Module 1: Bronchial Asthma: Severity and Control

Learning Group No: 3 Mentors Name: Dr. Lincy Jaison Submitted by: Dr. Preeti Bawa

Abstract: Bronchial asthma is a disease exhibiting a spectrum of severity in clinical

presentation. These symptoms are widespread with variety in airway obstruction which can be made reversible by attending to the patient as early as possible. As the prevalence rate of asthma is more therefore more children and adult population are affected. Based on proper history and various tests, asthma is diagnosed carefully. Asthma is known to be an inflammatory disease therefore the main treatment aim is to decrease the inflammation by use of anti inflammatory drugs. Previously herbal remedies were put forward and thought that patients would show compliance to this treatment. There were no strong evidences for recommending herbal therapy. Inhaled corticosteroids are considered to be the best therapy for asthma. As patient compliance is poor for these treatment modalities therefore newer methods have been evolved for asthma treatment. Recent studies have shown that the molecular level of asthma is mediated by immune pathways leading to the production of IL-4, IL-5, and IL-3. Therefore there is an increase interest seen in development of phenotypes and airway remodeling of asthma by gene-ADAM33. Thermoplasty and other monoclonal antibodies are some recent advances for treatment of asthma.

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Introduction: Bronchial asthma is an inflammatory disorder associated with airway hyper

responsiveness leading to recurrent episodes of wheezing, breathlessness, chest tightness and coughing particularly at night or early morning. depending on severity: 1) Mild Intermittent Asthma. 2) Mild Persistent Asthma. 3) Moderate Persistent Asthma. 4) Severe Persistent Asthma.
[1]

Asthma can be classified into four levels

Patho physiology of Asthma:

Asthma is considered to be an inflammatory condition. Mast cells and inflammatory cells in the lungs lead to spectrum of mediators as follows: 1) Release of immediate mediators like Histamine, protease enzymes and TNF which are stored in granules. 2) Phospholipids from the cell membrane are released followed by mediator synthesis like Prostaglandins, leukotrienes, PAF. 3) Activation of genes followed by protein synthesis, interleukins and TNF.[2] The above mentioned mediators constrict the bronchial smooth muscle causing mucosal edema, hyperemia and production of viscous secretion altogether leading to airway obstruction. Therefore the inflammation perpetuates by cell to cell communication and aggregation of more inflammatory cells. This leads to the Hypertrophy of the bronchial smooth muscle causing damage to epithelium and in turn accentuating the hyper reactivity. Enhanced vagal discharge and airway remodeling worsens the disease [2].

Prevalence of Asthma:
The prevalence of asthma is 200 million worldwide with a mortality rate of 0.2 million per year. The prevalence rate is more than 15 million in India as reported in different field studies and specific population. The onset of asthma occurs at any age but children and young adults are
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more affected. There are variety of factors like the host and environment leading to the development of asthma. These predisposing factors are usually genetic, atopy, airway hyper responsiveness, gender and race/ ethnicity. [7] The Environmental factors include: a) Indoor and outdoor allergens b) Occupational sensitizers c) Tobacco smoking and air pollution d) Respiratory and parasitic infection e) Socio economic status and family size f) Diet, drugs and obesity.

The Global Initiative for Asthma (GINA) aim is to increase the awareness towards asthma. The occurrence of asthma is seemed to rise as community becomes urbanized with adoption of westernized lifestyle. According to GINA classification, mild asthma including intermittent and persistent asthma affects between 50% -75% of patients. Mild asthma is seen to be more common in all age groups. [3] An occurrence range of 0.12 to 0.77 patients per year, mild asthma can lead to severe exacerbation. 30%- 40% of mild asthma represent with severe exacerbation which requires emergency consultation. Mild asthma being the most frequent form of the disease, diagnosis and management usually requires physicians attention. [3, 7]

Diagnosis of Asthma:

