Asthma: Achievements and Questions in Front

Author

Pharmaceutical Sciences Research Center, Shaheed Beheshti University of Medical Sciences, Tehran, Iran

Abstract

       Asthma, which is mainly distinguished by airway inflammation and bronchial hyper responsiveness, is known as one of the most common chronic diseases worldwide. It also is the most frequent chronic respiratory disorder amongst all age groups. On one side of the asthma story, there are massive investment of time, effort and money, a large number of pharmaceutical and academic research studies, health service modifications and revised guidelines. On the other side, there are unacceptably high, but mostly preventable, morbidity and mortality rates, socio-economic burdens and psychological problems due to asthma. A considerable proportion of doctor’s workload, hospital resources, health utilization costs, days off from school and work are caused by asthma. Our knowledge about this disorder and its complications is still on demand. There are significant questions regarding asthma and its pathophysiology which should be answered. National, regional and local initiatives are needed to be established to help health systems to overcome socio-economic burdens due to this disease. These could only be done if a clear picture of this respiratory disorder and its management achievements are available. This review article is an approach to present an image about asthma and its management based on the current understandings of the nature of this disorder.

Keywords


1. Definition of asthma

     Recent understanding of different medical fields including allergy and immunology, molecular and cell biology, histology, pharmacology and epidemiology have led to a better understanding about asthma and its management. It has been recognized that inflammatory processes are important characteristics of asthma leading to airway obstruction and bronchial hyperresponsiveness.However, there is still a lack of information about natural history, pathophysiology and the understanding of specific causes and marker(s) of asthma [1, 2]. This could be because of the complex pathophysiology of asthma, which engages series of events in the cytokine network. Findings obtained in the last decade, shows that the cysteinyl leukotrienes (C4, D4 and E4) are among the important mediators involved in the pathogenesis of asthma. In addition, pathogenesis of asthma has been linked to the production of type 2 cytokines. Current animal and human studies have highlighted a major role for CD4(+) and CD8(+) T lymphocytes in the development of allergen induced airway responses. However, there is increasing evidence of Th1/Tc1mediated processes in the aetiopathology of asthma [3-7].

     In a joint workshop held by the National Heart, Lung and Blood Institute (NHLBI) and World Health Organization (WHO) [8], an operational description of asthma based on the inflammatory nature of this disorder was defined:

     “Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. The chronic inflammation causes an associated increase in airway hyperresponsiveness that leads to recurrent episodes of wheezing,breathlessness, chest tightness, and coughing,particularly at night or in the early morning.These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneouslyor with treatment.”

 

2. Epidemiology of asthma

     Asthma occurs in all countries regardless of the level of development. In general, epidemiological studies have shown that its prevalence is higher in affluent and western populations compared to non affluent countries. In some areas of the UK, Australia, New Zealand and Ireland there is a 40% prevalence rate of asthma in children, whilst in less affluent countries such as Indonesia, China, India and Ethiopia values as low as 3% have been reported [1]. Unfortunately, there is no precise statistical information about this disease and its social and economic impact in Iran. This would mainly be a result of poordatabase and recording systems available in Iran. Nevertheless, reports confirm that the prevalence of asthma is increasing in all over the world [9]. Factors underlying this increase are unclear. However, it may be related to environmental factors including increasing exposure to allergens, pollutants and their synergistic interaction with allergic sensitization [1, 8]. For example passive smoking during infancy may be associated with an allergic sensitization to common aeroallergens [10]. Urbanization (related to higher pollution rates) [11] and dietary factors [12,13] are also reported to be associated with asthma prevalence. However, their role has not been clearly confirmed. In England no significant tendency has been found for asthma to be diagnosed more often in urban compared with rural areas [9].

     It seems that in addition to the prevalence of asthma, its severity (and the related morbidity) has also increased. This increase is suggested by the rise in hospital admissions as well as a higher usage of anti asthma medications [1]. The socio economic status may be involved in the increased severity that may be related to problems in obtaining adequate medical care and to poor housing environment. Other factors underlying the increased asthma morbidity may be attributed to the following factors [8, 14-21]:

      Under prescribing of anti-inflammatory drugs and over reliance on bronchodilators.

     Absence of monitoring the lung function using serial measurements of Peak Expiratory Flow Rate (PEFR).

     Delay in seeking medical help during an exacerbation and difficulty in access to medicinal care.

Non-concordance/compliance withtherapy and management plans.These factors could be worsen by patient(e.g. language, psychosocial factors, poor knowledge and poor understanding of the condition) and physician (e.g. time limited,poor communication and performance skills)barriers. All these may have a negative impact on asthma educational interventions [22- 27].

