Comparison between Inhaled Corticosteroid and Montelukast in

Uncontrolled Asthma among the Children below 5 Years Age.

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 (1-3).
Asthma is the most common chronic disease in children(4). 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 (6).

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(7-9). Asthma is a condition characterized by
variable airflow obstruction, airway hyper-responsiveness (AHR) and airway
inflammation which is usually, but not invariably, eosinophilic (10, 11). 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(12, 13).
Asthma is the most common chronic disease in children in many low- and middle-income
countries (14). In these settings, the burden of childhood asthma is increasing and is associated

with severe disease because of many factors. 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(14).
The global prevalence of asthma ranges 118% of the population although it varies widely in
different countries (15). The WHO has estimated that 15 million disability-adjusted life-years
are lost annually due to asthma, representing 1% of the total global disease burden(16). Annual
worldwide deaths from asthma have been estimated at 250,000 and mortality does not appear to
correlate well with prevalence (17). 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 (18-20). 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(21-23). 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 utilization of healthcare resources and limitation of the earning capacity of the
individuals and families is an added problem (24, 25). 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 (26).
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(27) . Most asthmatics have hyperresponsive airways(6). This
makes them more sensitive than non-asthmatics to bronchoconstricting environmental exposures
which, in their turn, may enhance responsiveness(28). The main inducers of airway inflammation

are viral infections, antigens, occupational stimuli and pollutants(29). 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(30).This narrowing is
almost always reversible in children with treatment. 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 (31).Family history of atopy, maternal history of asthma, and the presence of smokers in the
house were risk factors for the manifestation of asthma(32-34). Early rhino viral wheezing is the
predictor of subsequent asthma development in high-risk children (35).
A clinical diagnosis of asthma is suggested by symptoms such as episodic breathlessness,
wheezing, cough and chest tightness (36). 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(37).
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(38). Interactions between
environmental and genetic factors result in airway inflammation leading to airway obstruction in
the form of bronchospasm, mucosal edema, and mucus plug (39). 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(40). The resulting over distention
helps maintain airway patency, thereby improving expiratory flow; however, it also alters
pulmonary mechanics and increases the work of breathing(41). 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 (42-44).
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. Asthma education is an essential part of the
treatment of this disease. The effective management of asthma implies effective partnership
between the patient and the health care providers (45). Asthma self-management education
improves patient -outcomes and can be cost effective(46). 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(47-50).

REVIEW OF LITERATURE
EPIDEMIOLOGY
Asthma is a common chronic disease of childhood which causes considerable morbidity. Asthma
affects 1 in 13 school-age children and is a leading cause of office and emergency department
visits, hospitalizations, and school absenteeism. Estimating the prevalence of asthma in the
community is important in assessing the impact of asthma at the level of population(3). The
prevalence of Asthma varies widely.
Asthma is now one of the most important diseases of childhood in developed countries. In the
International Study of Asthma and Allergies in Childhood (ISAAC) study, the highest asthma
prevalence was observed in westernized English-speaking countries (e.g., the United Kingdom,
Australia, and New Zealand), with much lower prevalence rates in Eastern Europe, India, China,
other countries in Asia, and Africa(51). Although there are considerable geographical differences
in its presentation, bronchial asthma is an illness in constant increase in the entire world(2). The
prevalence of asthma has gradually increased over the past 20 years in developed countries.
Westernization of way of life is associated with increased prevalence of atopy, allergic rhinitis
and asthma (52). In a landmark study signifying the effect of geography and life style conducted
in Chine showed Asthma symptoms in Chinese adolescents were lowest among residents of
mainland China, were greater for those in Hong Kong and those who had immigrated to Canada,
and were highest among those born in Canada. These findings suggest that environmental factors
and duration of exposure influence asthma prevalence (53). Similarly colleagues from Ecuador
have shown that the prevalence of asthma increases with increasing levels of urbanization in
transitional communities, and factors associated with greater socioeconomic level and changes

