آسم - Asthma

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ASTHMA 

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TABLE Definition Pathogenesis Physiology Physical Findings Evaluation Risk factors for asthma Management and Treatment 

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DEFINITI ON 

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While asthma is readily recognized in its classic presentation, with intermittent cough, wheeze, and shortness of breath brought on by characteristic triggers and relieved by bronchodilating medications, it is difficult to provide a definition that distinguishes asthma from similar and overlapping conditions. In the absence of a definitive laboratory test or biomarker, asthma has defied precise definition, one acceptable to all disciplines (including clinicians, physiologists, and pathologists). Clinically, its symptoms are non-specific. Physiologically, asthma is characterized by bronchial hyperresponsiveness, the tendency of airways to narrow excessively in response to a variety of stimuli that provoke little or no bronchoconstriction in persons without airway disease, but bronchial hyperresponsiveness is not unique to asthma. Pathologically, asthma may be described broadly as "a chronic inflammatory disorder of the airways" .However, this description omits the characteristic waxing and waning of air flow obstruction in asthma and fails to distinguish asthma from other inflammatory airways disorders, such as chronic bronchitis or bronchiolitis. 

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The Expert Panel 3 of the National Asthma Education and Prevention Program “a common chronic disorder of the airways that is complex and characterized by variable and recurring symptoms, air flow obstruction, bronchial hyperresponsiveness, and an underlying inflammation. The interaction of these features of asthma determines the clinical manifestations and severity of asthma and the response to treatment." 

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The Global Initiative for 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 air flow limitation." 

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Many of the features described above for asthma overlap with chronic obstructive pulmonary disease (COPD). Sometimes the distinction between asthma and COPD is clear: chronic exercise limitation and persistent air flow obstruction in a middle-aged or older person with a history of more than 20 pack-years of cigarette smoking point to a diagnosis of COPD. In COPD, pre- and post- bronchodilator pulmonary function testing may confirm little or no reversibility of the air flow obstruction. At other times, however, the distinction is less clear, such as when patients with COPD exhibit episodic symptoms and a large reversible component to their air flow obstruction. 

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Reactive airways disease is an imprecise term that has been used to describe transient symptoms of cough and wheeze when confirmation of a diagnosis of asthma is lacking. Although it may be appropriate as a description of intermittent wheezing in very young children in whom a diagnosis of asthma cannot yet be definitively ascertained, it should be avoided in adolescents and adults in whom additional testing is available to confirm or exclude a diagnosis of asthma . Reactive airways dysfunction syndrome (RADS) refers to an airway disorder resulting from an intense exposure to an inhaled chemical irritant or noxious gas. It is characterized by asthma-like features of bronchial hyperresponsiveness and air flow obstruction. Table 

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[|_| PATHOGENES Is 

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Airway biopsies obtained by bronchoscopy have demonstrated that inflammation in asthma generally involves the same cells that play prominent roles in the allergic response in the nasal passages and skin, whether the individual is atopic or not. This supports the belief that the consequences of mast cell activation, mediated by a variety of cells, cytokines, and other mediators, are key to the development of clinical asthma. 

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Early phase reactions In human studies of allergen bronchoprovocation, allergen inhalation by a sensitized individual leads to within several minutes. This is called the early response and correlates with the release bronchoconstriction of mast cell mediators during the immediate hypersensitivity reaction. These mediators, including histamine, prostaglandin D2, and cysteinyl leukotrienes (LTC4, D4, and E4), contract airway smooth muscle (ASM) directly, and may also stimulate reflex neural pathways Late phase reactions This early phase reaction is sometimes followed by a late phase recurrence of bronchoconstriction several hours later. The late phase response coincides with an influx of inflammatory cells, including innate immune cells such as monocytes, dendritic cells, and neutrophils, and cells associated with adaptive immunity such as T lymphocytes, eosinophils, and basophils. The mediators released by these cells also cause ASM contraction that is largely reversible by beta-agonist administration However, the observation that beta-agonists do not completely reverse air ‎flow obstruction caused by allergen inhalation is evidence that the late |‏ ا ‎phase reaction is more complex than just ASM contraction. ‎ 

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Mast cell 1) Initial allergen exposure is followed by elaboration of specific IgE antibodies. Regulation of specific IgE production appears related to an overexpression of Th2 type T cell responses relative to the Th1 type; this overexpression is likely due to a combination of genetic and environmental influences. 2) After allergen specific IgE antibodies are synthesized and secreted by plasma cells, they bind to high-affinity receptors (FC-epsilon-RI) on mast cells (and basophils). 3) When an allergen is subsequently inhaled and comes into contact with mucosal mast cells, it cross links allergen specific IgE antibodies on the mast cell surface; rapid degranulation and mediator release follow in a calcium dependent process. This is known as the early or immediate phase reaction, which is described in the next section. 

