Joint Incidence of Asthma and Rhinitis in Macedonia



M Zdraveska*, 1, D Dimitrievska 1, D Todevski, A Gjorcev1, E Janeva1, I Pavlovska2, B Zafirova-Ivanovska2
1 Pulmology and Allergy Clinic Skopje, Macedonia
2 Institute of Epidemiology and Biostatistics with Medical Informatics, Medical Faculty, Skopje, Macedonia


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© Zdraveska et al.; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

* Address correspondence to this author at the Bul. Partizanski odredi 149 1-53, 1000 Skopje, Macedonia; Tel: +389 71 400765; Fax: +389 2 3211468; E-mail: mzdraveska@gmail.com


Abstract

The concept of “united airways disease”, based on many similar features and mutual interactions in the pathogenesis of asthma (A) and rhinitis (R), has led to an integral approach to their management. We conducted this study to determine the quantity of the problem of joint incidence of A and R in R. Macedonia, and, perhaps to obtain information on a potential causative effect of the two diseases.

Three hundred eighty six patients, who presented with wheezing and/or upper respiratory symptoms at the Pulmology and Allergy Clinic, Skopje, were included during a period of 48 months. The presence of bronchial hyperreactivity – BHR (positive histamine challenge), atopy (prick test to seasonal or perennial inhaled allergens), rhinitis symptoms (such as nasal secretion and obstruction) and X-ray of paranasal sinuses was registered by a specially designed questionnaire. R was diagnosed in 106 of the subjects (27.5%), and A in 280 (72.5%). Among the patients with A, co-incidence with R was found in 219 (76.5%). Including X-ray of paranasal sinuses to the diagnostic protocol increased this percentage to over 90% (256 patients). From the 219 patients with A and R together, 127 (57.99%) had positive atopy. On the other hand, 19 (18.0%) of the rhinitis-only patients had positive BHR without asthma symptoms. The follow up of the rhinitis patients with positive BHR revealed 4 patiets who developed asthma within 36 months, but this was also the case with 2 of the subjects with R and negative BHR. In conclusion, the co-incidence of A and R in our material is 78.21%, or 91.4% (including sinusitis); a greater co-existence of A and R is found in atopic patients. The patients with allergic R are at high risk for developing A and should be monitored in the future and the R symptoms should be adequately treated in order to minimize the risk for developing asthma.

Keywords: Asthma, rhinitis, epidemiology, united airways, joint incidence.



INTRODUCTION

Allergic diseases such as asthma, rhinitis, conjunctivitis, urticaria-angioedema, and atopic dermatitis share a high and increasing prevalence throughout the world. Affecting between 25 and 50% of the population, they impair the health and the quality of life of the subjects, causing a global financial and social burden to individuals and societies. The substantial progress that has been achieved in the knowledge of the mechanisms underlying allergic diseases shows that they share multiple pathophysiologic similarities and might be various phenotypic expressions of a process, systemic in nature, therefore requiring a global diagnostic, as well as therapeutic approach to the allergic patient [1-3].

The co-existence of asthma and rhinitis is documented in numerous epidemiological studies. Both entities share similar epidemiologic parameters (such as increasing prevalence, especially in developed countries), common histological and functional characteristics as well as pathophysiologic mechanisms. The common airway is triggered by similar agents and the impact of the upper on the lower airways is documented in numerous studies [4-6].The joint incidence of rhinitis and asthma and their mutual influence has been noted since ancient times, as Galenus recommended “purging nostrils of secretions to relieve the lungs“. The link between hay fever and asthma was described in the late nineteenth century by Bostok and Blakely, and Rackeman (1920) found that “lesions of the nose lead to development of asthma”. In the past decades, genetic research provided scientific basis of these observations, and numerous studies lead to publishing guidelines and recommendations such as the Global initiative for asthma (GINA) and the Allergic Rhinitis and its impact on Asthma (ARIA) [7, 8], which recognize the interactions between these two entities and support a global therapeutic and diagnostic approach to allergic patients. The need of a wider perspective to allergic patients is also emphasized by the numerous epidemiologic studies which confirm that rhinitis precedes asthma in 6-20% of cases. Verdiani refers that perennial rhinitis is associated with greater risk for development of airway hyperresponsivenes, and in a 14-yers follow up study, Johnstone found that 50% of children with allergic rhinitis develop asthma in the following 3-4 years [9].

