A worldwide increase in the prevalence of asthma has been reported in recent years. With an increase in prevalence comes an increased burden of disease in terms of morbidity, mortality and compromised quality of life. The economic burden in terms of utilization of healthcare resources and limitation of the earning capacity of the individuals and families is an added problem. Various indicators such as disability adjusted life years and healthy life years have been used to define the economic burden. The data from Asian countries regarding these parameters in scarce, underlining the need of systematic studies in these countries, especially those that are resource poor. The present review highlights the varying prevalence of asthma in Asia and assesses the likely economic burden for the future.

The prevalence of asthma symptoms has been assessed by the International Study of Asthma and Allergies in Childhood (ISAAC) in several Asian Countries using a standardized questionnaire. The results of the ISAAC study suggest substantial worldwide variations in the prevalence of symptoms of allergic rhinoconjunctivitis, asthma ad atopic aczema. As part of the ISAAC study, prevalence surveys were conducted among representative samples of school children for locations in Europe, Asia, Africa, Australia and North and South America.² In total 257,800 children aged 6–7 years from 91 centres in 38 countries and 463,801 children aged 13–14 years from 155 centres in 56 countries were surveyed. Written symptom questionnaires translated from English into the local language were self completed by the 13–14 year olds and completed by the parents of the 6–7 year olds. Within each age group the global pattern was broadly consistent across each of the symptom categories. The lowest prevalence of asthma was found in parts of Eastern Europe and South and Central Asia. In Asia, the prevalence ranged for 1.5% in Nepal to 6.2% in Hong Kong and the United Arab Emirates. High prevalence was reported from centres in several regions. These differences, if real, may offer important clues to environmental influences on allergy and underline the need for planned allocation and distribution of resources. Another survey estimated the prevalence of childhood asthma in urban areas in China in order to assess the influences of asthma on patients social lives and their families.³ A nationwide randomized survey, covering 43 cities in 31 provinces, on the prevalence of childhood asthma was carried 4out by the National Paediatric Cooperative Group of Asthma Research from June to October

We compared the healthcare utilisation and work days lost for individuals with and without asthma in Chandigarh, India. Individual data on self-perceived asthma problems, self-reported utilisation of outpatient care and official data on inpatient care and work days lost were obtained from our Allergy and Asthma Clinic. Independent t-tests were performed to compare average differences in primary care visits, emergency room visits. days in hospital and work days lost for parents and patients. Compared with the general population individuals with asthma were found to make outpatient department visits and emergency visits and be hospitalised according to the following ratios: 3.1/1.0. 7.9/ 1.0 and 9.3/ 1.0/year, respectively. For work days lost, the ratio was 3.9/1.0. All differences were statistically significant. The self-reported data provided evidence of the burden of asthma to individuals and society. There is a great degree of variability in the healthcare standards in various private and government-funded facilities in India. General private practitioners deliver a large 9proportion of health care at a relatively higher cost. Hence generalisation of the estimation of expenditure is flawed due to a lack of uniformity in the cost structure of healthcare services.

Asthma is known to reduce the quality of life of its sufferers. Most studies relating to quality of life come from the developed world. Appropriate measures to estimate quality of life in developing countries with diverse cultural beliefs, values and convictions are practically non-existent. Some attempts have been made in this direction but the wider applicability of these measures needs to be validated.¹² Asthma education and quality of life in the community have been studied in the South Asian population residing in the UK.¹³ It was evaluated whether asthma morbidity in minority groups can be reduced by preventative healthcare measures delivered in the relevant ethnic dialects. Clinical outcomes and quality of life from a community-based project investigating white European (W/E) and Indian subcontinent (ISC) ethnic groups with asthma living in deprived inner city areas of Birmingham, UK were reported. Six hundred and eightynine asthmatic subjects (345 W/E, 344 ISC) of mean (SD) age 34.5 (15) years (range 11–59) and mean forced expiratory volume less than 80% predicted were interviewed in English Punjabi Hindi or Urdu. Subjects randomised to the active limb of a prospective, open, randomised, controlled, parallel group, 12-month follow-up study underwent 10individually based asthma education and optimisation of drug therapy with 4-monthly follow up (active intervention), Control groups were only seen at the beginning and end of the study. Urgent or emergency interactions with primary and secondary health care (clinical outcomes) and both cross-sectional and longitudinal data from an Asthma Quality of Life Questionnaire (AQLQ) were analysed. Clinical outcomes were available for 593 subjects. Fewer of the active intervention group consulted their general practitioner (GP) (41.8% vs 57.8%, OR 0.52, 95% CI 0.37-0.74) or were prescribed antibiotics (34.9% vs 5 1.2%, OR 0.51, 95% CI 0.36-0.72). However, by ethnicity, statistically significant changes only occurred in the W/E group with fewer also attending accident and emergency departments and requiring urgent home visits. Active intervention reduced the number of hospital admissions (10 vs 30), GP consultations (341 vs 476), prescriptions of rescue oral steroids (92 vs 177) and antibiotics (220 vs 340) but significant improvements by ethnicity only occurred in the active W/E group. AQLQ scores were negatively skewed to the higher values. Regression analysis showed that lower values were associated with ISC ethnicity. Longitudinal changes (for 522 subjects) in the mean AQLQ scores were small but statistically significant for both ethnic groups, with scores improving in the active group and worsening in the control group. It was concluded that active intervention only improved clinical outcomes in the W/E group, AQLQ scores, although lower in the ISC group, were improved by active intervention in both ethnic groups.

It is estimated that asthma accounts for about one in every 250 deaths worldwide. Comparison of asthma 11mortality between different countries has been made using asthma mortality rates in the 5–34-years age group because the diagnosis of asthma mortality is firmly established in this age group. Many deaths are preventable as they are due to suboptimal long-term medical care and delay in obtaining help during the final attack. Standardised data on deaths due to asthma are not available in most South Asian countries. We have had more than 7000 patients with asthma registered in our Allergy and Asthma Clinic since 1973 who come from different parts of the country: the majority come from the Northern region. Not a single death has been recorded in any of these patients who have had variable periods of follow-up.

Disability-adjusted life years (DALYs) is a measure of the burden of disease that assesses the years of healthy life lost due to disease or illness. DALYs combine information about morbidity and mortality in terms of healthy years lost. The calculation of disease-specific health loss in DALY s is the sum of years of life lost (YLLs) and years lived with disability (YLDs) weighted for severity. Each state of health is assigned a disability weighting by an expert panel on a scale from zero (perfect health) to one (death). To calculate the burden of a disease the disability weighting is multiplied by the number of years lived in that health state and is added to the number of years lost due to that disease. The number of DALYs lost due to asthma worldwide has been estimated to be about 15 million/year Worldwide, asthma accounts for around 1% of all DALYs lost, which reflects the high prevalence and severity of asthma. Asthma was the 25th leading cause of DALYs lost worldwide in 2001. The number 12of DALYs lost due to asthma is similar to that for diabetes, liver cirrhosis or schizophrenia. The burden of disease in terms of DALYs has not been calculated for most Asian countries: however some indirect attempts have been made. While developing a draft measure of the burden of diseases in Sri Lanka using DALYS.¹⁴ computation was done for 100 disease categories identified to reflect the disease pattern in Sri Lanka. Factors that were considered for the calculation of DALYs were incidence, degree of disability, duration of illness and age at onset. Injuries, ischaemlc heart disease, asthma, disease of the pulmonary circulation and burns contribute to 55% of the burden of disease in Sri Lanka. The highest burden was due to non-communicable diseases. as their duration and degree of disability are high. YLDs contribute nearly two-thirds of the DALYs worldwide and are particularly important in developing countries where infant and child mortality is still high. These were estimated for India under the global burden of disease study in 1990. A study estimated different causes of YLDs in rural areas of India. Pneumonia was the top cause responsible for YLDs; heart attacks bronchitis and asthma had lower YLDs.¹⁵ For children living in developing countries. A study has identified the major causes of ill health that are Inadequately covered by established health programmes.¹⁶ Injuries and non-communicable diseases notably asthma, epilepsy, dental caries, diabetes mellitus and rheumatic heart disease have been identified as growing in significance. In countries where resources are scarce, it is to be expected that increasing importance will be attached to the development and implementation of measures against these problems. This study evaluated the major causes of ill health that are not covered by global health programmes 13among children in developing countries. Assessments were based on a set of death and disability estimates. Causes of death were classified as: (1) infectious, maternal, perinatal and nutritional conditions: (2) non-communicable diseases: or (3) injuries. DALYs were used in estimates of disease burden. Childhood disease burden In 1990 among regions, age groups and sex were compared using DALYs/1000 population and presented in table form. Among childhood disease burdens infectious, perinatal and nutritional disorders ranked first (72%), followed by non-communicable diseases including asthma (15%) and injuries (13%); these values are significantly higher in developing countries than in developed regions. This study has special relevance for South Asia where programmes directed against infectious, nutritional and perinatal disorders need to be applied to the control of non-communicable diseases. The importance of community involvement, family education and social marketing needs emphasising in the formulation and implementation of these control measures. In the last decade a number of quantitative epidemiological studies of specific diseases have been undertaken in developing countries. This allows for the first time, estimation of the total burden of disease (mortality and morbidity) attributable to use of solid fuels in adult women and young children who jointly receive the highest exposures because of their household roles. Few such studies are available to date for adult men or children over 5 years of age. A paper has evaluated the existing epidemiological studies and applied the resulting risks to Indian households dependent on such fuels (>75%).¹⁷ Allowance was made for the existence or improved stoves with chimneys and other factors that may lower exposure. Attributable risks were calculated in 14reference to the demographic conditions and patterns of each disease in India. Sufficient evidence was available to estimate risks most confidently for acute respiratory infections chronic obstructive pulmonary disease and lung cancer. Estimates for tuberculosis asthma and blindness were of intermediate confidence. Estimates for heart disease had the lowest confidence. Insufficient quantitative evidence is currently available to estimate the impact on adverse pregnancy outcomes (e.g. low birth weight and stillbirth). The resulting conservative estimates indicate that 400,000–550,000 premature deaths can be attributed annually to use of biomass fuels in these population groups due to respiratory diseases including asthma.

Patients with difficult-to-treat or suboptimally controlled asthma consume a disproportionate share of asthma healthcare resources.¹⁸ Treatment strategies that minimise exacerbations may decrease the need for unscheduled medical services reduce emergency department visits and minimize asthma-related hospitalisations. Poor control of symptoms is a major issue that can result in adverse clinical and economic outcomes. Prescribing costs are the most obvious visible expense in asthma care but these are only the tip of the iceberg. We need to take all factors into account when considering the overall cost of asthma treatments and recognise that treatment which results in better asthma control may reduce both direct and indirect costs. To assess this accurately health economic evaluations need to be undertaken in relevant settings on representative populations. They need to use appropriate measures of asthma outcome. Drug related costs need to take into account savings 15made by decreased costs of other prescribed medication and patient factors. We need information that is applicable to the types of patients we see in the real world to make proper cost analyses. Such information can come from good-quality randomised trials, retrospective analysis of research databases and observational studies, or using primary care clinical and prescribing databases.¹⁹ Asthma self-management training can significantly affect the health status and resource use of patients with chronic asthma.²⁰ A randomised controlled trial on chronic asthmatic patients was conducted in a tertiary care centre in India. The intervention group (153 patients) received four training sessions in addition to the regular care provided to the control group (150 patients). Health status and resource use were measured at baseline and over a 1-year follow-up period. The intervention group had significantly better health status (measured by breathing ability) fewer productive days lost and lower resource use (hospitalisations and emergency room visits) than the control group. Total annual costs (direct and indirect) were also lower, although physician costs were not included in the assessment. It was concluded that the incorporation of asthma self-management training as part of clinical management of asthma can result in improvements in health status and reductions in hospital use.

Allergic asthma is a disease characterized by intermittent airway obstruction that causes difficulty in breathing and, in the most severe cases, death from asphyxiation. Ultimately, airway obstruction is mediated by hyperresponsive bronchial smooth muscle, secreted airway glycoproteins, and inflammatory debris produced by airway goblet cells and other cells, as well as edema or swelling of the airway wall. Although the precise basis for the development of airway inflammation in patients with asthma is not fully defined, recent developments in experimental models have helped us understand some basic mechanisms that take place in at least some forms of asthma. Mouse models are not exact replica of human asthma; however, they have helped to understand some of the basic mechanisms involved in the production of this disease.¹ Observations from mouse models of allergic asthma support many existing paradigms, although some novel discoveries in mice are yet to be verified in humans.

Most of the classic descriptions of the pathologic patterns of asthma have been derived from autopsy studies.^2–4 These studies based on individuals who died in status asthmaticus describe overinflation of 19the lungs and mucus plugs occluding medium-sized bronchi, small bronchi, and bronchioles. In recent articles, however, there are descriptions derived from bronchoscopic biopsies.^5–13 These studies have provided a bronchoscopic and pathologic description of early and mild forms of the disease. It is well known that overinflation is seen in asthmatic patients. This gross appearance is seen in individuals who die in status asthmaticus, but the lungs may appear normal between attacks. The lungs fill the chest cavity during status asthmaticus and do not collapse when the pleural space is opened. Overdistention must be distinguished from emphysema because emphysema implies destruction of alveolar parenchyma, which rarely occurs in asthmatic patients, most likely because the asthmatic attacks are intermittent. In contrast, bronchiectasis can be seen as a complication of asthma and has been described in 15% to 20% of patients.^2–4

Airways of asthmatic patients may be normal or they may show only mild histologic changes between asthmatic attacks. Mucous plugs made of heavily viscous inspissated mucus fill both bronchi and bronchioles. These plugs appear to be produced by both submucosal gland hypertrophy and goblet cell hyperplasia. It has been reported that the proportion of both mucin and goblet cells in the epithelium may be up to 3 times higher in asthmatic patients than in controls.¹⁴

A series of progressive structural changes of the airways is known as airway remodeling. These 20changes most likely occur as a result of repeated episodes of inflammation with production of matrix proteins and growth factors by inflammatory cells.¹⁵ It is also possible that repeated damage to the epithelium, with subsequent repair, may lead to airway remodeling.¹⁶ It is conceivable that airways that undergo significant remodeling may not respond to bronchodilators because of reduced elasticity, increased muscle mass, and mucosal edema.¹⁷

A number of well-known changes occur in the airway epithelium of asthmatic patients. Goblet cell hyperplasia is a common histopathologic finding, although not specific for asthma.^{18, 19} Other common findings are the presence of mucus plugs²⁰ and squamous metaplasia. Areas of denuded epithelium are seen occasionally. It has been proposed that patients with significant epithelial desquamation present with persistent rather than intermittent asthma¹² as a result of direct exposure of nerve endings to factors that would trigger the inflammatory response; whorls of detached epithelium may form Creola bodies and Curschmann spirals. The airway wall can be thickened from edema, an increase in smooth muscle, and an increase in the size of the submucosal mucous glands. Airways are infiltrated by eosinophils. Mucus may contain many eosinophils with Charcot-Leyden crystals.²¹

Light microscopy has revealed that what has been interpreted in the old literature as basement membranes are usually thicker in asthmatic 21individuals than in nonasthamtic individuals.^{2, 8} However, in a manner reminiscent of the situation seen by the pathologist in collagenous colitis, what light microscopic studies refer to as “basement membrane thickening” has been determined by ultrastructural and immunohistochemical studies to be deposition of types III and V collagen as well as fibronectin beneath the true basement membrane that is usually of normal thickness.⁸ The mechanism of production of this reticular basement membrane is controversial but it has been suggested that activated eosinophils are involved through the production of cytokines such as transforming fibroblast growth factor (TGF-β), which is a potent profibrotic cytokine.²² In some studies, basement membrane in central airways from nonasthmatic individuals measures between 6 and 10 mm, but in asthmatic patients it ranges from 11 to 22 mm.²³

Bronchial submucosal glands are increased in size in individuals with asthma, but at some stage, patients with chronic bronchitis also show increased bronchial submucosal glands, which is the basis for the Reid index in chronic bronchitis.^24–27 In fact, increased bronchial submucosal glands apparently are found in individuals with recent onset of asthma rather than in patients with long-standing asthma.²⁸

Patients dying of status asthmaticus have a 2-fold to 3-fold increase in the amount of airway smooth muscle, especially in the medium-sized bronchi. This finding has been well documented by several 22morphometric studies.^29–31 Smooth muscle thickness in asthmatic patients appears to increase with age.³² It has been proposed that myofibroblasts play a role in this smooth muscle thickening and also in the reticular basement membrane thickening because of the production and deposition of fibronectin in the bronchial mucosa.³³ Presence of myofibroblasts has been associated with local expression of TGF-β produced by eosinophils and fibroblasts;³⁴ some studies show that basal TGF-β1 levels in the airways are elevated in atopic asthma. The TGF-β1 is upregulated 24 hours after allergen stimulation.³⁵ It is thought that these levels increase further in response to allergen exposure. These findings are consistent with the hypothesis that TGF-β1 plays an important role in airway wall remodeling in asthma.

Asthma is a chronic inflammatory condition, and evidence of inflammation can be observed in mild, moderate, and severe disease. However, the relative magnitude, type of inflammatory cells, and site of the inflammatory infiltrate may differ among patients. Many cells are involved in the immune and inflammatory responses to allergens in asthma; these include T cells, eosinophils, mast cells, and neutrophils. The role of the activated T lymphocyte in controlling and perpetuating chronic inflammation in asthma has received much attention.³⁶ In some studies, T cell activation can be related to measures of asthma severity, such as the degree of airway narrowing or airway hyperresponsiveness (AHR), as well as the bronchial eosinophil response.³⁷ The association between tissue eosinophilia and asthma is strong, but the degree of tissue eosinophilia varies 23with each case and with the duration of the terminal episode.^38–39 Dendritic cells and their subtypes are key antigen-presenting cells that respond rapidly to antigenic challenge with kinetics similar to those of neutrophils.⁴⁰ They form an interface between innate and adaptive immunity and orchestrate both primary and secondary immune responses.⁴¹ They are present throughout the respiratory tree and number approximately 500 cells per mm2 within the epithelium.⁴² Inflammatory cells and immune responses are regulated by a number of immune mediators that are secreted from inflammatory and structural cells. In this review, we focus on cytokines and chemokines and their possible role in the immunobiology of asthma.

