• allergic rhinitis;
  • asthma;
  • desloratadine;
  • pathophysiology;
  • pharmacoeconomics


  1. Top of page
  2. Abstract
  3. Advances in biomedical research of allergy
  4. Changing the management of allergy
  5. Conclusions
  6. References

Our understanding of the pathophysiology of allergy has moved to the molecular level, while study of epidemiology and genetics has revealed risks of developing allergies based on environmental and genetic profiles, and pharmacoeconomic data have enabled accurate measurement of the immense burden of allergic disease. These advances in allergy research have affected its management, particularly the search for new antiallergy therapies. New therapies should intervene in the systemic allergy inflammatory cascade and provide clinical efficacy that extends to multiple allergic disease states. In addition, these new therapies should present no additional safety issues, offer improvements over existing therapies, and have an impact on disease-impaired quality of life. In vitro studies show that desloratadine, a new, once-daily, nonsedating, selective histamine H1-receptor antagonist, blocks the systemic allergy cascade at multiple points. Desloratadine 5 mg once daily relieves the symptoms of chronic idiopathic urticaria and of both seasonal (SAR) and perennial allergic rhinitis. In patients with concomitant asthma and SAR, asthma symptoms are relieved and β2-agonist medication use is decreased by desloratadine. Unlike many other second-generation histamine H1-receptor antagonists, desloratadine provides the added benefit of efficacy against nasal obstruction in SAR. Desloratadine improves quality of life by decreasing the impact of allergic symptoms on sleep and on daily activities.

Since the early 1990s, several advances have been made in the biomedical research and medical treatment of allergy. Understanding of the pathophysiology of allergy has moved to the molecular level, enabling the discovery of new treatment targets and new tools to assess drug efficacy and safety. The fields of epidemiology and genetics have converged to reveal risks of developing disease, based on environmental and genetic profiles. This may allow the identification of those at risk before the disease is clinically apparent. Pharmacoeconomic studies allow both the costs of illness and the benefits of wellness to be measured, thus enabling accurate measurement of the burden of allergic disease.

In this article, the effect of advances in the biomedical research of allergy is illustrated with data on desloratadine, a new selective histamine H1-receptor antagonist.

Advances in biomedical research of allergy

  1. Top of page
  2. Abstract
  3. Advances in biomedical research of allergy
  4. Changing the management of allergy
  5. Conclusions
  6. References


Allergy is now understood to be a systemic inflammatory disease (Fig. 1). Multiple inflammatory mediators have been identified (1–3). These include cytokines, such as the interleukins (IL-3, IL-4, IL-5, IL-9, and IL-13), which promote the production of immunoglobulin E (IgE), airway hyperresponsiveness, the overproduction of mucus, and the development of eosinophils and mast cells, all of which are associated with chronic allergic inflammation. Other inflammatory mediators that have been identified are chemokines, such as 1) eotaxins, 2) RANTES (regulated on activation, normal T cell expressed and secreted), 3) monocyte chemoattractant proteins (e.g. MCP-2 and MCP-3) (3), and 4) thymus- and activation-regulated chemokine (TARC) (4,5). These chemotactic cytokines have the ability to attract and activate leukocytes. Adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1), vascular cellular adhesion molecule-1 (VCAM-1), and selectins (e.g. selectin-P, selectin-E) (3,6), are surface ligands that mediate cell-to-cell adhesion and diapedesis. Chemokines recruit eosinophils and basophils, and adhesion molecules promote the accumulation of inflammatory cells, processes that are central to the maintenance of chronic allergic inflammation.


Figure 1. Pathways leading to acute and chronic allergic reactions. Acute allergic reactions are due to the antigen-induced release of histamine and lipid mediators from mast cells. In the skin and upper airways, basophils (not shown) may also participate in allergic tissue reactions. Chronic allergic reactions, including the late-phase reaction, may depend on a combination of pathways, including the recruitment of eosinophils, the liberation of mast cell products by histamine-releasing factors, and neurogenic inflammation involving neurotrophins and neuropeptides. MHC, major histocompatability complex. Adapted from (1).

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Epidemiology and genetics

The prevalence of allergic rhinitis varies widely, from 1% to 40%, according to the population studied and to the conditions and methods of assessment (3). Prevalence varies widely in different geographic locations; worldwide, the 1-year prevalence ranged from 0.8–14.9% among children aged 6–7 years, and from 1.4–39.7% among adolescents aged 13–14 years (7). Furthermore, the incidence and prevalence of allergy has been rising in many countries (8–11).