The diagnosis is mainly based on clinical examination. Careful

history taking should include wheezing (in cold), dyspnoea, chest tightness and cough at night, chronic phlegm production and cough. The diagnosis for asthma can be viewed as a two step approach. Step 1: Clinical findings, diagnosis and attempts taken to rule out asthma mimics while Step 2: Confirmation of diagnosis as based on laboratory investigation. The physician focus particularly on the obstruction of patients airflow and detection of reversible airway obstruction is done by physical or physiological examination. [1]

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The examination is done for the confirmation of the diagnosis. During an asthma attack wheezing can be heard by a stethoscope. The obstruction is considered to be reversible if wheezing disappears by treatment or when the triggering factors are removed. The diagnostic tests include: 1) Spirometry 2) Peak Flow Meter 3) Bronchial provocation 4) Other tests Spirometry: To determine the reversible obstruction of airway the most reliable method is spirometry. It is a test used to measure the quantity of inhaled and exhaled air from the lungs. Ideally, patient exhales for at least 6 seconds. This test measures the amount and time of exhaled air. The exhaled air in first second is termed as FEV1 which is measured and compared to the total amount of exhaled air. If the amount exhaled air is less as compared to the total exhaled, the patient is said to have obstruction. It can also be repeated to test the reversibility. If the values performed after the bronchodilator administration are better than the prebronchodilator values the obstruction is considered to be reversible. [1] Peak Expiratory Flow: Due to varied clinical presentation of asthma, patient may not be able to exhibit normal value for above mentioned tests. Peak Expiratory Flow (PEF) rate monitoring is recommended in such cases. In this the patient is asked to perform the flow meter test twice daily for 2 weeks and the results are recorded. A peak flow meter should be used to record the peak flow rates in the morning and evening for a patient to confirm the reversibility and severity. A 20% diurnal variation is considered to be diagnostic of reversible airway obstruction. [1] Bronchial Provocation: Sometimes a patient may show suspected asthma related obstruction that is not demonstrated in spirometry and peak flow rate therefore the diagnosis may be provided by bronchial provocation. It identifies the hyper responsiveness of the airways by making the patient take an aerosolized chemical (histamine and methacholine) called as a brunch spastic agonist that triggers the hype responsive reaction. [1]

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Other Tests: These tests may be used to rule out other diseases and to evaluate the asthma severity. These tests include: a) Chest X- rays b) Skin allergy test to demonstrate any specific allergens c) PA View skull.

Historical perspective for Asthma Treatment: As of now asthma cannot be treated

permanently, it can be controlled with drugs and herbal therapy. Herbal Therapy: There was an increasing interest seen with complementary and alternative treatment. The reports of the surveys conducted have shown that 11%- 40% of asthma patients may have used herbal therapy. The evidence for clinical effectiveness of these herbal therapies was still questionable but some trials had shown improvements in lung function and symptoms. AKL1, a new botanical mixture was developed to treat asthma and is available as capsule formulations. This mixture contains the following ingredients: 1) Synthetically derived phytochemical component: Picrorhiza kuroa, ( apocynin.) 2) Zinziber officinale and 3) A standard extract of Ginkgo biloba. The herbal treatment regimen was usually 2 capsules twice daily with various ingredients being marked as health supplements. The asthma patients using herbal therapy had shown reduction in attacks, reduced use of bronchodilator and inhalational corticosteroids and also decreased hospitalization rates. The above mentioned reports contributed to the anti asthmatic activity of the botanical product. There was also an extensive reduction seen in cough and sputum production. The anecdotal trial also looked into the efficacy of the botanical agent as an Add on therapy for adult patients having uncontrolled asthma with standard medication. [4] AKL1 trial was conducted with a primary endpoint of this mixture on peak lung function, PEF values and the secondary was to compare the changes in FEV, asthma related health status, asthma control and exacerbations, cough related status, average short acting agonist medication use and other parameters like blood pressure, hematology and Liver function tests. [4]
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No significant changes were noticed in the baseline parameters of patients. No considerable changes were observed in the lung function of the patients. No statistical changes were found in the secondary outcomes also. Herbal therapies are often supposed to be more natural and more acceptable than the standard treatment therefore further research trials are required for a more effective add on therapy. If this mixture certainly has an effect on asthma, it might be just that it is affecting the disease manifestations which are not dependant on bronchospastic event and may improve the symptoms and hence the impact of the disease on individual is independent of any effects on broncho- constriction. To investigate this possibility further studies are needed. Considering all these points a further larger studies are necessary to elaborate the effects of AKL1 on asthma symptom control, exacerbation and health status of the patient. [4]

