Ministry of Health of the Republic of Moldova [309580]

Ministry of Health of the Republic of Moldova

Public Institution “NicolaeTestemițanu” State University of Medicine and Pharmacy of the Republic of Moldova

FACULTY OF MEDICINE

Department of Internal Medicine Semiology

DIPLOMA THESIS

Bronchial Asthma: Etiology, Pathophysiology, Symptoms,

Diagnosis and Management

Elaborated by:

Scientific adviser:

Chisinau, 2017

CONTENTS

BRONCHIAL ASTHMA

I. INTRODUCTION………………

1.1 Actuality and theoretical importance and applied value of the thesis

1.2 The purpose of the study……………

1.3 Objectives of the study ………

II. BIBLIOGRAPHICAL ANALYSIS………

2.1 Etiology…………………

2.2 Risk Factors…

2.3 Epidemiology………

2.4 Pathophysiology

2.4.1 Genetics

3.0 Classification………….

3.1 Clinical manifestations……

3.2 Complications and their management…

3.3 Methods of diagnosis

3.4 Differential diagnosis…

3.5. Treatment and prevention

3.6 Prognosis …..

III. BRONCHIAL ASTHMA AND COPD

4.1 Summary………

4.2 Recommendation……….

4.3 Dietary strategies…..

4.4 Discussion…..

4.5 Conclusions……..

5. BIBLIOGRAPHY AND REFERENCES…………………………………………………

6. APPENDIX AND ATTACHMENTS ……………………………………………….

INRODUCTION

Asthma is a serious global health problem affecting all age groups. [anonimizat]. Although some countries have seen a [anonimizat], [anonimizat], disruption to the family.

[anonimizat], international surveys provide ongoing evidence for suboptimal asthma control in many countries. [anonimizat], [anonimizat], and to develop means to implement and evaluate effective asthma management programs.

[anonimizat]. Many of the world’s population live in areas with inadequate medical facilities and meager financial resources. [anonimizat], which are the cornerstone of care for asthma patients of all severity. [anonimizat], so the pricing of asthma medications continues to be an issue of urgent need and a growing area of research interest.

Key facts about Bronchial Asthma

Asthma is one of the major noncommunicable diseases. It’s a [anonimizat].

Some 235 million people currently suffer from asthma. It is a common disease among children.

[anonimizat]- [anonimizat].

Among the most common risk factors for bronchial asthma are inhaled substances and particles that may provoke allergic reactions or irritate the airways. [1]

Asthma is a chronic inflammatory disorder of the airways. [anonimizat], and potential prevention of the disease.

The immunohistopathologic features of asthma include inflammatory cell infiltration:

— Neutrophils (especially in sudden-onset, fatal asthma exacerbations; occupational asthma, and patients who smoke)

— Eosinophils

— Lymphocytes

— Mast cell activation

— Epithelial cell injury

Airway inflammation contributes to airway hyperresponsiveness, airflow limitation, respiratory symptoms, and disease chronicity. In some patients, persistent changes in airway structure occur, including sub-basement

fibrosis, mucus hypersecretion, injury to epithelial cells, smooth muscle hypertrophy, and

angiogenesis.

Gene-by-environment interactions are important to the expression of asthma. Atopy, the genetic predisposition for the development of an immunoglobulin E (IgE)-mediated response to common aeroallergens, is the strongest identifiable predisposing factor for developing asthma. Viral respiratory infections are one of the most important causes of asthma exacerbation and may also contribute to the development of asthma.

THE PURPOSE OF THE STUDY: to achieve a deep and critical understanding of the Bronchial Asthma and its possible gaps or limitations evaluating the most relevant literature sources

OBJECTIVES OF THE STUDY

To collect the material in order to make a critical analysis of the topic

To study the immediate and long term results of the research

To discuss the underlying etiological causes and associated conditions of Broncial Asthma

To analyze the clinical manifestations and complications of the disease

To determine the diagnostic possibilities of instrumental studies of the disease

To evaluate the appropriate management and treatment for Bronchial Asthma

The methods of investigation

Contrastive analysis

Generalization

Description

Comparison

Observation and compact selection

Action research, consulting work

DEFINITION

Definition 1. Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation. It is defined by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over time and in intensity, together with variable expiratory airflow limitation [2].