The systemic nature of allergy is highlighted by the increased risk, among patients who already have an allergic disease, of developing other allergic diseases (12). Further evidence of a comorbid association is provided by the extremely high prevalence of asthma among patients with allergic rhinitis (2). Large longitudinal epidemiological studies have found that allergic rhinitis generally precedes the onset of asthma (13–15), although disease occurs throughout the airways (16); 30–80% of asthmatic patients have allergic rhinitis, and 20–40% of those with allergic rhinitis have asthma (17).

Geographic variation in the prevalence of allergy and the increasing prevalence with time imply environmental influences. It has been suggested that improvements in hygiene and the use of vaccinations and antibiotics to control infections in early life may deprive the developing immune system of exposure to microbial antigens, which is necessary to stimulate Th1 lymphocytes and prevent immune dominance by Th2 lymphocytes. Atopic (IgE-mediated) allergic disease is characterized by immunopathological dominance by Th2 lymphocytes (1). Based on the assumption that older siblings act as vectors for microbial exposure of younger children, the “hygiene” theory is supported by the findings that young children with older siblings are less likely to suffer from atopic allergic diseases or to develop asthma and wheezing (18–20). Th2 lymphocyte dominance may also be favoured by neonatal allergen sensitization via diet or birth during the pollen season, or even by antenatal allergen sensitization via maternal exposure (21–24).

In addition to environmental factors, multiple genetic factors have been linked to atopic allergic diseases, although the latter may be heterogeneic between different ethnic groups (25,26). Furthermore, triggering cofactors may be necessary for disease manifestation in persons with an underlying genetic predisposition and who are susceptible because of environmental priming. Genetic factors that have been identified include the presence of specific HLA alleles and polymorphisms of the high-affinity receptor for IgE (FcεRI), the IL-4 family of cytokine genes, cluster of differentiation 14 (CD14), and other loci (21,27–30). Triggering cofactors may include respiratory viral infection and exposure to allergens, tobacco smoke, and air pollutants (31–34).


The economic costs of allergy are enormous. Allergic disease results in not only significant healthcare expenditure (direct costs) but also costs to society because of decreased work efficiency and increased absenteeism (indirect costs). Furthermore, the burden of allergic diseases on people can cause important decreases in psychosocial well-being.

Allergic rhinitis is estimated to cost billions of euros/dollars (€/$) annually in direct and indirect costs (35–38). In addition to increased absenteeism, the quality and quantity of work produced declines because of decreased cognitive function (learning, memory, and decision-making) and psychomotor function. Over-the-counter allergy medications with sedative effects further compromise cognitive function and, subsequently, productivity (38). The consequences of allergic rhinitis on psychosocial well-being are illustrated by its association with higher rates of depression and anxiety disorder, as revealed by analysis of a healthcare claims database of more than 600 000 privately insured people in the USA (39). In the latter study, prescription treatment of allergic rhinitis moderated the increased healthcare expenditure associated with psychological comorbidity.

The economic effect of asthma is also immense. The annual direct healthcare costs and indirect costs of asthma were estimated to approach €/$1 billion in Switzerland in 1997 (40), to approach €/$3 billion in Germany in 1996, even without inclusion of the cost of outpatient physician services (41), and to exceed €/$10 billion in the USA in 1994 (42). Direct medical costs for asthma exceed indirect medical costs in both Europe and the USA (40,42–44). In European studies published within the last few years, the estimated total direct and indirect costs annually per patient have ranged from approximately €/$2000 to €/$3000 (45–47). Estimated annual direct and indirect costs per patient increased several-fold with increasing disease severity from mild to severe (46,48). Estimated costs were higher in the elderly than in other adults, reflecting greater severity of disease, and measures of quality of life were significantly worse (P < 0.001) (49). Also, estimated costs were higher in adults than in children, likely reflecting losses in productivity (47,48). Employed people with asthma are estimated to lose an average of 12 days of productivity annually (50).

Changing the management of allergy

  1. Top of page
  2. Abstract
  3. Advances in biomedical research of allergy
  4. Changing the management of allergy
  5. Conclusions
  6. References

Ideally, antiallergy therapies should target the systemic allergy cascade, demonstrate broad clinical efficacy in multiple disease manifestations of allergy, show improved clinical efficacy over existing therapies with no additional safety issues, and have an effect on disease-impaired quality-of-life measures.

