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Comparison between Inhaled Corticosteroid and Montelukast in

Uncontrolled Asthma Among the Children below 5 Years Age.

ABSTRACT:
Asthma is a leading cause of chronic disease in children globally,(1) , About 300 million people
worldwide have asthma and by 2025 it has been estimated that a further 100 million will be
affected. Asthma accounts for one in every 250 deaths worldwide and 1% of all disability
adjusted life years .(2) The diagnosis and management of asthma in young children is difficult,
since there are many different wheezy phenotypes with varying underlying etiologies and
outcomes.(1) In preschool children one third of all children haves symptoms of recurrent cough,
wheeze and chest tightness before the age of six, but only 40% of these wheezing preschoolers
will continue to have asthma. In older school-aged children the majority of the children have
asthma.(3)
However, in children 5 years and younger, the clinical symptoms of asthma are variable and
non-specific (4). The categories of symptoms that are highly suggestive of a
diagnosis of asthma include frequent episodes of wheeze (more than once a
month), activity-induced cough or wheeze, nocturnal cough in periods without viral
infections, absence of seasonal variation in wheeze, and symptoms that persist
after 3yrs of age. A large number of alternative causes of recurrent wheezing must
be considered and excluded in this age group (5).There are no global epidemiological

studies of asthma or wheezy illnesses in children under 5 years of age. Reasons for this include
difficulty in making a confident diagnosis, a lack of objective diagnostic criteria, logistical and
ethical problems and the variability of the expression of wheezy illnesses in children 5 years and

under.(1) . The goal of asthma management is to achieve disease control; however, despite the
availability of effective and safe medications, One reason for this is the fear of long-term side
effects from the regular use of inhaled corticosteroids (ICSs ) (6)The enormous prevalence of
asthma and the reluctance to prescribing the adequate controller therapy was the basic aim
behind this study. We lack a consensus protocol for the choice of adequate controller therapy.
Currently there are guidelines which address the management of asthma in young children. This
review discusses the approach to manage young children with asthma based on the
recommendations of the GINA guidelines.

OBJECTIVES:
Inhaled corticosteroids are more effective than Montelukast in reducing exacerbations in
uncontrolled bronchial asthma in children 6 months to 5 years of age.
STUDY DESIGN:
Randomized controlled trial study.
SETTING:
Pediatric Unit 1 Bolan Medical Complex Hospital Quetta from March 2011 to august 2011.
METHODS:
Children 6 months to 5 years of age were admitted to the ward via OPD and emergency. The
patients parents were informed about the study duration and informed consent was taken.
Baseline tests including CBC, Chest X-ray and blood sugar were done. The patients who
fulfilled the inclusion criteria were included in the study. The patients were classified into
uncontrolled asthma according to the GINA guidelines. Patient comfort and temperature
maintenance were kept in consideration. Patients were given ICS and tab Montelukast by lottery
method to remove the bias. Those receiving ICS were named as group A and those receiving
Montelukast were labeled as B .The doses for ICS was 200 microgram per day for uncontrolled
asthma. Leukotriene modifiers was given in a dose of 4 mg once a day below 1 year and 5 mg
once a day above 1 year. They were followed up monthly for up to 6 months. Patients who were
admitted to emergency department in exacerbation or status was considered as treatment failure.
The results of the study were analyzed after six months.

RESULTS:
In 6 months duration of study, out of 2400 participants,1200 were prescribed an inhaled
glucocorticosteroids and 1200 were put on montelukast. majority of the patients enrolled for the
study were boys . Ages of children range from 6 months to 60 months with a mean age of 32
months and SD____________________.both the therapies were well tolerated.compared with
Montelukast,children treated with an ICS had more rescue free days(number of days without use
of systemic steroids) in order of 84% vs 76% for montelukast.consequently,nocturnal cough was
also relieved with reduction in the percentage of days with beta agonist use and improvement in
patient perceived asthma control and quality of life.On the other hand,Montelukast was
associated with increase use of systemic steroids higher percentage of patients with an asthma
attack(32.2% vs25.6%) as compared with an ICS.the majority of children who were prescribed
ICS, stepped down from the treatment in the following three months of study trial.
CONCLUSIONS:
Based on the variability of presentations, difficulty in making a prompt diagnosis of asthma and
lack of studies done on children 6 months to 5 years of age, this study provided reliable
information for choosing an adequate controller therapy.asthma control is purely clinical,assesed
with the number of more rescue free days, no nocturnal cough and no limitation of daily
activities and all these favourable outcomes were associated with the being adherent to an
ICS.So , ICS proved to be the most effective controller therapy in this age group.

INTRODUCTION:
Asthma in childhood is a heterogeneous disease with different phenotypes
and variable clinical manifestations, which depend on the age, gender,
genetic background, and environmental influences of the patient. {Chung,
2011 #6743}Asthma is the most common chronic disease in children. The
burden of asthma is experienced not only in terms of healthcare costs but
also as lost productivity and reduced participation in family life(5). Asthma is
characterized physiologically by variable airflow obstruction and airway hyperresponsiveness (7)
For patients with symptoms consistent with asthma, but normal lung
function, measurements of airway responsiveness to methacholine,
histamine, mannitol, adenosine monophosphate or exercise challenge may
help to establish a diagnosis of asthma(5). Asthma is a condition
characterized by variable airflow obstruction, airway hyper-responsiveness
(AHR) and airway inflammation which is usually, but not invariably,
eosinophilic {Elias, 2003 #6270}... Clinical diagnosis of asthma is often based on the
presence of symptoms, such as cough, wheeze, breathlessness, and chest tightness and other
diagnostic testing is essential {Killeen, 2013 #6114;Killeen, 2013 #6271}
Asthma is the most common chronic disease in children in many low- and middle-income
countries. In these settings, the burden of childhood asthma is increasing and is associated with
severe disease.this is because of These include under-diagnosis of childhood asthma, access to
care, ability of healthcare workers to manage asthma, availability and affordability of inhaled
therapy, environmental control of potential triggers, education of healthcare providers and of the
public, and cultural or language issues.{Zar, 2012 #6414}

the global prevalence of asthma ranges 118% of the population in different countries (5) The
WHO has estimated that 15 million disability-adjusted life-yrs are lost annually due to asthma,
representing 1% of the total global disease burden . Annual worldwide deaths from asthma have
been estimated at 250,000 and mortality does not appear to correlate well with prevalence
{Bateman, 2008 #6436}. There has been a sharp increase in the global prevalence, morbidity,
mortality, and economic burden associated with asthma over the last 40 years, particularly in
children. The increasing number of hospital admissions for asthma, which are most pronounced
in young children, reflect an increase in severe asthma, poor disease management, and poverty.
{Braman, 2006 #6423}. A worldwide increase in the prevalence of asthma has been reported in
recent years. With an increase in prevalence comes an increased burden of disease in terms of
morbidity, mortality and compromised quality of life. The economic burden in terms of
utilisation of healthcare resources and limitation of the earning capacity of the individuals and
families is an added problem.. The data from Asian countries regarding these parameters is
scarce, underlining the need for systematic studies in these countries, especially those that are
resource poor. {Singh, 2005 #6437}.
The chronic inflammation of asthma is associated with airway hyperresponsiveness that leads to
recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at
night or in the early morning (5) . Most asthmatics have hyperresponsive airways. This makes
them more sensitive than non-asthmatics to bronchoconstricting environmental exposures which,
in their turn, may enhance responsiveness. The main inducers of airway inflammation are viral
infections, antigens, occupational stimuli and pollutants. Although exercise, airway cooling and
hyper- or hypotonic aerosols are potent stimuli of bronchoconstriction, it is questionable if
airway inflammation is involved in their mode of action.{Kerrebijn, 1986 #6689}. This

narrowing is almost always reversible in children with treatment.{Rossi, 2000 #6701. The
symptoms occur or worsen in the presence of Aeroallergens like house dust mites, pets,
cockroach, pollens and fungi, exercise, respiratory infections,tobacco smoke and strong
emotional expressions like laugh, cry, shouting,etc. {Paramesh, #6967}. family history of atopy,
maternal history of asthma, and the presence of smokers in the house were risk factors for the
manifestation of asthma. {Camelo-Nunes, 1997 #6921} Early rhinoviral wheezing is the
predictor of subsequent asthma development in high-risk children.{Emuzyte, 2009 #6759}
A clinical diagnosis of asthma is suggested by symptoms such as episodic breathlessness,
wheezing, cough and chest tightness . Episodic symptoms after an incidental allergen exposure,
seasonal variability of symptoms and a positive family history of asthma and atopic disease are
also helpful diagnostic guides. The patterns of these symptoms that strongly suggest an asthma
diagnosis are:
variability; precipitation by nonspecific irritants, such as smoke, fumes, strong smells or
exercise; worsening at night; and responding to appropriate asthma therapy(global gina)
In susceptible individuals, inflammation causes(14):

Increased bronchial hyper responsiveness to various stimuli

Recurrent episodes of wheezing, breathlessness, chest tightness, and cough

Widespread, variable airflow obstruction that is often reversible with


treatment

Airway responsiveness can be defined as the ease with which airways narrow in response to
various no allergic and no sensitizing stimuli, including inhaled pharmacologic agents, such as

histamine and methacholine, and physical stimuli, such as exercise.(15) Interactions between
environmental and genetic factors result in airway inflammation leading to airway obstruction
in the form of bronchospasm, mucosal edema, and mucus plug. Airway obstruction causes
increased resistance to airflow and decreased expiratory flow rates. These changes lead to a
decreased ability to expel air and may result in hyperinflation. The resulting over distention helps
maintain airway patency, thereby improving expiratory flow; however, it also alters pulmonary
mechanics and increases the work of breathing.(16) Childhood asthma is a major concern for the
patient and the care given. The morbidity leads to greater number of school days off affecting
daily activities and simultaneously the impact on childs psyche. The studies previously done has
shed more light on the age group five and above. The beneficial results of the study will affect
the outcome of asthma morbidity and mortality and will lessen its consequent effects. The
fostering of children is one of the most important sections of society which is being overlooked
and therefore requires due attention and prudent care. Their growth and development have
strong reflection on the future of a country. early attention to the morbid events leads to less
harm to children, less costly interventions. Any ignorance at this stage, would ultimately lead to
gross social harm, so treating asthma with appropriate drugs before it gets worse is more wise
and according to GINA guidelines inhaled corticosteroids are the most effective controller
medications available.(17)
Evidence suggests that appropriate treatment of asthma leads to less morbidity with less number
of school absteeinism in children(5) The goals of asthma treatment are to limit the frequency,
severity and costliness of asthmatic episodes through extensive education of physicians, children
and caregivers. The four components of asthma management include regular assessment and
monitoring, control of factors that contribute to or aggravate symptoms, pharmacologic therapy

and education of children and their care givers.(18) Asthma education is an essential part of the
treatment of this disease. The effective management of asthma effective partnership between
the patient and the health care provider.(17) Asthma self-management education improves
patient -outcomes and can be cost effective.(19) Reducing a patients exposure to risk factors
(e.g., smoking cessation, reducing exposure to second hand smoke, reducing or eliminating
exposure to occupational agents known to cause symptoms, and avoiding foods/additives/drugs
known to cause symptoms) improves the control of asthma and reduces medication needs.(17)

REVIEW OF LITERATURE
Asthma can be defined as a diffuse obstructive lung disease caused by inflammation of the
airways, increased mucus production, contraction of bronchial smooth muscles, with
hyperactivity of airways to a variety of stimuli, a high degree of reversibility of obstructive
processes which may occur spontaneously or as a result of treatment.(20)
EPIDEMIOLOGY
Asthma has presented itself as a huge burden throughout the world. Asthma is a public problem
with an estimated 300 million individuals affected worldwide.(21) WHO has estimated that 15
million DALYS are lost annually due to asthma representing 1% of the total global disease
burden (5). Annually, worldwide deaths from asthma have been estimated at 250,000 and
mortality does not appear to correlate well with prevalence.(22)
PATHOPHYSIOLOGY

Factors influencing Development and Expression Of Asthma can be classified as precipitating


factors and Host factors.(5) Precipitating factors includes, Allergens like food, animal, mold,
spores, pollens, insects, infective agents and drugs; Irritants like paint odors, sprays, perfumes,
chemicals, smoke, cold air, cold water and cough; Weather changes; Infection like viral, fungal
(aspergillosis), bacterial (B. Pertussis), and parasitic (Toxocara, ascariasis); Exercise (70 % of all
asthmatics); Emotional factors; GER- (Nocturnal Symptoms); Allergic rhinitis; Endocrine menstrual cycles, oral contraceptive pills and hyperthyroidism; Sinusitis (Nocturnal symptoms).
(5) While Host factors includes,
Genes: Genetic studies indicate that multiple genes are involved in the pathogenesis of this
disease, and chromosomal regions likely to harbor asthma currently susceptibility genes have
been replicated in several studies. Furthermore, interaction between susceptibility genes and
environmental factors is probable and is a challenge being pursued by investigators worldwide
(23). Family studies have identified a number of chromosomal regions associated with asthma
susceptibility. The most consistently replicated regions are on chromosomes 2q, 5q, 6p, 12q and
13q (23). Similarly, Patient response to the asthma drug classes, bronchodilators, inhaled
corticosteroids and leukotriene modifiers, are characterized by a large degree of heterogeneity,
which is attributable in part to genetic variation (24).

Obesity: Epidemiological data indicate that obesity increases the prevalence and incidence
of asthma. Obesity results in important changes to the mechanical properties of the
respiratory system, and these obesity-related factors appear to exert an additive effect to the
asthma-related changes seen in the airways.(25). Prevalence of asthma and overweight has
increased simultaneously during the past decades (26).Obesity is capable of reducing
pulmonary compliance, lung volumes, and the diameter of peripheral respiratory airways,
and may influence on airway hyperresponsiveness. The increase of adipose tissue in obese
subjects leads to a systemic inflammatory state, which produces a rise in the serum
concentrations of several pro-inflammatory cytokines, chemokines and adipokines (27).

