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Comparison between Inhaled Corticosteroid and Montelukast in

Uncontrolled Asthma among the Children below 5 Years Age.

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).


patients with symptoms consistent with asthma, but normal lung function,







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 1–18% 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 child’s 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 patient’s 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).

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
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).

1%(71).6% of White children(79).1% and wheezes ever 30. Turkey prior physician diagnoses of asthma was 4. Colleagues from Norway concluded that lifetime prevalence of asthma was 20.1%(73). Even in a particular country.1%). In Jordan the prevalence of physician diagnosed asthma was 4. recent studies have shown that the prevalence in Asia is increasing. Several large Swiss epidemiologic studies confirmed both. There are also gender differences in the prevalence of asthma.3%(80). boys.5%.2%. and the health impact of moderate air pollution levels and of factors associated with the 'western lifestyle'(82).g.8%)(74).However. while 9. In a Malaysian study the prevalence of asthma was 8.7% in the state of Israel (75).1% for preschool children(72).7%).1% (76).5 to 3. current asthma 11.0% of Bangladeshi children reported ever asthma compared with 11. The prevalence of asthma in school age children age 13-14 years old was 13. an English study showed that 18.8% (77). In a Lebanese study by Musharafae the prevalence of asthma was 8. In the Turkish study conducted in Ankara the prevalence of asthma was 8.In Turkish Cyprus the prevalence of physician diagnosed asthma was 11. and the two genders was obtained as 3.2% (CI.1%) and 3. 2.3% (CI.4%(70).3%(78). 3.2 to 4. although the rate of increase has slowed in the more developed Asian cities(1).5 to 5. In Edirine . The prevalence of physician-diagnosed asthma was 9. doctor diagnosis of asthma 16. Behbehani from Kuwait showed the prevalence of asthma to be 16.2% of Black Caribbean children and 5. 4.9% (CI.Moreover it was found that the prevalence among Bedouin children was more than city children(9. A study conducted in Taiwan found that boys had significantly higher prevalence of wheezing and rhinitis than girls while .1%. the prevalence of asthma varies by race e.6% reported the use of asthma medicine (81). the high prevalence of asthma(9.5% versus 8.9%). respectively(3). In Iran a study found that the pooled prevalence for girls. 3.

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

animal. 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. 98). insects(84) b) Drugs(85) c) Irritants(47) like paint odors. The most consistently replicated regions are on chromosomes 2q. chemicals. which is attributable in part to genetic variation(97. 5q.(Nocturnal Symptoms) Allergic rhinitis(90) Endocrine(91) . Similarly. Furthermore. perfumes. mold. interaction between susceptibility genes and environmental factors is probable and is a challenge being pursued by investigators worldwide (94. inhaled corticosteroids and leukotriene modifiers. cold air. Precipitating factors a) Allergens like food. Patient response to the asthma drug classes. Pertussis). fungal (aspergillosis). and chromosomal regions likely to harbor asthma currently susceptibility genes have been replicated in several studies (93). . and parasitic f) g) h) i) j) k) (Toxocara. sprays. 95). 12q and 13q (96). ascariasis)(84) Exercise (70 % of all asthmatics)(87) Emotional factors(88) Gastro esophageal reflux(89) . bronchodilators.menstrual cycles. cold water and cough d) Weather changes e) Infection like viral.RISK FACTORS FOR DEVELOPING ASTHMA Factors influencing Development and Expression Of Asthma can be classified as precipitating factors and Host factors. spores. smoke(86). bacterial (B. are characterized by a large degree of heterogeneity. 6p. Family studies have identified a number of chromosomal regions associated with asthma susceptibility. pollens.

such as cigarette smoke.Obesity: Epidemiological data indicate that obesity increases the prevalence and incidence of asthma (99). Food and drinks that are high in sulphites include concentrated fruit juice. and the diameter of peripheral respiratory airways. Prevalence of asthma and overweight has increased simultaneously during the past decades . Indoor conditions. chemokines and adipokines (102). child’s age and possibly genetics. It depends on the allergen. the dose. chemical fumes and atmospheric pollution may trigger asthma. However. may trigger asthma(105). time of exposure. prawns and many processed or pre- . jam. it is known as anaphylaxis. A child with a food allergy may have an asthma attack as part of an allergic reaction to a food(106). the relationship between the allergen exposure and sensitization is not straight forward. and these obesity-related factors appear to exert an additive effect to the asthma-related changes seen in the airways(100). Some children have allergies to nuts or other foods. 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). which produces a rise in the serum concentrations of several pro-inflammatory cytokines. The increase of adipose tissue in obese subjects leads to a systemic inflammatory state.Obesity is capable of reducing pulmonary compliance.sulphites are naturally occurring substances found in some food and drink. lung volumes. Airborne irritants. Foods containing sulphites . Sex: Male sex is a risk factor for asthma. and may influence on airway hyperresponsiveness(101). can trigger asthma in children who are allergic to them(104). dust mites and animal fur or feathers. such as mold or damp and occasionally chemicals in carpets and flooring materials. Obesity results in important changes to the mechanical properties of the respiratory system. They are also sometimes used as a food preservative. When this is severe. Allergens: Allergens. such as pollen.

because of the high levels of physical activity in the childhood (110). which includes aspirin and ibuprofen.cooked meals. holding one's breath and hyperventilating. post-exertional airway rewarming. Para influenza virus affects the respiratory tract in children. Viral Infections: RSV. The kind of physical activities that can bring on asthma symptoms include not only exercise. followed by the Para influenza viruses. The symptoms of exerciseinduced asthma usually go away within a few hours. a child with exercise-induced asthma does not need to limit his or her overall physical activity (112). crying. but also laughing. occasionally trigger asthma in children(107). water loss. With proper treatment. sometimes causing bronchitis (inflammation of the bronchi) or pneumonia. is the chief cause of hospitalization for respiratory tract illness in young children(108). 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). and this is a common problem. and the role of several mediators have been proposed as possible mechanisms responsible for the airway obstruction induced by exercise(30) . Some types of viral infections can also trigger asthma.Heat loss. . 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) . even in case of controlled asthma. Medicines. Exercise: Exercise-induced bronchoconstriction (EIB) has a high prevalence in children with asthma. Most children with asthma will not have this trigger. such as the class of painkillers called non-steroidal anti-inflammatory drugs (NSAIDs).

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

macrophages. smooth muscle cells. These include mast cells. with chronic inflammation inducing structural changes or remodeling(116). hyperplasia of mucus-secreting cells. but also endotoxin or allergen exposure. endothelial cells. asthma was recognized also as an inflammatory disease. airway hyperresponsiveness. and airway inflammation(115). neutrophils. Together. T lymphocytes. these inflammatory mediators are responsible for the diffuse bronchial inflammation. are able to recruit neutrophils. and fibroblasts are all capable of synthesizing and releasing inflammatory mediators acute consequences of asthma are bronchoconstriction. Airway epithelial cells. basophils. IL-8. and new vessel formation (angiogenesis) . increased thickness of the airway smooth muscle layer (hyperplasia and hypertrophy). In a second step. Viruses. and platelets(117).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. Asthma is a complex chronic inflammatory disease of the airways that involves the activation of many inflammatory and structural cells. which involve large and small airways(118) . Inflammatory cells. via an IL-8 production by activated macrophages or epithelial 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. The first mechanism identified as important for asthma was bronchial hyperresponsiveness. dendritic cells. such as fibrosis (particularly under the epithelium). and of proinflammatory mediators. eosinophils. plasma exudation. all of which release inflammatory mediators that result in the typical pathophysiological changes of asthma. and mucus hypersecretion(118). This chronic inflammation may result in structural changes in the airway.

g. contribute to the chronicity of the disease. Other constituent airway cells. 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. Finally. TNF-alpha. TNF-alpha. which are critical in cellular defense .The initial physiopathological event of inflammatory response in the production of "primary cytokines". smooth muscle hyperplasia. Other factors. endothelial cells. IL-1 and IL-6 can act on hypothalamus-hypophisis-surrenal axis and. integrins). Two types of Th lymphocytes have been characterized: Th1 and Th2(124). and epithelial cells. IL-1 and IL-6 by macrophages(119). 2) inflammatory damage of restricted areas (organ pathology). Th1 cells produce interleukin (IL)-2 and IFN-α. mucus hypersecretion..R. Airway inflammation in asthma may represent a loss of normal balance between two "opposing" populations of Th lymphocytes. can determine a negative feedback on the cytokines gene expression and a physiological anti-inflammatory mechanism (121) . epithelial cells. cellderived mediators influence smooth muscle tone and produce structural changes and remodeling of the airway (123). eosinophils. desquamation of the epithelium. and airway remodeling are present. such as adhesion molecules (e. T lymphocytes play an important role in the regulation of airway inflammation through the release of numerous cytokines(122).). through cortisol release. macrophages. Varying degrees of mononuclear cell and eosinophil infiltration.I. and activated T lymphocytes. These and other cytokines trigger the progress and amplification of inflammatory process involving secondary mediators and inflammatory cells (Th1/Th2-type cytokines)(120).S. selectins. are critical in directing the inflammatory changes in the airway. Some of the principal cells identified in airway inflammation include mast cells. such as fibroblasts.