Targeting the systemic allergy cascade

The systemic nature of allergy demands targeting of the broad systemic allergy cascade. Many new and experimental treatment options have been designed to target specific inflammatory mediators of the allergy cascade, including IgE, cytokines, integrins (for which cell adhesion molecules are the physiological ligand), chemokines, and neurokinins (Table 1). However, the primary treatment options currently available for the management of allergy remain histamine H1-receptor antagonists, sympathomimetics (α and β), glucocorticosteroids (topical/systemic/intranasal/inhaled), and mast cell stabilizers (51). β-adrenoceptor agonists do not appear to target the allergy cascade or reduce chronic allergic inflammation in vivo, despite inhibitory effects on inflammatory cells in vitro (52). Rather, these and α-adrenoceptor agonists act on the downstream manifestations of allergic inflammation: bronchial hyperresponsiveness and nasal vascular congestion, respectively (52–54). Both mast cell stabilizers and glucocorticosteroids act by inhibiting the allergy cascade. However, glucocorticosteroids lack selectivity for the allergy cascade, exerting potent anti-inflammatory and immunosuppressive actions throughout the body via effects on leukocyte circulatory kinetics and function, and on inflammatory mediators (e.g. prostaglandins, histamine, leukotrienes, interleukins, interferon-γ, and tumour necrosis factor-α) (55). This may result in the well-known complications of glucocorticosteroid therapy.

Table 1.  Newer treatment options, and products under development, that target specific inflammatory mediators
TargetProductsAllergy indications*
  • *

    Approved or proposed.

FcεRIAnti-FcεRI monoclonal antibodyAllergic rhinitis, asthma
Immunoglobulin EOmalizumab (anti-IgE monoclonal antibody; Xolair)Allergic rhinitis, asthma
Interleukin-4Interleukin-4 receptor (Nuvance); others in developmentAsthma
Interleukin-5Mepolizumab, SCH 55700/CDP 835, and SB-240563 (anti-IL-5 monoclonal antibody)Asthma
IntegrinSB-683698 (VLA4 integrin antagonist) and R411 (integrin antagonist); othersAsthma
LeukotrieneZafirlukast and montelukast (leukotriene inhibitors; Accolate and Singulair)Asthma
NeurokininSR-140333 and saredutant (neurokinin antagonists)Asthma
Platelet-activating factorPafase (PAF-acetyl hydrolase)Asthma

The primary mechanism of action of H1-receptor antagonists in allergic diseases is to block the action of histamine at the H1-receptor. However, in vitro experiments have suggested that some histamine H1-receptor antagonists may exhibit additional mechanisms (56); for example, desloratadine inhibits the release or generation of inflammatory mediators by mast cells, basophils, and other cells (57). Leukotriene C4, prostaglandin D2, tryptase, granulocyte macrophage colony-stimulating factor (GM-CSF), RANTES induced by tumour necrosis factor-α, P-selectin and ICAM-1 induced by histamine, several interleukins (IL-1β, IL-3, IL-4, IL-5, IL-6, IL-8, IL-13, IL-18), and platelet-activating factor are among the mediators affected by desloratadine in vitro. Furthermore, in vitro studies revealed that desloratadine decreases the chemotaxis and activation of eosinophils and neutrophils and significantly down-regulates the expression of CD11b on polymorphonuclear leukocytes, suggesting inhibition of transmigratory capacity (58). In atopic patients with SAR who were administered desloratadine 20 mg daily (n = 13) for a week, supernatants of peripheral blood mononuclear cells (PBMCs) showed increased expression of interferon-γ (type 1 cytokine) and decreased expression of IL-4, IL-5, and IL-10 (type 2 cytokines), compared with supernatants of PBMCs of those administered placebo (n = 6) (59). Also, desloratadine recipients had increased natural killer (NK) cell activity and decreased circulating basophils, eosinophils, and serum VCAM-1.

Efficacy against multiple disease manifestations of allergy

Given the systemic nature of allergy, targeting of the allergy cascade should result in efficacy against multiple disease manifestations. Desloratadine 5 mg once daily is effective in the treatment of both seasonal allergic rhinitis (SAR) and perennial allergic rhinitis. In people with SAR and symptoms of asthma, desloratadine relieves asthma symptoms and decreases the use of rescue medication. Desloratadine also relieves the symptoms of chronic idiopathic urticaria (CIU), 5 mg once daily being superior to placebo in controlling pruritus and total symptoms beginning with the first dose and throughout the 6 weeks of the study (Fig. 2) (60).


Figure 2. Desloratadine therapy in chronic idiopathic urticaria (CIU), as demonstrated in a double-blind, randomized, placebo-controlled, multicentre trial that included 190 patients aged 12 years and above with at least a 6-week history of CIU and experiencing a flare of at least moderate severity. Mean percentage reduction in total symptom score (TSS) from baseline. *P < 0.001; †P = 0.002. Reproduced with permission from (69).