Current Concepts in Treatment for Asthma: There are various current concepts being
developed as an approach to achieve better Quality of Life. To lower the worldwide burden of asthma GINA guidelines are developed and followed by physicians to make the patients receive the appropriate therapy. .There are five recommended steps of these guidelines to manage asthma. The drugs used in asthma management can be grouped as controllers and relievers. The treatment for newly developed asthma commences from step 2. These steps are as followed: Step 1: A reliever is used at every step as it is the indicator for quality of asthma control. A rapidly acting bronchodilator is used. Step 2: Inhaled corticosteroids (ICS) is the drug of choice for asthma. Montelukast can also be used. Step 3: Combination of low dose ICS and Long acting agonist (LABA) is used Step 4: High dose of ICS is used with Montelukast and Theophylline. Step 5: If patient is suffering from allergic asthma, use of Anti IgE is preferred [1, 8]. Other concepts are: 1) SMART (Symbicort Maintenance and reliever therapy) concept involving a fixed combination of Budesonide and Formetrol to control acute asthma.

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2) GOAL (Gaining optimal asthma control) concept which involves relatively high doses of Fluticasone and Salmetrol. Fundamental drug therapy of asthma generally aims to decrease the inflammatory reaction by anti inflammatory drugs. Inhaled corticosteroids (ICS) are the preferred therapy as it provides targeted delivery of drug and faster acting. In 2006 these guidelines were also implemented to achieve asthma control in pediatric patients. A randomized study was conducted which has shown a significant and positive outcome with use of Combined Strategy (ICS+ LABA). These guidelines achieve a good asthma control with reduced exacerbations as it identifies the goals of asthma treatment. Currently the patients with mild asthma do not just have a well controlled asthma but they are able to make it well controlled with low intensity treatment of ICS, leukotriene modifiers or with 2 agonists which are considered as easy to treat asthma[5,8]. Newer therapeutic interventions are required for patients who are refractory to standard treatment with ICS and LABA. The current guidelines implement the use of corticosteroids which may cause increased morbidity for those associated with allergic type of asthma. Recent studies and trials have shown that the pathology of asthma is mediated by immune pathways which are driven by Th-2 type CD4 and T cells producing characteristic IL-4, IL-5, and IL- 3. The response to asthma is poor due to heterogeneity of disease. Therefore the need to understand the cellular and molecular basis stands out to be an important aspect in asthma. Hence the need to detect phenotypes as the targeted therapy is required to treat underlying disease condition.

Newer Treatment Approaches for Asthma: The Th-2 inflammatory phenotypes are
considered to be allergic condition for asthma. This leads to the development of characteristic interleukins such as IL-4, IL-5, and IL-3. Specific biologic blockers should be developed for Th2 pathway to determine its role in asthma. It will also serve as an efficacy and safety approach for treatment. As Th-2 pathway plays an important role in other biological pathways therefore it should be weighed along with its adverse effects in blocking of these pathways. Since asthma has a complex and heterogeneous pathogenesis, therefore these immune modulators will be required to identify the subgroups in severe asthma [5].

