SEARCH

SEARCH BY CITATION

Keywords:

  • allergy;
  • asthma;
  • comorbidity;
  • immunoglobulin E;
  • rhinitis

Abstract

  1. Top of page
  2. Abstract
  3. Epidemiological evidence
  4. Relationship between rhinitis and asthma
  5. Rhinitis and nonspecific bronchial hyperresponsiveness
  6. Causative agents in rhinitis and asthma
  7. ’Bidirectional’ relationship between nasal and bronchial inflammation: bronchial challenge of rhinitis patients leads to nasal inflammation (and vice versa)
  8. Bronchial inflammation in rhinitis
  9. Bronchial biopsies in rhinitis
  10. Bronchial allergen challenge in rhinitis
  11. Thunderstorm-induced asthma
  12. Viral infection of the nose induces asthma and bronchial inflammation
  13. Nasal and sinus inflammation in asthma
  14. Similarities and differences between nasal and bronchial inflammation in asthma
  15. Sinus involvement in asthma
  16. Allergic inflammation is both local and systemic
  17. The role of IgE
  18. Bone marrow involvement
  19. In situ haemopoiesis
  20. The ’allergic march’
  21. Allergic rhinitis as a risk factor for asthma
  22. Rhinitis and asthma: a continuum of disease
  23. Impact of rhinitis and asthma on quality of life
  24. Therapeutic consequences
  25. Drugs administered locally
  26. Drugs administered orally
  27. Specific immunotherapy
  28. Anti-IgE monoclonal antibody
  29. Treatment of rhinitis reduces asthma severity
  30. Impact of rhinitis on asthma costs
  31. Conclusions
  32. References

There is compelling evidence of a close relationship between the upper and lower airways in asthma and rhinitis. Rhinitis is present in the majority of patients with asthma, and a significant minority of patients with rhinitis have concomitant asthma. Similarities between the two conditions occur in the nature of the inflammation present in the target tissues. A common initiating step in the inflammatory process of allergic airways disease is the presence of immunoglobulin E providing an adaptor molecule between the offending allergen and inflammatory cell activation and mediator release. Differences in the two conditions arise largely from the structural differences between the nose and the lungs. In an asthmatic, concomitant allergic rhinitis increases healthcare costs and further impairs quality of life. The presence of rhinitis should always be investigated in children and young adults with asthma. Subjects with allergic rhinitis have an increased risk of developing asthma and may form a suitable population for secondary intervention to interrupt the ‘allergic march’.

Asthma and allergies, including rhinoconjunctivitis and atopic dermatitis, are common throughout the world, with a high burden of morbidity and cost. As the nasal and bronchial mucosa has similarities and most patients with asthma also have rhinitis (1–3), the concept of ‘one airway, one disease’ has arisen. However, not all patients with rhinitis present with asthma and there are some differences between the two conditions (4).

Relationship between rhinitis and asthma

  1. Top of page
  2. Abstract
  3. Epidemiological evidence
  4. Relationship between rhinitis and asthma
  5. Rhinitis and nonspecific bronchial hyperresponsiveness
  6. Causative agents in rhinitis and asthma
  7. ’Bidirectional’ relationship between nasal and bronchial inflammation: bronchial challenge of rhinitis patients leads to nasal inflammation (and vice versa)
  8. Bronchial inflammation in rhinitis
  9. Bronchial biopsies in rhinitis
  10. Bronchial allergen challenge in rhinitis
  11. Thunderstorm-induced asthma
  12. Viral infection of the nose induces asthma and bronchial inflammation
  13. Nasal and sinus inflammation in asthma
  14. Similarities and differences between nasal and bronchial inflammation in asthma
  15. Sinus involvement in asthma
  16. Allergic inflammation is both local and systemic
  17. The role of IgE
  18. Bone marrow involvement
  19. In situ haemopoiesis
  20. The ’allergic march’
  21. Allergic rhinitis as a risk factor for asthma
  22. Rhinitis and asthma: a continuum of disease
  23. Impact of rhinitis and asthma on quality of life
  24. Therapeutic consequences
  25. Drugs administered locally
  26. Drugs administered orally
  27. Specific immunotherapy
  28. Anti-IgE monoclonal antibody
  29. Treatment of rhinitis reduces asthma severity
  30. Impact of rhinitis on asthma costs
  31. Conclusions
  32. References

Epidemiological evidence consistently demonstrates the frequent coexistence of asthma and rhinitis in the same patients.

Asthma is present in 20–50% of patients with rhinitis (5–8). In one study, 20 000 households were screened for symptoms of rhinitis and 84% (16 786 households) responded (9). Patients qualified as having perennial rhinitis if they had at least two rhinitis symptoms regularly for at least 6 months of the year, without any period of remission. Allergic associations were not looked for. The point prevalence of perennial rhinitis was 4.1%. Perennial rhinitis was strongly associated with a history of asthma [13.4% of patients with perennial rhinitis vs 3.8% of patients without; odds ratio (OR) 3.26].

The majority of patients with asthma present with symptoms of seasonal or perennial allergic rhinitis. However, it has been shown that perennial rhinitis is a risk factor for asthma independent of allergy. In epidemiological studies, rhinitis was found to occur in up to 80% of patients with asthma (7). In a group of 1245 subjects with documented asthma, 24% had seasonal allergic rhinitis only, 6% had perennial allergic rhinitis only and 22% were considered to have both (7). In some large clinical studies rhinitis is present in nearly all the patients with asthma; in one study over 95% had a history of allergic rhinitis and 73% had current seasonal allergies (10). Leynaert et al. analysed data from 34 centres participating in the European Community Respiratory Health Survey (7) using a random sample of 20–44-year-old subjects. Subjects were diagnosed with perennial rhinitis if they had any nasal allergies, including hay fever, and symptoms in the presence of animals, feathers (quilts, etc.) or in dusty areas of the house. Subjects with perennial rhinitis (n = 1412) were more likely to have concurrent asthma than control subjects (n = 5198). After adjusting for sex, age, smoking habit, family history of asthma, geographical area, and season at the time of examination, asthma was strongly associated with rhinitis not only among atopic subjects [OR = 8.1; 95% confidence interval (CI) = 5.4, 12.1] but also among nonatopic subjects (OR = 11.6; 95% CI = 6.2, 21.9). The strong association between perennial rhinitis and asthma in nonatopic subjects remained when the analysis was restricted to atopic or nonatopic subjects with immunoglobulin E (IgE) levels of 80 kIU/l or less. These results are consistent with the hypothesis that rhinitis is an independent risk factor for asthma. Data from northern Sweden also demonstrate the association between asthma and allergic rhinitis, and show that an adult with a family history of asthma or rhinitis has a three- to four-fold increased risk for developing asthma and a two- to six-fold increased risk for developing rhinitis compared with adults without a family history (11). The Copenhagen Allergy Study (12) investigated the frequency of asthma and rhinitis related to exposure to pollens, animal dander or mites. For people with pollen allergy, 41% of those with pollen-related rhinitis also had pollen-related asthma. Pollen-related asthma was almost nonexistent (0.1%) in those without pollen-related rhinitis. For the other allergens, the respective figures were 52 and 0.2% in subjects with animal dander allergy, and 41 and 1% for mite allergy. In all cases, therefore, more than 99% of subjects with allergic asthma also had allergic rhinitis. The risk of asthma among subjects with allergic rhinitis was calculated to be up to 300 times that among subjects without allergic rhinitis.

However, the results observed in developing countries may differ from those in western populations. A recent study showed that allergic rhinitis is far less common among asthmatic subjects in rural China than in asthmatic subjects in industrialized countries with a western lifestyle (13).

Rhinitis and nonspecific bronchial hyperresponsiveness

  1. Top of page
  2. Abstract
  3. Epidemiological evidence
  4. Relationship between rhinitis and asthma
  5. Rhinitis and nonspecific bronchial hyperresponsiveness
  6. Causative agents in rhinitis and asthma
  7. ’Bidirectional’ relationship between nasal and bronchial inflammation: bronchial challenge of rhinitis patients leads to nasal inflammation (and vice versa)
  8. Bronchial inflammation in rhinitis
  9. Bronchial biopsies in rhinitis
  10. Bronchial allergen challenge in rhinitis
  11. Thunderstorm-induced asthma
  12. Viral infection of the nose induces asthma and bronchial inflammation
  13. Nasal and sinus inflammation in asthma
  14. Similarities and differences between nasal and bronchial inflammation in asthma
  15. Sinus involvement in asthma
  16. Allergic inflammation is both local and systemic
  17. The role of IgE
  18. Bone marrow involvement
  19. In situ haemopoiesis
  20. The ’allergic march’
  21. Allergic rhinitis as a risk factor for asthma
  22. Rhinitis and asthma: a continuum of disease
  23. Impact of rhinitis and asthma on quality of life
  24. Therapeutic consequences
  25. Drugs administered locally
  26. Drugs administered orally
  27. Specific immunotherapy
  28. Anti-IgE monoclonal antibody
  29. Treatment of rhinitis reduces asthma severity
  30. Impact of rhinitis on asthma costs
  31. Conclusions
  32. References

Many patients with allergic rhinitis have a physiological behaviour distinct from that of patients with asthma or normal subjects. They have increased bronchial sensitivity to methacholine or histamine (14, 15), especially during and slightly after the pollen season (16, 17). However, there are large differences in bronchial responsiveness between patients with asthma and patients with rhinitis that are not explained by the allergen type or IgE levels (18). In addition, the bronchial mucosa is much more responsive in asthma (compared with controls) than the nasal mucosa is in allergic rhinitis, probably for structural reasons (19).

Causative agents in rhinitis and asthma

  1. Top of page
  2. Abstract
  3. Epidemiological evidence
  4. Relationship between rhinitis and asthma
  5. Rhinitis and nonspecific bronchial hyperresponsiveness
  6. Causative agents in rhinitis and asthma
  7. ’Bidirectional’ relationship between nasal and bronchial inflammation: bronchial challenge of rhinitis patients leads to nasal inflammation (and vice versa)
  8. Bronchial inflammation in rhinitis
  9. Bronchial biopsies in rhinitis
  10. Bronchial allergen challenge in rhinitis
  11. Thunderstorm-induced asthma
  12. Viral infection of the nose induces asthma and bronchial inflammation
  13. Nasal and sinus inflammation in asthma
  14. Similarities and differences between nasal and bronchial inflammation in asthma
  15. Sinus involvement in asthma
  16. Allergic inflammation is both local and systemic
  17. The role of IgE
  18. Bone marrow involvement
  19. In situ haemopoiesis
  20. The ’allergic march’
  21. Allergic rhinitis as a risk factor for asthma
  22. Rhinitis and asthma: a continuum of disease
  23. Impact of rhinitis and asthma on quality of life
  24. Therapeutic consequences
  25. Drugs administered locally
  26. Drugs administered orally
  27. Specific immunotherapy
  28. Anti-IgE monoclonal antibody
  29. Treatment of rhinitis reduces asthma severity
  30. Impact of rhinitis on asthma costs
  31. Conclusions
  32. References

Among the causative agents inducing asthma and rhinitis, some [e.g. allergens and aspirin (20)] affect both the nose and the bronchi. Most inhaled allergens are associated with nasal (5) and bronchial symptoms but in epidemiological studies differences have been observed. Although reservations have been expressed about the role of allergen exposure as the primary major cause of asthma (21), the prevalence of IgE sensitization to indoor allergens (house dust mites and cat allergens) correlates positively with both the frequency of asthma and its severity (22, 23). Alternaria (24, 25) and insect dusts (26) have also been found to be linked with asthma, but pollen sensitivity has not been found to be associated with asthma in epidemiological studies (27, 28). On the contrary, pollen sensitivity is always associated with rhinitis (5).

Occupational diseases represent an interesting model to study the relationships between rhinitis and asthma. Subjects with occupational asthma often report symptoms of rhinoconjunctivitis. The most common triggers of occupational asthma can also induce occupational rhinitis:

  • Isocyanates (29, 30).
  • • 
    Flour and grain. Bakers often present with rhinitis and asthma (31). In the 1970s and 1980s Swedish bakers were found to have a higher (× 2) risk of developing rhinitis than nonbakers (32). Grain handlers also present rhinitis, even in developing countries (33).
  • • 
    Wood dust can induce rhinitis and asthma but the mechanisms for these reactions are still unclear (34, 35).
  • • 
    Glutaraldehyde (36).
  • • 
    Solder/colophony (37, 38).
  • • 
    Laboratory animals (39–41).
  • • 
    Resins and glues (37, 42, 43).
  • • 
    Latex (44, 45).
  • • 
    Persulphates (46).

Rhinitis is less pronounced than asthma with low molecular weight agents. However, rhinitis often appears before asthma in the case of high molecular weight agents such as those derived from small mammals (47–49), raw green beans (50), flour (51, 52) or latex (53, 54). In many patients, nasal symptoms occur before bronchial symptoms, suggesting that it may be possible to prevent the development of asthma. In addition, rhinitis caused by some low molecular weight agents is associated with or develops into occupational asthma (55–58), highlighting the importance of cessation of allergen exposure in occupational allergic rhinitis in order to prevent asthma.