 

3. Risk factors and triggers of asthma

     Risk factors and triggers are involved in the onset and development of asthma as well as the development of asthma exacerbations.These risk factors can be classified into three main groups [8]:

      Predisposing factors that give rise to a susceptibility for the disease. These include atopy and gender. Atopy, demonstrated by increased serum IgE, appears to be the strongest identifiable predisposing factor for asthma. In addition, it has been shown that patients with the worst asthma could be the most atopic, too. Atopic diseases occur in families and thus it could be concluded that atopy is at least partly under genetic control. Furthermore, asthma and airway hyperresponsiveness has been reported to occur in families, but for asthma the evidence of a genetic control is less convincing. Gender is a predominant factor in childhood asthma (usually under age of 10), when asthma is more prevalent in boys than girls mostly because of the narrower airways and increased airways’ tone in boys in this age group. In addition, gender differences in childhood asthma could be partly explained by gender differences in allergen sensitivities.

      Causal factors sensitize the airways and cause asthma. Allergens and chemical agents are the most important risk factors for the onset of asthma. These include indoor and outdoor allergens (environmental factors). Examples of these allergens are domestic mites, animal allergens, cockroach allergens,fungi, pollens, drugs such as aspirin and other nonsteroidal anti inflammatory drugs, and occupational sensitizers for instance flour,coffee bean dust, grain or wood dust, cotton dust, proteins and enzymes.

     Asthma triggers include a further exposure to the causal factors that have already sensitized the airways of an asthmatic patient.These can cause recurrent asthma exacerbations by inducing airway inflammation together with immediate and/or delayed broncho constriction. Triggers also include exercise and hyperventilation, exposure to cold air, irritant gases such as sulfur dioxide, weather changes, extreme emotional stress and food additives. These factors can not cause asthma to develop, but once it is present, they can lead to asthma exacerbation.

     Contributing factors that either enhance the likelihood of asthma deterioration upon exposure to a causal factor or may even increase the susceptibility to asthma. These factors include respiratory infections, small size at birth, diet, air pollution (outdoor and indoor pollutants), and smoking (passive or active).Figure 1 illustrates the interaction between environmental (causal and trigger factors) and genetic factors (predisposing) that can contribute to chronic respiratory inflammation.

 

4. Covariates and explanatory factors associated with asthma morbidity

      In addition to the risk factors which are directly related with asthma incidence and prevalence, there are several parameters recognized as covariates for asthma morbidity.Some of these factors are described below: 

     Socioeconomic status: A strong link between deprivation, lower social class and many common chronic diseases e.g. chronic respiratory disorders, diabetes, arthritis and heart disorders has been reported [28]. A direct significant correlation between asthma morbidity and socioeconomic variables is also documented by several studies [29-32].

     Ethnicity: Some studies have revealed that there could be a relationship between ethnicity and the pattern of anti-asthma drugs usage [32-35]. Others have reported a relationship between ethnicity and the morbidity or mortality rate of asthmatics. The diversity which exists in ethnicity groups could be a source of different lifestyles, health believes and response to health care programs [36-38].

     Workload of doctors at the primary care level: A higher workload on the services offered by doctors could be associated with a lower quality of asthma prescribing and therefore resulting in a poor asthma control along with a higher morbidity rate [39-43].

     Gender: There is evidence that there could be gender related morbidity, mortality and health inequalities because of socioeconomic differences confounded by age, employment status, cultural and biological factors [44].There are reports confirming a higher consultation rate and steroid usage (inhaled and oral) by asthmatic women [45, 46].Female gender is also reported as a risk factor for asthma hospitalization [42, 43, 47-49].

     Smoking: It is confirmed that smoking could increase the frequency and severity of symptoms in asthmatics [50, 51]. The same findings are reported for environmental tobacco smoke exposure, i.e. passive smoking [52, 53].

     History of allergy: Allergen exposure has been identified as a risk factor for asthma severity, acute attacks and hospital admissions [42, 43, 54, 55]. It has been reported that children with continuous exposure to higher concentrations of house dust mite allergens could be at a greater risk of readmission to hospital [56], or suffer from increased asthma symptoms [57].

     Age of asthma onset: The age of asthma symptoms onset is one of the factors that could adversely influence the normal physiology of distal, parenchymal and proximal airways. Uncontrolled asthma over a long time can cause a remodelling of the airways which is reflected by reduced airflow rates and increased airway responsiveness [58-60]. In addition, patient with a longer history of asthma may have higher morbidity [61].

     Respiratory infection: The large number of infectious organisms reaching the airways, including viruses and bacteria, along with the susceptibility of asthmatic patients to respiratory tract infections (RTIs) could explain the high rate of the respiratory infections in asthmatic patients [62, 63].Studies have also reported these infections as triggers associated with asthma morbidity [64-66].

     Seasonal covariates: Studies with different settings and study populations have reported various seasonal patterns associated with anti-asthma drugs usage, asthma morbidity and mortality [67- 69]. No precise relationship has been found.


 Figure 1. The interaction between environmental and genetic factors that give rise to respiratory inflammation.

 

Table 1. Asthma classification based on the severity of airways obstruction [70].