Definition 2. Asthma is a major noncommunicable disease characterized by recurrent attacks of breathlessness and wheezing, which vary in severity and frequency from person to person. Symptoms may occur several times in a day or week in affected individuals, and for some people become worse during physical activity or at night [3].

CHARACTERI S T I CS OF CLI NICAL ASTHMA

􀀎 Symptoms

􀀎 Airway obstruction

􀀎 Inflammation

􀀎 Hyperresponsiveness

WHO estimates that 235 million people currently suffer from asthma. Asthma is the most common noncommunicable disease among children. Asthma is a public health problem not just for high-income countries; it occurs in all countries regardless of the level of development. Most asthma-related deaths occur in low- and lower-middle income countries. Asthma is under-diagnosed and under-treated. It creates substantial burden to individuals and families and often restricts individuals’ activities for a lifetime. WHO's programme objectives are: 1) surveillance to map the magnitude of asthma, analyse its determinants and monitor trends, with emphasis on poor and disadvantaged populations; 2) primary prevention to reduce the level of exposure to common risk factors, particularly tobacco smoke, frequent lower respiratory infections during childhood, and air pollution (indoor, outdoor, and occupational exposure); 3) improving access to cost-effective interventions including medicines, upgrading standards and accessibility of care at different levels of the health care system [3]. Beginning with the recognition of the increase in asthma prevalence from the early 1980s, a pattern often called the “asthma epidemic,” asthma has become a primary public health concern [4]. In Republic of Moldova it was estimated that there were over 160 thousand asthmatics , approximately 4.0% of population [5]. 14% of the world’s children experience asthma symptoms. 8.6% of young adults (aged 18-45) experience asthma symptoms. 4.5% of young adults have been diagnosed with asthma and/or are taking treatment for asthma. The burden of asthma is greatest for children aged 10-14 and the elderly aged 75-79. Asthma is the 14th most important disorder in the world in terms of the extent and duration of disability.[6]

ASTHMA MORTALITY Deaths due to asthma are uncommon but are of serious concern because many of them are preventable. Most deaths certified as caused by asthma occur in older adults, although comparisons of mortality rates have tended to focus upon children and younger adults. Over the past 50 years, mortality rates in these younger age groups have fluctuated markedly in several high-income countries, attributed to changes in medical care for asthma, especially the introduction of new asthma medications.[6]

PHENOTYPES AND ENDOTYPES

Asthma is a complex disease or a syndrome that includes several disease variants. A disease ‘phenotype’ describes ‘clinically observable characteristics’ of a disease without direct relationship to an underlying pathophysiology. ‘Endotypes’, however, describe subtypes of a disease defined by an intrinsically ‘distinct pathogenetic mechanism’. In asthma, phenotypes describe clinical and morphologic characteristics as well as unique responses to treatment. Phenotypes are clinically relevant in terms of presentation, triggers, and treatment response but do not necessarily relate to or give insights into the underlying pathological mechanism. Asthma endotypes, however, describe disease subtypes based on cellular and molecular mechanisms,

including the reactivity of structural cells. Understanding these events would allow us to understand and classify asthma endotypes by the use of biomarkers from body fluids and/or affected tissues [7]. Historically, asthma has been divided into two distinct phenotypes termed extrinsic and intrinsic asthma . Both phenotypes are characterized by eosinophilic inflammation (Walker C, Bode E, Boer L, Hansel TT, Blaser K, Virchow JC Jr. Allergic and nonallergic asthmatics have distinct patterns of Tcell activation and cytokine production in peripheral blood and bronchoalveolar lavage. Am Rev Respir Dis 1992) Accordingly, any successful definition of an endotype should eventually link the key pathogenic mechanism with avclinical phenotype of asthma. An acceptable starting point to define endotypes would be the identification of correspondingvmolecular biomarkers for such a pathogenetic mechanism. (Fig 1).