’Bidirectional’ relationship between nasal and bronchial inflammation: bronchial challenge of rhinitis patients leads to nasal inflammation (and vice versa)

  1. Top of page
  2. Abstract
  3. Epidemiological evidence
  4. Relationship between rhinitis and asthma
  5. Rhinitis and nonspecific bronchial hyperresponsiveness
  6. Causative agents in rhinitis and asthma
  7. ’Bidirectional’ relationship between nasal and bronchial inflammation: bronchial challenge of rhinitis patients leads to nasal inflammation (and vice versa)
  8. Bronchial inflammation in rhinitis
  9. Bronchial biopsies in rhinitis
  10. Bronchial allergen challenge in rhinitis
  11. Thunderstorm-induced asthma
  12. Viral infection of the nose induces asthma and bronchial inflammation
  13. Nasal and sinus inflammation in asthma
  14. Similarities and differences between nasal and bronchial inflammation in asthma
  15. Sinus involvement in asthma
  16. Allergic inflammation is both local and systemic
  17. The role of IgE
  18. Bone marrow involvement
  19. In situ haemopoiesis
  20. The ’allergic march’
  21. Allergic rhinitis as a risk factor for asthma
  22. Rhinitis and asthma: a continuum of disease
  23. Impact of rhinitis and asthma on quality of life
  24. Therapeutic consequences
  25. Drugs administered locally
  26. Drugs administered orally
  27. Specific immunotherapy
  28. Anti-IgE monoclonal antibody
  29. Treatment of rhinitis reduces asthma severity
  30. Impact of rhinitis on asthma costs
  31. Conclusions
  32. References

To analyse nasobronchial cross-talk, inflammation and the expression of adhesion molecules was studied in nasal and bronchial mucosa after allergen provocation. In one study, endobronchial allergen challenge induced nasal and bronchial symptoms as well as reductions in pulmonary and nasal function (59). In this study, the number of eosinophils increased in the challenged bronchial mucosa, in the blood and in the nasal mucosa 24 h after bronchial challenge (Fig. 1). Moreover, eotaxin-positive cells in the nasal lamina propria and enhanced expression of interleukin (IL)-5 in the nasal epithelium were found 24 h after bronchial challenge.

image

Figure 1. Local and systemic inflammation in allergic rhinitis. (A) anatomic links between the nose and lower airway, (B) inhalation of allergens leads to a local inflamatory reaction in the nose and bronchi due to an IgE-mediated reaction, (C) during the IgE-mediated inflammatory reaction chemokines, cytokines and other chemotactic factors are released into the circulation, (D) these factors act on the bone marrow to induce the differentiation of eosinophil/basophil progenitors, (E) the IL5 receptor-positive progenitor cells circulate into the peripheral blood, (F) and reach the upper and lower airways leading to the concept of systemic inflammation.

Download figure to PowerPoint

In a second study, bronchial and nasal biopsy specimens were taken before and 24 h after nasal provocation (60). At 24 h, an influx of eosinophils was detected in the nasal epithelium and lamina propria, as well as in the bronchial epithelium and lamina propria. Increased expression of ICAM-1, as well as increased percentages of ICAM-1+, VCAM-1+, and E-selectin+ vessels, were seen in both nasal and bronchial tissue of patients with allergic rhinitis. The number of mucosal eosinophils correlated with the local expression of ICAM-1, E-selectin, and VCAM-1 in these patients.

These studies show that allergen provocation of either the nose or the bronchi results in generalized airway inflammation (60).

Bronchial biopsies in rhinitis

  1. Top of page
  2. Abstract
  3. Epidemiological evidence
  4. Relationship between rhinitis and asthma
  5. Rhinitis and nonspecific bronchial hyperresponsiveness
  6. Causative agents in rhinitis and asthma
  7. ’Bidirectional’ relationship between nasal and bronchial inflammation: bronchial challenge of rhinitis patients leads to nasal inflammation (and vice versa)
  8. Bronchial inflammation in rhinitis
  9. Bronchial biopsies in rhinitis
  10. Bronchial allergen challenge in rhinitis
  11. Thunderstorm-induced asthma
  12. Viral infection of the nose induces asthma and bronchial inflammation
  13. Nasal and sinus inflammation in asthma
  14. Similarities and differences between nasal and bronchial inflammation in asthma
  15. Sinus involvement in asthma
  16. Allergic inflammation is both local and systemic
  17. The role of IgE
  18. Bone marrow involvement
  19. In situ haemopoiesis
  20. The ’allergic march’
  21. Allergic rhinitis as a risk factor for asthma
  22. Rhinitis and asthma: a continuum of disease
  23. Impact of rhinitis and asthma on quality of life
  24. Therapeutic consequences
  25. Drugs administered locally
  26. Drugs administered orally
  27. Specific immunotherapy
  28. Anti-IgE monoclonal antibody
  29. Treatment of rhinitis reduces asthma severity
  30. Impact of rhinitis on asthma costs
  31. Conclusions
  32. References

Some studies have examined the bronchial mucosa in atopic nonasthmatic patients or in patients with allergic rhinitis. They have shown a slight increase in the size of the basement membrane (61) and a moderate eosinophilic inflammation (62) in patients with allergic rhinitis.

Natural exposure to pollen during the season provokes an increase in airway responsiveness in nonasthmatic subjects with seasonal allergic rhinitis and also induces inflammatory cell recruitment and IL-5 expression, leading to bronchial inflammation (63).

Bronchial allergen challenge in rhinitis

  1. Top of page
  2. Abstract
  3. Epidemiological evidence
  4. Relationship between rhinitis and asthma
  5. Rhinitis and nonspecific bronchial hyperresponsiveness
  6. Causative agents in rhinitis and asthma
  7. ’Bidirectional’ relationship between nasal and bronchial inflammation: bronchial challenge of rhinitis patients leads to nasal inflammation (and vice versa)
  8. Bronchial inflammation in rhinitis
  9. Bronchial biopsies in rhinitis
  10. Bronchial allergen challenge in rhinitis
  11. Thunderstorm-induced asthma
  12. Viral infection of the nose induces asthma and bronchial inflammation
  13. Nasal and sinus inflammation in asthma
  14. Similarities and differences between nasal and bronchial inflammation in asthma
  15. Sinus involvement in asthma
  16. Allergic inflammation is both local and systemic
  17. The role of IgE
  18. Bone marrow involvement
  19. In situ haemopoiesis
  20. The ’allergic march’
  21. Allergic rhinitis as a risk factor for asthma
  22. Rhinitis and asthma: a continuum of disease
  23. Impact of rhinitis and asthma on quality of life
  24. Therapeutic consequences
  25. Drugs administered locally
  26. Drugs administered orally
  27. Specific immunotherapy
  28. Anti-IgE monoclonal antibody
  29. Treatment of rhinitis reduces asthma severity
  30. Impact of rhinitis on asthma costs
  31. Conclusions
  32. References

Patients with seasonal rhinitis who had no history of asthma developed a bronchoconstriction on endobronchial allergen challenge. Lavage carried out after challenge demonstrated the presence of pro-inflammatory mediators and cytokines as well as the recruitment of inflammatory cells (64, 65).

Pulmonary inflammation after segmental ragweed challenge was examined in allergic asthmatics and nonasthmatics (66). A total of 46 ragweed-allergic subjects took part in these studies. The subjects had normal or near-normal pulmonary function, were not on chronic medication, and were characterized by their skin sensitivity to intradermal ragweed injection, their nonspecific responsiveness to methacholine, and the presence (or absence) of a late asthmatic response after whole-lung antigen challenge. Contrary to expectations, the pulmonary inflammatory response, 24 h after segmental ragweed challenge, was the same in subjects with rhinitis as it was in subjects with asthma and rhinitis, as measured by numbers of total cells, macrophages, lymphocytes, eosinophils, and neutrophils in the bronchoalveolar lavage fluid (BAL). Thus, the lungs seem equipped to produce an IgE-mediated inflammatory response in allergic subjects whether asthma is clinically evident or not.

Thunderstorm-induced asthma

  1. Top of page
  2. Abstract
  3. Epidemiological evidence
  4. Relationship between rhinitis and asthma
  5. Rhinitis and nonspecific bronchial hyperresponsiveness
  6. Causative agents in rhinitis and asthma
  7. ’Bidirectional’ relationship between nasal and bronchial inflammation: bronchial challenge of rhinitis patients leads to nasal inflammation (and vice versa)
  8. Bronchial inflammation in rhinitis
  9. Bronchial biopsies in rhinitis
  10. Bronchial allergen challenge in rhinitis
  11. Thunderstorm-induced asthma
  12. Viral infection of the nose induces asthma and bronchial inflammation
  13. Nasal and sinus inflammation in asthma
  14. Similarities and differences between nasal and bronchial inflammation in asthma
  15. Sinus involvement in asthma
  16. Allergic inflammation is both local and systemic
  17. The role of IgE
  18. Bone marrow involvement
  19. In situ haemopoiesis
  20. The ’allergic march’
  21. Allergic rhinitis as a risk factor for asthma
  22. Rhinitis and asthma: a continuum of disease
  23. Impact of rhinitis and asthma on quality of life
  24. Therapeutic consequences
  25. Drugs administered locally
  26. Drugs administered orally
  27. Specific immunotherapy
  28. Anti-IgE monoclonal antibody
  29. Treatment of rhinitis reduces asthma severity
  30. Impact of rhinitis on asthma costs
  31. Conclusions
  32. References

Bronchial challenge studies indicate that patients with nasal symptoms can only react if the allergen is properly administered into the airways. It may be argued that the doses of allergen inducing bronchial reactions are far greater than those naturally occurring during allergen exposure, but abnormal bronchial exposure appears to exist in thunderstorm-induced asthma (67–70). This has been associated with grass pollen allergy (67, 71, 72) and has recently been linked to greatly increased ambient concentrations of pollen grains caused by thunderstorm outflows (73). As the aerodynamic size of pollen grains ranges from 10 to 100 μm and only a fraction of them can be deposited into the bronchi, most patients only present with rhinitis. However, when exposed to water, pollen allergens are released in submicronic particles, the starch granules, which can reach the lower airways and induce asthma (74). An Australian study showed that subjects with a prior history of allergic rhinitis were at significantly increased risk of asthma exacerbations during thunderstorms (OR 6.01), confirming the close relationship between upper and lower airways (75).

Viral infection of the nose induces asthma and bronchial inflammation

  1. Top of page
  2. Abstract
  3. Epidemiological evidence
  4. Relationship between rhinitis and asthma
  5. Rhinitis and nonspecific bronchial hyperresponsiveness
  6. Causative agents in rhinitis and asthma
  7. ’Bidirectional’ relationship between nasal and bronchial inflammation: bronchial challenge of rhinitis patients leads to nasal inflammation (and vice versa)
  8. Bronchial inflammation in rhinitis
  9. Bronchial biopsies in rhinitis
  10. Bronchial allergen challenge in rhinitis
  11. Thunderstorm-induced asthma
  12. Viral infection of the nose induces asthma and bronchial inflammation
  13. Nasal and sinus inflammation in asthma
  14. Similarities and differences between nasal and bronchial inflammation in asthma
  15. Sinus involvement in asthma
  16. Allergic inflammation is both local and systemic
  17. The role of IgE
  18. Bone marrow involvement
  19. In situ haemopoiesis
  20. The ’allergic march’
  21. Allergic rhinitis as a risk factor for asthma
  22. Rhinitis and asthma: a continuum of disease
  23. Impact of rhinitis and asthma on quality of life
  24. Therapeutic consequences
  25. Drugs administered locally
  26. Drugs administered orally
  27. Specific immunotherapy
  28. Anti-IgE monoclonal antibody
  29. Treatment of rhinitis reduces asthma severity
  30. Impact of rhinitis on asthma costs
  31. Conclusions
  32. References

A large number of asthma exacerbations, in both children and adults, are caused by nasal viral infections (76). Rhinoviruses are the major cause of common cold and a trigger of acute asthma exacerbations (77). Experimental upper respiratory (intranasal) rhinovirus infection increases airway hyperreactivity and late asthmatic reactions following allergen challenge (78). Rhinoviruses can also infect the lower airways during natural and experimental intranasal exposure (79–81). These findings suggest that asthma exacerbations may be partly induced through viral enhancement of lower airway inflammation following nasal viral infection.

Similarities and differences between nasal and bronchial inflammation in asthma

  1. Top of page
  2. Abstract
  3. Epidemiological evidence
  4. Relationship between rhinitis and asthma
  5. Rhinitis and nonspecific bronchial hyperresponsiveness
  6. Causative agents in rhinitis and asthma
  7. ’Bidirectional’ relationship between nasal and bronchial inflammation: bronchial challenge of rhinitis patients leads to nasal inflammation (and vice versa)
  8. Bronchial inflammation in rhinitis
  9. Bronchial biopsies in rhinitis
  10. Bronchial allergen challenge in rhinitis
  11. Thunderstorm-induced asthma
  12. Viral infection of the nose induces asthma and bronchial inflammation
  13. Nasal and sinus inflammation in asthma
  14. Similarities and differences between nasal and bronchial inflammation in asthma
  15. Sinus involvement in asthma
  16. Allergic inflammation is both local and systemic
  17. The role of IgE
  18. Bone marrow involvement
  19. In situ haemopoiesis
  20. The ’allergic march’
  21. Allergic rhinitis as a risk factor for asthma
  22. Rhinitis and asthma: a continuum of disease
  23. Impact of rhinitis and asthma on quality of life
  24. Therapeutic consequences
  25. Drugs administered locally
  26. Drugs administered orally
  27. Specific immunotherapy
  28. Anti-IgE monoclonal antibody
  29. Treatment of rhinitis reduces asthma severity
  30. Impact of rhinitis on asthma costs
  31. Conclusions
  32. References

In normal subjects, the structure of the airway mucosa shows similarities between the nose and the bronchi. Both nasal and bronchial mucosa are characterized by a pseudostratified epithelium with columnar, ciliated cells resting on a basement membrane. In the submucosa, vessels, mucous glands, structural cells (fibroblasts), some inflammatory cells (essentially monocytic cells, lymphocytes, and mast cells) (82, 83) and nerves are present.

There are also differences between the nose and the bronchi. The nose is richly supplied with a subepithelial capillary and arterial system and venous cavernous sinusoids. This rich vascularization is a key feature of the nasal mucosa and changes in the vasculature may lead to severe nasal obstruction (84). On the contrary, the bronchi are characterized by the presence of smooth muscle from the trachea to the bronchioles, accounting for the bronchoconstriction of asthma (85).

Recent advances in the understanding of the cellular and molecular biology of airways diseases have clearly shown that inflammation plays a critical role in the pathogenesis of asthma and rhinitis. The same inflammatory cells appear to be present in the nasal and bronchial mucosa (86). A growing number of studies show that the inflammation of nasal and bronchial mucosa is sustained by a similar inflammatory infiltrate, comprising eosinophils, mast cells, T-lymphocytes, and cells of the monocytic lineage (86–89). In addition, the same pro-inflammatory mediators (histamine and cysteinyl leucotrienes), Th2 cytokines (IL-4, IL-5, IL-13, GM-CSF) (86, 90–92), chemokines (RANTES and eotaxin) (93) and adhesion molecules (94–96) appear to be involved in both nasal and bronchial inflammation in patients with rhinitis and asthma.

However, there are major differences between the two sites. Although the bronchial and, especially, the nasal mucosa are exposed to the same environmental insults, epithelial shedding is more pronounced in the bronchi than in the nasal mucosa of patients suffering from both asthma and rhinitis (97). The intensity of the inflammation may not be identical. In patients with moderate–severe asthma, eosinophilic inflammation is more pronounced in the bronchi than in the nasal mucosa (97), whereas in patients with mild asthma inflammation appears to be similar in both sites. Moreover, eosinophilic inflammation of the nasal mucosa exists in asthma patients without any symptoms (98). However, the remodelling of the airways that can be found in the bronchial mucosa appears to feature less extensively in the nasal mucosa.