In spite the contemporary recommendations, both asthma and rhinitis are still highly sub-diagnosed and seldom treated simultaneously, especially in Macedonia, where the treatment of allergic diseases is separated on the basis of shock organs; thus patients are distributed to either dermatologists, respiratory or ear, nose and throat (ENT) specialists, depending on their dominant complaint. This approach usually leads to treating one allergic manifestation, often without even recognizing the existence of symptoms deriving from other shock organs. The translation of the GINA and ARIA guidelines in Macedonia, as well as publishing the National guidelines for treatment of asthma in 1996 [10], imposed the need of recognizing the problem of joint incidence of asthma and rhinitis and developing a protocol for a global diagnostic approach to the patients.

OBJECTIVE

To determine the joint incidence of asthma and rhinitis in our population, the influence of atopy on the incidence of asthma, rhinitis, the coexistence of both, and the importance of positive BHR in the development of asthma in atopic and nonatopic patients with rhinitis.

MATERIALS AND METHODS

In order to determine the joint incidence of asthma and rhinitis in our population, we designed a prospective study, conducted at the National Center for Asthma and COPD at the Pulmology and Allergy Clinic in Skopje, in the period of 48 months. All patients who consulted the outpatient service of the Clinic with either symptoms of asthma, rhinitis, or both were eligible and were designated to a predefined diagnostic protocol. A total of 386 patients were enrolled in the study and followed the following protocol:

General data and basic demographic features were collected from all of the patients.

The diagnostic protocol for asthma followed the GINA recommendations (clinical presentation, standard reversibility test with 400 mcg of salbutamol. Broncho-provocation test with metacholine was performed in patients where asthma could not be confirmed with reversibility test, subjects with rhinitis symptoms only, or subjects with normal lung function at initial evaluation.

Presence of atopy was documented with standard skin prick tests to seasonal and perennial allergens.

Rhinitis was diagnosed with the presence of symptoms such as sneezing, rhinorhea, obstruction. Detection of sinusitis was included by registering the presence of post-nasal drip and adding routine X-ray for paranasal sinuses to the protocol.

Patients with rhinitis/rhinosinusitis alone were additionally followed for the period of duration of the study by follow up visits every 6 moths, actively looking for incidence of symptoms or lung function parameters for newly developed asthma.

Statistical Methods

Program Statistica for Windows was used for statistical data workup. Categorical variables were showed by absolute and relative numbers, while numerical series were analyzed with measures of central tendency as well as with measures of dispersion. Probable existence of association, i.e. significance determination in the analyzed difference among separate statistical series was tested by Pearson’s χ² test.

The risk factors were quantified through calculation of risks with Odds ratio (OR), having a role in occurrence of the disease, and with the Confidence intervals (CI - 95%), the statistical significance at error level less than 0.05 (p) was defined.

RESULTS

The characteristics of the patients enrolled in the study are shown Table 1.

Table 1..

Characteristics of the patients.


