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Keywords:

  • asthma;
  • chronic rhinosinusitis;
  • epidemiology;
  • GA2LEN

Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Funding
  8. Author contributions
  9. Conflict of interests
  10. References
  11. Supporting Information

To cite this article: Jarvis D, Newson R, Lotvall J, Hastan D, Tomassen P, Keil T, Gjomarkaj M, Forsberg B, Gunnbjornsdottir M, Minov J, Brozek G, Dahlen SE, Toskala E, Kowalski ML, Olze H, Howarth P, Krämer U, Baelum J, Loureiro C, Kasper L, Bousquet PJ, Bousquet J, Bachert C, Fokkens W, Burney P. Asthma in adults and its association with chronic rhinosinusitis: The GA2LEN survey in Europe. Allergy 2012; 67: 91–98.

Abstract

Background:  The prevalence of asthma and its association with chronic rhinosinusitis (CRS) have not been widely studied in population-based epidemiological surveys.

Methods:  The Global Allergy and Asthma Network of Excellence (GA2LEN) conducted a postal questionnaire in representative samples of adults living in Europe to assess the presence of asthma and CRS defined by the European Position Paper on Rhinosinusitis and Nasal Polyps. The prevalence of self-reported current asthma by age group was determined. The association of asthma with CRS in each participating centre was assessed using logistic regression analyses, controlling for age, sex and smoking, and the effect estimates were combined using standard methods of meta-analysis.

Results:  Over 52 000 adults aged 18–75 years and living in 19 centres in 12 countries took part. In most centres, and overall, the reported prevalence of asthma was lower in older adults (adjusted OR for 65–74 years compared with 15–24 years: 0.72; 95% CI: 0.63–0.81). In all centres, there was a strong association of asthma with CRS (adjusted OR: 3.47; 95% CI: 3.20–3.76) at all ages. The association with asthma was stronger in those reporting both CRS and allergic rhinitis (adjusted OR: 11.85; 95% CI: 10.57–13.17). CRS in the absence of nasal allergies was positively associated with late-onset asthma.

Conclusion:  Geographical variation in the prevalence of self-reported asthma was observed across Europe, but overall, self-reported asthma was more common in young adults, women and smokers. In all age groups, men and women, and irrespective of smoking behaviour, asthma was also associated with CRS.

In the 1990s, the European Community Respiratory Health Survey (ECRHS) reported substantial geographical variation in the prevalence of asthma in young adults (1) and showed, in both cross-sectional (2) and longitudinal (3) analyses, that asthma was associated with allergic rhinitis. Other studies suggest that other nasal disorders, such as ‘sinus troubles’ may also be associated with asthma (4). Chronic rhinosinusitis (CRS) is an inflammatory condition of the mucosa of the nose or sinuses and includes conditions in which inflammation of the sinus may occur secondary to an inflammation of the nasal mucosa. Until recently, few epidemiological studies have collected standardized information on CRS.

The Global Allergy and Asthma Network of Excellence (GA2LEN) has developed a questionnaire to assess the presence of CRS in epidemiological studies (5), using criteria set out in The European Position Paper on Rhinosinusitis and Nasal Polyps (EP3OS) (6). This questionnaire has been included in a multicentre European study in which one of the primary aims was to assess the prevalence of asthma in adults of all ages. A report describing substantial geographical variation in CRS prevalence in Europe using the information collected has been published. (7).

In this report, we aim to (i) describe the prevalence of reported asthma in adults, including older age groups, and (ii) assess the relationship of asthma with CRS. This is important because the generations who have formed part of the ‘allergy epidemic’ are now ageing, and further information on the pattern of disease in these older age groups is needed for health service planning. Furthermore, there is little epidemiological data in either young or older adults on the association of asthma with CRS.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Funding
  8. Author contributions
  9. Conflict of interests
  10. References
  11. Supporting Information

Survey

The core protocol for the GA2LEN survey required participating centres to identify a random sample of at least 3000 adults aged 15–74 years from an available population-based sampling frame. In 2008–2009, potential participants were sent a short questionnaire by mail, and at least three attempts were made to elicit a response. The questionnaire collected information on age, gender, smoking and the presence of symptoms of asthma (including age of onset), CRS and allergic rhinitis.

Definition of outcomes

Asthma was defined as reporting having ever had asthma AND reporting at least one of the following symptoms in the last 12 months (i) wheeze or whistling in the chest, (ii) waking with chest tightness, (iii) waking with shortness of breath, and (iv) waking with an attack of coughing.