Sinus involvement in asthma

  1. Top of page
  2. Abstract
  3. Epidemiological evidence
  4. Relationship between rhinitis and asthma
  5. Rhinitis and nonspecific bronchial hyperresponsiveness
  6. Causative agents in rhinitis and asthma
  7. ’Bidirectional’ relationship between nasal and bronchial inflammation: bronchial challenge of rhinitis patients leads to nasal inflammation (and vice versa)
  8. Bronchial inflammation in rhinitis
  9. Bronchial biopsies in rhinitis
  10. Bronchial allergen challenge in rhinitis
  11. Thunderstorm-induced asthma
  12. Viral infection of the nose induces asthma and bronchial inflammation
  13. Nasal and sinus inflammation in asthma
  14. Similarities and differences between nasal and bronchial inflammation in asthma
  15. Sinus involvement in asthma
  16. Allergic inflammation is both local and systemic
  17. The role of IgE
  18. Bone marrow involvement
  19. In situ haemopoiesis
  20. The ’allergic march’
  21. Allergic rhinitis as a risk factor for asthma
  22. Rhinitis and asthma: a continuum of disease
  23. Impact of rhinitis and asthma on quality of life
  24. Therapeutic consequences
  25. Drugs administered locally
  26. Drugs administered orally
  27. Specific immunotherapy
  28. Anti-IgE monoclonal antibody
  29. Treatment of rhinitis reduces asthma severity
  30. Impact of rhinitis on asthma costs
  31. Conclusions
  32. References

While the coexistence of asthma and rhinosinusitis has been recognized in the medical literature for many years (99), the question of whether rhinosinusitis is a precipitating factor for bronchial asthma is still debated. Current knowledge suggests that rhinosinusitis and asthma are linked by a common process that is mainly inflammatory, with eosinophils and airway epithelium having a central pathogenetic role. The association of chronic rhinosinusitis with asthma and allergy appears to be restricted to the asthmatic population with an extensive sinonasal disease, and the presence of peripheral eosinophilia in patients with rhinosinusitis indicates a high likelihood of extensive sinus disease (100). In a study assessing sinonasal involvement in patients with either mild–moderate or severe (corticosteroid-dependent) asthma, the proportion of patients with symptoms of rhinosinusitis was similar in both groups (74% in corticosteroid-dependent asthma and 70% in mild–moderate asthma) (101). All corticosteroid-dependent asthmatics had sinus abnormalities on computed tomography (CT) scan compared with 88% of the mild-moderate asthmatics. The clinical and CT scan scores were higher in the corticosteroid-dependent asthmatics, indicating a relationship between severity of asthma and the features of sinus disease. In both groups, the CT scan scores were correlated to the clinical scores (101). In another recent study examining sinus CT scans of patients with severe asthma, the same close relationship was observed (102). Moreover, in this study, it was shown that chronic sinusitis in severe asthma is related to sputum eosinophilia suggesting that the extent of inflammation in the nasal mucosa is related to lung function and inflammation in the bronchial mucosa in patients with severe asthma. The high prevalence of sinus disease in both groups provides further evidence of the close relationship between the upper and lower airways in asthma.

In contrast to patients with asthma, <10% of patients with chronic obstructive pulmonary disease (COPD) have nasal symptoms. Mucosal biopsies do not usually detect any nasal inflammation in these patients (103) and CT scans show few abnormalities. Thus, the nasal and sinus inflammation in asthmatics seems to be related specifically to asthma and is not a feature of all bronchial diseases (101).

Allergic inflammation is both local and systemic

  1. Top of page
  2. Abstract
  3. Epidemiological evidence
  4. Relationship between rhinitis and asthma
  5. Rhinitis and nonspecific bronchial hyperresponsiveness
  6. Causative agents in rhinitis and asthma
  7. ’Bidirectional’ relationship between nasal and bronchial inflammation: bronchial challenge of rhinitis patients leads to nasal inflammation (and vice versa)
  8. Bronchial inflammation in rhinitis
  9. Bronchial biopsies in rhinitis
  10. Bronchial allergen challenge in rhinitis
  11. Thunderstorm-induced asthma
  12. Viral infection of the nose induces asthma and bronchial inflammation
  13. Nasal and sinus inflammation in asthma
  14. Similarities and differences between nasal and bronchial inflammation in asthma
  15. Sinus involvement in asthma
  16. Allergic inflammation is both local and systemic
  17. The role of IgE
  18. Bone marrow involvement
  19. In situ haemopoiesis
  20. The ’allergic march’
  21. Allergic rhinitis as a risk factor for asthma
  22. Rhinitis and asthma: a continuum of disease
  23. Impact of rhinitis and asthma on quality of life
  24. Therapeutic consequences
  25. Drugs administered locally
  26. Drugs administered orally
  27. Specific immunotherapy
  28. Anti-IgE monoclonal antibody
  29. Treatment of rhinitis reduces asthma severity
  30. Impact of rhinitis on asthma costs
  31. Conclusions
  32. References

Allergic responses involve a cascade of inflammatory events, which link reactive tissues in the target organ to the systemic disorder. Allergen-specific IgE antibodies together with mast cells and basophils play a central role in initiating the inflammatory cascade. In addition, two major mechanisms have been demonstrated to contribute to the increased number of eosinophils in the inflamed airways of allergic subjects: recruitment and persistence of inflammatory cells into the airways, and the presence of bone marrow progenitors in the inflamed airway tissues.

The role of IgE

  1. Top of page
  2. Abstract
  3. Epidemiological evidence
  4. Relationship between rhinitis and asthma
  5. Rhinitis and nonspecific bronchial hyperresponsiveness
  6. Causative agents in rhinitis and asthma
  7. ’Bidirectional’ relationship between nasal and bronchial inflammation: bronchial challenge of rhinitis patients leads to nasal inflammation (and vice versa)
  8. Bronchial inflammation in rhinitis
  9. Bronchial biopsies in rhinitis
  10. Bronchial allergen challenge in rhinitis
  11. Thunderstorm-induced asthma
  12. Viral infection of the nose induces asthma and bronchial inflammation
  13. Nasal and sinus inflammation in asthma
  14. Similarities and differences between nasal and bronchial inflammation in asthma
  15. Sinus involvement in asthma
  16. Allergic inflammation is both local and systemic
  17. The role of IgE
  18. Bone marrow involvement
  19. In situ haemopoiesis
  20. The ’allergic march’
  21. Allergic rhinitis as a risk factor for asthma
  22. Rhinitis and asthma: a continuum of disease
  23. Impact of rhinitis and asthma on quality of life
  24. Therapeutic consequences
  25. Drugs administered locally
  26. Drugs administered orally
  27. Specific immunotherapy
  28. Anti-IgE monoclonal antibody
  29. Treatment of rhinitis reduces asthma severity
  30. Impact of rhinitis on asthma costs
  31. Conclusions
  32. References

Immunoglobulin E antibody production is part of the body's immune response to parasitic invasion, especially through the skin or mucous membranes (104). In allergic individuals, this protective mechanism is misdirected against noninvasive elements that come into contact with these surfaces. Allergic asthma and rhinitis are commonly associated with raised circulating levels of IgE (105), and the increased presence of total serum IgE is a risk factor for asthma even in nonallergic individuals (106). Following sensitization, IgE antibodies produced by B-cells bind to the high-affinity receptors on mast cells, basophils and some other cell types. Mast cell accumulation in the airway mucosa is an important pathophysiological event in allergic rhinitis and asthma as inhaled allergens impact the mucosal surfaces of the nose and/or lungs. The common initiating step in the acute processes of the allergic inflammatory cascade is allergen cross-linking of specific IgE molecules bound to the mast cells, which triggers the release of mediators such as histamine, leucotrienes and platelet activating factor (107). The immediate response depends on the structure of the target organ: typically, itching, sneezing, rhinorrhoea, and blockage in the nose (108), with bronchoconstriction and wheeze caused by smooth muscle contraction in the lungs.

Late phase allergic reactions, and chronic inflammatory changes in the asthmatic lung which involve T cells as well as mast cells and eosinophils, are less understood (107). Further involvement of IgE is implicated; however, through the array of pro-inflammatory cytokines derived from mast cells, including the Th2-type cytokines IL-4 and IL-13 that may account for localized B-cell IgE production in the airway tissues (109–111). In addition, antigen presenting and secondary inflammatory cells, including macrophages, dendritic cells, and eosinophils, are known to express the high-affinity IgE receptor in both asthma and allergic rhinitis (112–114).

Interestingly, it has been shown that IgE is produced in the local lymphoid tissues and locally in both the nasal and bronchial mucosa (115–116). There is a local synthesis of ɛ-germline gene transcripts, IL-4, and IL-13 in allergic nasal mucosa after ex vivo allergen exposure (117), a persistent IgE synthesis in the nasal mucosa of hay fever patients (118) and an increase in allergen-specific IgE in the BAL after segmental allergen challenge in atopic asthma patients (119). A local expression of ɛ-germline gene transcripts and RNA for the ɛ heavy chain of IgE was found in the bronchial mucosa in atopic and nonatopic asthmatics (111).

Bone marrow involvement

  1. Top of page
  2. Abstract
  3. Epidemiological evidence
  4. Relationship between rhinitis and asthma
  5. Rhinitis and nonspecific bronchial hyperresponsiveness
  6. Causative agents in rhinitis and asthma
  7. ’Bidirectional’ relationship between nasal and bronchial inflammation: bronchial challenge of rhinitis patients leads to nasal inflammation (and vice versa)
  8. Bronchial inflammation in rhinitis
  9. Bronchial biopsies in rhinitis
  10. Bronchial allergen challenge in rhinitis
  11. Thunderstorm-induced asthma
  12. Viral infection of the nose induces asthma and bronchial inflammation
  13. Nasal and sinus inflammation in asthma
  14. Similarities and differences between nasal and bronchial inflammation in asthma
  15. Sinus involvement in asthma
  16. Allergic inflammation is both local and systemic
  17. The role of IgE
  18. Bone marrow involvement
  19. In situ haemopoiesis
  20. The ’allergic march’
  21. Allergic rhinitis as a risk factor for asthma
  22. Rhinitis and asthma: a continuum of disease
  23. Impact of rhinitis and asthma on quality of life
  24. Therapeutic consequences
  25. Drugs administered locally
  26. Drugs administered orally
  27. Specific immunotherapy
  28. Anti-IgE monoclonal antibody
  29. Treatment of rhinitis reduces asthma severity
  30. Impact of rhinitis on asthma costs
  31. Conclusions
  32. References

In patients with allergic diseases, allergen provocation can activate a systemic response that provokes inflammatory cell production by the bone marrow (120). There is considerable evidence in animal models and humans that the bone marrow plays an integral role in allergic inflammation (121). In response to allergen exposure in the airway, bone marrow (white blood cell) progenitors proliferate and differentiate, which leads to persistent increases in eosinophil numbers. Signalling between the lung and bone marrow after allergen exposure further suggests that allergy is a systemic disease. Although the nature of the signal-mediating activation of the bone marrow after airway allergen exposure is unknown, several pathways have been implicated, including allergen-induced haemopoietic growth factors, cell trafficking, and stimulation of resident bone marrow cells. A common thread in all these pathways is the importance of IL-5 (114).

After release and differentiation of progenitor cells, eosinophils, basophils and mast cells are typically recruited to tissues in atopic individuals. An understanding of the signalling process at the molecular level that leads to these interactions between the bone marrow and the target organ, especially the airways, may open up new avenues of therapy for allergic inflammatory disease (122, 123). Studies that support the critical involvement of the bone marrow in the development of eosinophilic inflammation of the airways indicate the systemic nature of these conditions.

In situ haemopoiesis

  1. Top of page
  2. Abstract
  3. Epidemiological evidence
  4. Relationship between rhinitis and asthma
  5. Rhinitis and nonspecific bronchial hyperresponsiveness
  6. Causative agents in rhinitis and asthma
  7. ’Bidirectional’ relationship between nasal and bronchial inflammation: bronchial challenge of rhinitis patients leads to nasal inflammation (and vice versa)
  8. Bronchial inflammation in rhinitis
  9. Bronchial biopsies in rhinitis
  10. Bronchial allergen challenge in rhinitis
  11. Thunderstorm-induced asthma
  12. Viral infection of the nose induces asthma and bronchial inflammation
  13. Nasal and sinus inflammation in asthma
  14. Similarities and differences between nasal and bronchial inflammation in asthma
  15. Sinus involvement in asthma
  16. Allergic inflammation is both local and systemic
  17. The role of IgE
  18. Bone marrow involvement
  19. In situ haemopoiesis
  20. The ’allergic march’
  21. Allergic rhinitis as a risk factor for asthma
  22. Rhinitis and asthma: a continuum of disease
  23. Impact of rhinitis and asthma on quality of life
  24. Therapeutic consequences
  25. Drugs administered locally
  26. Drugs administered orally
  27. Specific immunotherapy
  28. Anti-IgE monoclonal antibody
  29. Treatment of rhinitis reduces asthma severity
  30. Impact of rhinitis on asthma costs
  31. Conclusions
  32. References

Another important mechanism, termed ‘in situ haemopoiesis’ (124), depends on the production of haemopoietic cytokines by inflamed airway tissues from patients with allergic rhinitis (125–127) and nasal polyposis (128). By generating a particular local ‘microenvironment’, these cytokines promote the differentiation and maturation of eosinophil progenitors that populate the nasal or bronchial mucosa (129, 130). It is therefore more likely that a truly systemic response to the application of inflammatory stimuli to the airway mucosa should be associated with an activation of the aforementioned mechanisms.