IL5. 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. but not necessarily unique. Airway remodeling is associated with structural changes due to long-standing inflammation and may profoundly affect the extent of reversibility of airway obstruction(126). IL-9. inflammation appears to be a major factor in determining the degree of airway hyper responsiveness (129). it also alters pulmonary mechanics and increases the work of breathing. Airflow Obstruction: Airflow obstruction can be caused by a variety of changes. generates a family of cytokines (IL-4. Treatment directed . including acute bronchoconstriction.mechanisms in response to infection. airway edema. feature of asthma. IL-6. The mechanisms influencing airway hyperresponsiveness are multiple and include inflammation. Th2. These changes lead to a decreased ability to expel air and may result in hyperinflation(127). and structural changes. The degree to which airway hyperresponsiveness can be defined by contractile responses to challenges with methacholine correlates with the clinical severity of asthma(128). thereby improving expiratory flow. in contrast. Chronic mucous plug formation consists of an exudate of serum proteins and cell debris that may take weeks to resolve. dysfunctional neuro-regulation. Airway obstruction causes increased resistance to airflow and decreased expiratory flow rates. and airway remodeling. however. chronic mucous plug formation. and IL-13) that can mediate allergic inflammation. The resulting over distention helps maintain airway patency. Airway Hyperresponsiveness: Airway hyperresponsiveness—an exaggerated bronchoconstrictor response to a wide variety of stimuli—is a major.

2007 Aug. Definition. and Natural History of Asthma Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. which are present on the surface of the respiratory tract. National Asthma Education and Prevention Program. . Antigens attaches to surface IgE on sensitized mast cells resulting in activation of mast cells and a cascade of biochemical reactions. Figure 1: The Interplay and Interaction Between Airway Inflammation And The Clinical Symptoms And Pathophysiology Of Asthma. From: Section 2. Pathophysiology and Pathogenesis of Asthma.toward reducing inflammation can reduce airway hyperresponsiveness and improve asthma control. and Blood Institute (US). These IgE antibodies have become reversibly fixed to the surface receptors of mast cells and basophils (130). Third Expert Panel on the Diagnosis and Management of Asthma. Steps at Cellular Level: IgE antibodies are synthesized by the plasma cells. Bethesda (MD): National Heart. Lung.

which develops 6 to 8 hours after the exposure to allergen.This results in degranulation and release of preformed mediators (early phase mediatorshistamine. Arachidonic acid is formed through the activation of phospholipase. leukotrienes are formed via the lipoxygenase pathway and prostaglandins via the cyclooxygenase pathway (131).specific T and B cells. allergens cross-link to mast cell. thus causing the activation of membrane and cytosolic pathways. After re-exposure. the synthesis of prostaglandins (PGs) and leukotrienes (LTs).E4 collectively called slow releasing substances of anaphylaxis) The development of allergic asthma exists of three phases. Inhaled allergens that escape the mucociliary clearance are taken up and processed by antigen presenting cells (APCs). These late phase mediators are responsible for the late reaction. Crucial in the development of airway inflammation in allergic asthma is the allergic cascade(132). Interactions between those cells elicit responses that are characterized and influenced by secreted cytokines and the presence or absence of cell-bound costimulatory molecules.bound specific IgE.D4. Activation of T helper (Th) cells by APCs leads to the production of cytokines that regulate the iso. and . which subsequently trigger the release of preformed mediators. Once synthesized. such as histamine. PAF) within 30 minutes (39). heparin. These APCs then migrate to the draining lymph nodes where the processed allergen is presented to allergen. from the nasal mucosa to the lung pleura(133). the early-phase asthmatic reaction (EAR) and the late-phase asthmatic reaction (LAR). NCF. 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. Each phase is characterized by the production and interplay of various cell-derived mediators. ECF.type switch of B cells in their production of IgE(134). From arachidonic acid. which are distributed throughout the respiratory tract.(LEUKOTRIENES C4. namely the induction phase.

Figure 2: Factors Limiting Airflow In Acute And Persistent Asthma. which is characterized by constriction of ASM cells. This EAR is immediate. resulting in structural changes. enhanced AHR and recruitment of inflammatory cells. vascular leakage. including airway wall thickening. ASM cell hyperplasia and hypertrophy.broblast hyperplasia.the transcription of cytokines by mast cells. . goblet cell hyperplasia. and epithelial hypertrophy. lasting 30–60 min and 4–6 h later followed by the LAR. mucus production. The late-phase is characterized by excessive inflammation of the airways. These mediators cause the so-called EAR. This is collectively known as airway remodeling(135). myofi. subepithelial fibrosis.

g. Together with IL-9. National Asthma Education and Prevention Program. Mast cells are involved in the pathophysiology of asthma through their capacity to secrete a wide variety of mediators after activation by allergens(137). Of these. IL-9. they are also important in mast cell development. IL-4. diagnosis. and cytokines and growth factors (e. This causes cross-linking of Fc RI receptors. IL-6. mucus overproduction and AHR(132). such as interleukin (IL)-2.upon mast cells degranulate and synthesize pro-inflammatory molecules. Lung. are processed by APCs. Polosa R. 368.g.Source: Adapted and reprinted from The Lancet. IL-4. tumor necrosis factor (TNF). and Natural History of Asthma Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. 2007 Aug. PGs and LTs).g. Definition. From: Section 2. Mediators produced by mast cells can be divided into preformed mediators (e.. and Blood Institute (US). . IL-13. allergens enter the airways. Third Expert Panel on the Diagnosis and Management of Asthma. histamine). The mechanisms. newly synthesized lipid mediators (e. and management of severe asthma in adults. Re-exposure to a previously met allergen leads to its binding on IgE antibodies that are attached to mast cell Fc RI receptors. IL10. Activation of Th cells leads to the production of various cytokines.. Here. IL-3. where. IL-9 and IL-13 are the most important in the development of asthma. and are brought to the lymph nodes. Holgate ST. interferon (IFN). with permission from Elsevier. 780–93. IL-18. they are presented to T and B cells. Early-phase asthmatic reaction Mast cells: The most crucial cell types in the EAR are mast cells. TNF- and GM- CSF(136). Induction of the allergic reaction: During the induction phase. Bethesda (MD): National Heart. IL-4 and IL-13 play a role in isotope switching to IgE production. IL-12. Copyright (2006). Pathophysiology and Pathogenesis of Asthma. IL-5. IL-5.

on activation.dings. promote accumulation of inflammatory cells and potentiate histamine-induced smooth muscle contraction(138). activate fibroblasts. 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 . endothelial cells. Preformed mediators are packaged within secretory granules in the mast cell and. Tryptase is used as a marker of mast cell degranulation. are released into the extracellular environment within minutes. venule permeability.g. and carboxypeptidase) and proteoglycans (heparin and chondroitin sulphate E). e. These molecules have various effects in the asthmatic airway. VEGF(130). 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). proteases (tryptase.TNF. Chymase has a procollagen proteinase activity and is probably directly toxic to the airway cells(138). Children with atopy are more likely to retain TH2 type phenotype(140). The function of tryptase in vivo is unknown. nerve end. Histamine exerts effects on smooth muscle cells (contraction). 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 .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. recruitment of inflammatory cells. but in vitro it can cleave complement C3 and C3a. chymase. and mucus secretion. Principal granule constituents include histamine.

