ASTHMA (1-48) PDF

DISEASES OF RESPIRATORY SYSTEM 1.ASTHMA 2.Hypersensitivity Pneumonitis 3.Community Acquired pneumoni WHAT IS ASTHMA?GINA Heterogeneous disease typically characterized by Chronic airway inflammation History of respiratory symptoms including Wheezing Repetitive coughing Dyspnea Chest ti...

DISEASES OF RESPIRATORY SYSTEM 1.ASTHMA 2.Hypersensitivity Pneumonitis 3.Community Acquired pneumoni WHAT IS ASTHMA?GINA Heterogeneous disease typically characterized by Chronic airway inflammation History of respiratory symptoms including Wheezing Repetitive coughing Dyspnea Chest tightness plus Variable expiratory airflow limitation all of which vary over time and in intensity.  ASTHMA (Characterized HARRISON) by episodic airway obstruction Airway hyperresponsiveness accompanied by airway inflammation. Airway obstruction is reversible, but in a subset of asthmatics, a component of the obstruction may become irreversible. Airway inflammation is eosinophilic  ASTHMA Other symptoms ⚬ Exercise limitation caused by episodes of bronchoconstriction ⚬ Excess mucus production.  EPIDEMIOLOGY most common chronic disease associated with significant morbidity and mortality, with ~241 million people affected globally. THE PATHWAY TO THE DEVELOPMENT OF ASTHMA THE PATHWAY TO THE DEVELOPMENT OF ASTHMA  MECHANISMS LEADING TO ACUTE AND CHRONIC AIRWAY OBSTRUCTION 1.Airway Hyperresponsiveness 2. Inflammatory Cells 3.Airway Smooth Muscle 4.Subepithelial Collagen Deposition and Matrix Deposition 5.Airway Epithelium 6.Vascular Proliferation 7.Airway Edema 8.Epithelial Goblet Cell Metaplasia and Mucus Hypersecretion 9.Neuronal Proliferation  1.AIRWAY HYPERRESPONSIVENESS Hallmark of asthma Acute or excess narrowing response of the airways in reaction to inhaled agents Hyperresponsiveness occurs at the level of the airway smooth muscle–acting agents such as histamine or methacholine Due to indirect activation of airway narrowing mechanisms as a result of stimulation of inflammatory cells  bronchoconstrictors, airway edema and/or mucus secretion and/ or stimulation of sensory nerves that can act on the smooth muscle or inflammatory cells. PATHOPHYSIOLOGY 2.INFLAMMATORY CELLS 3. AIRWAY SMOOTH asthmatics have evidence of MUSCLE 1.Hyperresponsive to stimuli chronic inflammation in the 2.Hypertrophy and hyperplasia can airways. lead to airway wall thickening inflammation is Eosinophilic in 3.airway smooth-muscle cells can nature. In some patients, produce chemokines and neutrophilic inflammation may cytokines that promote airway be predominant, especially in inflammation and promote the those with more severe asthma. survival of inflammatory cells, esp Mast cells are also more mast cells. frequent.  4.SUBEPITHELIAL COLLAGEN DEPOSITION AND MATRIX Thickening of the subepithelial DEPOSITION basement membrane occurs as a result of deposition of repair-type collagens and tenascin, periostin, fibronectin, and osteopontin primarily from myofibroblasts under the epithelium. deposition can also narrow the airway lumen and decrease its ability to relax and thus can contribute to chronic airway obstruction. 5.AIRWAY EPITHELIUM Airway epithelium disruption takes the form of separation of columnar cells from the basal cells. The damaged epithelium is hypothesized to form a trophic unit with the underlying mesenchyme.  6.VASCULAR PROLIFERATION Significant degree of angiogenesis thought to be secondary to elaboration of angiogenic factors in the context of airway inflammation. Inflammatory mediators can result in leakage from postcapillary venules, which can contribute to the acute and chronic edema of the airways. 7.AIRWAY EDEMA Submucosal edema can be present as an acute response in asthma and as a chronic contributor to airway wall thickening. 8. EPITHELIAL GOBLET CELL METAPLASIA AND MUCUS HYPERSECRETION Chronic inflammation can result in the appearance and proliferation of mucus cells -> Increase mucus production -> Mucus plugs can obstruct medium-size airways and can extend into the small airways. 9. NEURONAL PROLIFERATION Neurotrophins, which can lead to neuronal proliferation, are elaborated by smooth-muscle cells, epithelial cells, and inflammatory cells. Neuronal inputs can regulate smooth-muscle tone and mucus production, which may mediate acute bronchospasm and potentially chronically increased airway tone.  