 

a: Forced Expiratory Volume in the first second
b: Peak Expiratory Flow Rate


5. Classification of asthma based on the severity

     A classification of the degree of airways obstruction in asthmatic subjects is important for guiding therapeutic recommendations. The Australian National Asthma Campaign group has classified asthma into three groups (mild, moderate, and severe) according to the signs and symptoms as shown in Table 1.In this classification if a patient is using regular inhaled corticosteroids, he/she should not be categorized as mild [70]. A similar classification has been presented by the Global Initiatives for Asthma. In this classification, asthma severity is divided into four groups of intermittent, mild persistent, moderate persistent and severe persistent. However, the British Thoracic Society (BTS) guidelines for asthma management have a different definition of asthma severity. In this guideline, severity is defined based on the treatment stage. It states: “in treated patients the current operational definition of severity should be the treatment step needed to maintain good, or best possible control in terms of symptoms, lifestyle and lung function” [71]. In the BTS guidelines a four step by step approach for the management of chronic asthma in children under 5 years of age as well as a five step by step protocol for adults and school children have been recommended. Table 2 represents the treatment plan introduced for asthmatics > 5 years of age. For children under 5 years of age, except some minor changes, the step by step protocol is similar to that of over five years.

     The BTS guidelines have four main categories for the severity of asthma exacerbations at the accident and emergency department level. In this classification, the severity of an attack is based on the immediate measurement of the PEFR and comparing this measurement with the best or predicted PEFR for each individual patient. In this regard, four main categories have been identified:

     Mild: >75% of the best/predicted PEFR

     Moderate: 50-75% of the best/predicted PEFR

     Severe: 33-50% of the best/predicted PEFR

     Life threatening:

     < 33% of the best/predicted PEFR

 

Table 2. Step-by-step approach for the management of chronic asthma in adults and schoolchildren (>5 years old) according to the BTS guidelines [72]


6. Asthma management: Goals and medical treatment

     Many interventions have attempted to establish or modify treatment protocols for asthma. A good asthma service should lead to the following outcomes:

      Prevention of asthma attacks

      Reduction of asthma morbidity

      Limitation of asthma mortality

     The final aim of asthma therapy is to obtain a normal pulmonary function and abolish symptoms. The main target, therefore, is to improve the condition so that asthmatic patients could live as normal and as active a life as possible with a minimum physical and psychosocial disruption. Asthma treatment is symptomatic and directed at maximizing the reversibility of the airway obstruction and minimizing adverse effects. The risks of each individualized treatment plan must, therefore, be considered against the risks of the disease [2, 19].

     It is recommended that asthma management to be conducted in three main directions:

 a-Patient education and self-management: Patient education and self-management plans are a major part of the current asthma management initiatives. Patients should be informed about the nature of their problem, medication(s), appropriate inhaler technique, self-monitoring of their asthma (e.g. using a Peak Expiratory Flow Meter), exacerbation symptoms and action plans needed to apply at the time of an asthma attack. This is very important in patient-oriented management protocols and in creating a two-way relationship between patients and health professionals (concordance) towards a better control on their asthma.

b-Non-pharmacological treatment: An avoidance from different risk factors and triggers, which are involved in asthma development or exacerbation, is a major goal of the current management protocols [71].

c- Pharmacological treatment: There are two main physiological problems associatedwith asthma, inflammation and bronchoconstriction. Consequently, there are two main therapeutic groups of drugs which are used, bronchodilators and anti-inflammatory agents.Considering the inflammatory nature of asthma, corticosteroids are known as the key drug in the treatment of asthma. Table 3 represents asthma medications and their mechanisms of action [8, 72].

     Xanthines (theophylline and its saltaminophylline) as another group of bronchodilators are used in the management of asthma. Present guidelines recommend the use of oral theophylline as an additional bronchodilator in patients who remainsymptomatic with moderate to high-dose of inhaled corticosteroids (stages 3 and 4 of the BTS guidelines). Currently, usage of this group is restricted. This mainly is due to a very narrow therapeutic index of theophylline and its potentially serious side effects. In addition, limited access to facilities required for theophylline therapeutic drug monitoring (TDM) forces the doctors to be cautious in prescribing this drug, in particular for newly diagnosed asthmatic patients. Although theophylline has shown some anti-inflammatory effects, this remains to be confirmed by further studies [71, 73]. Aminophylline could be given as an intravenous injection in the treatment of severe asthma attacks when there is no rapid response to nebulized beta-2 agonists [72].

     Leukotriene modifiers including leukotriene receptor antagonists (LTRAs), e.g. montelukast sodium, pranlukast and zafirlukast, and a 5- lipoxygenase inhibitor i.e. zileuton, are a new class of medications for the treatment of asthma. They specifically inhibit the action of the inflammatory mediators (leukotrienes C4 and D4). These mediators have a potent broncho-constrictive effect and can increase mucus production. Leukotrienes can also attract eosinophils into the tissues and deteriorate the inflammatory process. The precise role of the LTRAs in asthma is still to be determined. However, they are likely to be useful as a preventive treatment in asthma. Their recommended indications are: prevention of day and nighttime symptoms, treatment of aspirin-sensitive asthma patients, prevention of exerciseinduced broncho constriction and in patients not responding to other therapies [70].