The ’allergic march’

  1. Top of page
  2. Abstract
  3. Epidemiological evidence
  4. Relationship between rhinitis and asthma
  5. Rhinitis and nonspecific bronchial hyperresponsiveness
  6. Causative agents in rhinitis and asthma
  7. ’Bidirectional’ relationship between nasal and bronchial inflammation: bronchial challenge of rhinitis patients leads to nasal inflammation (and vice versa)
  8. Bronchial inflammation in rhinitis
  9. Bronchial biopsies in rhinitis
  10. Bronchial allergen challenge in rhinitis
  11. Thunderstorm-induced asthma
  12. Viral infection of the nose induces asthma and bronchial inflammation
  13. Nasal and sinus inflammation in asthma
  14. Similarities and differences between nasal and bronchial inflammation in asthma
  15. Sinus involvement in asthma
  16. Allergic inflammation is both local and systemic
  17. The role of IgE
  18. Bone marrow involvement
  19. In situ haemopoiesis
  20. The ’allergic march’
  21. Allergic rhinitis as a risk factor for asthma
  22. Rhinitis and asthma: a continuum of disease
  23. Impact of rhinitis and asthma on quality of life
  24. Therapeutic consequences
  25. Drugs administered locally
  26. Drugs administered orally
  27. Specific immunotherapy
  28. Anti-IgE monoclonal antibody
  29. Treatment of rhinitis reduces asthma severity
  30. Impact of rhinitis on asthma costs
  31. Conclusions
  32. References

Atopic dermatitis, asthma, and allergic rhinitis are common comorbidities. Skin symptoms and food allergy are generally the first allergic symptoms to occur in life. Asthma is often present by the second or third year but rhinitis appears to develop later, in particular pollen-induced rhinitis (131, 132). However, allergic rhinitis is not easily diagnosed in infants, making epidemiological studies difficult in young children. A recent study following 94 young children with atopic dermatitis showed a good prognosis for dermatitis (improvement in 87%) but an increased risk of developing asthma (in 43% of the children) or allergic rhinitis (in 45%) before 7 years of age (133). The risk of developing either form of respiratory allergy was especially high in children at an early age with specific IgE to a panel of foods. An increased risk of allergic airway disease associated with atopic dermatitis in early infancy has been shown in other studies (134), and it has been suggested that infants with early signs of atopic dermatitis and a family history of atopic disease are candidates for intervention to prevent the development of respiratory allergies.

In the International Study of Asthma and Allergies in Children (ISAAC), it was difficult to compare rhinitis and asthma in the younger age groups (6–7-year olds) as rhinitis often starts later in life than asthma (131–133). In adolescents in New Zealand, asthma is often more common than rhinitis, but in the same country lower prevalences of asthma are associated with lower prevalences of rhinoconjunctivitis (135). The age of onset of atopy may be an important confounding factor for the development of asthma and rhinitis or rhinitis alone. In an Australian study, it was found that atopy acquired in early life (before the age of 6 years) is an important predictive factor for asthma continuing into late childhood, whereas atopy acquired later was strongly associated with seasonal allergic rhinitis only (136, 137).

Allergic rhinitis as a risk factor for asthma

  1. Top of page
  2. Abstract
  3. Epidemiological evidence
  4. Relationship between rhinitis and asthma
  5. Rhinitis and nonspecific bronchial hyperresponsiveness
  6. Causative agents in rhinitis and asthma
  7. ’Bidirectional’ relationship between nasal and bronchial inflammation: bronchial challenge of rhinitis patients leads to nasal inflammation (and vice versa)
  8. Bronchial inflammation in rhinitis
  9. Bronchial biopsies in rhinitis
  10. Bronchial allergen challenge in rhinitis
  11. Thunderstorm-induced asthma
  12. Viral infection of the nose induces asthma and bronchial inflammation
  13. Nasal and sinus inflammation in asthma
  14. Similarities and differences between nasal and bronchial inflammation in asthma
  15. Sinus involvement in asthma
  16. Allergic inflammation is both local and systemic
  17. The role of IgE
  18. Bone marrow involvement
  19. In situ haemopoiesis
  20. The ’allergic march’
  21. Allergic rhinitis as a risk factor for asthma
  22. Rhinitis and asthma: a continuum of disease
  23. Impact of rhinitis and asthma on quality of life
  24. Therapeutic consequences
  25. Drugs administered locally
  26. Drugs administered orally
  27. Specific immunotherapy
  28. Anti-IgE monoclonal antibody
  29. Treatment of rhinitis reduces asthma severity
  30. Impact of rhinitis on asthma costs
  31. Conclusions
  32. References

Asthma develops more commonly in patients with perennial rhinitis. The Children's Respiratory Study (6) showed that the presence of physician-diagnosed allergic rhinitis in infancy was independently associated with a doubling of the risk of developing asthma by 11 years of age. In adults, allergic rhinitis as a risk factor for asthma was shown in a 23-year follow-up of college students (138). Significantly more (10.5%) of the students originally diagnosed with allergic rhinitis went on to develop asthma compared with 3.6% of those who did not have rhinitis.

This study was recently confirmed by two other studies. A study examined risk factors for onset and remission of allergic rhinitis and asthma in Swedish adults (139). The onset of asthma was associated with allergic rhinitis (OR = 4.9), sensitization to pets (OR = 2.4), and smoking (OR = 3.0). The onset of asthma was strongly associated with allergic rhinitis among atopics (OR = 5.7), but the onset of asthma and rhinitis also tended to be related among nonatopics (OR = 3.5). A strong association between smoking and onset of asthma was found among nonatopics (OR = 5.7).

In a longitudinal community population, the extent to which rhinitis is an independent risk factor for adult-onset asthma was examined (140). Rhinitis was a significant risk factor for asthma (crude OR, 4.13; 95% CI, 2.88–5.92). After adjustment for years of follow-up, age, sex, atopic status, smoking status, and presence of COPD, the magnitude of the association was reduced but still highly significant (adjusted OR, 3.21; 95% CI, 2.19–4.71). After stratification, rhinitis increased the risk of development of asthma by about three times both among atopic and nonatopic patients and by more than five times among patients in the highest IgE tertile. Patients with rhinitis with persistent and severe nasal symptoms and a personal history of physician-confirmed sinusitis had an additional increased risk of asthma development. The authors concluded that rhinitis is a significant risk factor for adult-onset asthma in both atopic and nonatopic subjects.

It is, however, not clear whether allergic rhinitis represents an earlier clinical manifestation of allergic disease in atopic subjects who later develop asthma or if the nasal disease itself is a causative factor in asthma. Both are reasonable hypotheses, and the results of the study described earlier (7) – showing that perennial rhinitis is an important risk factor for asthma in atopic and nonatopic subjects – support both theories. As only a proportion of patients with allergic rhinitis develop asthma, it seems that the presence of an additional, as-yet unidentified ‘lung factor’ is a prerequisite. In clinical terms, additional criteria will be required to strengthen the power of a predictive tool for developing asthma (141).

Nevertheless, it will be interesting to know if treatment of a subject with allergic rhinitis can achieve prevention against the secondary development of asthma. A reduction in raised serum levels of IgE that are typically part of the atopic phenotype would be of interest in this regard, and anti-IgE may therefore be a candidate for this type of prophylaxis.

Rhinitis and asthma: a continuum of disease

  1. Top of page
  2. Abstract
  3. Epidemiological evidence
  4. Relationship between rhinitis and asthma
  5. Rhinitis and nonspecific bronchial hyperresponsiveness
  6. Causative agents in rhinitis and asthma
  7. ’Bidirectional’ relationship between nasal and bronchial inflammation: bronchial challenge of rhinitis patients leads to nasal inflammation (and vice versa)
  8. Bronchial inflammation in rhinitis
  9. Bronchial biopsies in rhinitis
  10. Bronchial allergen challenge in rhinitis
  11. Thunderstorm-induced asthma
  12. Viral infection of the nose induces asthma and bronchial inflammation
  13. Nasal and sinus inflammation in asthma
  14. Similarities and differences between nasal and bronchial inflammation in asthma
  15. Sinus involvement in asthma
  16. Allergic inflammation is both local and systemic
  17. The role of IgE
  18. Bone marrow involvement
  19. In situ haemopoiesis
  20. The ’allergic march’
  21. Allergic rhinitis as a risk factor for asthma
  22. Rhinitis and asthma: a continuum of disease
  23. Impact of rhinitis and asthma on quality of life
  24. Therapeutic consequences
  25. Drugs administered locally
  26. Drugs administered orally
  27. Specific immunotherapy
  28. Anti-IgE monoclonal antibody
  29. Treatment of rhinitis reduces asthma severity
  30. Impact of rhinitis on asthma costs
  31. Conclusions
  32. References

There are similarities and differences between nasal and bronchial mucosa in rhinitis and asthma. It appears that most asthmatics also present with rhinitis, whereas only a fraction of rhinitis patients present with clinically demonstrable asthma (although a higher proportion of patients have nonspecific bronchial hyperresponsiveness). It seems that the epithelial-mesenchymal trophic unit exists from the nose to the bronchiolar-alveolar junction and that the same inflammatory cells are present throughout the airways, suggesting a continuum of disease.

However, there are differences in terms of exposure to allergens and noxious agents – the nose being more exposed than the lower airways. There are also major structural differences between the nasal and bronchial mucosa: the former has a large vascular supply whereas the latter has smooth muscle. Airway smooth muscle is of paramount importance in asthma owing to its contractile properties, but it may also contribute to the pathogenesis of the disease by increased proliferation (142), and the expression and secretion of pro-inflammatory mediators and cytokines (143).

It is therefore possible that the difference between rhinitis and asthma is that in the former there is an epithelial-mesenchymal trophic unit (144) whereas in the latter there is an epithelial-mesenchymal-muscular trophic unit (Fig. 2).

image

Figure 2. The same inflammatory cells are present in an epithelial-mesenchyma trophic unit from the nose to the bronchiolar–alveolar junction, however, there are structural differences. In rhinitis there are numerous blood vessels, which cause nasal obstruction whereas in asthma bronchial smooth muscle causes bronchial obstruction (149). Eos, eosinophils; Neut, neutrophils; MC, mast cells; Ly, lymphocytes; MP, macrophages.

Download figure to PowerPoint

Impact of rhinitis and asthma on quality of life

  1. Top of page
  2. Abstract
  3. Epidemiological evidence
  4. Relationship between rhinitis and asthma
  5. Rhinitis and nonspecific bronchial hyperresponsiveness
  6. Causative agents in rhinitis and asthma
  7. ’Bidirectional’ relationship between nasal and bronchial inflammation: bronchial challenge of rhinitis patients leads to nasal inflammation (and vice versa)
  8. Bronchial inflammation in rhinitis
  9. Bronchial biopsies in rhinitis
  10. Bronchial allergen challenge in rhinitis
  11. Thunderstorm-induced asthma
  12. Viral infection of the nose induces asthma and bronchial inflammation
  13. Nasal and sinus inflammation in asthma
  14. Similarities and differences between nasal and bronchial inflammation in asthma
  15. Sinus involvement in asthma
  16. Allergic inflammation is both local and systemic
  17. The role of IgE
  18. Bone marrow involvement
  19. In situ haemopoiesis
  20. The ’allergic march’
  21. Allergic rhinitis as a risk factor for asthma
  22. Rhinitis and asthma: a continuum of disease
  23. Impact of rhinitis and asthma on quality of life
  24. Therapeutic consequences
  25. Drugs administered locally
  26. Drugs administered orally
  27. Specific immunotherapy
  28. Anti-IgE monoclonal antibody
  29. Treatment of rhinitis reduces asthma severity
  30. Impact of rhinitis on asthma costs
  31. Conclusions
  32. References

Quality of life has been found to be impaired both in patients with asthma (145) and in patients with allergic rhinitis (146), but the relative burden of these diseases has only been investigated in a population-based study (147). Answers to the SF-36 questionnaire were analysed from 850 subjects recruited in two French centres participating in the European Community Respiratory Health Survey. Both asthma and allergic rhinitis were associated with an impaired quality of life, and 78% of patients with asthma also had allergic rhinitis. Subjects with allergic rhinitis but not asthma (n = 240) were more likely than subjects with neither asthma nor rhinitis (n = 349) to report problems with social activities, difficulties with daily activities as a result of emotional problems, and poorer mental well-being. Patients with both asthma and allergic rhinitis (n = 76) experienced more physical limitations than patients with allergic rhinitis alone, but no difference was found between these two groups in the domains relating to social/mental health (Fig. 3). Asthma was not found to further impair the quality of life of subjects with allergic rhinitis for the domains related to mental disability and well-being.

image

Figure 3. Results from the SF-36 questionnaire undertaken by 850 subjects participating in the European Community Health Survey, which illustrate the significant impact of allergic rhinitis and asthma on quality of life (147). Mean scores for SF-36 in control subjects (white bars, n = 349), patients with allergic rhinitis (grey bars, n = 240) and patients with both asthma and allergic rhinitis (black bars, n = 76). The first three concepts, on the left, are related to physical health; the last three, on the right, are primarily related to mental health; the other two concepts are related to both. The results of the Wilcoxon tests for comparisons between the different groups and control subjects are expressed with stars; no star indicates a P value > 0.05; one star, 0.01 ≤ P < 0.05; two stars, 0.001 ≤ P < 0.01; three stars, P < 0.001; the written P values correspond to the test between subjects with rhinitis alone and subjects with both asthma and rhinitis.

Download figure to PowerPoint

Asthma and rhinitis are common chronic conditions that affect adults of working age, but little is known about their relative impact on work loss and decreased productivity. Using random-digit telephone dialling, a population-based survey was carried out in adults aged 18–50 years in northern California. One hundred and twenty five persons with asthma (with or without concomitant rhinitis) and 175 persons with rhinitis alone were interviewed (148). Participation in any adult labour force as onset of the condition was lower among those with asthma (88%) than among those with rhinitis alone (97%) (P = 0.002). In contrast, among those still employed, decreased job effectiveness was more frequently reported in the rhinitis group (43 of 121; 36%) in comparison with asthmatics (14 of 72; 19%). It seems clear that both asthma and rhinitis negatively affect work productivity. Those with asthma are less likely to be employed at all, while among those in employment rhinitis is a more potent cause of decreased work effectiveness. The economic impact of asthma and rhinitis and related conditions may be underappreciated.