Cytokines are a family of small glycosylated proteins that are involved in cell-to-cell signaling, cellular growth, differentiation, proliferation, chemotaxis, immunomodulation, immunoglobulin isotype switching, and apoptosis. The actions of cytokines are mediated through specific cytokine receptors on the surfaces of target cells. Although cytokines usually have effects on adjacent cells, they can act at a distance and can have effects on the cells producing the cytokines themselves. Many of these cytokines exhibit pleiotropy and have overlapping functions, making their individual roles in the pathogenesis of asthma and allergic disease difficult to differentiate. Among these cytokines are T cell-derived molecules such as the so-called T helper-1 (Th1) cells [interleukin (IL)-2, interferon (IFN)-g, and IL-12], Th2 cells (IL-4, -5, -9, -13, and -25), Th3 or T regulatory cytokines (IL-10) and transforming growth factor beta (TGF-β)], and Th-17 cells (IL-17A and -17F), all of which are involved in 24the regulation of cell-mediated and humoral immunities. Although the distinction between Th1 and Th2 cells in humans is not as clear as in mice, there is overwhelming evidence in the literature supporting the notion that allergic inflammation is driven by an imbalance between Th1 and Th2 cytokines, favoring the Th2 arm of the immune response. Recently, Th-17-associated cytokines were also implicated in asthma immunobiology

A central mediator in atopic asthma is the IgE antibody, which is produced by sensitized allergen-specific B cells. Allergens are antigens that can (a) elicit hypersensitivity or allergic reactions and (b) increase IgE levels in the serum in susceptible subjects subsequent to stimulation. By presenting the allergen fragments in conjunction with the major histocompatibility complex (MHC), B cells can activate specific Th2 cells to produce numerous cytokines, leading to further B cell activation and antibody release. IgE antibodies bind to the high-affinity IgE receptor Fc epsilon receptor I (FceRI) that is present on mast cells, eosinophils, and basophils, thereby sensitizing these cells to antigen exposure. Subsequently, cross-linking of adjacent IgE-FceRI complexes by allergens triggers (a) the degranulation of cytoplasmic vesicles containing histamine and (b) the de novo formation of eicosanoids and reactive oxygen species. This results in smooth muscle contraction, mucous secretion, and vasodilatation, all of which are hallmarks of asthma. IgE-producing B cells play a critical role in allergic inflammation; consequently, factors responsible for their activation-namely IgE-associated cytokines such as IL-4, IL-9, and IL-13.

Eosinophils are prominent in allergic airway disease and are still considered by many to be the hallmark of asthma. Otherwise, eosinophils form part of the host defense against parasitic infestation. The biological activity exerted by these cells is largely attributable to their release of prestored granular proteins, including eosinophil cationic protein, eosinophil peroxidase, and major basic protein. These potent cytotoxic proteins have been found in high concentrations in the sputum of asthmatic patients and are thought to play an important role in the epithelial damage observed in asthmatic patients. In addition to cytotoxic proteins, eosinophils can synthesize and release oxygen radicals and lipid mediators (e.g., LTB4, LTC4, and PAF), as well as numerous cytokines (e.g., IL-1, -2, -3, -4, -5, -6, -10, -12, and -13; TNF-α and GMCSF) and chemokines (e.g., IL-8, RANTES, and MIP-1a)

It has long been known that architectural and structural changes occur in the airways of asthmatic patients. These changes include collagen (type III and IV) and fibronectin deposition, increased thickness of subepithelial basement membrane, goblet cell hyperplasia, increased ASM mass and size, angiogenesis, and fibrosis, all of which collectively contribute to the phenomenon known as airway remodeling. The functional consequences of airway remodelling include persistent AHR and mucous hypersecretion, which contribute to increased susceptibility to asthma exacerbations. The mechanisms involved in airway remodeling are poorly understood, but research in the past three to five years 26suggests that the balance between matrix metalloproteinases and tissue inhibitors of metalloproteinases may play a role in this process. Moreover, the increase in Airway Smooth Muscle content, along with a change in the phenotype of fibroblasts to contractile myofibroblasts, may explain the permanent reduction in airway caliber, which is steroid insensitive and typical in patients with severe forms of the disease. The predominant remodeling-associated cytokines include TGF-β, PDGF, IL-6, IL-11, IL-13, IL-17, and IL-25.

It is now generally accepted that adult atopic disease is characterized by the expression of T cell immunity to common airborne environmental allergens, which is polarized toward the Th2-cytokine profile; in nonatopics, Th1- skewed immunity is observed. As a result, shifting the balance from Th2 to Th1 immunomodulatory cytokines such as IL-10, IL-12, and IFN-γ may be important for the treatment of allergic inflammation. IL-10 is primarily known as an inhibitory cytokine; however, it can exert both immunosuppressive and immunostimulatory effects. IL-10 was originally identified as a product of murine Th2 cells, but in humans IL-10 is produced by Th0, Th1, and Th2 cells and also by activated monocytes, mast cells, and macrophages.⁴³ IL-10 curtails the effects of proinflammatory cytokines (e.g., TNF-a, IL- 1b, IL-6, IL-8, and MIP-1a) released during an allergic reaction. In addition, IL-10 can inhibit eosinophil survival and migration by preventing the release of chemoattractants such as RANTES and IL-8 from human ASM cells.⁴⁴ Its other actions include downregulation of the IL-4-induced isotype switching 27of activated B cells⁴⁵, which prevents IgE synthesis. IL-10 may inhibit Th2- driven inflammation, and it is also known to inhibit the differentiation of Th1 cells, thereby preventing the release of IFN-γ and IL-2. Other members of the IL-10 family of cytokines are IL-19, IL-20, IL-22, and IL-24. Like IL-10, they are considered to be anti-inflammatory cytokines and are produced by a variety of cell types, including monocytes, keratinocytes, mast cells, and lymphocytes. IFN-γ is the most important cytokine in cell-mediated immunity; it controls the balance of Th1/Th2 development. IFN-γ is produced by Th1 cells and has an inhibitory effect on Th2 cells. IFN-γ inhibits allergic responses by preventing isotype switching of IgE and IgE production in B cells.⁴⁶ The main sources of IFN-γ are Th1 cells. However, IFN-γ can also be produced by cytotoxic T cells and natural killer (NK) cells. Importantly, IFN-γ stimulates monocytes, NK cells, and neutrophils to increase their cytokine production, phagocytosis, adherence, respiratory burst, and NO production, thereby promoting cell-mediated cytotoxic responses at the site of inflammation. IL-12 is produced by antigen-presenting cells including B cells, monocytes, macrophages, Langerhans cells, and dendritic cells, as well as neutrophils and mast cells. IL-12 promotes T cell differentiation toward a Th1-mediated response by stimulating NK and T cells to produce IFNγ while suppressing the expansion and differentiation of IL-4 secreting Th2 cells.⁴⁷ The biologically active form of IL-12 is a heterodimer consisting of the p40 subunit and the p35 subunit, which are expressed by different genes. The effects of IL-12 have been extensively studied in small animal models of allergic inflammation and consistently demonstrate that this cytokine is involved in reduction of allergen-specific IgE, abolition of AHR, and airway 28eosinophilia.^{48, 49} However, this effect of IL-12 is critically dependent on the timing of its administration. The most effective protection against allergen-induced inflammation is observed when IL-12 is administered early in the active sensitization process and thus when it can act in synergy with IL-18.⁵⁰ IL-18, also known as IFN-g-inducing factor, is a potent inducer of IFN-γ production by T cells, NK cells, and B cells.⁵¹

Chemokines are small cytokines (8-10 kDa) involved primarily in a process called chemotaxis, whereby they attract and regulate leukocyte trafficking into the tissues by binding specific seven-transmembrane-spanning G proteincoupled receptors. To date, more than 40 chemokines have been described and have been classified into four subclasses according to their structure: CXC, CC, C, and CX3C. The two main groups are CXC (a chemokines) and CC (b chemokines). CXC chemokines include IL-8 and IP-10, which primarily target neutrophils. Eotaxin, RANTES, MCP-1-MCP-4, macrophage inhibitory protein (MIP)-1a, and MIP-1b are typical CC chemokines, which target monocytes, T cells, and eosinophils. For this reason, CC chemokines are thought to have the greatest relevance in the pathogenesis of asthma. Although the primary role of chemokines is chemotaxis, chemokines have a variety of other functions, including direct effects on T cell differentiation. MIP- 1a, MIP-1b, and RANTES can promote the development of IFN-γ-producing Th1 cells by stimulating IL- 12 production from antigen-producing cells. However, MCP-1, MCP-2, MCP-3, and MCP-4 can increase T cell production of IL-4 and can decrease antigen-producing cells' production of IL-12, resulting in a Th2 phenotype.

The reasons for the increasing prevalence of allergic respiratory diseases in developed countries and in undeveloped countries that develop a Western lifestyle remain unclear. For many years, lower respiratory tract infections in early life have been recognized as primary triggers of asthma exacerbations in young children. Using both epidemiological and virology data, prospective studies have convincingly shown that viral and not bacterial respiratory infections precipitate reactive airway symptoms.⁵² It is now believed that the development of bacteria-induced, non-wheezing lower respiratory tract infection in childhood may protect against the development of atopy and asthma in later life. Microbial exposure helps to skew the immune response away from allergic phenotype and toward the normal adult nonatopic immune response.⁵³ The longer the immune system takes to adapt postnatally to its functionally mature state, the greater is the risk for allergic sensitization.⁵⁴ The hygiene hypothesis suggests that decreasing levels of exposure to infections and/or commensal microbial stimuli in developed countries, particularly during the induction of primary Th1/Th2 responses to allergens in early life, may be responsible for the increased prevalence of asthma. There is ample epidemiological evidence to support this hypothesis.⁵⁵ The reported increase in atopy inversely correlates with a steady decline in the extent to which people in Western societies are exposed to infectious diseases such as whooping cough, measles, tuberculosis, and influenza.⁵⁶ Bacterial lipopolysaccharide (LPS) or endotoxin has been suggested as a potential mediator of these effects. LPS is a major component of the outer 30membrane of ubiquitous gram-negative bacteria. Gram-negative infections make up a significant proportion of clinical respiratory tract infections among children in early life; thus, there is ongoing and chronic environmental exposure to gram-negative organisms and their components/products. In common house dust, LPS makes up a significant proportion of dust weight, and a significant correlation has been reported between domestic LPS exposure and clinical severity of asthma in adults.⁵⁷ Toll is a Drosophila receptor that is involved in antifungal immune responses. Toll like receptors (TLRs) are a large family of evolutionarily conserved receptors from Toll that sense invasion by microorganisms through the recognition of specific pathogen-associated molecule patterns and that produce immediate innate responses. To date, 10 TLRs (TLR1- 10) have been identified in humans and in mice.⁵⁴ TLRs are single-transmembrane-domain receptors that have a cytoplasmic signaling portion homologous to the IL-1 receptor. Although the TLRs differ in their extracellular domain structure, similar cytoplasmic domains allow TLRs to use the same signaling molecules. Different TLRs recognize different ligands. TLR3 is a cell-surface receptor for doublestranded RNA; hence, it may be implicated in viral recognition. TLR5 is specific for bacterial flagellin, whereas TLR9 is a receptor for unmethylated CpG motifs, which are abundant in bacterial DNA. In mammals, TLR4 is the principal receptor responsible for LPS induced signal transduction.⁵⁸ Recognition of LPS by TLR4 is aided by two accessory proteins: CD14 and MD-2. TLR4 is expressed at particularly high levels by cells of the innate immune system, such as monocytes, dendritic cells, macrophages, and endothelial cells.^59–62 TLR4 expression is thought to be related to LPS sensitivity,⁶³ 31and it was recently demonstrated in murine macrophages that TLR expression and function decline with age.^{64, 65}

Pediatric asthma is a major global health problem, which exerts a substantial burden on the family, healthcare services and on the society as a whole. Although the first symptoms of asthma can occur at any age, recurrent episodes of wheezing and airway obstruction manifest before the age of 6 years in most patients. This suggests that asthma, at any age, is likely to originate in childhood or earlier, therefore, observation in children and models of early life or infant airway injury and repair will provide important clues to the inception and pathogenesis of this disorder. It is believed that the expression of the asthmatic phenotype is dependent upon two major factors: a genetic predisposition and environmental interactions. It is the combination of these inferences that ultimately determines whether asthma develops and what time these processes manifest. There is an inverse association between infectious burden in early life and the development of atopy and asthma. Children who have frequent respiratory infections and pneumonia have a lower prevalence of asthma. Such findings suggest that increased exposure to infections in infancy may protect against the development of asthma. Several investigators have proposed the “hygiene hypothesis” as a mechanism by which these protective effects are produced. The hygiene hypothesis postulates that reduced exposure to 39environmental influences (such as infections) that produce a Th1 type immune response has led to a persistence of “fetal” immune responses that are Th2 skewed and that persistence of Th2 type responses has led to increased, susceptibility to allergic disease. During early childhood there is a transition from the fetal Th2 cytokine phenotype to the adult Th1 cytokine phenotype. The timing of this transition is influenced by both environmental and genetic factors. Microbial exposure is thought to be the major environmental trigger for the maturation of immune responses in the newborn.¹ Moreover, there are indications that exposure to an environment with a high bacterial load is particularly important in the first year of life in order to acquire protection from asthma and other allergic diseases. Keeping, this in mind, this follow up study of infants, has been designed to study the effect of bacterial infections on the neonate immune response.

The continuous increase in asthma can not only be due to the genetic defects but may be due to the environmental factors. Viewing the neonatal immune system and exposure to infections we need to know how infections in infancy can delay the adverse effects of immune responses. The Th2 biased immune response of the neonate switches to Th1 response with time by various harmful and harmless exposures to microbes. But with increasing cleaner environments and thus decreased exposures the switch does not take place at the appropriate time during infancy, and results in the persistence of Th2 responses which leads to the fatal allergic reactions. Evidence from the ISAAC study showed that the distribution of childhood 40asthma varies between global populations from less than 2% to approx 33% of the population. Furthermore, the prevalence also appears to vary within countries. Prevalence has been recorded to be 17–30% in the UK, New Zealand, and Australia, whereas low prevalence (1-7%) areas include Eastern Europe, China and South Asian countries. For example across India it ranges from less than 5% to approximately 20%.² This variation has been attributed to the healthcare in the western world, which leads to a diminished or different exposure to infection early in life. This exposure renders the immune system susceptible to an atopic response³ which also includes childhood respiratory disease, allergen exposure, dietary changes⁴ and socioeconomic differences.⁵ Till date, there have been few studies on the role of natural killer cells and other components of the innate immune response, in this regard, but this should be studied in both animal model and in humans. Taking into account the complexity of asthma, the cost of time and money as well as the problems faced by the asthma patients one has the reason to justify the extensive efforts put by the researchers to relieve the suffering caused by these disorders. The immune system serves to protect the host from infection and cancer but some of the inappropriate responses of the immune system can lead to variety of diseases. The common dysfunctions of the immune system are allergies and asthma, and both of them are serious health problems. Exposure to the antigen or allergen triggers an IgE mediated release of molecules that cause symptoms ranging from sneezing and dermatitis to inflammation of the lungs in an asthmatic attack.