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Light chain 9 مه سا ‎wn‏ سا ‎on‏ ۱۳ 

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Eosinophils The eosinophil is the most characteristic cell that accumulates in asthma and allergic inflammation. While the presence of eosinophils is often related to disease severity, some patients with asthma do not have eosinophilic infiltration of the airways . Activated eosinophils produce lipid mediators, such as leukotrienes and platelet activating factor, that mediate smooth muscle contraction; toxic granule products (eg, major basic protein, eosinophil-derived neurotoxin, eosinophil peroxidase, or eosinophil cationic protein) that can damage airway epithelium and nerves; and cytokines, such as granulocytemacrophage colony stimulating factor (GM-CSF), transforming growth factors (TGF)-alpha and beta, and interleukins that may be involved in airway remodeling and fibrosis. Eosinophils are recruited or activated by the hematopoietin interleukin 5 (IL-5), by the eotaxin family of chemokines via the eosinophil-selective chemokine receptor CCR3, and by Toll-like receptors (TLR) . 

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Th2 lymphocytes The T cell population in infiltrating the asthmatic airway is characterized by the Thelper 2 subset (Th2) of lymphocytes that produces a restricted panel of cytokines, including interleukin (IL)-3, IL-4, IL-5, IL-13, and GM-CSF, but not interferon gamma, when stimulated with antigen . Th2 lymphocytes also express the chemokine receptors (CCR4 and CCR8) and the chemoattractant receptor (CR)-like molecule (CRTH2), a receptor for prostaglandin D2 (PGD2), suggesting potential interactions between the mast cell and chemotactic signals that target eosinophils and Th2 cells and that sustain airway inflammation . The actions of the following cytokines produced by Th2 lymphocytes strongly suggest that they play critical roles in asthma and allergic responses. IL-3 is a survival factor for eosinophils and basophils. IL-4 helps in the differentiation of uncommitted T cells into Th2 cells, switch of B-lymphocyte immunoglobulin synthesis to IgE production, and selective endothelial cell expression of vascular cell adhesion molecule-1 (VCAM-1) that mediates eosinophil, basophil, and T cell specific recruitment. IL-5 is the major hematopoietic cytokine regulating eosinophil production and survival. IL-13 appears to contribute to airway eosinophilia, mucous gland hyperplasia, airway fibrosis, and remodeling . GM-CSF is also a survival factor for eosinophils. The anti-IL-5 monoclonal antibodies (benralizumab, mepolizumab, and reslizumab) and the anti-IL-4 receptor alpha antibody (dupilumab) that interrupts both IL-4 and IL-13 signalling are in widespread use for severe uncontrolled asthma, demonstrating the important role that these cytokines play in asthma pathogenesis. 

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NKT cells It is hypothesized that invariant natural killer T (iNKT) cells direct or modulate asthma inflammation . iNKT cells express a conserved T-cell receptor (V[alpha]24-J[alpha]18), which is capable of recognizing glycolipid antigens, such as those from plant pollens. They rapidly produce both IL-4 and IL-13, which are involved in airway inflammation and IgE production. Basophils While Th2 lymphocytes are a major source of the cytokines thought to participate in asthma, the basophil, in addition to producing histamine and leukotrienes, is a potent producer of IL-4 and IL-13, exceeding levels produced by T cells . 

