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Review Article

J. Med. Sci., 15 (3): 122-129


1st April, 2015
JMS (ISSN 1682-4474) is an DOI: 10.3923/jms.2015.122.129
International, peer-reviewed
scientific journal that publishes An Overview and Update on Asthma and its Management
original article in experimental
& clinical medicine and related M.G. Rajanandh
disciplines such as molecular
biology, biochemistry, genetics, Asthma has been declared as a disease of major public health importance by the World
biophysics, bio-and medical Health Organization (WHO). An optimal strategy for asthma management and
technology. JMS is issued eight prevention was implemented in 1992 by the Global Initiative for Asthma (GINA) which
was constituted by WHO and the National Heart, Lungs and Blood Institute (NHLBI).
times per year on paper and
Asthma has affected 300 million people worldwide and 255,000 people died of asthma
in electronic format. in 2005. Each decade prevalence of asthma increases by 50%. The disease is predicted
to affect an additional 100 million population by 2025. The present article deals with the
For further information about detailed review of pathophysiology, classification, diagnosis and management of
this article or if you need asthma.
reprints, please contact:
Key words: Asthma, WHO, NHLBI, GINA
M.G. Rajanandh
Department of Pharmacy Practice,
Faculty of Pharmacy,
Sri Ramachandra University, Pour,
Chennai, 600116, Tamilnadu, India

ANSI
Asian Network for Scientific Information
Department of Pharmacy Practice, Faculty of Pharmacy, Sri Ramachandra University,
Pour, Chennai, 600116, Tamilnadu, India

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J. Med. Sci., 15 (3): 122-129, 2015