One of the striking advances in the last decade has been the recognition that cytokines and chemokines play a critical role in orchestrating, perpetuating and amplifying the inflammatory response leading to the pathophysiology of asthma.⁸ The inflammation characteristics of asthma are different from other respiratory infections. Subsets of T-helper (Th) lymphocytes have been defined and are distinguishable by a differing pattern of cytokine release. Th1 type cells stimulate the recruitment and activity of macrophages and mononuclear phagocytes and are involved in the cellular immunity activated by microbial antigens typically resulting in IgG antibody production without an increase in IgE.⁹ They produce interleukin (IL)-2, interferon (IFN)-γ and tumor necrosis factor. Th2 responses are important in the 42allergic response and asthma, producing the cytokines IL-4, −5, −6, −10 and −13 and are involved in the humoral immune response with elevated IgE levels and eosinophil.⁹ Complex antagonistic interrelationship exists between the two subsets and the cytokine milieu. Th2 cytokines play an important role in the pathophysiology of allergic diseases, including asthma and have shown to be very useful therapeutic targets in the future management of allergic diseases. Considering this several approaches inhibiting these cytokines are now being tested in clinical trials or are in active development.⁸ Soluble interleukin (IL)-2 receptor levels are raised in children with asthma, suggesting that activated T cells are important in childhood asthma. Current data supports the predominance of a T helper 2 phenotype in allergic asthma.¹⁰ Allergens induce CD4+ T helper cells to produce type-2 (Th2) cytokines such as IL-4, IL- 5, IL-6, IL-10 and IL-13. IL-5 attracts and activates eonsinophils while IL-4 is essential for B cell isotype switching to Ig E. CD 8 + T cells may lead to Ig E class switching via IL-13 rather than IL-4. These events lead to eosinophilic bronchitis, mucus-hyper secretion and bronchial smooth muscle contraction.¹¹ However, some studies suggest that T helper type 1 (Th 1) cytokines such as IL-2, interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-γ) and IL-15 may promote allergic inflammation as well¹²,¹³. Leukocyte migration is essential for immune surveillance of the body's tissues, and for focusing immune cells to sites of antigenic challenge. The control of leukocyte migration depends on the combined actions of the various adhesion molecules, as well as a vast array of chemotactic cytokines (chemokines) and their receptors. The chemokine receptors comprise two groups, th e CC receptors 1 to 8 (CCR 1-8) that bind CC 43chemokines, and the CXC receptors 1–4 (CXCR 1–4), which bind CXC chemokines¹⁴,¹⁵. In general, the CC chemokines and their receptors effect the migration of monocytes, eosinophils, basophils and T cells,¹⁶ whereas CXR1 and CXCR2, which are two IL-8 receptors, effect the migration of neutrophils.¹⁴ Many recent findings indicate that chemokine receptors are differentially expressed on memory T cells depending on their polarization¹⁷,¹⁸ with Th 1 lymphocytes expressing CCR5 and CXC3, and Th2 lymphocytes CCR3, CCR4, and CCR8. As a consequence, selective chemotactic stimuli contribute to the differential positioning of Th1 and Th2 cells within tissues¹⁷,¹⁹. These results indicate that differential expression of chemokine receptors in Th1 versus Th2 system can serve as markers of these responses and tools to modulate polarized versions of T cell-dependent immunity. The decline in infectious diseases is due in part to the development of better sanitation and a cleaner living environment. Lately, various scientists have proposed a theory known as the Hygiene Hypothesis as the cause of increasing asthma prevalence. According to this theory the society has been too successful in its fight against infectious organisms and has eliminated contact with many harmless bacteria and microbes that actually help the immune system build its defenses against more toxic infections. The immune system consists of two basic parts: Th1 lymphocytes, which are specialized white blood cells that directly attack infected cells, and Th2 lymphocytes, which try to prevent foreign organisms from invading cells. Researchers speculate that newborn's bodies primarily rely on Th2 response and the Th1 system can only develop by being exposed to “practice” infections with microbes that cause no harm. Martinez and Holt, 1999 have proposed that 44the hygiene hypothesis postulates that reduced exposure to environmental influences (such as infections) that produce a Th1-type immune response has led to a persistence of “fetal” immune responses that are Th2 skewed and that persistence of Th2 type responses has led to increased susceptibility to allergic disease.²⁰ Studies indicate that exposure to an environment with a high bacterial load is particularly important in the 1st yr of life in order to acquire protection from asthma and other allergic diseases.²¹ Moreover, in humans there is an association between protection against allergy and the presence of antibodies specific for orofecal microbes but not the presence of antibodies against airborne viruses.²² Pregnancy is considered as a Th2 state and there is some evidence that the neonatal immune response is biased toward theTh2 type. When a mother is pregnant, her pregnancy is controlled by cytokines, and requires a suppression of her immune system with a predominance ofTh2 cytokines in order not to reject the baby. A “Thl” driven immune system would treat the baby as a graft from the father, thereby leading to miscarriage. After the Th2-skewed baby is born, the mother's immune system changes back to normal very quickly and breast milk quickly starts the process of changing the baby's balance towards Thl dominance. Microbial infections early in infancy can protect the baby from the development of atopy and asthma later, as the stimulus for normal postnatal maturation of the immunoinflammatory response may be provided by microbial stimulation.²³,²⁴ The first year of life is the time when the “difference” between “vaccine” and “natural” immunity is important. The portal of entry of antigens and switching pathways of the Th1 system from Th2 type teach and mature the immune system which in turn help to prevent both allergy 45development and auto-immune diseases. Cytokines, which protect the fetus from cytokine immune responses, could also affect the development of the fetal immune system. High levels of Th2 like cytokines could reduce secretion of IFN γ and other Th1 cytokines from the fetus, which could bias the developing neonatal immune system towards production of Th2 like cytokines and promote allergy. This concept is supported by studies of cytokine productions from neonatal T cells, which have generally been found to produce relatively low levels of IFN γ and to overproduce Th2 like cytokines. Michel et al (1992) has reported that lipopolysaccharide inhalation (20mg) could induce a local bronchial inflammation as well as a systemic inflammatory response in asthmatic subjects.²⁵ Endotoxins are very potent proinflammatory substances²⁶ present in a variety of domestic²⁵ and occupational dusts.²⁷ The mechanism by which endotoxin exposure may protect against the development of atopic immune responses and diseases are not fully understood. It has been suggested that by the time a child reaches school age, high levels of environmental exposures to endotoxin have resulted in a marked suppression of the capacity for the cytokine production in response to activation of the innate immune system. Studies have indicated that exposure during the first year of life to stables and other aspects of farm life that are likely to reflect exposure to microbial products has a strong protective effect against the occurrence of asthma and atopy at school age. It is currently accepted that respiratory viral infections are important “trigger factors” in the development of allergic respiratory diseases, particularly asthma.²⁸ Unlike viral infections, bacterial infections do not generally trigger asthma and in fact, early exposure to bacterial products may protect the 46individual from development of atopy and asthma later in life.²³ This mechanism further contributes to the variations in the frequency of atopy and asthma that have been reported between first- and second-world countries and points to an inverse relationship between disease prevalence and socioeconomic status. Various workers have demonstrated different kinds of cytokine productions at the time of birth and on acquiring infection during infancy. Karlsson et al. (2002) have demonstrated that gram positive bacterial strains induce high levels of IL-12 in both cord cells and adult cells, where as gram negative bacterial strains are poor inducers of IL-12.²⁹ Apart from the genetic parameters environmental influences are also important determinant in the development of an atopic or asthmatic phenotype. Primary exposure to environments those rich in airborne antigens like house dust mite and orally encountered antigens (Bjorksten et al. 1998) can lead to atopy in genetically affected individuals. The effects of air pollutants, lifestyle factors and urbanization on the development of atopy and asthma are controversial. The environmental factors, which account for atopy and asthma include urban versus rural settings, dietary factors, exercise patterns, experienced infections, or the use of antibiotics which might influence deviation of the immune system away from Th2 responses and towards Th1 responses. Infants who are exclusively breast-fed appear to have decreased risk for development of food allergy than infants who are not breast-fed or who have other food exposures. Moreover urbanization is thought to be a key feature in the development of asthma and atopy. Also decreased incidence of infection and frequent use of antibiotics may also contribute to the development of atopy. Immunization conveys the same immunity to a specific 47disease as catching the disease does. It's the same immune mechanism and results in the same immune response. Natural immunity does provide higher levels of protective antibodies than vaccination, but the type of protection is the same. However, relying on the natural immunity only, means risking the neonate's life and leaving a chance for the disease to develop with severe complications. It was observed by Ota et al., (2002) that Mycobacterium bovis, Bacillus Calmettle Guerin (BCG)3 vaccination induces a potent Th1-type immune response at birth in humans as in mice.³⁰ Today it is the time when scientists are trying to eradicate diseases right from the root with the help of DNA based medicines. Apart from the mutations in interleukin region, there are studies, which strongly suggest that adenosine plays an important role in the pathogenesis of disorders like asthma, COPD and the intestinal disorders.³¹ Adenosine is a purine nucleoside that is produced by dephosphorylation of 5' AMP by the membrane associated enzyme 5 nucleotidase and is liberated intracellularly by cleavage of the high energy bonds of adenosine triphosphate, adenosine diphosphate and cyclic 5' AMP. Adenosine release was originally demonstrated during myocardial hypoxia,³² although there is now evidence that all cells are capable of producing adenosine in times of energy deficit. Adenosine can be released by lung tissue in times of hypoxia, such as after allergen induced bronchoconstriction, when the circulating levels of adenosine have bee shown to be 3 times the base line concentrations. Adenosine is a potent mediator of mast cell degranulation and thus may contribute to the inflammatory changes observed in asthma. On the other hand, adenosine inhibits eosinophil degranulation. A3 receptors have been recently identified on human eosinophils. Recent 48studies have revealed that mice, which accumulate high levels of endogenous adenosine owing to a deficiency of the adenosine catabolizing enzyme, adenosine deaminase, develop a pulmonary phenotype with mast cell mediated inflammation resembling the symptoms of asthma.³¹ Such evidence along with the observations that patients suffering from asthma have elevated pulmonary adenosine levels as well as augmented expression of adenosine receptors, suggest that increased adenosine signalling could be an important feature of asthma and chronic obstructive pulmonary disease.

Asthma is a chronic inflammatory disease of the airways¹ that, if untreated or inadequately treated, can dramatically impair quality of life and can be lifethreatening. The rationale behind treatment of asthma is that emergency treatment is more expensive than planned treatment and that guideline determined asthma care can be more cost effective.¹ Asthma is a reversible airway disease and patient may exhibit normal lung function between exacerbations but a component of chronic inflammation also goes on leading to chronic impairment in pulmonary function in the long run. The current therapy in asthma controls the symptoms but does not modify the disease. Expert panel guidelines by the National Heart, Lung and Blood institute recognise inhaled corticosteroids (ICS) as the preferred treatment for initiating therapy in children with persistent asthma. Treatment with inhaled corticosteroids (ICS) improves lung function and reduces asthma symptoms. For children who remain symptomatic despite treatment with low dose ICS, the preferred treatment is addition of long acting β₂ agonist (LABA) to low dose ICS rather than an increase in the dose of ICS. This approach further improves lung function and quality of life in patients with moderate to severe persistent asthma. The 55medications can be delivered via a number of different types of inhaler devices; these differ in the efficiency with which they deliver the drug to the lower respiratory tract. There are currently three commonly used ICS available as licensed preparations in India for children aged under 12 years: beclometasone dipropionate (BDP), budesonide (BUD) and fluticasone propionate (FP). Two of the ICS are available as licensed preparations in combination with LABA: FP used in combination with salmeterol/formoterol (SAL) and BUD used in combination with formoterol fumarate (FF).

According to National Asthma Education and Prevention Program (NAEPP), working definition of asthma is, “Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role: in particular, mast cells eosinophils, T lymphocytes, macrophages, neutrophils and epithelial cells. In susceptible individual, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning.² Asthma constitutes about 1% of total global disease burden. Global prevalence of asthma, which is on the increasing trend, is 4.8 – 13.2%.³ According to WHO, 15 million DALYS (disability adjusted life years) are lost annually due to asthma. The prevalence of asthma in India is 3.3%.⁹ The increased prevalence of asthma has been associated with an increase in atopic sensitization and other allergic disorders such as eczema and rhinitis. Recent studies have demonstrated that asthma can be associated with impaired lung growth during childhood and a progressive decline in pulmonary function in adulthood, and hence the need to establish early treatment of childhood asthma. The clinical manifestations of asthma and underlying airway inflammation though variable; reflect the different aspects of the disease, as acute vs. chronic inflammation corresponding to intermittent vs. persistent asthma.

As per GINA (Global Initiative for Asthma) guidelines there are five essential components of asthma management and prevention program:

Different studies have used various parameters for symptom scores. The Grampian study included sleep disturbances and restriction of activity. Woolcock et al included daytime and night-time symptoms and rescue salbutamol use. Greening et al included cough, breathlessness, wheeze. Whereas Gallant² et al included breathlessness, cough, rescue salbutamol use, night time symptoms. In our clinical studies, asthma symptom score consists of 6 items to be scored namely history of day time cough, history of nocturnal cough, wheezing, difficulty in breathing and use of rescue salbutamol and limitation of activity. A score of zero will be given for absence and one for the 58presence of each of the items. Thus the total score could vary from 0 to 42. Well constructed symptom based management plan has been shown equivalent to objective measurement especially in mild asthma.

Medications in asthma can be classified as controllers or relievers. Controllers are anti-inflammatory drugs (steroidal or non-steroidal) taken daily on long-term basis, to keep the disease under control (minimizing exacerbations, symptoms and the need of reliever medications). Of all the anti-inflammatory drugs, the most potent are inhaled corticosteroids (ICS). The other drugs which can be used are systemic corticosteroids, inhaled long acting b2 agonists (LABA), leukotriene receptor antagonists (LTRA), theophylline, cromolyn and nedocromil, and other systemic steroid sparing drugs. Relievers are medications used on an as per needed basis that act quickly to reverse bronchoconstriction and relieve its symptoms. They include rapid-acting inhaled β₂-agonists, inhaled anticholinergics, short-acting theophylline, and short-acting oral β₂ agonists. Rapid-acting inhaled β₂-agonists are the medications of choice for relief of bronchoconstriction in both adults and children of all ages.

Inhaled corticosteroids are currently the most effective anti-inflammatory medications for the treatment of persistent asthma. Studies have demonstrated their efficacy in reducing asthma symptoms, improving 59quality of life, improving lung function, decreasing airway hyper responsiveness, controlling airway inflammation, reducing frequency and severity of exacerbations and reducing asthma mortality.¹ However, they do not cure asthma, and when they are discontinued deterioration of clinical control follows within weeks to months in a proportion of patients. The side effects of ICS are limited to a small, transient reduction in growth velocity.¹⁰ Although anti-inflammatory drugs are the mainstay of therapy in persistent asthma, many patients continue to have troublesome symptoms, exacerbations and compromised lung function despite use of ICS therapy. Theses patients require either • Medium to high dose ICS (or) addition of • LABA (or) LTRA to ICS Addition of LABA (or) LTRA to ICS acts to decrease dose of ICS and thereby decreasing the long term systemic steroid induced side effects on growth and bone mineral density.¹² Long acting b2 agonists (LABA): includes:

These drugs should not be used as monotherapy as they have no role in controlling airway inflammation. Addition of long-acting inhaled β₂ agonists to a daily regimen of ICS improves symptom scores, decreases nocturnal asthma, improves lung function, decreases the use of rapid-acting inhaled β₂ agonists, reduces the number of exacerbations, and achieves clinical control of asthma in more patients, more rapidly, and at a lower dose of ICS than ICS given alone.^13–15 Studies show that when compared to a therapy with an ICS above combination with LABA addresses inflammation and smooth muscle dysfunction, the 2 main components of asthma. In addition, salmeterol possesses several non bronchodilator properties that 60may contribute to its therapeutic effects. For example, salmeterol has demonstrated inhibitory effects in vascular permeability; platelet-activating factor induced eosinophil accumulation, and the release of mast cell mediators from the lung. In vitro also it has demonstrated ability to prime the glucocorticoid receptor for activation of corticosteroids. These findings suggest that the above combination has as broad scope of activity in treatment of asthma. The side effects expected with this combination include oropharyngeal candidiasis, tachycardia, and tremors.

Leukotriene modifiers: includes

In LABA component, mechanism of action is bronchodilation through β₂ receptor stimulation which leads to increased cAMP formation in bronchial smooth muscle and their relaxation.

For both the budesonide/formoterol and salmeterol/fluticasone combinations, the addition of a LABA to the ICS component for patients not adequately controlled on ICS alone has been shown to produce greater improvements in pulmonary function and symptomatology and reduction in the exacerbation rate than higher doses of ICS alone.^{11, 12} O'Byrne et al¹³ reported the results of a one-year trial in which patients with mild persistent asthma were stratified according to whether they were currently receiving an ICS or not.63

66Among 698 patients who were initially corticosteroid- free, treatment with budesonide plus formoterol resulted in comparable reductions in the risk of severe exacerbations and symptom-free days as budesonide alone (60% and 48%, respectively) and an improvement in lung function. For patients already receiving an ICS, addition of formoterol proved more effective than doubling the ICS dose alone, reducing the risk for severe exacerbations by 43% and reducing the number of poorly controlled days by 30%. In a separate study, the addition of formoterol to ongoing budesonide therapy reduced the rates of severe and mild asthma exacerbations by 63% and 62%, respectively, compared with a reduction of 49% and 37% for the same dose of budesonide alone Similar beneficial effects have been reported when salmeterol was added to ICS therapy. The beneficial effect of adding salmeterol to fluticasone has also been compared with an increased dose of fluticasone alone in patients with moderate to severe asthma, with marked improvements in lung function and symptom control.¹¹

Asthma is a chronic inflammatory disorder of the airways, causing recurrent episodes of wheezing, breathlessness, chest tightness and cough. Increase in prevalence in many countries over the recent decades, highlights the need for a greater understanding of the risk factors for asthma. Many causes have been postulated and dietary change is one of several causal factors implicated in this trend. In the past two decades the evidence base on the relation between diet and asthma has increased substantially. Asthma is a multifactorial disease with a large series of causative, inducing, triggering and aggravating factors, each of which help shape the disease phenotype in the single patient by interacting with the expression of his/her unique genetic background at a given age. Because asthma is the result of interaction between genetic and environmental factors, increasing prevalence is certainly the result of changes in environmental factors. The hypothesis made to explain the epidemic trend fall into two main groups: one that points to increasing exposure to aggressive factors, and the other that implicates decreasing exposure to protective factors. The most cited aggressive factors are airborne indoor or outdoor pollutants, high salt intake, indoor allergens, drugs and vaccines. The proposed protective factors are antioxidants, microbial burden and physical exercise. 73This increasing prevalence has affected both rural and urban communities, suggesting that local environmental factors such as exposure to allergens or industrial air pollutions are not the sole cause.¹ In the last few years, nutrition has represented an important conditioning factor of many cardiovascular, gastro-intestinal and chronic pulmonary diseases. So it has been hypothesized that dietary constituents influence the immune system and thus, may also be actively involved in the onset of asthma and other allergic diseases.² The possible role of diet in the development of asthma can be described as follows: first, a food allergen can cause asthma. Second, there is role of breast-feeding for prevention of asthma later in life. Third, a low intake of anti oxidative dietary constituents might be a risk factor for asthma.³ Moreover, role of cations such as sodium, potassium and magnesium has been described in development of asthma. Finally, intake of fatty acids especially the role of omega-3 and omega-6 fatty acids plays a beneficial and detrimental role respectively in cause of asthma.

It is reported in the United States that about 6-8% of infants and about 1.5% of adults are allergic to food.⁴ Food is very important cause of asthma but is often overlooked, as usual skin tests are often negative and history is often not helpful. Children are more sensitive to foods than adults. Deaths in children, adolescents, and adults who ingested foods to which they were highly allergic have been reported.^5,6 These deaths are often caused by “hidden” ingredients in the food to which the individual is allergic. Sulfites and sulfating 74agents such as sulfur dioxide, sodium bisulfite, potassium bisulfite, sodium metasulfite, potassium metasulfite, sodium sulfite – both occurring naturally or used in food processing, have been found to trigger asthma. Egg is one of the most allergenic of all foods, and minute amounts of egg can result in asthma symptoms within minutes, including anaphylaxis. This is also seen after contact with egg through non-oral routes.⁷ Reactions may occur first time in a child who is given egg. Although ovalbumin, ovomucoid, and ovotransferrin have been identified as the major allergens in egg white, 10 other unnamed allergens of lesser importance have been identified. These allergens are also present in egg yolk but in lesser quantities. Some preservatives and additives may provoke asthma. Examples of such provoking compounds are - preservatives e.g. sulfur dioxide and sodium benzoate, colourants (natural or synthetic) e.g. tartrazine, flavour enhancers e.g. monosodium glutamate and salicylates e.g. aspirin like substances found in many foods. It has been postulated that asthma associated with chewing betel-nuts is chemically mediated by cholinergic stimulation.⁸ Children sensitive to food have higher rates of hospitalization due to asthma. In addition, children sensitive to food require more steroid medications to manage their asthma symptoms. Presence of food sensitization may be a useful marker for identifying children with more severe asthma. In an Indian study, it was found that deterioration in asthma can be prevented by specific food avoidance in many patients.9 The only proven treatment for food allergy is strict elimination of the relevant offending allergen(s). It should be noted here; however that elimination diet may lead to unwanted side effects such as malnutrition and eating disorders. But if successful, the food induced symptoms will certainly 75disappear. The diet revision should be complete and comprehensive to resolve them. It can be presumed that symptomatic reactivity is lost over time. Approximately, one third of children and adults lose their clinical reactivity after 1–2 years of allergen avoidance.

The epithelial lining of the respiratory system, by virtue of its large surface area and its role in gas exchange and host defense, is vulnerable to oxidant damage. The toxicity of oxidants which are directly inhaled such as cigarette smoke and air-pollution or generated through inflammatory process such as in response to allergen and viral infection, is normally balanced by the protective activity of an array of endogenous antioxidant defense system which may be functionally dependent on adequate supply of nutritional antioxidants. Reactive oxygen species, released from eosinophils, alveolar macrophages, and neutrophils, seem to play a key role in asthma. They may directly contract airway smooth muscles; stimulate histamine release from mast cells and mucus secretion. Asthma is, therefore, also associated with oxidative-antioxidative imbalance. Antioxidant status may affect asthma risk by influencing the development of the asthmatic immune phenotype, the asthmatic response to antigen provocation, or the inflammatory response during and after asthma attack. Antioxidants such as vitamin-A/β-carotene, vitamin-C, vitamin-E and selenium are important dietary constituents which may prevent oxidative injury. Therefore, they may reduce inflammation caused by allergen exposure.76

Vitamin-C: Vitamin-C is the most extensively investigated among antioxidants and has been shown to be associated with a reduced risk of asthma. Lower plasma and leukocyte concentration of vitamin-C has been associated with a high prevalence of asthma in adults and in children,¹¹ increased respiratory symptoms, reduced pulmonary functions^10,12 and increased airway responsiveness. Supplementation with vitamin-C has been shown to decrease asthma severity and frequency, exercise induced bronchospasm and airway responsiveness to methacholine. A 100 mg increase in vitamin-C intake per day is associated with an approximately 10–50 ml increase in forced expiratory volume in one second (FEV1). Vitamin-C is a free radical scavenger present in intracellular and extracellular lung fluids and protects against endogenous as well as exogenous oxidants. It is the most abundant antioxidant substance present in the extracellular fluid in the lung and contribute to the regeneration of membrane bound oxidized vitamin-E to function again. Vitamin-C is known to have a general antihistamine effect. It also inhibits the prostaglandins production. Most of the exacerbations of asthma in children have been associated with upper respiratory tract viral infections, especially rhinovirus. There are suggestions that vitamin- C supplementation may affect the susceptibility to common cold in subjects with low intake of vitamin-C. Moreover, vitamin-C reduces the duration of episodes and the severity of symptoms of the common cold. Natural sources of vitamin-C are citrus fruits and red and yellow pepper.