towards a more urban lifestyle may be particularly important(54). In Netherlands a "Western"

diet was found to increase the risk of frequent respiratory symptoms at 3 and 4 years of age (55).
Malmstorm from Finland showed that while the prevalence of mild and moderate asthma has
increased, the occurrence of severe asthma has remained essentially unchanged (56). In a
multicenter study noted the prevalence of childhood asthma and availability of indoor swimming
pools in Europe are linked to pool chlorine in the rise of childhood asthma in industrialized
countries(57).
In India the prevalence of Asthma was reported to be 2.4%(58). In another study conducted in
Tamil Nadu it was found that though the prevalence of diagnosed childhood asthma was about
5% in both urban and rural areas, the prevalence of 'breathing difficulty' and nocturnal cough was
significantly higher among urban children in the age group of 6-12 year(59). In another study
from rural India the prevalence of 10.7% in children of grade 7 and 8(60).
A study from Hong Kong quoted the prevalence of Asthma to be 11%(61). In Japan Tanaka and
other workers noted a prevalence of 7.6%(62). The highest prevalence of asthma was also
reported from Japan which was 25.6% in children aged 13-14 years. (63). In Taiwan Liao and
others found the prevalence of asthma was 7.0%(64). Another epidemiological study from
Taipei, Taiwan showed the prevalence of asthma to have risen from 1.30% in 1974 to 5.07% in
1985, with boys dominating in both studies(65). Moreover some studies have suggested
that a diet with a high intake of fat and simple sugars and low intake of fruit, vegetables and rice
is associated with an increased risk of asthma in Taiwanese children(66).Workers from Turkey
reported the prevalence of Asthma to be 1.9% (67). A Thai study showed the prevalence of
asthma to be 8.8(68). Workers from Siri Lanka showed the prevalence of asthma to be 17%(69).

However, recent studies have shown that the prevalence in Asia is increasing, although the rate
of increase has slowed in the more developed Asian cities(1).
In Iran a study found that the pooled prevalence for girls, boys, and the two genders was
obtained as 3.2% (CI; 2.5 to 3.9%), 4.3% (CI; 3.5 to 5.1%) and 3.9% (CI; 3.2 to 4.7%),
respectively(3).In Turkish Cyprus the prevalence of physician diagnosed asthma was 11.4%(70).
In the Turkish study conducted in Ankara the prevalence of asthma was 8.1%(71). In Edirine ,
Turkey prior physician diagnoses of asthma was 4.1% for preschool children(72). In Jordan the
prevalence of physician diagnosed asthma was 4.1%(73).Moreover it was found that the
prevalence among Bedouin children was more than city children(9.5% versus 8.8%)(74). The
prevalence of asthma in school age children age 13-14 years old was 13.7% in the state of Israel
(75). In a Lebanese study by Musharafae the prevalence of asthma was 8.1% (76). Behbehani
from Kuwait showed the prevalence of asthma to be 16.8% (77). In a Malaysian study the
prevalence of asthma was 8.3%(78). Even in a particular country, the prevalence of asthma
varies by race e.g. an English study showed that 18.2% of Black Caribbean children and 5.0% of
Bangladeshi children reported ever asthma compared with 11.6% of White children(79).
Colleagues from Norway concluded that lifetime prevalence of asthma was 20.2%; current
asthma 11.1%, doctor diagnosis of asthma 16.1% and wheezes ever 30.3%(80). The prevalence
of physician-diagnosed asthma was 9.5%, while 9.6% reported the use of asthma medicine (81).
Several large Swiss epidemiologic studies confirmed both, the high prevalence of

asthma(9.1%), and the health impact of moderate air pollution levels and of factors associated
with the 'western lifestyle'(82).
There are also gender differences in the prevalence of asthma. A study conducted in Taiwan
found that boys had significantly higher prevalence of wheezing and rhinitis than girls while

younger children tend to have higher prevalence of the disorders than those that are older in age
(83).