dendritic cells (DCs). and has antitumor effects (143). Increased numbers of eosinophils exist in the airways of most. 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. B lymphocytes secrete IgE. generate leukotrienes. which is associated with Th2 cell differentiation and IgE synthesis. but not all. Cytokines: Mast cells play a role in more persistent or chronic inflammatory responses through the release of multifunctional cytokines. GM-CSF. and IL-6. TNF- is a major cytokine produced by mast cells. their role in allergic diseases has not been well defined. ASM and BECs. They also have a role in release of growth factors and airway remodeling . B Lymphocytes: In allergic diseases. numerous . These cells contain inflammatory enzymes. IL-4 is responsible for switching B cells to IgE(142). endothelial cells. which are critical for eosinophil development and survival. In addition. However. They may release basic proteins that may damage the airway epithelial cells.regulation with suppression of TH1 responses(141). Increases in eosinophils often correlate with greater asthma severity. and IL-16. neutrophils. persons who have asthma (144). it up regulates endothelial and epithelial adhesion molecules. IL-3. increases AHR. and express a wide variety of pro-inflammatory cytokines. macrophages. like eosinophils. T cells. Other cytokines produced by mast cells include IL-4. and IL-5. CXC-chemokine ligand (CXCL) 8 (IL-8).

contraction. they may be a determinant of a lack of response to corticosteroid treatment (147). activation. during acute exacerbations. and infection by respiratory viruses can cause epithelial cells to produce more inflammatory mediators or to injure the epithelium itself. recruitment and activation of inflammatory cells. The repair process. and in the presence of smoking(146). The generation of inflammatory mediators. Neutrophils: Neutrophils are increased in the airways and sputum of persons who have severe asthma. 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).studies show that treating asthma with corticosteroids reduces circulating and airway eosinophils in parallel with clinical improvement(145). activation. Their pathophysiological role remains uncertain. but leukotriene B4 may contribute to these processes. Epithelial Cells: Airway epithelium is another airway lining cell critically involved in asthma. and alteration in lung function is still under study. and hypertrophy—events that can influence airway dysfunction of asthma(126). following injury to the . The regulation of neutrophil recruitment. the airway smooth muscle cell can undergo proliferation. 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). As a consequence of airway inflammation and the generation of growth factors.

cartilage breakdown and angiogenesis.epithelium. reproduction. which amplify the inflammatory response. which is critical in tissue repair and remodeling. Chemokines. Key cytokines include IL-1β and TNF-α. metaplasia. Cytokines. Th2-derived cytokines include IL-5. The ECM is a dynamic structure. . Prostaglandin E2. and tissue resorption and remodeling (149). which is needed for eosinophil differentiation and survival. and equilibrium between synthesis and degradation of ECM components is required for the maintenance of its homeostasis. Recent studies of . and its homeostasis plays an important role in the breakdown and deposition of ECM in the airway wall(150). MMP’S are responsible for the development. thus furthering the obstructive lesions that occur in asthma(30).Endothelin-1. Airway Remodeling: Ongoing inflammation may result in structural remodeling: wall thickening. The balance MMPs are thought to play a central role in between MMPs and TIMPs. hypertrophy and hyperplasia of airway cells. MMPs are als o implicated in alteration of angiogenesis and smooth muscle hyperplasia processes. 8-Isoprostane). Cytokines: Direct and modify the inflammatory response in asthma and likely determine its severity. and IL-4 which is important for Th2 cell differentiation and with IL-13 is important for IgE formation(151). may be abnormal in asthma. subepithelial fibrosis. The most prominent mediators of airway remodeling are Matrix metalloproteinases. Lipid mediators (Prostaglandin D2. called the ECM. which prolongs eosinophil survival in airways. Leukotriene B and ADAM33(148). morphogenesis. Cysteinyl leukotrienes. and GM-CSF. Vascular endothelial growth factor. Matrix metalloproteinases: Connective tissue cells produce and secrete an array of macromolecules forming a complex network filling the extracellular space of the submucosa.

Vascular Endothelial Growth Factor: vascular endothelial growth factors (VEGF) induce expression of connective tissue growth factor and collagen (153). eosinophils and CD34+ cells are the major source of VEGF.Prostaglandins appear to have several effects on the airways.release and collagen deposition from lung fibroblasts. and is related to the number of vessels and mast cells. monoclonal antibodies against IL-5 or soluble IL-4 receptor) have not shown benefits in improving asthma outcomes. plasma exudation. as well as to the basement membrane thickness(148). Prostaglandin E2 is also an important PG produced in inflammatory processes(155). and effects on inflammatory cells. Lipid Mediators: Prostaglandin D2. such as CCL7 and CCL22 also contribute to the development of pulmonary fibrosis. PGE2 inhibits . Other CC-chemokines.. compared with that of control subjects. Macrophages.treatments directed toward single cytokines (e. sensitization of nerve endings.g. CCL2 is increased in asthma. Chemokines: Among them. PGD2 and PGF2 cause bronchoconstriction in asthmatic patients. and is a well-established profibrogenic mediator in vitro and in vivo by inducing TGF. including bronchoconstriction. The expression of VEGF is up regulated in the bronchial mucosa of mild to moderate asthmatic patients. and by recruiting Th2 cells in the lung(124). neutrophils and basophils. but not in healthy subjects(154). Endothelin 1: Endothelin (ET)-1 may be involved in airway remodeling: it is mitogenic for ASM cells and fibroblasts. It is the most important bronchoprotective metabolite yet identified in the airways(156). and also stimulates collagen synthesis (152). PGD2 is involved in the recruitment of inflammatory cells because it stimulates the chemotaxis of Th2 cells. eosinophils.

Cys-LTs mediate several steps in airway inflammation. vascular leakage and possibly also airway remodeling(158). bronchoconstriction and edema(157). Alterations in ADAM33 activity may underlie abnormalities in the function of ASM cells and fibroblasts linked to airway remodeling and AHR. ADAM33: A disintegrin and metalloproteinase (ADAM) 33 has been a focus of interest in the last few years(159). and remodeling(160).the release of mediators from mast cells. monocytes. This leads to degranulation and the release of mediators. Cysteinyl Leukotrienes: There is substantial evidence that cys-LTs (LTC4. plasma exudation and mucus secretion also increase eosinophilic inflammation. Abnormal activity of this gene can lead to altered airway function. Summary of mediators released by the various cell types that are involved in the early and late . PGE2 and PGI2 are vasodilators and therefore should theoretically increase leakage in asthmatic. ADAM33 has been linked to asthma in a study of 460 white families. It plays a role in non-specific smooth muscle hyperresponsiveness. Leukotriene B4: Leukotriene B4 is a potent neutrophil chemoattractant that enhances neutrophilendothelial interactions and stimulates neutrophil activation. 8-Isoprostane: Isoprostanes are inflammatory metabolites derived from arachidonic acid. They decrease mucociliary clearance and are potent mediators of bronchoconstriction. inflammation. including inflammatory cell recruitment. enzymes and superoxides. neutrophils and eosinophils. LTD4 and LTE4) play an important role in asthma(131).

IL-5. LTE4). leukotrienes (cys-LTs: LTC4. LTD4.. chemokines (CXCL8. chemokines (CCL2. cytokines (IL-4. IL-5. and IL-13) Early asthmatic reaction Mast cells Histamine. IL-10. ECP. cytokines (IL-1.. cytokines (TNF. chymase. leukotrienes (cys-LTs: LTC4. TNF. GMCSF). IL-2. IL-11. IL-3. cytokines . CCL5) Neutrophils Leukotrienes (LTA4. proteases (tryptase. LTD4. IL-9. TGF. prostaglandins (PGD2). IL-5. IL-8. TXA2. IL-16. CCL3. IL-6. proteoglycans (heparin. EP. LTE4). LTB4). IL-4. CCL11) Basophils Histamine. and GM-CSF). TGF. IL-13) Late asthmatic reaction Eosinophils MBP. IL-6. IL-4.. IL-12. leukotrienes (LTC4). and carboxypeptidase).asthmatic reaction Cell source Released mediators Induction phase T cells Cytokines (IL-4. EDN. IL-3. PAF. chondroitin sulphate E).. CCL3.

TNF. chemokines (CCL11. TNF. proteases (elastase. CXCL1. IL-4. ECM proteins Bronchial epithelial cells Cytokines (IL-6. TGF. cytokines (GM-CSF. chemokines (CCL1. CXCL8). CXCL8) Endothelial cells ICAM-1. CCL22) Macrophages Cytokines (IL-1. chemokine (CXCL8). CCL7. NO Dendritic cells Chemokines (CCL2. CCL22. CXCL8). IL-10. IL-5.). P-selectin) Airway smooth muscle cells Chemokines (CCL5. IFN. hydrogen peroxide). PECAM-1. CXCL6.. CCL17. ICAM-2. myeloperoxidase. prostaglandins (PGE2). microbicidal products (lactoferrin. CCL3. chemokines (CXCL8). lipids. IL-6). reactive oxygen intermediates (superoxide. CCL22. GM-CSF). IL-9. CCL17. IL-13.. CCL13.(IL-1 .). lysozyme). ROS. ICAM-1 . gelatinase B). CCL11. IL-6. collagenase. selectins (Eselectin. VCAM-1. PAF. NO T cells Cytokines (IL-3. IL-6. GM-CSF). IL-6. CCL4.