Therapeutic consequences

  1. Top of page
  2. Abstract
  3. Epidemiological evidence
  4. Relationship between rhinitis and asthma
  5. Rhinitis and nonspecific bronchial hyperresponsiveness
  6. Causative agents in rhinitis and asthma
  7. ’Bidirectional’ relationship between nasal and bronchial inflammation: bronchial challenge of rhinitis patients leads to nasal inflammation (and vice versa)
  8. Bronchial inflammation in rhinitis
  9. Bronchial biopsies in rhinitis
  10. Bronchial allergen challenge in rhinitis
  11. Thunderstorm-induced asthma
  12. Viral infection of the nose induces asthma and bronchial inflammation
  13. Nasal and sinus inflammation in asthma
  14. Similarities and differences between nasal and bronchial inflammation in asthma
  15. Sinus involvement in asthma
  16. Allergic inflammation is both local and systemic
  17. The role of IgE
  18. Bone marrow involvement
  19. In situ haemopoiesis
  20. The ’allergic march’
  21. Allergic rhinitis as a risk factor for asthma
  22. Rhinitis and asthma: a continuum of disease
  23. Impact of rhinitis and asthma on quality of life
  24. Therapeutic consequences
  25. Drugs administered locally
  26. Drugs administered orally
  27. Specific immunotherapy
  28. Anti-IgE monoclonal antibody
  29. Treatment of rhinitis reduces asthma severity
  30. Impact of rhinitis on asthma costs
  31. Conclusions
  32. References

Although asthma and allergic rhinitis commonly occur together, treatments for one condition could potentially alleviate the coexisting condition.

Medications for asthma and rhinitis can be administered via local (intranasal, intra-ocular or inhaled (intrabronchial), oral and parenteral routes. There are advantages (and some drawbacks) to administering the drug directly into the target organ (149). Moreover, some drugs like cromoglycate or nedocromil are not absorbed when given orally and are only effective when administered locally. In patients suffering from asthma and rhinitis, local administration of drugs requires that they are given both nasally and bronchially and this may decrease compliance to treatment which is low in asthma and rhinitis.

Drugs administered locally

  1. Top of page
  2. Abstract
  3. Epidemiological evidence
  4. Relationship between rhinitis and asthma
  5. Rhinitis and nonspecific bronchial hyperresponsiveness
  6. Causative agents in rhinitis and asthma
  7. ’Bidirectional’ relationship between nasal and bronchial inflammation: bronchial challenge of rhinitis patients leads to nasal inflammation (and vice versa)
  8. Bronchial inflammation in rhinitis
  9. Bronchial biopsies in rhinitis
  10. Bronchial allergen challenge in rhinitis
  11. Thunderstorm-induced asthma
  12. Viral infection of the nose induces asthma and bronchial inflammation
  13. Nasal and sinus inflammation in asthma
  14. Similarities and differences between nasal and bronchial inflammation in asthma
  15. Sinus involvement in asthma
  16. Allergic inflammation is both local and systemic
  17. The role of IgE
  18. Bone marrow involvement
  19. In situ haemopoiesis
  20. The ’allergic march’
  21. Allergic rhinitis as a risk factor for asthma
  22. Rhinitis and asthma: a continuum of disease
  23. Impact of rhinitis and asthma on quality of life
  24. Therapeutic consequences
  25. Drugs administered locally
  26. Drugs administered orally
  27. Specific immunotherapy
  28. Anti-IgE monoclonal antibody
  29. Treatment of rhinitis reduces asthma severity
  30. Impact of rhinitis on asthma costs
  31. Conclusions
  32. References

Glucocorticosteroids are the most effective drugs when used topically in the nose and the bronchi for the treatment of rhinitis and asthma. The intranasal treatment of rhinitis using glucocorticosteroids was found to improve asthma in some but not all studies (150). Symptoms (151, 152) and pulmonary function tests (151) were improved, and, exercised-induced asthma (153) or BHR (152, 154, 155) were reduced. These data suggest that treating nasal inflammation may help in controlling asthma. However, a number of aspects, such as the extent to which the pathophysiology of the two diseases overlaps and whether treating one will affect the other, still remain to be clarified.

Little is known about the effects of intrabronchially administered glucocorticosteroids on nasal disease. A study examined the effects of intrabronchially administered budesonide (avoiding nasal deposition of the drug) on nasal allergic disease in patients with seasonal allergic rhinitis, but without asthma (156). During the birch pollen season, budesonide reduced seasonal eosinophilia both in the circulation and in the nose along with an attenuation of seasonal nasal symptoms. Nasal and systemic anti-eosinophil actions are produced at commonly employed dose levels of orally inhaled budesonide.

Drugs administered orally

  1. Top of page
  2. Abstract
  3. Epidemiological evidence
  4. Relationship between rhinitis and asthma
  5. Rhinitis and nonspecific bronchial hyperresponsiveness
  6. Causative agents in rhinitis and asthma
  7. ’Bidirectional’ relationship between nasal and bronchial inflammation: bronchial challenge of rhinitis patients leads to nasal inflammation (and vice versa)
  8. Bronchial inflammation in rhinitis
  9. Bronchial biopsies in rhinitis
  10. Bronchial allergen challenge in rhinitis
  11. Thunderstorm-induced asthma
  12. Viral infection of the nose induces asthma and bronchial inflammation
  13. Nasal and sinus inflammation in asthma
  14. Similarities and differences between nasal and bronchial inflammation in asthma
  15. Sinus involvement in asthma
  16. Allergic inflammation is both local and systemic
  17. The role of IgE
  18. Bone marrow involvement
  19. In situ haemopoiesis
  20. The ’allergic march’
  21. Allergic rhinitis as a risk factor for asthma
  22. Rhinitis and asthma: a continuum of disease
  23. Impact of rhinitis and asthma on quality of life
  24. Therapeutic consequences
  25. Drugs administered locally
  26. Drugs administered orally
  27. Specific immunotherapy
  28. Anti-IgE monoclonal antibody
  29. Treatment of rhinitis reduces asthma severity
  30. Impact of rhinitis on asthma costs
  31. Conclusions
  32. References

Orally administered drugs may have an effect on both nasal and bronchial symptoms. Oral H1 antihistamines represent the first line treatment of allergic rhinitis. Although some studies have found a modest effect of H1 antihistamines on asthma symptoms (157), these drugs are not recommended for the treatment of asthma (158). Leucotriene modifiers were shown to be effective in controlling symptoms of mild to moderate asthma and seasonal allergic rhinitis (159). Oral glucocorticosteroids are highly effective in the treatment of rhinitis and asthma but side-effects after long-term use are common.

Specific immunotherapy

  1. Top of page
  2. Abstract
  3. Epidemiological evidence
  4. Relationship between rhinitis and asthma
  5. Rhinitis and nonspecific bronchial hyperresponsiveness
  6. Causative agents in rhinitis and asthma
  7. ’Bidirectional’ relationship between nasal and bronchial inflammation: bronchial challenge of rhinitis patients leads to nasal inflammation (and vice versa)
  8. Bronchial inflammation in rhinitis
  9. Bronchial biopsies in rhinitis
  10. Bronchial allergen challenge in rhinitis
  11. Thunderstorm-induced asthma
  12. Viral infection of the nose induces asthma and bronchial inflammation
  13. Nasal and sinus inflammation in asthma
  14. Similarities and differences between nasal and bronchial inflammation in asthma
  15. Sinus involvement in asthma
  16. Allergic inflammation is both local and systemic
  17. The role of IgE
  18. Bone marrow involvement
  19. In situ haemopoiesis
  20. The ’allergic march’
  21. Allergic rhinitis as a risk factor for asthma
  22. Rhinitis and asthma: a continuum of disease
  23. Impact of rhinitis and asthma on quality of life
  24. Therapeutic consequences
  25. Drugs administered locally
  26. Drugs administered orally
  27. Specific immunotherapy
  28. Anti-IgE monoclonal antibody
  29. Treatment of rhinitis reduces asthma severity
  30. Impact of rhinitis on asthma costs
  31. Conclusions
  32. References

The indications of specific immunotherapy in allergic asthma and rhinitis have been separated in some guidelines (160). This artificial separation has led to unresolved issues (161, 162) possibly because the allergen-induced IgE-mediated reaction has not been considered to be a multi-organ disease (163). It is therefore important to consider specific immunotherapy based on allergen sensitization rather than on the disease itself as most patients with allergic asthma also present rhinitis or rhinoconjunctivitis (149). Immunotherapy can also alter the atopic phenotype by restoring the normal equilibrium between Th1 and Th2 lymphocytes (164). This form of therapy is currently under investigation in subjects with allergic rhinitis as a means of prevention of secondary asthma, and initial results are encouraging (165).

Anti-IgE monoclonal antibody

  1. Top of page
  2. Abstract
  3. Epidemiological evidence
  4. Relationship between rhinitis and asthma
  5. Rhinitis and nonspecific bronchial hyperresponsiveness
  6. Causative agents in rhinitis and asthma
  7. ’Bidirectional’ relationship between nasal and bronchial inflammation: bronchial challenge of rhinitis patients leads to nasal inflammation (and vice versa)
  8. Bronchial inflammation in rhinitis
  9. Bronchial biopsies in rhinitis
  10. Bronchial allergen challenge in rhinitis
  11. Thunderstorm-induced asthma
  12. Viral infection of the nose induces asthma and bronchial inflammation
  13. Nasal and sinus inflammation in asthma
  14. Similarities and differences between nasal and bronchial inflammation in asthma
  15. Sinus involvement in asthma
  16. Allergic inflammation is both local and systemic
  17. The role of IgE
  18. Bone marrow involvement
  19. In situ haemopoiesis
  20. The ’allergic march’
  21. Allergic rhinitis as a risk factor for asthma
  22. Rhinitis and asthma: a continuum of disease
  23. Impact of rhinitis and asthma on quality of life
  24. Therapeutic consequences
  25. Drugs administered locally
  26. Drugs administered orally
  27. Specific immunotherapy
  28. Anti-IgE monoclonal antibody
  29. Treatment of rhinitis reduces asthma severity
  30. Impact of rhinitis on asthma costs
  31. Conclusions
  32. References

The anti-IgE antibody, omalizumab, has been shown to be safe and effective in separate populations of patients with seasonal and perennial allergic rhinitis (166, 167) (Fig. 4), and in children and adults with moderate–severe allergic asthma (168–170). Studies are ongoing to assess its effectiveness in patients with comorbid allergic airway disease, and to investigate whether a course of treatment could reduce the risk of developing asthma. Its systemic activity and ability to reduce levels of IgE regardless of allergen specificity may be especially advantageous in these respects.

image

Figure 4. Results from a randomized, placebo-controlled parallel group study in 250 adults with seasonal allergic rhinitis illustrating the efficacy of the anti-IgE monoclonal antibody omalizumab. Average daily nasal symptom severity scores (with SEs) for the entire randomization period are shown for the intent-to-treat analysis. A highly statistically significant difference was found between omalizumab-treated patients and placebo-recipients (166).

Download figure to PowerPoint

Treatment of rhinitis reduces asthma severity

  1. Top of page
  2. Abstract
  3. Epidemiological evidence
  4. Relationship between rhinitis and asthma
  5. Rhinitis and nonspecific bronchial hyperresponsiveness
  6. Causative agents in rhinitis and asthma
  7. ’Bidirectional’ relationship between nasal and bronchial inflammation: bronchial challenge of rhinitis patients leads to nasal inflammation (and vice versa)
  8. Bronchial inflammation in rhinitis
  9. Bronchial biopsies in rhinitis
  10. Bronchial allergen challenge in rhinitis
  11. Thunderstorm-induced asthma
  12. Viral infection of the nose induces asthma and bronchial inflammation
  13. Nasal and sinus inflammation in asthma
  14. Similarities and differences between nasal and bronchial inflammation in asthma
  15. Sinus involvement in asthma
  16. Allergic inflammation is both local and systemic
  17. The role of IgE
  18. Bone marrow involvement
  19. In situ haemopoiesis
  20. The ’allergic march’
  21. Allergic rhinitis as a risk factor for asthma
  22. Rhinitis and asthma: a continuum of disease
  23. Impact of rhinitis and asthma on quality of life
  24. Therapeutic consequences
  25. Drugs administered locally
  26. Drugs administered orally
  27. Specific immunotherapy
  28. Anti-IgE monoclonal antibody
  29. Treatment of rhinitis reduces asthma severity
  30. Impact of rhinitis on asthma costs
  31. Conclusions
  32. References

Two very recent studies showed that treating allergic rhinitis reduces health care utilization for comorbid asthma. In a first study, a retrospective cohort study was carried out with 1994–95 MarketScan claims data. The cohort was limited to patients with both allergic rhinitis and asthma, aged 12–60 years, who were continuously enrolled and had no evidence of COPD (171). The study sample population consisted of 4944 patients with allergic asthma, approximately 73% of who were treated for allergic rhinitis. The risk of an asthma-related event (hospitalizations and emergency department visits) for the treated group was about half of the untreated group.

In another study, Adams et al. attempted to find out whether treatment for rhinitis can reduce the risk for emergency department (ED) visits for asthma (172). A retrospective cohort was studied in members of a managed care organization aged >5 years who were diagnosed with asthma during October 1991 to September 1994. Of the 13 844 eligible persons, 1031 (7.4%) had an ED visit for asthma. The overall relative risk (RR) for an ED visit among those who received intranasal corticosteroids was 0.7 (95% CI, 0.59–0.94). When different rates of dispensing for intranasal steroids were examined, a reduced risk of ED visits was seen in those with >0–1 (RR, 0.7; 95% CI, 0.57–0.99) and >3 (RR, 0.5; 95% CI, 0.23–1.05) dispensed prescriptions per year.

These two studies show that treatment of nasal conditions, particularly with intranasal steroids, confers significant protection against exacerbations of asthma leading to ED visits for asthma.

Impact of rhinitis on asthma costs

  1. Top of page
  2. Abstract
  3. Epidemiological evidence
  4. Relationship between rhinitis and asthma
  5. Rhinitis and nonspecific bronchial hyperresponsiveness
  6. Causative agents in rhinitis and asthma
  7. ’Bidirectional’ relationship between nasal and bronchial inflammation: bronchial challenge of rhinitis patients leads to nasal inflammation (and vice versa)
  8. Bronchial inflammation in rhinitis
  9. Bronchial biopsies in rhinitis
  10. Bronchial allergen challenge in rhinitis
  11. Thunderstorm-induced asthma
  12. Viral infection of the nose induces asthma and bronchial inflammation
  13. Nasal and sinus inflammation in asthma
  14. Similarities and differences between nasal and bronchial inflammation in asthma
  15. Sinus involvement in asthma
  16. Allergic inflammation is both local and systemic
  17. The role of IgE
  18. Bone marrow involvement
  19. In situ haemopoiesis
  20. The ’allergic march’
  21. Allergic rhinitis as a risk factor for asthma
  22. Rhinitis and asthma: a continuum of disease
  23. Impact of rhinitis and asthma on quality of life
  24. Therapeutic consequences
  25. Drugs administered locally
  26. Drugs administered orally
  27. Specific immunotherapy
  28. Anti-IgE monoclonal antibody
  29. Treatment of rhinitis reduces asthma severity
  30. Impact of rhinitis on asthma costs
  31. Conclusions
  32. References

Yawn et al. examined the incremental medical care costs of concomitant allergic rhinitis and asthma (8). For each member of a population-based asthma cohort, medical charts were used to record age at first diagnosis of asthma, the presence and age of any diagnosis of allergic rhinitis and the total, ambulatory and respiratory care-related costs of medical care. Yearly medical care charges were, on average, 46% higher for those with asthma and concomitant allergic rhinitis than for persons with asthma alone, after controlling for age and sex.