RISK FACTORS FOR DEVELOPING ASTHMA

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

factors and Host factors.
Precipitating factors
a) Allergens like food, animal, mold, spores, pollens, insects(84)
b) Drugs(85)
c) Irritants(47) like paint odors, sprays, perfumes, chemicals, smoke(86), cold air, cold
water and cough
d) Weather changes
e) Infection like viral, fungal (aspergillosis), bacterial (B. Pertussis), and parasitic
f)
g)
h)
i)
j)
k)

(Toxocara, ascariasis)(84)
Exercise (70 % of all asthmatics)(87)
Emotional factors(88)
Gastro esophageal reflux(89) - (Nocturnal Symptoms)
Allergic rhinitis(90)
Endocrine(91) - menstrual cycles, oral contraceptive pills and hyperthyroidism
Sinusitis(92) (Nocturnal symptoms)

Host factors
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 (93). Furthermore, interaction between susceptibility genes and
environmental factors is probable and is a challenge being pursued by investigators worldwide
(94, 95). 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 (96). 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(97, 98).

Obesity: Epidemiological data indicate that obesity increases the prevalence and incidence
of asthma (99). 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(100). Prevalence of asthma and overweight has
increased simultaneously during the past decades .Obesity is capable of reducing pulmonary
compliance, lung volumes, and the diameter of peripheral respiratory airways, and may
influence on airway hyperresponsiveness(101). 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 (102).

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 (103).
Allergens: Allergens, such as pollen, dust mites and animal fur or feathers, can trigger asthma in
children who are allergic to them(104). 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(105). 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. 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(106). 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(107).
Viral Infections: RSV, followed by the Para influenza viruses, is the chief cause of
hospitalization for respiratory tract illness in young children(108). 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. 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(109).
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 (110). 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% (111) .Heat
loss, water loss, post-exertional airway rewarming, and the role of several mediators have been
proposed as possible mechanisms responsible for the airway obstruction induced by exercise(30)
. 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 exerciseinduced 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 (112).

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(113). Increased consumption of linoleic acid, found in polyunsaturated fatty acids
(PUFAs), is thought to be linked to asthma, eczema and allergic rhinitis through increase in the
synthesis of prostaglandin-E2 (PGE2), resulting in allergic sensitization(114).

PATHOPHYSIOLOGY

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. Asthma is characterized by reversible airway obstruction,
airway hyperresponsiveness, and airway inflammation(115). 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(116). 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(117). Airway epithelial cells, smooth muscle cells, endothelial cells,
and fibroblasts are all capable of synthesizing and releasing inflammatory mediators acute
consequences

of

asthma

are

bronchoconstriction,

plasma

exudation,

and

mucus

hypersecretion(118). 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(118) . 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)

.The initial physiopathological event of inflammatory response in the production of "primary

cytokines", TNF-alpha, IL-1 and IL-6 by macrophages(119). These and other cytokines trigger
the progress and amplification of inflammatory process involving secondary mediators and
inflammatory cells (Th1/Th2-type cytokines)(120). When the amplification of inflammatory
process is excessive ("cytokines storm")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 anti-inflammatory mechanism
(121) . 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(122).
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, cellderived mediators influence smooth muscle tone and produce structural changes and remodeling
of the airway (123).
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(124). 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(125). 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(126). 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(127). The resulting over distention helps maintain airway
patency, thereby improving expiratory flow; however, it also alters pulmonary mechanics and
increases the work of breathing.
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(128).
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 (129). Treatment directed

toward reducing inflammation can reduce airway hyperresponsiveness and improve asthma
control.

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 (130). 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 mediatorshistamine, ECF, NCF, heparin, PAF) within 30 minutes (39). Arachidonic acid is formed through
the activation of phospholipase. From arachidonic acid, leukotrienes are formed via the
lipoxygenase pathway and prostaglandins via the cyclooxygenase pathway (131). 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)
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(132). 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(133). 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 cell-bound 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(134). 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(135).