INTRODUCTION prostaglandin D-2 (PGD2), which contribute to the symptoms


of asthma. Inflammatory mediators were also produced by
Global Initiative for Asthma (GINA) program defined structural cells of the airways and they contribute to the
asthma as a chronic persistent inflammatory disease of the perseverance of inflammation in other ways (Rajanandh et al.,
airways, which is characterized by recurrent attacks of 2015).
breathlessness and wheezing due to chronic airway As the disease becomes more progressive and persistent,
inflammation, reversible airway obstruction and hyper other factors such as edema, mucus hyper-secretion,
responsiveness to a variety of specific and nonspecific stimuli inflammation, mucus plugs and structural changes such as
(Fanta, 2009; GINA., 2014). The severity and frequency of hypertrophy and hyperplasia of the airway smooth muscle
asthma are varying from person to person. In an individual, it further limit the bronchial air flow (Hirst et al., 2004). Due to
may occur from hour to hour and day to day. Failure to augmentation of goblet cells in the airway epithelium, it leads
recognize and avoid triggers may result in an asthma attack, to mucus hyper-secretion and increased size of sub-mucosal
respiratory distress and even death (Rai et al., 2007). glands. These latter changes are usually not responded with
Since, asthma is a complex disease condition, the risk usual treatment (Cohn et al., 2004).
factors are not absolutely understood (Aggarwal et al., Bronchial Hyper Responsiveness (BHR) is an exaggerated
2006). However, the risk factors for asthma can be divided as broncho-constriction response to a wide variety of stimuli. It
causal factors (Eg. Host factors such as genetic, gender is a major feature of asthma. The mechanisms influencing
and obesity, which influence the development of the BHR are dysfunctional neuro-regulation, structural changes
disease) (Ober, 2005; Gilmour et al., 2006) and triggers and inflammation. Among these factors, inflammation appears
(Eg. environmental factors such as, allergens, infections, to be a major one in determining the degree of BHR.
occupational irritants, indoor or outdoor air pollution, tobacco Treatment directed towards reducing the inflammation can
smoking, diet, drugs, strong emotions, etc., which affect the reduce BHR and improve asthma control (Akbari et al., 2006).
expression of asthma) (Busse and Lemanske, 2001; Eder et al., In some patients, permanent structural changes may occur in
2006). The present article deals with the detailed review of the airway, which leads to progressive loss of lung function. It
pathophysiology, classification, diagnosis and management of could be neither prevented nor reversible by current therapy.
asthma. Airway remodeling leads to structural changes such as
thickening of the sub-basement membrane, airway smooth
STATEMENT OF PROBLEM muscle hyperplasia and hypertrophy, sub-epithelial fibrosis,
mucous gland hyperplasia and hyper-secretion (Kuipers and
Asthma is not only a public health problem for developed Lambrecht, 2004; Peters-Golden, 2004).
countries, but also to developing countries like India,
China, etc. At least one person dies from asthma in Ireland CLASSIFICATION
every week. In India, estimates indicate a prevalence of
15-20 million asthmatics (To et al., 2002; Braman, 2006; Asthma is classified into intermittent and persistent type.
Smith, 2000; Masoli et al., 2004; Jindal, 2007). Worldwide, Under persistent, further it is divided into mild persistent,
the economic costs associated with asthma are estimated to moderate persistent and severe persistent by the National
exceed as that of tuberculosis, HIV and AIDS. The number of Asthma Education and Prevention Program (NAEPP)
Disability Adjusted Life Years (DALYs) lost due to asthma (Rajanandh et al., 2014a). This classification is determined by
worldwide is estimated to be 15 million per year, which is symptoms and lung function i.e., based on severity. However,
similar to that for diabetes, liver cirrhosis and schizophrenia. this is useful at initial visit before prescribing controller
It is estimated that asthma accounts for one in every therapy.
250 deaths worldwide (Bousquet et al., 2005). These deaths From the above classification of asthma, it is very difficult
are due to poor medical care for prolonged periods and delay to predict the treatment required for patients and the patient’s
in obtaining help during the final attack. response to treatment. Therefore, GINA classified asthma not
only by the severity of its underlying disease but also its
PATHOPHYSIOLOGY responsiveness to therapy.
According to GINA’s level of control, asthma is classified
Being an inflammatory disorder of the airways, asthma as controlled, partially controlled and uncontrolled as
involves several inflammatory cells and multiple mediators illustrated in Table 1 and 2. Asthma control is the degree to
that result in characteristic pathophysiological changes. which the goals of therapy are met and are used at every
Inflammatory cells like mast cells, eosinophils and Th2 cells subsequent visit to determine response to therapy (GINA.,
are released during inflammatory process of asthma. These 2014). However, classification of asthma by severity is
cells release mediators such as chemokine, cysteinyl used for research purposes and for initial assessment of a
leukotrienes, cytokines, histamine, nitric oxide and patient.

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J. Med. Sci., 15 (3): 122-129, 2015

Table 1: Classification of asthma based on severity


Clinical features Intermittent Mild persistent Moderate persistent Severe persistent
Day-time symptoms Less than 2 days a week More than 2 days a week but do not occur daily Daily Throughout each day
Nocturnal symptoms Less than 2 days per month More than 2 per month but not weekly More than 1 times a Often and sometimes
week but do not every night
happen daily
Lung function >80% >80% 60-80% #60%
Normal activities Do not interfere Attacks may affect daily activity Attacks may affect
daily activity or sleep Severely limit daily
physical activities
Exacerbations Infrequent Occasional Occasional Frequent

Table 2: Classification of asthma based on level of control


Characteristics Controlled (All of the following) Partly controlled (Any measure present in a week) Uncontrolled
Day-time symptoms Twice or less per week More than twice per week Three or more features of partly
Nocturnal symptoms None Any controlled asthma in a week
Lung function Normal <80 % predicted
Normal activities None Any
Exacerbations None One or more per year Once in a week