     Ketotifen (and other H1 blockers from the same group of anti-histamines) is also an anti-allergic agent, which may inhibit mast cell activation or mast cell mediator release (similar to that of cromoglycates). However, its efficacy in asthma has not been sufficiently documented [8, 72].

     During the recent years, difficult-to-treat asthma which is mainly dependent to maximal topical and additional systemic glucocorticoid therapy has been tried to be treated with other T cell immunomodulatory agents as adjuvant therapies. Gold salts have had a modest but significant glucocorticoid-sparing effect in severe asthma, however, lung function was not improved and not all patients respond. Metaanalysis of trials of methotrexate has revealed that concomitant weekly methotrexate for a minimum of 3 to 6 months enables significant (approximately 20%) overall reduction in oral glucocorticoid requirements, although only approximately 60% of patients showed a significant response. There was little effect on lung function. Cyclosporine, administered for at least 3 months, could be effective in only a proportion of patients with oral glucocorticoid-dependent asthma, where it may improve disease severity and/or enable oral glucocorticoid dosage reductions. The macrolides tacrolimus (FK506) and sirolimus (rapamycin) have shown final effects similar to those of cyclosporine. Presently, the evidence that intravenous immunoglobulin (Ig) is effective in patients with glucocorticoid dependent asthma is ambiguous. Brequinar sodium, mycophenolate mofetil and leflunomide, newly-synthesised inhibitors of synthesis of pyrimidines and purines, theoretically may be beneficial for therapy of patients with oral glucocorticoid-dependent asthma. Humanized anti-CD4, anti-IgE and anti-interleukin (IL) 5 monoclonal antibodies, and other cytokine inhibitors such as soluble IL-4 receptor are still on trials.

     The worth of the immunomodulatory drugs, explained above, is limited since: (i) not all patients respond and response cannot be predicted; (ii) the high incidence of unwanted effects makes it difficult to assess overall benefit/risk ratios. There are increased risk of opportunistic potentially fatal infection and (in theory) neoplasia as well as other serious unwanted effects e. g. dermatitis, hepatic and renal dysfunction, proteinuria, interstitial pneumonitis, fever, aseptic meningitis and urticaria; (iii) there are many relative and absolute contraindications to therapy; and (iv) there is lack of knowledge about the long-term effects, beneficial or damaging, of therapy [74-77].

 

 Table 3. Medications used commonly for the pharmacological treatment of asthma [8, 72].


7. New inhaler devices and delivery systems

     Chloro-fluoro-carbones (CFCs) are known as one of the chemicals responsible for damages to the ozone layer. At the Montreal Convention in 1987, it was decided to limit usage of CFCs [78]. In this respect, pharmaceutical companies have been encouraged to look for environmentally friendly preparations to substitute the current CFC-inhalers. In the recent years two main groups of preparations i.e. hydro-fluoro-alkane (HFA) inhalers and dry powder inhalers (DPIs) were introduced to the market. These new systems are going to be used instead of the traditional metered dose inhalers (MDIs), which are the most frequently prescribed delivery systems [79, 80]. This means that in the near future, there will be no CFC inhaler available and that all patients using them will have to transfer to HFA (CFC-free) inhalers and/or DPIs. Most HFA inhalers are reformulated at the same potency as their CFC equivalent. However, they look, feel, weigh, and taste slightly different and therefore patients and doctors should be aware of these differences [78]. On the other hand, the new inhalers may have different clinical effects or efficacy compared to existing CFC inhalers.For example, it is documented that when switching from a CFC-beclomethasone product to a HFA-beclomethasone, dose of the corticosteroid should be halved, because HFA product achieves the same effect at half the dose as the CFC preparation [81].

     Dry powder inhalers are another group of new delivery systems used for inhalation. DPIs can be divided into two groups: powder inhalers which use accurate factory-dispensed dose of medication sealed in individual units, including Spinhaler (available as Intal), Rotahaler, Diskhaler, Inhalator, Accuhaler (Discus), and Easi-Breath inhalers; the second group of DPIs includes reservoir powder inhalers such as Turbuhaler and Clickhaler. Since DPIs are actuated by the patient’s own inhalation and do not need shaking before use then they are generally considered easy to use correctly (unlike MDIs that should be shaken before use and patients need to coordinate inhalation with actuation). However, in DPIs internal resistance of the device is a problem. Patients that cannot achieve the recommended inhalation flow may not gain maximum benefit from their medicine. Studies have shown that a higher inspiratory flow through a DPI could increase drug delivery to the lungs and therefore could result in a better clinical response [82]. Because not all asthmatics could achieve the minimal inspiration flow rate, therefore it is necessary to identify the appropriate device for each individual patient before deciding to prescribe a DPI. This could be determined using an inspiratory flow meter e.g. In-Check Dial®. This instrument is a low-range inspiratory flow meter that has a selectable resistance. It is calibrated to enable the measurement of airflow as the patient using a DPI.