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Desloratadine 5 mg once daily relieves the nasal and non-nasal symptoms of allergic rhinitis, both SAR and perennial allergic rhinitis. Two multicentre, randomized, double-blind, placebo-controlled, parallel-group investigations were conducted in patients with SAR, one during the spring allergy season (172 and 174 patients in the desloratadine and placebo groups, respectively) and one during the autumn allergy season (164 patients in each group) (61). Patients aged 12 years or older with a minimum 2-year history of SAR were randomized to desloratadine 5 mg or placebo once daily for 14 days, following a 3-day run-in period. Nasal symptoms (itching, stuffiness/congestion, rhinorrhoea, and sneezing) and non-nasal symptoms (itching or burning eyes, itching of ears or palate, eye redness, and tearing) reflective of the previous 12 h were scored in the morning and the evening. The primary efficacy assessment was the mean change from baseline in the total symptom score (TSS) averaged over the 2-week study period. The 28% (spring) and 30% (autumn) reduction in the TSS produced by desloratadine was significantly greater than the reduction produced by placebo (13% (P < 0.01) and 22% (P = 0.02), respectively) (Fig. 3). Similar results were obtained in the treatment of perennial allergic rhinitis, in which the 4-week average change in instantaneous TSS showed a significantly greater reduction from baseline with desloratadine treatment than with placebo (P = 0.005) (Fig. 4) (62).


Figure 3. Desloratadine therapy in seasonal allergic rhinitis. Mean percentage reduction in morning/evening reflective total symptom score (TSS) from baseline. *P < 0.01; †P = 0.02. Adapted from (61).

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Figure 4. Desloratadine efficacy in perennial allergic rhinitis: mean percentage reduction in morning/evening instantaneous total symptom score (TSS) from baseline. *P = 0.005. Adapted from (62,70).

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In patients with SAR and mild-to-moderate asthma, desloratadine relieves symptoms of both conditions. Two multicentre, randomized, double-blind, placebo-controlled, parallel-group investigations were conducted in a total of 613 patients aged 15 years or older who had a minimum 2-year history of SAR and concomitant mild-to-moderate asthma that worsened during the autumn/winter allergy season (63). Participants had to have a prespecified severity of symptoms of SAR and asthma for 3 days before baseline assessment, a forced expiratory volume in 1 s (FEV1) of at least 70% of predicted value, and asthma symptoms controlled by inhaled bronchodilators only. Patients were excluded if they used corticosteroids, antihistamines, decongestants, or more than 12 albuterol inhalations per day. Following a 3–4-day screening period, patients were randomized to desloratadine 5 mg or placebo once daily for 4 weeks. Symptoms from the previous 12 h were scored in the morning and the evening, including asthma symptoms (cough, wheeze, and difficulty breathing) and the nasal and non-nasal symptoms of SAR. Desloratadine recipients achieved a significantly greater decrease from baseline in the total asthma symptom score than placebo recipients during the first 2 weeks (P = 0.003) and for the entire 4-week study period (P = 0.022) (Fig. 5). The once-daily desloratadine regimen also reduced the use of albuterol to control asthma symptoms (P ≤ 0.003 vs. placebo), while maintaining the FEV1.


Figure 5. Desloratadine (DL) therapy in seasonal allergic rhinitis and concomitant asthma. Mean change from baseline in reflective total asthma symptom score from baseline. P = 0.003 for the difference between desloratadine and placebo during days 1–15; P = 0.02 for the difference between desloratadine and placebo during days 1–29. Adapted from (63).

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Efficacy and safety: improved clinical profile

New treatment options should have superior safety with equivalent clinical benefits to existing therapies, or demonstrable additional benefits over existing therapies with no loss of safety. Unlike many existing second-generation H1-receptor antagonists, desloratadine provides the added benefit of efficacy against nasal obstruction.

Efficacy against nasal obstruction

Desloratadine once daily demonstrates activity against nasal obstruction (64), whether assessed subjectively as congestion and/or stuffiness scored over a range from 0 (none) to 3 (severe), or objectively as nasal airflow (in ml/s) measured by nasal rhinomanometry.

The efficacy of desloratadine was documented subjectively during the pollen season in patients with symptomatic SAR or with concurrent SAR and asthma in multicentre, double-blind, placebo-controlled studies (64,65). Three studies, each of which enrolled approximately 300 patients with symptomatic SAR, demonstrated relief of the symptom of nasal obstruction with administration of desloratadine 5 mg once daily (65). Symptoms were assessed twice daily, in the morning and the evening, and were reflective of the previous 12 h. The change from baseline was averaged over the study duration (either 2 or 4 weeks). Baseline scores ranged from 2.20 to 2.39, and desloratadine therapy resulted in a mean reduction in scores of 0.50–0.56 (21.3–23.5%). This effect was significant in comparison with the 0.35–0.40 (13.6–16.2%) mean reduction in the scores of the placebo groups (P < 0.05 for each study). In the studies of patients with history of 2 years or more of concurrent SAR and asthma, desloratadine 5 mg once daily produced significant relief of congestion after the first dose (64).