. Respiratory symptoms that begin at or persist through ages 3 to 4 years are highly diagnostic of asthma. wheezing without colds and allergic rhinitis) has been shown to predict the presence of asthma in later childhood (167). Intermittent dry coughing and expiratory wheezing are the most common chronic symptoms of asthma(161). non-focal chest pain(162).CLASSIFICATION AND DIAGNOSIS OF ASTHMA. cough and chest tightness(36).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. and responding to appropriate asthma therapy(163) . wheezing. symptom) is particularly common in children and is often more problematic at night. if not only. fumes. seasonal variability of symptoms and a positive family history of asthma and atopic diseases are helpful diagnostic studies. precipitation by nonspecific irritants. and deterioration when treatment is stopped. evaluations during the day can be normal(166) . Younger children are more likely to report intermittent. Cough-variant asthma (patients have chronic cough as their principal. such as smoke. worsening at night. The patterns of these symptoms that strongly suggest an asthma diagnosis are: variability. Episodic symptoms after an incidental allergen exposure. Marked clinical improvement during the treatment. A clinician should consider asthma if the child has physical activity induced cough or wheeze(164) . strong smells or exercise. supports a diagnosis of asthma(165). Children with cough variant asthma do not wheeze . A clinical diagnosis of asthma is suggested by symptoms such as episodic breathlessness. A useful method for confirming the diagnosis of asthma in children aged ≤5 years is a trial of treatment with short-acting bronchodilators and inhaled glucocorticosteroids.

Late Onset Wheeze/Asthma These children have asthma which often persists throughout childhood and into adult life.Three categories of wheezing have been described in children 5 years and younger. This is often associated with prematurity and parental smoking(168). . The symptoms normally persist through school age and sometimes till the age of 12.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 . These patients have atopic background often with eczema and airway pathology which is characteristic of asthma (170).cold air and less common in . Cough Variant Asthma: Patients with cough variant asthma have chronic cough as their principal symptom. Persistent Early Onset Wheeze (before the age of 3) these children have recurrent episode of wheeze associated with acute viral upper respiratory tract infections. The cause of episode is usually respiratory syncytial virus in those under the age of 2 and other viruses in older children. evaluations during the day time can be normal. It is more problematic at night. Exercise Induced Bronchoconstriction: Typically develops within 5 to 10 min after completing exercise(it rarely occurs during exercise). 170). have neither evidence nor family history or atopy (169. Transient Early Wheezing outgrows in the first three years. 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).

Differential diagnosis . Rapid improvement of symptoms after inhaled beta 2 agonist use supports the diagnosis of asthma(110). Differential Diagnoses Table humid climate.

Upper respiratory tract conditions Allergic rhinitis Chronic rhinitis Sinusitis Adenoidal or tonsillar hypertrophy Nasal foreign body Middle respiratory tract conditions Laryngotracheobronchomalacia Larayngotracheobronchitis (e. 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 .g. cyst or stenosis Vocal cord dysfunction Vocal cord paralysis Tracheoesphageal fistula Vascular ring. pertusis) Laryngeal web.

greatly enhance diagnostic confidence(173).Laboratory Findings: Lung function tests help to confirm the diagnosis of asthma and to determine disease severity. 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. forceful and prolonged expiratory maneuver. Spirometry is helpful as an objective measure of airflow limitation. Generally an FEV1/FVC ratio < 0. Valid spirometric measures depends on a patient’s ability to properly perform a full. 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 . 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 . and particularly the demonstration of reversibility of lung function abnormalities. 1. then the highest FEV 1 effort of the three is used(174). If the FEV 1 (forced expiratory volume in 1 sec) is within 5 % on 3 attempts. measurements of lung function to confirm airflow limitation. feasible in children >6 years of age. 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).80 indicates significant airflow obstruction(175).

Exercise challenges (aerobic exercise or running for 6 to 8 min) can help identify children with an exercise induced bronchospasm. but normal lung function. could improve overall asthma control(179).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. 5. It has been also proposed that adjusting anti-inflammatory drugs guided by the monitoring of exhaled NO. Bronchoprovocation challenges: Patients with symptoms consistent with asthma. mannitol. and to predict upcoming asthma exacerbations (178).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). exhaled NO is very useful to verify adherence to therapy. In asthma. Studies of exercise challenges in school aged children typically identify an additional 5-10 % with exercise induced bronchospasm and previously unrecognized asthma(177). histamine. 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 asthmatic patients. . measurements of airway responsiveness to methacholine. 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.FEV1 typically decreases during or after exercise by >15%. 3.

During asthma exacerbations. In extreme cases. hyper-lucent lung fields in bronchiolitis obliterans) and complications during asthma exacerbations (109). poor air entry. 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). Physical Examination: The most usual abnormal physical finding is wheezing on auscultation(181). indicate areas of hypoventilation due to obstruction(180). Decreased breath sounds in some of the lung fields. nasal flaring and accessory respiratory muscle use(183). Chest radiographs can be helpful in identifying abnormalities that are hallmarks of asthma masqueraders (aspiration pneumonitis. the greater extent of airways obstruction causes labored breathing and respiratory distress. airflow may be so limited that wheezing cannot be heard. Crackles indicate excess mucus production and inflammatory exudate in airways in severe exacerbations. suprasternal and intercostal recessions. expiratory wheezing and a prolonged expiratory phase is heard on auscultation (182).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). .

and combination therapies with long-acting beta agonists and glucocorticosteroids. symptoms. reliever use and lung function) and future risk (e. Controllers are medications taken daily on a long term basis to keep asthma under clinical control chiefly through their antiinflammatory effects. . or exhaled nitric oxide. They include inhaled glucocorticosteroids. exacerbations and lung function decline) Clinical studies have shown that asthma can be effectively controlled by intervening to suppress and reverse the inflammation.g. Furthermore. Children who are very well controlled on low doses of inhaled corticosteroids may be able to come off treatment. Medications to treat asthma can be classified as controllers or relievers (187).g. Complete control of asthma is commonly achieved with treatment. as well as treating the bronchoconstriction and related symptoms (186). 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. leukotriene receptor antagonists. and the cost of treatment required to achieve this goal(171). spirometry. all patients must be continually reviewed to monitor that control has been achieved and is maintained. Drug therapy can then be adjusted according to the patient’s level of control. 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.Asthma control: As the goal of asthma treatment is to achieve control. potential for adverse effects. the aim of which should be to achieve and maintain control for prolonged periods with due regard for the safety of treatment. Its assessment should incorporate the dual components of current clinical control (e.

The most commonly used relievers are inhaled short-acting beta agonists and short acting oral beta 2. Relievers are used on an as needed basis to quickly reverse bronchoconstriction and relieve symptoms. 188).anti-IgE and other steroid-sparing therapies (22. 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 or . wheeze ANY(cough.(189) Table 2: Levels of Asthma Control.

instability. ease of use.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. side effects) Features that are associated with increased risk of adverse events in the future include: Poor clinical control. intravenous and intramuscular routes) (188. The choice of inhaler device should include consideration of the efficacy of the drug delivery. rapid decline in lung function. ever admission to critical care for Asthma. 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. exposure to cigarette smoke. orally or parenterally (by subcutaneous. frequent exacerbations in the past year. cost. . Different age groups require different inhalers for effective therapy. safety. 190) .activities active child: plays or difficult breathing difficult breathing during and runs without during vigorous play. low FEV1. vigorous play. high dose medications ROUTES OF ADMINSTRATION: Asthma treatment can be administered in a variety of ways: inhaled.