 

8. Conclusion

     Asthma is a complex disorder and its management and treatment outcomes are multi-dimensional concepts. The relationship between disease management and clinical outcomes, therefore, could be considerably affected by potential confounding factors.Although not perfectly, considerable progress has been made in understanding asthma pathophysiology and aetiology. Despite knowledge currently available, day-by-day exciting new reports are published. Today, even genetic factors have been reported to have an impact on the extent of the therapeutic response to anti-asthma medications [83]. However, there are still some unknown and dark corners which need to be revealed:

Who are more likely to suffer from asthma (high-risk groups)?

 Which characteristics/factors make some patients more susceptible to asthma morbidity?

How are these characteristics/factors related to higher morbidity rates?

What should be done and what newer medication/formulations or management protocols should be introduced to minimize the suffering due to asthma?

 Which patients are going to have the most benefit from the newly introduced protocols/medications and how?

At present there are no precise answers to these questions.

 

[1] Chung KF, Adcock I. Asthma mechanisms and protocols. New Jersey: Humana Press, 2000;

pp.1-29.

[2] Kelly HW. Asthma. In: Koda-Kimbel MA, Young LY, (editors). Applied therapeutics: the clinical use of drugs. 5th ed. Washington: Applied Therapeutics Inc., 1992; pp.15.1 – 15.24.

[3] Hartl D, Greise M, Nicolai T, Zissel G, Prell C, Konstantopoulos N, Gruber R, Reinhardt D,

Schendel DJ, Krauss-Etschmann S. Pulmonary chemokines and their receptors differentiate

children with asthma and chronic cough. J Aallergy Clin Immunol 2005; 115: 728-36.

[4] Kuepper M, Bratke K, Julius P, Ogawa K, Nagata K, Luttman W, Virchow JC Jr. Increase in killerspecific secretory protein of 37 kDa in bronchoalveolar lavage fluid of allergenchallenged

patients with atopic asthma. Clin Exp llergy 2005; 35: 643-9.

[5] Muratov V, Barck C, Bylin G, Kallstorm E, Hallden G, van Hage M, Elvin K, Lundahl J. Aallergen challenge alters intracellular cytokine expression. Scan J Immunol 2005; 62: 161-7.

[6] Schaller MA, Lundy SK, Hhuffnagle GB, Lukacs NW. CD8+ T cell contributions to allergen induced pulmonary inflammation and airway hyperreactivity. Eur J Immunol 2005; 35: 2061-70.

[7] Evans JF. Cysteinyl leukotriene receptors. Prostaglandins Other Lipid Mediat. 2002; 68-

69: 587-97.

[8] National Hearth, Lung and Blood Institute and World Health Organisation Workshop report:

global strategy for asthma management and prevention [Online], 2004 [Accessed 2005 April 04]; aAvailable from: URL: http://www.ginasthma.com/Guidelineitem.asp??l1 =2&l2=1&intId=60.

[9] National Asthma Campaign. The national asthma audit. London; 1999/2000.

[10] Murray AB, Morrison BJ. Effect of passive smoking on asthmatic children who have and who have not had atopic dermatitis. Chest 1992; 101: 16-8.

[11] von Mutius E, Fritzsch C, Weiland SK, Roll G, Magnussen H. Prevalence of asthma and allergic disorders among children in united Germany: a descriptive comparison. Br Med J 1992; 305:1395-9.

[12] Black PN, Sharpe S. Dietary fat and asthma: is there a connection? Eur Respir J 1997; 10: 6-12.

 [13] Burney PG, Neild JE, Twort CH, Chinn S, Jones TD, Mitchell WD, Bateman C, Cameron IR.Effect of changing dietary sodium on the airway response to histamine. Thorax 1989; 44: 36-41.

[14] Salamzadeh J, Wong ICK., Hosker H, Chrystyn H. The relationship between the quality of prescribing and practice appointment rates with asthma management data in those admitted to hospital due to an acute exacerbation. Respir Med 2005; 99: 735-41.

[15] Adams RJ, Smith BJ, Ruffin, RE. Factorsassociated with hospital admissions and repeat

emergency department visits for adults with asthma. Thorax 2000; 55: 566-73.

[16] Salamzadeh J, Habibi M, Fahimi F, Boroumand B. Astudy of possible predictors associated with hospitalization in 198 asthmatic outpatients refereed to the Labbafi-nezhad university hospital in Tehran. In: Valizadeh H, Azarmi Sh, Ghobe Zarrin N, (editors). 9th Iranian Seminar of Pharmaceutical Sciences. Abstracts of contributions; Tabriz, Iran, 2004 August 23-26; Tabriz, Iran:. Tabriz University of Medical Sciences; 2004; p. 282.

[17] Coakley AL, Johnson AJ. Inhaled steroids for asthma: a qualitative study exploring patients’

views and the meeting of educational needs within inhaler packaging. Asthma J 1999; 4: 175-8.