Sex: Male sex is a risk factor for asthma. Before the age of 4 years the prevalence is twice as
great in boys as in girls but after this the difference narrows and by adulthood the prevalence is
greater in women.(28)
Allergens: Allergens, such as pollen, dust mites and animal fur or feathers, can trigger asthma in
children who are allergic to them. Airborne irritants, such as cigarette smoke, chemical fumes
and atmospheric pollution may trigger asthma. Indoor conditions, such as mold or damp and
occasionally chemicals in carpets and flooring materials, may trigger asthma.(29) However, the
relationship between the allergen exposure and sensitization is not straight forward. It depends
on the allergen, the dose, time of exposure, childs age and possibly genetics.(30) Some children
have allergies to nuts or other foods. A child with a food allergy may have an asthma attack as
part of an allergic reaction to a food. When this is severe, it is known as anaphylaxis. Foods
containing sulphites - sulphites are naturally occurring substances found in some food and drink.
They are also sometimes used as a food preservative. Food and drinks that are high in sulphites
include concentrated fruit juice, jam, prawns and many processed or pre-cooked meals. Most
children with asthma will not have this trigger. Medicines, such as the class of painkillers called
non-steroidal anti-inflammatory drugs (NSAIDs), which includes aspirin and ibuprofen,
occasionally trigger asthma in children.(31)
Viral Infections: RSV, followed by the parainfluenza viruses, is the chief cause of hospitalization
for respiratory tract illness in young children (32)Some types of viral infections can also trigger
asthma. Para influenza virus affects the respiratory tract in children, sometimes causing
bronchitis (inflammation of the bronchi) or pneumonia.(33) A number of long term prospective

studies of children admitted to the hospital with documented RSV infection have shown that
approximately 40% of these continue to wheeze or have asthma in later childhood.(34)
Exercise: Exercise-induced bronchoconstriction (EIB) has a high prevalence in children with
asthma, and this is a common problem, even in case of controlled asthma, because of the high
levels of physical activity in the childhood (35). Exercise induced asthma is the conventional
term for transient airway narrowing in a known asthma in association with strenuous exercise
usually lasting 5-10 minutes with a decline in pulmonary function by at least 10% (36). .Heat
loss, water loss, postexertional airway rewarming, and the role of several mediators have been
proposed as possible mechanisms responsible for the airway obstruction induced by exercise
{Cypcar, 1994 #526. The kind of physical activities that can bring on asthma symptoms include
not only exercise, but also laughing, crying, holding one's breath and hyperventilating. The
symptoms of exercise-induced asthma usually go away within a few hours. With proper
treatment, a child with exercise-induced asthma does not need to limit his or her overall physical
activity.(37)
Diet: studies reveal that infants fed formulas of intact cow's milk or soy protein compared with
breast milk have a higher incidence of atopic dermatitis and wheezing illnesses in early
childhood {Friedman, 2005 #542}.. increased consumption of linoleic acid, found in
polyunsaturated fatty acids (PUFAs), is thought to be linked to asthma, eczema and allergic
rhinitis throuth increase in the synthesis of prostaglandin-E2 (PGE2), resulting in allergic
sensitisation .decreased use of anti-oxidant (in the form of fruits and vegetables) associated with
an increase in prevalence of asthma and rhinitis (38).
The pathophysiology of asthma is complex and involves interlinked connection of airway
inflammation, intermittent airflow obstruction and bronchial hyper responsiveness.
Airway inflammation: Airway hyperresponsiveness (AHR) and airway inflammation are key
pathophysiological features of asthma (39). Asthma is characterized by reversible airway
obstruction, airway hyperresponsiveness, and airway inflammation(40). The first mechanism
identified as important for asthma was bronchial hyperresponsiveness. In a second step, asthma
was recognized also as an inflammatory disease, with chronic inflammation inducing structural
changes or remodeling (40). Asthma is a complex chronic inflammatory disease of the

airways that involves the activation of many inflammatory and structural cells, all of
which release inflammatory mediators that result in the typical pathophysiological
changes of asthma. These include mast cells, macrophages, eosinophils, T
lymphocytes, dendritic cells, basophils, neutrophils, and platelets. Airway epithelial
cells, smooth muscle cells, endothelial cells, and fibroblasts are all capable of
synthesizing and releasing inflammatory mediators (41)acute consequences of
asthma are bronchoconstriction, plasma exudation, and mucus hypersecretion.
Inflammatory cells, such as activated eosinophils and neutrophils identified in
sputum and bronchial lavages (BL) in severe acute asthma from children and adults
are associated with increased levels of IL-5, IL-8, and of proinflammatory mediators.
Viruses, but also endotoxin or allergen exposure, are able to recruit neutrophils, via
an IL-8 production by activated macrophages or epithelial cells. Together, these
inflammatory mediators are responsible for the diffuse bronchial inflammation,
which involve large and small airways (42). This chronic inflammation may result in
structural changes in the airway, such as fibrosis (particularly under the epithelium),
increased thickness of the airway smooth muscle layer (hyperplasia and
hypertrophy), hyperplasia of mucus-secreting cells, and new vessel formation
(angiogenesis) (41).The initial physiopathological event of inflammatory response
in the production of "primary cytokines", TNF-alpha, IL-1 and IL-6 by macrophages.
These and other cytokines trigger the progress and amplification of inflammatory
process involving secondary mediators and inflammatory cells (Th1/Th2-type
cytokines). When the amplification of inflammatory process is excessive ("cytokines
storm") a "pro-inflammatory cytokines pathology" can occur and that can
determine: 1) systemic inflammatory response syndrome (S.I.R.S.); 2) inflammatory
damage of restricted areas (organ pathology). TNF-alpha, IL-1 and IL-6 can act on
hypothalamus-hypophisis-surrenal axis and, through cortisol release, can determine
a negative feedback on the cytokines gene expression and a physiological antiinflammatory mechanism (43). Many different inflammatory cells are involved in
Asthma. Mast cells are clearly important in initiating the acute responses to allergen
and probably to other indirect stimuli, such as exercise and hyperventilation
(41).Macrophages, which are derived from blood monocytesMacrophages therefore
have the capacity to initiate a particular type of inflammatory response via the
release of a certain pattern of cytokines (41).The mechanism of inflammation in asthma

may be acute, sub-acute, or chronic (44), and the presence of airway edema and mucus secretion
also contributes to airflow obstruction and bronchial reactivity. Varying degrees of mononuclear
cell and eosinophil infiltration, mucus hypersecretion, desquamation of the epithelium, smooth
muscle hyperplasia, and airway remodeling are present. Some of the principal cells identified in
airway inflammation include mast cells, eosinophils, epithelial cells, macrophages, and activated
T lymphocytes. T lymphocytes play an important role in the regulation of airway inflammation
through the release of numerous cytokines. Other constituent airway cells, such as fibroblasts,
endothelial cells, and epithelial cells, contribute to the chronicity of the disease. Other factors,
such as adhesion molecules (e.g. selectins, integrins), are critical in directing the inflammatory
changes in the airway. Finally, cell-derived mediators influence smooth muscle tone and produce
structural changes and remodeling of the airway. Chronic inflammation of the airways is
associated with increased bronchial hyperresponsiveness, which leads to bronchospasm and
typical symptoms of wheezing, shortness of breath, and coughing after exposure to allergens,
environmental irritants, viruses, cold air, or exercise. In some patients with chronic asthma,
airflow limitation may be only partially reversible because of airway remodeling (hypertrophy
and hyperplasia of smooth muscle, angiogenesis, and subepithelial fibrosis) that occurs with
chronic untreated disease.
Airway inflammation in asthma may represent a loss of normal balance between two "opposing"
populations of Th lymphocytes. Two types of Th lymphocytes have been characterized: Th1 and
Th2. Th1 cells produce interleukin (IL)-2 and IFN-, which are critical in cellular defense
mechanisms in response to infection. Th2, in contrast, generates a family of cytokines (IL-4, IL5, IL-6, IL-9, and IL-13) that can mediate allergic inflammation.
Airflow Obstruction: Airflow obstruction can be caused by a variety of changes, including acute
bronchoconstriction, airway edema, chronic mucous plug formation, and airway remodeling.
Acute bronchoconstriction is the consequence of Ig E-dependent mediator release upon
exposure to aeroallergens and is the primary component of the early asthmatic response. Airway
edema occurs 6-24 hours following an allergen challenge and is referred to as the late asthmatic
response. Chronic mucous plug formation consists of an exudate of serum proteins and cell
debris that may take weeks to resolve. Airway remodeling is associated with structural changes
due to long-standing inflammation and may profoundly affect the extent of reversibility of
airway obstruction. Airway obstruction causes increased resistance to airflow and decreased

expiratory flow rates. These changes lead to a decreased ability to expel air and may result in
hyperinflation. The resulting overdistention helps maintain airway patency, thereby improving
expiratory flow; however, it also alters pulmonary mechanics and increases the work of
breathing.(45)
Airway Hyperresponsiveness. Airway hyperresponsivenessan exaggerated bronchoconstrictor
response to a wide variety of stimuliis a major, but not necessarily unique, feature of asthma.
The degree to which airway hyperresponsiveness can be defined by contractile responses to
challenges with methacholine correlates with the clinical severity of asthma. The mechanisms
influencing airway hyperresponsiveness are multiple and include inflammation, dysfunctional
neuro regulation, and structural changes; inflammation appears to be a major factor in
determining the degree of airway hyper responsiveness. Treatment directed toward reducing
inflammation can reduce airway hyperresponsiveness and improve asthma control.(17)

Figure 1: The Interplay and Interaction Between Airway Inflammation And The Clinical Symptoms And
Pathophysiology Of Asthma.
From: Section 2, Definition, Pathophysiology and Pathogenesis of Asthma, and Natural History of Asthma
Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma.
National Asthma Education and Prevention Program, Third Expert Panel on the Diagnosis and Management of Asthma.
Bethesda (MD): National Heart, Lung, and Blood Institute (US); 2007 Aug.

Steps at Cellular Level: IgE antibodies are synthesized by the plasma cells, which are present on
the surface of the respiratory tract. These IgE antibodies have become reversibly fixed to the
surface receptors of mast cells and basophils. Antigens attaches to surface IgE on sensitized mast
cells resulting in activation of mast cells and a cascade of biochemical reactions. This results in
degranulation and release of preformed mediators (early phase mediators-histamine, ECF, NCF,
heparin, PAF) within 30 minutes. Arachidonic acid is formed through the activation of
phospholipase. From arachidonic acid, leukotrienes are formed via the lipoxygenase pathway
and prostaglandins via the cyclooxygeanse pathway.These late phase mediators are responsible
for the late reaction, which develops

6 to 8 hours after the exposure to allergen.

(LEUKOTRIENES C4,D4,E4 collectively called slow releasing substances of anaphylaxis)

To understand the mechanism of asthma, it is necessary to have an idea about the normal
functioning of the respiratory system and how this disease disrupts this activity. Airways connect
the lungs with the external environment. Upper airway connection includes trachea, larynx,
nasopharynx and nostrils through which the air comes in and goes out of the body. Lower
airways include the bronchial tree. This consists of two bronchi. The bronchi are further subdivided into bronchioles. There are two types of bronchioles membranous and respiratory.
Gaseous exchange takes place at the respiratory bronchioles level. A normal respiratory system
lining consists of cilliary epithelial cells. The cillia propel any foreign body or particle upwards,
towards the pharynx. This helps in the removal of any harmful foreign particles. There are some
glands situated in the bronchial walls. These glands secrete water, electrolyte, mucin etc. in the
lumen. There are various mediators including inflammatory mediators that control these
secretions. There are different cells present in the airway, each having some specific functions in
the normal respiratory activity. These are goblet cells which secrete mucin, basophil cells,
lymphocytes, mast cells and smooth muscle cells.
The development of allergic asthma exists of three phases, namely the induction phase, the
early-phase asthmatic reaction (EAR) and the late-phase asthmatic reaction (LAR). Each phase
is characterized by the production and interplay of various cell-derived mediators. Crucial in
the development of airway inflammation in allergic asthma is the allergic cascade. Inhaled
allergens that escape the mucociliary clearance are taken up and processed by antigen presenting

cells (APCs), which are distributed throughout the respiratory tract, from the nasal mucosa to the
lung pleura. These APCs then migrate to the draining lymph nodes where the processed allergen
is presented to allergen- specific T and B cells. Interactions between those cells elicit responses
that are characterized and influenced by secreted cytokines and the presence or absence of cellbound costimulatory molecules. Activation of T helper (Th) cells by APCs leads to the
production of cytokines that regulate the iso- type switch of B cells in their production of IgE.
Once synthesized, IgE antibodies circulate in the blood binding to the high-affinity IgE receptor
Fc RI that is present on mast cells in tissue or on peripheral blood basophils. After re-exposure,
allergens cross-link to mast cell- bound specific IgE, thus causing the activation of membrane
and cytosolic pathways, which subsequently trigger the release of preformed mediators, such as
histamine, the synthesis of prostaglandins (PGs) and leukotrienes (LTs), and the transcription of
cytokines by mast cells. These mediators cause the so-called EAR, which is characterized by
constriction of

ASM

cells, vascular leakage, mucus production, enhanced

AHR and

recruitment of inflammatory cells. This EAR is immediate, lasting 3060 min and 46 h later
followed by the LAR. The late-phase is characterized by excessive inflammation of the airways,
resulting in structural changes, including airway wall thickening, subepithelial fibrosis, goblet cell
hyperplasia, myofi- broblast hyperplasia, ASM cell hyperplasia and hypertrophy, and epithelial
hypertrophy. This is collectively known as airway remodeling.

Figure 2: Factors Limiting Airflow In Acute And Persistent Asthma.


Source: Adapted and reprinted from The Lancet, 368, Holgate ST, Polosa R. The mechanisms, diagnosis, and management of
severe asthma in adults, 78093. Copyright (2006), with permission from Elsevier.
From: Section 2, Definition, Pathophysiology and Pathogenesis of Asthma, and Natural History of Asthma
Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma.
National Asthma Education and Prevention Program, Third Expert Panel on the Diagnosis and Management of Asthma.
Bethesda (MD): National Heart, Lung, and Blood Institute (US); 2007 Aug.