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(136). 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(132).

Early-phase asthmatic reaction

Mast cells: The most crucial cell types in the EAR are mast cells. Mast cells are involved in the
pathophysiology of asthma through their capacity to secrete a wide variety of mediators after
activation by allergens(137). 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(130). 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. 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(138). 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(138). 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(139). These molecules have various effects in the asthmatic airway, e.g.
recruitment of inflammatory cells, bronchoconstriction and mucus secretion.
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(140).
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(141). 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(142).
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

up regulates endothelial and epithelial adhesion molecules, increases AHR, and has antitumor
effects (143). 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 (144). 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. 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 . In addition, numerous

studies show that treating asthma with corticosteroids reduces circulating and airway eosinophils
in parallel with clinical improvement(145).
Neutrophils: Neutrophils are increased in the airways and sputum of persons who have severe
asthma, during acute exacerbations, and in the presence of smoking(146). Their
pathophysiological role remains uncertain; they may be a determinant of a lack of response to
corticosteroid treatment (147).

The regulation of neutrophil recruitment, activation, and

alteration in lung function is still under study, but leukotriene B4 may contribute to these
processes.
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 (119).
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(126).
Epithelial Cells: Airway epithelium is another airway lining cell critically involved in asthma.
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(30).
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,

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

leukotrienes,

Leukotriene B and ADAM33(148).

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 (149).
The balance MMPs are thought to play a central role in between MMPs and TIMPs, which
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(150). MMPs are als o implicated in
alteration of angiogenesis and smooth muscle hyperplasia processes.
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(151). 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.
Chemokines: Among them, CCL2 is increased in asthma, 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(124). Other CC-chemokines, such
as CCL7 and CCL22 also contribute to the development of pulmonary fibrosis.
Endothelin 1: Endothelin (ET)-1 may be involved in airway remodeling: it is mitogenic for ASM
cells and fibroblasts, and also stimulates collagen synthesis (152).
Vascular Endothelial Growth Factor: vascular endothelial growth factors (VEGF) induce expression of
connective tissue growth factor and collagen (153). 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(148).
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. 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(154).

Prostaglandin E2 is also an important PG produced in inflammatory processes(155). It is the

most important bronchoprotective metabolite yet identified in the airways(156). 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(157).
Cysteinyl Leukotrienes: There is substantial evidence that cys-LTs (LTC4, LTD4 and LTE4)
play an important role in asthma(131). Cys-LTs mediate several steps in airway inflammation,
including inflammatory cell recruitment, vascular leakage and possibly also airway
remodeling(158). 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(159). ADAM33 has been linked to asthma in a study of 460 white families. Abnormal
activity of this gene can lead to altered airway function, inflammation, and remodeling(160).
Alterations in ADAM33 activity may underlie abnormalities in the function of ASM cells and
fibroblasts linked to airway remodeling and AHR.

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

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

Early asthmatic reaction

Mast cells

Histamine; proteases (tryptase, chymase, and

carboxypeptidase);

proteoglycans

(heparin,

chondroitin sulphate E); prostaglandins (PGD2);

leukotrienes (LTC4); cytokines (TNF- , IL-3, IL-4,
IL-5, IL-6, IL-8, IL-16, and GM-CSF); chemokines
(CCL2, CCL3, CCL11)
Basophils

Histamine; leukotrienes (cys-LTs: LTC4, LTD4,

LTE4); cytokines (IL-4, IL-13)

Late asthmatic reaction

Eosinophils

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)

Neutrophils

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
T cells

Cytokines (IL-3, IL-4, IL-5, IL-6, IL-9,

IL-10, IL-13, GM-CSF); chemokines
(CCL1, CCL22)

Macrophages

Cytokines (IL-1, IL-6, IFN- , TNF- );

chemokines (CXCL8); lipids; PAF;
ROS;