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Innate immunity 1) Airway epithelial cells express TLR on their surface, including TLR 4, a receptor that recognizes lipopolysaccharide (LPS). In addition to being a constituent of gram negative bacteria, LPS is a contaminant of inhalational allergens like house dust and animal dander. Ina mouse model of asthma, inhalation of house dust extract appears to trigger airway epithelial cell TLR 4, leading to elaboration of the proallergenic cytokines IL-5, IL-13, 1L-25, 1-33, and thymic stromal lymphopoietin (TSLP) 2) Innate lymphoid cells Type 2 (ILC2) are a group of innate immune cells that are potent producers of Th2 cytokines, particularly IL-5 and 11-13, as well as IL-4 under certain conditions. They are directly activated by the epithelial cytokines IL-25, IL-33, and TSLP; lipid mediators from mast cells, such as PGD2 and cysteinyl leukotrienes; and by viruses and allergens. These features suggest an important role for ILC2 in Th2 inflammation that is non-allergic . 3) Dendritic cells, which form a network of innate immune cells within the airway, are increased in asthma and after allergen challenge . These cells are essential, not only to the initial induction of specific or adaptive immunity due to their role in antigen processing and presentation, but also in the effector phase of response to allergen following host sensitization 4) Neutrophils are the predominant granulocyte in the airways of some patients with severe, glucocorticoid- dependent asthma, sudden fatal asthma, and asthma exacerbations . Their exact role in the pathogenesis of severe asthma is not known. | Table 

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ا ‎PHYSIOLOG‏ ‎Y‏ 

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Variable narrowing of the airway lumen causing variable reductions in air flow is a pathognomonic feature of asthma. Mechanisms causing air flow limitation include contraction of airway smooth muscle, thickening of the airway wall due to edema or cellular components, plugging of airways with mucus or cellular debris, and airway remodeling. 1. Smooth muscle Contraction and relaxation of airway smooth muscle (ASM) accounts for much of the rapid changes in air flow limitation characterizing asthma and is the basis for beta-agonist therapy that directly relaxes ASM. Bronchoconstriction may be due to direct effects of contractile agonists released from inflammatory cells or reflex neural mechanisms. As an example, mast cell and eosinophil mediators, such as leukotrienes C4, D4, and E4 and histamine, are potent bronchoconstrictors. Airway inflammation occurs throughout the tracheobronchial tree; varying degrees of obstruction of different diameter airways may determine disease physiology. In theory, obstruction in large airways leads to air flow limitation and decreased flow rates, while obstruction in small airways (ie, diameter less than 2 mm) leads to airway closure at low lung volumes, air trapping with an increase in residual volume, and in many cases, dynamic hyperinflation . The relative contributions of small and large airways to air flow obstruction have also been evaluated. Marked (sevenfold) increases in resistance in small airways have been documented in patients with mild asthma, despite normal spirometry; the small airways appear to be a key site of airway closure due to ASM contraction. However, the notion that the small airways are the predominant site of airway narrowing in asthma has been challenged by ‏مت ها مد یراب نی نک و اد با ۱ بای اد ی یپ زب دزی ]امه تما اه قي | يي یا‎ sts ‏ری‎ 

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Mucus plugging .2 Mucus plugs appear to contribute to air flow limitation in chronic severe asthma . CT scans have demonstrated mucus plugs in at least 1 of 20 lung segments in 58 percent of subjects with asthma . In addition, high mucus plug scores (plugs in =4 segments) on CT scans correlate with air flow limitation on spirometry and sputum eosinophilia. 3. AIRWAY REMODELING While many patients have intermittent asthma symptoms and normal physiologic testing between asthma episodes, increasing evidence suggests that a subset of patients with asthma have irreversible air flow obstruction, which is believed to be caused by airway remodeling . Airway remodeling refers to structural changes in the airways that may cause irreversible air ow limitation, superimposed on the 

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|__| PHYSICAL FINDINGS 

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Widespread, high-pitched, musical wheezes are a characteristic feature of asthma, although wheezes are not specific for asthma and are usually absent between asthma exacerbations. Wheezes are heard most commonly on expiration, but can also occur during inspiration. Asthmatic wheezing usually involves sounds of multiple different pitches, starting and stopping at various points in the respiratory cycle and varying in tone and duration over time. It is different from the monophasic wheezing of a local bronchial narrowing (eg, due to an aspirated foreign body or bronchogenic cancer), which has single pitch and repeatedly begins and ends at the same point in each respiratory cycle. Physical findings that suggest severe air flow obstruction in asthma include tachypnea, tachycardia, prolonged expiratory phase of respiration (decreased I:E ratio), and a seated position with use of extended arms to support the upper chest ("tripod position") . Use of the accessory muscles of breathing (eg, sternocleidomastoid) during inspiration and a pulsus paradoxus (greater than 12 mmHg fall in systolic blood pressure during inspiration) are usually found only during severe asthmatic attacks. However, these signs are insensitive manifestations of severe air flow obstruction; their absence does not exclude the possibility of a severe asthmatic attack. Importantly, the presence or absence of wheezing on physical examination is a poor predictor of the severity of air flow obstruction in asthma. 