The efficacy of desloratadine was documented both objectively and subjectively outside of the pollen season in SAR patients exposed to an experimental allergen challenge in an environmental chamber. Three single-dose studies demonstrated the efficacy of desloratadine 5 mg in relieving subjectively documented nasal obstruction; administration of desloratadine after initial allergen challenge caused a greater change (improvement) from baseline than did placebo in the nasal obstruction symptom score (P ≤ 0.02) (66). A subsequent placebo-controlled crossover study in 47 patients with SAR assessed the ability of desloratadine 5 mg once daily for 7 days to prevent nasal obstruction during exposure to artificially and strictly maintained levels of antigen throughout 6 h of testing outside of the regular pollen season (67). During allergen challenge, periodic assessment was made of objective nasal obstruction, nasal secretions, and nasal and non-nasal SAR symptom severity. Nasal obstruction was documented objectively as nasal airflow (mL/s), measured by active anterior rhinomanometry immediately before (baseline) and every 30 min during allergen exposure.

Desloratadine administration was associated with less decrease from baseline, as compared with placebo, in the mean nasal airflow at most assessment times (primary endpoint) and in the mean severity score for the symptom of nasal obstruction at all assessment times. Desloratadine administration was associated with significantly less severely decreased nasal airflow within 30 min of allergen exposure (P < 0.02), a benefit that continued throughout the 6-h period of allergen exposure (Fig. 6). With desloratadine, nasal secretions were also less (P < 0.001), and symptoms were less severe, including nasal congestion (P < 0.002), rhinorrhoea, and sneezing (67).


Figure 6. Mean change (decrease) from baseline nasal airflow (in ml/s) in response to allergen exposure after treatment with desloratadine 5 mg (DL) or placebo every morning for 7 days. P values refer to comparison between desloratadine and placebo. *P = 0.005. From (67).

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A systematic evaluation of double-blind, placebo-controlled studies assessed the effects of cetirizine, fexofenadine, loratadine, and desloratadine on nasal obstruction (68). Only studies that used clinically approved drug doses and specifically reported effects on nasal obstruction (congestion) were included. Placebo effects were factored out, and severity scores were standardized. Desloratadine was the only agent that consistently reduced nasal congestion greater than placebo in all studies analysed (Fig. 7).


Figure 7. Systematic review of double-blind, placebo-controlled studies that examined the activity of second-generation histamine H1-receptor antagonists on nasal obstruction. Adapted from (68).

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Desloratadine is tolerated well (65). In controlled clinical studies, the rate of reported anticholinergic and sedative effects was similar to that with placebo. Also, there were no clinically significant abnormalities in electrocardiographic parameters, laboratory profiles, or vital signs.

Improved quality-of-life measures

Given the burden of allergic diseases on psychosocial well being, one goal of treatment should be the improvement of quality of life. Desloratadine improves quality of life by decreasing the effect of allergic symptoms on sleep and daily activities. A multicentre, randomized, double-blind, placebo-controlled study of 190 patients with CIU of at least 6 weeks' duration determined that desloratadine 5 mg once daily improved both CIU-impaired sleep and CIU-impaired ability to conduct daily activities – an effect that was evident after the first dose and was maintained throughout the 6 weeks of the study (P < 0.05) (60). In a German postmarketing study of nearly 50 000 patients, SAR caused moderate or severe interference with daily activities in 40% of patients before desloratadine therapy, compared with only 3% during therapy. Similarly, before therapy 34.3% of patients experienced moderate or severe disruption of sleep, compared with only 2.6% during therapy (57).


  1. Top of page
  2. Abstract
  3. Advances in biomedical research of allergy
  4. Changing the management of allergy
  5. Conclusions
  6. References

Scientific, genetic, epidemiological, and pharmacoeconomic research has transformed our understanding of allergy. New endpoints for research and new therapeutic targets have become clear. Efficacy endpoints of antiallergy treatment are also changing. Ideally, new antiallergy therapies should intervene in the systemic allergic inflammatory cascade, with broad clinical efficacy in multiple allergic disease states, an improved clinical efficacy profile compared with existing therapies, and a positive impact on disease-impaired quality-of-life measures.