A group of authors have identified another phenotypes [8, 9] Some of the most common include: 1)Allergic asthma: this is the most easily recognized asthma phenotype, which often commences in childhood and is associated with a past and/or family history of allergic disease such as eczema, allergic rhinitis, or food or drug allergy. Examination of the induced sputum of these patients before treatment often reveals eosinophilic airway inflammation. Patients with this asthma phenotype usually respond well to inhaled corticosteroid (ICS) treatment. 2) Non-allergic asthma: some adults have asthma that is not associated with allergy. The cellular profile of the sputum of these patients may be neutrophilic, eosinophilic or contain only a few inflammatory cells (paucigranulocytic). Patients with non-allergic asthma often respond less well to ICS.

3) Late-onset asthma: some adults, particularly women, present with asthma for the first time in adult life. These patients tend to be non-allergic, and often require higher doses of ICS or are relatively refractory to corticosteroid treatment. 4) Asthma with fixed airflow limitation: some patients with long-standing asthma develop fixed airflow limitation that is thought to be due to airway wall remodeling. 5) Asthma with obesity: some obese patients with asthma have prominent respiratory symptoms and little eosinophilic airway inflammation.

The various clinical expressions of asthma prove the involvement of environmental factors that interact with the airways to cause acute and chronic inflammation, and the different contributions of smooth muscle contraction, edema and remodeling of the formed elements of the airways. Being very Heterogeneous , asthma manifest different response to therapies. Asthma is considered a good example of gene–environment interactions, although no single gene or environmental factor accounts for the disease.

Pathophysiology and Pathogenesis of Asthma

Airway inflammation in asthma is a multicellular process involving mainly eosinophils, neutrophils, CD41T lymphocytes and mast cells, with eosinophilic infiltration being the most striking feature [10].

Fig. 2 Cross-section of a small asthmatic airway showing abundant inflammation both inside and outside the smooth muscle and remodeling as evidenced by thedeposition of new matrix beneath the

epithelium and in all layers of the airway. (Holgate & Polosa 2006).

A fundamental feature of asthma associated with allergic sensitization is the function of the airway to recognize common environmental allergens and to generate a Th2 cytokine response to them. Recognizing that in excess of 40% of the Western population is atopic, only about 7% express their atopy in the form of asthma [11]. Therefore, the most important answer to find is what mechanisms are responsible for the specific expression of atopy in the conducting airways and why certain patients despite being really atopic have no manifestations of bronchial asthma?

Airflow limitation in asthma is recurrent and caused by a variety of changes in the airway. These include:

􀀎 Bronchoconstriction. In asthma, the dominant physiological event leading to clinical symptoms is airway narrowing and a subsequent interference with airflow. In acute exacerbations of asthma, bronchial smooth muscle contraction (bronchoconstriction) occurs quickly to narrow the airways in response to exposure to a variety of stimuli including allergens or irritants. Allergen-induced acute bronchoconstriction results from an IgE-dependent release of mediators from mast cells that includes histamine, tryptase, leukotrienes, and prostaglandins that directly contract airway smooth muscle. [12] Aspirin and other nonsteroidal anti-inflammatory drugs can also cause acute airflow obstruction in some patients, and evidence indicates that this non-IgE-dependent response also involves mediator release from airway cells. [13] In addition, other stimuli (including exercise, cold air, and irritants) can cause acute airflow obstruction. The mechanisms regulating the airway response to these factors are less well defined, but the intensity of the response appears related to underlying airway inflammation. Stress may also play a role in precipitating asthma exacerbations. The mechanisms involved have yet to be established and may include enhanced generation of pro-inflammatory cytokines.