AIRWAY INFLAMMATION (TYPE 2 AND NON–TYPE 2 INFLAMMATION)  TYPE 2 INFLAMMATION NON–TYPE 2 PROCESSES an immune response involving the innate and Non–type 2 processes can exist either in adaptive arms of the immune system to promote combination with type 2 inflammation or barrier immunity on mucosal surfaces. without type 2 inflammation. It is associated with the type 2 subset of CD4+ This type of inflammation is more T-helper cells, which produce the cytokines commonly seen in severe asthma that interleukin (IL) 4, IL-5, and IL-13. has not responded to the common anti- IL-4 inflammatory therapies, such as ⚬ induces B-cell isotype switching to production corticosteroids, that usually suppress of IgE. type 2 inflammation. ⚬ IgE binding to basophils and mast cells, In some cases, it may also be associated results in environmental sensitivity to with chronic infection, occasionally with allergens atypical pathogens such as Mycoplasma, ⚬ The products released from these cells perhaps accounting for the response of include type 2 cytokines as well as direct some of these patients to macrolide activators of smooth-muscle constriction and antibiotics. It is also commonly seen in edema. reactive airway dysfunction syndrome IL-5 ⚬ role in regulating eosinophils. ⚬ It controls formation, recruitment, and survival of these cells. IL-13  MEDIATORS 1.Cytokines 2.Fatty Acid Mediators 3.Nitric Oxide 4.Reactive Oxygen Species 5.Chemokines  Cytokines Fatty Acid Mediators IL-4, IL-5, and IL-13 are the Proinflammatory mediators Cysteinyl leukotrienes (leukotrienes C4, major cytokines associated D4, and E4) with type 2 inflammation. ⚬produced by eosinophils and mast IL-9, IL-6, IL-17, tumor cells ⚬potent smooth-muscle constrictors necrosis factor α (TNF-α), ⚬ stimulate mucus secretion, recruit IL-1β, and IL-8 have been allergic inflammatory cells, cause implicated in non–type 2 microvascular leakage, modulate inflammation. cytokine production, and influence neural transmission. Non-cysteinyl leukotriene ⚬produced by neutrophils, macrophages and epithelial cells ⚬potent neutrophil chemoattractant. Prostaglandins ⚬for the most part proinflammatory. ⚬activation of these receptors upregulates type 2 inflammation.  Nitric Oxide Reactive Oxygen Species Chemokines potent vasodilator Release of reactive oxygen Chemokines are mucus production species result in oxidative secreted by the and smooth-muscle stress in the surrounding epithelium, proliferation tissue. inflammatory cells and produced by epithelial ⚬ affect smooth-muscle attract inflammatory cells contraction cells into the airways. it can be detected in ⚬ increase mucus secretion include exhaled breath. ⚬ airway eotaxin-an eosinophil hyperresponsiveness chemoattractant) ⚬ Epithelial shedding. ETIOLOGIC MECHANISMS, RISK FACTORS, TRIGGERS, AND COMPLICATING COMORBIDITIES  HERITABLE PREDISPOSITION Asthma has a strong genetic predisposition. Family and twin studies suggest a 25–80% degree of heritability Many of the genes related to asthma have been associated with risk for atopy. ATOPY genetic tendency toward specific IgE production in response to allergen exposure. Serum levels of IgE correlate closely with the development of asthma. the most consistently identified include ORMDL3/ GSDMB (in the 17q21 chromosomal region), ADAM33, DPP-10, TSLP, IL-12, IL-33, ST2, HLA-DQB1, HLA- DQB2, TLR1, and IL6R.  EXPOSURES AND RISK FACTORS  Allergic Sensitization Tobacco and Allergen Exposure EXPOSUR the development of allergic sensitization involves an interplay between heritable Maternal smoking and secondhand smoke exposure are ES AND susceptibility and allergen exposure. Allergen exposure during vulnerable associated with increased childhood asthma. RISK developmental periods is believed to increase the risk of development of Childhood secondhand smoke exposure increased asthma risk FACTORS allergic sensitization in those with a tendency toward atopy. twofold. Active smoking is estimated to increase the incidence of asthma by up to fourfold in adolescents and young adults.  Air Pollution Infections Early life exposure to Respiratory infections pollution increases the risk of development of asthma can precipitate asthma deteriorations. EXPOSUR thought to be attributed to levels of nitrogen dioxide Incidence and frequency of human ES AND exposure. most risk lies with carbon rhinovirus and respiratory syncytial RISK monoxide and nitric dioxide, virus infections in FACTORS with marginal effects of sulfur dioxide. children are associated with development of. asthma Mycoplasma pneumoniae infection has been associated with the development of asthma  Occupational Diet Exposures Occupational asthma is estimated to prenatal diet or vitamin defi- account for 10–25% of adult-onset ciency may alter the risk of asthma. The occupations associated with the developing asthma. Vitamin D insufficiency may EXPOSUR most cases in European Community Health Surveys were nursing and increase asthma risk and supplementation may ES AND cleaning. decrease such risk. Studies suggest that RISK maternal supplementation with vitamins C and E and FACTORS zinc may decrease asthma in children Maternal polyunsaturated fatty acid supplementation may decrease childhood asthma risk. Increased maternal sugar intake may increase childhood asthma risk.  