1. Pathophysiology of Asthma

2. Asthma – NAEPP Definition
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 individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning.
A wheeze is a high-pitched, whistling sound created by turbulent airflow through an obstructed airway.
These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. The inflammation also causes an associated increase in the existing bronchial hyperresponsiveness (BHR) to a variety of stimuli.
BHR = the tendency of airways to narrow excessively in response to triggers that have little or no effect in normal individuals.
Reversibility of airflow limitation may be incomplete in some patients with asthma
This definition encompasses the important heterogeneity of the clinical presentation of asthma by describing the scientific and clinically accepted characteristics of asthma. National Asthma Education and Prevention Program.
The latter definition has features that overlap with the description of chronic obstructive pulmonary disease (COPD). Besides historic features (eg, age of onset, history of cigarette smoking), the characteristic that best distinguishes asthma from COPD is the degree of reversibility of airflow obstruction.
The airflow obstruction of asthma is generally largely reversible, while that of COPD is minimally and incompletely reversible

3. GINA Definition of Asthma
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.

5. Epidemiology
Asthma is a problem worldwide, with an estimated 300 million affected individuals. It is estimated that asthma causes 346,000 deaths worldwide every year,6 with widely varying case fatality rates that may reflect differences in management.
It is an under-diagnosed and under-treated condition.
Asthma is the most common chronic disease of childhood.
Children younger than 4 years of age have the highest rate of emergency department visits and hospitalizations.
by early adulthood, 30 to 70% will markedly improve or be symptom-free
Higher prevalence in minorities
urbanization
poor access to care
Significant burden on healthcare system
Can be life-threatening if not properly managed
education is key to prevention of death from asthma
In adults, most longitudinal studies have suggested a more rapid rate of decline in lung function in asthmatics than in nonasthmatic normals, primarily reflected in forced expiratory volume in 1 second (FEV1). 4 However, the annual decline in FEV1 is less than in smokers or in patients with a diagnosis of emphysema. In general, individuals with less frequent asthma attacks and normal lung function on initial assessment have higher remission rates, whereas smokers have the lowest remission and highest relapse rates. 4 The level of BHR tends to predict the rate of decline in FEV1, with a greater decline with high levels of BHR. 2 Thus airways obstruction in asthma not only may become irreversible but also may worsen over time owing to airway remodeling (see below). 2,4 However, most patients do not die from long-term progression of their disease and their life-span is not different from the general population. 4
As with prevalence and morbidity, mortality from acute exacerbations of asthma has been decreasing over the past 10 years, with 3,565 deaths reported in Despite the relatively low number of asthma deaths, 80% to 90% are preventable. 2 Most deaths from asthma occur outside the hospital, and death is rare after hospitalization. The most common cause of death from asthma is inadequate assessment of the severity of airways obstruction by the patient or physician and inadequate therapy. The most common cause of death in hospitalized patients is also inadequate or inappropriate therapy. Thus the key to prevention of death from asthma, as advocated by the U.S. National Asthma Education and Prevention Program (NAEPP), is education. 2

6. Prevalence of asthma in children aged 13-14 years
GINA 2015 Appendix Box A1-1; figure provided by R Beasley
© Global Initiative for Asthma

7. Etiology
Asthma is a partially heritable complex syndrome that results from a complex interaction of genetic and environmental factors.
Genetic predisposition (predispose individuals to, or protect them from, developing asthma)
Atopy (genetically determined state of hypersensitivity to environmental allergens, manifested as the presence of positive skin-prick tests or the clinical response to common environmental allergens = genetically mediated predisposition to an excessive IgE reaction)
linked with metalloproteinase genes (ADAM33)
Environmental exposure (influence susceptibility to development of asthma in predisposed individuals, precipitate asthma exacerbations, and/or cause symptoms to persist)
risk factors
socioeconomic status
family size
tobacco smoke (Maternal smoking during pregnancy or exposure to secondhand smoke after birth increases the risk of childhood asthma)
allergen exposure (tree and grass pollen, house dust mites, household pets, molds)
urbanization
decreased exposure to common childhood infectious agents
hygiene hypothesis.
Atopy may be defined as the state of having IgE antibodies to specific allergens, which is a prerequisite for developing allergic disease
genetically mediated predisposition to an excessive IgE reaction