􀀎 Airway edema. As the disease becomes more persistent and inflammation more

progressive, other factors further limit airflow. These include edema, inflammation, mucus hypersecretion and the formation of inspissated mucus plugs, as well as structural changes including hypertrophy and hyperplasia of the airway smooth muscle. These latter changes may not respond to usual treatment.

􀀎 Airway hyperresponsiveness. Airway hyperresponsiveness—an exaggerated

bronchoconstrictor response to a wide variety of stimuli—is a major, but not necessarily unique, feature of asthma. The degree to which airway hyperresponsiveness can be defined by contractile responses to challenges with methacholine correlates with the clinical severity of asthma. The mechanisms influencing airway hyperresponsiveness are multiple and include inflammation, dysfunctional neuroregulation, and structural changes; inflammation appears to be a major factor in determining the degree of airway hyperresponsiveness. Treatment directed toward reducing inflammation can reduce airway hyperresponsiveness and improve asthma control.

􀀎 Airway remodeling. In some persons who have asthma, airflow limitation may be only partially reversible. Permanent structural changes can occur in the airway these are associated with a progressive loss of lung function that is not prevented by or fully reversible by current therapy. Airway remodeling involves an activation of many of the structural cells, with consequent permanent changes in the airway that increase airflow obstruction and airway responsiveness and render the patient less responsive to therapy. [14] These structural changes can include thickening of the sub-basement membrane, subepithelial fibrosis, airway smooth muscle hypertrophy and hyperplasia, blood vessel proliferation and dilation, and mucous gland hyperplasia and hypersecretion. Regulation of the repair and remodeling process is not well established, but both the process of repair and its regulation are likely to be key events in explaining the persistent nature of the disease and limitations to a therapeutic response.

PATHOPHYSIOLOGIC MECHANISMS IN THE DEVELOPMENT OF AIRWAY INFLAMMATION

Inflammation has a central role in the pathophysiology of asthma. As noted in the definition of asthma, airway inflammation involves an interaction of many cell types and multiple mediators with the airways that eventually results in the characteristic pathophysiological features of the disease: bronchial inflammation and airflow limitation that result in recurrent episodes of cough, wheeze, and shortness of breath. The processes by which these interactive events occur and lead to clinical asthma are still under investigation. Moreover, although distinct phenotypes of asthma exist (e.g., intermittent, persistent, exercise-associated, aspirin-sensitive, or severe asthma), airway inflammation remains a consistent pattern. The pattern of airway inflammation in asthma, however, does not necessarily vary depending upon disease severity, persistence, and duration of disease. The cellular profile and the response of the structural cells in asthma are quite consistent.

Inflammatory Cells

Lymphocytes. An increased understanding of the development and regulation of airway inflammation in asthma followed the discovery and description of subpopulations of lymphocytes, T helper 1 cells and T helper 2 cells (Th1 and Th2), with distinct inflammatory mediator profiles and effects on airway function. After the discovery of these distinct lymphocyte subpopulations in animal models of allergic inflammation, evidence emerged that, in human asthma, a shift, or predilection, toward the Th2-cytokine profile resulted in the eosinophilic inflammation characteristic of asthma [15]. In addition, generation of Th2 cytokines (e.g., interleukin-4 (IL-4), IL-5, and IL-13) could also explain the overproduction of

IgE, presence of eosinophils, and development of airway hyperresponsiveness. There also may be a reduction in a subgroup of lymphocytes, regulatory T cells, which normally inhibit Th2 cells, as well as an increase in natural killer (NK) cells that release large amounts of Th1 and Th2 cytokines. [16] T lymphocytes, along with other airway resident cells, also can determine the development and degree of airway remodeling. Although it is an oversimplification of a complex process to describe asthma as a Th2 disease, recognizing the importance of n families of cytokines and chemokines has advanced our understanding of the development of airway inflammation. [17]

Mast cells. Activation of mucosal mast cells releases bronchoconstrictor mediators (histamine, cysteinyl-leukotrienes, prostaglandin D2). [18] Although allergen activation occurs through high-affinity IgE receptors and is likely the most

relevant reaction, sensitized mast cells also may be activated by osmotic stimuli to account for exercise-induced bronchospasm (EIB). Increased numbers of mast cells in airway smooth muscle may be linked to airway hyperresponsiveness. [19] Mast cells can release a large number of cytokines to change the airway environment and promote inflammation even though exposure to allergens is limited.