Obesity Medications Multiple studies suggest Use of H2 blockers and proton pump inhibitors in EXPOSUR that obesity may be a risk factor for development of pregnancy has been ES AND childhood and adult asthma. associated with an increased risk of asthma in RISK Adipokines and IL-6 have been thought to play a children ; however, another study found a FACTORS pathobiologic role. small risk for H2 blockers only. Conflicting data have been presented on the risk of perinatal acet- aminophen and early childhood acetaminophen use. I  Prenatal and Endogenous Perinatal Risk Developmental Risk Preeclampsia Factors and pre- Factors maturity have been Asthma is more prevalent among boys than girls, age EXPOSUR associated with increased risk of asthma 20 reversing (more prevalent ES AND Babies born by cesarean among women) by age 40. section are at higher risk for RISK asthma. Atopy is more prevalent among boys in childhood, FACTORS Those with neonatal jaundice are also at increased risk. and they have reduced airway size compared with Breast-feeding reduced early girls. wheezing but has a less subset of women develop clear effect on later asthma around menopause. incidence of asthma. Pregnancy may precipitate or aggravate asthma as well.  High- Fungi and Allergic Concentration Airway Mycoses Irritant Exposure 1 to 2% of patients with asthma may have an exposure andtoRADS a high concentration of irritant agents IgE-mediated sensitization to colonization of the airway by fungi, EXPOSUR that rapidly (usually within hours) produces bronchospasm Aspergillus fumigatus- most common fungus causing such a reaction ES AND and bronchial hyper- activity is Allergic bronchopulmonary aspergillosis (ABPA) known as RADS. Causative ⚬ type 2 airway inflammatory response to RISK agents include oxidizing and aspergillus reducing agents in an aerosol ⚬ IgE >1000 IU/mL FACTORS or high levels of particulates. ⚬ eosinophils >500/μL ⚬ Positive skin test to Aspergillus ⚬ Specific IgE and IgG antibodies to Aspergillus. ⚬ Patients may have intermittent mucus plugging and central bronchiectasis. ⚬ Treatment: systemic antifungal treatment with itraconazole or voriconazole and oral corticosteroids.  Exercise-Induced Symptoms in Athletes Exercise- induced airway narrowing in EXPOSUR elite athletes undertaking extreme exercise in strenuous condition. ES AND The condition may involve additional RISK mechanisms including direct epithelial FACTORS injury. Reported in swimmers possibly related to pool chlorination.  TRIGGERS OF AIRWAY NARROWING  TRIGGERS OF AIRWAY NARROWINg Allergens Irritants Many asthmatics report Sensitization allergens through increased symptoms on production of allergen-specific IgE reactions to inhalation of pollens, mold, exposure to strong odors, smoke, combustion or dust; insects (especially products, cleaning fluids, cockroaches); animals; occupational or per- fumes. materials; seasonal worsening of The effects are short-lived, asthma; Chronic exposure may lead to although chronic exposure and large-quantity persistent symptoms. exposures (can lead to long-lasting or permanent symptoms.  TRIGGERS OF AIRWAY NARROWINg Viral Infections Exercise and Cold/Dry Air Exercise may be a trigger to exacerbations can be asthmatic bronchoconstriction triggered by upper in patients with asthma. respiratory infections. Increased airway reactivity Hyperventilation that occurs with exercise dries the airway after viral infections lining, causing release of generally persists for 4–6 bronchoconstrictive mediators. weeks but, in some cases, may be associated with permanent changes and impairment.  TRIGGERS Air Pollution Drugs OF AIRWAY Increased rates of NARROWINg exacerbations have Beta blockers may trigger bronchospasm even when been associated used solely in ophthalmic preparations. with increased Beta blocker use may be a ambient ozone, cause of difficult-to-control sulfur dioxide, and asthma. Aspirin may precipitate nitrogen dioxide, bron- chospasm in those among other air with aspirin-exacerbated respiratory disease pollutants. Angiotensin-converting enzyme (ACE) inhibitors (and to a lesser extent angiotensin receptor blockers) may cause cough.  TRIGGERS OF AIRWAY NARROWINg Occupational Stress Exposures episodic and/or recurrent Asthmatics may exposures to workplace report increased irritants and/or sub- symptoms with stances to which one has stress. become sensitized can The mechanisms are produce symptoms. poorly understood. Symptoms are reduced when patients are away from exposures on weekends or vacation.  