillation technique. The effect could be blocked by previous intrabronchial application of an anticholinergic drug. In laryngectomised patients, who no longer have a connection between the upper and the lower airways, a cold stimulus into the nose also caused bronchoconstriction. So the cold effect must be based on a reflex mechanism.
Article
Although there are theoretical reasons to suggest that atopy might predispose to non-allergic bronchial hyperresponsiveness, previous studies have yielded conflicting results. We assessed this by determining the atopic status and bronchial responsiveness to inhaled histamine in 400 randomly selected college students. An atopy score was determined as the number of "+"s from a standard battery of seven allergy prick skin tests each graded from + to +, and the atopic status was graded as non-atopic (no +'s) mildly atopic (1 to 4 +'s), moderately atopic (5 to 8 +'s), or markedly atopic (greater than 8 +'s). Non-allergic bronchial responsiveness to inhaled histamine was measured with a standardized histamine inhalation test from which the histamine provocation concentration producing a 20% FEV1 fall (PC20) was calculated. The prevalence of bronchial hyperresponsiveness to histamine (PC20 less than or equal to 8 mg/ml) was 10.3% in the entire population. There was a progressive increase from 6.1% in the non-atopic group to 33% in the markedly atopic group (p less than 0.001). In 43 subjects with both measurable atopy score (greater than or equal to 1) and PC20 (less than or equal to 16 mg/ml), a regression of atopy score vs. log PC20 produced a small (r = -0.36) but significant (p less than 0.02) correlation. These data indicate a significant relationship exists between atopic status and increased non-allergic bronchial responsiveness to histamine. Although cause and effect cannot be inferred from this study, it is hypothesized that atopy is one factor, among others, which predisposes to non-allergic bronchial hyperresponsiveness.
Article
In both seasonal and perennial rhinitis there is epithelial mast cell accumulation and tissue infiltration by eosinophils. Activation of these cells can be observed by electron microscopy and by elevated levels of tryptase and eosinophil cationic protein in nasal lavage fluid. Furthermore, seasonal increases in the antigen presenting cell (Langerhans' cell) are also evident. Investigations into the mechanisms involved in cell accumulation and activation reveals upregulation of leucocyte endothelial adhesion molecules and an increase in interleukin-4 (IL-4) in naturally occurring rhinitis, while mRNA for IL-4, IL-5 and granulocyte macrophage colony stimulating factor activity and lavage tumour necrosis factor-alpha (TNF alpha) levels are increased following local allergen challenge. These cytokines may be derived from a variety of sources, including mast cells, eosinophils and T-lymphocytes, and contribute to the underlying inflammatory process in rhinitis.
Article
To determine whether the cessation of exposure to isocyanates is associated with structural changes of the airway wall in sensitized subjects, we studied bronchial biopsies from 10 subjects with occupational asthma induced by toluene diisocyanate (TDI). Bronchial challenges with TDI and methacholine were performed and biopsies were taken on two occasions, at diagnosis and 6 to 21 mo after cessation of exposure to TDI. After bronchoscopy, biopsies were formalin-fixed or snap-frozen in liquid nitrogen and then processed for a quantitative histochemical and immunohistochemical analysis. After cessation of exposure, we observed a significant decrease of the sensitivity to TDI (p < 0.05), of the thickness of subepithelial fibrosis (p < 0.007), and of the numbers of subepithelial fibroblasts (p < 0.05), mast cells (p < 0.02), and lymphocytes (p < 0.03) as compared with values at diagnosis. By contrast, the nonspecific bronchial hyperresponsiveness and the numbers of macrophages and eosinophils did not change. In conclusion, in patients with occupational asthma induced by TDI, the cessation of exposure to the sensitizing agent is associated with a reduced thickness of subepithelial fibrosis and with a reduced number of subepithelial fibroblasts, mast cells, and lymphocytes in the bronchial mucosa, suggesting a remodeling of the airway wall with the avoidance of the specific stimulus.