Induction of the allergic reaction:


During the induction phase, allergens enter the airways, are processed by APCs, and are brought
to the lymph nodes. Here, they are presented to T and B cells. Activation of Th cells leads to
the production of various cytokines, such as interleukin (IL)-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL10, IL-12, IL-13, IL-18, interferon (IFN)- , tumor necrosis factor (TNF)- , TNF-

and GM-

CSF.(46) Of these, IL-4, IL-5, IL-9 and IL-13 are the most important in the development of
asthma. IL-4 and IL-13 play a role in isotope switching to IgE production. Together with IL-9,
they are also important in mast cell development, mucus overproduction and AHR.(47)

Early-phase asthmatic reaction


Mast cells: The most crucial cell type in the EAR are mast cells.(48) Mast cells are involved in
the pathophysiology of asthma through their capacity to secrete a wide variety of mediators
after activation by allergens. Re-exposure to a previously met allergen leads to its binding on
IgE antibodies that are attached to mast cell Fc RI receptors. This causes cross-linking of Fc
RI receptors, where- upon mast cells degranulate and synthesize pro-inflammatory molecules.
Mediators produced by mast cells can be divided into preformed mediators (e.g. histamine),
newly synthesized lipid mediators (e.g. PGs and LTs), and cytokines and growth factors (e.g.
TNF, VEGF. Preformed mediators are packaged within secretory granules in the mast cell and,
on activation, are released into the extracellular environment within minutes. Principal granule
constituents include histamine, proteases (tryptase, chymase, and carboxypeptidase) and
proteoglycans (heparin and chondroitin sulphate E). Histamine exerts effects on smooth muscle
cells (contraction), endothelial cells, venule permeability, nerve end- dings, and mucus
secretion.(49) The function of tryptase in vivo is unknown, but in vitro it can cleave
complement C3 and C3a, activate fibroblasts, promote accumulation of inflammatory cells and
potentiate histamine-induced smooth muscle contraction.(49, 50) Tryptase is used as a marker
of mast cell degranulation. Chymase has a procollagen proteinase activity and is probably
directly toxic to the airway cells. Other mast cell proteases likely contribute to activation of
protein cascades and inflict local tissue damage
Lipid Mediators include PGs and LTs, inflammatory metabolites derived from the peroxidation
of arachidonic acid. These molecules have various effects in the asthmatic airway, e.g.
recruitment of inflammatory cells, bronchoconstriction and mucus secretion.

(51)

T Lymphocytes: T lymphocytes play a very important role in coordinating the inflammatory


response in asthma through the release of specific pattern of cytokines resulting in the
recruitment and survival of eosinophils and maintenance of mast cells in airway .The
programming of T lymphocytes is due to antigen presenting cells such as dendritic cells which
may migrate from epithelium to regional lymph nodes or which interact with lymphocytes
resident in airway musosa. Children with atopy are more likely to retain TH2 type phenotype.
(46)
Regulatory T cells suppresses the immune response through the release of inhibitory cytokines

such as IL-10 and transforming growth factor beta and play an important role in immune
regulation with suppression of TH1 responses.(52) However, their role in allergic diseases has
not been well defined.
B Lymphocytes: In allergic diseases, B lymphocytes secrete IgE. IL-4 is responsible for
switching B cells to IgE.(53)
Cytokines: Mast cells play a role in more persistent or chronic inflammatory responses through
the release of multifunctional cytokines. TNF-

is a major cytokine produced by mast cells; it

upregulates endothelial and epithelial adhesion molecules, increases AHR, and has antitumor
effects. Other cytokines produced by mast cells include IL-4, which is associated with Th2 cell
differentiation and IgE synthesis, IL-3, GM-CSF, and IL-5, which are critical for eosinophil
development and survival, and IL-6, CXC-chemokine ligand (CXCL) 8 (IL-8), and IL-16.
Late-phase asthmatic reaction
The late-phase of the asthmatic reaction is characterized by excessive inflammation of the
airways resulting in structural changes induced by various mediators derived from
inflammatory cells, like eosinophils, neutrophils, T cells, macrophages, dendritic cells (DCs),
endothelial cells, ASM and BECs.
Increased numbers of eosinophils exist in the airways of most, but not all, persons who have
asthma. These cells contain inflammatory enzymes, generate leukotrienes, and express a wide
variety of pro-inflammatory cytokines. Increases in eosinophils often correlate with greater
asthma severity.(17) They may release basic proteins that may damage the airway epithelial
cells. They also have a role in release of growth factors and airway remodeling (4) In addition,
numerous studies show that treating asthma with corticosteroids reduces circulating and airway
eosinophils in parallel with clinical improvement.(17, 37)
Neutrophils: Neutrophils are increased in the airways and sputum of persons who have severe
asthma, during acute exacerbations, and in the presence of smoking. Their pathophysiological
role remains uncertain; they may be a determinant of a lack of response to corticosteroid
treatment.(54)

The regulation of neutrophil recruitment, activation, and alteration in lung

function is still under study, but leukotriene B4 may contribute to these processes.(17, 45)

Macrophages: Macrophages are the most numerous cells in the airways and also can be activated
by allergens through low-affinity IgE receptors to release inflammatory mediators and cytokines
that amplify the inflammatory response.(17)
Resident cells of the airway: ASM is not only a target of the asthma response (by undergoing
contraction to produce airflow obstruction) but also contributes to it (via the production of its
own family of pro-inflammatory mediators). As a consequence of airway inflammation and the
generation of growth factors, the airway smooth muscle cell can undergo proliferation,
activation, contraction, and hypertrophyevents that can influence airway dysfunction of
asthma.(17)
Epithelial Cells: Airway epithelium is another airway lining cell critically involved in asthma.
(55) The generation of inflammatory mediators, recruitment and activation of inflammatory cells,
and infection by respiratory viruses can cause epithelial cells to produce more inflammatory
mediators or to injure the epithelium itself. The repair process, following injury to the
epithelium, may be abnormal in asthma, thus furthering the obstructive lesions that occur in
asthma.(17)
Airway Remodeling: Ongoing inflammation may result in structural remodeling: wall
thickening, subepithelial fibrosis, metaplasia, hypertrophy and hyperplasia of airway cells,
cartilage breakdown and angiogenesis. The most prominent mediators of airway remodeling are
Matrix metalloproteinases, Cytokines, Chemokines, .Endothelin-1, Vascular endothelial growth
factor,
leukotrienes,

Lipid mediators (Prostaglandin D2, Prostaglandin E2, 8-Isoprostane), Cysteinyl


Leukotriene B and ADAM33.

Matrix metalloproteinases: Connective tissue cells produce and secrete an array of macromolecules forming a complex network filling the extracellular space of the submucosa, called
the ECM. The ECM is a dynamic structure, and equilibrium between synthesis and degradation
of ECM components is required for the maintenance of its homeostasis. MMPS are responsible
for the development, morphogenesis, reproduction, and tissue resorption and remodeling. The
balance MMPs are thought to play a central role in between MMPs and TIMPs is critical in
tissue repair and remodeling, and its homeostasis plays an important role in the breakdown and

deposition of ECM in the airway wall. MMPs are als o implicated in alteration of angiogenesis
and smooth muscle hyperplasia processes.(56)
Cytokines: Direct and modify the inflammatory response in asthma and likely determine its
severity. Th2-derived cytokines include IL-5, which is needed for eosinophil differentiation and
survival, and IL-4 which is important for Th2 cell differentiation and with IL-13 is important for
IgE formation. Key cytokines include IL-1 and TNF-, which amplify the inflammatory
response, and

GM-CSF, which prolongs eosinophil survival in airways. Recent studies of

treatments directed toward single cytokines (e.g., monoclonal antibodies against IL-5 or soluble
IL-4 receptor) have not shown benefits in improving asthma outcomes.(17)
Chemokines: Among them, CCL2 is increased in asthma,(57) and is a well-established
profibrogenic mediator in vitro and in vivo by inducing TGF- release and collagen deposition
from lung fibroblasts, and by recruiting Th2 cells in the lung. Other CC-chemokines, such as
CCL7 and CCL22 also contribute to the development of pulmonary fibrosis.(58)
Endothelin 1: Endothelin (ET)-1 may be involved in airway remodeling: it is mitogenic for ASM
cells and fibroblasts, and also stimulates collagen synthesis.(58)
Vascular Endothelial Growth Factor: Vascular endothelial growth factor (VEGF) induce
expression of connective tissue growth factor and collagen.(59) Macrophages, eosinophils and
CD34+ cells are the major source of VEGF. The expression of VEGF is up regulated in the
bronchial mucosa of mild to moderate asthmatic patients, compared with that of control subjects,
and is related to the number of vessels and mast cells, as well as to the basement membrane
thickness.(60)
Lipid Mediators: Prostaglandin D2- Prostaglandins appear to have several effects on the
airways, including bronchoconstriction, plasma exudation, sensitization of nerve endings, and
effects on inflammatory cells.(61) PGD2 is involved in the recruitment of inflammatory cells
because it stimulates the chemotaxis of Th2 cells, eosinophils, neutrophils and basophils, PGD2
and PGF2

cause bronchoconstriction in asthmatic patients, but not in healthy subjects

Prostaglandin E2 is also an important PG produced in inflammatory processes. It is the most


important bronchoprotective metabolite yet identified in the airways. PGE2 inhibits the release
of mediators from mast cells, monocytes, neutrophils and eosinophils. PGE2 and PGI2 are
vasodilators and therefore should theoretically increase leakage in asthmatic.
8-Isoprostane: Isoprostanes are inflammatory metabolites derived from arachidonic acid. It
plays a role in non-specific smooth muscle hyperresponsiveness, bronchoconstriction and
edema.
Cysteinyl Leukotrienes: There is substantial evidence that cys-LTs (LTC4, LTD4 and LTE4)
play an important role in asthma. Cys-LTs mediate several steps in airway inflammation,
including inflammatory cell recruitment, vascular leakage and possibly also airway remodeling.
They decrease mucociliary clearance and are potent mediators of bronchoconstriction; plasma
exudation and mucus secretion also increase eosinophilic inflammation.
Leukotriene B4: Leukotriene B4 is a potent neutrophil chemoattractant that enhances neutrophilendothelial interactions and stimulates neutrophil activation. This leads to degranulation and the
release of mediators, enzymes and superoxides.
ADAM33: A disintegrin and metalloproteinase (ADAM) 33 has been a focus of interest in the last
few years. ADAM33 has been linked to asthma in a study of 460 white families.(62) Abnormal
activity of this gene can lead to altered airway function, inflammation, and remodeling.
Alterations in ADAM33 activity may underlie abnormalities in the function of ASM cells and
fibroblasts linked to airway remodeling and AHR.(58)

Summary of mediators released by the various cell types that are involved in the early and late
asthmatic reaction
Cell source
Released mediators
Induction phase
T cells
Early asthmatic reaction
Mast cells

Cytokines (IL-4, IL-5, IL-9, and IL-13)


Histamine; proteases (tryptase, chymase, and
carboxypeptidase);
proteoglycans
(heparin,
chondroitin sulphate E); prostaglandins (PGD2);
leukotrienes (LTC4); cytokines (TNF- , IL-3, IL-4,

Basophils
Late asthmatic reaction
Eosinophils

Neutrophils

T cells

Macrophages

Endothelial cells
Airway smooth muscle cells
Bronchial epithelial cells

IL-5, IL-6, IL-8, IL-16, and GM-CSF); chemokines


(CCL2, CCL3, CCL11)
Histamine; leukotrienes (cys-LTs: LTC4, LTD4,
LTE4); cytokines (IL-4, IL-13)
MBP; ECP; EDN; EP; leukotrienes (cys-LTs: LTC4,
LTD4, LTE4); cytokines (IL-1, IL-2, IL-3, IL-4, IL-5,
IL-6, IL-10, IL-11, IL-12, TNF- , TGF- , TGF- , GMCSF); chemokines (CXCL8, CCL3, CCL5)
Leukotrienes (LTA4, LTB4); PAF; TXA2; cytokines
(IL-1 , IL-6, TNF- , TGF- ); chemokine (CXCL8);
proteases (elastase, collagenase, gelatinase B);
microbicidal products (lactoferrin, myeloperoxidase,
lysozyme); reactive oxygen intermediates (superoxide,
hydrogen peroxide); NO
Cytokines (IL-3, IL-4, IL-5, IL-6, IL-9,
IL-10, IL-13, GM-CSF); chemokines
(CCL1, CCL22)
Cytokines (IL-1, IL-6, IFN- , TNF- );
chemokines (CXCL8); lipids; PAF;
ROS;
NO
Dendritic
cells
Chemokines (CCL2, CCL3, CCL4,
CCL17, CCL22, CXCL8)
ICAM-1, ICAM-2; PECAM-1; VCAM-1; selectins (Eselectin, P-selectin)
Chemokines (CCL5, CCL7, CCL11, CCL13, CXCL8);
cytokines (GM-CSF, IL-6); prostaglandins (PGE2); ECM
proteins
Cytokines (IL-6, GM-CSF); chemokines (CCL11, CCL17,
CCL22, CXCL1, CXCL6, CXCL8); ICAM-1

CLASSIFICATION AND DIAGNOSIS OF ASTHMA.