Vitamin-E: Vitamin-E effects have been studied and there is evidence of beneficial effects of vitamin-E on 77asthma. There is evidence of an inverse association between vitamin-E intake and both allergen skin sensitization and total serum Ig-E levels in adults.¹³ High vitamin-E intake is associated with reduced asthma incidence. Vitamin-E is present in extracellular lung fluid and lipid membrane, where it converts oxygen radicals and lipid proxy radicals to less reactive forms. Thus vitamin- E is a membrane stabilizer and principle defense against oxidant induced membrane injury by breaking the lipid peroxidation chain reaction. Vitamin-E seems to suppress neutrophil migration and inhibits Ig-E production. It may be immunomodulatory and also able to influence T-helper cell development in direction of Th1, subtype.14

Vitamin-A and b -Carotene: Vitamin-A and b-carotene have protective effect in asthma.¹⁵ Vitamin-A derivatives of retinol influence the development, maintenance, differentiation, and regeneration of lung epithelial cells and may play a central role in the development of airway disease. Vitamin-A/ ²-carotene are lipid soluble and acts by their antioxidant action that helps to prevent membrane lipid oxidation.

Other Vitamins: Asthmatics are typically deficient in vitamin-B complex (especially vitamin-B6 and B12) and folic acid and supplementing these subjects with multivitamins can help to reduce asthma symptoms. A deficiency of vitamin-B6 has been found in many asthma patients. This may be due to the fact that the medications in many asthma inhalers interfere with the absorption of vitamin-B6 by the body. In mild to average cases, the addition of vitamin-B6 supplement to the diet appears to lessen the occurrence of asthma attacks.^16,17 It has been found in a study that vitamin-B12 taken in large doses can decrease likelihood that asthmatics react to foods with sulfites.78

Flavones and flavanoids are naturally occurring antioxidants found particularly in fruits and red wine, which may account for protective effect associated with these fruits. These are also mast cell stabilizer. In a study, whole blood levels of antioxidants carotenoids, lycopene, lutein, ²-cryptoxanthin, ±-carotene and ²-carotene were measured and found to be significantly lower in asthma patients than in controls.

Several studies have demonstrated a reduced risk of asthma in relation to a high fruit intake. High intake of fruits is associated with a reduced risk of decline in FEV1, over a time. The FEV1 in subjects with a high intake of fruits (once per week or more) is about 80–100 ml higher than in subjects with a low intake (less than once per week).^18,19 In an Indian study, it was suggested that eating vegetables and fruits are protective for asthma/wheeze. Fruits and vegetables are better than vitamins pills. In a study it was found that daily intake of fruits and vegetables in infancy decrease the risk of asthma more than that by the intake of extra vitamins and cod liver oil supplements. It has also been found that fruits, rather than vegetables are more constantly related with increased level of lung functions. This may be explained by the fact that fruits are high in vitamin-C, which may be more important dietary antioxidant.

Selenium: Among minerals, selenium has been most strongly associated with asthma. Studies have demonstrated decreased selenium intake and 79decreased serum levels in patients with asthma. Selenium deficiency may greatly increase the risk of asthma.^20,21 Selenium functions as a cofactor for the antioxidant enzyme glutathione peroxidase, which is proposed to counter oxidation and to reduce the synthesis and release of leukotriene B4, an inflammatory mediator. Selenium may also, along with vitamin-C, attenuate the activation of nuclear factor kappa-b, a transcription factor that upregulates inflammatory cytokines associated with the asthmatic immune response.²²

Magnesium: Magnesium has several biological effects of potential relevance to asthma, including bronchodilatation when given intravenous in acute severe asthma.²³ There is also strong evidence of protection by dietary magnesium against asthma. In a study, reduced magnesium intake was found to be associated with brittle asthma.²⁴ These effects of magnesium are mediated by its properties of smooth muscle relaxation and mast cell stabilization. Milk and other dairy products, whole grains, nuts, legumes, leafy green vegetables are good sources of magnesium.

Sodium: It has been shown that bronchial reactivity to histamine is related to 24 hours urinary sodium excretion. Bronchial reactivity appears to increase with greater salt intake. Studies have linked increasing dietary salt intake with worsening asthma symptoms and increased bronchodilators use.^25,26 Following sodium restriction in three double blind clinical trials, improvements were noted in airway responsiveness, FEV1 and asthma symptoms. Research suggests that the effects of sodium are limited to individuals with asthma. Dietary sodium may increase airway reactivity and cause bronchoconstriction through potentiation of the electrogenic sodium pump in the membrane of the airway smooth muscles.80

Trace Minerals: There are evidences linking copper, zinc and manganese with asthma. Copper and zinc have role in antioxidant defense as cofactor in superoxide dismutase. Zinc is an essential trace mineral for most immune mechanisms in the body to function, including lymphocyte (T-cell) function.²⁷ Zinc deficiency may also lead to an enhanced Th2 immune response. Manganese has been found deficient in bronchial biopsies of asthmatic patients, indicating manganese replenishment could help in treatment of asthma.²⁸

Dietary fatty acids have important role in asthma.^29,30 Intake of omega-3 fatty acids is potentially beneficial and of omega-6 fatty acids is detrimental to asthma. Reduced omega-3 fatty acid/omega-6 fatty acid ratio leads to high chances of asthma. Mechanisms of action proposed for dietary polyunsaturated omega-6 and omega-3 fatty acids include modification of gene expression, signal transduction pathways and production of eicosanoids, the prostaglandins and leukotrienes which are potent inflammatory mediators. Well studied beneficial effect of fish in asthma is attributed to the presence of omega-3 fatty acids in fish oil. Fish oil contains eicosapentaenoic acid (EPA) and docasahexaenoic acid (DHA) which are competitive substrates for arachidonic acid for generation of inflammatory mediators. In humans, the principal substrate for eicosanoid production is arachidonic acid, an unsaturated fatty acid. The production of eicosanoids by inflammatory cells begins with the release of arachidonic acid from membrane phospholipids by phospholipase enzymes, and subsequent metabolism by cycloxygenase or 81lipoxygenase, enzymes and subsequent prostaglandin or leukotriene products. The derivatives of arachidonic acid (an omega-6 fatty acid) are leukotriene B4 (LTB4), a potent neutrophil chemoattractant and a pro-inflammatory mediator and cysteinyl series of LT (LTC4, D4, E4) which produce potent smooth muscle contraction and bronchoconstriction. In contrast, EPA and DHA (omega-3 fatty acids), as well as inhibiting arachidonic acid metabolism, is a substrate for the less active prostanoids (e.g. thromoxane A3) and LT (LTB5) and so has the potential to reduce airway inflammation, severe bronchoconstriction and airway hyper responsiveness. EPA also reduces the production of cytokine- tumor necrosis factor- ± (TNF-²) which increases airway responsiveness. On the other hand, omega-6 fatty acids such as linoleic acid, may influence the development of allergic sensitization by increasing the formation of prostaglandin E2 (PGE2), thus promoting Th2 lymphocyte response and Ig-E generation. Fish oil may therefore alleviate certain inflammatory respiratory diseases, preserve normal airway resistance, and modulate allergic sensitization.

Among amino acids, of particular interest are the amino acids: cystine, methionine, glycine and glutamic acid, which collectively contribute to glutathione metabolism³² which is an important antioxidant that may influence susceptibility to asthma. Cystine, is of particular interest, as it may be converted to reduced form of cysteine by macrophages, which thus increases intracellular glutatione. Arginine, the precursor for nitric oxide, which has been shown to be elevated in asthma and glutamine, which has powerful 82antibacterial properties in vivo are also of interest. In addition, phenylalanine is potentially important since uncontrolled phenylketonuria is associated with increased plasma Ig-E and atopic dermatitis. Studies have drawn attention to tryptophan, where the metabolic pathways may differ in asthmatic subjects as compared to control subjects, as demonstrated by elevated urinary kynurenic acid and xanthenuric acid excretion in children with asthma.³³ In a study, there was strong inverse relationship between fasting plasma glycine level and asthma risk. It is therefore, possible that changes in the pattern of amino acids intake arising from an overall increase in the proportion of protein from animal sources may have contributed to the rise in asthma prevalence that has occurred in the most developed countries.

The plasticity of the immune system in early life suggests that it will be dietary influences at this stage that will have the greatest impact. Indeed, early exposure to cow's milk protein has been linked to the development of atopy and asthma. Studies indicate that prolonged and exclusive breast feeding significantly decreases the risk of asthma and other allergic diseases among children.^35,36 Guidelines recommend that exclusive breast feeding for the first 6 months with introduction of solids thereafter decreases the chance to develop asthma or eczema than when fed solids earlier. Recent WHO feeding guidelines propose the introduction of solids after the sixth months following exclusive breast feeding for the prevention of asthma and atopy.³⁴ Even introduction of milk other than breast milk before the age of 4 months of age has been found a significant risk factor for all 83asthma and atopy related outcomes in children aged 6 years. Incidence of allergy to cow's milk has been estimated to be from 0.3% to 7% in general infants and from 14% to 30% in “Suspected allergic” infants. In general, cow's milk has been designated the food allergen most commonly affecting children. It has been recommended that if breast feeding is not possible;consider supplementing infants with omega-3 fatty acids, lactobacillus probiotics and protein hydrolyzed formula. In nut shell breast feeding was found to be protective for asthma. This protective effect may operate through several mechanisms. These include the exclusion of milk other than breast milk (and its potentially allergic components) from the infant's diet, and the provision of immunomodulatory, anti-inflammatory, nutritional, or other components in human milk. Several lines of evidence suggest that maternal dietary antioxidant intake during pregnancy may have relevant antenatal influence. Maternal vitamin-E intake during pregnancy has the potential to influence postnatal susceptibility to asthma and atopic diseases by modulating fetal and neonatal Th-cell response during initial encounter with allergens. Similarly, maternal fish oil intake during pregnancy may protect offspring from asthma.

Evidence that the gut microflora may be associated with the development of atopy comes from studies comparing Estonian infants with Swedish infants. Estonian infants have a low prevalence of atopy and display greater gut colonization with lactobacillus and Eubacteria, whereas Swedish infants, who have a higher prevalence of atopy, display greater levels of Clostridium difficile.³⁷ Furthermore, iso-caproic acid, 84a compound associated with C. difficile, has been detected almost exclusively in allergic infants, and the levels of other compounds associated with Lactobacillus flora were higher in non-atopic infants. Thus it has been suggested that promotion of Lactobacillus and other potentially beneficial gut micro-organisms may protect against the development of atopic disease. Breast feeding promotes gut colonization with bifidobacterium and thus reduces chances of atopy and/or asthma. Another method with potential to enhance the numbers of potentially beneficial organisms in the gut is the use of probiotics. Dietary supplementation with probiotics has shown encouraging results in asthma. In a double blind, randomized, placebo controlled trial, lactobacillus (given prenatally to mothers and then postnatally for 6 months to their infants) resulted in 50% reduction in the rate of atopic eczema at the age of two years.³⁸ Thus, the role of probiotics can be considered to prevent asthma. A key factor with probiotic intervention is that it does not cause any harm. Indeed, probiotics certainly result in a more friendly gut flora, witch may have other beneficial effect on health apart from reducing rates of atopic diseases. The probiotics may provide a natural means of beneficially modulating the immune system. However, the mechanism remains unclear and more data needs to be available before conclusion can be made on their ability to impact on the development of the other allergic disease including asthma.

Summary: Nutrients or nutrient groups implicated in the etiology of asthma and their postulated mechanism of effect Nutrient(s) Activity and potential mechanisms of effect Vitamin A, C, E Antioxidant; protection against endogenous and exogenous oxidant inflammation Vitamin C Prostaglandin 85inhibition Vitamin E Membrane stabilization, inhibition of IgE production Flavones and flavonoids Antioxidant; mast cell stabilization Magnesium Smooth muscle relaxation, mast cell stabilization Selenium Antioxidant cofactor in glutathione peroxidise Copper, Zinc Antioxidant cofactors in superoxide dismutase n-3 fatty acids Leukotriene substitution, stabilization of inflammatory cell membranes Polyunsaturated and trans Increased eicosanoid production fatty acids (n6) Sodium Increased smooth muscle contraction.

According to International Consensus report from National Heart Lung and Blood Institute NIH, USA (1997) asthma is defined as “a chronic inflammatory disorder of airways in which many cells play a role. In susceptible individuals this inflammation causes symptoms which are usually associated with wide spread but variable airflow obstruction that is often reversible either spontaneously or with treatment, and it also causes an associated increase in airway responsiveness to a variety of stimuli.”¹ Drug treatment of asthma is directed towards treating bronchial inflammation and relieving bronchoconstriction. Although inhaled corticosteroids are the cornerstone for anti inflammatory therapy, several newer immunomodulatory agents are in the horizon for treating bronchial asthma. Newer inhaled corticiosteroids are also being tested in children and will be available for clinical use soon.

Inhaled corticosteroids are currently the most effective agents used to treat chronic asthma. However systemic side-effects limit the dose in which inhaled steroids can be administered for long term therapy. Adrenal 90suppression, abnormalities of glucose metabolism growth impairment, cataract formation are some of the dreaded side-effects of high dose inhaled steroids taken over a prolonged period. The major aim in development of novel steroids is to have high topical activity but no or significantly low systemic bioavailability. Some of the newer steroids that have been developed are as follows.

Ciclesonide is a newly developed inhaled steroid that is undergoing evaluation in children which has on site activation. It is a new generation, non halogenated, glucocorticoid with high local anti-inflammatory properties. It has essentially no bioavailability. It is an ester prodrug which is not directly active and has no binding affinity for glucocorticoid receptors. Binding affinity of activatecd ciclesonide is about 100 times its unbounded form. Pharmakokinetically, the onsite activated drug concept leads to blunted and delayed peak concentrations of the active metabolite of this drug. Activated ciclesonide is very rapidly metabolized to inactive breakdown products.²

Soft Steroids: A soft drug is active by itself, has therapeutic efficacy at the site of application and is rapidly and predictably inactivated during its systemic uptake and distribution. A soft ICS should have sufficient metabolic stability for inducing the desired anti inflammatory effect at the airways and the lung target but during its systemic uptake and distribution it has to be inactivated by further metabolic routes, in addition to hepatic CYP 450.³

Loteprednol etabonate: Loteprednol etabonate (LE) 91is a soft drug which is being tested for respiratory use. So far it has been used for ophthalmic indications. Lactone Derivatives: These are a novel class of soft GCSs that have recently been developed. These drugs have stability in their target organ but high lability in blood.

A century has passed since it was first recognized that a soluble factor in serum is capable of transferring wheal and flare reactions to intradermal injection of allergen, but it was not until 1968 that IgE was recognized as the antibody responsible.⁴ With the demonstration of a strong association between increased serum levels of IgE and bronchial hyperreactivity and skin test reactivity to allergens, IgE came to be regarded as playing a central role in the pathogenesis of diseases associated with immediate hypersensitivity reactions, like anaphylaxis, allergic rhinitis and asthma.⁵ The mechanisms by which IgE plays this central role are thought to depend on its binding to high-affinity receptors (FceRI receptors) on mast cells and basophils, and perhaps also to low affinity receptors (FceRII receptors) on macrophages, dendritic cells, B lymphocytes, and other cells. On exposure to a specific allergen, allergen molecules crosslink adjacent Fab components of IgE on the cell surface, activating intracellular signal transduction. In mast cells, this cascade leads to the release of histamine, tryptase, and other preformed mediators. Antigen-antibody bridging also leads to the synthesis and realease of other chemicals, including prostaglandin D2, leukotrienes, and cytokines like TNF-α and IL-4 and IL-5. These compounds in turn cause vascular leakage, smooth muscle contraction, 92mucus secretion, and the attraction and activation of lymphocytes, eosinophils, neutrophils and other inflammatory cells.⁶ Considering this pivotal role of IgE in asthma anti IgE has found its place in new drug development.⁷

Omalizumab: is a recombinant humanized monoclonal antibody which specifically binds to the Ce3 domain of immunoglobin E, the site of high affinity IgE receptor binding. It is indicated in allergic rhinitis and asthma. Improvements in asthma symptoms and health-related quality-of-life, and a significant reduction in the frequency of asthma exacerbations were seen in allergic asthmatic patients treated with omalizumab. Omalizumab was also effective in the treatment of children with allergic asthma demonstrating improvements in health-related quality-of-life and significant dosage reductions of inhaled corticosteroids. Administration of omalizumab to patients with allergic rhinitis resulted in a rapid dose-dependent suppression of serum free IgE levels. Omalizumab significantly improved health-related quality-of-life and nasal symptoms in patients with seasonal allergic rhinitis. Antihistamine requirements were also significantly reduced following treatment. Adverse events were infrequent in clinical trials of omalizumab, and not significantly different from placebo. The most frequent drug-related event was mild to moderate urticaria. Dosage and administration in clinical trials

Allergic asthma: 150–300mg every 4 wks or 225–375mg every 2 wks (dependent on bodyweight and baseline IgE).93

Allergic rhinitis: 300mg every 3–4 wks (frequency dependent on baseline IgE)

Interleukin 4 receptor (IL-4R) on the cell surface is a hetorodimeric complex consisting of a specific high-affinity α-chain that binds to IL-4 and a second chain that can be either the common γ-chain shared with multiple cytokine receptors or the IL-13 receptors-chain. Soluble forms of α-chain IL-4R occur naturally in patients with allergic inflammation and may represent an autoregulatory pathway for IL-4 inhibition. By acting as a decoy to bind to circulating IL-4 and neutralize its activity, its high specificity and affinity make it ideal as an IL-4R.

The promising data in preclinical studies led to preliminary investigations where IL-4R proved safe and effective in the treatment of patients with asthma.⁹ IL-4R was associated with statistically significant improvement in asthma symptom score and β₂-agonist use. Scores on the third section of the AQLQ (patient's perception of general health and physical functioning) worsened in the placebo group and improved in the IL-4R 1.5-mg group (p>0.05). Methacholine testing showed decreased sensitivilty in 6 out of 8 patients tested in the 1.5-mg group. Exhaled NO scores were significantly improved among patients receiving IL-4R, demonstrating an anti-inflammatory effect.94

IL-5 inhibitors are being developed as specific anti-eosinophil directed therapies for the treatment of asthma and other allergic diseases. Strategies include blocking receptor binding, inhibiting release of cytokines from T cells, and using blocking monoclonal antibodies directed against IL-5. Several preclinical studies have been completed using monoclonal antibodies directed against IL-5, with promising results in terms of beneficial effects on airways hyperresponsiveness (AHR) and tissue eosinophilia. More recently, anti-IL-5 monoclonal antibodies have been administered to patients with mild allergic asthma using an allergen challenge model. Anti-IL-5 causes clear and longterm reduction in both blood and sputum eosinophils with no significant effect on either AHR or the late asthmatic reaction to inhaled allergen. Thus, IL-5 is an attractive target for antieosinophil-directed therapy, and further studies are ongoing to assess the efficacy of anti-IL-5 monoclonal antibodies in asthma.