NO

Dendritic

cells

Chemokines (CCL2, CCL3, CCL4,

CCL17, CCL22, CXCL8)
Endothelial cells

ICAM-1, ICAM-2; PECAM-1; VCAM-1; selectins (Eselectin, P-selectin)

Airway smooth muscle cells

Chemokines (CCL5, CCL7, CCL11, CCL13, CXCL8);

cytokines (GM-CSF, IL-6); prostaglandins (PGE2); ECM
proteins

Bronchial epithelial cells

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(36). Intermittent dry coughing and expiratory wheezing are
the most common chronic symptoms of asthma(161). Younger children are more likely to report
intermittent, non-focal chest pain(162). 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. 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(163) . A
clinician should consider asthma if the child has physical activity induced cough or
wheeze(164) . A useful method for confirming the diagnosis of asthma in children aged 5years
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(165).
Respiratory symptoms that begin at or persist through ages 3 to 4 years are highly diagnostic of
asthma. 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(166) . Children with cough variant asthma do not wheeze .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 (167).

Three categories of wheezing have been described in children 5 years and younger.
Transient Early Wheezing outgrows in the first three years. This is often associated with
prematurity and parental smoking(168).
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 (169, 170). The symptoms normally persist through school age and
sometimes till the age of 12. 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(171).
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 (170).
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.
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. Rapid improvement of symptoms after inhaled beta 2 agonist use supports
the diagnosis of asthma(110).
Differential Diagnoses

Table 1.Differential diagnosis

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

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(172).

A trial of treatment with short-acting bronchodilators and inhaled

glucocorticosteroids with marked clinical improvement supports the diagnosis of asthma

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(173). The degree of reversibility in forced expiratory volume in one
second (FEV1) that indicates a diagnosis of asthma is generally accepted as 12% and 200 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
expiratory maneuver, feasible in children >6 years of age. If the FEV 1 (forced expiratory volume
in 1 sec) is within 5 % on 3 attempts, then the highest FEV 1 effort of the three is used(174).
Generally an FEV1/FVC ratio < 0.80 indicates significant airflow obstruction(175). 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

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 (174).
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(176).
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(177).
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 (178). It has been also
proposed that adjusting anti-inflammatory drugs guided by the monitoring of exhaled NO, could
improve overall asthma control(179).

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(180).
Physical Examination:
The most usual abnormal physical finding is wheezing on auscultation(181). During asthma
exacerbations, expiratory wheezing and a prolonged expiratory phase is heard on auscultation
(182). Decreased breath sounds in some of the lung fields, indicate areas of hypoventilation due
to obstruction(180). 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(183). In extreme cases, airflow may be so limited
that wheezing cannot be heard.
Radiology:
The 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 (184). 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 (109).

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) (185)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. 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(171). 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)
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
(186). 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 goal of asthma treatment is to achieve and maintain clinical control. Medications to treat
asthma can be classified as controllers or relievers (187). Controllers are medications taken daily
on a long term basis to keep asthma under clinical control chiefly through their antiinflammatory 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 (22, 188). Relievers are used on an as needed basis
to quickly reverse bronchoconstriction and relieve symptoms.

The most commonly used

relievers are inhaled short-acting beta agonists and short acting oral beta 2.(189)

Table 2: Levels of Asthma Control.

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

CONTROLLED
(all

of

UNCONTROLLED

the CONTROLLED(any

following)
Day time symptoms

PARTLY

measure in any week)

NONE(less

ASTHMA(3

more

features in any week)

than More than twice per More

twice per week week(lasting

or

than twice per

for week(lasting for hours or

lasting

for minutes and rapidly recur or partly relieved by

minutes

and relieved

rapidly

by

short short

relieved acting

acting

bronchodilators)

by short acting bronchodilators)

bronchodilators)
Nocturnal symptoms

NONE(no
nocturnal

ANY(may

cough during sleep or wakes sleep or wakes with cough

during sleep)
Limitations

cough ANY(may cough during

of NONE(fully

with cough or wheeze) or wheeze)