A clinical diagnosis of asthma is suggested by symptoms such as episodic breathlessness,


wheezing, cough and chest tightness(5). Intermittent dry coughing and expiratory wheezing are
the most common chronic symptoms of asthma. younger children are more likely to report
intermittent, non-focal chest pain.(63) Episodic symptoms after an incidental allergen exposure,
seasonal variability of symptoms and a positive family history of asthma and atopic diseases are

helpful diagnostic studies. (64) The patterns of these symptoms that strongly suggest an asthma
diagnosis are: variability; precipitation by nonspecific irritants, such as smoke, fumes, strong
smells or exercise; worsening at night; and responding to appropriate asthma therapy (5).
Studies have shown that nocturnal airflow obstruction is associated with increased release of
histamine overnight (65). A clinician should consider asthma if the child has Physical activity
induced cough or wheeze(66) .. A useful method for confirming the diagnosis of asthma in
children aged 5yrs is a trial of treatment with short-acting bronchodilators and inhaled
glucocorticosteroids. Marked clinical improvement during the treatment, and deterioration when
treatment is stopped, supports a diagnosis of asthma (5). Three categories of wheezing have been
described in children 5 years and younger (67).
Transient Early Wheezing outgrows in the first three years. This is often associated with
prematurity and parental smoking (66).
Persistent Early Onset Wheeze (before the age of 3) these children have recurrent episode of
wheeze associated with acute viral upper respiratory tract infections, have neither evidence nor
family history or atopy. The symptoms normally persist through school age and sometimes till
the age of 12 (66). The cause of episode is usually respiratory syncytial virus in those under the
age of 2 and other viruses in older children. . There is now convincing evidence that children
who develop lower respiratory symptoms during infection with respiratory syncytial virus (RSV)
in early life are at increased risk of developing asthma-like symptoms during the school
years(68)
Late Onset Wheeze/Asthma these children have asthma which often persists throughout
childhood and into adult life. These patients have atopic background often with eczema and
airway pathology which is characteristic of asthma.(64)
Differential Diagnoses

Airway Foreign Body

Allergic and Environmental Asthma

Alpha1-Antitrypsin Deficiency

Aspergillosis

Bronchiectasis

Bronchiolitis

Chronic Obstructive Pulmonary Disease

Churg-Strauss Syndrome

Cystic Fibrosis

Foreign Body Aspiration

Gastroesophageal Reflux Disease

Heart Failure

Pulmonary Embolism

Pulmonary Eosinophilia

Airway Foreign Body : Often, the child presents after a sudden episode of coughing or choking
while eating with subsequent wheezing, coughing, or stridor. However, in numerous cases, the
choking episode is not witnessed, and, in many cases, the choking episode is not recalled at the
time the history is taken.
Aspiration Syndromes: Acute aspiration may manifest as coughing, wheezing, fever, and
chest discomfort. In the setting of massive aspiration, the patient may present with cyanosis
and/or pulmonary edema, which may progress to severe respiratory distress syndrome
Bronchiolitis: Infants may become increasingly fussy and have difficulty feeding during the 2
to 5-day incubation period. A low-grade fever, usually less than 101.5F, and increasing coryza
and congestion usually follow the incubation period. Over a period of 2-5 days, RSV infection
progresses from the upper to the lower respiratory tract, and this progression leads to the
development of cough, dyspnea, wheezing, and feeding difficulties. Severe cases progress to
respiratory distress with tachypnea, nasal flaring, retractions, irritability and possibly cyanosis.
Gastroesophageal Reflux: The symptoms of gastroesophageal reflux are most often directly
related to the consequences of emesis (egg, poor weight gain) or result from exposure of the
typically cry and report sleep disturbance and decreased appetite.(69)
Cystic Fibrosis: The hallmark signs and symptoms of cystic fibrosis are salty tasting skin, poor
growth and poor weight gain despite a normal food intake,(70) accumulation of thick, sticky
mucus, frequent chest infections, and coughing or shortness of breath.

Table 1.Differential diagnosis(63)


Upper respiratory tract conditions
Allergic rhinitis
Chronic rhinitis
Sinusitis
Adenoidal or tonsillar hypertrophy
Nasal foreign body
Middle respiratory tract conditions
Laryngotracheobronchomalacia
Larayngotracheobronchitis (e.g. pertusis)
Laryngeal web, cyst or stenosis
Vocal cord dysfunction
Vocal cord paralysis
Tracheoesphageal fistula
Vascular ring, sling or external mass compressing the airway(tumor)
Foreign body aspiration
Chronic bronchitis from tobacco smoke exposure
Toxic inhalations
Lower Respiratory Tract Conditions
Bronchopulmonary dysplasia(chronic lung disease of preterm infants)
Viral bronchiolitis
Gastroesophageal reflux

Bronchiectasis
Bronchiolitis obliterans
Interstitial lung disease
Hypersensitivity pneumonitis
Pulmonary eosinophilia,churg strauss syndrome
Pulmonary hemosidrosis
Tuberculosis
Pneumonia
Pulmonary edema(congestive heart failure)
Medications associated with chronic cough
Acetylcholinesterase inhibitors
Beta adrenergic antagonists
Angiotensin converting enzyme inhibitors

Laboratory Findings:
Lung function tests help to confirm the diagnosis of asthma and to determine disease severity.
Pulmonary function testing: Use of spirometry and other lung function measures are
difficult to perform in young children below the age of 5 years old and are not suitable for
routine use. A trial of treatment with short-acting bronchodilators and inhaled
glucocorticosteroids with marked clinical improvement supports the diagnosis of asthma(67)

Peak Expiratory Flow Rate(PEFR), Forced Expiratory Volume in one second (FEV1) and
FEV1/FVC Reversibility test with bronchodilator shown by improvement of at least 12% and
above within 10 -20minutes of 2 agonist aerosol inhalation in FEV1 (71).
For patients .5 yrs of age, measurements of lung function to confirm airflow limitation, and
particularly the demonstration of reversibility of lung function abnormalities, greatly enhance
diagnostic confidence. The degree of reversibility in forced expiratory volume in one second
(FEV1) that indicates a diagnosis of asthma is generally accepted as o12% and o200 mL from
the pre-bronchodilator value
1. Spirometry is helpful as an objective measure of airflow limitation.valid spirometric measures
depends on a patients ability to properly perform a full, forceful and prolonged expiratiory
maneuver ,feasible in children >6 years of age. If the FEV1 (forced expiratory volume in 1 sec) is
within 5 % on 3 attempts, then the highest FEV1 effort of the three is used. Generally an
FEV1/FVC ratio < 0.80 indicates significant airflow obstruction (5). Use of spirometry and other
lung function measures are difficult to perform in young children below the age of 5 years old
and are not suitable for routine use (67)
2. Bronchodilator response to inhaled beta agonist (albuterol) is greater in asthmatic patients
than non-asthmatic: an improvement in FEV1 of more than or equal to 12% or >200 ml is
consistent with asthma (71).
3. Bronchoprovocation challenges:patients with symptoms consistent with asthma, but normal
lung function, measurements of airway responsiveness to methacholine, histamine, mannitol,
adenosine monophosphate or exercise challenge may help to establish a diagnosis of asthma can
be helpful in diagnosing asthma and optimizing asthma management (5)..
4. Exercise challenges (aerobic exercise or running for 6 to 8 min) can help identify children
with an exercise induced bronchospasm. In asthmatic patients,FEV1 typically decreases during
or after exercise by >15%.The onset of exercise induced bronchospasm in usually within 15
minutes after a vigorous exercise challenge and can spontaneously resolve within 30 to 60 min.
Studies of exercise challenges in school aged children typically identify an additional 5-10 %
with exercise induced bronchospasm and previously unrecognized asthma.

5. Measuring exhaled nitric oxide (FENO)


Exaled nitric oxide (FeNO) is considered a good noninvasive marker to assess airway
inflammation in asthma and allergic rhinitis. In asthma, exhaled NO is very useful to verify
adherence to therapy, and to predict upcoming asthma exacerbations. It has been also proposed
that adjusting anti-inflammatory drugs guided by the monitoring of exhaled NO, could improve
overall asthma control (72).
No tests diagnose asthma in this age group. The therapeutic trial of treatment with quick relievers
and inhaled steroids for 8 12 weeks showing improvement during therapy and relapse after
stopping therapy is diagnostic of asthma (66).

Diagnosis of Asthma:
Cough, wheeze and breathlessness are classical features of asthma syndrome (73)
Episodic symptoms after an incidental allergen exposure, seasonal variability of
symptoms and a positive family history of asthma and atopic disease are also
helpful diagnostic guides. The patterns of these symptoms that strongly suggest an
asthma diagnosis are: variability; precipitation by nonspecific irritants, such as
smoke, fumes, strong smells or exercise; worsening at night; and responding to
appropriate asthma therapy (5).
Respiratory symptoms that begin at or persist through ages 3 to 4 years are highly
diagnostic of asthma(74).
Cough-variant asthma (patients have chronic cough as their principal, if not only,
symptom) is particularly common in children and is often more problematic at night;
evaluations during the day can be normal (5) Children with cough variant asthma do
not wheeze (73).

A simple clinical index based on the presence of a wheeze before the age of 3 and the presence
of one major risk factor (parental history of asthma or eczema) or two of three minor risk
factors(eosinophilia, wheezing without colds and allergic rhinitis) has been shown to predict the
presence of asthma in later childhood (67).
Goals and principles of management
The goal of asthma therapy is asthma control. Control implies that the asthmatic child is able to
lead a normal and physically active life. The criteria for normal lifeare to:

be completely free from any symptoms, i.e. cough,wheeze and breathlessness


attend school regularly and participate fully in all school activities, including sport
sleep restfully, free from night-time cough and/or wheeze
grow and develop normally
minimise the number of attacks of acute asthma and avoid hospitalisation
avoid or minimise medication-related side-effects(75).
Cough Variant Asthma: Patients with cough variant asthma have chronic cough as their
principal symptom. It is more problematic at night, evaluations during the day time can be
normal.(64)
Exercise Induced Bronchoconstriction: typically develops within 5 to 10 min after completing
exercise(it rarely occurs during exercise).Patients experience typical asthma symptoms which
resolves spontaneously within 30 to 45 min. Exercise induced bronchoconstriction can develop
in any climatic condition but is more when patient is breathing dry ,cold air and less common in
hot, humid climate.(64) Rapid improvement of symptoms after inhaled beta 2 agonist use
supports the diagnosis of asthma.(64)
Physical Examination:
The most usual abnormal physical finding is wheezing on auscultation (5)During asthma
exacerbations, expiratory wheezing and a prolonged expiratory phase is heard on auscultation.
Decreased breath sounds in some of the lung fields, indicate areas of hypoventilation due to
obstruction. Crackles indicate excess mucus production and inflammatory exudate in airways in
severe exacerbations, the greater extent of airways obstruction causes labored breathing and
respiratory distress, poor air entry, suprasternal and intercostal recessions, nasal flaring and
accessory respiratory muscle use. In extreme cases, airflow may be so limited that wheezing
cannot be heard.(63)

Radiology:
Th findings of chest radiographs (poster anterior and lateral view) in children with asthma often
appear to be normal except of nonspecific findings of hyperinflation (flattening of diaphragm)
and per bronchial thickening. Chest radiographs can be helpful in identifying abnormalities that
are hallmarks of asthma masqueraders(aspiration pneumonitis, hyper-lucent lung fields in
bronchiolitis obliterans) and complications during asthma exacerbations.(63)
Asthma control:
As the goal of asthma treatment is to achieve control,all patients must be continually reviewed to
monitor that control has been achieved and is maintained. This can be achieved with various
tools such as a symptom assessment questionnaire or Asthma Control Test (ACT) or monitoring
of pulmonary function with peak expiratory flow rates, spirometry, or exhaled nitric oxide. Drug
therapy can then be adjusted according to the patients level of control.Children who are very
well controlled on low doses of inhaled corticosteroids may be able to come off treatment (67).
Complete control of asthma is commonly achieved with treatment, the aim of which should be to
achieve and maintain control for prolonged periods with due regard for the safety of treatment,
potential for adverse effects, and the cost of treatment required to achieve this goal (5).. Its
assessment should incorporate the dual components of current clinical control (e.g. symptoms,
reliever use and lung function) and future risk (e.g. exacerbations and lung function decline)
(76).it should be noted that inhaled glucocorticoid improve clinical control and reduce future
risk(5)

Table 2. Levels Of Asthma Control.(64)


Assessment of current clinical control (preferably over 4 weeks)
CHARACTERISTIC

CONTROLLED
PARTLY
(all
of
the CONTROLLED(any
following)
measure in any week)

UNCONTROLLED
ASTHMA(3
or
more
features in any week)

Day time symptoms

NONE(less than
twice per week
lasting
for
minutes
and
rapidly relieved
by short acting
bronchodilators)

Nocturnal symptoms

NONE(no
ANY(may
cough ANY(may cough during
nocturnal cough during sleep or wakes sleep or wakes with cough
during sleep)
with cough or wheeze) or wheeze)

Limitations
activities

of NONE(fully
active child: plays
and runs without
symptoms)

Need for reliever


medication

2 d per week

More than twice per


week(lasting
for
minutes and rapidly
relieved
by short
acting
bronchodilators)

More
than twice per
week(lasting for hours or
recur or partly relieved by
short
acting
bronchodilators)

ANY(cough, wheeze ANY(cough, wheeze or


or difficult breathing difficult breathing during
during vigorous play, vigorous play, laughing
laughing)
More than 2 days per More than 2 days per week
week

ASSESSMENT OF FUTURE RISK (risk of exacerbations, instability, rapid decline in lung


function, side effects)
Features that are associated with increased risk of adverse events in the future include:
Poor clinical control, frequent exacerbations in the past year, ever admission to critical care for
Asthma, low FEV1, exposure to cigarette smoke, high dose medications

MANAGEMENT OPTIONS

Clinical studies have shown that asthma can be effectively controlled by intervening
to suppress and reverse the inflammation, as well as treating the
bronchoconstriction and related symptoms. Furthermore, early intervention to stop
exposure to the risk factors that sensitised the airway may help improve the control
of asthma and reduce medication needs (5)
The goal of asthma treatment is to achieve and maintain clinical control.
Medications to treat asthma can be classified as controllers or relievers. Controllers
are medications taken daily on a long term basis to keep asthma under clinical
control chiefly through their anti-inflammatory effects. They include
inhaled glucocorticosteroids, leukotriene receptor antagonists, and combination
therapies with long-acting beta agonists and glucocorticosteroids, anti-IgE and other
steroid-sparing therapies. Relievers are used on an asneeded basis to quickly
reverse bronchoconstriction and relieve symptoms. The most commonly used
relievers are inhaled short-acting beta agonists (67).., inhaled anticholinergics, short
acting theophyllines and short acting oral beta 2 agonists(5)Bateman, 2008 #5335}
ROUTES OF ADMINSTRATION:

Asthma treatment can be administered in a variety of ways: inhaled, orally or parenterally (by
subcutaneous, intravenous and intramuscular routes) .The major advantage of inhaled therapy is
that the drug is directly delivered to the airways producing higher local concentrations and less
systemic side effects.(77)
Different age groups require different inhalers for effective therapy. The choice of inhaler
device should include consideration of the efficacy of the drug delivery, cost, safety, ease of
use, convenience and documentation or its in patients age group. Although nebulizers have
been the mainstay of inhalation therapy in childhood asthma for many years, these devices are
cumbersome, bulky, time-consuming, and expensive to use. As a result, over the past decade the
emphasis of inhalation therapy in children has shifted from nebulizers to metered-dose inhalers
(MDI) in combination with spacer devices (78).Spacers retain large drug particles that would be
deposited in the oropharynx, so reducing oropharyngeal side-effects and systemic absorption and
availability of inhaled drug. This consideration is especially important for ICS with poor firstpass metabolism such as beclomethasone dipropionate (BDP) and budesonide (75). the vast
majority of children of all ages with acute severe asthma can be managed effectively and safely
by 2 agonists delivered via MDI/spacer(78) . Nebulisers have imprecise dosing, are expensive,

waste large amounts of drug into the surrounding air, are time-consuming to use and care for, and
require maintenance (75).