Conclusions

  1. Top of page
  2. Abstract
  3. Epidemiological evidence
  4. Relationship between rhinitis and asthma
  5. Rhinitis and nonspecific bronchial hyperresponsiveness
  6. Causative agents in rhinitis and asthma
  7. ’Bidirectional’ relationship between nasal and bronchial inflammation: bronchial challenge of rhinitis patients leads to nasal inflammation (and vice versa)
  8. Bronchial inflammation in rhinitis
  9. Bronchial biopsies in rhinitis
  10. Bronchial allergen challenge in rhinitis
  11. Thunderstorm-induced asthma
  12. Viral infection of the nose induces asthma and bronchial inflammation
  13. Nasal and sinus inflammation in asthma
  14. Similarities and differences between nasal and bronchial inflammation in asthma
  15. Sinus involvement in asthma
  16. Allergic inflammation is both local and systemic
  17. The role of IgE
  18. Bone marrow involvement
  19. In situ haemopoiesis
  20. The ’allergic march’
  21. Allergic rhinitis as a risk factor for asthma
  22. Rhinitis and asthma: a continuum of disease
  23. Impact of rhinitis and asthma on quality of life
  24. Therapeutic consequences
  25. Drugs administered locally
  26. Drugs administered orally
  27. Specific immunotherapy
  28. Anti-IgE monoclonal antibody
  29. Treatment of rhinitis reduces asthma severity
  30. Impact of rhinitis on asthma costs
  31. Conclusions
  32. References

Rhinitis is a very common comorbidity of asthma and common mechanisms exist. An initiative in collaboration with WHO, termed Allergic Rhinitis and its Impact on Asthma (ARIA), has been developed to assess the association between asthma and rhinitis (149). It has recently been proposed that physicians should consider the diagnosis of rhinitis in all asthmatics (8). New therapies such as anti-IgE which act early in the allergic cascade, thereby preventing the initiation of the inflammatory process in both asthma and allergic rhinitis, may provide a promising option for future treatment of these conditions.