Article
To investigate cellular differentials in natural airway narrowing of steroid-dependent asthmatic individuals, we performed bronchoalveolar lavage (BAL) on 10 inpatients with asthma treated only with bronchodilators during episodes of natural airway narrowing evaluated by serial monitoring of peak expiratory flow (PEF), and on nine normal volunteers. We confirmed that the airway narrowing was not completely reversed by salbutamol aerosol just before the BAL study, but was completely reversed by administration of systemic steroid after the BAL study. Thus, the natural airway narrowing investigated in this study consisted not only of the constriction of airway smooth muscle, but also of edema of the airway mucosa and/or secretion in airways. Both the numbers and percentages of eosinophils and alcian blue-positive cells in BAL fluids from the asthmatic subjects were significantly higher than those of normals, but the numbers and percentages of neutrophils, lymphocytes, and macrophages were not. Thus, eosinophils and alcian blue-positive cells selectively increased in the airways during the natural airway narrowing. Because we found that the metachromatic cells consisted of two types, with a single nucleus and with segmented nuclei, we further examined basophil chemotactic activity (BCA) in BAL fluids. We showed that BCA was significantly higher in the asthmatic (79.3 +/- 17.2 cells/5 hpf) than in the normal subjects (6.2 +/- 1.6 cells/5 hpf), and also that the activity was more strongly correlated with the cells having segmented nuclei (p = 0.95) than with all of the cells (p = 0.73).(ABSTRACT TRUNCATED AT 250 WORDS)
Article
The tissue density of eosinophils and the degree of activation of eosinophils in the nasal mucosa of allergic and nonallergic rhinopathic patients were studied by a combination of the immunogold method, which uses EG2 antibody which binds to the secreted form of eosinophils, and the Luna method. The tissue density of eosinophils and the degree of EG2-positivity were higher in the allergic nasal mucosa than in the nonallergic nasal mucosa. The eosinophils in the tissue were mainly EG2-positive in contrast with those in the vessels. Epithelial shedding was rarely observed and was not related to the tissue density of eosinophils or EG2-positivity. Our results suggest that the eosinophils in the allergic nasal mucosa are activated in the tissue, not in the vessel.
Airway inflammation has emerged as an important contributor to mechanisms of asthma. Furthermore, the presence of airway inflammation is present even in the absence of severe symptoms. To study the mechanisms by which bronchial inflammation can occur in asthma, a number of models have been developed including the airway response to antigen in allergic subjects. The pattern that has emerged from such studies indicates prompt pulmonary mast-cell activation and the apparent initiation of an inflammatory response. This inflammatory response develops over hours and is important in the later and more persistent development of bronchial obstruction. The eosinophil is an important cell in this process as are proinflammatory cytokines generated from activated lung mononuclear cells. The consequence of this multiple cell, multiple proinflammatory product interaction is the establishment of a self-perpetuating, redundant process by which asthma severity increases.
Article
Eosinophils are thought to play an important role in the symptomatology and pathophysiology of allergic rhinitis. Most quantitative studies on eosinophils in nasal mucosa have focused on the dynamics of eosinophils in the acute and late phases of the allergic reaction by using different cell sampling techniques. Little is known about the dynamics of eosinophils during a more prolonged period of allergen exposure and the activation of eosinophils induced by allergen challenge. The aim of this study was to investigate the dynamics and activation of the eosinophils in the nasal mucosa of patients with an isolated grass pollen allergy during an out-of-season 2-week allergen exposure, mimicking the natural grass pollen season. Seventeen patients with isolated grass pollen allergy and four control subjects were challenged daily with the allergen during a 2-week period in the winter. Nasal brush specimens were obtained before provocation and each day during the provocation period. Biopsy specimens were obtained once before, six times during, and once after the provocation period. Preparations made of nasal brush and nasal biopsy specimens were stained with the monoclonal antibody BMK 13 and Giemsa stain as paneosinophil markers and with the monoclonal antibody EG2 to identify activated eosinophils. We found significant increases in the total number of eosinophils and the number of activated eosinophils in the epithelium and lamina propria. These increases were most explicit in the second week. BMK 13 was found to be a paneosinophil marker superior to Giemsa staining. Eosinophils are not only involved in the acute and late phases of the allergic reaction but are probably even more involved in the chronic phase.
Article
Allergy rhinitis results from an IgE-mediated allergy associated with nasal inflammation of variable intensity. The mechanisms of allergic rhinitis have been clarified using nasal challenge with allergen or proinflammatory mediators and measuring cells and mediators released during the early- and late-phase allergic reaction. However, the priming effect of the nasal mucosa is of importance since a single challenge does not perfectly mimic the ongoing allergic reactions induced by repeated allergen exposure. In seasonal and chronic allergic rhinitis, the same cells and mediators are of importance but nonspecific nasal hyperreactivity develops. The regulation of the inflammation of allergic rhinitis is dependent on adhesion molecules and cytokines.