  1. Top of page
  2. Abstract
  3. Advances in biomedical research of allergy
  4. Changing the management of allergy
  5. Conclusions
  6. References
  • 1
    Kay AB. Allergy and allergic diseases. First of two parts. N Engl J Med 2001;344: 3037.
  • 2
    Canonica GW. Introduction to the nasal and pulmonary allergy cascade. Allergy 2002;57(Suppl. 75):812.
  • 3
    Bousquet J, Van Cauwenberge P, Khaltaev N. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol 2001;108(5 Suppl.):S147S334.
  • 4
    Sekiya T, Yamada H, Yamaguchi M et al. Increased levels of TH2-type CC chemokine thymus and activation-regulated chemokine (TARC) in serum and induced sputum of asthmatics. Allergy 2002;57: 173177.
  • 5
    Terada N, Nomura T, Kim WJ et al. Expression of C-C chemokine TARC in human nasal mucosa and its regulation by cytokines. Clin Exp Allergy 2001;31: 18091812.
  • 6
    Kanwar S, Johnston B, Kubes P. Leukotriene C4/D4 induces P-selectin and sialyl Lewis (x)-dependent alterations in leukocyte kinetics in vivo. Circ Res 1995;77: 879887.
  • 7
    Strachan D, Sibbald B, Weiland S et al. Worldwide variations in prevalence of symptoms of allergic rhinoconjunctivitis in children: the International Study of Asthma and Allergies in Childhood (ISAAC). Pediatr Allergy Immunol 1997;8: 161176.
  • 8
    Ciprandi G, Vizzaccaro A, Cirillo I, Crimi P, Canonica G. Increase of asthma and allergic rhinitis prevalence in young Italian men. Int Arch Allergy Immunol 1996;111: 279283.
  • 9
    Aberg N, Hesselmar B, Aberg B, Eriksson B. Increase of asthma, allergic rhinitis and eczema in Swedish schoolchildren between 1979 and 1991. Clin Exp Allergy 1995;25: 815819.
  • 10
    Evans R III, Mullally DI, Wilson RW et al. National trends in the morbidity and mortality of asthma in the US. Prevalence, hospitalization and death from asthma over two decades: 1965–1984. Chest 1987;91: 65S74S.
  • 11
    Aberg N. Asthma and allergic rhinitis in Swedish conscripts. Clin Exp Allergy 1989;19: 5963.
  • 12
    Broder I, Higgins MW, Mathews KP, Keller JB. Epidemiology of asthma and allergic rhinitis in a total community, Tecumseh, Michigan. IV. Natural history. J Allergy Clin Immunol 1974;54: 100110.
  • 13
    Settipane G, Settipane RJ, Hagy GW. Long term risk factors for developing asthma and allergic rhinitis: a 23-year follow-up study of college students. Allergy Proc 1994;15: 2125.
  • 14
    Anderson HR, Pottier AC, Strachan DP. Asthma from birth to age 23: incidence and relationship to prior and concurrent atopic status. Thorax 1992;47: 537542.
  • 15
    Jenkins MA, Hopper JL, Flander LB et al. The associations between childhood asthma, and atopy, and parental asthma, hay fever and smoking. Paediatr Perinat Epidemiol 1993;7: 6776.
  • 16
    Lombardi C, Passalacqua G, Gargioni S et al. The natural history of respiratory allergy: a follow-up study of 99 patients up to 10 years. Respir Med 2001;95: 912.
  • 17
    Corren J. Allergic rhinitis and asthma: how important is the link? J Allergy Clin Immunol 1997;99: S781S786.
  • 18
    Ball TM, Castro-Rodriguez JA, Griffith KA, Holberg CJ, Martinez FD, Wright AL. Siblings, day-care attendance, and the risk of asthma and wheezing during childhood. N Engl J Med 2000;343: 538543.
  • 19
    Openshaw PJ, Hewitt C. Protective and harmful effects of viral infections in childhood on wheezing disorders and asthma. Am J Respir Crit Care Med 2000;162(2: 2):S40S43.
  • 20
    Karmaus W, Botezan C. Does a higher number of siblings protect against the development of allergy and asthma? A review. J Epidemiol Community Health 2002;56: 209217.
  • 21
    Cookson W. The alliance of genes and environment in asthma and allergy. Nature 1999;402(Suppl. 6760):B5B11.
  • 22
    Warner JA, Jones AC, Miles EA, Colwell BM, Warner JO. Prenatal origins of asthma and allergy. Ciba Found Symp 1997;206: 220228,228–232(discussion).
  • 23
    Eriksson NE, Holmen A. Skin prick tests with standardized extracts of inhalant allergens in 7099 adult patients with asthma or rhinitis. Cross-sensitizations and relationships to age, sex, month of birth and year of testing. J Invest Allergol Clin Immunol 1996;6: 3646.