‘Current late-onset asthma’ was defined as asthma reported to have started at or after the age of 16 (‘current early-onset asthma’ was reported to have an onset before 16 years of age).

Chronic rhinosinusitis was defined following the EP3OS criteria, that is, the presence of at least two of the following symptoms for at least 12 weeks in the past year: (i) nasal blockage, (ii) nasal discharge, (iii) facial pain or pressure or (iv) reduction in sense of smell with at least one of the symptoms being nasal blockage or nasal discharge.

Allergic rhinitis was defined as a positive response to the question ‘Do you have any nasal allergies or hay fever?’

Analysis

Prevalences, odds ratios and relative risk ratios were estimated using logistic regression with Huber variances. Sampling probability weights were used to standardize prevalences by gender and 5-year age group (15–19 to 70–74) to a European Standard Population.

Odds ratios for asthma with respect to gender, 10-year age group and smoking status (current smoker, ex-smoker and lifetime nonsmoker) were assessed in each centre using two logistic regression models, one with these factors only and the other with additional information on smoking, measured as pack-years. In this latter adjustment, the odds ratios for 25 and 50 pack-years were determined, assuming the effects of other exposure levels to be interpolated quadratically, using the spline method (8).

Odds ratios for asthma with respect to CRS were estimated in all subjects, lifetime nonsmokers smokers only, men, women, and 20-year age groups (15–34, 35–54 and 55–74) with adjustments as appropriate for gender, 10-year age group, smoking status, and pack-years.

Relative risk ratios for early-onset and late-onset asthma with CRS only, nasal allergies only, or both conditions were estimated using multinomial logistic regression models, with no asthma as the baseline outcome level with adjustments similar to above.

For all analyses, centre effect estimates were averaged using geometric mean odds ratios weighted by sample number. Heterogeneity between centres was measured using Wald chi-squared tests and the I-squared (9). The potential influence of nonresponse on prevalence estimates was assessed as previously described (7). All analyses were conducted in Stata Version 11 (10).

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Funding
  8. Author contributions
  9. Conflict of interests
  10. References
  11. Supporting Information

Response

Twenty-five centres (15 countries) took part in the survey. Centres in Munich, Oslo and Athens (all participants <30 years old) and three in Russia (not population based) were excluded as they did not follow the full protocol. This report presents information from 19 centres (12 countries).

Table 1 shows the response rate and the crude prevalence of asthma, CRS and allergic rhinitis in each participating centre. Response rates varied from centre to centre with no consistent evidence that those with asthma or allergic rhinitis replied earlier than those without these conditions (Somers’ D P > 0.05). As reported earlier (7), there was limited evidence that those with CRS tended to respond later than those without CRS in some centres.

Table 1.   Response rate and prevalence of asthma, chronic rhinosinusitis and allergic rhinitis (directly standardized to European Standard Population) in all participants by centre
CountryCentreResponded and provided information on date of birth and genderMedian age (IQR)% male% smokePrevalence (%) asthmaPrevalence (%) asthma (lifetime nonsmokers only)Prevalence (%) chronic rhinosinusitis by EP3OS criteriaPrevalence (%) allergic rhinitis
n/NRate
SwedenGothenburg8619/1500057.542.9 (29.8–57.7)44.916.17.16.38.226.5
Stockholm5887/1000058.943.1 (31.2–57.4)45.816.78.67.89.628.9
Umea6055/1000060.542.6 (28.0–57.8)46.09.811.210.98.125.8
Uppsala6114/1000061.143.2 (29.0–58.1)45.013.09.59.08.627.6
FinlandHelsinki1809/551032.841.0 (28.5–58.5)47.326.47.87.96.939.9
DenmarkOdense3340/500066.846.6 (34.0–59.2)46.926.28.67.77.826.1
PolandKatowice2672/600044.544.8 (29.5–58.0)45.930.85.23.917.333.4
Krakow1267/500025.344.9 (29.2–58.6)41.423.57.17.819.741.6
Lodz1772/500035.448.8 (31.4–59.0)44.627.66.05.014.436.2
UKLondon1825/500036.545.8 (35.3–57.7)41.717.211.411.410.033.5
Southampton1191/500023.850.0 (37.1–61.3)43.220.414.211.811.232.7
NetherlandsAmsterdam3191/500063.848.8 (37.4–59.6)45.320.76.45.514.328.4
BelgiumGhent1851/502936.844.9 (31.3–57.2)45.923.97.67.518.827.5
GermanyBrandenburg2252/555240.848.2 (37.6–61.2)44.225.36.36.86.922.6
Duisburg1158/500023.247.6 (35.5–61.0)45.728.710.19.614.129.6
FranceMontpellier1385/500027.747.9 (34.2–58.3)41.322.810.38.813.343.9
MacedoniaSkopje3613/450080.339.4 (25.7–52.9)46.037.85.15.08.241.3
ItalyPalermo965/250038.639.3 (27.9–51.8)37.223.210.710.810.927.0
PortugalCoimbra2162/487744.343.0 (32.1–57.2)40.114.616.816.827.132.9
All centres57128/11896848.044.4 (30.6–57.9)44.820.18.58.210.930.4