DIAGNOSIS However, measurement of specific IgE in serum is more


expensive, whereas skin allergy test is simple, rapid to
As early diagnosis and management of asthma may perform, low cost and high sensitivity. Skin tests with
improve the long term prognosis of the disease, special allergens represent the primary diagnostic tool in determining
attention is required in under diagnosis, delayed diagnosis and allergic status (Kaplan et al., 2009).
misdiagnosis of asthma (Rajanandh et al., 2014b).
Measurement of airway responsiveness: Measurement of
Symptoms: Wheezing, cough, breathlessness and chest airway responsiveness is useful for patients with normal
tightness are the prime symptoms of asthma. Episodic spirometer value, but consistent asthma symptoms.
symptoms after an incidental exposure of allergen, positive Measurements of airway responsiveness to histamine,
family history and seasonal variability of symptoms are also methacholine, mannitol or exercise challenge may help in
the useful marker in the diagnosis of asthma (Kim and Rhee,
diagnosing of asthma (Dipiro, 2005; Arshad et al., 2003).
2010).
Coding: Once diagnosis is confirmed, every patient should be
Physical examination: The most typical abnormal physical
finding in asthma is wheezing on auscultation, which confirms coded for asthma. Asthma patients are coded under ICPC as
the presence of airway limitation. Seldom, in severe asthma R96 and ICD-10 as J45 (Nageswari et al., 2014).
exacerbations, wheezing may not be present due to severe
obstruction in airflow and ventilation (Shaw et al., 2005). MANAGEMENT
However, other physical findings such as drowsiness,
cyanosis, tachycardia, difficulty in speaking, hyper inflated Pharmacological management: Stepwise approach is
chest, intercostal recession and use of accessory muscles designed to individualize the therapy for asthma patients
reflect the severity of exacerbation (Holgate and Polosa, (Fig. 1). The drugs used for the treatment of bronchial asthma
2006). are broadly classified as controllers and relievers (Suda et al.,
2009; Chapman, 2003; Barnes, 2003).
Measurements of lung function: Asthma patients in general
have poor recognition of their symptoms and perception of Controllers: Controllers or preventers are the medications
symptom severity. Pulmonary function assessment measures which are taken on a long term basis to keep the asthma under
the severity of airflow limitation, its reversibility and control. They include corticosteroids (inhaled or systemic),
variability and thereby confirms the diagnosis of asthma long acting β2-agonists, leukotriene antagonists, sustained
(Rajanandh et al., 2014c). release theophylline, anti IgE, oral anti-allergic compounds
Spirometry is the most recommended tool to measure the
and mast cell stabilizers.
airflow limitation and reversibility. It measures the %
predicted Forced Expiratory Volume in 1 sec (FEV1). The
$12% (or $200 mL) improvement in the reversibility of % Corticosteroids: The anti-inflammatory action of
predicted FEV1 conforms the presence of asthma (Ilango et al., corticosteroids is mediated through the glucocorticoid
2013). receptors. It may act by directly inhibiting the production of
proinflammatory cytokines and thereby suppress the
Measurement of allergic status: Allergic status in asthma can production of anti-inflammatory mediators and proteins such
be identified by measuring IgE and skin allergy tests. as lipoprotein-1 and β2 adrenergic receptors.

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J. Med. Sci., 15 (3): 122-129, 2015

Reduce
Level of control Treatment action

Controlled Maintain and f ind lowest controlled step


Partly controlled Consider stepping up to gain control

Increase
Uncontrolled Step up until controlled

Exacerbation Treat as exacerbation

Reduce Treatment steps Increase

Step 1 Step 2 Step 3 Step 4 Step 5

Asthma education environmental control

As-needed rapid acting


2-agonist As needed rapid-acting 2-ago nist

Select one Select one Add one or more Add one or both
Medium or high-dose Oral
Low-dose ICS Low-dose ICS plus glucocorticosteroid
ICS plus long-acting
long-acting 2-agonists
2-agonist (lowest dose)

Medium or high-dose Leukotriene modif ier


Controller options ICS low-dose ICS plus sustained release
Leukotriene modifier Anti-lgE treatment
leukotriene modif ier theophylline

Low-dose ICS plus


sustained release
theophylline

Fig. 1: Stepwise asthma management for adults-GINA guideline reproduced with permission of the GINA