  • 24
    Quoix E, Bessot JC, Kopferschmitt-Kubler MC, Fraisse P, Pauli G. Positive skin tests to aero-allergens and month of birth. Allergy 1988;43: 127131.
  • 25
    Cookson WO. Asthma genetics. Chest 2002;121(Suppl. 3):7S13S.
  • 26
    Toda M, Ono SJ. Genomics and proteomics of allergic disease. Immunology 2002;106: 110.
  • 27
    Marsh DG, Hsu SH, Roebber M et al. HLA-Dw2: a genetic marker for human immune response to short ragweed pollen allergen Ra5. I. Response resulting primarily from natural antigenic exposure. J Exp Med, 1982;155: 14391451.
  • 28
    Hill MR, Cookson WO. A new variant of the beta subunit of the high-affinity receptor for immunoglobulin E (Fc epsilon RI–beta E237G): associations with measures of atopy and bronchial hyper-responsiveness. Hum Mol Genet 1996;5: 959962.
  • 29
    Marsh DG, Neely JD, Breazeale DR et al. Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations. Science 1994;264: 11521156.
  • 30
    Baldini M, Lohman IC, Halonen M, Erickson RP, Holt PG, Martinez FD. A polymorphism* in the 5′ flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E. Am J Respir Cell Mol Biol 1999;20: 976983.
  • 31
    Green RM, Custovic A, Sanderson G, Hunter J, Johnston SL, Woodcock A. Synergism between allergens and viruses and risk of hospital admission with asthma: case-control study. BMJ 2002;324: 763.
  • 32
    Salvi S. Pollution and allergic airways disease. Curr Opin Allergy Clin Immunol 2001;1: 3541.
  • 33
    Lodrup Carlsen KC, Carlsen KH. Effects of maternal and early tobacco exposure on the development of asthma and airway hyperreactivity. Curr Opin Allergy Clin Immunol 2001;1: 139143.
  • 34
    Piedimonte G. The association between respiratory syncytial virus infection and reactive airway disease. Respir Med 2002;96(Suppl. B):S25S29.
  • 35
    Fineman SM. The burden of allergic rhinitis, beyond dollars and cents. Ann Allergy Asthma Immunol 2002;88(Suppl. 1):27.
  • 36
    Dessi P, Allaert FA, Urbinelli R, Verriere JL. Medico-economic aspects of the management of perennial allergic rhinitis in general medicine. Allerg Immunol (Paris) 1998;30: 277283.
  • 37
    Kessler RC, Almeida DM, Berglund P, Stang P. Pollen and mold exposure impairs the work performance of employees with allergic rhinitis. Ann Allergy Asthma Immunol 2001;87: 289295.
  • 38
    Crystal-Peters J, Crown WH, Goetzel RZ, Schutt DC. The cost of productivity losses associated with allergic rhinitis. Am J Manag Care 2000;6: 373378.
  • 39
    Cuffel B, Wamboldt M, Borish L, Kennedy S, Crystal-Peters J. Economic consequences of comorbid depression, anxiety, and allergic rhinitis. Psychosomatics 1999;40: 491496.
  • 40
    Szucs TD, Anderhub H, Rutishauser M. The economic burden of asthma: direct and indirect costs in Switzerland. Eur Respir J 1999;13: 281286.
  • 41
    Weissflog D, Matthys H, Virchow JC Jr. Epidemiology and costs of bronchial asthma and chronic bronchitis in Germany. Dtsch Med Wochenschr 2001;126: 803808.
  • 42
    Weiss KB, Sullivan SD, Lyttle CS. Trends in the cost of illness for asthma in the United States, 1985–1994. J Allergy Clin Immunol 2000;106: 493499.
  • 43
    Nowak D, Volmer T, Wettengel R. Bronchial asthma – a cost of illness analysis. Pneumologie 1996;50: 364371.
  • 44
    Smith C. A national estimates of the economic costs of asthma. Am J Respir Crit Care Med 1997;156: 797793.
  • 45
    Gallefoss F, Bakke PS. Cost-effectiveness of self-management in asthmatics: a 1-yr follow-up randomized, controlled trial. Eur Respir J 2001;17: 206213.
  • 46
    Serra-Batlles J, Plaza V, Morejon E, Comella A, Brugues J. Costs of asthma according to the degree of severity. Eur Respir J 1998;12: 13221326.
  • 47
    Szucs TD, Anderhub HP, Rutishauser M. Determinants of health care costs and patterns of care of asthmatic patients in Switzerland. Schweiz Med Wochenschr 2000;130: 305313.
  • 48