[18] O’Callaghan C, Barry P. Delivering inhaled corticosteroids to patients: if side effects are important, why are we so ignorant of the dose inhaled? Br Med J 1999; 318: 410-1.

[19] Clark NM, Gong M. Management of chronicdisease by practitioners and patients: are we

teaching the wrong things? Br Med J 2000; 320:572-5.

[20] Stevenson FA. The strategies used by general practitioners when providing information about medicines. Patient Educ Couns 2001; 43: 97-104.

[21] Ordonez GA, Phelan PD, Olinsky A, Robertson CF. Preventable factors in hospital admissions for asthma. Arch Dis Child 1998; 78: 143-7.

[22] Bosley CM, Fosbury JA, Cochrane GM. The psychological factors associated with poor compliance with treatment in asthma. Eur Respir J 1995; 8: 899-904.

[23] FitzGerald JM, Turner MO. Delivering asthma education to special high risk group. Patient Educ Couns 1997; 32: S77-S86.

[24] Gruffydd-Jones K. Compliance: the challenge in asthma management.; London: Miller Freeman UK Ltd. 1998; pp.1-8.

[25] Raherison C, Tunon-De-Lara JM, Vernejoux JM, Taytard A. Practical evaluation of asthma exacerbation self-management in children and adolescents. Respir Med 2000; 94: 1047- 52.

[26] Salamzadeh J, Fahimi F, Habibi M, Boroumand B. Astudy of inhaler technique in asthmatics and its explanatory parameters. In: Valizadeh H, Azarmi Sh, Ghobe Zarrin N, eds. 9th Iranian Seminar of Pharmaceutical Sciences. Abstracts of contributions; 2004 August 23-26; Tabriz, Iran. Tabriz university of Medical Sciences; 2004; pp. 283. In: Valizadeh H, Azarmi S, Ghobe Zarrin N, (editors). 9th Iranian Seminar of Pharmaceutical Sciences. Abstracts of contributions; Tabriz, Iran, 2004 August 23-26: Tabriz University of Medical Sciences; p. 283.

[27] Salamzadeh J, Habibi M, Boroumand B. Peak Expiratory Flow Rate (PEFR) in asthmatic patients: what are possible predictors? In: Valizadeh H, Azarmi Sh, Ghobe Zarrin N, eds. 9th

Iranian Seminar of Pharmaceutical Sciences.Abstracts of contributions; 2004 August 23-26;

Tabriz, Iran. Tabriz university of Medical Sciences; 2004; p. 278.

[28] Eachus J, Williams M, Chan P, Smith GD, Grainge M, Donovan J, Frankle S. Deprivation

and cause specific morbidity: evidence from the Somerset and Avon survey of health. Br Med J

1996; 312, 287-92.

[29] Minkovitz CS, Andrews JS, Serwint JR. Rehospitalization of children with asthma. Arch Pediatr Adolesc Med 1999; 153: 727-30.

[30] Majeed A, Bardsley M, Morgan D, O’Sullivan C, Bindman AB. Cross sectional study of primary care groups in London: association of measures of socioeconomic and health status with hospital admission rates. Br Med J 2000; 321, 1057-60.

[31] Watson JP, Cowen P, Lewis RA. The relationship between asthma admission rates, routes of admission, and socioeconomic deprivation. Eru Respir J 1996; 9: 2087-93.

[32] Salamzadeh J, Patel MG, Wong ICK, Wright DJ, Chrystyn H. Characteristics of general

practices with different asthma prescribing. Pharma J (suppl) 2000, 265: R52.

[33] Gottlieb D J, Beiser AS, O’Connor GT. Poverty, race, and medication use are correlates of asthma hospitalization rates. Chest 1995; 108: 28-35.

[34] Finkelstein JA, Brown RW, Schneider LC, Weiss ST, Quintana JM, Goldmann DA, Homer CJ. Quality of care for pre-school children with asthma: the role of social factors and practice

setting. Pediatrics 1995; 95: 389-94.

[35] Duran-Tauleria E, Rona RJ, Chinn S, Burney P. Influence of ethnic group on asthma treatment in children in 1990-1: national cross sectional study. Br Med J 1996; 313: 148-52.

[36] Apter AJ, Reisine ST, Affleck G, Barrows E, ZuWallack RL. The influence of demographic

and socioeconomic factors on health-related quality of life in asthma. J Allergy Clin Immunol

1999; 103: 72-8.

[37] Gilthorpe MS, Lay-Yee R, Wilson RC, Griffiths RK, Bedi R. Variations in hospitalization rates for asthma among Black and minority ethnic communities. Respir Med 1998; 92: 642-8.

[38] Moudgil, H., Marshall, T. and Honeybourne, T. Asthma education and quality of life in the community: a randomized controlled study to evaluate the impact on white European and Indian

subcontinent ethnic groups from socioeconomically deprived areas in Birmingham, UK. Thorax 2000; 55: 177-183.