Variables  Number (N)  %
Patients No 386
Gender
 Female gender  214  55.4
 Male gender  172  44.6
Age (yr)
16-20  48  12.4
21-30  88  22.8
31-40 91  23.6
>41  159  41.2
Age (average) 37.7±13.4
Asthma diagnosis
With athma 280 72.5
Without athma (Rhinitis only) 106 27.5
Rhinitis
With rhinitis  325  84.2
Without rhinitis  61  15.8
X-ray of paranasal sinuses
Positive for rhinosinusitis 302  78.2
Negative for rhinosinusitis  84  21.8
Atopic status
Positive seasonal allergens 109  28.2
Positive perenial allergens  72  18.6
Positive seasonal and perenial allergens  55  14.2
No atopy detected  105  39.0
Atopic status in asthma-only patients  61  
Positive seasonal allergens 6  9.8
Positive perenial allergens  6  9.8
Positive seasonal and perenial allergens  1  1.6
No atopy detected  48  78.6
Subgroup- asthma patients 280
Asthma and Rhinitis-coexistence  219  76.5
Asthma and Rhinosinusitis (X-ray) 256  91,4
Asthma without rhinitis  61  21.7
Asthma without rhinosinusitis  24  8.6
Table 2..

Prevalence of bronchial hyperresponsiveness (BHR).


Variables Number (N) % Male % Female %
BHR - total of tested pts 160  77 48.1 83 51.9
Positive 61 38.8 24 39.3 37 60.7
Negative 99 61.2 53 53.5 46 46.5
BHR in pts with asthma symptoms and normal FEV1 54 19 35.2 35 64.8
Positive 42 77.8 12 28.6 30 71.4
Negative 12 22.2 7 58.3 5 41.6
BHR in patients with rhinitis only 106 58 54.7 48 45.3  
Positive 19 18.0 12 63.2 7 36.8  
Negative 87 82.0 46 52.9 41 47.1
Table 3..

Estimation of the risk to have asthma depending on the presence of atopy.


Variables  With Asthma1 Without asthma2 OR3 95% CI4
Atopy (in all subjects)
Positive 141 95 0.11 0.06-0.23
Negative 139 11 1.00
Χ² = 49.9 (p = 0.000)
Atopy (male subjects)
Positive 59 54 0.08 0.03-0.23
Negative 55 4 1.00
Χ² = 27.3 (p = 0.000)
Atopy (female subjects)
Positive 82 41 0.17 0.07-0.39
Negative 84 7 1.00  
Χ² = 19.8 (p = 0.000)
Table 4..

Estimation of the risk to have asthma depending on the presence of rhinitis.


Variables  With Asthma1 Without Asthma2 OR3 95% CI4
Rhinitis (in all subjects)
Positive 219 106 0.01 0.001-0.273
Negative 61 0.5 1.00
Χ² = 26.5 (p = 0.000)
Rhinitis (male subjects)
Positive 96 58 0.04 0.002-0.753
Negative 18 0.5 1.00
Χ² = 7.8 (p = 0.000)
Rhinitis (female subjects)
Positive 123 48 0.03 0.001-0.484
Negative 43 0.5 1.00
Χ² = 14.6 (p = 0.000)
Table 5..

Estimation of the risk to have rhinitis depending on the presence of atopy.


Variables With Rhinitis1 Without Rhinitis2 OR3 95% CI4
Atopy (in all subjects)
Positive 222 14 7.23 3.81-13.73
Negative 103 47 1.00
Χ² = 44.5 (p = 0.000)
Atopy (in men)
Positive 108 5 6.10 2.06-18.11
Negative 46 13 1.00
Χ² = 11.0 (p = 0.000)
Atopy (in women)
Positive 114 9 7.55 3.39-16.82
Negative 57 34 1.00
Χ² = 29.4 (p = 0.000)
Table 6..

Determination of atopy as a risk factor for asthma versus asthma and rhinitis.

Pearson Chi-square: 23,4330, df=1, p=,000001


Summary Table: Expected Frequencies (Atopy_A+R.sta) Marked cells have counts > 10 Pearson Chi-square: 23,4330, df=1, p=,000001
Atopy_0_1 Asthma Asthma+Rhinitis Row
0 30,28214 108,7179 139,0000
1 30,71786 110,2821 141,0000
All Grps 61,00000 219,0000 280,0000
Table 6a..