Article
Fluticasone propionate aqueous nasal spray, a new topical corticosteroid, has been proved to be an effective treatment for seasonal allergic rhinitis. We studied the effect of fluticasone propionate on nasal symptoms, circulating eosinophils, and nasal inflammation in patients with seasonal allergic rhinitis after high-load pollen exposure. Moreover, we examined its efficacy in preventing the increase in bronchial responsiveness to methacholine (PD20) during the pollen season. We conducted a double-blind, placebo-controlled, parallel-group study in patients who had a history of allergic rhinitis in response to pollens of grass and Parietaria species and were living in northern Italy. After a run-in period of 2 weeks, 24 patients were treated with fluticasone propionate (200 micrograms, once daily), and 26 patients received matched placebo for 6 weeks, starting from the beginning of the pollen season. Assessment of efficacy was based on scores of daily nasal symptoms. Nasal lavage was performed at the end of the season, and differential cell count was expressed as percent of total cells. PD20 methacholine was measured at the beginning and end of the season and after the season had ended. Fluticasone propionate significantly reduced nasal obstruction, itching, and rhinorrhea. Eosinophils in blood (p < 0.01) and nasal lavage (p < 0.001) were also reduced. Moreover, fluticasone significantly attenuated the decrease in mean PD20 methacholine (from 1.95 to 0.89 mg) compared with placebo (from 1.38 to 0.37 mg: p < 0.01). After the season, no difference in PD20 methacholine was found between treatment groups. The results of this study indicate that fluticasone propionate is effective in decreasing nasal symptoms and eosinophil inflammation in patients with seasonal allergic rhinitis after high-load pollen exposure. Our results also demonstrate that treatment with fluticasone propionate partially prevents the increase in bronchial responsiveness provoked by the inhalation of seasonal pollens in allergic rhinitis.
Article
There have been many studies concerning pathological changes in bronchial mucosa from asthmatics; however, few studies has been carried out to evaluate pathological changes according to the severity of asthma. This study was designed to evaluate the cellular components in bronchoalveolar lavage fluid (BALF) and histological abnormalities in asthmatics according to the severity of asthma. Bronchoalveolar lavages, bronchoscopic biopsies and ultrastructural examinations were performed in 13 asthmatics and 11 (BAL) or four (biopsies) non-asthmatic controls. The proportions of epithelial cells and correlations with PC20Meth which reflects bronchial hyperresponsiveness. Light microscopic examination revealed loss of epithelium, inflammatory cell infiltrations and thickening of the basement membrane which also showed significant correlation with PC20Meth. Hypertrophy of airway smooth muscles and hyperplasia of mucous glands were prominent in asthmatics but there was no difference according to the severity of asthma. Ultrastructural examination revealed that basement membrane thickening on light microscopic examination is due to the increased subepithelial collagen deposition with normal thickness of basal lamina. These data suggest that loss of epithelial cells, infiltration of inflammatory cells, especially eosinophils, and increased deposition of subepithelial collagen play major roles in determining the severity of asthma and non-specific bronchial hyperresponsiveness.
Article
The extent to which the bronchial vasculature contributes to airway wall thickening in large and small airways in patients with asthma is unknown. The aim of this study was to quantify the number and the area occupied by blood vessels in the airway submucosa of patients with and without asthma. We used the monoclonal antibody Factor VIII to measure the blood vessels between the airway basement membrane and the outer border of the smooth muscle. In large cartilaginous airways in patients with fatal asthma, the number and area of large blood vessels were increased and the number and area of small blood vessels were decreased, compared with that in patients with nonfatal asthma and control subjects. However, the total number of blood vessels and the total area occupied by blood vessels per square millimeter in the airway submucosa were similar in patients with fatal asthma or nonfatal asthma and in control subjects in all airway size groups. Blood vessels were distended to a mean value of 80% of their estimated maximal area. The increased number of larger vessels in patients with fatal asthma raises the possibility that vascular congestion associated with an acute severe asthma attack may distend blood vessels. The finding of similar numbers of blood vessels per square millimeter of submucosa in control subjects and in patients with asthma suggests that blood vessels increase in number in patients with asthma only in proportion to increased airway wall area. It is unlikely that submucosal vessels could act as capacitance vessels and significantly alter inner airway wall thickness.