Eosinophils. Increased numbers of eosinophils exist in the airways of most, but not all, persons who have asthma. [20] These cells contain inflammatory enzymes, generate leukotrienes, and express a wide variety of pro-inflammatory cytokines. Increases in eosinophils often correlate with greater asthma severity. In addition, numerous studies show that treating asthma with corticosteroids reduces circulating and airway eosinophils in parallel with clinical improvement. However, the role and contribution of eosinophils to asthma is undergoing a reevaluation based on studies with an anti-IL-5 treatment that has significantly reduced eosinophils but did not affect asthma control. [21] Therefore, although the eosinophil may not be the only primary effector cell in asthma, it likely has a distinct role in different phases of the disease.

Neutrophils. Neutrophils are increased in the airways and sputum of persons who have severe asthma, during acute exacerbations, and in the presence of smoking. Their pathophysiological role remains uncertain; they may be a determinant of a lack of response to corticosteroid treatment. [22] The regulation of neutrophil recruitment, activation, and alteration in lung function is still under study, but leukotriene B4 may contribute to these processes. [23]

Dendritic cells. These cells function as key antigen-presenting cells that interact with allergens from the airway surface and then migrate to regional lymph nodes to interact with regulatory cells and ultimately to stimulate Th2 cell production from naïve T cells. [24]

Macrophages. Macrophages are the most numerous cells in the airways and also can be activated by allergens through low-affinity IgE receptors to release inflammatory mediators and cytokines that amplify the inflammatory response. [25]

Resident cells of the airway. Airway smooth muscle is not only a target of the asthma response (by undergoing contraction to produce airflow obstruction) but also contributes to it (via the production of its own family of pro-inflammatory mediators). As a consequence of airway inflammation and the generation of growth factors, the airway smooth muscle cell can undergo proliferation, activation, contraction, and hypertrophy—events that can influence airway dysfunction of asthma.

Epithelial cells. Airway epithelium is another airway lining cell critically involved in asthma. [26] The generation of inflammatory mediators, recruitment and activation of inflammatory cells, and infection by respiratory viruses can cause epithelial cells to produce more inflammatory mediators or to injure the epithelium itself. The repair process, following injury to the epithelium, may be abnormal in asthma, thus furthering the obstructive lesions that occur in asthma.

Inflammatory Mediators

Chemokines are important in recruitment of inflammatory cells into the airways and are mainly expressed in airway epithelial cell. [17] Eotaxin is relatively selective for eosinophils, whereas thymus and activation-regulated chemokines (TARCs) and macrophage-derived chemokines (MDCs) recruit Th2 cells. There is an increasing appreciation for the role this family of mediators has in orchestrating injury, repair, and many aspects of asthma.

Cytokines direct and modify the inflammatory response in asthma and likely determine its severity. Th2-derived cytokines include IL-5, which is needed for eosinophil differentiation and survival, and IL-4 which is important for Th2 cell differentiation and with IL-13 is important for IgE formation. Key cytokines include IL-1β and tumor necrosis factor-α (TNF-α), which amplify the inflammatory response, and granulocyte-macrophage colony-stimulating factor (GM-CSF),

which prolongs eosinophil survival in airways. Recent studies of treatments directed toward single cytokines (e.g., monoclonal antibodies against IL-5 or soluble IL-4 receptor) have not shown benefits in improving asthma outcomes.