There is limited experience with anti-IL-5 monoclonal antibody treatment in human trials. Despite significant reductions in blood and sputum eosinophils, there was no detectable effect on the allergen-induced LAR or AHR to histamine.¹⁰ This provides the noval insight that eosinophils may not be a prerequisite for the LAR and AHR, and has relevance to the pathogenesis and treatment of asthma. The limited effects on the LAR and AHR following anti- IL-5 treatment may be due to the involvement of residual eosinophils as well as a number of other cell types such as allergen-specific T 95cells and mast cells. This has led to a questioning of the role of the eosinophil in human allergen challenge models of asthma, and in clinical asthma.¹¹ A large-scale clinical study on the effect of multiple doses of anti-IL-5 on bone marrow, blood, skin and lung tissue eosinophils will provide further insight into the role of eosinophils in the clinical pathogenesis of allergy and asthma.

Among its myriad of biological actions, the second messenger cAMP relaxes airway smooth muscle, suppresses the actions of immune and inflammatory cells, and modulates pulmonary nerve activity. Thus, increasing cAMP content in these tissues should be of substantial benefit in the treatment of pulmonary disorders such as asthma.¹² PDE4 is a major cAMP-metabolizing enzyme in immune and inflammatory cells, airway smooth muscle and pulmonary nerves. Hence PDE4 inhibitors produce a wide range of pharmacological actions that, if replicated in the clinic, may be beneficial in the therapy of asthma. These include anti-inflammatory effects, bronchodilation, 96and modulation of pulmonary nerves. Indeed, initial clinical data on these agents are encouraging, and suggest that PDE4 inhibitors may have broad utility in the treatment of pulmonary disease. However, full knowledge of the therapeutic value of this novel compound class awaits the outcome of long-term clinical trials. There are strong therapeutic rationales for the use of PDE4 inhibitors in asthma. PDE4 inhibitors are pluripotent anti-inflammatory agents, with actions against eosinophils, T lymphocytes, monocytes and macrophages, and neutrophils. These agents also suppress pulmonary edema and have the unique capacity to inhibit the activity of excitatory (contractile) nonadrenergic noncholinergic nerves, while simultaneously potentiating inhibitory (relaxant) nonadrenergic noncholinergic nerves. Their ability to suppress airway smooth muscle mitogenesis hints that PDE4 inhibitors may impact the airway remodelling that occurs in severe, long-standing asthma.^13,14 The principal toxicological observation with both selective PDE4 and nonselective PDE inhibitors is a focal, necrotizing vasculitis in rodents. The relationship between this and the testicular and thymic atrophy also observed in rats is currently under investigation.

The LABAs salmeterol and formoterol have both prolonged airway smooth muscle effects and non-bronchodilator activity. They have a complementary mode of action to the topical anti-inflammatory effects of corticosteroids, and inhibit mucosal oedema, increase mucociliary transport and reduce respiratory tract infection. In asthma, LABAs are currently positioned as ‘add-on’ therapy, where combination 97with inhaled steroids results in better lung function and symptom control, decreased rescue medication and fewer exacerbations.

In addition to the well-documented increase in β₂-adrenoceptors induced by corticosteroids, LABAs, such as salmeterol, increase steroid-dependent translocation of the glucocorticoid receptor from the cell cytosol to the nucleus, via a possible mitogen-activated protein kinase (MAPK)- mediated phosphorylation mechanism, leading to a ‘priming’ of the receptor. This complementary mechanism of action of the LABAs is reflected in vitro, for example, as an increase in steroid-induced eosinophil apoptosis, additive inhibition of cellular cytokine and chemokine release, and potentiation of respiratory mucosal cytoprotection. In asthmatic patients, the additional of salmeterol to low-dose inhaled steroids decreases the number of eosinophils and reduces mast cells and CD4+ T cells in airway tissue], and significantly inhibits the degree of angiogenesis occurring as part of the remodelling process. These effects were not observed with higher doses of corticosteroids, and may contribute to the increased clinical efficacy with LABA/steroid combination therapy.

In addition to their long-acting bronchodilator activity, LABAs have been shown to produce a clinically relevant reduction in inhaled steroid dose, and salmeterol, unlike salbutamol, significantly decreases exacerbations in patients with moderate to severe disease. However, the most important role for LABAs in asthma is as an ‘add-on’ combination therapy with inhaled steroids. This concept was first developed by 98a multi-centre study in the UK in asthmatics not controlled on low-dose steroid. Treatments were divided into one group, where the dose of inhaled steroid (beclomethasone dipropionate) was increased 2.5-fold, whilst the other had salmeterol (50 g b.d.) added to their existing steroid. In terms of lung function and symptoms, the salmeterol combination group improved more than the increased steroid group.

The leukotrienes (LTs) are eicosanoids derived from membrane constituent arachidonic acid. The cysteinyl LTs LTC4, LTD4 and LTE4 are potent airway smooth muscle constrictors with a much longer duration of action than other smooth muscle constrictors.¹⁸ Several potent and selective anti-LTs have been developed, which have demonstrated the critical role of cysteinyl LTs in asthma pathobiology. The anti-LTs have now been extensively evaluated in clinical trials in patients with persisting asthma, several of which are available to treat the disease. It is theoretically possible to inhibit the production of the LTs by inhibition of any of the enzymes in their biosynthetic pathway. However, as of this time, the only enzyme that has been selectively inhibited in human studies is 5-lipoxygenase. It has also been possible to interrupt LT formation by preventing the binding of arachidonic acid to the 5-lipoxygenase-activating protein¹⁹ Cysteinyl leukotrienes are products of the 5-LO pathway. They are potent mediators of allergic bronchospasm and inflammation. Considerable effort in the pharmaceutical industry has focussed on the development of 100agents that modulate their synthesis or actions. Recently, three selective antagonists of the cysLT1 receptor have been launched for the treatment of asthma. This review summarizes the discovery and development of this new class of asthma therapy.

Respirable antisense oligonucleotides (RASONs): are a new, drug class targeting respiratory disease. Lung represents a unique target for antisense intervention. The lining surfactant is composed of zwitterionic lipids that are cationic at lung pH. Cationic lipids improve the uptake of antisense oliginucleotides into cells. Surfactant secretion is known to be regulated by an interplay of Adenosine 102A1 and A2 receptors with A1 receptors inhibiting surfactant secretion and A2 receptors enhancing it. Recent evidence indicated that surfctant secretion is diminished in asthma and may contribute significantly to bronchial hyperresponsiveness. The upregulaton of A1 receptor in asthma may therefore be responsible for loss of surfactant providing a further impetus to develop agents capable of attenuating A1 receptor function. The lung represents unrespirable antisense oligonucleotides functionally, but not genetically, ablate gene expression by blocking the template function of target respiratory messenger RNAs by as yet incompletely defined mechanisms The first respirable antisense oligonucleotide, EPI-2010, has now reached clinical trials. It has shown intriguing initial indications of efficacy and the potential to be the first once-per-week asthma preventation. Respirable antisense oligonucletides are capable of addressing targets, have proven to be intractable to traditional ‘small molecule’ approaches, against which newer monoclonal antibody strategies may also not be optimal. The target properties of respiratory messenger RNAs are strikingly different from those of respiratory protein enabling respirable antisense oligonucleotides to offer the potential of longer duration of effect, increased specificity of effect, and lack of systemic side effects compared with either traditional small molecule protein antagonists or monoclonal antibodies.

Respiratory allergies include allergic rhinitis, sinusitis and asthma. Increasing attention has been devoted to the relationship between rhinitis and asthma, (i.e. between the upper and the lower respiratory airways) that was first noted in epidemiological studies¹ and later supported by clinical observations. The atopic march² refers to the natural history of allergic or atopic manifestations characterized by a typical sequence of clinical symptoms and conditions appearing during a certain age period and persisting over a number of years. In general the clinical features of atopic eczema occur first and precede the development of asthma and allergic rhinitis. The “hygiene hypothesis” proposes that the increase in allergic diseases reflects a decrease in infections during childhood. Clinical trials also suggest that the exposure to microbes through the gastrointestinal tract powerfully shapes immune function. Intestinal microbiota differs in infants who later develop allergic diseases, and feeding probiotics to infants at risk has been shown to reduce their rate of developing eczema. This has prompted studies of administering probiotics in prevention as well as treatment of respiratory allergy. We hereby discuss the status of probiotics in respiratory allergy.

Approximately 300 million people worldwide currently have asthma, with prevalence increasing globally by 50% every decade.³ Prevalence is high (>10%) in developed countries and, although data are still missing, rates are increasing in developing regions as they become more westernized.³ Globally, the economic costs associated with asthma exceed those of tuberculosis and HIV/AIDS combined.⁴ Developed economies can expect to spend 1 to 2% of their health-care budget on asthma.³ Rhinitis often coexists with asthma (upto 78% of asthma patients have AR, and 38% of patients with AR have asthma). The aggravation of AR coincides with exacerbation of asthma; accordingly, treatment of nasal inflammation reduces bronchospasm, asthma-related emergency department visits, and hospitalizations.

Infants are born with a “Th2 bias” in immune function, and the cell-mediated immunity, necessary for effective defense against intracellular pathogens, requires production of Th1 cytokines.⁵ The capacity to induce protective Th1 immune responses develops early in life, primarily over the first year, but appears to be delayed in children predisposed to atopy.⁶ In fact, Th2 polarization appears to be more prominent and to persist until a greater age in such children.⁷ Knowing that Th1-dependent immune function matures through infancy, and that the maturity of this function may affect the risk of developing allergic diseases, invites speculation as to how maturation of immune function 108might be accelerated. Clues as to a possible approach can be inferred from close consideration of the hygiene hypothesis. The “hygiene hypothesis” for the increase in prevalence of allergic diseases This was first put forward by Strachan when he noted an inverse association between family size and the rate of allergic disease, with the greatest protection being associated with the number of older siblings.⁸ Strachan proposed that the development of allergic disease is prevented by infections in early childhood, and the rise in prevalence is a consequence of the smaller family size and greater hygiene of modern Western societies. Subsequent studies have confirmed a negative association between the risk of developing allergic disease and sibling rank, and have further shown a positive association with higher socioeconomic status.⁹ This idea, that exposure to nonpathogenic microbes might play a role in preventing the development of asthma and other allergic diseases, was greatly advanced by studies of stool flora in infants from populations with different rates of allergic disease.^10–13 Collectively, these studies demonstrate the importance of gut microbial community, and suggest that differences in microbial community composition and increased abundance of specific bacterial species correlate with development of atopy.

Probiotics are “live micro-organisms administered in adequate amounts which confer a beneficial physiological effect on the host”.¹⁴ There are a number of possible means by which probiotics may improve 109health, one of which is the immunomodulation of local immunity (that maintains gut wall integrity)¹⁵ and systemic immunity (that enhances non-specific and specific arms of the immune system).^16–19 Interfering in the gut flora through ingestion of live microbiota (probiotics), could favour the correct maturation of the immune system, and reduce development of allergy in childhood and later life. It has been seen that the risk of asthma and allergy is lower in children raised in households with domestic animals^20,21 or in bedrooms with high levels of endotoxin.²² Especially compelling is the finding that the risk of asthma and allergy is lower in adults with serologic evidence of infection with microbes transmitted by the “feco-oral” route.²³ Taken together, these observations suggest a protective effect of microbial exposure on development of respiratory allergy.

There is currently no cure for these diseases, though a wide range of treatment modalities have been used to control symptoms. Recently, anti-IgE antibody (omalizumab), immunotherapy^24,25 anti TNF-a and vitamins have been tried. Many of these treatment modalities do not act through modification of actual inflammatory pathways which underlies the pathophygiologic basis of these diseases. The treatment regimens can be time consuming and expensive for those affected and their families, and there is need for new treatment modalities which are effective, cheap and simple to administer. For individuals with persistent or severe disease, the treatment options are limited.

A recent meta-analysis²⁶ done on preventive role of probiotics in allergic diseases involving 1549 infants, 110has shown that there is insufficient evidence to recommend probiotics for prevention of allergic diseases (asthma, rhinitis, eczema, food allergy), although there was a beneficial effect on eczema found on sub-group analysis. They inferred that studies using L. rhamnosus have been the most homogenous in reporting beneficial outcomes. There has been no meta-analysis done on role of probiotics in treatment of allergic respiratory diseases. Evidence from Randomized controlled trials (RCTs) (Table 7.1), have shown variable results. There have been nine good quality RCTs done on role of probiotics in treatment of respiratory allergies. Study done by Giovannini²⁷ showed that the probiotics group is having longer time free from and lower cumulative number of episodes of asthma/rhinitis. But on separating the two outcomes, they found no statistical difference between probiotics and placebo group in asthmatic children, but the annual number of rhinitis episode was lower in children with rhinitis. Similarly studies done by others^29,33,34 have shown beneficial effects of probiotics on symptom-medication score of allergic rhinitis. Among these 9 RCTs, 2 studies did not find any beneficial effects of probiotics in allergic rhinitis/asthma. One study²⁸ did not find any beneficial effect on allergic nasal and lung symptoms induced by birch-pollen and another³² found no difference in mean daily peak flows or changes in spirometric values or lung function tests in adults with moderate asthma. Three studies reported on quality of life score (PRQLQ), with two^30,31 showing improvement of PRQLQ in rhinitis patients and another³² showing no improvement in asthma patients. All these trials have used different doses and durations as well as different strains of probiotics. The studies on asthma have used only 111Lactobacillus (sp; acidophilus, rhamnosus, casei) as the probiotic strain; whereas studies on allergic rhinitis have used Bifidobacterium (sp; longum) as well as Lactobacillus strains. It has been hypothesized that some probiotic strains and/or their fermentation products are responsible for improvement of allergic rhinitis³⁴ and the immunostimulatory effect of Lactobacillus may be dose dependant.³⁶ Whatever the dose and duration of probiotics was used in these studies, no beneficial effect was found in subjects with asthma. None of these studies have reported any significant adverse events related to probiotics.

The administration of living organisms, even if considered normal and non-pathogenic as probiotics, must be regarded as potentially dangerous in individuals with primary or acquired immunodeficiency. Anecdotal cases of severe infections or fatalities linked to bifidobacteria or lactobacilli have been reported. Thus, meningitis caused by bifidobacterium was described in an infant treated with probiotics³⁷ and a patient became fatally septicaemic with a vancomycin resistant strain of Lactobacillus rhamnosus contained in a live yogurt.³⁸ While rare, Lactobacillus is recognized as a potential cause of endocarditis,³⁹ even in the absence of probiotic supplementation. Experts estimate that the risk of developing an infection from a Lactobacillus probiotic is “neglible,” happening in less than 1 case per 1 million users of probiotic supplements.⁴⁰ Like lactobacillemia, biofidobactermia is extremely rare and, when reported, is usually associated with problems during pregnancy or delivery.³⁹112

116Presently there are no reports of bifidobacterial sepsis occurring in conjunction with probiotic use.⁴¹ Instead of infections, the most common adverse effects associated with lactobacilli and bifidobacterial probiotics are transient flatulence and bloating. It is said that these temporary symptoms are a “die-off” effect as probiotic bacteria crowd out and eliminate pathogenic intestinal bacteria. Overall, it appears that probiotics are safe for most individuals, even when compared with the host's own commensal flora. However, as probiotic supplementation does involve ingestion of live micro-organisms, caution is warranted, particularly in people with central venous catheters and compromised immune systems, including transplant recipients.

While there is no doubt that symptom control of respiratory allergic diseases are achieved through judicious use of anti-allergy medications, probiotics are increasingly recognized as safe and effective adjuncts for treating respiratory allergy. Moreover, clinical trials have shown that they are useful in allergic rhinitis, though there is doubtful/no role in mild and moderate asthma. Large clinical trials with evaluation of clinically relevant outcomes are needed before probiotics are recommended for use in allergic respiratory diseases.

There has been an increasing prevalence of asthma in the past decade both globally as well as in our country and with that has come the recognition of the magnitude of morbidity it entails.^1,2 Missed school days, increased hospitalizations, retarded growth and even death may result from a deficient management of these children. In any chronic disease the effectiveness of therapy depends on ‘how good’ is the treatment and ‘how well’ the patient takes it. Effective treatment options (inhaled medications) are now available which when properly used help in decreasing morbidity associated with asthma and improving the quality of life of the children. However there is a big barrier from the prescription pads to therapeutic effectiveness in the patient. This is largely because the patient does not take the medication the way we would like him to, or in short is non-adherent. Since the outcome of treatment plans works only as well as the patient adherence to therapy, it is worthwhile to look at how well the patient is following what we tell him. Adherence to medication can be defined as the degree to which use of medication by the patient corresponds with the prescribed regimen.³ The term adherence and compliance are used interchangeably in medical parlence. However these are not synonymous. The term ‘adherence’ suggests a more active role for the patient than the word ‘compliance’ which implies that 122the patient passively submits to the prescribers authority and is obedient with a treatment regimen. Adherence on the other hand, implies a choice made voluntarily by a patient to closely follow a treatment plan. Adherence is influenced by diverse and complex factors including the eccentricities of human behavior and is difficult to predict even in the same patient at different times. Often physicians underplay the importance of adherence assuming it to be a problem of the poor, uneducated or with intense psychosocial dysfunction and are notoriously poor at identifying non-adherence.

It is conservatively estimated that 50% of medication dependent patients of chronic diseases do not follow prescribed regimens.⁴ Studies in asthma using electronic monitoring devices attached to MDIs record rate of medication use of about 50% only.^5,6 In UK Coutts et al examined patient adherence to antiinflammatory therapy using electronic monitoring and noted under use of inhaled corticosteroids on 55% of study days.⁵ In another similar study by these authors in preschool children, complete adherence was seen only on half of the study days and only 77% of prescribed doses were taken over the 2 month period.⁶ In a survey of patients with asthma attending our clinic some form of non adherence was seen in upto 68% of cases (Table 8.1).

Adherence in asthma alternates even in the same individual between fully adherent when symptomatic to non-adherent when asymptomatic. Adherence pattern also differs at different times for different 123drugs. Non-adherence may be in form of not fulfilling prescriptions, omission of doses, incorrect medication, incorrect dosages or schedules, premature discontinuation of drugs, not following advice to avoid allergens and sub optimal inha lation technique.^4,7,8

We did a study to find out types of non adherent behavior in patients attending our outpatient and asthma clinic and found all types of non adherent behavior is rampant.

Unrecognized non adherence decreases the effectiveness of asthma therapy. Non-adherence can result 125in an increased rate of illness exacerbation, hospitalization, emergency department visits and asthma related deaths.^9,10 Further if non-adherence goes unnoticed, medical decisions may be compromised and patient may be exposed to potentially detrimental and costly changes in therapeutic regimen, e.g. the treating physician may hike the dose of the drugs, add a new drug or order fresh investigations to look for alternate causes in view of persisting symptoms.⁹

Adherence to medication in asthma also seems to be related to wide range of diverse factors like age and sex of the patient, financial status of the family, cultural beliefs, educational level of the parents. Duration of disease and disease severity are also important in determining the adherence to asthma treatment. Milgrom et al demonstrated that “prednisolone” bursts were more common in poorly adherent patients.¹¹ Shrunk et al followed adherence in patients enrolled for CAMP trial and found adherence problems to be greater in patients who had been longer in the trial.¹² Adherence behavior is also affected by patient's perception of his or her disease and parental concerns about safety of corticosteroids.¹³ Type of medication used, dosing schedule, improvement of symptoms with medication also affect adherence to asthma therapy. Patient education about nature of disease and medications also improves adherence to asthma treatment.