Article
Dysfunction of the upper and lower airways frequently coexist, and they appear to share key elements of pathogenesis. Data from epidemiologic studies indicate that nasal symptoms are experienced by as many as 78% of patients with asthma and that asthma is experienced by as many as 38% of patients with allergic rhinitis. Studies also have identified a temporal relation between the onset of rhinitis and asthma, with rhinitis frequently preceding the development of asthma. Patients with allergic rhinitis and no clinical evidence of asthma commonly exhibit nonspecific bronchial hyperresponsiveness. The observation that management of allergic rhinitis also relieves symptoms of asthma has heightened interest in the link between these diseases. Intranasal corticosteroids can prevent increases in nonspecific bronchial reactivity and asthma symptoms associated with seasonal pollen exposure. Similarly, among patients with perennial rhinitis, daily asthma symptoms, exercise-induced bronchospasm, and bronchial responsiveness to methacholine are reduced after administration of intranasal corticosteroids. Antihistamines, with or without decongestants, reduce seasonal rhinitis symptoms, asthma symptoms, and objective measurements of pulmonary function among patients with rhinitis and asthma. The mechanisms that connect upper and lower airway dysfunction are under investigation. They include a nasal-bronchial reflex, mouth breathing caused by nasal obstruction, and pulmonary aspiration of nasal contents. Nasal allergen challenge results in increases in lower airway reactivity within 30 minutes, suggesting a neural reflex. Improvements in asthma associated with increased nasal breathing may be the result of superior humidification, warming of inspired air, and decreased inhalation of airborne allergens. Postnasal drainage of inflammatory cells during sleep also may affect lower airway responsiveness. A link between allergic rhinitis and asthma is evident from epidemiologic, pathophysiologic, and clinical studies. Future research, however, is needed to determine whether nasal therapy can alter the natural history of asthma.
Article
As symptoms of allergic rhinitis are generally thought to disappear with increasing age, we decided to follow up our allergic rhinitis patients to ascertain whether their disease had regressed or progressed, and whether they had developed respiratory symptoms. At our department, between 1979 and 1982, allergic rhinitis was diagnosed in 108 patients. In 1993, 82 of the patients (40 women, 42 men; mean age 36 years), none of whom had received immunotherapy, answered a questionnaire concerning the status of their allergic rhinitis, and any development of the disease during the interim. Of the 82 patients, one was free of allergic symptoms and 39% had become better; symptoms were unchanged in 39% of cases, and worse in 21%. Six percent had suffered from asthma at presentation, 6% had developed asthma in the interim, and 34% reported other lower airways symptoms. Neither sex nor age at diagnosis was a determinant of the course of allergic rhinitis. Thus, in contrast to findings in other studies, the severity of allergic rhinitis seems to have increased among our patients.
Article
Airway-wall remodeling leading to thickening of the bronchial wall in asthma has been invoked to account for airflow obstruction and increased bronchial reactivity to provocative stimuli. Bronchial-wall changes characteristic of asthma are thought to include increased vascularity with vasodilatation. The contention that inflammatory mediators cause bronchial vasodilatation and that growth factors may induce increased vascularity is based on little structural evidence. We took bronchoscopic biopsies from the major airways of 12 subjects with mild asthma and 11 control subjects, and evaluated bronchial vessel numbers and size, using computerized image analysis after staining for type IV collagen in vessel walls. The airways of asthmatic subjects were significantly more vascular (17.2 +/- 4.2 versus 10.3 +/- 1.9%, p < 0.001), with more vessels (738 +/- 150 versus 539 +/- 276 vessels/mm2 [mean +/- SD], p < 0.05) than those of the controls. There were significantly more asthmatic bronchial than control vessels with a cross-sectional area greater than 300 microns2 (19.4 versus 12.7%, p < 0.05). These findings provide the first confirmatory evidence that bronchial biopsies from patients with mild asthma are more vascular than those of normal controls, that there are more vessels in asthmatic airways, and that asthmatic bronchial vessels are larger than controls.
