Asthma: Achievements and Questions in Front

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.