Few other concerns arise about adherence in children. Since the responsibility of giving medication lies with the parents, Children from troubled families may find 126it difficult to adhere to therapies. At on older age the adolescent may be rebellious and detest medication. They may feel stigmatized and conceal medication.

Nothing is more important in promoting adherence to medication than a sound patient clinician relationship.¹⁴ The key to establishing this relationship is open communication, which clinicians foster by demonstrating attentiveness, giving encouragement, active conversation, and eliciting and allaying patient concerns. By using these open communication skills and listening carefully, the clinician may uncover personal beliefs or concerns that may affect adherence.¹⁵ If the patient knows, likes and trusts his doctor he or she is most likely to be motivated to be adherent to the therapeutic regimen. In present day management of asthma a great emphasis is placed on patient education and self-management strategies but none of these are likely to succeed unless the patient - physician relationship is maintained. Education and communication is not merely a lecture or hand out, but a dialogue, a two way process between doctor and the patient.¹⁶ Asking about patient concerns showing empathy, demonstrating technique, giving feedback and giving suggestions about setting priorities in treatment will all help convince the patient that the patient is committed to the partnership effort and help improve adherence.¹⁶ The concept of partnership between patient and physician is a therapeutic and professional relationship specifically designed to promote adherence of the patient to the medical regimen that will result in optimal control of disease. It makes patient an active participant in deciding treatment plans.¹⁵127

Most individuals will prefer not to take any medication. I f medication is needed they will take the least amount and for the shortest period possible. Medication, which needs to be taken once or twice daily, is better adhered to patients' preference also needs to be kept in mind when prescribing. Adolescent boys would not like to carry along a MDI with spacer but might adhere if a dry powder inhaler that can be securely pocketed is prescribed. Also in the context of developing countries cost may be important issue that can limit adherence.¹⁷

Patient education aims to alleviate patients and caregivers' concerns and provides knowledge and skills about asthma. The basis of this approach is the belief that patients who are more knowledgeable about their disease and the treatments being used are more motivated and more likely to adhere to an asthma treatment plan. Issues, which need to be a part of these education plans should be addressed with the patient and his/her family, should include information on nature of the disease, nature of treatment and how to use treatment.¹⁸ Patients need to be educated on possible allergens and triggers and how to suitably modify treatment to avoid these. Recognition and management of exacerbations and development of self-monitoring and self-assessment skills.¹⁸ An individualized asthma action plan needs to be discussed and negotiated with the patient. Information about the basic pathophysiology of asthma is the foundation of patient education. Patients should be informed as far as possible in their own language that asthma is a chronic disease and 128inflammation is the primary mechanism that occurs in asthma attack. All asthma patients and there family members should know the symptoms of asthma and should be able to determine when these symptoms worsen. Patients who are able to monitor response to therapy may be more inclined to be adherent to asthma treatment. PEFR monitoring is a technique that may be used, however it is essential that patient be adequately instructed on how to use this device. Patients should also be made familiar with environment control strategies. In addition to assisting patients in establishing priorities and explaining how to implement environmental controls, the clinician should explain the rationale for these measures. Additionally patients may be informed about the immediate and delayed responses to these allergens. Last but not the least patients should be educated about their medication; the information should encompass mechanism of action, expected outcome of treatment, importance of correct technique, common and serious adverse effects of each medication. It is very important that the patient understands which medications are prescribed for immediate relief and which are for long-term control. Further since adherence with medications that do not have a immediate benefit is poor, the long-term benefits of controller medication should be emphasized. Because parents may have concerns regarding long-term use of corticosteroids, special effort must be made to address them.¹³

Behavioral strategies include use of techniques like reminders, reinforcement, monitoring, changing health beliefs and contracting to influence nonadherent behavior. These strategies should be followed in day-to-day practice for maximal patient adherence.¹⁸

Self-management plans that encompass both behavioral and educational aspects have been developed. The most recent set of guidelines have the following points.²⁰

Wheezing is typically described as a `whistling´ sound audible during respiration. While it is a frequent symptom during infancy and early childhood, it can extend into older childhood and even adulthood. <sup>1</sup> It is a sound most parents and caregivers are familiar with. However, it often has different connotations and many parents use the term loosely to describe noisy breathing that has better nomenclature. A survey of parents, who described `wheezing´ in their infants, showed that many reclassified the sound when they were shown a video film that depicted different lung sounds in infants. Only a minority of parents continued to describe the sounds as `wheezing´.^2,3 This error in labelling a sound is not restricted to lay persons, but also occurs among physicians caring for children.

For all practical purposes, wheezing reflects narrowing of small airways. This may occur due to actual narrowing of airway calibre through contraction of airway smooth muscle, accumulation of mucus and secretions in the airways and narrowing of airway lumen by extrinsic compression. Whatever be the aetiology, the narrowed airway usually permits 135airflow into the lungs, but restricts movement outwards. This results in the typical whistling sound described as wheezing. Thus wheezing can occur in infants in a variety of clinical conditions besides bronchiolitis and asthma. These include lower respiratory tract infection including pneumonia, cystic fibrosis, gastro-esophgeal reflux, micro-aspirations and congenital anomalies such as tracheo bronchomalacia and compression of the airway by vascular rings. Aspiration of a foreign body into the airway also results in narrowing of the lumen and wheezing. One other condition that must be remembered in wheezing infants is congestive cardiac failure, particularly against a backdrop of congenital cardiac defects. The two most common clinical diagnoses entertained in wheezing infants are bronchiolitis and infantile asthma. Both these terms are often used interchangeably and even managed without making a distinction between them. However the treatment, clinical course and long term prognosis of these conditions vary widely and necessitate an accurate understanding of the pathophysiological process. Bronchiolitis is a frequent acute respiratory tract affection among infants characterized by fever, coryza, cough, expiratory wheezing, and respiratory distress.⁴ It is usually viral in origin with respiratory syncytial virus (RSV) being the major causative organism.⁵ However, other viruses including adenovirus, rhinovirus, influenza virus and parainfluenza virus can result in identical disease, as also Mycoplasma pneumoniae.⁶ Recently the human metapneumovirus (HMPV) has been identified as an agent that induces a similar illness.⁷ Conservative estimates suggest that one of every ten infants suffers from bronchiolitis and about 20% of them have to undergo hospitalization for this.⁸136

Broadly, infantile wheezing has been categorized as viral-induced wheezing and wheezing associated with allergy/atopy. The two types have a rough proportion of 2:1 among wheezing infants. Majority of these infants have a single episode of acute wheezing, normal pulmonary functions, require minimal medical attention and are unlikely to wheeze in the future. The clinical diagnosis of bronchiolitis would be appropriate in most of these infants and there is no need for further investigations. The other cohort of babies with wheezing has associated allergy/atopy either in themselves or a close family member. These are likely to develop wheezing in later 137life as well and have deterioration in pulmonary function. Atopy has been identified as the major risk factor associated with recurrence of wheezing in later life.¹¹ There is a lot of ongoing research to identify specific allergens that can induce this phenomenon. House dust, pollen and dust mite have been identified as definite triggers. There is also evidence that early exposure to household pets particularly dogs may be associated with an atopic tendency. Atopy may manifest with recurrent wheezing, allergic rhinitis or non-respiratory tract conditions such as conjunctivitis and eczema. A family history of asthma and presence of atopic state are probably the strongest pointers towards an asthmatic tendency. Based on the presence or absence of these characteristics, an “allergy index” has been proposed that has a significant negative predictive value, in that greater than 95% infants with a negative index will not develop asthma in later childhood.¹² There are possibly prenatal and perinatal risk factors that increase the risk of wheezing in infancy. One of the proposed factors is maternal smoking, whereas breast feeding seems to have a protective effect. The presence of siblings in the family and attendance at day care centres increased the risk of wheezing. There is some evidence that boys are more likely to wheeze than girls. The onset of some types of food allergy in early childhood is also associated with later wheezing episodes. Besides, these, the exact role of several other factors such as cognitive skills of the caregiver, parental anxiety, nature of housing, family income and ethnicity have not been delineated so far. Nevertheless, the mere presence or absence of one or more of the proposed risk factors does not man that an infant will wheeze in later childhood or develop asthma. Therefore some investigative modalities have been incorporated that include measurement of serum 138levels of IgE in response to a variety of antigens, eosinophil cationic protein (ECP) and nasal smear eosinophilia. These have varying degrees of sensitivity, specificity and predictive value. It is now increasingly believed that there is an immunologically mediated mechanism in childhood asthma. Activated T-cells produce interleukins and other cytokines that result in bronchconstriction. The relative proportion of T helper 1 (Th1) and T helper 2 (Th2) cells determines the type of response that a particular infant will exhibit in response to an antigenic stimulus. It is believed that early in neonatal life, the body´s immune system `chooses´ a Th1 or Th 2 type of response. Those with a Th 2 type of response are more likely in later life to have allergic disorders whereas those with a Th1 type of response are protected from such diseases.

There is a tendency to treat every wheezing episode as bronchiolitis and when the response is inadequate, to resort to a trial with bronchodilators or corticosteroids as in the therapy for asthma. This may work in some patients, but is an unscientific method of management. The mainstay of management in bronchiolitis is good supportive care with the inhalation of cool humidified oxygen. Several pharmacological modalities have been tried in bronchiolitis, but only the use of nebulized epinephrine (racemic or otherwise) has been proven to be of benefit on improvement of symptoms,¹³ although the evidence on this is not unequivocal.¹⁴ Use of inhaled bronchodilators,¹⁵ corticosteroids,¹⁶ specific therapy such as ribavarin,¹⁷ RSV immunoglobulin¹⁸ and modifications in supportive care such as nebulisation with a helium-oxygen mixture etc. have not been clearly shown to be of benefit in the 139short or long term. There is some evidence that some of these treatment measures may reduce the risk of wheezing in later life, but there is as yet no treatment guideline on the management of bronchiolitis. It must be emphasized that the value of clinical trials of various therapeutic modalities in bronchiolitis is often limited by poor methodological quality including imprecise definitions, inadequate recruitment criteria and low power. Likewise, the beneficial effects of some modalities such as surfactant or immunoglobulin may be restricted to a subset of infants with bronchiolitis. International guidelines for the treatment of asthma in children do not describe the management of wheezing in infants. However, those who are diagnosed as bronchial asthma after careful consideration of the clinical profile, family history and some basic tests such as nasal smear for eosinophils, will receive treatment as per the standard guidelines and evidence-based medicine.¹⁹ In addition, efforts have to be made to identify trigger factors and ensure avoidance of the same. Ongoing research is required to study the long term effects of management of infantile asthma, on clinical profile, growth and prognosis. Other conditions resulting in wheezing need management based on the underlying cause. Thus congenital anomalies of the respiratory or cardiovascular system need surgical correction wherever feasible. Similarly, pharmacological and non-pharamacological interventions for the management of gastroesophageal reflux will be ameliorative in that condition. A detailed discussion on the treatment of these conditions is beyond the scope of this article.

Most infants who have an episode of wheezing will not undergo the experience again. They are likely to 140have normal respiratory function and no impairment in later life. Two-thirds of infants with recurrent wheezing are likely to outgrow their symptoms during the subsequent five years or so.²⁰ On the other hand, children who have a severe episode, require intensive care or undergo mechanical ventilation during the acute episode are more likely in later life to manifest with hyper-reactive airway disease.

Food allergy is defined as an adverse immunological response to food that is reproducible under blinded conditions. As a result of changing environmental conditions, westernized life style, air pollution, and the consumption of lots of additives and preservatives with foods, food allergy and asthma are increasing worldwide. Allergic Rhinitis (hay fever or “indoor/outdoor,” “seasonal,” “perennial” or “nasal” allergies): characterized by nasal stuffiness, sneezing, nasal itching, clear nasal discharge, and itching of the roof of the mouth and/or ears.^1,2,3

Here are the basic ideas about asthma causes and treatment:

The three basic treatment choices are:

Many studies of food allergy involve patients with food-induced asthma; the asthma is easily recognized if symptoms begin within a few hours of eating food and the asthma is associated with other symptoms of food allergy. Eczema and asthma are often associated in atopic patients with food allergy. It is reported that in a group of 320 children with atopic dermatitis 55% 145had asthma.⁵ Food challenges triggered respiratory symptoms in 59% of including rhinitis, laryngeal edema, wheezing and dyspnea. Gastrointestinal symptoms occurred in 41% of positive challenges. Often, asthma is treated only as an airborne allergy problem or as a problem unrelated to allergic processes and the possible role of food allergy is neglected.

“Food allergy is a very important cause of asthma but is often overlooked. It is important because it may cause severe symptoms of asthma and still has a high mortality despite improvements in drug therapy. It is overlooked because the usual skin tests are often negative and the history is often not helpful as symptoms appear gradually hours or days after ingestion of the food.” IgE and Non-IgE mechanisms can cause asthma. Patients with no positive skin tests were shown to react to foods. In our studies, Milk, Wheat, Egg, Banana, Mango, Rice, Groundnut, Fish, were the main foods implicated. Other manifestations of food allergy are typical in 65% of the asthmatic patients. Diet revision with elimination of foods or a “low allergen” diet was used to induce remission of symptoms then foods were re-introduced to determine reactivity. The role of food allergy in patients with bronchial complaints is still underestimated by clinicians because: (1) of the death of information in this area (2) The involvement of foods in patients with allergic disorders is complex and has various forms. (3) The diagnostic procedures and confirmation of adverse reactions to foods is difficult. In a study of mechanisms increasing circulating immune complexes (IgE and IgG) were demonstrated following challenges with allergenic foods (egg) and correlated with symptoms. Complexes peaked at 24 hours after food ingestion and the appearance of symptoms was followed only later. Twelve of the 14 subjects studied 146had asthma; associated problems were eczema, rhinitis, arthralgia, urticaria, and diarrhoea. In a review of 320 children and young adults with atopic dermatitis 55% had asthma. With food challenges respiratory symptoms occurred in 236 (42%) including nasal symptoms, dyspnea, wheezing, and laryngeal edema. Chronic coughs may mean allergic bronchitis with or without asthma. Food allergy patients are often given antibiotics repeatedly, since allergic symptoms and infection symptoms are similar. Antibiotics may offer no benefits and may increase the risk of further allergic reactions. Many patients report long-term deterioration after repeated or prolonged antibiotic use. This apparent adverse effect of antibiotics has been blamed on yeast overgrowth in GIT, but the real reason is probably more complex. Food allergens travel from the digestive tract to the lungs. Food allergens may be found in the blood stream in circulating immune complexes that trigger the release of immune mediators in the bloodstream. These chemicals cause a variety of symptoms, including constriction of the bronchial smooth muscle in the lungs; this is the first event of an asthmatic attack. Airflow is reduced in the narrowed tubes. Air has a harder time leaving the lungs than entering-the result is prolonged noisy expiration. If you listen with a stethoscope, you will hear scattered whistles from the narrowed bronchi on breathing out. Later, the small tubes in the lung swell and plug with increased mucus secretion, making the obstruction to airflow worse. This inflammatory, obstructive phase is the most important mechanism of chronic asthmatic bronchitis. Our patients usually have asthma with associated symptoms that suggest a whole-body food allergy problem.

Food Allergen: Most prevalent in very young children and frequently outgrown, food allergies are 147characterized by a broad range of allergic reactions. Symptoms may include itching or swelling of lips or tongue; tightness of the throat with hoarseness; nausea and vomiting; diarrhoea; occasionally chest tightness and wheezing; itching of the eyes; decreased blood pressure or loss of consciousness and anaphylaxis. Although some researchers would argue that an allergic component contributes to more than 80% of young asthmatics and approximately 40% of adult asthmatics who experience the association between diet and non-food allergies are widely ignored. It is reported in the United States that about 6-8% of infants and about 1.5% of adults are allergic to food. Food is very important cause of asthma but is often overlooked, as usual skin tests are often negative and history is often not helpful. In most of the patients, symptoms appear gradually hours or days after ingestion of the food. It has been estimated that less than 10% of asthmatics may notice that their symptoms are provoked by certain foods or drinks.^7,9–11 The majority of these deaths are due to severe allergy to peanut and nuts, and asthma appears to be an important risk factor for this form of allergy. Sensitivity can occur by ingestion of minute quantities of food allergens and even by inhalation of food allergens carried in air or in cooking fumes. A food allergic reaction is presumed to be the result of abnormal immunological responses, consisting both of IgE mediated and non-Ig-E-mediated response after ingestion of a relevant food. Sensitization occurs as a result of pinocytosis of antigenic protein molecules by intestine mucosal cells (perhaps in the Peyer's Patches) and induction of an IgE antibody response. Subsequent entry of antigen into the blood-stream provokes an IgE-mediated reaction. The representative symptoms of food allergy are “Oral allergy syndrome” with oral and perioral 148itching and rash, gastrointestinal symptoms such as nausea, vomiting and diarrhoea, and dermatological manifestations such as urticaria and eczema.¹² We have seen infants develop rashes after a traditional bath with milk or curd. Food allergy can cause both immediate and delayed patterns of asthma. Effect of foods on asthma can be mediated through increase in synthesis of prostaglandin-E2 (PG-E2). This can in turn promote the formation of IgE and consequently allergic sensitization. Immediate food reaction (Type-I allergy mediated by IgE), can cause sudden, dramatic and life threatening asthma, is one consequence of anaphylactic reaction to food. Delayed patterns of food allergy (Non-IgE-mediated) can cause more persistent inflammatory form of chronic asthma. This is among the most neglected causes of intrinsic asthma. Skin tests do not show delayed pattern of food allergy.

Common foods causing asthma are milk, eggs, fish, peanuts, soy, yeast, cheese, wheat, rice and chocolates.^4,6,8 Food preservatives can also trigger an asthma attack. Additives such as sodium bisulfite, potassium bisulfite, sodium metabisulfite, potassium metabisulfite and sodium sulfite are commonly used in food processing or preparation and can be found in foods such as: Dried fruits or vegetables, Potatoes (packaged and some prepared), wine and beer, bottled lime or lemon juice, shrimp (fresh, frozen or prepared) pickled foods.

Skin test - For most people, skin tests are the most accurate and least expensive way to confirm suspected allergens. There are two types of allergen skin tests. In prick/scratch testing, a small drop of the possible allergen is placed on the skin, followed by lightly pricking or scratching with a needle through the drop. In intra-dermal (under the skin) testing, a very small amount of allergen is injected into the outer layer of skin. With either test, if you are allergic to the substance, you will develop redness, swelling and itching at the test site within 20 minutes. You may also see a “wheal” or raised round area that looks like a hive. Usually, the larger the wheal, the more sensitive you are to the allergen.

Patch test - This test determines if you have contact dermatitis. Your doctor will place a small amount of a possible allergen on your skin, cover it with a bandage and check your reaction after 48 hours. If you are allergic to the substance, you should develop a rash.