[39] Salamzadeh J, Patel M, Wong I, Wright D, Chrystyn H. Analysis of the impact of practice

characteristics and social deprivation on prescribing quality for asthma. Thorax (suppl.) 1999; 54: A54.

[40] Law MR, Morris JK. Why is mortality higher in poorer areas and in more Northern areas of

England and Wales? J Epidemiol Community Health 1998; 52: 344-52.

[41] Hippisley-Cox J, Hardy C, Pringle M, Fielding K, Carlisle R, Chilvers C. The effect of deprivation on variations in general practitioners’ referral rates: cross sectional study of computerized data on new medical and surgical outpatient referrals in Nottinghamshire. Br Med J 1997; 314: 1458 -61.

[42] Salamzadeh J, Wong ICK, Hosker HSR, ChrystynH. A logistic regression analysis of predictors for asthma hospital re-admissions. Iranian J

Pharma Res (IJPR) 2003; 2: 5-9.

[43] Salamzadeh J, Wong ICK, Hosker HSR, Chrystyn H. A cox regression analysis of covariates for asthma hospital readmissions. J Asthma 2003;40: 645-52.

[44] Matthews S, Manor O, Power C. Social inequalities in health: are there gender differences?

Soc Sci Med 1999; 48: 49-60.

[45] Sexton M, Althuis MD, Santanello N, Hyndman S, Williams R, Schmeidler D. Sex differences in the use of asthma drugs: cross sectional study. Br Med J 1998; 317: 1434-37.

[46] Yuksel N, Ginther S, Man P, Tsuyuki RT. Underuse of inhaled corticosteroids in adults with asthma. Pharmacother 2000; 20: 387-93.

[47] Heard AR, Campbell DA, Ruffin RE, Smith B, Luke CG, Roder DM. Rehospitalization for

asthma within 12 months: unequal rates on the basis of gender at two hospitals. Aust N Z J Med

1997; 27: 669-71.

[48] Mitchell EA, Bland JM, Thompson JMD. Risk factors for readmission to hospital for asthma in childhood. Thorax 1994; 49: 33-6.

[49] Prescott E, Lange P, Vestbo J, Jensen G, Schnohr P, Appleyard M, Nyboe J, Grenbaeck M,

Nordestgaard B. Effect of gender on hospital admissions for asthma and prevalence of selfreported asthma: a prospective study based on a sample of the general population. Thorax 1997;52: 287-9.

[50] Langhammer A, Johnsn R, Holmen J, Gulsvik A, Bjermer L. Cigarette smoking gives more

respiratory symptoms among women than among men: The Nord-Trondelag health study (HUNT).J Epidemiol Community Health 2000; 54: 917-22.

[51] Siroux V, Pin I, Oryszczyn MP, Le Moual N, Kauffmann F. Relationship of active smoking to asthma and asthma severity in the EGEA study. Epidemiological study on the genetics and environment of asthma. Eur Respir J 2000; 15: 470-7.

[52] Eisner MD, Yelin EH, Henke J, Shiboski SC, Blanc PD. Environmental tobacco smoke and

adult asthma: the impact of changing exposure status on health outcomes. Am J Respir Crit Care

Med 1998; 158: 170-5.

[53] Gurkan F, Ece A, Haspolat K, Derman O, Bosnak M. Predictors for multiple hospital admissions in children with asthma. Can Respir J 2000; 7: 163-6.

[54] Rosas I, McCartney HA, Payne RW, Calderon C, Lacey J, Chapela R, Ruiz-Velazco S. Analysis of the relationship between environmental factors (aeroallergens, air pollution, and weather) and asthma emergency admissions to a hospital in Mexico City. Eur J Allergy Clin Immunol 1998; 53: 394-401.

[55] Miles J, Cayton R, Ayres J. Atopic status in patients with brittle and non-brittle asthma: a

case-control study. Clin Exp Allergy 1995; 25: 1074-82.

[56] Sporik R, Platts-Mills TAE, Cogswell JJ. Exposure to house dust mite allergen of children

admitted to hospital with asthma. Clin Exp Allergy 1993; 23: 740-6.

[57] Warner JA, Warner JO. Allergen avoidance in childhood asthma. Respir Med 1991; 85: 101-5.

[58] Cassino C, Berger KI, Goldring RMIA, Narmann RG, Kammerman S, Ciotoli C, Reibman J. Duration of asthma and physiologic outcomes in elderly non-smokers. Am J Respir Crit Care

Med 2000; 162: 1423-8.

[59] Sears MR. Consequences of long-term inflammation: the natural history of asthma. Clin

Chest Med 2000; 21: 315-29.

[60] Zeiger RS, Dawson C, Weiss S. Relationship between duration of asthma and asthma severity among children in the childhood asthma management programme. J Allergy Clin Immunol 1999; 103: 376-87.

[61] Foroutan N, Habibi M, Salamzadeh J. Designing a new questionnaire to evaluate asthma morbidity. Canadian Society for Pharmaceutical Sciences. 8th Annual Symposium of Canadian Society for Pharmaceutical Sciences: accelerating drug discovery and development. Toronto, Canada; 2005, May 30- June 2, p.64.