Controller Medications
Controller medications for children include inhaled and systemic glucocorticosteroids,
leukotriene modifiers, long acting inhaled 2-agonists, theophylline, cromones, and long-acting
oral 2-agonists.
Inhaled glucocorticosteroids.
Role in Therapy -Inhaled glucocorticosteroids are the most effective controller therapy for
asthma in children with rapid improvement in symptoms and lung function, even at low doses of
inhaled glucocorticosteroids .Duration of treatment should continue till bronchial hyperresponsiveness improves (67). In children of all ages, maintenance treatment with inhaled
glucocorticosteroids controls asthma symptoms, reduces the frequency of acute exacerbations
and the number of hospital admissions, improves quality of life, lung function, and bronchial
hyperresponsiveness, and reduces exercise-induced bronchoconstriction. Dose-response studies
and dose titration studies in children. demonstrate marked and rapid clinical improvements in
symptoms and lung function at low doses of inhaled glucocorticosteroids (e.g., 100-200 g
budesonide daily),(79) and mild disease is well controlled by such doses in the majority of
patients. Inhaled steroids are now used at a much earlier stage in asthma therapy, and there is a
strong argument for their early introduction in both adults and children to prevent asthma
morbidity and mortality and possibly the structural changes resulting from uncontrolled chronic
inflammation, which may lead to irreversible airflow obstruction in some patients(80) .Early
intervention with inhaled budesonide is associated with improved asthma control
and less additional asthma medication use (81). nebulized budesonide reduced the
need for oral glucocorticoid therapy and also improved lung function in children
under the age of three years (82). Increasing to higher doses provides little further
benefit in terms of asthma control but increases the risk of side-effects. However,
there is marked individual variability of responsiveness to inhaled
glucocorticosteroids, and because of this and the recognised poor adherence to
treatment with inhaled glucocorticosteroids, many patients will require higher doses
to achieve full therapeutic benefit (5). Symptom control and improvements in lung function

occur rapidly (after 1 to 2 weeks), although longer treatment (over the course of months) and

sometimes higher doses may be required to achieve maximum improvements in airway


hyperresponsiveness(10). When glucocorticosteroid treatment is discontinued, asthma control
deteriorates within weeks to months (67).
Desirable properties in an inhaled glucocorticoid are high topical potency, low systemic
bioavailability of the portion of the dose swallowed by the patient, and rapid metabolic clearance
of any glucocorticoid that reaches the systemic circulation. After inhalation a large proportion of
the inhaled dose, 80 to 90 percent, is deposited on the oropharynx and swallowed. It is then
available for absorption into the systemic circulation through the liver (Figure 1FIGURE 1) This
fraction is markedly reduced if the glucocorticoid is administered through a large-volume spacer
attached to a metered-dose inhaler (82).

nhaled corticosteroid (ICS) dosing categories in children and adults

Corticosteroid Trade name

Daily ICS dose, mcg

Children (6 to 11 years of age)


Adults (12 years of age and over)
Low

Medium

High

Low

Medium

Beclomethasone dipropionate HFA QVAR


500

High
200 201400

>400 250 251

>500

Budesonide* Pulmicort Turbuhaler

400 401800

>800 400 401800

>800
Ciclesonide* Alvesco
Fluticasone

>400 200 201400

Flovent MDI and spacer; Flovent Diskus

251500
(83)

200 201400

>500

200 201500

>400
>500 250

Side effects -The majority of studies evaluating the systemic effects of inhaled
glucocorticosteroids have been undertaken in children older than 5 years.(84)

Growth: Asthma and its level of control may directly affect growth in the same way as
most chronic diseases of childhood .Recent studies have confirmed that poorly controlled
asthma may itself adversely affect growth.(85). Continuous administration of ICSs in low
to medium dose over many years is well tolerated. (86). Low doses do not have clinically
deleterious side effects on the bones, growth, eye, or hypothalamo-pituitary-adrenal-axis.
However, they do not normalize lung function and prevent structural changes in the
airway wall in all asthmatic patients (87). Effect of ICS on growth depends on dose and
duration of intake as well as the susceptibility of the growth phase during which the child
inhales steroids(88) . With all inhaled corticosteroids given at high dosage, there is likely
to be a dual effect due to topical bioactivity from the airway dose as well as
prednisonelike activity from the systemic bioavailable dos(88). The use of a large spacer
device has been shown to reduce the incidence of both topical and systemic adverse
effects from inhaled steroids (89). Height measurements made over a period of less than 1
year are liable to error and misinterpretation(90) . The delay in pubertal growth is,
however, also associated with a delay in skeletal maturation so that the bone age of the
child corresponds to the height. Ultimately, there is no decrease in attained adult height,
though it is reached at a later age than normal . This difference in growth pattern seems to
be unrelated to the use of inhaled corticosteroids and is more pronounced in those
children with the most severe asthma(85) . in school-age children asthma should be
treated first with inhaled steroids. It is probable that the best combination of efficacy and
safety can be achieved by using low steroid doses (91).

Hypothalamic-pituitary-adrenal (HPA) axis. Long-term follow-up studies in children


concluded that Budesonide inhalation suspension is well tolerated, with little or no effect
on growth and hypothalamic-pituitary-adrenal axis function Thus it is a valuable
therapeutic alternative to systemic corticosteroid therapy in infants and young

children(92). With sensitive techniques, dose-dependent adrenal suppression has been


documented in children treated with inhaled steroids but generally this effect has no
clinical relevance (89). Most children develop biochemical evidence of adrenal
suppression after treatment with medium to high doses of ICs (93). At higher doses,
small changes in HPA axis function can be detected with sensitive methods

Bones and Glucocorticosteroids in Children: One of the greatest concerns of


long-term corticosteroid therapy for asthma is its potential for adverse effects
on bone turnover, resulting in an increased risk for osteoporosis and fracture

No studies have reported any statistically significant increase of risk of fractures in


children taking inhaled glucocorticosteroids. . In 157 asthmatic children receiving inhaled
budesonide for 3 to 6 years, bone density measurement was not significantly different
compared with that in asthmatic controls who had not received steroids(94) . Low doses
do not have clinically deleterious side effects on the bones, growth, eye, or hypothalamopituitary-adrenal-axis. However, they do not normalize lung function and prevent
structural changes in the airway wall in all asthmatic patients (87). Calcium
supplementation may be necessary in children with asthma treated with inhaled steroids
since this treatment may cause reduction in osteocalcin, a marker of osteoblast activity
and bone formation(89) .OCS (continuous or intermittent) is associated with an increased
risk of fracture and cataracts in children and continuous treatment also with increased
risk of adrenal insufficiency and growth retardation (95). Bone mineral density may be
decreased by high doses of inhaled glucocorticoids, but their effect is confounded by the
fact that patients taking these drugs also receive intermittent courses of oral
glucocorticoids. Oral glucocorticoid therapy is a well-known cause of osteoporosis and
an increased risk of vertebral and rib fractures (82),. A study showed that 6 months of
ICS therapy (mean dose 0.4 mg/day) had no significant adverse effect on bone
metabolism in asthmatic children (96).

Cataracts.. Long-term administration of medium dose ICSs does not increase the risk of
cataracts or osteopenia in children and young adults (86).

Central nervous system effects: Despite the propensity of glucocorticoids to cause


psychiatric disturbance including emotional lability, euphoria, depression,

aggressiveness, and insomnia only eight patients have been described in whom
psychiatric symptoms developed during inhaled glucocorticoid therapy (82).

Oral candidiasis, hoarseness, and bruising. Oropharyngeal candidiasis and dysphonia


are the most commonly recognized adverse effects of therapy, but these topical
phenomena cause no significant morbidity and are easily managed(97). Spacers reduce
the incidence of oral candidiasis.. The use of spacer devices and mouth rinsing may
reduce local and systemic adverse effects (98). A 3-6 yr treatment of children with
inhaled budesonide at an average daily dose of about 500 microg is not associated with
an increased occurrence of posterior subcapsular cataract, bruises, tendency to bruise,
hoarseness or other noticeable voice changes (99)..

Dental side effects. recent studies have provided little evidence for an asthmacaries
causative relationship, However, Asthma is one of the most common chronic medical
conditions in childhood which is considered high risk for caries. The most recent reports
have concluded that the individualistic nature of asthmatic condition, through either its
disease status or its pharmacotherapy (different combinations of medicaments), carries
several factors for an increased caries risk (100).

Effects on Connective Tissue There are reports of increased skin bruising and
purpura in patients receiving high doses of inhaled beclomethasone, but the
amount of intermittent glucocorticoids they received is not known. Easy
bruising linked to inhaled glucocorticoids is more frequent in elderly patients;
there are no reports of this problem in children (82).

Other local side effects. The long-term use of inhaled glucocorticosteroids is not
associated with an increased incidence of lower respiratory tract infections, including
tuberculosis (82).

Leukotriene modifiers.
The leukotrienes are potent inflammatory mediators in asthma and contribute to
increased mucus production, bronchoconstriction and eosinophil infiltration. These

compounds are produced via the lipoxygenase pathway by mast cells, eosinophils
and alveolar macrophages(101)
Clinical studies have demonstrated that leukotriene modifiers have a small and
variable bronchodilator effect, reduce symptoms (including cough) , improve lung
function, and reduce airway inflammation and asthma exacerbations. However,
when used alone as controller, the effects of leukotriene modifiers are less than
those of low doses of inhaled glucocorticosteroids and, in patients already on
inhaled glucocorticosteroids, leukotriene modifiers cannot substitute for this
treatment without risking the loss of asthma control. Leukotriene modifiers used as
add-on therapy may reduce the dose of inhaled glucocorticosteroids required by
patients with moderate to severe asthma , and may improve asthma control in
patients whose asthma is not controlled with low or high doses of inhaled
glucocorticosteroid(5)s.

Leukotriene modifiers provide clinical benefit in children older than 5 years at all levels of
severity, but generally less than that of low-dose inhaled glucocorticosteroids Leukotriene
modifiers provide partial protection against exercise-induced bronchoconstriction within hours
after administration with no loss of bronchoprotective effect(102).
LTRAs have been proposed as alternative first-line therapy to ICSs for episodic or mild
persistent asthma who have difficulty in utilising inhalation treatment, with poor compliance, or
where exercise-induced bronchospasm (EIB) is a dominant component of asthma .(102)
, LTRAs are approved for treatment of both allergic rhinitis and asthma(102)

Side effects -No safety concerns have been demonstrated from the use of leukotriene modifiers in
children (102).
Long-acting inhaled 2-agonists.
Role in therapy -Long-acting inhaled 2-agonists are primarily used as add-on therapy in
children older than 5 years whose asthma is insufficiently controlled by medium doses of inhaled
glucocorticosteroids or as single-dose therapy before vigorous exercise. Monotherapy with long
acting inhaled 2-agonists should be avoided Long-acting inhaled 2-agonists have mainly been
studied in children older than 5 years as add-on therapy for patients whose asthma is not

controlled on low to high doses of inhaled glucocorticosteroids. Significant improvements in


peak
Flow and other lung function measurements have been found in most studies. However, their
effects on other outcomes such as symptoms and need for reliever medication have been less
consistent and have only been observed in about half of the trials conducted. Combination
products containing an inhaled glucocorticosteroid and long-acting inhaled 2-agonists are
preferred to long-acting inhaled 2-agonists and inhaled glucocorticosteroids administered by
separate inhalers.
In Children 5 years and younger, the effect of long-acting inhaled 2-agonists has not been
adequately studied. Combination therapy with budesonide and formoterol used both as
maintenance and rescue has been shown to reduce asthma exacerbations in children ages 4 years
and older with moderate to severe asthma.

Side effects: long acting inhaled beta 2 agonists are not the recommended option when more than
one controller is required. If used, long-acting 2-agonists should only be used in combination.
With an appropriate dose of inhaled glucocorticosteroid as determined by a physician, preferably
in a fixed combination inhaler.

THEOPHYLLINE: Role in therapy -Theophylline has been shown to be effective as


monotherapy and as add-on treatment to inhaled or oral glucocorticosteroids in children older
than 5 years. Maintenance treatment offers a marginal protective effect against exercise-induced
bronchoconstriction. Add-on treatment with theophylline has been found to improve asthma
control and reduce the maintenance glucocorticosteroid dose necessary in children with severe
asthma treated with inhaled or oral glucocorticosteroids. A few studies in children 5 years and
younger also suggest some clinical benefit. However, the efficacy of theophylline is less than that
of low-dose inhaled glucocorticosteroids. Plasma theophylline levels were maintained within the
therapeutic range of 5-110 mol/L (5-10 g/ml). Sustained-release products are preferable for
maintenance therapy, since they enable twice-daily dosing. Measurement of plasma theophylline

levels is not necessary in otherwise healthy children when doses less than 10 mg/kg/day are used.
However, when higher doses are used or when drugs that may increase theophylline levels are
also used

chronically, plasma theophylline levels should be measured two hours before

administration of the next dose once steady state has been (after 3 days)
Side effects -The most common side effects of theophylline are anorexia, nausea, vomiting, and
headache. Mild central nervous stimulation, palpitations, tachycardia, arrhythmias, abdominal
pain, diarrhea, and, rarely, gastric bleeding may also occur. These side effects are mainly seen
At doses higher than 10 mg/kg/day.
Anti-IgE.
Role in therapy - Anti-IgE (omalizumab) has proven efficacy in children age 6 to 12 years with
moderate-to-severe and severe persistent allergic (IgE-mediated) asthma. A one-year study
valuated the efficacy and safety of anti- IgE in 627 children with IgE-mediated asthma
inadequately controlled on doses of inhaled glucocorticosteroid equivalent to 200 g/day
fluticasone propionate or higher (mean dose 500 g/day) A substantial number of children with
difficult asthma will have higher IgE levels than the upper limit of IgE recommended for therapy
*1,300 IU). It is unknown if these patients will still benefit from omalizumab therapy. There are
no tests which can currently be recommended in order to predict who will respond. Anti-IgE
therapy is expensive.(79, 103-106)
Side effects: Drug-related adverse events in anti-IgE treated patients are mild to moderate in
severity and include urticaria, rash, flushing, and pruritus.(106)
Cromones: sodium cromoglycate and nedocromil sodium. Sodium cromoglycateand
nedocromil sodium have limited role in the long term treatment of asthma in children. One metaanalysis has concluded that long-term treatment with sodium cromoglycate is not significantly
better than placebo for management of asthma in children. Studies of the use of these
medications in children 5 years and younger are sparse and results are conflicting.
Side effects -Cough, throat irritation, and bronchoconstriction occur in a small proportion of
patients treated with sodium cromoglycate. A bad taste, headache, and nausea are the most
common side effects of nedocromil.