8. Risk Factors for Asthma- GINA 2014
Recent observations indicate that the microbiome (i.e. the collection of microorganisms and their genetic
material), both within the host and in the host’s surrounding environment, may contribute to the development
and/or prevention of allergic diseases and asthma.
In rural settings, the prevalence of childhood asthma is reduced and this has been linked to the presence of bacterial endotoxin in these environments. In rural settings, the diversity of microbial exposure in house dust has been correlated inversely with the risk of developing asthma. On the other hand, delivery by Caesarean section is a significant risk factor for development of asthma

9. Sex
In childhood, male sex is a risk factor for asthma. Prior to the age of 14, the prevalence of asthma is nearly twice as great in boys as in girls. As children grow older, the difference in prevalence between the sexes narrows, and by adulthood the prevalence of asthma is greater in women than in men. The reasons for this sex-related difference are not clear; one potential contributor is differences in lung and airway size, which are smaller in males than in females in infancy, but larger in females in adulthood.
Obesity
The prevalence and incidence of asthma are increased in obese subjects (body mass index >30 kg/m2), particularly in women with abdominal obesity. Inappropriate attribution of shortness of breath may contribute to over-diagnosis, but one study found that over-diagnosis of asthma was no more common in obese than in non-obese patients. It is not known why asthma develops more frequently in the obese. Potential contributing factors include changes in airway function due to the effects of obesity on lung mechanics; the development of a pro-inflammatory state in obesity; and an increased prevalence of comorbidities, genetic, developmental, hormonal or neurogenic influences.

10. Adult-onset asthma not uncommon may be related to: atopy,
nasal polyps,
aspirin sensitivity
(Samter's syndrome = The classic triad of aspirin sensitivity, nasal polyps, and asthma),
sinusitis,
occupational exposure (e.g., wood dusts, chemicals),
recurrence of childhood asthma.
In people with aspirin intolerance, aspirin frequently induces bronchial constriction, causing wheezing and asthma. It's reported that about 10 percent of all people with aspirin have conditions that are induced or associated with aspirin sensitivity. People with aspirin intolerance are also more likely to develop rhinosinusitis (inflammation of the nasal mucosa and sinuses) and nasal polyps. The classic triad of aspirin sensitivity, nasal polyps, and asthma is known as Samter's syndrome.

11. Asthma phenotypes
Asthma is a heterogeneous disease, with different underlying disease processes. Recognizable clusters of demographic, clinical and/or pathophysiological characteristics are often called ‘asthma phenotypes’. In patients with more severe asthma, some phenotype-guided treatments are available. However, to date, no strong relationship has been found between specific pathological features and particular clinical patterns or treatment responses. More research is needed to understand the clinical utility of phenotypic classification in asthma.

12. Many phenotypes have been identified. Some of the most common include:
• 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.
• 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.
• 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.
• 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.
• Asthma with obesity: some obese patients with asthma have prominent respiratory symptoms and little eosinophilic airway inflammation.

13. Pathophysiology The major characteristics of asthma include:
Airflow obstruction
bronchospasm, edema, mucus hypersecretion
Airway inflammation
Bronchial hyperresponsiveness (BHR)
The degree of bronchial hyperreactivity of asthmatics correlates with the clinical course of their disease, which is characterized by periods of remissions and exacerbations.
Airway remodeling
Mediated by eosinophils, T cells, mast cells, macrophages, epithelial cells, fibroblasts, bronchial smooth muscle cells
Failure to adequately minimize severe and long-term airway inflammation in asthma may result in airway remodeling in some patients.
Airway remodeling refers to structural changes, including an alteration in the amount and composition of the extracellular matrix in the airway wall leading to airflow obstruction that eventually may become only partially reversible
The degree of bronchial hyperreactivity of asthmatics correlates with the clinical course of their disease, which is characterized by periods of remissions and exacerbations. During times of remission, a more intense stimulus is required to produce bronchospasm than during times of increased symptoms. Numerous theories have been proposed to explain the bronchial hyperreactivity found in asthma, yet none fully explains the phenomenon. Inflammation appears to be the primary process in the pathogenesis of bronchial hyperreactivity; however, neurogenic imbalances in the airways also may play a significant role.5 Inflamed airways are hyperreactive (i.e., irritable). Hyperreactivity can be measured in the physician's office by having the patient inhale small concentrations of nebulized methacholine or histamine or by exercise (e.g., treadmill). The concentration of aerosolized P.22p3
methacholine or histamine that decreases the forced expiratory volume in 1 second (FEV1) by 20% is referred to as the PD20 or the PC20 (provocative dose or concentration that decreases the FEV1 by 20%).2 An indicator of optimal anti-inflammatory therapy is an increase in the PD20 over time as the airways become less inflamed and therefore less hyperreactive.