Inhaled corticosteroids (ICS): The use of ICS has preventing bronchoconstriction due to various triggers, they
revolutionized the management of asthma. It has reduced also affect eosinophil reflux, micro vascular permeability
asthma morbidity and improved the health status of patients. proliferation of airway smooth muscle cells in chronic severe
ICS is the most effective anti-inflammatory drugs for the asthma, mucous secretion, mucociliary transport and
management of persistent asthma. e.g. Beclomethasone, interaction with nerves. They reduce broncho-constriction
budesonide, ciclesonide, flunisolide, fluticasone, mometasone induced by several natural triggers of asthma, including
and riamcinolone. exercise, cold air, allergen and aspirin. It can be used as an
add-on therapy with ICS in patients with persistent asthma.
Systemic corticosteroids: They are used in case of severe This may reduce the dose of ICS. eg. Montelukast, pranlukast
uncontrolled asthma. Its long term use beyond two weeks is and zafirlukast.
limited because of its adverse effects. Oral preparation is
preferred over parental therapy for long term use. eg. Sustained release theophylline (SR-T): Theophylline is a
Methylprednisolone, triamcinolone, prednisolone and xanthine derivative drug used in asthma over the past six
prednisone. decades. Because of its narrow therapeutic index, it warrants
routine monitoring of its levels in the blood. The SR-T can be
Long acting β2-agonists (LABA): It includes formoterol and used as an add-on therapy with ICS. Doxofylline, a new
salmeterol. The LABA are the preferred and most effective methyl xanthine derivative, is shown to have similar efficacy
bronchodilators for the treatment of bronchial asthma. It has a with significantly less side effects. It works by relaxing the
rapid onset of action. It directly acts on airway smooth muscle muscle around the airways in the lungs, which allow them to
by stimulating β2 receptor which in turn increases cyclic AMP widen and makes breathing easier. It also improves contraction
level and produces antagonism to broncho-constriction. It of the diaphragm and decreases the response of the airways to
should never be used as monotherapy and it is most effective irritants.
when used in combination with ICS. The fixed dose
combination has been developed to achieve the clinical Mast cell stabilizers: Sodium cromoglycate and nedocromil
control, eg. Budesonide plus formoterol and fluticasone plus sodium are the best non-steroidal anti-inflammatory drug,
salmeterol. available currently for asthma. They control the symptoms and
BHR and reduces the number of acute exacerbations with an
Leukotriene antagonists (LTA): They are non-steroid class acceptable safety profile. They prevent the activation of many
of oral medication. The LTA besides being effective in inflammatory cells, particularly mast cells, eosinophils and

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J. Med. Sci., 15 (3): 122-129, 2015

epithelial cells, but not lymphocytes. These drugs are CRTh2 antagonists: Chemo-attractant Receptor-homologous
particularly effective in children with milder asthma. Their use molecule expressed on Th2 cells (CRTh2) is a G-protein
in adults is limited. coupled receptor expressed by Th2 lymphocytes, eosinophils
and basophils. The receptor mediates the activation and
Anti IgE: The IgE plays a vital role in the initiation and chemotaxis of these cell types in response to PGD2. The PGD2
propagation of the inflammatory cascade. Omalizumab is a is released through mast cell degranulation in the initial phase
recombinant humanized monoclonal antibody directed against of IgE-mediated reactions. This process is also thought to
IgE. The usual dose of omalizumab depends on patient’s occur at the site of inflammation (Pettipher et al., 2007).
serum IgE level. Treatment with antiIgE reduces the Several CRTh2 antagonists are now in development for asthma
exacerbation rate in severe persistent asthma and may improve with promising initial results.
asthma control. However, the treatment is costly and is
suitable for highly selected patients who are not controlled on Endothelin antagonists: Endothelin-1 is a potent
maximal doses of ICS. vasoconstrictor. Its use results in increased pulmonary vascular
resistance. It also has proliferative effects on vascular smooth
Oral anti allergic compounds: Oral anti allergic compounds muscle cells. Endothelin antagonists are approved for the
includes ozagrel (available in India), tazanolast, pemirolast, treatment of pulmonary hypertension and might be useful in
repirinast, tranilast, celatrodast, amelexanox and ibudilast. treating the structural changes that occur in asthma and COPD
Antiasthmatic effects of these drugs appear to be limited. (Undem, 2001), but so far they have not been tested.