. waste large amounts of drug into the surrounding air. Nebulizers have imprecise dosing. This consideration is especially important for ICS with poor firstpass metabolism such as beclomethasone dipropionate (BDP) and budesonide (191).convenience and documentation or it’s in patient’s age group.Spacers retain large drug particles that would be deposited in the oropharynx. and require maintenance . are time-consuming to use and care for. time-consuming. and expensive to use. these devices are cumbersome. 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) . The vast majority of children of all ages with acute severe asthma can be managed effectively and safely by β2 agonists delivered via MDI/spacer (189). As a result. bulky. are expensive. so reducing oropharyngeal side-effects and systemic absorption and availability of inhaled drug. Although nebulizers have been the mainstay of inhalation therapy in childhood asthma for many years.

and bronchial hyperresponsiveness. Inhaled steroids are now used at a much earlier stage in asthma therapy.. long acting inhaled β2-agonists. reduces the frequency of acute exacerbations and the number of hospital admissions. theophylline. Nebulized budesonide reduced the need for .Early intervention with inhaled budesonide is associated with improved asthma control and less additional asthma medication use . even at low doses of inhaled glucocorticosteroids (192) . and reduces exercise-induced bronchoconstriction(194). and long-acting oral β2-agonists. lung function. 100-200 μg budesonide daily). cromones.Duration of treatment should continue till bronchial hyperresponsiveness improves (193).g. improves quality of life. Inhaled glucocorticosteroids Inhaled glucocorticosteroids are the most effective controller therapy for asthma in children with rapid improvement in symptoms and lung function. which may lead to irreversible airflow obstruction in some patients(195) . 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. In children of all ages. maintenance treatment with inhaled glucocorticosteroids controls asthma symptoms. leukotriene modifiers. 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. and mild disease is well controlled by such doses in the majority of patients(192).Controller Medications Controller medications for children include inhaled and systemic glucocorticosteroids.

asthma control deteriorates within weeks to months (198). However. It is then available for absorption into the systemic circulation through the liver. 80 to 90 percent. there is marked individual variability of responsiveness to inhaled glucocorticosteroids. Corticosteroid Trade name Children (6 to 11 years of age) Adults (12 years of age and over) . When glucocorticosteroid treatment is discontinued. Increasing to higher doses provides little further benefit in terms of asthma control but increases the risk of side-effects. low systemic bioavailability of the portion of the dose swallowed by the patient. Symptom control and improvements in lung function occur rapidly (after 1 to 2 weeks).(199) This fraction is markedly reduced if the glucocorticoid is administered through a large-volume spacer attached to a metered-dose inhaler. although longer treatment (over the course of months) and sometimes higher doses may be required to achieve maximum improvements in airway hyperresponsiveness (10). and because of this and the recognized poor adherence to treatment with inhaled glucocorticosteroids. Desirable properties in an inhaled glucocorticoid are high topical potency. is deposited on the oropharynx and swallowed. and rapid metabolic clearance of any glucocorticoid that reaches the systemic circulation. After inhalation a large proportion of the inhaled dose. many patients will require higher doses to achieve full therapeutic benefit(197) .oral glucocorticoid therapy and also improved lung function in children under the age of three years (196) .

Flovent Diskus¶ 251–500 >500 ≤200 201–500 >400 >500 ≤250 .Beclomethasone dipropionate ≤200 201–400 >400 HFA QVAR Inhaled corticosteroid (ICS) dosing categories in children and adults Low Medium † High Low ≤250 251–500 Medium High >500 Budesonide* Pulmicort Turbuhaler‡ ≤400 401–800 >800 ≤400 401–800 >800 Ciclesonide* Alvesco§ Fluticasone ≤200 201–400 >400 ≤200 201–400 Flovent MDI and spacer.

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). however. Height measurements made over a period of less than 1 year are liable to error and misinterpretation.Side effects -The majority of studies evaluating the systemic effects of inhaled glucocorticosteroids have been undertaken in children older than 5 years. . With all inhaled corticosteroids given at high dosage. 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) . It is probable that the best combination of efficacy and safety can be achieved by using low steroid doses (205). growth. or hypothalamo-pituitary-adrenal-axis(200). 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). eye. In school-age children asthma should be treated first with inhaled steroids. . also associated with a delay in skeletal maturation so that the bone age of the child corresponds to the height (204). However. there is no decrease in attained adult height. Ultimately. The delay in pubertal growth is. they do not normalize lung function and prevent structural changes in the airway wall in all asthmatic patients (201). though it is reached at a later age than normal (205). Low doses do not have clinically deleterious side effects on the bones. Continuous administration of ICSs in low to medium dose over many years is well tolerated.  Growth: Asthma and its level of control may directly affect growth in the same way as most chronic diseases of childhood. 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) .

However. Most children develop biochemical evidence of adrenal suppression after treatment with medium to high doses of ICS(208). Long-term follow-up studies in children concluded that inhaled steroids are well tolerated. they do not normalize lung function and prevent structural changes in the airway wall in all asthmatic patients. resulting in an increased risk for osteoporosis and fracture. Bone mineral density may be decreased by high doses of inhaled glucocorticoids. with little or no effect on growth and hypothalamic-pituitary-adrenal axis function(200). small changes in HPA axis function can be detected with sensitive methods. 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). Thus it is a valuable therapeutic alternative to systemic corticosteroid therapy in infants and young children. or hypothalamo-pituitary-adrenal-axis (209). but their effect is confounded by the fact that patients taking these drugs . Calcium supplementation may be necessary in children with asthma treated with inhaled steroids since this treatment may cause reduction in osteocalcin. eye. dose-dependent adrenal suppression has been documented in children treated with inhaled steroids but generally this effect has no clinical relevance (207). growth. No studies have reported any statistically significant increase of risk of fractures in children taking inhaled glucocorticosteroids (204).  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. At higher doses. With sensitive techniques. Low doses do not have clinically deleterious side effects on the bones. Hypothalamic-pituitary-adrenal (HPA) axis.

The use of spacer devices and mouth rinsing may reduce local and systemic adverse effects. The most recent reports have concluded that the individualistic nature of asthmatic condition.However. Asthma is one of the most common chronic medical conditions in childhood which is considered high risk for caries.also receive intermittent courses of oral glucocorticoids. aggressiveness. and bruising. depression.  Oral candidiasis. and insomnia — inhaled corticosteroids are not associated with any adverse effects(207).  Effects on Connective Tissue. carries several factors for an increased caries risk (214) . There are reports of increased skin bruising and purpura in patients receiving high doses of inhaled beclomethasone. Long-term administration of medium dose ICSs does not increase the risk of cataracts or osteopenia in children and young adults (212) . hoarseness. Oropharyngeal candidiasis and dysphonia are the most commonly recognized adverse effects of therapy. euphoria. but these topical phenomena cause no significant morbidity and are easily managed(213). but the amount of intermittent glucocorticoids they received is not known.  Dental side effects. Spacers reduce the incidence of oral candidiasis. Easy bruising linked to inhaled . through either its disease status or its pharmacotherapy (different combinations of medicaments). Cataracts. Recent studies have provided little evidence for asthma caries causative relationship . Oral glucocorticoid therapy is a well-known cause of osteoporosis and an increased risk of vertebral and rib fractures.  Central nervous system effects: Despite the propensity of glucocorticoids to cause psychiatric disturbance — including emotional lability.

including tuberculosis. reduce symptoms (including cough) . and reduce airway inflammation and asthma exacerbations(217). The long-term use of inhaled glucocorticosteroids is not associated with an increased incidence of lower respiratory tract infections. leukotriene modifiers cannot substitute for this treatment without risking the loss of asthma control(218). the effects of leukotriene modifiers are less than those of low doses of inhaled glucocorticosteroids and. bronchoconstriction and eosinophil infiltration(216). These compounds are produced via the lipoxygenase pathway by mast cells. improve lung function. \ Leukotriene modifiers.glucocorticoids is more frequent in elderly patients. However. Leukotriene modifiers used as add-on therapy may reduce the dose of inhaled glucocorticosteroids required by patients with moderate to severe asthma. when used alone as controller. there are no reports of this problem in children(215).  Other local side effects. eosinophils and alveolar macrophages Clinical studies have demonstrated that leukotriene modifiers have a small and variable bronchodilator effect. in patients already on inhaled glucocorticosteroids. The leukotrienes are potent inflammatory mediators in asthma and contribute to increased mucus production. and may improve .

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. Long-acting inhaled β2-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). LTRAs have been proposed as alternative first-line therapy to ICSs for episodic or mild persistent asthma who have difficulty in utilizing inhalation treatment. Leukotriene modifiers provide clinical benefit in children older than 5 years at all levels of severity. 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 . Monotherapy with long acting inhaled β2-agonists should be avoided(165). with poor compliance. However. or where exercise-induced bronchospasm (EIB) is a dominant component of asthma(220.asthma control in patients whose asthma is not controlled with low or high doses of inhaled glucocorticosteroids(219). Role in therapy -Long-acting inhaled β2-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). 221) . Long-acting inhaled β2-agonists. 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 . Significant improvements in peak flow and other lung function measurements have been found in most studies.