Blood tests - Allergen blood tests (also called Radioallergosorbent tests [RAST], Enzyme-Linked 150Immunosorbent Assays [ELISA], Fluorescent Allergosorbent tests [FAST], Multiple Radioallergosorbent tests [MAST] or Radioimmunosorbent tests [RIST] are sometimes used when people have a skin condition or are taking medicines which interfere with skin testing. The lab adds the allergen to the blood sample, and then measures the amount of antibodies the blood produces to attack the allergens. However, it is important to establish a clinical correlation with the positive tects.

Allergen immunotherapy (also called allergy vaccine therapy) involves subcutaneous injections of gradually increasing quantities of specific allergens to an allergic patient until a dose is reached that will raise the patient's tolerance to the allergen over time, thereby minimizing symptomatic expression of the disease. Because the proteins and glycoproteins used in allergen immunotherapy are extracted from materials such as pollens, molds, pelt, and insect venoms, they were originally called allergen extracts. In 1998, the World Health Organization (WHO) proposed the term “allergen vaccine” to replace “allergen extract,” because allergen immunotherapy is an immune modifier just as vaccines are.¹ The efficacy of allergen immunotherapy has been known since 1911, when Noon injected an extract of grass pollen into a person in England whose allergic symptoms coincided with the pollination of grass.² Since then, controlled studies have shown that allergen immunotherapy is effective in patients with allergic rhinitis, allergic conjunctivitis, allergic asthma, and allergic reactions to Hymenoptera venom.^3–6 Patients with one or more of these diagnoses are considered for immunotherapy if 153they have well-defined, clinically relevant allergic triggers that markedly affect their quality of life or daily function, and if they do not attain adequate symptom relief with avoidance measures and pharmacotherapy.

Allergen-specific immunotherapy (SIT) has been used for almost a century as a desensitizing therapy for allergic diseases and represents the only curative and specific method of treatment. Administration of appropriate ions of allergen extracts has been shown to be reproducibly effective when patients are carefully selected. The mechanisms by which allergen-SIT has its effects include the modulation of T-cell and B-cell responses and related antibody isotypes as well as effector cells of allergic inflammation. The balance between allergen-specific T-regulatory (Treg) and TH2 cells appears to be decisive in the development of allergic and healthy immune responses against allergens.^7–9 Treg cells consistently represent the dominant subset specific for common environmental allergens in sensitized healthy individuals. In contrast, there is a high frequency of allergen-specific TH2 cells in patients with allergy. The induction of a tolerant state in peripheral T cells represents an essential step in allergen-SIT. Peripheral T-cell tolerance is characterized mainly by generation of allergen-specific Treg cells leading to suppressed T-cell proliferation and TH1 and TH2 cytokine responses against the allergen. This is accompanied by a significant increase in allergen-specific IgG, Ig A and a decrease in IgE in the late stage of the disease. In addition, decreased tissue infiltration of mast cells and eosinophils and their mediator release including circulating basophils takes place. There is increasing 154evidence to support IL-10 and/or TGF-β secreting Treg cells^8–10 and immunosuppressive cytokines as key players in mediating successful allergen-SIT and a healthy immune response to allergens. In sensitized individuals, peripheral T-cell tolerance represents the key mechanism in healthy immune responses to allergens. Peripheral tolerance to allergens induced by allergen-SIT involves control of the allergen-specific immune response in multiple phases including specific T-cell suppression, generation of non-inflammatory antibody isotypes such as IgG4 and IgA, suppression of IgE and type 1 hypersensitivity responses and suppression of late phase reaction and mast cells, eosinophils, and basophils.¹¹ Taking the recent advances in knowledge of peripheral tolerance mechanisms into account, developments of safer approaches and more efficient methods of allergen-SIT await.

The allergens for which immunotherapy is known to be effective are pollens,^{5, 6} cat dander,¹² dust mites,¹³ cockroaches,¹⁴ and fungi.¹⁵ Allergy immunotherapy 155cannot be used for food allergies because the risk of anaphylaxis is too great. For immunotherapy to be effective, an optimal dose of each allergen must be determined. When a patient has multiple sensitivities caused by related and unrelated allergens, vaccines containing mixtures of these allergens may be prescribed. As multiple vaccines are mixed, not only will the concentration of each allergen be decreased, but certain allergens will interact. For example, fungi, dust mites, insect venoms, and cockroach have high proteolytic enzyme activity and may be combined with each other but should not be mixed with other allergens.

Durham and colleagues¹⁶ conducted a randomized, double-blind, placebocontrolled trial to look at effects in patients who had received three to four years of immunotherapy. They were able to demonstrate a marked reduction in allergy symptom scores and antiallergic medication usage, as well as an alteration in the natural course of allergic disease. Preliminary reports suggest that immunotherapy for allergic rhinitis may reduce the risk for later development of asthma in children.^17,18 In addition, early treatment with allergen immunotherapy in children who were sensitive only to house dust mites reduced development of sensitivity to other allergens.¹⁹ In contrast to the use of antiallergic medication, allergen immunotherapy has the potential to alter the natural course of allergic disease and prevent progression or development of multiple allergies. Consequently, many allergists have suggested its use earlier in the course of allergic disease. In 2000, the Immunotherapy Committee of the American Academy of Allergy, 156Asthma, and Immunology (AAAAI) provided a five-year cost comparison of medication usage and single-injection allergen immunotherapy for allergic rhinitis. The cost of medications is much greater than that of single injection immunotherapy. Long term costs deriving from the morbidity and complications of allergic diseases are not established, but allergies usually begin early in life and persist if not treated with allergen immunotherapy. A reasonable assumption is that allergen immunotherapy dramatically lowers the cost of treating allergic diseases.

Sub-cutaneous Immunotherapy (SCIT): Currently subcutaneous immunotherapy is established as effective treatment for patients with allergic rhinitis²⁰ and allergic bronchial asthma.²¹ In their updated meta-analysis using 75 trials including 3506 participants (36 trials of immunotherapy for house mite allergy; 20 pollen allergy trials; ten animal dander allergy trials; two cladosporium mould allergy, one latex and six trials looking at multiple allergens), Abramson et al²¹ confirmed that allergen specific immunotherapy can significantly reduce asthma symptoms and medication requirements. Whilst inhaled corticosteroid therapy remains the mainstay of asthma management, any reduction in this type of treatment while maintaining good asthma control would be welcome. There was no consistent effect of immunotherapy upon lung function and there was significant heterogeneity in the trials that reported PEFR measurements Patients randomised to immunotherapy were significantly less likely to develop increased nonspecific bronchial hyperresponsiveness 157(BHR), and there were modest improvements in indices of nonspecific BHR. Allergen immunotherapy significantly reduced allergen specific BHR. Not surprisingly it would appear that allergen immunotherapy has a greater effect upon allergen specific BHR than upon nonspecific BHR. The finding that allergen immunotherapy significantly and homogeneously improves allergen specific bronchial BHR is clinically important. Patients with brittle extrinsic (allergic) asthma are at risk of sudden deterioration when exposed to increased levels of an aeroallergen to which they are sensitive. An intervention that reduces the risk of an acute episode of asthma under these circumstances may be clinically useful. Currently, the measurement of allergen specific BHR is the only accurate method of assessing such a risk. There is some evidence that house dust mite extracts may reduce asthma symptoms and allergen specific BHR compared to house dust extracts. One study even suggested that house dust extracts alone could reduce allergen specific BHR, challenging the view that such extracts are antigenically inactive. However taken together, these results are consistent with the greater efficacy of house dust mite extracts compared with placebo. Although not consistently reported in the randomised controlled trials, there are well recognised adverse effects of immunotherapy. Three recent studies^22–24 reported the incidence of non-fatal systemic reactions to inhalant allergen immunotherapy. The total number of participants was 4768 and the studies recorded events over 7 to 12 years. The incidence of systemic reactions was one per 1250 to one per 2206 injections. Most reactions were mild. Deaths due to allergen immunotherapy were extremely rare, with estimates ranging from one per one million to one per two million injections.158

Sub-lingual Immunotherapy (SLIT): Meta-analyses have confirmed that SLIT is effective therapy for allergic rhinitis,²⁵ including in pediatric patients,²⁶ and for allergic asthma.²⁷ A meta-analysis of 21 trials involving 959 subjects with allergic rhinitis found a significant reduction in symptoms and medication use, but no clear relationship between results and the dose or duration of therapy could be established.²⁵ The pediatric rhinitis study, which included trials with 484 subjects, found significant improvement in symptoms with pollen, but not house dust mite extracts, and with treatment for more than 18 months, but not with briefer treatment.²⁵ Twenty-five studies with 1706 participants were included in the asthma metaanalysis.²⁷ Although the evidence found in the meta-analysis was not very strong, the results from assessing all parameters suggested SLIT reduced asthma expression.

Allergen immunotherapy is safe, but the potential for an adverse reaction isalways present. Although these reactions are rare, they can be life-threatening. In 1924, Lamson reported the first case of death following immunotherapy.³² A statistical review of the literature about systemic reactions following allergen immunotherapy by Lockey and colleagues³³ found that severe systemic reactions occurred in less than 1 percent of the patients receiving conventional immunotherapy in the United States. From 1985 to 1993 in the United States, 52.3 million administrations of immunotherapy resulted in 35 deaths. These numbers equate to a mortality incidence of less than one per 1 million.³⁴ Patients with medical conditions that reduce their ability to survive systemic allergic reactions are not candidates for allergen immunotherapy. Examples of such conditions include chronic lung disease with a forced expiratory volume in one second (FEV1) of less 160than 50 percent, beta-blocker or angiotensin-converting enzyme (ACE) inhibitor therapy, uncontrolled hypertension and major organ failure. Allergen immunotherapy also cannot be used in patients who would have difficulty reporting signs and symptoms of a systemic reaction, such as children younger than three or four years. Patients who have not been compliant with other forms of therapy are not likely to be compliant with immunotherapy, thus necessitating frequent alteration in dosage schedules and increasing the chance for errors. Patients should be assessed with each injection for newly acquired risks that may not have been present at the beginning of allergen immunotherapy. Patients with severe, poorly controlled asthma are at higher risk for systemic reactions to immunotherapy injections than patients with stable, well-controlled asthma.³³ Some physicians measure peak expiratory flow readings in all patients with asthma before administering allergen immunotherapy and with hold injections if the reading is less than 70 percent of predicted.

Anaphylaxis is the most serious risk related to allergen immunotherapy. The vaccines must be administered in a setting with trained professionals who are equipped to recognize and treat anaphylaxis.³⁵ A retrospective study found that most systemic reactions occurred within 30 minutes of injection.³⁶ Hence, the current recommendation is to allow at least 20 to 30 minutes of observation following an injection. Patients who have had a systemic reaction after more than 30 minutes following an injection require longer observation; in addition, they should be given injectable epinephrine to carry and instructions about how to use it. Nonetheless, reactions may occur without warning signs or symptoms, and documentation of informed consent must be obtained from the patient.161

Given the persistence of the protective effect after discontinuing immunotherapy on the development of new sensitizations and progression to asthma, it is not surprising that there is also persistence of reduction of clinical symptoms.^37–39 This has been shown most convincingly by a double-blind study in which subjects who had received 3 or 4 years of timothy grass immunotherapy were randomized to continue receiving monthly maintenance injections of grass extract or to receive placebo injections.³⁹ After 3 more years, there was no difference in control of symptoms or medication use between the 2 groups.

Immunotherapy remains the only truly disease-modifying treatment for asthma and allergic rhinitis. It restores the normal immune response to common allergens. It can prevent new sensitizations in monosensitized individuals and prevent the development of clinical asthma in those with only rhinitis. Furthermore, its salutary effects continue for years after completion of the course of treatment. The factors limiting the greater use of immunotherapy are concerns of safety and the inconvenience of prolonged build-up and maintenance treatment schedules. Numerous approaches to improve the safety and increase the convenience of immunotherapy are being studied. The only one currently in clinical use is sublingual administration of the allergen extracts. Evidence for the effectiveness of this approach is quite convincing. There remain questions to be resolved including optimal dosing, frequency, and duration of 162treatment. There is also the question of the effectiveness of administration of mixes of multiple allergen extracts sublingually. Finally, SLIT appears to be, at least in the short term, less effective than SCIT. It is likely there is a place for both approaches to immunotherapy in the treatment armamentarium. Other new approaches to immunotherapy are under study. These include modified recombinant allergens, peptides, immunostimulatory DNA sequences covalently bound to allergenic proteins, and fusion proteins designed to give an inhibitory signal to mast cells and basophils. Whether any of these approaches will replace current immunotherapy practices depends on the demonstration of increased safety and convenience, cost effectiveness, and retention of the efficacy of current injection immunotherapy.

Asthma has a genetic predisposition but it needs environmental factors to initiate the events leading to clinical development of allergy. Asthma affects children in many ways and can result in a significantly decreased quality of life, with reduced exercise tolerance and increased school absences.¹ Furthermore the symptoms of asthma diagnosed in childhood persist into adulthood. For example, 50% of children with asthma referred to one hospital clinic had on going symptoms in adulthood some 30 years later.² Current asthma treatment palliates but does not cure symptoms. Better understanding of asthma pathogenesis in children is essential for future advances in asthma management. In many developing countries, increasing Westernization is associated with a rapid rise in the prevalence of previously uncommon atopic disorders. Not with standing the importance of genetic factors, the time frame over which these increases have occurred makes it implausible that they could be the result of genetic changes, highlighting the importance of environmental factors in the pathogenesis of allergic sensitization and the expression of atopic diseases. Both observational and interventional studies continue to shed new light on the critical influence of early life events - such as events in pregnancy, exposure to allergens and endotoxin, pet ownership, infections, family size - and have 168highlighted important gene-environment interactions that modify the relationships between environmental exposures and atopic outcomes.

Early childhood respiratory infections were associated with an increased asthma risk, whereas early contact with older children was linked to permanent protection against asthma and increased the chances of remission of childhood asthma. These patterns of association were independent of the presence or absence of allergen-specific IgE, suggesting that exposure to microbial infections can partially interfere with an acquired predisposition to asthma. Similarly, otitis media and other infections in infancy may protect against allergic sensitization in older children and teenagers.^3,4 Household endotoxin levels appear to be inversely associated with a subsequent diagnosis of eczema, even after adjusting for income, season of birth and gender.⁵

The effect of family pets on the development of atopic disease remains controversial. While few would argue with the recommendation that sensitized patients should minimize exposure to cats and dogs, it is becoming increasingly clear that avoidance of such exposures is ineffective in preventing sensitization in young children and may indeed be counterproductive.⁶ Early exposure to cats appears to protect against cat allergy and subsequent asthma ^{7– 9} and may also reduce sensitization to other allergens,⁷ while other investigators report no relationship between cat allergen exposure and atopy or asthma outcomes.¹⁰ Dog ownership in early life also appears to be 169associated with reduced allergic sensitization and atopic dermatitis. ^8,11 Dogs, rodents, birds and other furry or feathered animals in the home may contribute in varying degrees to the animal allergens within the home. Dogs may have breed-specific allergens and are less uniformly allergenic than cats.¹² Rodent allergens can come from pets or pests in the home. Birds and feathers have been suggested as allergenic; however, it may be that the dust mites associated with feathers (including feathers in pillows and clothes) are the culprits ¹³ The type of microbial exposure during immune system maturation may influence the development of atopy and asthma. In children with the CD14 - 159C allele who had regular contact with household pets, serum IgE levels were higher than with the T allele.¹⁴ The opposite occurred in children with regular contact with stable animals where the C allele was associated with lower IgE levels.

Living on a farm with continuous exposure to the animals has been found to cut down the risk of many allergic diseases and asthma. It has been reported that the protection against these diseases starts building even before birth. Life in a farm means continuous exposure to the animal bacteria through direct animal exposure or through unpasteurized milk consumption. The researchers say that this exposure may suppress the development of specific immune cells that are related to asthma.

Exposure to moluds may lead to allergic sensitization and may exacerbate asthma or allergic rhinitis.¹⁵ At 170least 60 species of moulds have spores thought to be allergenic.¹⁶ Species of particular concern are Penicillium, Aspergillus, Cladosporium, Alternaria. On exposure to these species, nasal congestion, runny nose, sneezing, conjunctivitis, lacrimation, wheezing, chest tightness and shortness of breath may occur. Among patients studied, children are the most sensitive to molud allergens.¹⁷

House dust mites are tiny (up to 0.3 mm) animals related to ticks and spiders and live in housedust. There is not a house without them, but some houses contain huge numbers and other houses contain almost none. This does not only depend on cleanliness, but depends very much on the amount of moisture in the house; dry houses in very cold climates or on high mountains have few mites, but houses in temperate climates and normal altitudes have more. House dust mites eat the dust which comes from our skin all the time. They leave droppings everywhere they go. Their droppings contain left-over enzymes which the mites use to digest the skin dust. It is these enzymes which are the most important part of mite dust in causing asthma and other allergic diseases. In fact, house dust mites and their droppings are the most important cause of asthma worldwide. There is ample proof that living in surroundings with little or no mite dust improves or cures asthma in those people whose asthma is caused by it. Previous investigators have reported that exposure to domestic levels of Der p 1 in excess of 10 mg/g of dust in infancy is a risk factor for asthma in older

Prolonged delivery was associated with the development of atopy in a prospective birth cohort followed to the age of 20 years, whereas prenatal smoke exposure and childhood pets decreased the risk of atopy,²¹ suggesting that events in pregnancy or at birth may have an enduring effect on atopy many years later. Psychological stress in caregivers is reportedly associated with larger T-cell responses to allergens and higher total IgE levels in the first two years of life,²² while elevated body mass index and an early onset of puberty may be linked to persistence of asthma from childhood into adolescence.²³ Use of skin creams containing peanut oil and intake of soymilk or soy-based formula, are associated with the development of peanut allergy.²⁴ Despite asthma´s high prevalence and considerable quality of life implications, its pathogenesis in children is not completely understood. What has been established is that asthma is a complex condition, where both genetic and environmental factors are important.172

Exposure to environmental tobacco smoke (ETS) is a risk factor for asthma attacks in children.²⁵ Children with asthma and whose parents smoke have more frequent asthma attacks and more severe symptoms.^26–28 There is clear evidence of an association between exposure to environmental tobacco smoke and the development and exacerbations of asthma. Exposure to ETS also places children at increased risk for sinusitis, otitis media and bronchiolitis.^13,29 Exposure to environmental tobacco smoke may increase the risk of asthma in susceptible individuals. In a study of Puerto Rican and Mexican families, people with asthma with the CD14 ρ1437GG or GC genotypes and exposure to environmental tobacco smoke had a mean forced expiratory volume in 1 st lower by 8.6% of that predicted, compared with nonexposed individuals.³⁰

Improperly used or malfunctioning heating devices are a major source of combustion pollutants indoors. Possible sources of contaminants include gas ranges, especially if used for home heating; improperly vented fireplaces; inefficient or malfunctioning furnaces; stoves burning wood, coal, or other biomass; and unvented or improperly vented kerosene or gas space heaters. The combustion products from these devices include carbon monoxide (CO), nitrogen dioxide (NO₂), particulate matter and sulfur dioxide (SO₂). Although CO is a major health concern, it is not an irritating gas and is not likely by itself to exacerbate asthma. In combination, these combustion products will often exacerbate asthma symptoms.³¹173

Ozone is a major air pollutant with adverse effects on the lungs. In mice, regions of genetic linkage with ozone-induced lung injury include the tumour necrosis factor-α (alpha) (TNF) gene.³² A role for TNF polymorphism in susceptibility to childhood asthma in response to environmental ozone exposure has now also been established.³³ Air pollutants include diesel exhaust particles with particulate matters less than 10 mm or 2.5 mm. These diesel exhaust particles are thought to exert their detrimental effects through generation of reactive oxygen species. The glutathione- S-transferase genes protect from oxidant stress. Thus, carriers of the glutathione-S-transferase genes that result in loss of function may be at increased risk for respiratory morbidity when exposed to air pollution.