Relievers: Relievers are the medications which are used on as Inducible nitric oxide synthase inhibitors: Nitric Oxide
needed basis. They give quick action in reversing the (NO) production is increased in asthma and COPD as a result
of increased inducible NO synthase expression in the airways.
bronchoconstriction and relieve asthma related symptoms.
NO and oxidative stress generates proxy nitrite anion, leading
They include short acting β-2 agonists and anticholinergics.
to altered cell function. Several selective inducible NO
synthase inhibitors are now in development and one of these,
Short acting β2-agonists (SABA): They are generally known
L-N6-(1-Imminoethyl) Lysine (L-NIL), gave a profound and
as “rescue medications” since they stop asthma symptoms very
long-lasting reduction in the concentrations of NO in exhaled
quickly by opening the bronchial airways. The SABA are the
breath (Singh et al., 2007). However, in certain study,
best medicines for treating sudden or new asthma symptoms.
inducible NO synthase inhibitor was found to be ineffective in
They are also the drug of choice for relieving bronchospasm
asthma.
during acute exacerbations of asthma and for the pre-treatment
of exercise induced bronchoconstriction. Failure to achieve a Cytokine modifiers: Cytokines play a critical role in
quick response to SABA during exacerbation mandates perpetuating and amplifying the inflammation in asthma and
medical attention. e.g. salbutamol, terbutaline, fenoterol, COPD, suggesting that anti-cytokines may have therapeutic
reproterol, pirbuterol. potential. However, no significant improvement in FEV1 was
observed with antagonisms of IL-4 (Pitrakinra), IL-5
Anticholinergic agents: There are two anticholinergic (Reslizumab) and IL-13 (Lebrikizumab) in asthma patients
broncho-dilators currently available, namely ipratropium (Wenzel et al., 2007; Corren et al., 2011). The TNF-α plays a
bromide and tiotropium bromide. Ipratropium is used 4 times key role in amplifying airway inflammation, through the
per day, whereas tiotropium is used only once per day as its activation of NF-B and other transcription factors. In COPD
action lasts for 24 h. These are not quick relief medications, and severe asthma patients, anti-TNF-α blocking antibodies
but can be added to the bronchodilator effect for certain have been ineffective, at the expense of increasing infections
asthmatics with difficult-to-control symptoms. They are and malignancies (Rennard et al., 2007).
routinely used in the treatment of Chronic Obstructive
Pulmonary Disease (COPD). Chemokine receptor antagonists: Chemokines play a major
role in the recruitment of inflammatory cells, such as
Novel mediator antagonists: Blocking the receptors or eosinophils, neutrophils, macrophages and lymphocytes into
synthesis of inflammatory mediators is a logical approach to the lungs. An oral CCR1/CCR2 antagonist (navarixin) is
the development of new treatments for asthma and COPD. currently in clinical trials in patients with severe asthma
Since many mediators are involved, blocking a single mediator (Viola and Luster, 2008; Holz et al., 2010). The CCR4
is unlikely to be very effective, unless it plays a unique and antagonist (mogamulizumab) results in prolonged cytotoxic
key role in the disease process. Several specific mediator effects on Th2 cells and reduced lung inflammation in animal
antagonists have been found to be ineffective in asthma, models. This antibody is now in early clinical trials for asthma.
including antagonists or inhibitors of thromboxane, platelet Antagonism of CCR3 and CCR8 are ineffective in a primate
activating factor, bradykinin and tachykinins. model of asthma (Wang et al., 2013).