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Extrapulmonary physical findings in patients with asthma that can provide evidence in support of or against a diagnosis of asthma include the following: Pale, swollen membranes on examination of the nasal cavities with an otoscope and a cobblestone appearance to the posterior pharyngeal wall suggest associated allergic rhinitis, a common condition among patients with allergic asthma. Nasal polyps, which appear as glistening, gray, mucoid masses within the nasal cavities, should prompt questioning about concomitant aspirin sensitivity, anosmia, and chronic sinusitis. Since aspirin-exacerbated respiratory disease (asthma, nasal polyps, and aspirin sensitivity) is uncommon in childhood, the finding of nasal polyps in an adolescent with lower respiratory tract symptoms should lead to consideration of alternative diagnoses, specifically cystic fibrosis. Atopic dermatitis with typical lichenified plaques in a flexural distribution, especially of the antecubital and popliteal fossae, volar aspect of the wrists, ankles, and neck, may accompany asthma in adolescents and adults. In early childhood it is a risk factor for the later development of asthma, with as many as a third of children with atopic dermatitis progressing to asthma. Clubbing is not a feature of asthma; its presence should direct the clinician toward alternative diagnoses such as interstitial lung disease, lung cancer, and diffuse bronchiectasis, including cystic fibrosis. 

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Tripod position Inability to fie flat Leaning forward with arms and elbows supported on over bed table. Possible Etiology: COPD, Asthma in exacerbation, pulmonary edema, indicates moderate to severe respiratory distress, 

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Nasal polyps in nostril Adult chronic atopic dermatitis > Ter "Nasal ply appears lstening, ray or whit, mcd mses the asl Leben, byperpigmented pla inthe elbow Dense of 35. female with 

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re igre ge Ware War EVALUATION 

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The laboratory evaluation of a patient with suspected asthma is predominantly focused on pulmonary function testing. Other laboratory studies, including chest radiography, blood tests, and tests for allergy, are useful in selected patients but cannot of themselves establish or refute a diagnosis of asthma. 1. Pulmonary function testing: >Spirometry >Bronchodilator response >Bronchoprovocation testing >Peak expiratory flow > Exhaled nitric oxide 2. Blood tests 3. Tests for allergy 4. Imaging 

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Spirometry, in which a maximal inhalation is followed by a rapid and forceful complete exhalation into a spirometer, includes measurement of forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) . These measurements provide information that is essential to the diagnosis of asthma . We obtain baseline spirometry in virtually all patients with a suspected diagnosis of asthma. The results of spirometry can be used to determine the following: Determine whether baseline air flow limitation (obstruction) is present (reduced FEV1/FVC ratio) “Assess the reversibility of the obstructive abnormality by repeating spirometry after administration of a bronchodilator “Characterize the severity of air flow limitation (based on the FEV1 as a percentage of the normal predicted value) ’For patients with normal air flow (normal FEV1/FVC ratio), identify a restrictive pattern as an alternate explanation for dyspnea (eg, FVC <80 percent predicted) 

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‘An obstructive pattern on spirometry is identified numerically by a reduction in the ratio of FEV1 to FVC . When FEV1/FVC is reduced below normal (less than 0.70 or less than the lower limit of normal [LLN], which is the cut-off at the fifth percentile of the confidence interval provided electronically by modern computerized spirometers), air flow obstruction is present. When the FEV1/FVC ratio is normal or increased, there is no expiratory air flow obstruction. Having identified the presence of air flow obstruction by a reduction in FEV1/FVC, the severity of air flow obstruction is then categorized by the degree of reduction of the FEV1 below normal. The severity of air flow obstruction based on spirometry is graded as borderline, mild, moderate, and severe, although other grading systems can be used . These categories are used for pulmonary function interpretation and are NOT the same as categories used by the National Asthma Education and Prevention Program (NAEPP) guidelines to stage asthma severity. ‘An obstructive pattern can also be identified visually by inspection of the shape of the expiratory flow- volume curve that is often provided by modern spirometry equipment. A scooped, concave appearance to the expiratory portion of the flow-volume loop signifies diffuse intrathoracic air flow obstruction, typical of asthma and many other obstructive lung diseases. Inspection of the inspiratory and expiratory portions of the flow-volume loop can also be useful in identifying the characteristic patterns seen in upper airway obstruction . 