14. Pathology Found in Asthmatic Bronchus Compared to Normal Bronchus
Pathologic changes in asthmatics found at autopsy include
marked hypertrophy and hyperplasia of the bronchial smooth muscle,
mucous gland hypertrophy and excessive mucous secretion,
denuded epithelium and mucosal edema due to an exudative inflammatory reaction and inflammatory cell infiltration

15. Pathophysiology Epithelial cells
release eicosanoids, peptidases, matrix proteins, cytokines, nitric oxide
epithelial shedding
Eosinophils
release inflammatory mediators
leukotrienes, granule proteins
TH2 lymphocytes
produce cytokines that mediate allergic inflammation
TH1/TH2 imbalance
Mast cell degranulation
release histamine, leukotrienes, prostaglandins
Mucus plugs
epithelial & inflammatory cells
further airway obstruction
After exposure to an asthma-precipitating factor (e.g., aeroallergen), inflammatory mediators are released from bronchial mast cells, macrophages, T lymphocytes, and epithelial cells. These mediators direct the migration and activation of other inflammatory cells, most notably eosinophils, to the airways. Eosinophils release biochemicals (e.g., major basic protein and eosinophil cationic protein) that cause airway injury, including epithelial damage, mucus hypersecretion, and increased reactivity of smooth muscle.

16. Diagrammatic presentation of the relationship between inflammatory cells, lipid and preformed mediators, inflammatory cytokines, and proposed pathogenesis and clinical presentation in asthma.
(ECP, eosinophil cationic protein; GM-CSF, granulocyte-macrophage colony-stimulating factor; IAR, immediate asthmatic reaction; IFN, interferon; IL, interleukin; LAR, late asthmatic response; LT, leukotriene; MBP, major basis protein; PAF, platelet-activating factor; PG, prostaglandin.)
Early phase:
Activation and degranulation of mast cells and basophils results in an early phase response that involves an acute bronchoconstriction that usually lasts approximately 1 hour after allergen exposure
Late phase:
activated airway cells release inflammatory cytokines and chemokines, recruiting inflammatory cells into the lungs. The late phase response occurs 4 to 6 hours after the initial allergen challenge and results in a less intense bronchoconstriction as well as increased airway hyperresponsiveness and airway inflammation.
“late-phase” versus “early-phase” asthma.
The inhalation of specific allergens in atopic asthmatics produces immediate bronchoconstriction (measured by a drop in peak expiratory flow [PEF] or FEV1) that spontaneously improves over an hour or is reversed easily by inhalation of a β2-agonist. Although this early asthmatic response (EAR) is blocked by the preadministration of β2-agonists, cromolyn, or theophylline, a second bronchoconstrictive response often occurs 4 to 12 hours later. This late asthmatic response (LAR) often is more severe, more prolonged, and more difficult to reverse with bronchodilators than is the EAR. The LAR is associated with the influx of inflammatory cells and mediators as described previously. Bronchodilators do not block the LAR to allergen challenge; corticosteroids block the LAR but do not affect the EAR; and cromolyn blocks both.2

17. Epidemiology

19. ASTHMA COPD Airflow Limitation Small airway narrowing
Alv macrophage
Ep cells
CD8+ cell
(Tc1)
Neutrophil
Cigarette smoke
Small airway narrowing
Alveolar destruction
COPD
Allergens Y
Ep cells
Mast cell
CD4+ cell
(Th2)
Eosinophil
Bronchoconstriction
BHR
Reversible
Irreversible
Airflow Limitation