Long-acting oral 2-agonists.


Treatment with long-acting oral 2-agonist such as slow release formulations of salbutamol,
terbutaline, and bambuterol reduces nocturnal symptoms of asthma Due to their potential side
effects of cardiovascular stimulation, anxiety, and skeletal muscle tremor, their use is not
encouraged. If used, dosing should be individualized, and the therapeutic response monitored to
limit side effects.
Systemic glucocorticosteroids.
Because of the side effects of prolonged use, oral glucocorticosteroids in children with asthma
should be restricted to the treatment of acute severe exacerbations, whether viral-induced or
otherwise.

Reliever Medications
Rapid-acting inhaled 2-agonists and short-acting oral 2- agonists.
Role in therapy -Rapid-acting inhaled 2-agonistss are the most effective bronchodilators
available and therefore the preferred treatment for acute asthma in children of all ages. The
inhaled route results in more rapid bronchodilation at a lower dose and with fewer side effects
than oral or intravenous administration186. Furthermore, inhaled therapy offers significant
protection against exercise-induced bronchoconstriction and other challenges for 0.5 to 2 hours
(long-acting 2-agonists offer longer protection). This is not seen after systemic
administration188. Oral therapy is rarely needed and reserved mainly for young children who
cannot use inhaled therapy.
Side effects -Skeletal muscle tremor, headache, palpitations, and some agitation are the most
common complaints associated with high doses of 2-agonists in children. These complaints are
more common after systemic administration and disappear with continued treatment.

Anticholinergics
Role in therapy -Inhaled anticholinergics are not recommended for long-term management of
asthma in children.

ASTHMA MANAGEMENT AND PREVENTION:


The goals for successful management of asthma are to:
Achieve and maintain control of symptoms
Maintain normal activity levels, including exercise
Maintain pulmonary function as close to normal as
Possible
Prevent asthma exacerbations
Avoid adverse effects from asthma medications
Prevent asthma mortality.
Clinical studies have shown that asthma can be effectively controlled by intervening to suppress
and reverse the inflammation as well as treating the bronchoconstriction and related symptoms.
Furthermore, early intervention to stop exposure to the risk factors that sensitized the airway may
help improve the control of asthma and reduce medication needs.
The recommendations for asthma management are laid out in five interrelated components of
therapy:
1. Develop Patient/Doctor Partnership
2. Identify and Reduce Exposure to Risk Factors
3. Assess, Treat, and Monitor Asthma
4. Manage Asthma Exacerbations

5. Special Considerations.
The effective management of asthma requires the development of a partnership between the
person with asthma and his or her health care professional(s) (and parents/caregivers in the case
of children with asthma). The aim of this partnership is to enable patients with asthma to gain the
knowledge, confidence, and skills to assume a major role in the management of their asthma. His
approach is called guided self-management and has been shown to reduce asthma morbidity in
both adults

and children. Guided self-management may involve varying degrees of

independence, ranging broadly from patient-directed self-management in which patients make


changes without reference to their caregiver, but in accordance with a prior written action plan,
to doctor-directed self-management in which patients rely follow a written action plan, but refer
most major treatment changes to their physician at the

time of planned or unplanned

consultations.

ASTHMA EDUCATION
Education should be an integral part of all interactions between health care professionals and
patients, and is relevant to asthma patients of all ages. Although the focus of education for small
children will be on the parents and caregivers, children as young as 3 years of age can be taught
simple asthma management skills but regional issues and the developmental stage of the children
may affect the outcomes of such programs.
Education and the Patient Doctor Partnership
Goal: To provide the person with asthma, their family, and other caregivers with suitable
information and training so that they can keep well and adjust treatment according to a
medication plan developed with the health care professional
Key Components:

Focus on the development of the partnership

Acceptance that this is a continuing process

A sharing of information

Full discussion of expectations

Expression of fears and concerns

KEY COMPONENTS:

Diagnosis

Difference between relievers and controllers

Potential side effects of medications

Use of inhaler devices

Prevention of symptoms and attacks

Signs that suggest asthma is worsening and actions to take

Monitoring control of asthma

How and when to seek medical attention

The person then requires:

A written asthma action plan

Regular supervision, revision, reward, and reinforcement

Good communication is essential as the basis for subsequent good compliance/adherence


At the Initial Consultation
Early in the consultation the person with asthma needs information about the diagnosis and
simple information about the types of treatment available, the rationale for the specific
therapeutic interventions being recommended, and strategies for avoiding factors that cause
asthma symptoms. Different inhaler devices can be demonstrated, and the person with asthma
encouraged to participate in the decision as to which is most suitable for them. At the initial

consultation, verbal information should be supplemented by the provision of written or pictorial


information about asthma and its treatment.
Personal Written Asthma Action Plans
Personal written asthma action plans help individuals with asthma make changes to their
treatment in response to changes in their level of asthma control, as indicated by symptoms
and/or peak expiratory flow, in accordance with written predetermined guidelines. With these
action plans, the effects were also greater when the patients themselves both stepped up inhaled
glucocorticosteroids and added oral glucocorticosteroids, based on their symptoms or for peak
low-based. Patients experience a one-third to two-thirds reduction in hospitalizations, emergency
room visits, unscheduled visits to the doctor for asthma, missed days of work, and nocturnal
wakening. Thus, patients who are unable to undertake guided self-management can still achieve
benefit from a structured program of regular medical review.
Follow-Up and Review
Follow-up consultations should take place at regular intervals. At these visits, the patients
questions are discussed, and any problems with asthma and its initial treatment are reviewed.
Patients should be asked to demonstrate their inhaler device technique at every visit, with
correction and re-checking if it is inadequate. Follow-up consultations should also include
checking the persons adherence/compliance to the medication plan and recommendations for
reducing exposure to risk factors.

Example of Contents of Written Asthma Action Plan to Maintain Asthma Control

Your Regular Treatment:


1. Each day take ___________________________
2. Before exercise, take _____________________
WHEN TO INCREASE TREATMENT

Assess your level of Asthma Control


In the past week have you had:
Daytime asthma symptoms more than 2 times ? No Yes
Activity or exercise limited by asthma? No Yes
Waking at night because of asthma? No Yes
The need to use your [rescue medication] more than 2 times? No Yes
If you are monitoring peak flow, peak flow less than______? No Yes
if you answered Yes to three or more of these questions, your asthma is
Uncontrolled and you may need to step up your treatment.
HOW TO INCREASE TREATMENT
STEP-UP your treatment as follows and assess improvement every day:
_________________________________ [Write in next treatment step here]
Maintain this treatment for _____________ days [specify number]
WHEN TO CALL THE DOCTOR/CLINIC.
Call your doctor/clinic: _______________ [provide phone numbers]
If you dont respond in _________ days [specify number]
____________________________ [optional lines for additional instruction]
EMERGENCY/SEVERE LOSS OF CONTROL
3If you have severe shortness of breath, and can only speak in short sentences,
3 If you are having a severe attack of asthma and are frightened,
3If you need your reliever medication more than every 4 hours and are not

Improving.
1. Take 2 to 4 puffs ___________ [reliever medication]
2. Take ____mg of ____________

Improving Adherence
Although interventions for enhancing medication adherence have been developed, studies of
adults and children with asthma have shown that around 50% of those on Long-term therapy fail
to take medications as directed. Patient concern about side-effects of inhaled glucocorticosteroids
whether real or perceived may influence adherence. Specific drug and non-drug factors involved
in non-adherence are:

Factors Involved in Poor Adherence


Drug factors

1. Difficulties with inhaler devices Awkward regimes (e.g., four times daily or multiple
drugs)
2. Side effects
3. Cost of medication
4. Dislike of medication
5. Distant pharmacies

Non-drug factors
1. Misunderstanding or lack of instruction
2. Fears about side effects

3. Dissatisfaction with health care professionals


4. Unexpressed/discussed fears or concerns
5. Inappropriate expectations
6. Poor supervision, training, or follow-up
7. Anger about condition or its treatment
8. Underestimation of severity
9. Cultural issues
10. Stigmatization
11. Forgetfulness or complacency
12. Attitudes toward ill health
13. Religious issues.

SELF MANAGEMENT IN CHILDREN


A systematic review found that educational programs for the self-management of asthma in
children and adolescents led to improvements in lung function and feelings of self-control, and
reduced absences from school, the number of days with restricted activity, and the number of
emergency department visits . For children, symptom-based action plans are more effective than
those based on peak flows.

IDENTIFY AND REDUCE EXPOSURE TO RISK FACTORS


Asthma Prevention: Measures to prevent asthma may be aimed at the prevention of allergic
sensitization (i.e., the development of atopy, likely to be most relevant prenatally and
perinatally), or the prevention of asthma development in sensitized people. Other than preventing

tobacco exposure both in utero and after birth, there are no proven and widely accepted
interventions that can prevent the development of asthma.
The role of diet particularly breast-feeding, in relation to the development of asthma has been
extensively studied and, in general, infants fed formulas of intact cows milk or soy protein
compared with breast milk have a higher incidence of wheezing illnesses in early childhood.
Exclusive breastfeeding during the first months after birth is associated with lower asthma rates
during childhood.
Exposure to cats has been shown to reduce risk of atopy in some studies.
Exposure to tobacco smoke both prenatally and postnatally is associated with measurable
harmful effects, including effects on lung development45 and a greater risk of developing
wheezing illnesses in childhood. Passive smoking increases the risk of allergic sensitization in
children. Both prenatal and postnatal maternal smoking is problematic. Pregnant women and
parents of young children should be advised not to smoke.

Prevention of asthma Symptoms and exacerbations


Asthma exacerbations may be caused by a variety of factors, sometimes referred to as triggers,
including allergens, viral infections, pollutants, and drugs. Reducing a patients exposure to some
of these categories of risk factors (e.g., smoking cessation, reducing exposure to secondhand
smoke, reducing or eliminating exposure to occupational agents known to cause symptoms, and
avoiding foods/additives/drugs known to cause symptoms) improves the control of asthma and
reduces medication needs. In the case of other factors (e.g., allergens, viral infections and
pollutants), measures where possible should be taken to avoid these. Because many asthma
patients react to multiple factors that are ubiquitous in the environment, avoiding these factors
completely is usually impractical and very limiting to the patient. Thus, medications to maintain
asthma control have an important role because patients are often less sensitive to these risk
factors when their asthma is under good control. Patients with well-controlled asthma are less
likely to experience exacerbations than those whose asthma is not well controlled.
Indoor Allergens

Among the wide variety of allergen sources in human dwellings are domestic mites, furred
animals, cockroaches, and fungi.
Domestic mites. Domestic mite allergy is a universal health problem59. Since mites live and
thrive in many sites throughout the house, they are difficult to reduce and impossible to
eradicate. One study showed some efficacy of mattress encasing at reducing airway
hyperresponsiveness in children.
Furred animals. Complete avoidance of pet allergens is impossible, as the allergens are
ubiquitous and can be found in many environments outside the home, including schools65,
public transportation, and cat-free buildings. Although removal of such animals from the home is
encouraged, even after permanent removal of the animal it can be many months before allergen
levels decrease and the clinical effectiveness of this and other interventions remains unproven.
Cockroaches. Avoidance measures for cockroaches include eliminating suitable environments
restricting access (sealing entry sources such as around paperwork and doors), chemical control,
and traps. However, these measures are only partially effective in removing residual allergens,
Fungi. Fungal exposure has been associated with exacerbations from asthma and the number of
fungal spores can best be reduced by removing or cleaning mold laden objects. In tropical and
subtropical climates, fungi may grow on the walls of the house due to water seepage and
humidity. To avoid this, the walls could be tiled or leaned as necessary.

Outdoor Allergens
Outdoor allergens such as pollens and molds are impossible to avoid completely. Exposure may
be reduced by closing windows and doors, remaining indoors when pollen and mold counts are
highest, and using air conditioning if possible.
Indoor Air Pollutants
The most important measure in controlling indoor air pollutants is to avoid passive and active
smoking. Secondhand smoke increases the frequency and severity of symptoms in children with
asthma. Parents/ caregivers of children with asthma should be advised not to smoke and not to

allow smoking in rooms their children use. Other major indoor air pollutants include nitric oxide,
nitrogen oxides, carbon monoxide, carbon dioxide, sulfur dioxide, formaldehyde, and biological
(endotoxin)
Outdoor Air Pollutants
Several studies have suggested that outdoor pollutants aggravate asthma symptoms, possibly
having an additive effect with allergen exposure. Most epidemiological studies show a
significant association between air pollutantssuch as ozone, nitrogen oxides, acidic aerosols,
and particulate matterand symptoms or exacerbations of asthma. On occasion, certain weather
and atmospheric conditions, e.g., thunderstorms79 favor the development of asthma
exacerbations by a variety of mechanisms, including dust and pollution, increases in reparable
allergens, and changes in temperature/humidity. For patients with asthma that is difficult to
control, practical steps to take during unfavorable environmental conditions include avoiding
strenuous physical activity in cold weather, low humidity, or high air pollution; avoiding
smoking and smoke-filled rooms; and staying indoors in a climate-controlled environment.