Cysteinyl-leukotrienes are potent bronchoconstrictors derived mainly from mast cells. They are the only mediator whose inhibition has been specifically associated with an improvement in lung function and asthma symptoms. Recent studies have also shown leukotriene B4 can contribute to the inflammatory process by recruitment of neutrophils. [27]

Nitric oxide (NO) is produced predominantly from the action of inducible NO synthase in airway epithelial cells; it is a potent vasodilator. [28] Measurements of fractional exhaled NO (FeNO) may be useful for monitoring response to asthma treatment because of the purported association between FeNO and the presence of inflammation in asthma. [29]

Immunoglobulin E

IgE is the antibody responsible for activation of allergic reactions and is important to the pathogenesis of allergic diseases and the development and persistence of inflammation. IgE attaches to cell surfaces via a specific high-affinity receptor. The mast cell has large numbers of IgE receptors; these, when activated by interaction with antigen, release a wide variety of mediators to initiate acute bronchospasm and also to release pro-inflammatory cytokines to perpetuate underlying airway inflammation . Other cells, basophils, dendritic cells, and lymphocytes also have high-affinity IgE receptors. The development of monoclonal antibodies against IgE has shown that the reduction of IgE is effective in asthma treatment. [30] These clinical observations further support the importance of IgE to asthma.

CLASSIFICATION AF BRONCHIAL ASTHMA

Classification of asthma severity by clinical features before treatment.

ASTHMA AND COPD

The 2006 revision of the GOLD guidelines [2]defines COPD as:

a preventable and treatable disease with some significant extrapulmonary effects that may contribute to severity in individual patients. Its pulmonary component is characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles of gases.

(Global Strategy for Asthma Management and Prevention. Global Initiative for Asthma (GOLD)2006; Available from: URL: www.ginasthma.org )

Clinical features of COPD and asthma.

Asthma usually has its onset in early childhood. Howeveradult-onset asthma does existand many are unable to remember childhood events that would provide a clue to the early stages of asthma. Thereforeunless symptoms are continuous from childhoodthe onset of asthma symptoms in adult life may be hard to interpretespecially in the presence of other risk factors such as smoking. COPD typically becomes clinically apparent in the sixth and seventh decades of life. If an individual is physically activehe or she may notice reduced exercise tolerance earlier.

COPD in developed countries is mostly a disease of smokers. This is not necessarily true in developing countries where other risk factorssuch as heavy outdoor and indoor/occupational air pollutionmay be important risk factors that are causally related to COPD [2]. The relationship between asthma and smoking is complex. Individuals with asthma may be non-smokerssmokersor ex-smokers. Since asthma genes and genes leading to the susceptibility to develop airflow obstruction with smoking are common in the populationthe likelihood that an individual may have both is high. LikewiseCOPD may occur in lifetime non-smokers 13.; 14. ;  15.. In somethis may be longstanding asthma that may have been undiagnosed. In othersgenes that are as yet unrecognized may be responsible. Alpha-1 antitrypsin deficiency is the model for such a genotype.

Pulmonary function tests can also provide guidance. Both diseases are characterized by airflow obstruction except in the early or mild stages. In asthmalung function either remains normal or can be normalized with treatment in patients with mild intermittent or mild persistent disease [1]. COPDin comparison with asthmais defined by irreversible airflow limitationand this becomes progressively greater as the disease advances. Lung function in asthma is characterized by reversibility and variability. Reversibility refers to the short-term response to an inhaled bronchodilating agentand is preferably measured with spirometry or peak flow (acceptable but not as helpful as spirometry). Variability refers to the improvement and deterioration in symptoms and lung function over time (both short- and long-time periods) that is characteristic of asthma. The GINA guidelines[1] recommend that reversibility be defined as a ≥20% improvement post-bronchodilator in the 1-second forced expiratory volume (FEV1) or peak flow (PEF). GINA further defines variability as a diurnal variation in PEF of more than 20% (with twice daily readingmore than 10%).

TREATMENT

Goals of Asthma Therapy

Prevent recurrent exacerbations and minimize the need for emergency department visits or hospitalizations

Maintain (near‐) “normal” pulmonary function

Maintain normal activity levels (including exercise

and other physical activity)

Provide optimal pharmacotherapy with minimal or

no adverse effects

Conclusions.