Hormonal Factors women report a regular increase in TRIGGERS perimenstrual symptoms, and symptoms OF may worsen during perimenopause. This may be related to rapid fluctuations AIRWAY in estrogen levels. Pregnancy can precipitate worsening of NARROWI asthma in approximately one-third of pregnant patients. Ng  COMORBIDITIES  COMORBIDITIES THAT MAKE ASTHMA DIFFICULT TO CONTROL Obesity Gastroesophageal Reflux Rhinosinusitis And/Or Disease Nasal Polyposis Obese adults with asthma have more severe asthma The presence GERD predicts poorly controlled rhinosinusitis symptoms than lean adults poor quality of life and is an aggravate asthma by and are two to four times independent predictor of inflammatory and irritant effects more likely to be hos- asthma exacerbations. Treatment of symptomatic of the secretions on the lower pitalized with an asthma airway, neural reflexes, and exacerbation. reflux disease has been production of inflammatory shown to produce mediators and cells that improvements in airway produce systemic inflammation. function, symptoms, and Treatment with intranasal exacerbation frequency. corticosteroids has been shown to decrease airway reactivity and emergency department visits and hospitalizations.  COMORBIDITIES THAT MAKE ASTHMA DIFFICULT Vocal Cord Dysfunction TO CONTROL Chronic Anxiety/Depression Obstructive Increased rates of Now known as inducible Pulmonary asthma exacerbations laryngeal obstruction inappropriate narrowing Disease (COPD) with anxiety, Asthma-COPD of the larynx, producing depression, or chronic Overlap resistance to airflow. stress. Some patients It can complicate may be unable to asthma and mimic it. distinguish anxiety Commonly seen in attacks from asthma. women and patients with anxiety and depression. Definitive diagnosis involves laryngoscopy during symptomatic  DIAGNOSIS and evaluation  DIAGNOSIS and evaluation NEXT PPT  PRIMARY ASSESSMENT TOOLS FOR ESTABLISHING A DIAGNOSIS History Episodes of wheezing, shortness of breath, chest tightness, mucus pro- duction, or cough upon exposure to triggers Symptoms may be worse on arising in the morning or nocturnal symptoms alone. Patients frequently complain of symptoms with rapid changes of temperature or humidity. Exercise-induced symptoms are common with increased sensitivity to cold air. Exposure history should be obtained for home (e.g., pets, molds, dust, direct or secondhand smoke), work (work environment and exposure to occupational sensitizers), and recreational (e.g., hobbies, recreational inhalants) exposures. Up to two-thirds of patients with asthma will be atopic and almost half will have a history of rhinitis, with many complaining of intermittent sinusitis. Patients with adult-onset asthma, occupational history should be obtained and a history of reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) or use of new medications, such as beta blockers (includ- ing ophthalmic preparations) and ACE Physical Examination Physical findings may be normal. Many patients will have evidence of allergic rhinitis with pale nasal mucus membranes. Five percent or more of patients may have nasal polyps. Some patients will have wheezing on expiration (less so on inspiration). During an acute asthma attack, patients present with tachypnea and tachycardia, and use of accessory muscles can be observed. Wheezing, with a prolonged expiratory phase, is common during attacks, but as the severity of airway obstruction progresses, the chest may become “silent” with loss of breath sounds.  Pulmonary Function Assessment of Tests Airway PRIMARY Responsiveness ASSESSMENT In cases where pulmo- nary function tests are nonconfirmatory and the TOOLS FOR The peak expiratory flow rate (PEFR), forced expiratory volume in 1 s (FEV1), diagnosis remains in doubt, testing ESTABLISHING and the FEV1/forced vital capacity (FVC) to demonstrate increased reactivity ratio are reduced below the lower limit to provocative stim- uli in the A DIAGNOSIS of normal. laboratory can be undertaken. The flow-volume loop may show a Methacholine, a cholinergic agonist, characteristic scalloping inhaled in increasing concentrations These findings may not be present is most commonly used. A during acute attacks or on therapy provocative dose producing a 20% (especially after recent use of drop in FEV1 (PD20) is calculated, bronchodilators). Reversibility is defined as a ≥12% with a value ≤400 μg indicative of increase in the FEV1 and an absolute airway reactivity. Mannitol is used as increase of ≥200 mL at least 15 min well, and occasionally, hypertonic after administration of a β2-agonist or saline may be used. Challenge with after several weeks of corticosteroid exercise and/or cold, dry air can be therapy. Diurnal peak flow variability of performed, with a positive response >20% has also been proposed as an recorded if there is a ≥10% drop in indicator of reversible airways disease, FEV1 from baseline. In the case of but it is less reliable due to difficulties suspected with quality control and variability of environmental/occupational home assessments. Lung volumes and exposures, specific allergen diffusing capacity should be normal in