Occupational Exposures
Occupational exposures account for a substantial proportion of adult asthma. Once a patient has
become sensitized to an occupational allergen, the level of exposure necessary to induce
symptoms may be extremely low, and resulting exacerbations become increasingly severe.
Food and Food Additives
Food allergy as an exacerbating factor for asthma is uncommon and occurs primarily in young
children. Sulfites (common food and drug preservatives found in such foods as processed
potatoes, shrimp, dried fruits, beer, and wine) have often been implicated in causing. Food
Avoidance should not be recommended until an allergy has been clearly demonstrated (usually
by oral challenges)
Drugs

Some medications can exacerbate asthma. Aspirin and other no steroidal anti-inflammatory drugs
can cause severe exacerbations and should be avoided in patients with a history of reacting to
these agents. Beta-blocker drugs administered orally or intraocular may exacerbate
bronchospasm. Data suggest that patients with asthma who receive newer more cardio-selective
beta blockers within 24 hours of hospital admission for an acute coronary event have lower in
hospital mortality rates.
Influenza Vaccination
Patients with moderate to severe asthma should be advised to receive an influenza vaccination
every year or at least when vaccination of the general population is advised. However, routine
influenza vaccination of children and adults90 with asthma does not appear to protect them from
asthma exacerbations or improve asthma control.
Obesity
Increases in body mass index have been associated with increased prevalence of asthma
Emotional Stress:
Extreme emotional expressions (laughing, crying, anger, or fear) can lead to hyperventilation and
hypocapnia, that can cause airway narrowing
Others:
Rhinitis, sinusitis, and polyposis are frequently associated with asthma and need to be treated. In
children, antibiotic treatment of bacterial sinusitis has been shown to reduce the severity of
asthma. Gastroesophageal reflux can exacerbate asthma, especially in children, and asthma
sometimes improves when the reflux is corrected

TREATMENT.
Pharmacotherapy is the cornerstone of asthma management, with appropriate
medication and delivery devices to meet patients needs and circumstances.When
asthma is first diagnosed, it is convenient for initiation of treatment to classify it as
mild intermittent or persistent asthma that is mild, moderate or severe. Asthma
severity assessment is used to initiate therapy, while asthma control is determined
to monitor and adjust therapy(75)

Table IV. Classification of asthma severity based on symptoms and PEF in patients
presenting for the first time on no(75)
treatment
Mild intermittent
Severe persistent

Mild persistent

Moderate persistent

Symptoms 2 days/week <2 days/week but Daily symptoms Continual symptoms


not daily
Night-time 2 incidents/month 3 - 4 incidents/month >1 incident/week Frequent
symptoms
but not nightly
PEF (predicted) 80% predicted 80% predicted >60 - 80% 60%
PEF variability <20% 20 - 30% >30% >30%

The goal of asthma treatment, to achieve and maintain clinical control can be reached with a
pharmacological intervention developed in partnership between the patient, family and the
doctor. Each patient is assigned one of five treatment steps depending on their current level of
control and treatment is adjusted by changes in their asthma control status.(107)
Treatment involves steps 1 to 5,provide options of increasing efficacy except for step 5 where
issues of availability and safety influence the selection of treatment. Step 2 is the initial treatment
for most treatment nave patients with persistent asthma symptoms, in case of severely
uncontrolled symptoms, treatment should be commenced at step 3.(108)
At each treatment step,(109) a reliever medication(rapid onset bronchodilator)should be provided
for quick relief of symptoms. However, regular use of reliever medication is one of the elements
defining uncontrolled asthma and indicates controller treatment should be increased. Thus
reducing the need for reliever medication is the measure of success of treatment. The steps are
described as below:(110)

STEP 1: AS NEEDED RELIEVER MEDICATION


Step 1 is reserved for untreated patients with occasional day time symptoms(cough, wheeze,
dyspnea occurring twice or less per week) of short duration(lasting for few hours).between
episodes, the patient is asymptomatic with normal lung function and there is no nocturnal
awakening. When symptoms are more frequent or worsen periodically, patients require regular
controller treatment in addition to as needed reliever medication.(111)
TREATMENT I N STEP 1:
For the majority of patients in step 1,(112, 113) rapid acting inhaled beta 2 agonist is the
recommended treatment. Alternatives are: An inhaled anticholinergic, short acting oral beta 2
agonist or short acting theophylline. The alternatives medications have a slower onset of action
and higher risk of side effects.
Physical

activity

is

an

important

cause

of

asthma

symptoms.

Exercise

induced

bronchoconstriction indicates that asthma in uncontrolled and stepping up of treatment is


required which results in reduction of exercise induced symptoms.(114) for those in whom
exercise induced bronchoconstriction is the only manifestation or if patient still experience
exercise induced symptoms in otherwise well controlled asthma, a rapid acting inhaled beta 2
agonists taken prior to exercise is recommended.(115)
Alternatives are: Leukotriene modifiers, Chromones.
STEP 2:RELIEVER MEDICATION PLUS A SINGLE CONTROLLER
Low dose inhaled steroid is recommended as the initial controller treatment for asthma patients
of all ages. Suitable alternatives are:(116)
Leukotriene modifiers
STEP 3:RELIEVER MEDICATION PLUS ONE OR TWO CONTROLLERS:
The recommended option for all ages of asthma is to combine a low dose inhaled steroid with an
inhaled long acting beta 2 agonist,(117) either in combination or as separate components. The
low dose steroid is usually sufficient and need only to be increased if control is not achieved

within 3 to 4 months of this regime. The use of a long acting beta 2 agonist as monotherapy
reliever medication is discouraged since it must always be used with an inhaled steroid.
Another option for both adults and children is to increase to a medium dose inhaled steroid. For
patients of all ages on medium or high dose of inhaled steroid, delivered by mdi, use of a spacer
device is recommended to improve delivery to the airways, reduce oropharayngeal side effects
and reduce systemic absorption.(117)
Another option is to combine low dose inhaled steroid with a Leukotriene modifier.(118)
STEP 4:RELIEVER MEDICATION PLUS 2 OR MORE CONTROLLERS:
The preferred treatment for step 4 is to combine medium or high dose inhaled steroid with a long
acting beta 2 agonist, the use of high dose instead of medium dose steroid is of little benefit and
the high dose is recommended on a trial basis for 3 to 6 months when control cannot be achieved
with a medium dose steroid with a LABA or a third controller(Leukotriene modifier or a
sustained release theophylline).(5)
Prolonged use of high dose steroid is associated with increase potential for adverse effects. At
medium and high dose steroid, twice daily dosing is necessary for most but not all inhaled
glucocorticosteroids. With budesonide, efficacy may be increased with more frequent
dosing(four times daily)
Leukotriene modifiers as add on treatment to medium or high dose steroid have been shown to
provide benefit but usually less than that achieved with the addition of LABA.
The addition of low dose sustained release theophylline to medium or high dose steroid and
LABA may also provide benefit.
STEP 5: RELIEVER MEDICATION PLUS ADDITIONAL CONTROLLER OPTIONS:
Addition of oral glucocorticosteroids to other controller medications may be effective but its
associated with severe side effects and should only be considered if the patients asthma remains
severely uncontrolled on step 4 medications with daily limitations of activities and frequent
exacerbations. Patients should be counseled about the side effects and all other alternative
treatments must be considered.(5)

When control is not achieved with additions of high doses of inhaled or oral
glucocorticosteroids, addition of anti IgE to other controller medications has been shown to
improve control of allergic asthma.(119)
DURATIONS AND ADJUSTMENT OF TREATMENT:
For most classes of controller medications, controlled may be achieved within days of treatment
but full benefit may be evident after 3 to 4 months.in severe and chronically untreated cases, this
may take even longer.(5)
The reduced need for medication, once asthma is fully controlled is not understandable but may
represent reversal of some of the consequences of long term inflammation. Higher dose of antiinflammatory medication is required for this and to maintain this for prolonged periods.
Alternatively, reduced need may also represent spontaneous improvement as part of the cyclical
natural history of asthma. Rarely asthma may go into remission in children 5 years and younger
and during puberty.(120) Whatever the explanation in all patients, the minimum controlling dose
of the treatment must be sought through a process of regular follow up and staged dose
reduction.
At other times, treatment may need to be increased at times of loss of control or threat of loss of
control or an acute exacerbation which requires urgent treatment.
STEPPIND DOWN TREATMENT WHEN ASTHMA IS CONTROLLED:
There is little experimental data on optimal timings sequence and magnitude of treatment
reductions in asthma and the approach will differ from patient to patient depending on the
combination and doses of medications that were needed to achieve control. These changes
should ideally be made by agreement between patient and health care professional with full
discussion of potential consequences including the reappearance of symptoms and increased risk
of exacerbations:
When inhaled glucocorticosteroid alone in medium to high doses are being used, a 50%
reduction in dose should be attempted at 3 months interval.(121)

When asthma is controlled with a combination of inhaled glucocorticosteroid and a LABA, the
preferred approach is to begin by reducing the dose on inhaled steroid by approximately 50%
while continuing the LABA.(122) If control is maintained,(123) further reduction in steroid dose
should be attempted until a low dose is reached when the LABA may be stopped. An alternative
is to switch the combination treatment to once daily dosing.(124) A second alternative is to
discontinue the LABA at an earlier stage and substitute the combination treatment with inhaled
steroid monotherapy at the same dose contained in the combination inhaker,however,this is more
likely to lead to loss of control.
When asthma is controlled with inhaled steroid in combination with controllers other than
LABA,(125) the dose of inhaled steroid should be reduced by 50% until a low dose of inhaled
steroid is reached, then the combination treatment stopped as described as above
Controller treatment may be stopped if the patients asthma remains controlled on the lowest
dose of inhaled glucocorticosteroids with no recurrence of symptoms for an year.
STEPPING UP TREATMENT IN RESPONSE TO LOSS OF CONTROL:
Treatment has to be adjusted periodically in response to worsening asthma control which may be
recognized by the minor recurrences or worsening of symptoms. Treatment options are as
follows:
Rapid onset,(126) short acting or long acting beta2 agonist bronchodilators. Repeated dosing
with bronchodilators in this class provides temporary relief until the cause of worsening
symptoms passes. The need for repeated doses over more than one or two days signals the need
for

review

and

possible

increase

of

controller

therapy. Combination

of

inhaled

glucocorticosteroids and rapid and long acting beta 2 agonist bronchodilator(e.g.,formeterol) for
combined relief and control.(127) The combination of rapid and long acting beta 2 agonist
(formeterol) and an inhaled glucocorticosteroid(budesonide) in a single inhaler both as an
effective controller and reliever is effective in maintaining a high level of asthma control and
reduces exacerbation requiring systemic steroids and hospitalization.(128)
DIFFICULT TO TREAT ASTHMA:

Although clinical benefit is seen in majority of patients with asthma, some patients will not do so
even with best therapy. Patients who do not reach an acceptable level of control at step 4 of
treatment is said to be having difficult to treat asthma. These patients may have an element of
poor steroid responsiveness and may require higher doses of inhaled steroid than is routinely
recommended to treat asthma. There is currently no evidence to support continuing these high
doses of inhaled steroid beyond 6 months. Instead dose optimization should be pursued by
stepping down to a dose that maintains maximal level of control achieved on higher dose.(129)
Because very few patients are completely resistant to steroids, they are the mainstay therapy of
difficult to treat asthma while other diagnostic and therapeutic options should be considered as
vocal cord dysfunction,(130) compliance should be investigated and confirmed, complete
cessation of smoking should be considered weather current or past, other comorbidities that may
aggravate asthma should be investigated e.g., chronic sinusitis, gastroesophageal reflux, obesity
and obstructive sleep apnea. These comorbidities have been reported in higher percentages in
patients with difficult to treat asthma.(131-133) When these reasons for the lack of treatment
responses have been considered and addressed, a compromised level of control is accepted and
discussed with the patient to avoid futile over treatment. The objective then is to minimize
exacerbations and need for emergency medical interventions while achieving as high a level of
clinical control with as little disruption of activities and as few daily symptoms as possible. For
these difficult to treat patients, frequent rescue medication is accepted, as is a degree of chronic
functional lung impairment
ASTHMATIC EXACERBATION:
For children, the American Academy of Pediatrics has defined an asthma exacerbation as an
abrupt and/or progressive worsening of symptoms of shortness of breath, wheezing, chest
tightness, or some combination of these. Associated respiratory distress with documented and
quantified decreases in expiratory airflow when measurements of lung function are obtained. The
most common triggers for asthma exacerbations in both younger and older children are viral
respiratory tract infections; other typical factors are exposure to allergens and a suboptimal
control of asthma as a baseline. Acute exacerbations are a frequent cause of emergency
department (ED) visits More than 50% of children who present to the ED with an asthma
exacerbation are preschool age (<5 years) . Rosychuk et al recently reported that in Alberta,

nearly 10% of the paediatric ED visits resulted in an admission to hospital, with one death for
every 25,000 ED visits.(134-136)
Assessing the child in respiratory distress from an acute asthma attack
Effective treatment depends on an accurate and rapid assessment of disease severity upon
presentation.(137)

TABLE
Classification of asthma severity(138-141)
Impending

Clinical

Mild

features

Moderate

Severe

respiratory
failure

Mental status

Normal

Might look

Usually agitated

agitated

Normal activity Decreased


Activity

and

exertional activity

dyspnea
Speech

Normal

or

confused

Decreased
or activity

feeding (infant)
Speaks

Drowsy

in

phrases

infant, Unable to eat

stops feeding
Speaks in words

Unable to speak

Significant

Marked

respiratory

respiratory

distress. Usually distress at rest.


all
Work
breathing

of

Minimal

Intercostal

intercostal

substernal

retractions

retractions

Loud

and

accessory All

muscles

muscles

involved,
may

accessory

and involved,
display including

nasal

nasal flaring and flaring

and

paradoxical

paradoxical

thoraco-

thoraco-

abdominal

abdominal

movement

movement

pan- Wheezes
and be

might

Chest

Moderate

expiratory

audible

auscultation

wheeze

inspiratory

without

wheeze

stethoscope

The
silent

chest

is

(absence

of wheeze)