Article
We attempted to determine whether inflammation is present in induced sputum of patients with seasonal allergic rhinitis (AR) as compared with those with perennial asthma (AS) and examined its relationship with bronchial responsiveness to methacholine. Sputum was induced in 30 patients with seasonal rhinitis in response to grass pollens only and in 15 patients with stable, asymptomatic asthma. The AR group was divided according to methacholine PD20 value: the AR- group (n = 15) had a methacholine PD20 greater than 24 micromol; the AR+ group (n = 15) had a methacholine PD20 ranging between 2.2 and 19.6 micromol. In the AS group, methacholine PD20 ranged between 0.42 and 2.6 micromol. The percentage of eosinophils and metachromatic cells (alcian blue-positive) was assessed in sputum by light microscopy. Tryptase-positive cells and EG2+ cells were identified by immunocytochemistry with the mouse anti-human mast cell-tryptase monoclonal antibody and the monoclonal anti-eosinophil cationic protein antibody. We found that the number of eosinophils in the AS group was greater than that in the AR+ group (p < 0.05) and in the AR- group (p < 0.01). Moreover, the eosinophil count was lower in the AR- group compared with the AR+ group (p < 0.05). Similarly, the number of EG2+ cells was greater in the AS group than in the AR group (p < 0.02) and the AR- group (p < 0.05). Moreover, the EG2+ cell count was lower in the AR- group than in the AR+ group (p < 0.05). The number of mast cells and basophils in the AS group was greater than that in the AR group (p < 0.05 and p < 0.01, respectively). Mast cells in sputum were tryptase-positive. Basophils were present in sputum from 23% of patients with AR and 53% of patients with asthma. There was a significant correlation between methacholine PD20 and eosinophils (p < 0.005) and mast cells (p < 0.02) but not with basophils in those patients showing a measurable methacholine PD20 (AR+ and AS groups). Inflammatory cells are present not only in the airways of patients with asthma but also in airways of patients with seasonal AR, even outside natural exposure. Moreover, we provide evidence for the presence of basophils in sputum of patients with asthma even during clinical remission. The presence of bronchial responsiveness is associated with an increase in the number of eosinophils and metachromatic cells. Our findings are consistent with the hypothesis that eosinophils, as well as mast cells, contribute to bronchial responsiveness not only in AS but also in seasonal AR.
Article
Allergic rhinitis is a prevalent disease with significant morbidity. Studies of its pathophysiology in human subjects have been limited. Nasal biopsy specimens are difficult to obtain, and nasal secretions incompletely reflect the cellular and molecular events in the mucosa. IgE-mediated mast cell activation and the elaboration of factors promoting eosinophil development and chemotaxis are likely to participate in pathogenesis. We sought to develop a murine model of allergic rhinitis, to use it to assess the role of IgE in pathogenesis, and to study the effects of IL-5 and eotaxin in the nasal mucosa. A protein extract of Aspergillus fumigatus (Af) was instilled intranasally in mice. Histologic changes were examined in wild-type and IgE-deficient (IgE-/-) animals. The effect of eotaxin administration was assessed in wild-type and IL-5 transgenic mice. Af-treated mice developed a nasal mucosal eosinophil influx comparable to that described for humans. This histology was distinct from that observed in a murine model of Af-induced asthma. The pathology appeared over a time course similar to that reported for human subjects. There was no difference in the intensity of the mucosal inflammatory infiltrate of Af-treated IgE-/- mice compared with wild-type mice. Eotaxin was able to recruit eosinophils to the mucosa but only in IL-5 transgenic animals. We describe a murine model for allergic rhinitis with an eosinophilic infiltrate comparable to that found in human disease and have demonstrated that rhinitis can arise in the absence of IgE. We have shown that the eosinophil influx can be induced by eotaxin in the presence of IL-5.
Article
The purpose of this study is to examine the co-existence of asthma and allergic rhinitis among former college students who were diagnosed with these diseases either before or after their freshman year. A total of 738 former Brown University students (69% males and 31% females) who were evaluated and underwent skin testing during their freshman year completed a 23-year follow-up questionnaire inquiring of their history of allergies and asthma. The mean age of the participants at the time of the follow-up study was 40 years. In this group, the cumulative incidence of asthma was 11.3% (84/738), hay fever was 41.5% (306/738), and nonseasonal allergic rhinitis was 14.0% (103/738). The cumulative incidence of allergic rhinitis (hay fever) and/or nonseasonal allergic rhinitis (was 45.8% (338/738). Among the 84 individuals with a cumulative incidence of asthma, 63 (75.0%) had a history of hay fever, 27 (32.1%) had a history of nonseasonal allergic rhinitis, and 72 (85.7%) had a history of allergic rhinitis. Among the 306 participants with a cumulative incidence of hay fever, 63 (20.6%) had a history of asthma. Twenty-seven (26.2%) of the 103 individuals with a history of nonseasonal allergic rhinitis had a cumulative incidence of asthma. Among the 338 individuals with a cumulative incidence of allergic rhinitis 72 (21.3%) had a history of asthma. Among the participants with a history of both asthma and hay fever, 44.8% developed hay fever first, 34.5% developed asthma first, and 20.7% developed both diseases at the same time. Among the individuals with a history of asthma and nonseasonal allergic rhinitis, 38.5% developed nonseasonal allergic rhinitis first, 30.8% developed asthma first, and 30.8% developed both diseases at the same time. This study further demonstrates the frequent co-existence of asthma and allergic rhinitis. Among asthmatics, allergic rhinitis occurred in 85.7%. Only 14.3% of asthmatics did not have allergic rhinitis. Among individuals with allergic rhinitis, asthma occurred in 21.3%. Also, allergic rhinitis often precedes or occurs at the same time as asthma.