A+R related to A, for subjects with seasonal, perennial and combined allergy.


Summary Table: Expected Frequencies (Atopy_A+R.sta) Marked cells have counts > 10 Pearson Chi-square: 12,1623, df=1, p=,000488
Atopy Asthma Asthma+Rhinitis Row
0 37,02010 101,9799 139,0000
1 15,97990 44,0201 60,0000
All Grps 53,00000 146,0000 199,0000
Summary Table: Expected Frequencies (Atopy_A+R.sta) Marked cells have counts > 10 Pearson Chi-square: 7,98002, df=1, p=,004731
Atopy Asthma Asthma+Rhinitis Row
0 39,39572 99,6043 139,0000
2 13,60428 34,3957 48,0000
All Grps 53,00000 134,0000 187,0000
Summary Table: Expected Frequencies (Atopy_A+R.sta) Marked cells have counts > 10 Pearson Chi-square: 10,0822, df=1, p=,001498
Atopy Asthma Asthma+Rhinitis Row
0 39,59884 99,4012 139,0000
3 9,40116 23,5988 33,0000
All Grps 49,00000 123,0000 172,0000
Table 7..

Determination of the risk of development of rhinitis according to the presence of seasonal, perennial and sensitisation to both groups of allergens (seasonal and perennial allergy together).


Atopy Rhinitis (Positive) Rhinitis (Negative) OR - Odds ratio
Positive 103 6 7.8
Negative 103 47 1.00
c² = 25.87 p < 0.05; 95% Confidence interval (3.2 < OR < 19.1)
Atopy (Perennial) Rhinitis (Positive) Rhinitis (negaTive) OR - Odds Ratio
Positive 66 6 5.01
Negative 103 47 1.00
c² = 14.16 p < 0.05; 95% Confidence interval (2.03 < OR < 12.39)
Atopy (Seasonal and Perennial) Rhinitis (Positive) Rhinitis (Negative) OR - Odds Ratio
Positive 53 2 12.09
Negative 103 47 1.00
c² = 16.97 p < 0.05; 95% Confidence interval (2.8 < OR < 51.7)
Table 8..

Determination of the risk of development positive BHR in rhinitis-only patients, according to the presence of atopy in general.


Atopy BHR-Positive BHR-Negative OR - Odds Ratio
Positive 18 77 2.33
Negative 1 10 1.00

χ² = 0.15 (p = 0.695); p > 0.05; 95% Confidence interval (0.28 < OR < 19.45).

Table 9..

Determination of the risk of development of positive BHR in rhinitis-only patients, according to the presence of sensitization to seasonal allergens.


 Atopy
(Seasonal)
BHR-Positive BHR-Negative OR - Odds Ratio
Positive 6 43 1.39
Negative 1 10 1.00

χ² =0.05 (p = 0.821) p > 0.05; 95% Confidence interval (0.15 < OR < 12.92).

Table 10..

Determination of the risk of development of positive BHR in rhinitis-only patients, according to the presence of perennial allergy.


Atopy
(Perennial)
BHR-Positive BHR-Negative OR - Odds Ratio
Positive 6 18 3.33
Negative 1 10 1.00

χ² = 0.40 (p = 0.523) p > 0.05; 95% Confidence interval (0.35 < OR < 31.74).

Table 11..

Determination of the risk of development of positive BHR in rhinitis-only patients, according to the presence of combination of seasonal and perennial allergy.


Atopy (
Seasonal
and Perennial)
BHR-Positive BHR-Negative OR - Odds Ratio
Positive 6 16 3.75
Negative 1 10 1.00

χ² = 0.56 (p = 0.451) p >0.05 95% Confidence interval (0.39 < OR < 35.92).

The presence of bronchial hyperresponsiveness was tested in a total of 160 patients, 54 with asthma symptoms and normal FEV1 and 106 with rhinitis-only (Table 2).