References

  1. Top of page
  2. Abstract
  3. Epidemiological evidence
  4. Relationship between rhinitis and asthma
  5. Rhinitis and nonspecific bronchial hyperresponsiveness
  6. Causative agents in rhinitis and asthma
  7. ’Bidirectional’ relationship between nasal and bronchial inflammation: bronchial challenge of rhinitis patients leads to nasal inflammation (and vice versa)
  8. Bronchial inflammation in rhinitis
  9. Bronchial biopsies in rhinitis
  10. Bronchial allergen challenge in rhinitis
  11. Thunderstorm-induced asthma
  12. Viral infection of the nose induces asthma and bronchial inflammation
  13. Nasal and sinus inflammation in asthma
  14. Similarities and differences between nasal and bronchial inflammation in asthma
  15. Sinus involvement in asthma
  16. Allergic inflammation is both local and systemic
  17. The role of IgE
  18. Bone marrow involvement
  19. In situ haemopoiesis
  20. The ’allergic march’
  21. Allergic rhinitis as a risk factor for asthma
  22. Rhinitis and asthma: a continuum of disease
  23. Impact of rhinitis and asthma on quality of life
  24. Therapeutic consequences
  25. Drugs administered locally
  26. Drugs administered orally
  27. Specific immunotherapy
  28. Anti-IgE monoclonal antibody
  29. Treatment of rhinitis reduces asthma severity
  30. Impact of rhinitis on asthma costs
  31. Conclusions
  32. References
  • 1
    Vignola AM, Chanez P, Godard P, Bousquet J. Relationships between rhinitis and asthma. Allergy 1998;53: 833839.
  • 2
    Simons FE. Allergic rhinobronchitis: the asthma-allergic rhinitis link. J Allergy Clin Immunol 1999;104: 534540.
  • 3
    American Thoracic Society Workshop. Immunobiology of asthma and rhinitis. Pathogenic factors and therapeutic options. Am J Respir Crit Care Med 1999; 160: 17781787.
  • 4
    Vignola AM, Bousquet J. Rhinitis and asthma: a continuum of disease? Clin Exp Allergy 2001;31: 674677.
  • 5
    Sibbald B, Rink E. Epidemiology of seasonal and perennial rhinitis: clinical presentation and medical history. Thorax 1991;46: 895901.
  • 6
    Wright AL, Holberg CJ, Martinez FD, Halonen M, Morgan W, Taussig LM. Epidemiology of physician-diagnosed allergic rhinitis in childhood. Pediatrics 1994;94: 895901.
  • 7
    Leynaert B, Bousquet J, Neukirch C, Liard R, Neukirch F. Perennial rhinitis: an independent risk factor for asthma in nonatopic subjects: results from the European Community Respiratory Health Survey. J Allergy Clin Immunol 1999;104: 301304.
  • 8
    Yawn BP, Yunginger JW, Wollan PC, Reed CE, Silverstein MD, Harris AG. Allergic rhinitis in Rochester, Minnesota residents with asthma: frequency and impact on health care charges. J Allergy Clin Immunol 1999; 103: 5459.
  • 9
    Pariente P, Le-Pen C, Los F, Bousquet J. Quality-of-life outcomes and the use of antihistamines in a French national population-based sample of patients with perennial rhinitis. Pharmacoeconomics 1997;12: 585595.
  • 10
    Reicin A, White R, Weinstein SF, Finn AF Jr, Nguyen H, Peszek I, et al. Montelukast, a leukotriene receptor antagonist, in combination with loratadine, a histamine receptor antagonist, in the treatment of chronic asthma. Arch Intern Med 2000;160: 24812488.
  • 11
    Lundback B. Epidemiology of rhinitis and asthma. Clin Exp Allergy 1998;28(S.2):310.
  • 12
    Linneberg A, Nielsen NH, Madsen F, Frolund L, Dirksen A, Jorgensen T. Secular trends of allergic asthma in Danish adults. The Copenhagen Allergy Study. Respir Med 2001;95: 258264.
  • 13
    Celedon JC, Palmer LJ, Weiss ST, Wang B, Fang Z, Xu X. Asthma, rhinitis, and skin test reactivity to aeroallergens in families of asthmatic subjects in Anqing, China. Am J Respir Crit Care Med 2001;163: 11081112.
  • 14
    Townley R, Ryo U, Kolotin B, Kang B. Bronchial sensitivity to methacholine in current and former asthmatic and allergic rhinitis patients and control subjects. J Allergy Clin Immunol 1975;56: 429437.
  • 15
    Leynaert B, Bousquet J, Henry C, Liard R, Neukirch F. Is bronchial hyperresponsiveness more frequent in women than in men? A population-based study. Am J Respir Crit Care Med 1997;156: 14131420.
  • 16
    Sotomayor H, Badier M, Vervloet D, Orehek J. Seasonal increase of carbachol airway responsiveness in patients allergic to grass pollen. Reversal by corticosteroids. Am Rev Respir Dis 1984;130: 5658.
  • 17
    Boulet LP, Morin D, Milot J, Turcotte H. Bronchial responsiveness increases after seasonal antigen exposure in non-asthmatic subjects with pollen-induced rhinitis. Ann Allergy 1989;63: 114119.
  • 18
    Witteman AM, Sjamsoedin DH, Jansen HM, Van-der-Zee JS. Differences in nonspecific bronchial responsiveness between patients with asthma and patients with rhinitis are not explained by type and degree of inhalant allergy. Int Arch Allergy Immunol 1997;112: 6572.
  • 19
    Dahl R, Mygind N. Mechanisms of airflow limitation in the nose and lungs. Clin Exp Allergy 1998;2: 1725.
  • 20
    Szczeklik A, Stevenson DD. Aspirin-induced asthma: advances in pathogenesis and management. J Allergy Clin Immunol 1999;104: 513.
  • 21
    Pearce N, Douwes J, Beasley R. Is allergen exposure the major primary cause of asthma? Thorax 2000;55: 424431.
  • 22
    Sporik R, Holgate ST, Platts-Mills TA, Cogswell JJ. Exposure to house-dust mite allergen (Der p I) and the development of asthma in childhood. A prospective study. N Engl J Med 1990;323: 502507.
  • 23
    Peat JK, Tovey E, Toelle BG, Haby MM, Gray EJ, Mahmic A, et al. House dust mite allergens. A major risk factor for childhood asthma in Australia. Am J Respir Crit Care Med 1996;153: 141146.
  • 24
    Peat J, Tovey E, Mellis C, Leeder S, Woolcock A. Importance of house dust mite and Alternaria allergens in childhood asthma: an epidemiological study in two climatic regions of Australia. Clin Exp Allergy 1973;23: 812820.
  • 25
    Neukirch C, Henry C, Leynaert B, Liard R, Bousquet J, Neukirch F. Is sensitization to Alternaria alternata a risk factor for severe asthma? A population-based study. J Allergy Clin Immunol 1999;103: 709711.
  • 26
    Rosenstreich DL, Eggleston P, Kattan M, Baker D, Slavin RG, Gergen P, et al. The role of cockroach allergy and exposure to cockroach allergen in causing morbidity among inner-city children with asthma. N Engl J Med 1997;336: 13561363.
  • 27
    Gergen PJ, Turkeltaub PC. The association of individual allergen reactivity with respiratory disease in a national sample: data from the second National Health and Nutrition Examination Survey, 1976-80 (NHANES II). J Allergy Clin Immunol 1992;90: 579588.
  • 28
    Charpin D, Hughes B, Mallea M, Sutra JP, Balansard G, Vervloet D. Seasonal allergic symptoms and their relation to pollen exposure in south-east France. Clin Exp Allergy 1993;23: 435439.
  • 29
    Sari-Minodier I, Charpin D, Signouret M, Poyen D, Vervloet D. Prevalence of self-reported respiratory symptoms in workers exposed to isocyanates. J Occup Environ Med 1999;41: 582588.
  • 30
    Malo JL, Lemiere C, Desjardins A, Cartier A. Prevalence and intensity of rhinoconjunctivitis in subjects with occupational asthma. Eur Respir J 1997;10: 15131515.
  • 31
    Baur X. Baker's asthma: causes and prevention. Int Arch Occup Environ Health 1999;72: 292296.
  • 32
    Brisman J, Jarvholm B. Bakery work, atopy and the incidence of self-reported hay fever and rhinitis. Eur Respir J 1999;13: 502507.
  • 33
    Yach D, Myers J, Bradshaw D, Benatar SR. A respiratory epidemiologic survey of grain mill workers in Cape Town, South Africa. Am Rev Respir Dis 1985;131: 505510.
  • 34
    Wilhelmsson B, Jernudd Y, Ripe E, Holmberg K. Nasal hypersensitivity in wood furniture workers. An allergological and immunological investigation with special reference to mould and wood. Allergy 1984;39: 586595.
  • 35
    Kanerva L, Vaheri E. Occupational allergic rhinitis in Finland. Int Arch Occup Environ Health 1993;64: 565568.
  • 36
    Corrado OJ, Osman J, Davies RJ. Asthma and rhinitis after exposure to glutaraldehyde in endoscopy units. Hum Toxicol 1986;5: 325328.
  • 37
    Bardana EJ Jr, Andrach RH. Occupational asthma secondary to low molecular weight agents used in the plastic and resin industries. Eur J Respir Dis 1983;64: 241251.
  • 38
    Burge PS, Perks W, O'Brien IM, Hawkins R, Green M. Occupational asthma in an electronics factory. Thorax 1979;34: 1318.
  • 39
    Platts-Mills TA, Longbottom J, Edwards J, Heymann PW. Asthma and rhinitis related to laboratory rats: use of a purified rat urinary allergen to study exposure in laboratories and the human immune response. N Engl Reg Allergy Proc 1987;8: 245251.
  • 40
    Krakowiak A, Szulc B, Gorski P. Occupational respiratory diseases in laboratory animal workers: initial results. Int J Occup Med Environ Health 1997;10: 3136.
  • 41
    Seward JP. Medical surveillance of allergy in laboratory animal handlers. ILAR J 2001;42: 4754.
  • 42
    Kopferschmit-Kubler MC, Stenger R, Blaumeiser M, Eveilleau C, Bessot JC, Pauli G, et al. Asthma, rhinitis and urticaria following occupational exposure to cyanoacrylate glues. Rev Mal Respir 1996;13: 305307.
  • 43
    Kopp SK, McKay RT, Moller DR, Cassedy K, Brooks SM. Asthma and rhinitis due to ethylcyanoacrylate instant glue. Ann Int Med 1985;102: 613615.
  • 44
    Jaeger D, Kleinhans D, Czuppon AB, Baur X. Latex-specific proteins causing immediate-type cutaneous, nasal, bronchial, and systemic reactions. J Allergy Clin Immunol 1992;89: 759768.
  • 45
    Charous BL, Blanco C, Tarlo S, Hamilton RG, Baur X, Beezhold D, et al. Natural rubber latex allergy after 12 years: recommendations and perspectives. J Allergy Clin Immunol 2002;109: 3134.
  • 46
    Leino T, Tammilehto L, Hytonen M, Sala E, Paakkulainen H, Kanerva L. Occupational skin and respiratory diseases among hairdressers. Scand J Work Environ Health 1998;24: 398406.
  • 47
    Chan-Yeung M, Malo JL. Occupational asthma. N Engl J Med 1995;333: 107112.
  • 48
    Malo JL, Lemiere C, Desjardins A, Cartier A. Prevalence and intensity of rhinoconjunctivitis in subjects with occupational asthma. Eur Respir J 1997;10: 15131515.
  • 49
    Seward JP. Medical surveillance of allergy in laboratory animal handlers. ILAR J 2001;42: 4754.
  • 50
    Daroca P, Crespo JF, Reano M, James JM, Lopez-Rubio A, Rodriguez J. Asthma and rhinitis induced by exposure to raw green beans and chards. Ann Allergy Asthma Immunol 2000;85: 215218.
  • 51
    Gorski P, Krakowiak A, Ruta U. Nasal and bronchial responses to flour–inhalation in subjects with occupationally induced allergy affecting the airway. Int Arch Occup Environ Health 2000;73: 488497.
  • 52
    Heederik D, Houba R. An exploratory quantitative risk assessment for high molecular weight sensitizers: wheat flour. Ann Occup Hyg 2001;45: 175185.
  • 53
    Kujala V. A review of current literature on epidemiology of immediate glove irritation and latex allergy. Occup Med (Lond) 1999;49: 39.
  • 54
    Larese Filon F, Bosco A, Fiorito A, Negro C, Barbina P. Latex symptoms and sensitisation in health care workers. Int Arch Occup Environ Health 2001;74: 219223.
  • 55
    Piirila P, Estlander T, Hytonen M, Keskinen H, Tupasela O, Tuppurainen M. Rhinitis caused by ninhydrin develops into occupational asthma. Eur Respir J 1997;10: 19181921.
  • 56
    Piirila P, Estlander T, Keskinen H, Jolanki R, Laakkonen A, Pfaffli P, et al. Occupational asthma caused by triglycidyl isocyanurate (TGIC). Clin Exp Allergy 1997;27: 510514.
  • 57
    Moscato G, Galdi E, Scibilia J, Dellabianca A, Omodeo P, Vittadini G, et al. Occupational asthma, rhinitis and urticaria due to piperacillin sodium in a pharmaceutical worker. Eur Respir J 1995;8: 467469.
  • 58
    Quirce S, Baeza ML, Tornero P, Blasco A, Barranco R, Sastre J. Occupational asthma caused by exposure to cyanoacrylate. Allergy 2001;56: 446449.
  • 59
    Braunstahl GJ, Kleinjan A, Overbeek SE, Prins JB, Hoogsteden HC, Fokkens WJ. Segmental bronchial provocation induces nasal inflammation in allergic rhinitis patients. Am J Respir Crit Care Med 2000;161: 20512057.
  • 60
    Braunstahl GJ, Overbeek SE, Kleinjan A, Prins JB, Hoogsteden HC, Fokkens WJ. Nasal allergen provocation induces adhesion molecule expression and tissue eosinophilia in upper and lower airways. J Allergy Clin Immunol 2001;107: 469476.
  • 61
    Chakir J, Laviolette M, Boutet M, Laliberte R, Dube J, Boulet LP. Lower airways remodeling in nonasthmatic subjects with allergic rhinitis. Lab Invest 1996;75: 735744.
  • 62
    Djukanovic R, Lai CK, Wilson JW, Britten KM, Wilson SJ, Roche WR, et al. Bronchial mucosal manifestations of atopy: a comparison of markers of inflammation between atopic asthmatics, atopic nonasthmatics and healthy controls. Eur Respir J 1992;5: 538544.
  • 63
    Chakir J, Laviolette M, Turcotte H, Boutet M, Boulet LP. Cytokine expression in the lower airways of nonasthmatic subjects with allergic rhinitis: influence of natural allergen exposure. J Allergy Clin Immunol 2000;106: 904910.
  • 64
    Calhoun WJ, Jarjour NN, Gleich GJ, Stevens CA, Busse WW. Increased airway inflammation with segmental versus aerosol antigen challenge. Am Rev Respir Dis 1993;147: 14651471.
  • 65
    Calhoun WJ, Reed HE, Moest DR, Stevens CA. Enhanced superoxide production by alveolar macrophages and air–space cells, airway inflammation, and alveolar macrophage density changes after segmental antigen bronchoprovocation in allergic subjects. Am Rev Respir Dis 1992;145: 317325.
  • 66
    Shaver JR, O'Connor JJ, Pollice M, Cho SK, Kane GC, Fish JE, et al. Pulmonary inflammation after segmental ragweed challenge in allergic asthmatic and nonasthmatic subjects. Am J Respir Crit Care Med 1995;152: 11891197.
  • 67
    Packe GE, Ayres JG. Asthma outbreak during a thunderstorm. Lancet 1985;2: 199204.
  • 68
    Venables KM, Allitt U, Collier CG, Emberlin J, Greig JB, Hardaker PJ, et al. Thunderstorm-related asthma – the epidemic of 24/25 June 1994. Clin Exp Allergy 1997;27: 725736.
  • 69
    Anto JM, Sunyer J. Thunderstorms: a risk factor for asthma attacks (editorial; comment). Thorax 1997;52: 669670.
  • 70
    Bauman A. Asthma associated with thunderstorms (editorial; comment). Br Med J 1996;312: 590591.
  • 71
    Celenza A, Fothergill J, Kupek E, Shaw RJ. Thunderstorm associated asthma: a detailed analysis of environmental factors. Br Med J 1996;312: 604607.
  • 72
    Knox RB. Grass pollen, thunderstorms and asthma. Clin Exp Allergy 1993;23: 354359.
  • 73
    Marks GB, Colquhoun JR, Girgis ST, Koski MH, Treloar AB, Hansen P, et al. Thunderstorm outflows preceding epidemics of asthma during spring and summer. Thorax 2001;56: 468471.
  • 74
    Suphioglu C, Singh MB, Taylor P, Bellomo R, Holmes P, Puy R, et al. Mechanism of grass-pollen-induced asthma. Lancet 1992;339: 569572.
  • 75
    Girgis ST, Marks GB, Downs SH, Kolbe A, Car GN, Paton R. Thunderstorm-associated asthma in an inland town in south-eastern Australia. Who is at risk? Eur Respir J 2000;16: 38.
  • 76
    Gern JE, Busse WW. The role of viral infections in the natural history of asthma. J Allergy Clin Immunol 2000;106: 201212.
  • 77
    Johnston SL, Pattemore PK, Sanderson G, Smith S, Campbell MJ, Josephs LK, et al. The relationship between upper respiratory infections and hospital admissions for asthma: a time-trend analysis. Am J Respir Crit Care Med 1996;154: 654660.
  • 78
    Lemanske R Jr, Dick EC, Swenson CA, Vrtis RF, Busse WW. Rhinovirus upper respiratory infection increases airway hyperreactivity and late asthmatic reactions. J Clin Invest 1989;83: 110.
  • 79
    Papadopoulos NG, Johnston SL. Viruses and asthma exacerbations. Thorax 1998;53: 913914.
  • 80
    Papadopoulos NG, Bates PJ, Bardin PG, Papi A, Leir SH, Fraenkel DJ, et al. Rhinoviruses infect the lower airways. J Infect Dis 2000;181: 18751884.
  • 81
    Gern JE, Galagan DM, Jarjour NN, Dick EC, Busse WW. Detection of rhinovirus RNA in lower airway cells during experimentally induced infection. Am J Respir Crit Care Med 1997;155: 11591161.
  • 82
    Igarashi Y, Goldrich MS, Kaliner MA, Irani AM, Schwartz LB, White MV. Quantitation of inflammatory cells in the nasal mucosa of patients with allergic rhinitis and normal subjects. J Allergy Clin Immunol 1995;95: 716725.
  • 83
    Jeffery P. Bronchial biopsies and airway inflammation. Eur Respir J 1996;9: 15831587.
  • 84
    Holmberg K, Bake B, Pipkorn U. Nasal mucosal blood flow after intranasal allergen challenge. J Allergy Clin Immunol 1988;81: 541547.
  • 85
    King GG, Pare PD, Seow CY. The mechanics of exaggerated airway narrowing in asthma: the role of smooth muscle. Respir Physiol 1999;118: 113.
  • 86
    Bousquet J, Jeffery PK, Busse WW, Johnson M, Vignola AM. Asthma. From bronchoconstriction to airways inflammation and remodeling. Am J Respir Crit Care Med 2000;161: 17201745.
  • 87
    Bentley AM, Menz G, Storz C, Robinson DS, Bradley B, Jeffrey PK, et al. Identification of T lymphocytes, macrophages, and activated eosinophils in the bronchial mucosa in intrinsic asthma. Relationship to symptoms and bronchial responsiveness. Am Rev Respir Dis 1992;146: 500506.
  • 88
    Bentley AM, Jacobson MR, Cumberworth V, Barkans JR, Moqbel R, Schwartz LB, et al. Immunohistology of the nasal mucosa in seasonal allergic rhinitis: increases in activated eosinophils and epithelial mast cells. J Allergy Clin Immunol 1992;89: 877883.