SpO2 on room
air

>94%

9194%

<90%

TREATMENT:
The following treatment is institiuted to achieve rapid resolution of exacerbation
Oxygen:
To achieve arterial oxygen saturation of 95%,(142, 143) oxygen should be administered by nasal
cannula, by mask or rarely by head may box in some infants. PaCO2 worsen in some patients on
100% oxygen, especially with more severe airflow obstruction. Oxygen therapy should be
titrated against pulse oximetry to maintain satisfactory oxygen saturation.(144)
Rapid acting inhaled beta 2 agonists:
Rapid acting inhaled beta 2 agonists should be administered at regular intervals.(145) The closest
effective and efficient delivery is by MDI and a spacer device. Although most rapid acting beta 2
agonists have a short duration of effect .the long acting bronchodilator formoterol which has both
a rapid onset of action and long duration of effect,(146) has been shown to be equally effective
without increasing side effects, although it is considerably more expensive. A modestly greater
bronchodilator effect has been shown with levabuterol compared to racemic albuterol in both
children and adults with an asthma exacerbation.(147)
ADDITIONAL BRONCHODILATORS:
Ipratropium bromide:

The addition of nebulized beta 2 agonist to ipratropium bromide appears may produce better
bronchodilator than with either drug alone and should be administered before methylxanthines
are considered. Combination of beta 2 agonist and ipratropium bromide is associated with lower
hospitalization rates and greater improvement in lung functions. However once children with
asthma are hospitalized after intensive emergency department treatment, the addition of
nebulized ipratropium bromide to nebulized beta 2 agonist and systemic glucocorticosteroids
appears to confer no extra benefit.(148-151)
Theophyllines:
In view of safety and cost effectiveness of rapid acting beta 2 agonists, theophylline has a
minimal role in the management of acute asthma.(152) Its use is associated with severe and
potentially fatal side affects particularly those on sustained release theophyllines and there
bronchodilator effect is less than that of beta 2 agonist. However in one study of children with
near fatal asthma, IV theophylline provided greater benefit to patients also receiving aggressive
regime of inhaled and IV beta 2 agonist, inhaled ipratropium bromide and IV systemic
glucocorticosteroids.(146, 147, 153)
Systemic glucocorticosteroids:
Systemic glucocorticosteroids speed resolution of exacerbations and should be utilized in the all
but the mildest exacerbations especially if, the initial rapid acting beta 2 agonists fail to achieve
lasting improvement, the exacerbation develops even though the patient was already taking oral
glucocorticosteroids. Previous exacerbations require oral glucocorticosteroids.(5, 154, 155)
Oral steroids should are usually as effective as those administered IV and are preferred because
this route of delivery is less invasive and less expensive. If vomiting gas occurred, then
equivalent dose should be re-administered intravenously.in patients being discharged from the
emergency department, IM administration may be helpful especially if there are concerns about
compliance with oral therapy. Oral glucocorticosteroids require at least 4 hours producing
clinical improvement. Daily doses of system glucocorticosteroids equivalent to 60-80mg
methylprednisolone as a single dose or 300-400 mg hydrocortisone in divided doses are adequate
for hospitalized patients and 40 mg of methylprednisolone or 200 mg hydrocortisone is probably
adequate in most cases. An oral glucocorticosteroid dose of 1 mg/kg daily for 3-5 days is

adequate for treatment of exacerbations in children with mild persistent asthma. Two days of
oral dexamethasone can also be used to treat asthma exacerbations but there are concerns about
metabolic side effects if dexamethasone is continued beyond 2 days. Evidence suggests that there
is no need to taper the dose of oral steroids, either in the short term or over several weeks as
long as the patient is on the maintenance inhaled glucocorticosteroids.
Inhaled Steroids:
Inhaled steroids are effective as part of therapy for asthma exacerbations.in one study, the
combination of high dose inhaled glucocorticosteroids and salbutamol in acute asthma provided
greater bronchodilation than salbutamol alone and provide greater benefit than the addition of
systemic steroids across all parameters, including hospitalizations, especially patients with more
severe attacks. Inhaled steroids can be as effective as oral steroids in preventing relapses.
Patients discharged from the ED on prednisone and inhaled budesonide have a lower rate of
relapse than those on prednisone alone.
Magnesium:
IV magnesium sulphate (usually given as single 2g infusion given over 20 min)is not
recommended for routine use in asthma exacerbations but can reduce hospital admission rates in
certain patients including adults and children who fail to respond to initial treatment and
children whose FEV1 fails to improve above 60%predicted after 1 hour of care. Nebulized
salbutamol administered in isotonic magnesium sulphate provide greater benefit than if its
delivered in normal saline. IV magnesium sulphate has not been studied in young children.(156158)
Helium Oxygen Therapy:
A systematic survey of studies have evaluated that there is no role of helium oxygen compared to
helium alone.it might be considered for patients who do not respond to standard therapy.(159,
160)
Leukotriene Modifiers:
There is little data to suggest a role for leukotriene modifiers in acute asthma.(161)

Sedatives:
Sedation should be strictly avoided during exacerbations because of respiratory depressant effect
of anxiolytic and hypnotic drugs.(162)
PROGNOSIS

Although asthma clearly has been demonstrated to be associated with airway inflammation and
structural changes in adult patients,(163) the age when these changes begin in asthma has not yet
been defined precisely. Elevations in both inflammatory cells and mediators have been
demonstrated in bronchoalveolar lavage specimens obtained from preschool children who have
recurrent wheezing (Krawiec et al. 2001).(164) Recently, endobronchial biopsy specimens from
infants who have wheezing and documented airflow obstruction that was both reversible and
nonreversible following the administration of bronchodilator were compared to four other groups
of subjects: infants who had wheezing without airflow obstruction, school-aged children who
had difficult-to-control asthma, and both school-aged children and adults who did not have
asthma (Saglani et al. 2005).(165) In the infants who had wheezing, regardless of bronchodilator
reversibility or atopic status, the characteristic histopathologic features of thickening of the
laminar reticularis and eosinophil inflammation were absent. Taken together, these data indicate
that the airway inflammatory responses and structural changes that are characteristic of asthma
develop during the preschool years and may follow, and not precede, the physiologic changes
associated with asthma.(17) Among children 5 years of age and younger, the most common
cause of asthma symptoms is viral respiratory infection. At present, the relative contributions of
airway inflammation, bronchial smooth muscle abnormalities, or other structural factors in
producing wheeze with acute viral upper respiratory infections are unknown. Two general
patterns of illness appear in infants and children who have wheezing with acute viral upper
respiratory infections: a remission of symptoms in the preschool years and persistence of asthma
throughout childhood. No absolute markers are available to predict the prognosis of an individual
child; however, an asthma predictive index has been developed that identifies risk factors for
developing persistent asthma. Children under 3 years of age who had four or more episodes of
wheezing in the past year that lasted more than 1 day and affected sleep are significantly likely to
have persistent asthma after the age of 5 years if they also have either one of the following:
parental history of asthma, a physician diagnosis of atopic dermatitis, or evidence of sensitization

to aeroallergens, OR two of the following: evidence of sensitization to foods, 4 percent


peripheral blood eosinophilia, or wheezing apart from colds.(156)

DISCUSSION
Asthma is a major public health problem affecting 300 million individual worldwide.(17) It is
the leading cause of childhood hospitalizations and school absences despite recent advances in
management (166). Absence from school and days lost from school are reported as substantial
economic and social loss in Asia pacific region, India, Latin America, United Kingdom and
United States.(17) During the 6 month study period comparing the efficacy of inhaled steroid
with Montelukast,it was evident that the patients who were started treatment with inhaled
glucocorticosteroids had a significantly lower risk of experiencing an asthma-related
hospitalization or hospitalization/emergency department visit compared with montelukast. .As
shown in a previous study, fluticasone propionate, administered twice daily, significantly
reduced asthma exacerbations, asthma symptoms, and rescue medication use and was well
tolerated, with no clinically relevant systemic effects, as measured by growth velocity (167). IC
S was found to be superior than montelukast in nearly all measured outcomes (168) Montelukast
is a valid alternative to ICS especially in poorly compliant preschool children, or in subjects who
show adverse effects related to long-term steroid therapy (169). However, limited data is
available for age group 6 months to 5 years. Among 2400 patients selected for the study, of
which 1200 were prescribed inhaled corticosteroid and 1200 was given Montelukast. All selected
patients met the inclusion criteria, the patients who were put on inhaled steroids suffered less
frequent asthmatic exacerbations,less school days off and less nocturnal cough. Most of the
patients were in the age group 6 months to 2 years because of the more prevalence of non-atopic
asthma and transient wheezers in this age group. Wheeze of transient wheezers being primarily
triggered by respiratory syncytial virus infection.(170) however, their wheeze generally remit in
preschool years if its not accompanied by other risk factors of asthma like history of atopy or
parental allergies or history of allergic sensitization in any of the other sibs. These transient
wheezers have reduced airflow at birth, suggestive of narrowed airways which improve with
time.(63) The present study has suggested that asthma is more prevalent in males and the

previous work done revealed no consistent reasons for this sex-related difference. However, lung
size is smaller in males than in females at birth but larger in adulthood.(17) obesity is more
related to asthmatic episode, Obese people with asthma have lower lung function and more comorbidities compared with normal weight people with asthma.(17) Half of the patients met the
criteria for atopy with typical features of parental allergies and that in the sibs. This was the
group in which comprised of mostly the upper age limit of the study that is above 2 to 3 years.
They had the history of one or the other risk factor for asthma like exposure to smoke or humid
environment favoring the growth of fungus. Few patients had history of contact with pets at their
home. Early exposure to cat seems to increase the risk of sensitization to cat but not of asthma at
4 years of age. Dog ownership, on the other hand, appears to be associated with lowered risk of
sensitization to airborne allergens and asthma.(171) None of the patients had history of prenatal
exposure to smoke. Those who were breast fed had otherwise more protected from diarrheal
illnesses and other infections but in the context of my study, I didnt find a consistent protective
effect of breast feeding in the context of allergies. However, older studies demonstrated that early
breast feeding is associated with reduced asthmatic events,(172) in contrast to recent studies,
(173).Many of the patients had infantile eczema as a manifestation of atopic illness. Eczema was
twice as common in the PNC (19%) as in the asymptomatic children (10%).(174) Many of the
patients had Gastroesophageal reflux as risk factor of asthma (175). Wheeze is the most common
presenting complaint of every age group of my study, being more common in less than 1 year
because of compliant airways. Asthma is a heterogeneous condition with variable signs and
symptoms in patient groups (176) .Various asthmatic phenotypes is a challenge for the physician,
for differentiating it from other common infectious illnesses like tuberculosis and .most the
patients coming to Out Patient Department (OPD) with complaints of cough variant asthma are
misdiagnosed as Gastroesophageal reflux, postnasal drip, chronic sinusitis, and vocal cord
dysfunction. Cough variant asthma is an occult form of asthma of which the only sign or
symptom is chronic cough.(177) It is characterized as a persistent, nonproductive cough with
minimal or no wheezing and dyspnea and so the diagnosis is frequently overlooked(178).
Nocturnal cough is the most common and important symptom and an important marker of
uncontrolled bronchial asthma,(17) Many of the patients had complaints of nocturnal cough
before they get worse to exacerbation requiring systemic steroids. It is concluded from a study
that the clinical features of children with persistent nocturnal cough resembled those of the

asymptomatic population more closely than those of the polysymptomatic asthmatic population.
In this age group persistent nocturnal cough, in the absence of wheeze, shortness of breath or
tightness in the chest, is likely to be a manifestation of atypical or hidden asthma in only a
minority of cases.(179) Activity induced cough was also used as a marker of uncontrolled
asthma.(17)
Anti-leukotrienes agents are currently being studied as alternative first line agents to inhaled
corticosteroids in mild to moderate chronic asthma.Inhaled steroids at a dose of 400 mcg/day of
beclomethasone or equivalent are more effective than anti-leukotriene agents. Inhaled
glucocorticoids should remain the first line monotherapy for persistent asthma (180).
Teper et al. assessed the effect of fluticasone in children 620 months of age with recurrent
wheeze and risk factors (family history, atopy and decreased pulmonary function) for 6 months
(181).It was concluded from a study that ICS can be used to control active disease and to reduce
the burden of illness, but should not be used to prevent asthma in high-risk children (182) Early
intervention with inhaled budesonide is associated with improved asthma control and less
additional asthma medication use (81)
So,it is concluded that Inhaled glucocorticoids are very effective in controlling the symptoms of
asthma and in preventing exacerbations.The small risk of adverse effects at high doses of inhaled
glucocorticoids has to be set against the risks of not adequately controlling severe asthma. Since
the systemic absorption of inhaled glucocorticoids may be reduced by the use of spacer devices
with metered-dose inhalers and by mouth rinsing after the use of dry-powder inhalers, these
should be used whenever doses of 800 g per day or more are needed to control asthma(82).
Glucocorticoids may be administered either orally or, much more safely, by inhalation. Inhaled
glucocorticoids are equally effective in children, even younger ones. For example, nebulized
budesonide reduced the need for oral glucocorticoid therapy and also improved lung function in
children under the age of three years (82)
ANNEXURES:
There are two classifications of asthma,first on the initial visit and other assessing the clinical
control 4 to 6 weeks of the pharmacologic intervention. More recently, asthma control has been
introduced as a method to assess the adequacy of current treatment and inform asthma
management(183)
The initial classification

Asthma management plans depend on the severity of the asthmatic. Higher severity levels
warrant greater use of corticosteroids and prophylactic medications such as leukotriene inhibitors
and inhaled corticosteroids. The NIH guidelines categorizes severity levels into "steps" as
follows:
Step 1 (mild intermittent): Day symptoms two days per week or less and night symptoms two
nights per month or less. Chronic peak flow is 80% of expected or higher.
Step 2 (mild persistent): Day symptoms greater than two times per week, but less than once per
day or night symptoms greater than nights per month. Chronic peak flow is still 80% of expected
or higher.
Step 3 (moderate persistent): Day symptoms occur daily or night symptoms occur more than
once per week. Chronic peak flow is 60% to 80% of expected value.
Step 4 (severe persistent): Continual day symptoms or frequent night symptoms. Chronic peak
flow is less than or equal to 60% of expected value.
The use of peak flow in the above classification is not required in children 5 years and under.
Peak flow data is useful but not required for classification in older age groups, but most children
in this age range are capable of performing peak flows (12)

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