Univariant analysis for the presence of atopy, asthma and rhinitis was done, in order to determine their role as risk factors in the whole tested sample. The results show that the presence of atopy as well as rhinitis is a significant risk factor for bronchial asthma, independent of gender (OR 0.11; χ² = 49.9, p = 0.000 and OR 0.01; χ² = 26.5, p = 0.000). Atopy also proved to be an independent risk factor for the presence of rhinitis (OR 7.23; χ² = 44.5, p = 0.000). Analyzing the subgroup of asthma-only patients and its comparison to the A+R group showed that the presence of atopy is a significant risk factor for developing coexistence of asthma and rhinitis, but not asthma alone. In the subgroup of asthmatic with no signs of rhinitis, atopy was not detected in 78%, and the probability not to be atopic in this subgroup of patients was significantly higher (OR 3.745; 95% CI 1.94-7.22, p=0.0001) (Tables 3-5).

Furtehrmore, the attempt to estimate atopy as a risk factor for developing asthma alone, or coincidence of asthma and rhinitis, showed that there was a significant diference in having asthma, and the combination of asthma and rhinitis together, related to the presence of atopy. Subjects with positive atopy had a greater risk of coexistence of asthma and rhinitis (χ² =23.43, df=1, p=0.000001). The statistical analysis of separate types of allergy (seasonal, perenial and combined) are shown in Tables 6-6a.

Similar analysis of the risk of developing rhinitis depending on the presence of sensitisation to the tested groups of allergens showed that seasonal, perennial and combined allergy are associated to a significantly greater risk for developing rhinitis (Table 7).

All of the patients with isolated symptoms of rhinitis, who, at the time of evaluation had no asthma symptoms, underwent bronchoprovocation test with metacholine (BHR). An attempt was made to determine whether the presence of atopy plays a role in the risk of developing positive BHR in the subgroup of patients with rhinitis-only. The results shown in Tables 8-11 determine that the presence of atopy (especially perennial and combined sensitisation) increases the risk to have positive BHR in rhinitis-only patients- (OR 2,33; 3.33; 3.75 respectfully) but this difference does not reach statistical significance ( P>0.05 in all calculations).

The subgroup of patients who had only rhinitis symptoms at initial diagnosis and positive BHR, was followed every 6 months, from the moment of first diagnosis, during, and 1 year after the end of the study, for eventual incidence of clinical features of asthma. Out of 12 male subjects with positive BHR, 2 developed asthma symptoms; one 25, and the other 39 month after initial diagnosis. Two out of 7 females with positive BHR, developed clinically manifest asthma, 23 and 36 months after initial diagnosis, respectfully. Three of them had sensitization to both seasonal and perennial allergens, and one to perennial allergens alone. There was no statistical difference in the PD20 of metacholine between these 4 subjects and the rhinitis only, BHR positive patients who had not yet developed asthma symptoms.

Routine follow up of patients with only rhinitis and negative BHR, showed that two male patients also developed asthma symptoms 28 and 34 months after the metacholine testing. In both subjects allergy to perennial allergens was detected.

DISCUSSION

The primary outcome of our study was to determine the joint incidence of asthma and rhinitis in our population. The group of patients evaluated in this study is heterogeneous and the patients were not recruited only from the narrow region of Skopje. According to the knowledge of the authors, there is only one major study treating the incidence of asthma and rhinitis in Macedonia, done by the Institute of occupational medicine in Skopje- Collaborative Center of WHO, in which the prevalence of asthma is 5.4 % of the population, atopy is present in 34,8 %, and the prevalence of chronic rhinitis is 30.2% (23.1% allergic rhinitis; 16,5% seasonal AR and 6.7% perennial allergic rhinitis) [11]. The drawback of this study is that the results were based on self-reported diagnosis, later-on confirmed by testing for atopy and asthma. In our study, atopy was detected in 61% of the subjects (28.2% seasonal, 18,6% perennial and 14,2% both). On the other hand, analyzing the subgroup of asthma-only patients who did not present with rhinitis symptoms showed that atopy was present in only 21.4%. In the subgroup of all of the patients with asthma, atopy was detected in 50.4%, with no gender differences. The univariant analysis confirmed atopy as a independent risk factor for asthma, as well as for rhinitis, and for the coexistence of asthma and rhinitis. A strong association of atopy and asthma and rhinitis has been found in numerous studies [12]. Seasonal allergens are usually associated to allergic rhinitis, and indoor allergens to asthma, but recent studies show that more than 50% of patients with seasonal allergy suffer from perennial rhinitis and in general population, a large number of subjects sensitized to mites have mild intermittent allergic rhinitis [13].