ANY(cough,

wheeze ANY(cough,

wheeze

or

activities

active child: plays or difficult breathing difficult breathing during

and runs without during vigorous play, vigorous play, laughing

Need

for

reliever

symptoms)

laughing)

2 d per week

More than 2 days per More than 2 days per week

medication

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

ROUTES OF ADMINSTRATION:

Asthma treatment can be administered in a variety of ways: inhaled, orally or parenterally (by
subcutaneous, intravenous and intramuscular routes) (188, 190) .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.
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(189) .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 (191). 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 (189). Nebulizers 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 .

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
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 (192) .Duration of treatment should continue till bronchial hyperresponsiveness improves (193). 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(194). 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), and mild disease is well controlled by such doses in the majority
of patients(192). 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(195) .Early intervention with inhaled budesonide is associated with improved asthma
control and less additional asthma medication use . Nebulized budesonide reduced the need for

oral glucocorticoid therapy and also improved lung function in children under the age of three
years (196) . 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 recognized poor
adherence to treatment with inhaled glucocorticosteroids, many patients will require higher doses
to achieve full therapeutic benefit(197) . 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 (198).
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.(199) This fraction is
markedly reduced if the glucocorticoid is administered through a large-volume spacer attached to
a metered-dose inhaler.

Corticosteroid Trade
name

Children (6 to 11 years of age)

Adults (12 years of

age and over)

Beclomethasone
dipropionate

200 201400

>400

HFA

QVAR

Inhaled corticosteroid (ICS) dosing categories in children and adults

Low

Medium

High

Low

250 251500

Medium

High

>500

Budesonide* Pulmicort Turbuhaler

400 401800

>800 400 401800

>800
Ciclesonide* Alvesco
Fluticasone

200 201400

>400 200 201400

Flovent MDI and spacer; Flovent Diskus

251500

>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.

Growth: Asthma and its level of control may directly affect growth in the same way as
most chronic diseases of childhood. Continuous administration of ICSs in low to medium
dose over many years is well tolerated. . Low doses do not have clinically deleterious
side effects on the bones, growth, eye, or hypothalamo-pituitary-adrenal-axis(200).
However, they do not normalize lung function and prevent structural changes in the
airway wall in all asthmatic patients (201). 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(202) . 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
prednisone like activity from the systemic bioavailable dose(203). The use of a large
spacer device has been shown to reduce the incidence of both topical and systemic
adverse effects from inhaled steroids (202). Height measurements made over a period of
less than 1 year are liable to error and misinterpretation. 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 (204). Ultimately, there is no decrease in attained adult
height, though it is reached at a later age than normal (205). 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(206) . 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 (205).

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

concluded that inhaled steroids are well tolerated, with little or no effect on growth and
hypothalamic-pituitary-adrenal axis function(200). Thus it is a valuable therapeutic
alternative to systemic corticosteroid therapy in infants and young children. With
sensitive techniques, dose-dependent adrenal suppression has been documented in
children treated with inhaled steroids but generally this effect has no clinical relevance
(207). Most children develop biochemical evidence of adrenal suppression after treatment
with medium to high doses of ICS(208). 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 (204). Low doses do not have clinically deleterious side effects on
the bones, growth, eye, or hypothalamo-pituitary-adrenal-axis (209). However, they do
not normalize lung function and prevent structural changes in the airway wall in all
asthmatic patients. 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(210) .Oral Corticosteroids(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(211). 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.
Cataracts. Long-term administration of medium dose ICSs does not increase the risk of
cataracts or osteopenia in children and young adults (212) .

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

psychiatric disturbance including emotional lability, euphoria, depression,
aggressiveness, and insomnia inhaled corticosteroids are not associated with any
adverse effects(207).