    Graf von der Schulenburg JM, Greiner W, Molitor S, Kielhorn A. Cost of asthma therapy in relation to severity. An empirical study. Med Klin 1996;91: 670676.
  • 49
    Plaza V, Serra-Batlles J, Ferrer M, Morejon E. Quality of life and economic features in elderly asthmatics. Respiration 2000;67: 6570.
  • 50
    Ungar WJ, Coyte PC. Measuring productivity loss days in asthma patients. The Pharmacy Medicaton Monitoring Program Advisory Board. Health Econ 2000;9: 3746.
  • 51
    Meltzer EO. Pharmacological treatment options for allergic rhinitis and asthma. Clin Exp Allergy 1998;28(Suppl. 2):2736.
  • 52
    Barnes PJ. Effect of beta-agonists on inflammatory cells. J Allergy Clin Immunol 1999;104: S10S17.
  • 53
    Torphy TJ. Action of mediators on airway smooth muscle: functional antagonism as a mechanism for bronchodilator drugs. Agents Actions Suppl 1988;23: 3753.
  • 54
    Johnson DA, Hricik JG. The pharmacology of alpha-adrenergic decongestants. Pharmacotherapy 1993;13: 110S115S, 143S–146S(discussion).
  • 55
    Boumpas DT, Chrousos GP, Wilder RL, Cupps TR, Balow JE. Glucocorticoid therapy for immune-mediated diseases: basic and clinical correlates. Ann Intern Med 1993;119: 11981208.
  • 56
    Charlesworth EN, Massey WA, Kagey-Sobotka A, Norman PS, Lichtenstein LM. Effect of H1 receptor blockade on the early and late response to cutaneous allergen challenge. J Pharmacol Exp Ther 1992;262: 964970.
  • 57
    Bachert C. Therapeutic points of intervention and clinical implications: role of desloratadine. Allergy 2002;57(Suppl. 75):1318.
  • 58
    Huger M, Traidl-Hoffmann C, Kasche A, Ring J, Behrendt H. Influence of desloratadine on the chemotactic activity of human polymorphonuclear leukocytes. Allergy 2002;57(Suppl. 73):38.
  • 59
    Marshall G, Henninger E, Maniatis E, Ritter S, Salicru A, Messick C. Immunomodulatory effects of desloratadine: changes in type-1/type-2 cytokine expression in PBMC cultures. J Allergy Clin Immunol 2002;109(Suppl.):S206S207.
  • 60
    Ring J, Hein R, Gauger A, Bronsky E, Miller B. Once-daily desloratadine improves the signs and symptoms of chronic idiopathic urticaria: a randomized, double-blind, placebo-controlled study. Int J Dermatol 2001;40: 7276.
  • 61
    Meltzer EO, Prenner BM, Nayak A et al. Efficacy and tolerability of once-daily 5 mg desloratadine, an H1-receptor antagonist, in patients with seasonal allergic rhinitis assessment during the spring and fall allergy season. Clin Drug Invest 2001;21: 2532.
  • 62
    Dubuske L. Once-daily desloratadine reduces the symptoms of perennial allergic rhinitis for at least 4 weeks. J Allergy Clin Immunol 2001;107: S159.
  • 63
    Baena-Cagnani C. Desloratadine improved asthma symptoms and decreased beta 2-agonist use in patients with seasonal allergic rhinitis and concomitant asthma. Allergy 2001;56(Suppl. 68):22.
  • 64
    Bachert C. Decongestant efficacy of desloratadine in patients with seasonal allergic rhinitis. Allergy 2001;56(Suppl. 65):1420.
  • 65
    Geha RS, Meltzer EO. Desloratadine: a new, nonsedating, oral antihistamine. J Allergy Clin Immunol 2001;107: 751762.
  • 66
    Horak F, Stübner P, Zieglmayer R, Moser M, Kawina A, Engelbrecht W. Decongestant activity of desloratadine versus placebo in allergic rhinitis: results from 3 single-dose, placebo-controlled, allergen chamber trials. Allergy 2001;56(Suppl. 68):79.
  • 67
    Horak F, Stübner P, Zieglmayer R, Harris AG. Effect of desloratadine versus placebo on nasal airflow and subjective measures of nasal obstruction in subjects with grass pollen-induced allergic rhinitis in an allergen-exposure unit. J Allergy Clin Immunol 2002;109: 956961.
  • 68
    Daly A. Desloratadine reduces nasal congestion in SAR with greater magnitude than fexofenadine, cetrizine and loratadine. Allergy 2001;56(Suppl. 68):79.
  • 69
    Ring J, Hein R, Gauger A, Bronsky E, Miller B. Once-daily desloratadine improves the signs and symptoms of chronic idiopathic urticaria: a randomized, double-blind, placebo-controlled study. Int J Dermatol 2001;40: 7276.
  • 70
    Data on file. Schering-Plough, 2002.