Asthma and rhinitis have common pathogenetic mechan-isms as well as epidemiologic features, and an integrated approach is essential [14-16]. Various mechanisms have been reported, including the mutual microbiome and its immunomodulatory capacities influencing asthma and perhaps chronic rhinitis [17]. The joint incidence of asthma and rhinitis has been reported in many studies, and numbers as high as 75-95% of asthmatics having rhinitis are common [18,19]. Same findings apply to occupational circumstances as well, leading to a revision of the guidelines [20]. In recent studies rhinitis symptoms were found in 98.9% of asthmatics [21], and 20-38% of patients with allergic rhinitis have concomitant asthma. Furthermore, allergic rhinitis is considered an independent risk factor for developing asthma [22], but nowadays it is not clear whether rhinitis precedes asthma, or this condition merely represents an early stage of united airway disease, which in time, progresses to full manifestation of asthma. We tried to shed some light to this question by testing the BHR in the rhinitis-only patients, expecting to determine the presence of positive airway hyperresponsiveness in patients with no evident asthma symptoms at the time of evaluation. We found that 18 % of these patients had positive hyperresponsiveness, meaning that almost 1 out of 5 subjects are prone to developing, or better more, had developed asthma, although they initially did not meet GINA criteria for diagnosis. Subclinical changes in the lower airways are described and inflammatory mediators have been detected even in patients who do not have asthma [23], and it is well established that treatment of rhinitis may have a positive effect on the clinical presentation and control of asthma [24]. Similar results are reported in numerous studied leading to the recommendations in the 2008 updated ARIA guidelines that “allergic rhinitis (AR) is a risk factor for asthma, and patients with persistent rhinitis should be evaluated for asthma” [13]. Evaluation of atopy as a risk factor for positive BHR in patients with rhinitis in our study, showed that the presence of atopy (especially perennial and combined sensitisation) increases the risk to have positive BHR in rhinitis-only patients (OR 2,33; 3.33; 3.75 respectfully) but this difference does not reach statistical significance ( P>0.05 in all calculations). Ricconi et al. have reported that perennial atopy (or rhinitis) is associated with greater BHR than seasonal atopy [25], but such an association was not confirmed in our study.

The follow up of the patients enrolled in this study went on during the whole recruitment period, and one year after, with special regards to the patients only with rhinitis with and without airway hyperresponsiveness. There was no association to specific type of atopy nor statistical difference in the PD20 for metacholine between these 4 subjects and the rhinitis only, BHR positive patients who had not yet developed asthma symptoms.. Still, we conclude that the number of patients who developed asthma symptoms during the follow up period in our study was too small for conclusive statistical analysis.

New onset of asthma in patients previously diagnosed with rhinitis, with an incidence up to 2.2% has been described in several longitudinal studies [26-29] and rhinitis has been reported to arise with time, in patients who presented only with asthma symptoms, and these data even strongly confirm the concept of the “United airways” and the theory that asthma and rhinitis are actually one single disease, with variations of appearance of symptoms in time, and “the key to managing both disorders is prevention and relief of chronic allergic inflammation in both the upper and lower airways" [30].

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

Declared none.

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