Prevalence of asthma

Standardized to a European population, the prevalence of asthma varied substantially between centres (5.2% in Katowice, Poland to 16.8% in Coimbra, Portugal) (Fig. 1). The median prevalence of asthma in the 19 centres was 8.6% in Stockholm, Sweden. Centres that had a ‘high’ prevalence of asthma (the lower limit of the 95% confidence interval excluded 8.6%) were Umea, Uppsala, London, Southampton, Palermo and Coimbra. Centres with a ‘low’ prevalence of asthma (the upper limit of the 95% confidence interval excluded 8.6%) were Gothenburg, Katowice, Lodz, Amsterdam, Brandenburg and Skopje. A similar pattern of geographical variation was seen when the sample was restricted to lifetime nonsmokers (Table 1).

image

Figure 1.  The prevalence of asthma in each centre unstandardized and standardized to the European population (95% confidence intervals).

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Overall, asthma was less common in older age groups than younger age groups (Table 2), but this was not seen in all centres (Fig. 2). In the oldest age group (65–74 years), the prevalence of asthma was 7.6%, with substantial variation between countries (Gothenburg, Sweden: 4.7%, 95% CI: 3.6%–6.2%; Coimbra, Portugal 13.8%, 95% CI: 10.3–18.3%; Southampton, UK 13.8%, 95% CI: 9.6%–19.4%). Of note, asthma was more common in older than younger subjects in Skopje, Macedonia, the three Polish centres and in Helsinki, Finland (Fig. 2). The prevalence of asthma was consistently higher in females than males in all centres within the study (Table 2).

Table 2.   The mutually adjusted weighted geometric mean odds ratios of asthma for gender, age and smoking
Risk factorCases/totalModel 1 (adjusted for age, gender and smoking status only)Model 2 (adjusted as for Model 1 plus pack-years of smoking)
 Tests for heterogeneity of associations
OR (95% CI)OR (95% CI)I2P
  1. NI, not included in the analysis.

Gender
 Male1780/237011.001.00  
 Female2780/294841.26 (1.18, 1.34)1.28 (1.20, 1.37)00.77
10-year age group
 15–24749/79101.001.00  
 25–34975/101610.93 (0.84, 1.04)0.93 (0.83, 1.03)00.69
 35–44882/97860.84 (0.75, 0.94)0.82 (0.73, 0.92)40.90.033
 45–54764/96040.73 (0.66, 0.82)0.71 (0.63, 0.80)00.79
 55–64713/95090.70 (0.62, 0.78)0.66 (0.59, 0.75)40.30.036
 65–74477/62150.72 (0.63, 0.81)0.68 (0.60, 0.78)29.60.11
Smoking status
 Never2652/315561.00 (ref)1.00  
 Ex998/107581.25 (1.15, 1.36)1.17 (1.05, 1.31)30.40.1
 Current910/108711.16 (1.07, 1.26)1.04 (0.93, 1.16)35.90.061
Smoking exposure (pack-years)
 25NI1.18 (1.04, 1.33)35.60.063
50NI1.22 (1.01, 1.48)69.1<0.001
image

Figure 2.  The prevalence of asthma by 10-year age group and centre.

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Asthma was reported more frequently by current smokers than nonsmokers (Table 2) and was associated with cumulative tobacco use (adjusted OR for asthma comparing 50 pack-years of smoking with none: 1.22; 95% CI: 1.01–1.48). There was substantial variation in the direction and strength of this association between centres largely because of the low number of heavy smokers in some centres. Ex-smokers had more asthma than lifetime nonsmokers (OR 1.25 95% 1.15–1.36).

Asthma and CRS

In all centres, asthma was strongly and consistently associated with CRS (Fig. S1–shows country-specific estimates of the association), with some variation in the strength of these positive associations (overall OR: 3.48; 95% CI: 3.21–3.77; test for heterogeneity P = 0.001). Asthma was associated with CRS in men, in women and in all age groups (Table 3), even in analyses restricted to lifetime nonsmokers. In lifetime nonsmokers, the strength of the association was greater in men than women (difference in association by gender P = 0.001), there was no evidence that the association varied by age (difference in association by age group P = 0.72).