Article
Although asthma and rhinitis often coexist, it is still unknown whether they are characterized by a similar inflammatory profile. We studied eosinophilic infiltration, epithelial shedding and reticular basement membrane thickness in nasal and bronchial biopsies of six control subjects, 15 untreated allergic asthmatics with perennial rhinitis, and six corticosteroid-dependent (CSD) asthmatics. In nasal and bronchial biopsies, eosinophils were greater in untreated asthmatics than in control subjects and CSD asthmatics (p = 0.001). In untreated asthmatics, eosinophils were higher in bronchial than in nasal biopsies (p = 0.002). In nasal and bronchial biopsies, reticular basement membrane thickness was greater in untreated and CSD asthmatics than in control subjects (nasal: p < 0.008 and p < 0. 004; bronchial: p < 0.001 and p < 0.008). In untreated and CSD asthmatics, reticular basement membrane thickness was greater in bronchial than in nasal biopsies (p = 0.001; Wilcoxon's W test). Nasal epithelium was not shed in all the study groups. In untreated asthmatics, bronchial epithelium shedding was greater than in control subjects or CSD asthmatics (p < 0.005), and it was greater than nasal epithelium shedding (p < 0.006). This study has shown that, although concomitant, the extent of eosinophilic inflammation of reticular basement membrane thickness and of the epithelium shedding is greater in bronchial than in nasal mucosa of asthmatic patients with perennial rhinitis.
Article
Allergen challenge in some patients with respiratory allergy is followed by an early and a late reaction. To evaluate the duration of mediator release and inflammatory cell recruitment during the late antigen-induced nasal response. Eight patients with seasonal allergic rhinitis due to grass pollen underwent local challenge with the relevant allergen, a non-relevant allergen (Parietaria judaica), and nebulized saline solution. Nasal lavages were performed at baseline and 6, 24, 48, 72 h after challenge. Eosinophil cationic protein (ECP), leukotriene C4 (LTC4), leukotriene B4 (LTB4) myeloperoxidase (MPO) and prostaglandin D2 (PGD2) levels were radioimmunoassayed and histamine concentration was measured by an automated fluorometric method. Nasal challenge with the relevant antigen induced a response 6 h after stimulation, which subsided within 24 h. Eosinophilia, observed in the nasal lavages collected from 6 to 24 h after this challenge, was accompanied by ECP release. Neutrophilia were found in the nasal lavages collected from 6 to 24 h after challenge. The increase in neutrophil number correlated with MPO levels and LTB4 concentrations, but not with the intensity of nasal obstruction. Antigen challenge also induced significant recruitment of mononuclear cells 48 h after provocation. The challenge significantly raised histamine, but not PGD2, levels in the nasal lavages collected 6 h after provocation. A trend towards an increase in LTC4 levels in the nasal lavages collected 6 h after specific antigen challenge was also found. Nasal challenge with a non-relevant allergen or with saline solution did not cause either inflammatory cell recruitment or mediator release. Nasal challenge with the relevant antigen can induce a late response characterized by local accumulation of eosinophils, neutrophils and mononuclear cells persisting for 48 h and accompanied by release of ECP, MPO, LTB4 and histamine. These results indicate that a single antigen challenge in patients with allergic rhinitis causes prolonged inflammatory alterations which may contribute to the development of airway hyperreactivity.