Proper treatment can control asthma and avoiding asthma triggers can also decrease the severity of asthma.

Appropriate management of asthma can enable people to enjoy a good quality of life.

BIBLIOGRAPHIC REFERENCES

1. WHO. Asthma. 2013; Available from: http://www.who.int/mediacentre/factsheets/fs307/en/.

2. Global Strategy for Asthma Management and Prevention

(2016 update). 2016 [cited 2016 10.08.2016]; Available from: http://ginasthma.org/wp-content/uploads/2016/04/GINA-2016-main-report_tracked.pdf.

3. Key facts. Asthma. 2013 Updated November 2013

Available from: http://www.who.int/mediacentre/factsheets/fs307/en/.

4. Eder, W., M. Ege, and E. von Mutius, The asthma epidemic N Engl J Med 355 (21): 2226–2235. Find this article online, 2006.

5. Botnaru, V., Bolile aparatului respirator. 2001: Chisinau.

6. The Global Asthma Report 2014. 2014 7.08.17]; Available from: http://www.globalasthmareport.org/burden/burden.php

7. Lötvall, J., et al., Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. Journal of Allergy and Clinical Immunology, 2011. 127(2): p. 355-360.

8. Bel, E.H., Clinical phenotypes of asthma. Current opinion in pulmonary medicine, 2004. 10(1): p. 44-50.

9. Wenzel, S.E., Asthma phenotypes: the evolution from clinical to molecular approaches. Nature medicine, 2012. 18(5): p. 716-725.

10. Kay, A.B., The role of eosinophils in the pathogenesis of asthma. Trends in molecular medicine, 2005. 11(4): p. 148-152.

11. Beasley, R., J. Pekkanen, and N. Pearce, Has the role of atopy in the development of asthma been over‐emphasized? Pediatric pulmonology, 2001. 32(S23): p. 149-150.

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19. Brightling, C.E., et al., Mast-cell infiltration of airway smooth muscle in asthma. New England Journal of Medicine, 2002. 346(22): p. 1699-1705.

20. Williams, T.J., The eosinophil enigma. The Journal of clinical investigation, 2004. 113(4): p. 507-509.

21. Leckie, M.J., et al., Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. The Lancet, 2000. 356(9248): p. 2144-2148.

22. Fahya, J.V., et al., Prominent neutrophilic inflammation in sputum from subjects with asthma exacerbation. Journal of Allergy and Clinical Immunology, 1995. 95(4): p. 843-852.

23. Wenzel, S.E., Asthma: defining of the persistent adult phenotypes. The Lancet, 2006. 368(9537): p. 804-813.

24. Kuipers, H. and B.N. Lambrecht, The interplay of dendritic cells, Th2 cells and regulatory T cells in asthma. Current opinion in immunology, 2004. 16(6): p. 702-708.

25. Peters-Golden, M., The alveolar macrophage: the forgotten cell in asthma. American journal of respiratory cell and molecular biology, 2004. 31(1): p. 3-7.

26. Polito, A.J. and D. Proud, Epithelial cells as regulators of airway inflammation. Journal of Allergy and Clinical Immunology, 1998. 102(5): p. 714-718.

27. Gelfand, E.W. and A. Dakhama, CD8+ T lymphocytes and leukotriene B 4: novel interactions in the persistence and progression of asthma. Journal of Allergy and Clinical Immunology, 2006. 117(3): p. 577-582.

28. Strunk, R.C., et al., Mild to moderate asthma affects lung growth in children and adolescents. Journal of Allergy and Clinical Immunology, 2006. 118(5): p. 1040-1047.

29. Green, R.H., et al., Asthma exacerbations and sputum eosinophil counts. The Lancet, 2003. 361(9365): p. 1303.

30. Holgate, S., et al., The anti-inflammatory effects of omalizumab confirm the central role of IgE in allergic inflammation. Journal of Allergy and Clinical Immunology, 2005. 115(3): p. 459-465.