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J. Med. Sci., 15 (3): 122-129, 2015

Newer anti-inflammatory drugs Supplementation of diet rich in omega 3 fatty acids might
Phosphodiesterase inhibitors: Phosphodiesterase (PDE) reduce the inflammation associated with asthma (Thien et al.,
inhibitors are a drug that blocks one or more of the five 2001).
sub-types of the enzyme PDE, thereby preventing the
inactivation of cAMP in inflammatory cells and reduces cell Environmental factors: Series of the study states that, air
activation and release of inflammatory mediators. The PDE4 pollution and tobacco smoke may provoke acute asthma
is the major enzyme found in inflammatory and immune cells. attacks or aggravate existing condition.
The PDE4 inhibitors like roflumilast have proven its potential Patients with acute severe asthma are advised to receive
as anti-inflammatory drugs, especially in asthma, COPD and supplemental oxygen therapy by mask or nasal cannulae
rhinitis (Houslay et al., 2005). titrated to maintain the normal level of SaO2.
Mitogen activated protein kinase inhibitors: There are three
Immunotherapy in asthma: Use of specific immunotherapy
major Mitogen Activated Protein Kinase (MAPK) pathways
in the treatment of asthma is still controversial.
and these pathways are involved in chronic inflammation. The
Immunotherapy should not be regarded as an alternative to
p38 MAP kinase inhibitors such as SB203580 and RWJ67657
established forms of preventive therapy. Numerous studies
inhibit the synthesis of many inflammatory cytokines and
chemokines and therefore, they are in the process of have been conducted to explore the role of immunotherapy in
development for the treatment of asthma and COPD asthma (Abramson et al., 2010). The comparison was difficult
(Rajanandh et al., 2015). because of the inherent problems of trials involving asthma,
different allergen extract and dosage regimens. However,
Novel classes of bronchodilators: Ultra LABAs (once daily meta-analysis concluded that immunotherapy is a treatment of
β2-agonists) are in clinical trials which include indacaterol, option in highly selected patients with allergic asthma
olodaterol, carmoterol and vilanterol etc. These ultra LABAs (Rajanandh et al., 2014d).
should be in a fixed dose combination with corticosteroids.
Indacaterol plus mometasone and Fluticasone furoate plus Alternative and complementary therapies: It is common to
vilanterol are currently in clinical trial for the management of find patients with asthma, seeking medications from
asthma (Cazzola et al., 2011). alternative systems of medicine. Studies have shown that
patients use either complementary or alternative medicine only
Mast cell inhibitors: Mast cells are the main culprit in the if they are not satisfied with conventional medicine. Adverse
progression of asthma. The survival of mast cells in the effects of conventional medicines, holistic approach in the
airways depends on the stem cell factor. A persistent elevation disease management are also the reason for choosing
of stem cell factor in plasma concentration is observed in complementary and alternative medicine. A wide range of
asthmatics. Inhibition of stem cell factor is an effective 6-70% prevalence of use of complementary therapy for asthma
treatment modality in controlling asthma, which is proved in is reported (Partridge et al., 2003). Such treatments include
animal models (Makowska et al., 2009). Masitinib is a potent acupuncture, homeopathy, fish therapy, other herbal therapy,
blocker of c-Kit and provides some symptomatic benefit in including ayurvedic drugs, ionizers and spiritual healing which
patients with severe asthma. More selective c-Kit inhibitors are
are tried by many but have not stood the test of controlled
in development (Humbert et al., 2009).
clinical trials.
Non-pharmacological management: Non-pharmacological
ACKNOWLEDGMENTS
methods are not substitutes for recommended pharmacological
therapy. The effect of non-pharmacological management of
asthma is not well established and it requires more number Dr M.G.Rajanandh thanks Scientific Director, GINA for
of evidence based well controlled intervention studies the permission given to reproduce the stepwise asthma
(Dipiro, 2005). management diagram.

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