Table 3.   The adjusted odds ratio for asthma with chronic rhinosinusitis by gender and age in whole sample and restricted to lifetime nonsmokers
 Whole sample unadjustedWhole sample (adjusted*)Test for heterogeneityLifetime nonsmokers only (adjusted†)Test for heterogeneity
I2PI2P
  1. *Adjusted age, gender, smoking and pack-years of smoking as appropriate.

  2. †Adjusted for age and gender only.

  3. ‡Eterogeneity largely explained by OR of 0 in Palermo related to low sample size.

All subjects3.543.48 (3.21–3.77)57.40.0013.62 (3.24–4.04)52.00.005
Males4.024.12 (3.63–4.67)39.40.044.53 (3.81–5.38)28.60.12
Females3.233.12 (2.81–3.47)37.00.0543.10 (2.68–3.59)19.80.21
15–343.012.91 (2.53–3.35)00.593.14 (2.64–3.74)00.58
35–543.603.58 (3.13–4.09)16.00.263.49 (2.86–4.25)21.90.19
55+4.044.08 (3.47–4.79)41.80.0293.41 (2.64–4.42)74.6<0.0001‡

Asthma and CRS and nasal allergies

Overall, 56.7% of those reporting symptoms that fulfilled the EP3OS criteria for CRS also reported ‘hay fever or nasal allergies’.

Compared with those who had neither CRS nor allergic rhinitis, asthma was more common in those with CRS only (adjusted OR: 2.71; 95% CI: 2.30–3.20) and nasal allergies only (adjusted OR: 5.72; 95% CI: 5.27–6.21). However, participants who reported both CRS and nasal allergies were even more likely to report asthma (adjusted OR: 11.85; 95% CI: 10.57–13.17). This overall pattern was seen in all centres, although there was variation in the strength of the estimates.

About 49.5% of those with asthma reported that their disease began after the age of 16. CRS was strongly associated with both early-onset and late-onset asthma (RRR: 2.93; 95% CI: 2.59–3.32 and RRR: 3.85; 95% CI: 3.45–4.30, respectively). In Fig. 3(a,b), we show the results from the multinomial regression in which we examine the association of CRS only, nasal allergies only and CRS and nasal allergies with both early-onset asthma and late-onset asthma. Those with CRS only (compared with those who have neither CRS nor nasal allergies) report less early-onset asthma (RRR: 0.45; 95% CI: 0.35–0.57) but more late-onset asthma (RRR: 3.09; 95% CI: 2.51–3.81). The other combinations (nasal allergies only, nasal allergies plus CRS) are both positively associated with both early- and late-onset asthma.

image

Figure 3.  The association (relative risk ratio with 95% confidence interval) of early- and late-onset asthma with chronic rhinosinusitis only, nasal allergies only and CRS with nasal allergies.

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Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Funding
  8. Author contributions
  9. Conflict of interests
  10. References
  11. Supporting Information

This large multicentre European survey conducted in young, middle-aged and older adults shows wide variations in the prevalence of asthma. As in previous studies, the prevalence was high in the UK (1) and low in areas of the former Soviet Block (11), which in this survey included sites in Poland, Macedonia and the former East Germany (Brandenburg). Unlike previous studies (1), the prevalence of asthma in Southern Europe (Italy and Portugal) was not lower than in other parts of Europe.

Asthma was more common among younger participants. This is likely to reflect the increase in atopy and asthma that has occurred between generations (12–14) and is notably absent from the countries of Eastern Europe where the prevalence of asthma is still relatively low. However, asthma was not more common among the younger participants in Finland, a country in which generational increases in atopy and asthma have been well documented (15, 16) over the last twenty years.

We found strong and independent associations between asthma and both allergic rhinitis and chronic rhinosinusitis. These associations were consistent across all centres. An association between asthma and ‘nasal allergies or hay fever’(3) and ‘hay fever’ (17, 18) has been found in longitudinal studies, but this is not entirely explained by a common association with atopy as it also occurs in those with no sensitization to common aeroallergens (3, 19).

Our study is the first general population survey that has shown the association of asthma with chronic rhinosinusitis using symptoms proposed by EP3OS to define the nasal disorder rather than reported diagnoses. Compared with asking about diagnosed sinusitis, this approach has been shown to give at least as valid an indication of the presence of rhinosinusitis as confirmed by nasal endoscopy (5). Reported symptoms have the advantage of not being dependent on local health service practice and local use of diagnostic terms and are more appropriate for surveys, particularly when these are multicentre or, as in this case, multinational. Of the studies that have used physician diagnosis of disease, the Tucson longitudinal study has shown that chronic cough with wheeze is associated with doctor-diagnosed ‘sinus trouble’ (20) in children, and has shown a greater incidence of adult-onset asthma among those who reported ‘blocked or stuffy nose in the absence of a cold’ with physician diagnosed ‘sinus troubles’(4).