Article
Asthma exacerbation is associated with increased numbers of circulating CD34(+) progenitor cells, which may migrate to airways and develop into mature cells under the effects of cytokines and hematopoietic factors. Nitric oxide (NO) generation is enhanced in asthma and is known to suppress human hematopoiesis. We studied circulating progenitor cells in the blood of patients with varying severity of asthma and examined the contribution of NO to their proliferation into eosinophil-forming colonies ex vivo. With use of multiparameter flow cytometric analyses, the cell numbers and intracellular inducible NO synthase (iNOS) immunoreactivity of circulating CD34(+) cells in peripheral blood was measured. The serum level of GM-CSF or IL-5 was also determined. The colonies grown from progenitor cells were cultured in methylcellulose either in the presence or absence of growth factors, including GM-CSF, stem cell factor, and IL-3. A significantly greater number of circulating CD34(+) cells increased together with higher intracellular iNOS immunoreactivity in moderate asthmatics compared with mild intermittent asthmatics and healthy subjects. There was no significant difference in iNOS immunoreactivities or CD34(+) progenitor cell numbers between healthy subjects and those with mild intermittent asthma. Serum levels of GM-CSF or IL-5 were significantly higher in all asthmatics compared with healthy subjects and correlated with circulating CD34(+) cells. A greater number of colonies was grown either in the presence or absence of growth factors with a higher percentage of cells of eosinophil lineage in asthmatics than in health subjects. N(G)-nitro-L-arginine methyl ester potentiated and sodium nitroprusside inhibited the colony growth in both asthmatic and healthy subjects without a significant change in the percentage of eosinophil lineage. The production of NO from progenitor cells or other circulating cells may act in an autocrine or paracrine fashion to regulate progenitor cell growth and colony formation. However, this is not sufficient to control the increased proliferation of progenitor cells observed in asthma.
Article
The eosinophil chemotactic and activating effects of eotaxin and the known association of eosinophils with asthma suggest that eotaxin expression is increased during asthma exacerbations. We sought to determine whether plasma eotaxin levels are elevated in patients presenting for emergency treatment of acute asthma and to correlate eotaxin levels with disease activity and responses to treatment. A case-control study of plasma eotaxin levels was performed in the 46 patients who presented for emergency asthma treatment and 133 age-, sex-, and ethnicity-matched subjects with stable asthma. Plasma eotaxin levels were significantly higher in 46 patients with acute asthma symptoms and airflow obstruction (520 pg/mL [250, 1100 pg/mL]; geometric mean [-1 SD, +1 SD]) than in 133 subjects with stable asthma (350 pg/mL [190, 620 pg/mL]; P =.0008). Among the patients with emergency asthma flares, those who responded to asthma treatment with an increase in peak expiratory flow rate by an amount equal to at least 20% of their predicted normal value had lower eotaxin levels than those who did not (410 pg/mL [210, 800 pg/mL] and 660 pg/mL [300, 1480 pg/mL], respectively; P =.04). These findings imply that eotaxin either is mechanistically involved in acute asthma or serves as a biomarker for activity of the CCR3 receptor ligand system, which is functionally linked to asthma.
Article
Asthma is characterized by a 50- to 100-fold increase in the number of eosinophils relative to neutrophils in the bronchial mucosa. This increase is not the result of a single molecular event but of the cumulative and sequential effects of several approximately 4-fold increases in selective eosinophil versus neutrophil migration, occurring at a number of stages in the life cycle of the eosinophil. These steps include (1) effects on the bone marrow, mediated principally by IL-5, which result in a 4-fold increase in circulating eosinophils, (2) selective tethering of eosinophils to venular endothelium through the combined effects of P-selectin/P-selectin glycoprotein ligand 1 and very late activation antigen-4/vascular cell adhesion molecule-1, which has the potential for an up to 10-fold increase in eosinophil versus neutrophil adhesion, (3) selective chemotaxis under the influence of CC chemokines, and (4) prolonged survival, again mediated by IL-5. These events are integrated and directed by allergen-specific T H2 lymphocytes through the generation of IL-5, IL-4, and IL-13. The implications of this multistep process are that antagonists of IL-5, very late activation antigen-4, P-selectin glycoprotein ligand 1, and CCR3 as well as IL-4 and IL-13 each have the potential to markedly inhibit eosinophil recruitment in asthma. (J Allergy Clin Immunol 1999;104:917-26.)