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(213). Spacers reduce
the incidence of oral candidiasis. The use of spacer devices and mouth rinsing may
reduce local and systemic adverse effects.

Dental side effects. Recent studies have provided little evidence for asthma caries
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 (214) .

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(215).

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.

\
Leukotriene modifiers.
The leukotrienes are potent inflammatory mediators in asthma and contribute to increased mucus
production, bronchoconstriction and eosinophil infiltration(216). These compounds are produced
via the lipoxygenase pathway by mast cells, eosinophils and alveolar macrophages
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(217). 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(218).
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
glucocorticosteroids(219).
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(218). Leukotriene
modifiers provide partial protection against exercise-induced bronchoconstriction within hours
after administration with no loss of bronchoprotective effect.
LTRAs have been proposed as alternative first-line therapy to ICSs for episodic or mild
persistent asthma who have difficulty in utilizing inhalation treatment, with poor compliance, or
where exercise-induced bronchospasm (EIB) is a dominant component of asthma(220, 221) .
LTRAs are approved for treatment of both allergic rhinitis and asthma (222).
Side effects: No safety concerns have been demonstrated from the use of leukotriene modifiers in
children .
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(223). Monotherapy with
long acting inhaled 2-agonists should be avoided(165). 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(42). 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 (224).

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(225).
Side effects: Long acting inhaled beta 2 agonists are not the recommended option when more
than one controller is required(42). 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 (226).
THEOPHYLLINE: 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(227).
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(227, 228).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)(229).

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(230). 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(231). Mild central nervous stimulation, palpitations, tachycardia, arrhythmias,
abdominal pain, diarrhea, and, rarely, gastric bleeding may also occur(232). 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 (233). A one-year study
evaluated 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)(234). 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(235). 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(42).
Side effects: Drug-related adverse events in anti-IgE treated patients are mild to moderate in
severity and include urticaria, rash, flushing, and pruritus(236).
Cromones: sodium cromoglycate and nedocromil sodium. Sodium cromoglycate and
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(237). Studies of the use of these
medications in children 5 years and younger are sparse and results are conflicting(238, 239).
Side effects Cough, throat irritation, and bronchoconstriction occur in a small proportion of
patients treated with sodium cromoglycate(240). 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(241). 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 (242, 243).

Reliever Medications
Rapid-acting inhaled 2-agonists and short-acting oral 2- agonists.
Rapid-acting inhaled 2-agonistss are the most effective bronchodilators available and therefore
the preferred treatment for acute asthma in children of all ages(244). The inhaled route results in
more rapid bronchodilation at a lower dose and with fewer side effects than oral or intravenous

administration. Furthermore, inhaled therapy offers significant protection against exerciseinduced bronchoconstriction and other challenges for 0.5 to 2 hours (long-acting 2-agonists
offer longer protection)(245). This is not seen after systemic administration. 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 : Inhaled anticholinergics are not recommended for long-term management of
asthma in children(246).

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
(171). 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 (247):
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(248).
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(14). 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(249).
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

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(250). 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(251). 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(252). 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(253). 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
(254). 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(255).

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(197). Patient concern about side-effects of inhaled
glucocorticosteroids whether real or perceived may influence adherence. Specific drug and nondrug 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(253). For children, symptom-based action plans are more effective
than those based on peak flows(256).

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 (257).
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(258). Exclusive breastfeeding during the first months after birth is associated with
lower asthma rates during childhood (259, 260).
Exposure to cats has been shown to reduce risk of atopy in some studies(261).
Exposure to tobacco smoke both prenatally and postnatally is associated with measurable
harmful effects, including effects on lung development

and a greater risk of developing

wheezing illnesses in childhood(262). Passive smoking increases the risk of allergic sensitization
in children(263). Both prenatal and postnatal maternal smoking is problematic(264). 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(265). In the case of other factors (e.g., allergens, viral infections and
pollutants), measures where possible should be taken to avoid these (266). 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 (267).