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FEV,/FVC below the Sth percentile (lower limit of normalt ——N° see tegend below | Yes ۲ ves FEV >70 percent predicted —___—"__» mild obstruction | No ۷ FEV, 50 to 69 percent predicted ‏كلل‎ _» Moderate obstruction | No ۲ Yes FEV, <5S0 percent predicted ‏اس‎ Severe obstruction FVC below 80 percent of predicted? | Yes Obstruction plus low vital capacity 

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Volume, L Flow, L/s 

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uonesdxg uonesndsuy RV TLC RV TLC 6 RV TLC عو طون RV TLC Flow (L/second) (a) Normal flow-volume loop: the expiratory portion of the flow-volume curve is characterized by a rapid rise = he peak flow rate, followed by a nearly linear fall in flow. The inspiratory curve is a relatively symmetrical, saddle-shaped curve. (B) Dynamic (or variable, nonfixed) extrathoracic obstruction: flow limitation and flattening are noted on the inspiratory limb of the loop. (©) Dynamic (or variable, nonfixed) intrathoracic obstruction: flow limitation and flattening are noted on the expiratory limb of the loop. (D) Fixed upper airway obstruction (can be intrathoracic or extrathoracic): flow limitation and flattening are noted in both the inspiratory and expiratory limbs of the flow-volume loop. (E) Peripheral or lower airways obstruction: expiratory limb demonstrates concave upward, also called "scooped-out” or "coved" pattern. 

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Bronchodilator response We assess bronchodilator reversibility in almost all adult and adolescent patients with air flow limitation on their baseline spirometry, as recommended by the NAEPP guidelines. Acute reversibility of air flow obstruction is tested by administering 2 to 4 puffs of a quick-acting bronchodilator (eg, albuterol), preferably with a valved holding-chamber ("spacer"), and repeating spirometry 10 to 15 minutes later. Measurements can also be made before and after administration of nebulized bronchodilator. An increase in FEV1 of 12 percent or more, accompanied by an absolute increase in FEV1 of at least 200 mL, can be attributed to bronchodilator responsiveness with 95 percent certainty. The presence of a bronchodilator response, in isolation, is not sufficient to make the diagnosis of asthma, however. Bronchodilator responsiveness may be seen with other conditions, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis, non- cystic fibrosis bronchiectasis, and bronchiolitis. Asthma is typically distinguished from these other conditions by the capacity for a “large increase in FEV1. 

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The definition of a large bronchodilator response is not standardized; investigators generally classify a large response as at least 15 or 20 percent. However, there is no precise cut-off value that defines an "asthmatic" bronchodilator response. Occasionally, patients with asthma will have air flow obstruction on spirometry but fail to exhibit a 12 percent or greater increase in FEV1 following bronchodilator (a "false negative" response). Reasons for false negatives include the following: Inadequate inhalation of the bronchodilator due to problems using the metered-dose inhaler correctly Recent use of a quick-acting bronchodilator or other anti-asthmatic medications (eg, long-acting bronchodilators), resulting in near-maximal bronchodilation prior to testing » Minimal air flow obstruction at the time of testing (FEV1 already close to 100 percent) >In some patients with asthma, the presence of irreversible airways obstruction due to chronic airways inflammation or scarring Changes in the forced expiratory flow between 25 and 75 percent of the vital capacity (FEF25-75) observed over time or in response to bronchodilator are not used to diagnose asthma in adults; nor are decreases in the FEF25-75 used to characterize the severity of asthma. 

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Prebronchodilator Predicted Volume (liters) Flow (liters/second) 

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Bronchoprovocation testing Bronchoprovocation testing is available in most pulmonary function testing laboratories and is a useful tool for diagnosing asthma in patients with normal baseline air flow. Bronchoprovocation testing can be used to identify or exclude airway hyperresponsiveness in patients with atypical presentations (eg, normal baseline spirometry, no variability in air ow limitation with serial spirometry or peak ow) or isolated symptoms of asthma, especially cough. A provocative stimulus (eg, inhaled methacholine, inhaled mannitol, exercise, or hyperventilation of dry air) is used to stimulate bronchoconstriction. People with asthma are more sensitive (hyperresponsive) to such stimuli than those without asthma. 