[62] Jebrak G, Brugiere O, Uffredi ML. Impact of infections a chlamydia pneumonia infections on asthma. Presse Med 2000; 29: 1425-32.

[63] Reddel H, Ware S, Marks G, Salome C, Jenkins C, Woolcock A. Differences between asthma exacerbations and poor asthma control. Lancet

1999; 353: 364-9.

[64] Smith A, Nicholson K. Psychosocial factors, respiratory viruses and exacerbation of asthma.

Psychoneuroendocrinology 2001; 26: 411-20.

[65] Gern JE, Busse WW. The role of viral infections in the natural history of asthma. J Allergy Clin Immunol 2000; 106: 201-12.

[66] Micillo E, Bianco A, D’Auria D, Mazzarella G, Abbate GF. Respiratory infections and asthma. Eur J Allergy Clin Immunol (suppl) 2000; 55: 42-5.

[67] Salamzadeh J, Kebriayeezadeh A, Shalchi M. Drug utilization review of anti-asthma drugs

using Defined Daily Doses (DDD) in 28 provinces of Iran during the years 2000-2002. In: Valizadeh H, Azarmi S, Ghobe Zarrin N, (editors). 9th Iranian Seminar of Pharmaceutical Sciences. Abstracts of contributions; Tabriz, Iran, 2004 August 23-26: Tabriz University of Medical Sciences; p. 284.

[68] Fleming DM, Cross KW, Sunderland R, Ross, AM. Comparison of the seasonal patterns of

asthma identified in general practitioners episodes, hospital admissions, and deaths. Thorax 2000; 55: 662-5.

[69] Stedman JR, Anderson HR, Atkinson RW, Maynard RL. Emergency hospital admissions

for respiratory disorders attributable to summer time ozone episodes in Great Britain. Thorax

1997; 52: 958-63.

[70] National asthma council Australia (2005) Asthma management handbook [Online], 2002, [accessed April 4, 2005]. [Online] Available from URL: .

[71] British Thoracic Society, National Asthma Campaign, Royal College of Physicians of

London, General Practitioner in Asthma Group, British Association of Accident and Emergency

Medicine, British Paediatric Respiratory Society and Royal College of Paediatrics and Child

Health; The British guidelines on asthma management: 1995 review and position statement.

Thorax (suppl 1), 1997; 52: S1-S21.

[72] British Medical Association and Royal Pharmaceutical Society of Great Britain (2005)

British National Formulary (Number 49). Oxon: The Pharmaceutical Press, 2005.

[73] Tavakkoli A, Rees PJ. Drug treatment of asthma in the 1990s: Achievement and new strategies. Drugs 1999; 57: 1-8.

[74] Corrigan CJ. Asthma refractory to glucocorticoids: the role of newer immunosuppressants.

Am J Respir Med 2002; 1; 47-54.

[75] Corrigan CJ, Shiner RJ, Shakur BH, Ind PW. Methotrexate therapy of oral corticosteroiddependent asthmatics reduces serum immunoglobulins: correlation with clinical

response to therapy. Clin Exp Allergy 2005; 35:579-84.

[76] Karagiannidis C, Ruckert B, Hense G, Willer G, Menz G, Blaser K, Schmidt-Weber CB. Distinct leukcocyte redistribution after glococorticoid treatment among difficult-to treat asthmatic patients. Scand J Immunol 2005; 61: 187-96.

[77] Girgis SI, Nwokeji A, Shakur BH, Ind PW, Shiner RJ. The effect of steroid-sparing response to low-dose methotrexate on bone metabolism in glucocorticoid-dependent asthmatics. Clin Chim Acta 2004; 341: 157-63.

[78] General practitioners in asthma group. GPIAG opinion sheet no. 3. CFC to HFA: the transition [Online], 2001 [accessed 2002 May 1, 2002].

Available from: URL: http:// www.gpiagasthma. org/Opinions/opinion3.htm.
[79] Schlaeppi M, Edwards K, Fuller RW, Sharma Ret al. Patient perception of the Diskcus inhaler: a comparison with the Turbuhaler inhaler. Br J Clin Pract 1996; 50: 14-9.
[80] Sharma RK, Edwards K, Hallet C, Fuller RW. Perception among paediatric patients of the Discus
inhaler, a novel multidose powder inhaler for use in the treatment of asthma: comparison with the
Turbuhaler inhaler. Clin Drug Invest 1996; 11:145-53.
[81] Levy M, Hilton S, Barnes G. Asthma at your fingertips. 3rd ed. London: National Asthma and Respiratory Training Centre; 2000. pp.14, 164, 169, 180, 212.
[82] Persson G, Olsson B, Soliman S. The impact of inspiratory effort on inspiratory flow through Turbuhaler in asthmatic patients. Eur Respir J 1997; 10: 681-4.
[83] Gottlieb S. Personalizsed medicine comes one step closer for asthma. Br Med J 2000; 321: 724.