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These phenotypes are not only useful in a characteristic population but also provide information relevant to treatment decisions. Several biomarkers (pathological and physiological) have shown prediction of future risk of exacerbations and loss of function independent of clinical features of control. Measurement of these biomarkers may help to reflect the underlying inflammation and airway hyper responsiveness which may provide further information on future risks of adverse outcomes. It may also provide with additional information on patients adherence or response to treatment. This response to treatment may help as a guide for physicians for treatment decisions. Therefore these phenotypes may provide link between severity and control of asthma. Characterization of patients phenotypes will be increasingly important in development of novel targeted therapy. For example a biomarker from induced sputum may be useful in characterizing asthma phenotypes based on the extent and type of airway inflammation. These markers add to the independent information about patients underlying phenotypes and severity. Asthma control in patients is of main importance with regard to both their current status and future risk of adverse outcomes. More clinical trials are required to outweigh the toxicity of inhibition of pathways with these modulators [5].

Recent Advances: A joint consortium of researchers in UK and US has identified a gene

ADAM33 (a disintegrin and metalloprotease 33) positioned at chromosome 20p13involved in airway remodeling in asthma. It encodes for a protein which has four functions, amongst which one is to act like protease, thought to be responsible for the alteration of tissue seen in airway remodeling. The protease function presents a good target for development of new drug and also a similar discovery similar gene in mice has provided a useful animal model. [6] Efalizumab: A humanized IgG1 monoclonal antibody targeted against the lymphocyte function antigen-1 (LFA-1) -chain, CD11a. Blocking of LFA-1/intercellular adhesion molecule interactions could restrain the inflammation by blocking adhesion and activation of LFA-1positive leukocytes. [6] IDEC -152: A recent study has found out the safety, clinical activity, and pharmacokinetic profile of IDEC-152, an IgG1 anti-CD23 antibody, in mild-to-moderate asthma. [6]

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Bronchial thermoplasty: Used in cases of severe asthma that doesn't improve with other medications. This limits the ability of the airways tightening, making breathing easier and reducing attacks. As this procedure is not widely available therefore advanced study is needed to determine the positive effects of this therapy outweighing the possible side effects [6].

Conclusion: Current guidelines on asthma recommend daily use of anti inflammatory drugs,
whereas it is evident that many patients like to practice intermittent medication. Withdrawal of these drugs may cause recurrence of symptoms and exacerbations. Reduction in treatment with these drugs should not be measured until the patients have been on a control for 3 months. Majority of patients have shown dissatisfaction towards current treatment as it has shown more side effects and therefore a demand for improved novel therapy is required. There is also a need to improve patients education through enhanced patient and physician communication. As many other targets have been identified for the cause of the disease therefore current studies are going on development of targeted therapy.

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References: 1) Rai Sp, Patil Ap, Vardhan V, Marwah V , Pethe M, Pandey IM (2007) 'Best Treatment Guidelines For Bronchial Asthma', undefined, undefined(undefined), pp. undefined. 2) K.D Tripathi (2008) Essentials of Medical Pharmacology, 6th edn., New Delhi: Jaypee publishers. 3) Dusser D, Montani D, Chanez P et al (2007) 'Mild Asthma: An Expert Review On Epidemiology, Clinical Characteristics and Treatment Recommendation.', undefined, undefined (undefined), pp. undefined. 4) Thomas M, Sheran J, Smith N et al (2007) 'AKL1, A botanical mixture for the treatment of asthma: a randomized , double blind, placebo controlled, crossover study.', Bio Med Central, undefined(undefined), pp. undefined 5) Taylor .D.R, Bateman E.D, boulet L-p et al (2008) 'A new Perspective on concepts of asthma severity and control', ERS, 32(3), pp. 545-553. 6) Undefined (2008) asthma-causes-and-home-remedies, Available at: http://indialifestyle.blogspot.com (Accessed: 21-october-2010). 7) Canonica.G.W,Cagnani.B, Blaiss.M.S et al (2007) 'Unmet needs in asthma: Global Asthma phisician ans patient(GAPP) Survey: Global adult findings', undefined, undefined(undefined), pp. undefined. 8) Bousquet.J,Clark T.J.H, Hurd.S et al (2007) 'GINA guidelines on asthma and beyond', undefined, undefined(undefined), pp. undefined.
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