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The technical aspects of performing this type of testing, interpreting the results, and identifying the causes of false positive and false negative results are presented separately. A positive test (indicating bronchial hyperresponsiveness) is not entirely specific for asthma. Using a cut point of 8 mg/mL of methacholine or less to indicate the presence of hyperresponsiveness, as many as 5 percent of the normal population and a greater percentage of non-asthmatic persons with rhinitis will exhibit positive results. However, false negative results are uncommon, and a negative test (no significant decline in FEV1 at the highest dose of methacholine administered) performed in a patient o controller therapy for asthma reliably excludes the diagnosis of asthma. Other specialized provocation testing can be used when evaluating the role of a specific precipitating factor. Typical examples include measuring lung function before and after exercise when a diagnosis of exercise-induced bronchoconstriction related to asthma is suspected, and evaluation of possible occupational asthma by FEV1 or PEF measurements made before and after the work shift. 

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FEV, (percent of control) Baseline Saline 0.1 1.0 10 100 Methacholine (mg/mL) The effect of increasing the inhaled dose of methacholine in a healthy subject (red) and an asthmatic patient (blue). The provocative concentration is the amount of inhaled agonist required to drop the FEV, by 20 percent from the baseline (PC 29 FEV; ) and is much less in the asthmatic than in the normal subject: 0.8 mg/mL versus 20 mg/mL. In general, a PC29 =8 mg/mL is consistent with asthma; and a PC) > 16 mg/mL is considered a negative test. Thus, an increase in airway responsiveness is characterized by a decrease in the PC.29- 

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Peak expiratory flow The peak expiratory flow (PEF) is measured during a brief, forceful exhalation, using a simple and inexpensive device (approximately $20). We typically use PEF measurements to monitor patients with a known diagnosis of asthma or to assess the role of a particular occupational exposure or trigger, rather than as a tool for the primary diagnosis of asthma. Technique - The PEF maneuver can be performed sitting or standing. Proper technique involves taking a maximally large breath in, putting the peak flow meter quickly to the mouth, sealing the lips around the mouthpiece, and blowing out as hard and fast as possible into the meter. For PEE, the effort does not need to be sustained beyond one to two seconds. The maneuver is performed three times and '———_the highest of the three measurements is recorded ‏دبع‎ 

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Normal values - Average normal values for male and female adults are based upon height and age Average normal values for adolescents are based upon height .The range of normal values around the mean is up to 80 to 100 L/min. Interpretation of PEF - A single peak flow determination made in the doctor's office at the time that a patient is experiencing respiratory symptoms, if reduced from the normal predicted value, is suggestive of asthma. However, it is not diagnostic because a reduced peak flow is not specific for air flow obstruction and can be seen with other pulmonary processes. On the other hand, a reduced peak flow that improves by more than 20 percent approximately 10 to 20 minutes after administration of a quick-acting bronchodilator (eg, inhaled albuterol) provides supportive evidence favoring the diagnosis of asthma. Even with careful measurements, PEF may vary as much as 10 to 15 percent from one measurement to the next. PEF results that vary little over time (less than 10 percent of the maximal value) despite the presence of symptoms such as cough and shortness of breath argue against the diagnosis of asthma. In contrast, PEF values that repeatedly fall by more than 20 percent when symptoms are present and return to baseline as symptoms resolve are consistent with asthma. 

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Technique for peak flow measurement in asthma Move peak flow meter indicator to zero. Sit or stand up straight. Take in a deep breath, as deep as you can, Place peak low meter in your mouth and close your lips around the mouthpiece*, As soon as your lips are sealed around mouth piece, blow out as hard and fast as you can using your chest and belly muscles‘, This should take no more than 2 seconds, Write down the result. Repeat two more times (three total). Record the highest ofthe three values, * Nose clips ae not necessary. 4 Make sure to use ll of your breathing muses, not just your mouth muscles. This need a lot of fore, lke blowing outa candle several feet away. 