However. when higher doses are . the efficacy of theophylline is less than that of low-dose inhaled glucocorticosteroids. long-acting β2-agonists should only be used in combination with an appropriate dose of inhaled glucocorticosteroid as determined by a physician. If used. Combination products containing an inhaled glucocorticosteroid and long-acting inhaled β2-agonists are preferred to long-acting inhaled β2-agonists and inhaled glucocorticosteroids administered by separate inhalers (224). Maintenance treatment offers a marginal protective effect against exercise-induced bronchoconstriction. 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).conducted. Measurement of plasma theophylline levels is not necessary in otherwise healthy children when doses less than 10 mg/kg/day are used(230). the effect of long-acting inhaled β2-agonists has not been adequately studied. 228). Sustained-release products are preferable for maintenance therapy. In Children 5 years and younger. since they enable twice-daily dosing. Side effects: Long acting inhaled beta 2 agonists are not the recommended option when more than one controller is required(42). 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. 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). Plasma theophylline levels were maintained within the therapeutic range of 5-110 μmol/L (5-10 μg/ml)(229). preferably in a fixed combination inhaler (226).However.

and headache(231).300 IU(235). Side effects: Drug-related adverse events in anti-IgE treated patients are mild to moderate in severity and include urticaria. Sodium cromoglycate and nedocromil sodium have limited role in the long term treatment of asthma in children. Cromones: sodium cromoglycate and nedocromil sodium. Side effects : The most common side effects of theophylline are anorexia. rarely. Anti-IgE.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). tachycardia. palpitations. rash. and. arrhythmias.used or when drugs that may increase theophylline levels are also used chronically. A substantial number of children with difficult asthma will have higher IgE levels than the upper limit of IgE recommended for therapy *1. gastric bleeding may also occur(232). One metaanalysis has concluded that long-term treatment with sodium cromoglycate is not significantly .IgE in 627 children with IgE-mediated asthma inadequately controlled on doses of inhaled glucocorticosteroid equivalent to 200 μg/day fluticasone propionate or higher (mean dose 500 μg/day)(234). Role in therapy . diarrhea. nausea. vomiting. Anti-IgE therapy is expensive(42). It is unknown if these patients will still benefit from omalizumab therapy. A one-year study evaluated the efficacy and safety of anti. and pruritus(236). There are no tests which can currently be recommended in order to predict who will respond. These side effects are mainly seen at doses higher than 10 mg/kg/day. abdominal pain. flushing. Mild central nervous stimulation. plasma theophylline levels should be measured two hours before administration of the next dose once steady state has been (after 3 days).

headache. and the therapeutic response monitored to limit side effects. their use is not encouraged. and skeletal muscle tremor. A bad taste. Because of the side effects of prolonged use. Rapid-acting inhaled ß2-agonistss are the most effective bronchodilators available and therefore the preferred treatment for acute asthma in children of all ages(244). Due to their potential side effects of cardiovascular stimulation. terbutaline. whether viral-induced or otherwise (242. 239). Treatment with long-acting oral β2-agonist such as slow release formulations of salbutamol. and bronchoconstriction occur in a small proportion of patients treated with sodium cromoglycate(240). and nausea are the most common side effects of nedocromil. Studies of the use of these medications in children 5 years and younger are sparse and results are conflicting(238. Reliever Medications Rapid-acting inhaled ß2-agonists and short-acting oral ß2.better than placebo for management of asthma in children(237). anxiety. throat irritation. The inhaled route results in more rapid bronchodilation at a lower dose and with fewer side effects than oral or intravenous . dosing should be individualized. If used. and bambuterol reduces nocturnal symptoms of asthma(241). Systemic glucocorticosteroids. Side effects Cough. oral glucocorticosteroids in children with asthma should be restricted to the treatment of acute severe exacerbations.agonists. 243). Long-acting oral β2-agonists.

Anticholinergics : Inhaled anticholinergics are not recommended for long-term management of asthma in children(246). Side effects.5 to 2 hours (long-acting ß2-agonists offer longer protection)(245). including exercise • Maintain pulmonary function as close to normal as possible • Prevent asthma exacerbations • Avoid adverse effects from asthma medications . ASTHMA MANAGEMENT AND PREVENTION: The goals for successful management of asthma are to: • Achieve and maintain control of symptoms • Maintain normal activity levels. Skeletal muscle tremor. inhaled therapy offers significant protection against exerciseinduced bronchoconstriction and other challenges for 0. This is not seen after systemic administration. These complaints are more common after systemic administration and disappear with continued treatment. Furthermore.administration. headache. and some agitation are the most common complaints associated with high doses of ß2-agonists in children. palpitations. Oral therapy is rarely needed and reserved mainly for young children who cannot use inhaled therapy.

confidence. His approach is called guided self-management and has been shown to reduce asthma morbidity in both adults and children. The aim of this partnership is to enable patients with asthma to gain the knowledge. and Monitor Asthma 4. Furthermore. but in accordance with a prior written action plan. Manage Asthma Exacerbations 5. and skills to assume a major role in the management of their asthma. Special Considerations. 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). to doctor-directed self-management in which patients rely follow a written action plan. Develop Patient/Doctor Partnership 2.• Prevent asthma mortality. but refer . ranging broadly from patient-directed self-management in which patients make changes without reference to their caregiver. Treat. Assess. 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. Guided self-management may involve varying degrees of independence. 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). Identify and Reduce Exposure to Risk Factors 3.

and is relevant to asthma patients of all ages(14). Education and the Patient Doctor Partnership Goal: To provide the person with asthma. 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 . their family. Although the focus of education for small children will be on the parents and caregivers.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. 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.

reward. 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. and strategies for avoiding factors that cause asthma symptoms. With . At the initial consultation. and reinforcement. and the person with asthma encouraged to participate in the decision as to which is most suitable for them(250). the rationale for the specific therapeutic interventions being recommended. in accordance with written predetermined guidelines(251). verbal information should be supplemented by the provision of written or pictorial information about asthma and its treatment. 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. revision. Different inhaler devices can be demonstrated. 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. as indicated by symptoms and/or peak expiratory flow.

the effects were also greater when the patients themselves both stepped up inhaled glucocorticosteroids and added oral glucocorticosteroids. and any problems with asthma and its initial treatment are reviewed (254). Follow-Up and Review Follow-up consultations should take place at regular intervals. emergency room visits. Patients should be asked to demonstrate their inhaler device technique at every visit. At these visits. take _____________________ WHEN TO INCREASE TREATMENT . based on their symptoms or for peak low-based(252). missed days of work. and nocturnal wakening(253). Before exercise. Patients experience a one-third to two-thirds reduction in hospitalizations. the patient’s questions are discussed. with correction and re-checking if it is inadequate. Each day take ___________________________ 2. unscheduled visits to the doctor for asthma. Example of Contents of Written Asthma Action Plan to Maintain Asthma Control Your Regular Treatment: 1. Thus.these action plans. Follow-up consultations should also include checking the person’s adherence/compliance to the medication plan and recommendations for reducing exposure to risk factors(255). patients who are unable to undertake guided self-management can still achieve benefit from a structured program of regular medical review.

your asthma is Uncontrolled and you may need to step up your 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. 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. peak flow less than______? No Yes if you answered Yes to three or more of these questions. Call your doctor/clinic: _______________ [provide phone numbers] If you don’t respond in _________ days [specify number] ____________________________ [optional lines for additional instruction] .

Patient concern about side-effects of inhaled glucocorticosteroids whether real or perceived may influence adherence. Take 2 to 4 puffs ___________ [reliever medication] 2. 3 If you are having a severe attack of asthma and are frightened.EMERGENCY/SEVERE LOSS OF CONTROL 3If you have severe shortness of breath. 1. 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). 3If you need your reliever medication more than every 4 hours and are not Improving. Specific drug and nondrug factors involved in non-adherence are: Factors Involved in Poor Adherence Drug factors . and can only speak in short sentences.

Dissatisfaction with health care professionals 4. Side effects 3. Cost of medication 4. Stigmatization 11. Poor supervision. four times daily or multiple drugs) 2. Dislike of medication 5.g.1. Cultural issues 10. training. Fears about side effects 3. Misunderstanding or lack of instruction 2.. Religious issues. Anger about condition or its treatment 8. Unexpressed/discussed fears or concerns 5. Distant pharmacies Non-drug factors 1. Difficulties with inhaler devices Awkward regimes (e. Underestimation of severity 9. or follow-up 7. Attitudes toward ill health 13. Inappropriate expectations 6. Forgetfulness or complacency 12. .

the number of days with restricted activity. in relation to the development of asthma has been extensively studied and. in general. there are no proven and widely accepted interventions that can prevent the development of asthma (257).e.. and the number of emergency department visits(253). IDENTIFY AND REDUCE EXPOSURE TO RISK FACTORS Asthma Prevention: Measures to prevent asthma may be aimed at the prevention of allergic sensitization (i.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. the development of atopy. For children. and reduced absences from school. or the prevention of asthma development in sensitized people. infants fed formulas of intact cow’s milk or soy protein compared with breast milk have a higher incidence of wheezing illnesses in early . Other than preventing tobacco exposure both in utero and after birth. The role of diet particularly breast-feeding. likely to be most relevant prenatally and perinatally). symptom-based action plans are more effective than those based on peak flows(256).