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 problem(268). Since mites live and
thrive in many sites throughout the house, they are difficult to reduce and impossible to
eradicate(269). 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 schools, public
transportation, and cat-free buildings(270). 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
(271).
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 (272). 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 (273). 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 (274). 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)(275).
Outdoor Air Pollutants
Several studies have suggested that outdoor pollutants aggravate asthma symptoms, possibly
having an additive effect with allergen exposure (276). Most epidemiological studies show a
significant association between air pollutantssuch as ozone, nitrogen oxides, acidic aerosols,
and particulate matterand symptoms or exacerbations of asthma(277). On occasion, certain
weather and atmospheric conditions, e.g., thunderstorms 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(278).

Occupational Exposures
Occupational exposures account for a substantial proportion of adult asthma(279). 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(280).
Food and Food Additives
Food allergy as an exacerbating factor for asthma is uncommon and occurs primarily in young
children(281). 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
asthma(282). 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(283). Beta-blocker drugs administered orally or intraocular may exacerbate
bronchospasm(284).
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(285). However,
routine influenza vaccination of children and adults with asthma does not appear to protect them
from asthma exacerbations or improve asthma control(286).
Obesity

Increases in body mass index have been associated with increased prevalence of asthma(287)
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(288). 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.

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

Mild persistent

Moderate persistent

Severe 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%

Treatment involves steps 1 to 5(289); 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(290), in case of
severely uncontrolled symptoms, treatment should be commenced at step 3.
At each treatment step, 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(291). Thus
reducing the need for reliever medication is the measure of success of treatment. The steps are
described as below:
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.

TREATMENT I N STEP 1:
For the majority of patients in step 1, 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. 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.
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:
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, 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.
Another option is to combine low dose inhaled steroid with a Leukotriene modifier.
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).
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(225).

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.
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.
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.
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. 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.
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. If control is maintained, 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. 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, 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, 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. 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.
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.
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, 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. 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.
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.

TABLE
Classification of asthma severity
Impending
Clinical
Mild

Moderate

Severe

respiratory

features
failure
Might
Mental status

look

Normal

Drowsy

agitated

confused

Normal activity Decreased

Activity

and

exertional activity

dyspnea

Decreased
or activity

feeding (infant)
Speaks

Speech

or

Usually agitated

Normal

infant, Unable to eat

stops feeding

in
Speaks in words

Unable to speak

phrases
Work
breathing

of Minimal

Intercostal

and Significant

Marked

intercostal

substernal

respiratory

retractions

retractions

distress. Usually distress at rest.

respiratory

all

accessory All

muscles

muscles

involved,
may

accessory

and involved,
display including

nasal

nasal flaring and flaring

Loud

paradoxical

paradoxical

thoraco-

thoraco-

abdominal

abdominal

movement

movement

pan- Wheezes

might
The

Chest

Moderate

expiratory

and be

wheeze

chest

inspiratory

without

wheeze

stethoscope

(absence

of wheeze)
SpO2 on room
>94%

9194%

is

audible
silent

auscultation

and

<90%

air

TREATMENT:
The following treatment is institiuted to achieve rapid resolution of exacerbation

Oxygen:
To achieve arterial oxygen saturation of 95%, 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.
Rapid acting inhaled beta 2 agonists:
Rapid acting inhaled beta 2 agonists should be administered at regular intervals. 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, 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.
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.
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. 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.
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.
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.
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.
Leukotriene Modifiers:
There is little data to suggest a role for leukotriene modifiers in acute asthma.
Sedatives:
Sedation should be strictly avoided during exacerbations because of respiratory depressant effect
of anxiolytic and hypnotic drugs.
PROGNOSIS

Although asthma clearly has been demonstrated to be associated with airway inflammation and
structural changes in adult patients, 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). 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 difficultto-control asthma, and both school-aged children and adults who did not have asthma (Saglani et
al. 2005). 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. 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.

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
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

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