There are well over 300 agents reported to cause occupational asthma,³⁴ and an equal or greater number of agents and conditions at work can aggravate existing asthma. Numerous workplace biologic allergens can cause asthma, including natural rubber latex in medical care settings and animal allergens in research laboratories and veterinary offices. A wide range of airborne dusts, gases, fumes, and vapors can cause dose-related symptoms in individuals exposed to them in the workplace. Among the chemicals associated with occupational asthma, the acid anhydrides have been signal agents for study because of their inherent and complex biological activity and the wide range of associated occupational airway disease seen in exposed workers in various 174occupational settings.³⁵ In addition to traditional “dirty” workplaces, offices and other non-industrial indoor work environments can pose a risk for asthma. Sufficient evidence exists for associating the presence of mould or other agents in damp buildings to nasal and throat symptoms, cough, wheeze, and asthma symptoms in sensitized asthmatics.³⁶ There are other reports also that exposure to damp indoor environments and mold can lead to the development of asthma.^37,38 In practice, asthma is likely to be caused by combinations of several genetic and environmental factors, all of which should be considered when studying asthma pathogenesis. Environmental and lifestyle factors which have undergone rapid changes have therefore been recognized as the cause of the steep rise in allergic diseases and thus require a better understanding.

Asthma is a condition, often chronic, characterized by respiratory symptoms, variable airflow limitation and/or airway hyper-reactivity with symptoms causally related to family history, environmental influences, exposure to viruses and allergens as examples. The high economic burden associated with asthma is associated primarily with health care costs, missed work or school days. Families with patients suffering from asthma are always in search of a wonder cure for this disease. There is a wealth of information in traditional knowledge on this aspect which needs to be used and researched in a scientific way.¹ Drug therapy is normally used to control symptoms. However the use of complementary or alternative medicine (CAM) is widespread. In a UK survey of National Asthma Campaign members, only 41% said that they had not used CAM and of those 41%, 67% said that they would consider using CAM for their asthma in the future. The most popular forms of CAM in the study population were breathing techniques, homeopathy and herbs. A survey of CAM use in asthma or rhino sinusitis sufferers in the USA found that 42% of the study population had used some form of CAM for their condition in the 12 months prior to the study. Herbal treatments emerged as being the 180most commonly reported form of CAM being used. Another US survey of CAM use found that allergies and lung problems ranked as some of the most frequently reported medical conditions that CAM is used for. The most popular forms of CAM for these conditions were herbs, relaxation and spiritual healing. Why then, when there are effective treatments available for asthma do people turn to complementary or alternative medicine, especially given that evidence in support of treatments such as acupuncture and homeopathy are weak. The reasons for people turning to CAM can be divided into positive and negative motivations. Positive motivations include perceived effectiveness and safety; ‘spiritual’ or holistic nature of the therapy; personal control over treatment; good relationship with the therapist; and accessibility. Negative reasons include dissatisfaction with conventional methods; rejection of the ‘establishment’ and desperation. A study into the beliefs and motivations of CAM users in Canada supports this theory. It found that the two main reasons people used CAM were that it allows them to take a more active role in their health, and a feeling that conventional medicine was not effective for their health condition.

A systematic review has been conducted to determine the study quality of articles investigating ayurvedic/collateral herbs, the effectiveness/efficacy and safety profile, as reported in the studies. Literature searches were conducted using PubMed, EMBASE, Mantis, Ovid, Annotated Bibliography of Indian Medicine and Cochrane library to identify published trials on herbal 181medicines for asthma of which Ayruvedic herbals are a subset. Randomized Controlled Trials (RCTs) and Quasi-Experimental Designs (QEDs) were included in this systematic review. Herbs included in Traditional Chinese Medicine were excluded from this review. Forty-two articles were retrieved and 37 studies were ultimately reviewed utilizing 3 independent evaluators/1 arbitrator.

Yogic exercises are practised throughout the world for health and disease. These practices comprise of Meditation, Praanayam (breathing exercises) and yogic postures or Asanas.³ Bronchial asthma is a chronic inflammatory disease in which these exercises have been shown to have some positive effect. Breathing techniques are used by a large proportion of asthma sufferers. A systematic review was conducted aimed at determining whether or not these interventions are effective. Four independent literature searches identified six randomized controlled trials. The results of these studies are not uniform. Collectively the data imply that physiotherapeutic breathing techniques may have some potential in benefiting patients with asthma. The safety issue has so far not been addressed satisfactorily. It is concluded that too few studies have been carried out to warrant firm judgements. It has been recommended that further rigorous trials should be carried out in order to redress this situation. Some studies have been conducted in our country testing some of the yogic practices in treatment of bronchial asthma.⁴ The effects of two pranayama yoga breathing exercises on airway reactivity, airway calibre, symptom scores, and medication use in patients with mild asthma were assessed in a randomised, double-blind, placebo-controlled, crossover-trial. After baseline assessment over 1 week, 18 patients with mild asthma practised slow deep breathing for 15 min twice a day for two consecutive 2-week periods. During the active period, subjects were asked to breathe through a Pink City lung (PCL) exerciser—a device which imposes slowing of breathing and a 1:2 inspiration:expiration duration ratio equivalent to pranayama breathing methods; during the control period, subjects breathed through 185a matched placebo device. Mean forced expiratory volume in 1 s (FEV1), peak expiratory flow rate, symptom score, and inhaler use over the last 3 days of each treatment period were assessed in comparison with the baseline assessment period; all improved more with the PCL exerciser than with the placebo device, but the differences were not significant. There was a statistically significant increase in the dose of histamine needed to provoke a 20% reduction in FEV1 (PD20) during pranayama breathing but not with the placebo device. The usefulness of controlled ventilation exercises in the control of asthma should be further investigated.

A prospective, randomised, single blind, and controlled trial of a hypnotic technique was undertaken in 39 adults with mild to moderate asthma graded for low and high susceptibility to hypnosis.⁵ After a six week course of hypnotherapy 12 patients with a high susceptibility score showed a 74.9% improvement (p less than 0.01) in the degree of bronchial hyper-responsiveness to a standardised methacholine challenge test. Daily home recordings of symptoms improved by 41% (p less than 0.01), peak expiratory flow rates improved by 5.5% (p less than 0.01), and use of bronchodilators decreased by 26.2% (p less than 0.05). The improvement in bronchial hyper-reactivity occurred without a change in subjective appreciation of the degree of bronchoconstriction. A control group 17 patients and 10 patients undergoing treatment with low susceptibility to hypnosis had no change in either bronchial hyper-responsiveness or any of the symptoms recorded at home. This study shows the efficacy of a hypnotic technique in adult asthmatics 186who are moderately to highly susceptible to hypnosis. In authors experience use of meditation besides its spiritual effects has a positive role in stress relief. Certain yogasans specially suryanamaskar are particularly helpful for children. Techniques like Neti and Ujjai Pranayam are specially useful for allergies.

One round of Sun Salutation consists of two sequences, the first leading with the right foot in positons 4 and 9, the second leading with the left. Keep your hands in one place from positons 3 to 10 and try to co-ordinate your movements with your breathing. Start by practicing four rounds and gradually build up to twelve rounds.

Asthma is a chronic inflammatory disorder of the airways. Chronically inflamed airways are hyper-responsive; they become obstructed and airflow is limited (by bronchoconstriction, mucus plugs, and increased inflammation) when airways are exposed to various risk factors.

Asthma is one of the most common chronic diseases worldwide and unfortunately, the prevalence is increasing, especially among children. The prevalence of asthma symptoms in children varies from 0 to 30 percent in different population with the highest prevalence occurring in Australia, New Zealand and England.

Prevalence in India: International Study of Asthma and Allergies in children (ISAAC) has shown prevalence of atopic disorders raging from 3–17% in different areas in India. Asthma can be treated and controlled so that almost all children can:

Risk factors for asthma include host factors that predispose individuals to or protect them from developing asthma (genetic Predisposition, gender, and race) and environmental factors that influence the susceptibility to the development of asthma in predisposed individuals, precipitate asthma exacerbations and/or cause symptoms to persist. Exposure to allergies, viral and bacterial infections, diet, tobacco, smoke, socioeconomic status and family size are the main environmental factors that influence the susceptibility to the development of asthma in predisposed Individuals. Exposure to allergies and viral infections are the main environmental factors causing exacerbations of asthma and/or the persistence of symptoms in children. Asthma attacks (or exacerbations) are episodic, but airway inflammation is chronically present. For many patients, medications must be taken every day to control symptoms, improve lung functions, and prevent attacks. Medications may also be required to relieve acute symptoms, such as wheezing, chest tightness, and cough.

Asthma can often be diagnosed on the basis of symptoms. However, measurements of lung function, and particularly the reversibility of lung function abnormalities, greatly enhance diagnostic confidence in children 5 years and older.

Consider asthma if any of the following are present:

(Note: Eczema, hay fever or a family history of asthma or atopic disease are often associated with asthma.)

When using a peak flow meter, consider asthma if:

Name _____________________________________________________

Address ___________________________________________________

_____________________ Tel. No. _____________________________

Age ___________ Sex _____________ Date of birth _______________

Father's occupation __________________________________________

Mother's occupation _________________________________________

Age at onset of symptom_____________________________

Duration (in months) ________________________________________

Aggravating factors ____________________________ Relieving factor

Duration (in months) ________________________________________

No. of previous episodes _____________________________________

Aggravating factors _________________________________________

Relieving factors ___________________________________________

Which season is associated with symptoms? ____________________193

No. of family members _______________________________________

No. of cigarette/beedi smoked ________________________________

Duration of stay ___________________________________________

No. of previous hospitralizations _______________________________

Wt. _______________ (kg)    Ht/L _____________ (kg)

OFC ______________     HR _________________

RR _______________     BP _________________

Classification of severity

Treatment Plan

Follow-up date _____________

Date         Follow-up assessment195

The management programme for control of asthma includes:

The goals of management of asthma are to achieve:

The successful control, prevention and treatment of asthma is based on a partnership approach towards the child, his family members and the medical team. With the help of those on the health care team, children and their families can and should be participating actively in managing asthma.

Education is directed towards learning to:

An asthma management education plan should cover:

Control of asthma requires continual long-term care and monitoring. Monitoring includes review of symptoms and, as far as possible, measurement of lung function in children over 5 years of age.

A peak flow meter is a device that measures how well air moves out of your lungs. During an asthma attack the air tubes of the lungs begin to narrow slowly. The peak flow meter can be used to find out if there is narrowing in the airways hours, even days before you have any symptoms of asthma. By taking your medicine early (before symptoms) you may be able to stop the attack quickly and avoid a serious attack of asthma. Peak flow meters are as good to check your asthma as the blood pressure instrument used to check high blood pressure.

All children older than 5 years of age who have moderate to severe asthma should think about using a peak flow meter. Younger children can also be taught 202to use it. Ask your doctor to show you how to use a peak flow meter.

Find your personal best peak flow number Your personal best peak flow numbers is the highest peak flow number you can achieve over a 2-week period when your asthma is under good control. Good control is when you feel good and do not have any asthma symptoms. Each patient's asthma is different and your best peak flow may be higher or lower than the average usual number for someone of your height, weight and sex. This means that it is important for you to find your own personal best peak flow number, your own medicine plan needs to be based on your own personal best peak flow number. To find out your personal best peak flow number, take peak flow readings:

The Peak Flow Zone System: Once you know personal best peak flow number, your doctor will give you the numbers that tell you what to do. The peak flow numbers are put into zones that are set up like a traffic light. This will help what to do when your peak flow number changes. For example: Green Zone (80 to 100 percent of your personal best number) signals all clear: No asthma symptoms are present, and you may take your medicines as usual or do without medicines. Yellow Zone (50 to 80 percent of your personal best number) signals caution. You may be having an attack of asthma that requires an increase in your medicines. Or your overall asthma may not be under control, and the doctor may need to change your medicine plan. Red Zone (below 50 percent of your personal best number) signals a medical alert. You must take an inhaled bronchodilator immediately and call on your doctor.

Peak expiratory flow rate and peak flow meters Peak expiratory flow rate (PEFR) provides a simple, quantitative, reproducible measure of airway obstruction that can be obtained by using peak flow meters. PEFR measurements when done with a good effort correlate well with FEV I measured by Spirometry. PEFR is an objective measurements and it is as important as we measure blood pressure with a sphygmomanometer, or monitor blood glucose level of a diabetic.

PEFR measurement is a valuable clinical tool

For routine monitoring at most outpatient visits, measurement of PEF with a peak flow meter is generally a sufficient assessment of pulmonary function, particularly in mild intermittent, mild persistent and moderate persistent asthma. Patients with moderate-to-severe persistent asthma should learn how to monitor their PEF with a peak flow meter at home. PEFR measurement, however, are not sufficient to make a diagnosis or to fully evaluate physiologic impairment associated with asthma because PEFR is effort dependent and measures only large airway function. When patients learn how to take PEFR measurement at home, the doctor's ability to provide effective treatment is improved. Daily monitoring of PEFR helps for examples, in detecting early stages of airway hyperresponsiveness), providing objective criteria in planning, initiating, or 205terminating treatment, facilitating communication between patient and the doctor, and investigating specific allergens in school or workplace/ occupational exposures that may exacerbate symptoms

Several kinds of peak flow meters and spirometers are available, and the technique for use is similar for all. It is important to use a “low flow” peak flow meter for younger children. Appropriate ages for use are usually indicated by the manufacturer. To use a peak flow meter:

Daily PEF monitoring for 2 to 3 weeks is useful, when it is available, for establishing a diagnosis and treatment. If during 2 to 3 weeks a child cannot achieve 80 percent of predicted PEF (predicted values are provided with all peak flow meters), it is suggestive of bronchial asthma. As far as possible, one should try to use locally available norms. It may be necessary to determine the child's personal best value, e.g. following a course of oral glucocorticosteroid. Long-term PEF monitoring is useful, along with review of symptoms, for evaluating a child's response to therapy. 206PEF monitoring can also help detect early signs of worsening before symptoms occur.

Interpreting PEFR measurements: Most children's values are consistently higher or lower than average predicted norms. It is important for each child to establish a personal best PEFR value. This personal best value will be the standard against which subsequent measurements are evaluated by the patient and doctor. Personal best values can be established during a 2 to 3 week period in which the patient records PEFR measurement twice a day after period of maximum therapy. A course of oral steroids may be needed to establish this personal best, and if the personal best is below 80 percent of the predicted value, more aggressive therapy and continued daily monitoring are indicated. The personal best value should be revaluated at least every 6 months to establish changes in the child's personal best that occurs with growth. Periodic reassessed value can also be used to see progression of disease in children. Further, peak flow meter measurement should be correlated periodically with spirometry. The expected PEFR for boys and girls based on height are available locally. To differentiate asthma from chronic obstructive pulmonary disease, restrictive pulmonary disease or possible central airway obstruction, assessment of other pulmonary functions like lung volumes, inspiratory and expiratory flow volume loop may be required. Diffusing capacity test differentiates emphysema. Assessment of diurnal variation in peak expiratory flow over 1–2 weeks is recommended in asthma patients with normal spirometry findings. It is done on first awakening and between noon to 4 P.M. A difference of 20% between two measurements suggests asthma.207

PEFR variability: Can be calculated by measuring morning (8:00 AM) PEFR and every PEFR (4:00 PM) and using the formula:

To improve the control of asthma and reduce medication needs, children should avoid exposure to risk factors (allergens and irritants that make asthma worse). Primary prevention of asthma is not yet possible, but is being actively investigated. Prolonged exclusive breast feeding, avoidance of smoking and known allergenic foods for nursing mothers and recommended.

The number and frequency of medications increase (step up) as the need for asthma therapy increases, and decrease (step down) when asthma is under control.

Anti-inflammatory agents, particularly inhaled glucocorticosteroids, are currently the most effective long-term preventive medications and are effective in reducing asthma attacks.

There are two approaches to gaining control of asthma

Review treatment every 3–6 months once asthma is under control.

Consult with an asthma specialist when other conditions complicate asthma (e.g., sinusitis), the child does not respond to therapy, or treatment at steps 3 or 4 is required.

Devices available to deliver inhaled medication include pressurized metered-dose inhalers (pMDIs), breath-actuated metered dose inhalers, dry powder inhalers (DPIs), and nebulizers. Spacer (or holding chamber) devices make inhaler easier to use. Spacers also reduce systemic absorption and side effects of inhaled glucocorticosteroids. Teach children and their parents how to use inhaler devices, Different devices need different inhalation techniques.212

In general:

Using a metered dose inhaler or an aerosol inhaler is a good way to take asthma medicines because the medicine goes right to the lungs and not to other parts of the body.

It takes only 5 to 10 minutes for the medicine to have an effect compared to medicines in liquid or tablet form which can take 1 to 3 hours. Inhalers can be used by all asthma patients above the age of 6 years. A spacer or holding chamber attached to the inhaler can be used even for younger children (around 3 years). These devices are helpful to people having difficulty in using an inhaler. The inhaler must be cleaned often to prevent clogging that reduces the medicine flow:

Metered dose inhaler

Dry powder capsules (Rotacaps) are used differently. Put the capsule in the place indicated on the side of the Rotahaler, and rotate the Rotahaler to open it up.217

Checking how much medicine is left in the canister

Unless you use your inhaler correctly in a coordinated manner as described much of the medicine may end up on your tongue, on the back of your throat, or in the air. Use of a spacer or holding chamber can help solve this problem. A spacer or holding chamber is a device that attaches to a metered dose inhaler. It holds the medicine in its chamber long enough for you to inhale it in one or two slow deep breaths. The spacer makes it easy for you to use the medicines correctly (especially if your child is young or you have a hard time using just an inhaler). It helps you not to cough when using in inhaler. A spacer will also help prevent you from 218getting a yeast infection in your mouth (thrust) when taking inhaled steroid medicines.

Alternatively if the child cannot follow instructions for deep inhalation, let him breathe normally with the spacer mouthpiece in his mouth. In small babies spacers with valve can be kept vertical to open the valve by gravity.

A nebulizer is a device driven by a compressed air machine. It allows you to take asthma medicine in the form of a mist. It consists of a cup, a mouthpiece attached to a T-shaped part or a mask, and thin, plastic tubing to connect to the compressed air machine. It is used mostly by three types of patients:

A nebulizer helps make sure that they get the right amount of medicine Directions for using the compressed air machine may vary with different persons. Check it with your doctor.