” including allergens. avoiding these factors completely is usually impractical and very limiting to the patient. sometimes referred to as “triggers. including effects on lung development and a greater risk of developing wheezing illnesses in childhood(262). 260). allergens.g. . Exposure to tobacco smoke both prenatally and postnatally is associated with measurable harmful effects. Passive smoking increases the risk of allergic sensitization in children(263). and avoiding foods/additives/drugs known to cause symptoms) improves the control of asthma and reduces medication needs(265). Reducing a patient’s exposure to some of these categories of risk factors (e. Exposure to cats has been shown to reduce risk of atopy in some studies(261). 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. Both prenatal and postnatal maternal smoking is problematic(264). Because many asthma patients react to multiple factors that are ubiquitous in the environment.. measures where possible should be taken to avoid these (266).g. viral infections and pollutants).. Patients with well-controlled asthma are less likely to experience exacerbations than those whose asthma is not well controlled (267). reducing or eliminating exposure to occupational agents known to cause symptoms. reducing exposure to secondhand smoke. 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.childhood(258). In the case of other factors (e. viral infections. Exclusive breastfeeding during the first months after birth is associated with lower asthma rates during childhood (259. Thus. and drugs. smoking cessation. pollutants.

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).Indoor Allergens Among the wide variety of allergen sources in human dwellings are domestic mites. To avoid this. In tropical and subtropical climates. chemical control. including schools. Outdoor Allergens . Although removal of such animals from the home is encouraged. they are difficult to reduce and impossible to eradicate(269). Domestic mites: Domestic mite allergy is a universal health problem(268). One study showed some efficacy of mattress encasing at reducing airway hyperresponsiveness in children. Complete avoidance of pet allergens is impossible. Furred animals. and traps. Cockroaches. as the allergens are ubiquitous and can be found in many environments outside the home. the walls could be tiled or leaned as necessary. these measures are only partially effective in removing residual allergens (271). However. cockroaches. Since mites live and thrive in many sites throughout the house. 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. furred animals. fungi may grow on the walls of the house due to water seepage and humidity. and cat-free buildings(270). and fungi. Avoidance measures for cockroaches include eliminating suitable environments restricting access (sealing entry sources such as around paperwork and doors). public transportation.

formaldehyde. and staying indoors in a climate-controlled environment(278). carbon monoxide. Parents/ caregivers of children with asthma should be advised not to smoke and not to allow smoking in rooms their children use. or high air pollution. and changes in temperature/humidity. nitrogen oxides. increases in reparable allergens. carbon dioxide. Indoor Air Pollutants The most important measure in controlling indoor air pollutants is to avoid passive and active smoking (274). and particulate matter–and symptoms or exacerbations of asthma(277). low humidity. For patients with asthma that is difficult to control. Outdoor Air Pollutants Several studies have suggested that outdoor pollutants aggravate asthma symptoms. sulfur dioxide. acidic aerosols.. including dust and pollution.Outdoor allergens such as pollens and molds are impossible to avoid completely (273). nitrogen oxides. On occasion. and biological (endotoxin)(275). Secondhand smoke increases the frequency and severity of symptoms in children with asthma. certain weather and atmospheric conditions.g. possibly having an additive effect with allergen exposure (276). Most epidemiological studies show a significant association between air pollutants–such as ozone. Other major indoor air pollutants include nitric oxide. remaining indoors when pollen and mold counts are highest and using air conditioning if possible. Exposure may be reduced by closing windows and doors. thunderstorms favor the development of asthma exacerbations by a variety of mechanisms. practical steps to take during unfavorable environmental conditions include avoiding strenuous physical activity in cold weather. e. . avoiding smoking and smoke-filled rooms.

Beta-blocker drugs administered orally or intraocular may exacerbate bronchospasm(284). Sulfites (common food and drug preservatives found in such foods as processed potatoes. beer. However. routine influenza vaccination of children and adults with asthma does not appear to protect them from asthma exacerbations or improve asthma control(286). and wine) have often been implicated in causing asthma(282). Obesity . Food and Food Additives Food allergy as an exacerbating factor for asthma is uncommon and occurs primarily in young children(281). the level of exposure necessary to induce symptoms may be extremely low. 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). Once a patient has become sensitized to an occupational allergen.Occupational Exposures Occupational exposures account for a substantial proportion of adult asthma(279). dried fruits. 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). Food avoidance should not be recommended until an allergy has been clearly demonstrated (usually by oral challenges) Drugs Some medications can exacerbate asthma. shrimp. and resulting exacerbations become increasingly severe(280).

crying. antibiotic treatment of bacterial sinusitis has been shown to reduce the severity of asthma. In children. or fear) can lead to hyperventilation and hypocapnia that can cause airway narrowing Others: Rhinitis. anger. especially in children. 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 . Gastroesophageal reflux can exacerbate asthma.Increases in body mass index have been associated with increased prevalence of asthma(287) Emotional Stress: Extreme emotional expressions (laughing. and asthma sometimes improves when the reflux is corrected. sinusitis. Table IV. and polyposis are frequently associated with asthma and need to be treated(288).

30% >30% >30% Treatment involves steps 1 to 5(289). the patient is asymptomatic with normal lung function and there is no nocturnal awakening. .Night-time ≤2 incidents/month 3 . regular use of reliever medication is one of the elements defining uncontrolled asthma and indicates controller treatment should be increased(291). treatment should be commenced at step 3. However. At each treatment step. Step 2 is the initial treatment for most treatment naïve patients with persistent asthma symptoms(290). Thus reducing the need for reliever medication is the measure of success of treatment. in case of severely uncontrolled symptoms. a reliever medication(rapid onset bronchodilator)should be provided for quick relief of symptoms. dyspnea occurring twice or less per week) of short duration(lasting for few hours). 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. patients require regular controller treatment in addition to as needed reliever medication.between episodes.≤80% ≤60% PEF variability <20% 20 .4 incidents/month >1 incident/week Frequent symptoms but not nightly PEF (predicted) ≥80% predicted ≥80% predicted >60 . wheeze. When symptoms are more frequent or worsen periodically. provide options of increasing efficacy except for step 5 where issues of availability and safety influence the selection of treatment.

either in combination or as separate components. for those in whom exercise induced bronchoconstriction is the only manifestation or if patient still experience exercise induced symptoms in otherwise well controlled asthma. Exercise induced bronchoconstriction indicates that asthma in uncontrolled and stepping up of treatment is required which results in reduction of exercise induced symptoms. The alternatives medications have a slower onset of action and higher risk of side effects. a rapid acting inhaled beta 2 agonists taken prior to exercise is recommended. Physical activity is an important cause of asthma symptoms. Chromones. short acting oral beta 2 agonist or short acting theophylline. 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. The low dose steroid is usually sufficient and need only to be increased if control is not achieved within 3 . rapid acting inhaled beta 2 agonist is the recommended treatment.TREATMENT I N STEP 1: For the majority of patients in step 1. Alternatives are: Leukotriene modifiers. Alternatives are: An inhaled anticholinergic.

twice daily dosing is necessary for most but not all inhaled glucocorticosteroids. 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. use of a spacer device is recommended to improve delivery to the airways. 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). The addition of low dose sustained release theophylline to medium or high dose steroid and LABA may also provide benefit(225). . At medium and high dose steroid. 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. For patients of all ages on medium or high dose of inhaled steroid. reduce oropharayngeal side effects and reduce systemic absorption. Another option is to combine low dose inhaled steroid with a Leukotriene 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. delivered by mdi. Prolonged use of high dose steroid is associated with increase potential for adverse effects. With budesonide. Another option for both adults and children is to increase to a medium dose inhaled steroid.