We recognize that allergic rhinitis and CRS coexist, that the former may lead to the latter and that ‘chronic rhinosinusitis’, like ‘asthma’ reflects several phenotypes. Even though both rhinitis and sinus disease are associated with asthma, a review of patients with asthma taking part in trials of asthma therapy suggested that it was the co-existence of chronic rhinosinusitis, not allergic rhinitis, that was associated with lower asthma-related quality of life (21).

We found that chronic rhinosinusitis without allergic rhinitis was associated positively with adult-onset asthma and negatively with childhood-onset asthma. As with all studies that rely on recall there may be misclassification of the reported age at which asthma first began with a proportion classifying their disease as adult-onset when, in fact, they had symptoms in childhood (22). This could result in overestimation of the association of adult-onset disease with CRS and underestimation for childhood-onset disease. Our results are compatible with a small clinical study of adults with asthma in which all those who recalled their asthma beginning before the age of 16 (but not those with adult-onset asthma) reported they had asthma before they developed sinusitis (23) Chronic rhinosinusitis with polyps has been specifically associated with asthma (24, 25). We have no direct information on polyps, but we did ask about loss of smell, a symptom strongly associated with polyposis (26). We found a much stronger association of asthma with ‘CRS with loss of smell’ (OR: 4.25; 95% CI: 3.74–4.71) than of asthma with ‘CRS without a loss of a sense of smell’ (OR: 2.88; 95% CI: 2.59–3.21) (P-value for the difference <0.0001).

Response to the survey varied between centres and is only modest in some sites. Response bias is more likely to affect estimates of prevalence than estimates of association, but we found little evidence that nonresponse influenced the prevalence of CRS (7) and no evidence that late responders to the survey were more or less likely to report a history of nasal allergies or asthma. It is unlikely that the strong associations of asthma with chronic rhinosinusitis arose as a result of low response rates.

The associations we have observed are supported by clinical studies demonstrating that CRS is prevalent in those with severe asthma (27, 28) and a Swedish community–based study in which nasal blockage and rhinorrhea were more common in asthmatics with multiple respiratory symptoms than in those who reported few symptoms (29) These associations have been interpreted as chronic rhinosinusitis causing asthma because of the release of inflammatory mediators and cytokines from the diseased sinus tissue into the circulation (30) and recruitment of eosinophils into both upper and lower airways from the bone marrow and circulation (31). It has also been shown that Th2-biased eosinophilic inflammation within the sinuses may be amplified by the presence of Staphylococcal superantigens inducing polyclonal T-cell activation and local IgE formation (25, 32).

In summary, this large international survey has shown a wide variation in the prevalence of asthma across Europe and has shown a lower prevalence in the older age group, except in the former Soviet states and Finland. It has shown strong and independent associations between asthma and both rhinitis and chronic rhino-sinusitis. Better understanding of these conditions and their interdependence may lead to better management.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Funding
  8. Author contributions
  9. Conflict of interests
  10. References
  11. Supporting Information

Dr Torsten Zuberbier of Charite University and Head of GA2LEN provided extensive comments on this manuscript.

Funding

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Funding
  8. Author contributions
  9. Conflict of interests
  10. References
  11. Supporting Information

This study was conducted as part of Workpackage 1.2.1 of the Global Allergy and Asthma European Network (GA2LEN) funded through the Sixth European Union Framework program for research, contract no. FOOD-CT-2004-506378.

Author contributions

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Funding
  8. Author contributions
  9. Conflict of interests
  10. References
  11. Supporting Information

PB, WF, CB and J Bousquet developed the overall study design and the instruments that were used. RN conducted the statistical analysis. DJ wrote the manuscript. All authors were directly involved in the study design, data collection and data quality checks in their local centre. All authors contributed to the final manuscript.

References

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Funding
  8. Author contributions
  9. Conflict of interests
  10. References
  11. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Funding
  8. Author contributions
  9. Conflict of interests
  10. References
  11. Supporting Information

Figure S1. The adjusted association (OR plus 95% CI) of asthma with chronic rhinosinusitis in each participating centre.

FilenameFormatSizeDescription
ALL_2709_sm_FigE1.doc717KSupporting info item

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