Article
Background: Eosinophilic airway inflammation is the hallmark of asthma, but it has also been reported in other conditions such as allergic rhinitis. We have tested whether the analysis of cells and chemicals in sputum can distinguish between patients with mild allergic asthma, those with allergic rhinitis, and healthy controls. The relationship between inflammation markers in sputum and nonspecific bronchial hyperresponsiveness to methacholine (BHR) (PD20 and maximal response plateau [MRP] values) was also evaluated. Methods: We selected 31 mild asthmatics and 15 rhinitis patients sensitized to house-dust mite. As a control group, we studied 10 healthy subjects. Every subject underwent the methacholine bronchial provocation test (M-BPT) and sputum induction. Blood eosinophils and serum ECP levels were measured. Sputum cell differentials were assessed, and eosinophil cationic protein (ECP), tryptase, albumin, and interleukin (IL)-5 levels were measured in the entire sputum supernatant. Results: Blood eosinophils and serum ECP levels were higher in asthma patients and rhinitis than in healthy controls, but no difference between asthma patients and rhinitis patients was found. Asthmatics had higher eosinophil counts and higher ECP and tryptase levels in sputum than rhinitis patients or control subjects. Sputum albumin levels were higher in asthmatics than in controls. Rhinitis patients exhibited higher sputum eosinophils than healthy controls. An association between sputum eosinophil numbers and MPR values (r= -0.57) was detected, and a trend toward correlation between sputum ECP levels and PD20 values (r= -0.47) was found in the rhinitis group, but not in asthmatics. No correlation between blood eosinophilic inflammation and lung functional indices was found. Conclusions: Induced sputum is an accurate method to study bronchial inflammation, allowing one to distinguish between rhinitis patients and mildly asthmatic patients. The fact that no relationship was detected between sputum inflammation and BHR suggests that other factors, such as airway remodeling, may be at least partly responsible for BHR in asthma.
Article
Asthma and rhinitis often co-exist and there are data to suggest that they may be two ends of the same disease spectrum. Immunohistochemical studies have shown that eosinophilia in the airways is a feature of rhinitic patients without asthma. The aim of our study was to examine whether cellular infiltration exists in the nasal mucosa of asthmatics even in the absence of symptoms and signs of rhinitis. Nasal mucosa biopsies were taken from 27 non-atopic subjects and comprised nine asthmatic rhinitic patients (AR), eight asthmatic non-rhinitic patients (ANR) and 10 healthy control subjects (N). Bronchial mucosa biopsies were also taken simultaneously from some of the patients (n = 10) to determine whether there was an association between cellular infiltration in the nose and the lungs. The alkaline phosphatase-anti-alkaline phosphatase (APAAP) method was used on 6 microm thick cryostat sections using monoclonal antibodies against T cells (CD4, CD8), eosinophils (EG2) and mast cells (mast cell tryptase). Slides were counted blind and results expressed as cells per field. The results showed that eosinophil counts were higher in both asthma groups compared with control nasal biopsies (median values AR 8.3, ANR 9.2, N 2.1 cells per field, P < 0.01). Furthermore, there was a significant correlation between eosinophil cell counts in the nose and the airways (r = 0.851 P < 0.001). No differences in eosinophil numbers were detected between the two groups of asthmatics. Also, no differences were noted for any other cell type (i.e. CD4, CD8, tryptase) among the three study groups. These results show that eosinophil infiltration was present in the nasal mucosa of asthmatic patients even in the absence of rhinitis, and add further support to the hypothesis that asthma and rhinitis are clinical expressions of the same disease entity.
Article
Guidelines for the diagnosis and management of asthma have been available for the past 13 years and are updated regularly. However, asthma guidelines are rarely completely up-to-date because our knowledge about the pathophysiology and treatment of asthma is continually evolving. Guidelines are an increasingly familiar part of clinical practice and may have potential benefits and harms. The potential harms of guidelines can be minimized if they are rigorously developed using evidence-based medicine. Guidelines should identify key decisions and their consequences and should review the consequences of alternative decisions. In addition, guidelines should be simple, user-friendly and widely disseminated. Guidelines evolve over time and their recommendations should be supported by evidence from clinical trials. Evidence-based medicine is the new paradigm but the results and reaction to the recent meta-analysis on house-dust mite control measures highlights the need for care when incorporating such information into guidelines. Newer therapeutic agents such as the leukotriene receptor antagonists are included in the most recent revision of the GINA guidelines, but their position in asthma therapy is not yet fully established. In countries where asthma guidelines have been implemented, there appears to have been a reduction in the prevalence of moderate persistent asthma but no decrease in severe asthma. This indicates that there is still room for improvement.