controlled may be achieved within days of treatment but full benefit may be evident after 3 to 4 months. Alternatively. Patients should be counseled about the side effects and all other alternative treatments must be considered. DURATIONS AND ADJUSTMENT OF TREATMENT: For most classes of controller severe and chronically untreated cases. this may take even longer. The reduced need for medication. 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. Rarely asthma may go into remission in children 5 years and younger and during puberty. reduced need may also represent spontaneous improvement as part of the cyclical natural history of asthma. . Higher dose of antiinflammatory medication is required for this and to maintain this for prolonged periods. once asthma is fully controlled is not understandable but may represent reversal of some of the consequences of long term inflammation. When control is not achieved with additions of high doses of inhaled or oral glucocorticosteroids.STEP 5: RELIEVER MEDICATION PLUS ADDITIONAL CONTROLLER OPTIONS: Addition of oral glucocorticosteroids to other controller medications may be effective but it’s associated with severe side effects and should only be considered if the patient’s asthma remains severely uncontrolled on step 4 medications with daily limitations of activities and frequent exacerbations. addition of anti IgE to other controller medications has been shown to improve control of allergic asthma.

however. If control is maintained. the preferred approach is to begin by reducing the dose on inhaled steroid by approximately 50% while continuing the LABA. then the combination treatment stopped as described as above . 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. the dose of inhaled steroid should be reduced by 50% until a low dose of inhaled steroid is reached. When asthma is controlled with a combination of inhaled glucocorticosteroid and a LABA.this is more likely to lead to loss of control. further reduction in steroid dose should be attempted until a low dose is reached when the LABA may be stopped. 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. When asthma is controlled with inhaled steroid in combination with controllers other than LABA. 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. 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.At other times. An alternative is to switch the combination treatment to once daily dosing. a 50% reduction in dose should be attempted at 3 months interval.

short acting or long acting beta2 agonist bronchodilators. 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. The need for repeated doses over more than one or two days signals the need for review and possible increase of controller therapy.g.formeterol) for combined relief and control. Combination of inhaled glucocorticosteroids and rapid and long acting beta 2 agonist bronchodilator(e. 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. Repeated dosing with bronchodilators in this class provides temporary relief until the cause of worsening symptoms passes.Controller treatment may be stopped if the patient’s asthma remains controlled on the lowest dose of inhaled glucocorticosteroids with no recurrence of symptoms for an year. 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. There is currently no evidence to support continuing these high .. 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. Treatment options are as follows: Rapid onset. Patients who do not reach an acceptable level of control at step 4 of treatment is said to be having difficult to treat asthma.

chronic sinusitis. Because very few patients are completely resistant to steroids. obesity and obstructive sleep apnea. The most common triggers for asthma exacerbations in both younger and older children are viral respiratory tract infections. as is a degree of chronic functional lung impairment ASTHMATIC EXACERBATION: For children. chest tightness. other comorbidities that may aggravate asthma should be investigated e.doses of inhaled steroid beyond 6 months.. a compromised level of control is accepted and discussed with the patient to avoid futile over treatment. frequent rescue medication is accepted. complete cessation of smoking should be considered weather current or past. gastroesophageal reflux. other typical factors are exposure to allergens and a suboptimal . wheezing. When these reasons for the lack of treatment responses have been considered and addressed. compliance should be investigated and confirmed. the American Academy of Pediatrics has defined an asthma exacerbation as “an abrupt and/or progressive worsening of symptoms of shortness of breath. or some combination of these. Associated respiratory distress with documented and quantified decreases in expiratory airflow when measurements of lung function are obtained.g. Instead dose optimization should be pursued by stepping down to a dose that maintains maximal level of control achieved on higher dose. For these difficult to treat patients. 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. These comorbidities have been reported in higher percentages in patients with difficult to treat asthma. they are the mainstay therapy of difficult to treat asthma while other diagnostic and therapeutic options should be considered as vocal cord dysfunction.

Rosychuk et al recently reported that in Alberta.control of asthma as a baseline. 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. .000 ED visits. 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) . nearly 10% of the paediatric ED visits resulted in an admission to hospital. with one death for every 25.

Usually distress at rest. 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.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. respiratory .

all accessory All muscles muscles involved. display including nasal nasal flaring and flaring Loud paradoxical paradoxical thoraco- thoraco- abdominal abdominal movement movement pan. may accessory and involved.Wheezes might The Chest Moderate expiratory and be wheeze chest inspiratory without wheeze stethoscope (absence of wheeze) SpO2 on room >94% 91–94% is audible silent auscultation and <90% air TREATMENT: The following treatment is institiuted to achieve rapid resolution of exacerbation .

oxygen should be administered by nasal cannula. The closest effective and efficient delivery is by MDI and a spacer device.Oxygen: To achieve arterial oxygen saturation of 95%. although it is considerably more expensive. especially with more severe airflow obstruction. has been shown to be equally effective without increasing side effects. A modestly greater bronchodilator effect has been shown with levabuterol compared to racemic albuterol in both children and adults with an asthma exacerbation. However once children with asthma are hospitalized after intensive emergency department treatment. the addition of .the long acting bronchodilator formoterol which has both a rapid onset of action and long duration of effect. PaCO2 worsen in some patients on 100% oxygen. Rapid acting inhaled beta 2 agonists: Rapid acting inhaled beta 2 agonists should be administered at regular intervals. Oxygen therapy should be titrated against pulse oximetry to maintain satisfactory oxygen saturation. 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. by mask or rarely by head may box in some infants. Although most rapid acting beta 2 agonists have a short duration of effect . Combination of beta 2 agonist and ipratropium bromide is associated with lower hospitalization rates and greater improvement in lung functions.

Previous exacerbations require oral glucocorticosteroids. 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. Systemic glucocorticosteroids: Systemic glucocorticosteroids speed resolution of exacerbations and should be utilized in the all but the mildest exacerbations especially if. 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 . inhaled ipratropium bromide and IV systemic glucocorticosteroids. Oral glucocorticosteroids require at least 4 hours producing clinical improvement. the exacerbation develops even though the patient was already taking oral glucocorticosteroids. theophylline has a minimal role in the management of acute asthma. IM administration may be helpful especially if there are concerns about compliance with oral therapy. Theophyllines: In view of safety and cost effectiveness of rapid acting beta 2 agonists. If vomiting gas occurred. the initial rapid acting beta 2 agonists fail to achieve lasting improvement. 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. 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. then equivalent dose should be re-administered intravenously.nebulized ipratropium bromide to nebulized beta 2 agonist and systemic glucocorticosteroids appears to confer no extra patients being discharged from the emergency department.

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. 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: . 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. especially patients with more severe attacks.adequate in most one study. including hospitalizations. Patients discharged from the ED on prednisone and inhaled budesonide have a lower rate of relapse than those on prednisone alone. Evidence suggests that there is no need to taper the dose of oral steroids. Inhaled Steroids: Inhaled steroids are effective as part of therapy for asthma exacerbations. 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. 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. Inhaled steroids can be as effective as oral steroids in preventing relapses. either in the short term or over several weeks as long as the patient is on the maintenance inhaled glucocorticosteroids.

it might be considered for patients who do not respond to standard therapy. Taken together. the age when these changes begin in asthma has not yet been defined precisely. the characteristic histopathologic features of thickening of the laminar reticularis and eosinophil inflammation were absent. 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. 2005). Leukotriene Modifiers: There is little data to suggest a role for leukotriene modifiers in acute asthma. Recently. regardless of bronchodilator reversibility or atopic status. school-aged children who had difficultto-control asthma. 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. these data indicate that the airway inflammatory responses and structural changes that are characteristic of asthma develop during . 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. and both school-aged children and adults who did not have asthma (Saglani et al. In the infants who had wheezing. 2001).A systematic survey of studies have evaluated that there is no role of helium oxygen compared to helium alone.

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. the most common cause of asthma symptoms is viral respiratory infection. or wheezing apart from colds. the physiologic changes associated with asthma. Among children 5 years of age and younger. More recently. or other structural factors in producing wheeze with acute viral upper respiratory infections are unknown. a physician diagnosis of atopic dermatitis. and not precede.the preschool years and may follow. bronchial smooth muscle abnormalities. At present. however. asthma control has been introduced as a method to assess the adequacy of current treatment and inform asthma management The initial classification .first on the initial visit and other assessing the clinical control 4 to 6 weeks of the pharmacologic intervention. ≥4 percent peripheral blood eosinophilia. an asthma predictive index has been developed that identifies risk factors for developing persistent asthma. OR two of the following: evidence of sensitization to foods. the relative contributions of airway inflammation. No absolute markers are available to predict the prognosis of an individual child. ANNEXURES: There are two classifications of asthma. or evidence of sensitization to aeroallergens. 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.

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

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