  • 89
    Durham SR, Ying S, Varney VA, Jacobson MR, Sudderick RM, Mackay IS, et al. Cytokine messenger RNA expression for IL-3, IL-4, IL-5, and granulocyte/macrophage-colony-stimulating factor in the nasal mucosa after local allergen provocation: relationship to tissue eosinophilia. J Immunol 1992;148: 23902394.
  • 90
    Bradding P, Roberts JA, Britten KM, Montefort S, Djukanovic R, Mueller R, et al. Interleukin-4, -5, and -6 and tumor necrosis factor-alpha in normal and asthmatic airways: evidence for the human mast cell as a source of these cytokines. Am J Respir Cell Mol Biol 1994;10: 471480.
  • 91
    Bradding P, Feather IH, Wilson S, Bardin PG, Heusser CH, Holgate ST, et al. Immunolocalization of cytokines in the nasal mucosa of normal and perennial rhinitic subjects. The mast cell as a source of IL-4, IL-5, and IL-6 in human allergic mucosal inflammation. J Immunol 1993;151: 38533865.
  • 92
    Baraniuk JN. Pathogenesis of allergic rhinitis. J Allergy Clin Immunol 1997;99: S763S772.
  • 93
    Minshall EM, Cameron L, Lavigne F, Leung DY, Hamilos D, Garcia-Zepada EA, et al. Eotaxin mRNA and protein expression in chronic sinusitis and allergen-induced nasal responses in seasonal allergic rhinitis. Am J Respir Cell Mol Biol 1997;17: 683690.
  • 94
    Vignola AM, Campbell AM, Chanez P, Bousquet J, Paul-Lacoste P, Michel FB, et al. HLA-DR and ICAM-1 expression on bronchial epithelial cells in asthma and chronic bronchitis. Am Rev Respir Dis 1993;148: 689694.
  • 95
    Montefort S, Holgate ST, Howarth PH. Leucocyte-endothelial adhesion molecules and their role in bronchial asthma and allergic rhinitis. Eur Respir J 1993;6: 10441054.
  • 96
    Canonica GW, Ciprandi G, Pesce GP, Buscaglia S, Paolieri F, Bagnasco M. ICAM-1 on epithelial cells in allergic subjects: a hallmark of allergic inflammation. Int Arch Allergy Immunol 1995;107: 99102.
  • 97
    Chanez P, Vignola AM, Vic P, Guddo F, Bonsignore G, Godard P, et al. Comparison between nasal and bronchial inflammation in asthmatic and control subjects. Am J Respir Crit Care Med 1999;159: 588595.
  • 98
    Gaga M, Lambrou P, Papageorgiou N, Koulouris NG, Kosmas E, Fragakis S, et al. Eosinophils are a feature of upper and lower airway pathology in non-atopic asthma, irrespective of the presence of rhinitis. Clin Exp Allergy 2000;30: 663669.
  • 99
    Slavin RG. Asthma and sinusitis. J Allergy Clin Immunol 1992;90: 534537.
  • 100
    Newman LJ, Platts-Mills TA, Phillips CD, Hazen KC, Gross CW. Chronic sinusitis. Relationship of computed tomographic findings to allergy, asthma, and eosinophilia (published erratum appears in J Am Med Assoc 1994; 272: 852). J Am Med Assoc 1994;271: 3667.
  • 101
    Bresciani M, Paradis L, Des Roches A, Vernhet H, Vachier I, Godard P, et al. Rhinosinusitis in severe asthma. J Allergy Clin Immunol 2001;107: 7380.
  • 102
    ten Brinke A, Grootendorst DC, Schmidt JT, De Bruine FT, van Buchem MA, Sterk PJ, et al. Chronic sinusitis in severe asthma is related to sputum eosinophilia. J Allergy Clin Immunol 2002;109: 621626.
  • 103
    Vachier I, Chiappara G, Mezziane H, et al. Bronchial and nasal inflammation in asthma and COPD. Am J Respir Crit Care Med 2000;333: A50.
  • 104
    Sutton BJ, Gould HJ. The human IgE network. Nature 1993;366: 421428.
  • 105
    Sherrill DL, Stein R, Halonen M, Holberg CJ, Wright A, Martinez FD, et al. Total serum IgE and its association with asthma symptoms and allergic sensitization among children. J Allergy Clin Immunol 1999;104: 2836.
  • 106
    Beeh KM, Ksoll M, Buhl R. Elevation of total serum immunoglobulin E is associated with asthma in nonallergic individuals. Eur Respir J 2000;16: 609614.
  • 107
    Arshad SH, Holgate S. The role of IgE in allergen-induced inflammation and the potential for intervention with a humanized monoclonal anti-IgE antibody. Clin Exp Allergy 2001;31: 13441351.
  • 108
    Togias A. Unique mechanistic features of allergic rhinitis. J Allergy Clin Immunol 2000;105: 599604.
  • 109
    Pawankar R, Okuda M, Yssel H, Okumura K, Ra C. Nasal mast cells in perennial allergic rhinitics exhibit increased expression of the FcɛRI, CD40L, IL-4, and IL-13, and can induce IgE synthesis in B cells. J Clin Invest 1997;99: 14921499.
  • 110
    Klein Jan A, Vinke JG, Severijnen LWFM, Fokken WJ. Local production and detection of (specific) IgE in nasal B-cells and plasma cells of allergic rhinitis patients. Eur Respir J 2000;15: 491497.
  • 111
    Ying S, Humbert M, Meng Q, Pfister R, Menz G, Gould HJ, et al. Local expression of ɛ germline gene transcripts and RNA for the ɛ heavy chain of IgE in the bronchial mucosa in atopic and nonatopic asthma. J Allergy Clin Immunol 2001;107: 686692.
  • 112
    Rajakulasingam K, Durham SR, O'Brien F, Humbert M, Barata LT, Reece L, et al. Enhanced expression of high-affinity IgE receptor (FcɛRI) α chain in human allergen-induced rhinitis with co-localization to mast cells, macrophages, eosinophils, and dendritic cells. J Allergy Clin Immunol 1997;100: 7886.
  • 113
    Rajakulasingam K, Till S, Ying S, Humbert M, Barkons J, Sullivan M, et al. Increased expression of high-affinitiy IgE (FcɛRI) receptor-α chain mRNA and protein-bearing eosinophils in human allergen-induced atopic asthma. Am J Respir Crit Care Med 1998;158: 233240.
  • 114
    Menz G, Ying S, Durham SR, Corrigan CJ, Robinson DS, Hamid O, et al. Molecular concepts of IgE-initiated inflammation in atopic and nonatopic asthma. Allergy 1998;53: 1521.
  • 115
    Durham SR, Gould HJ, Thienes CP, Jacobson MR, Masuyama K, Rak S, et al. Expression of epsilon germ-line gene transcripts and mRNA for the epsilon heavy chain of IgE in nasal B cells and the effects of topical corticosteroid. Eur J Immunol 1997;27: 28992906.
  • 116
    Smurthwaite L, Durham SR. Local IgE synthesis in allergic rhinitis and asthma. Curr Allergy Asthma Rep 2002;2: 231238.
  • 117
    Cameron L, Hamid Q, Wright E, Nakamura Y, Christodoulopoulos P, Mulo S, et al. Local synthesis of epsilon germline gene transcripts, IL-4, and IL-13 in allergic nasal mucosa after ex vivo allergen exposure. J Allergy Clin Immunol 2000;106: 4652.
  • 118
    Smurthwaite L, Walker SN, Wilson DR, Birch DS, Merrett TG, Durham SR, et al. Persistent IgE synthesis in the nasal mucosa of hay fever patients. Eur J Immunol 2001;31: 34223431.
  • 119
    Wilson DR, Merrett TG, Varga EM, Smurthwaite L, Gould HJ, Kemp M, et al. Increases in allergen-specific IgE in BAL after segmental allergen challenge in atopic asthmatics. Am J Respir Crit Care Med 2002;165: 2226.
  • 120
    Denburg JA, Sehmi R, Saito H, Pil-Seob J, Inman MD, O'Byrne PM. Systemic aspects of allergic disease: bone marrow responses. J Allergy Clin Immunol 2000;106: S242S246.
  • 121
    Inman MD. Bone marrow events in animal models of allergic inflammation and hyperresponsiveness. J Allergy Clin Immunol 2000;106: S235S241.
  • 122
    Gaspar Elsas MI, Joseph D, Elsas PX, Vargaftig BB. Rapid increase in bone-marrow eosinophil production and responses to eosinopoietic interleukins triggered by intranasal allergen challenge. Am J Respir Cell Mol Biol 1997;17: 404413.
  • 123
    Inman MD, Ellis R, Wattie J, Denburg JA, O'Byrne PM. Allergen-induced increase in airway responsiveness, airway eosinophilia, and bone-marrow eosinophil progenitors in mice. Am J Respir Cell Mol Biol 1999;21: 473479.
  • 124
    Denburg JA, Otsuka H, Ohnisi M, Ruhno J, Bienenstock J, Dolovich J. Contribution of basophil/mast cell and eosinophil growth and differentiation to the allergic tissue inflammatory response. Int Arch Allergy Appl Immunol 1987;82: 321326.
  • 125
    KleinJan A, Dijkstra MD, Boks SS, Severijnen LA, Mulder PG, Fokkens WJ. Increase in IL-8, IL-10, IL-13, and RANTES mRNA levels (in situ hybridization) in the nasal mucosa after nasal allergen provocation. J Allergy Clin Immunol 1999;103: 441450.
  • 126
    Varga EM, Jacobson MR, Till SJ, Masuyama K, O'Brien F, Rak S, et al. Cellular infiltration and cytokine mRNA expression in perennial allergic rhinitis. Allergy 1999;54: 338345.
  • 127
    Lee CH, Lee KS, Rhee CS, Lee SO, Min YG. Distribution of RANTES and interleukin-5 in allergic nasal mucosa and nasal polyps. Ann Otol Rhinol Laryngol 1999;108: 594598.
  • 128
    Bachert C, Wagenmann M, Hauser U, Rudack C. IL-5 synthesis is upregulated in human nasal polyp tissue. J Allergy Clin Immunol 1997;99: 837842.
  • 129
    Cameron L, Christodoulopoulos P, Lavigne F, Nakamura Y, Eidelman D, McEuen A, et al. Evidence for local eosinophil differentiation within allergic nasal mucosa: inhibition with soluble IL-5 receptor. J Immunol 2000;164: 15381545.
  • 130
    Robinson DS, Damia R, Zeibecoglou K, Molet S, North J, Yamada T, et al. CD34(+)/interleukin-5Ralpha messenger RNA+ cells in the bronchial mucosa in asthma: potential airway eosinophil progenitors. Am J Respir Cell Mol Biol 1999;20: 913.
  • 131
    Kulig M, Bergmann R, Klettke U, Wahn V, Tacke U, Wahn U. Natural course of sensitization to food and inhalant allergens during the first 6 years of life. J Allergy Clin Immunol 1999;103: 11731179.
  • 132
    Kulig M, Klettke U, Wahn V, Forster J, Bauer CP, Wahn U. Development of seasonal allergic rhinitis during the first 7 years of life. J Allergy Clin Immunol 2000;106: 832839.
  • 133
    Gustafsson D, Sjoberg O, Foucard T. Development of allergies and asthma in infants and young children with atopic dermatitis–a prospective follow-up to 7 years of age. Allergy 2000;55: 240245.
  • 134
    Bergmann RL, Edenharter G, Bergmann KE, Forster J, Bauer CP, Wahn V, et al. Atopic dermatitis in early infancy predicts allergic airway disease at 5 years. Clin Exp Allergy 1998;28: 965970.
  • 135
    Asher MI, Barry D, Clayton T, Crane J, D'Souza W, Ellwood P, et al. The burden of symptoms of asthma, allergic rhinoconjunctivities and atopic eczema in children and adolescents in six New Zealand centres: ISAAC Phase One. N Z Med J 2001;114: 114120.
  • 136
    Peat JK, Salome CM, Woolcock AJ. Longitudinal changes in atopy during a 4-year period: relation to bronchial hyperresponsiveness and respiratory symptoms in a population sample of Australian schoolchildren. J Allergy Clin Immunol 1990;85: 6574.
  • 137
    von Mutius E, Weiland SK, Fritzsch C, Duhme H, Keil U. Increasing prevalence of hay fever and atopy among children in Leipzig, East Germany.Lancet 1998;351: 862866.
  • 138
    Settipane GA, Hagy GW, Settipane RJ. Long-term risk factors for developing asthma and allergic rhinitis: a 23-year follow-up study of college students. Allergy Proc 1994;15: 2125.
  • 139
    Plaschke PP, Janson C, Norrman E, Bjornsson E, Ellbjar S, Jarvholm B. Onset and remission of allergic rhinitis and asthma and the relationship with atopic sensitization and smoking. Am J Respir Crit Care Med 2000;162: 920924.
  • 140
    Guerra S, Sherrill DL, Martinez FD, Barbee RA. Rhinitis as an independent risk factor for adult-onset asthma. J Allergy Clin Immunol 2002;109: 419425.
  • 141
    Castro-Rodríguez JA, Holberg CJ, Wright AL, Martinez FD. A clinical index to define risk of asthma in young children with recurrent wheezing. Am J Respir Crit Care Med 2000;162: 14031406.
  • 142
    Panettieri R Jr., Murray RK, Eszterhas AJ, Bilgen G, Martin JG. Repeated allergen inhalations induce DNA synthesis in airway smooth muscle and epithelial cells in vivo. Am J Physiol 1998;274: L417L424.
  • 143
    Chung KF. Airway smooth muscle cells: contributing to and regulating airway mucosal inflammation? Eur Respir J 2000;15: 961968.
  • 144
    Holgate ST, Davies DE, Lackie PM, Wilson SJ, Puddicombe SM, Lordan JL. Epithelial-mesenchymal interactions in the pathogenesis of asthma. J Allergy Clin Immunol 2000;105: 193204.
  • 145
    Bousquet J, Knani J, Dhivert H, Richard A, Chicoye A, Ware JE Jr, et al. Quality of life in asthma. I. Internal consistency and validity of the SF-36 questionnaire. Am J Respir Crit Care Med 1994;149: 371375.
  • 146
    Bousquet J, Bullinger M, Fayol C, Marquis P, Valentin B, Burtin B. Assessment of quality of life in patients with perennial allergic rhinitis with the French version of the SF-36 Health Status Questionnaire. J Allergy Clin Immunol 1994;94: 182188.
  • 147
    Leynaert B, Neukirch C, Liard R, Bousquet J, Neukirch F. Quality of life in allergic rhinitis and asthma. A population-based study of young adults. Am J Respir Crit Care Med 2000;162: 13911396.
  • 148
    Blanc PD, Trupin L, Eisner M, Earnest G, Katz PP, Israel L, et al. The work impact of asthma and rhinitis. Findings from a population-based survey. J Clin Epidemiol 2001;54: 610618.
  • 149
    Bousquet J, Van Cauwenberge P, Khaltaev N. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol 2001;108: S147S334.
  • 150
    Watson WT, Becker AB, Simons FE. Treatment of allergic rhinitis with intranasal corticosteroids in patients with mild asthma: effect on lower airway responsiveness. J Allergy Clin Immunol 1993;91: 97101.
  • 151
    Pedersen B, Dahl R, Lindqvist N, Mygind N. Nasal inhalation of the glucocorticoid budesonide from a spacer for the treatment of patients with pollen rhinitis and asthma. Allergy 1990;45: 451456.
  • 152
    Foresi A, Pelucchi A, Gherson G, Mastropasqua B, Chiapparino A, Testi R. Once daily intranasal fluticasone propionate (200 μg) reduces nasal symptoms and inflammation but also attenuates the increase in bronchial responsiveness during the pollen season in allergic rhinitis. J Allergy Clin Immunol 1996;98: 274282.
  • 153
    Henriksen JM, Wenzel A. Effect of an intranasally administered corticosteroid (budesonide) on nasal obstruction, mouth breathing, and asthma. Am Rev Respir Dis 1984;130: 10141018.
  • 154
    Aubier M, Levy J, Clerici C, Neukirch F, Herman D. Different effects of nasal and bronchial glucocorticosteroid administration on bronchial hyperresponsiveness in patients with allergic rhinitis. Am Rev Respir Dis 1992;146: 122126.
  • 155
    Corren J, Adinoff AD, Buchmeier AD, Irvin CG. Nasal beclomethasone prevents the seasonal increase in bronchial responsiveness in patients with allergic rhinitis and asthma. J Allergy Clin Immunol 1992;90: 250256.
  • 156
    Greiff L, Andersson M, Svensson C, Linden M, Wollmer P, Brattsand R, et al. Effects of orally inhaled budesonide in seasonal allergic rhinitis. Eur Respir J 1998;11: 12681273.
  • 157
    Grant JA, Nicodemus CF, Findlay SR, Glovsky MM, Grossman J, Kaiser H, et al. Cetirizine in patients with seasonal rhinitis and concomitant asthma: prospective, randomized, placebo-controlled trial. J Allergy Clin Immunol1995; 95: 923932.
  • 158
    Van-Ganse E, Kaufman L, Derde MP, Yernault JC, Delaunois L, Vincken W. Effects of antihistamines in adult asthma: a meta-analysis of clinical trials. Eur Respir J 1997;10: 22162224.
  • 159
    Meltzer E, Malmstrom K, Lu S, Brenner B, Wei L, Weinstein S, et al. Concomitant montelukast and loratadine as treatment for seasonal allergic rhinitis: placebo-controlled clinical trial. J Allergy Clin Immunol 2000;105: 917922.
  • 160
    Bousquet J, Lockey R, Malling HJ. Allergen immunotherapy: therapeutic vaccines for allergic diseases. A WHO position paper. J Allergy Clin Immunol 1998;102: 558562.
  • 161
    Norman PS. Is there a role for immunotherapy in the treatment of asthma? (Yes editorial). Am J Respir Crit Care Med 1996;154: 12251226.
  • 162
    Barnes P. Is there a role for immunotherapy in the treatment of asthma? No. Am J Respir Crit Care Med 1996;154: 12271228.
  • 163
    Bousquet J, Demoly P, Michel FB. Specific immunotherapy in rhinitis and asthma. Ann Allergy Asthma Immunol 2001;87 (1 Suppl. 1):3842.
  • 164
    Durham SR, Till SJ. Immunologic changes associated with allergen immunotherapy. J Allergy Clin Immunol 1998;102: 157164.
  • 165
    Moller C, Dreborg S, Ferdousi HA, Halken S, Host A, Jacobsen L, et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J Allergy Clin Immunol 2002;109: 251256.
  • 166
    Ädelroth E, Rak S, Haahtela T, Aasand G, Rosenhall L, Zetterstrom O, et al. Recombinant humanized mAb-E25, an anti-IgE mAb, in birch pollen-induced seasonal allergic rhinitis. J Allergy Clin Immunol 2000;106: 253259.
  • 167
    Chervinsky P, Busse W, Casale T, Nayak A, Tripathy I, Fowler Taylor A, et al. Xolair® in the treatment of perennial allergic rhinitis (Abstract 513). J Allergy Clin Immunol 2001;107.
  • 168
    Milgrom H, Berger W, Nayak A, Gupta N, Pollard S, McAlary M, et al. Treatment of childhood asthma with anti-IgE antibody omalizumab. Pediatrics 2001;108 URL: http://www.pediatrics.org/cgi/content/full/108/2/e36.
  • 169
    Busse W, Corren J, Lanier BQ, McAlary M, Fowler-Taylor A, Cioppa GD, et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol 2001;108: 184190.
  • 170
    Solèr M, Matz J, Townley R, Buhl R, O'Brien J, Fox H, et al. The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics. Eur Respir J 2001;18: 254261.
  • 171
    Crystal-Peters J, Neslusan C, Crown WH, Torres A. Treating allergic rhinitis in patients with comorbid asthma: the risk of asthma-related hospitalizations and emergency department visits. J Allergy Clin Immunol 2002;109: 5762.
  • 172
    Adams RJ, Fuhlbrigge AL, Finkelstein JA, Weiss ST. Intranasal steroids and the risk of emergency department visits for asthma. J Allergy Clin Immunol 2002;109: 636642.