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Prtited peak expiratory 0۱ 0 ‏مسا‎ males age 0 to 70 years Predicted peak expiratory flow (PEF iters/ minute) fo females age 20 to 70 years Oita Gib Semin | Binet Sinden | Miceststen | Ginette icp vo tu hi pera bt secant an epee ps bests ping Wen ae) Fp wt det or eps bet ise chp einem pte pea et Tis ewes pci gti Wes 2 wT eas Debt Ue cla iva ado age beh, and race eb paanees ‏واه با زان‎ cleaae for aes aia hgh, nee ‏كتمهم‎ 

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Predicted average peak expiratory flow values for normal children (inches) 43 44 45 46 47 48 49 50 51 52 53 54 55 

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Limitations of PEF - PEF measurement has several shortcomings as a diagnostic tool for asthma, including : > Peak flow values often underestimate the severity of air flow obstruction. Significant air flow obstruction may be present on spirometry when the peak flow is within the normal range. > Reduced peak flow measurements may be seen in both obstructive and restrictive diseases. Spirometry and sometimes measurement of lung volumes are necessary to distinguish the two. > Peak flow measurements are not sufficient to distinguish upper airway obstruction (eg, vocal cord dysfunction) from asthma. Spirometry with a flow-volume loop is needed for evaluation of upper airway obstruction. » The validity of PEF measurements depends entirely upon patient effort and technique. Errors in performing the test frequently lead to underestimation of true values, and occasionally to overestimation, > Home PEF monitoring is unsupervised. Patients may produce higher values in the clinician's office with appropriate coaching to ensure a maximal effort. > Peak flow meters cannot be routinely calibrated, unlike spirometers. Thus, results will vary somewhat between different instruments and the accuracy of a particular peak flow meter may deteriorate over time. 

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Exhaled nitric oxide The measurement of nitric oxide in a patient's exhaled breath can aid in the diagnosis of asthma in combination with other tests, but a normal level does not exclude asthma. The test is based on the observation that eosinophilic airway inflammation associated with asthma leads to up- regulation of nitric oxide synthase in the respiratory mucosa, which in turn generates increased amounts of nitric oxide gas in the exhaled breath. The concentration of nitric oxide (fraction of exhaled nitric oxide [FENO]) in the exhaled breath of some persons with asthma is elevated above the low levels of FENO in normal individuals and those with stable, well controlled asthma. An elevated FENO (240 to 50 parts per billion) can help “rule in” asthma, although potentially confounding respiratory diseases (eg, allergic rhinitis, eosinophilic bronchitis) must be excluded. Treatment with oral and/or inhaled glucocorticoids reduces airway inflammation and levels of exhaled nitric oxide. 

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Blood tests No blood tests are available that can determine the presence or absence of asthma or gauge its severity. However, a complete blood count (CBC) with differential white blood cell analysis to screen for eosinophilia or significant anemia may be helpful in certain cases. We typically obtain a CBC and differential when asthma symptoms are severe, the patient presents to the hospital with an exacerbation, nasal polyposis is present, the chest radiograph is abnormal (eg, suggestive of eosinophilic pneumonia or eosinophilic granulomatosis with polyangiitis [Churg Strauss}), or a parasitic infection is suspected. »Markedly elevated eosinophil percentages (>15 percent) or counts (>1500 eosinophils/microL) may be due to allergic asthma, but should prompt consideration of alternative or additional diagnoses, including parasitic infections (eg, Strongyloides), drug reactions, and syndromes of pulmonary infiltrates with eosinophilia, including allergic bronchopulmonary aspergillosis, eosinophilic granulomatosis with polyangiitis, and hypereosinophilic syndrome. > Significant anemia can cause dyspnea that is unresponsive to asthma therapies and would require further evaluation to determine the causative process. 

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Tests for allergy Allergy tests are not useful for the diagnosis of asthma, but they can be helpful to confirm sensitivity to suspected allergic triggers of respiratory symptoms and to guide on-going management of asthma. We usually perform allergy testing in selected patients with a history of symptoms that occur upon exposure to particular aeroallergen(s) , persistent symptoms and suspicion of exposure to relevant allergens in the home environment (eg, pet animals, dust, cockroaches, or mice), and/or moderate-to-severe asthma symptoms despite conventional therapies. In addition to the peripheral blood eosinophil count mentioned above, the main tests for allergy are the total serum immunoglobulin E (IgE) level and the tests for specific allergic sensitization, which include blood testing for specific IgE antibody to inhalant allergens and skin testing with extracts of inhalant allergens. 

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Imaging — In the absence of comorbid illness, the chest radiograph is almost always normal in patients with asthma. However, many clinicians, including ourselves, obtain a chest radiograph for new-onset, moderate-to-severe asthma in adults over age 40 to exclude the occasional alternative diagnosis that may mimic asthma (eg, the mediastinal mass with tracheal compression or heart failure). The cost-effectiveness of this approach has not been evaluated. In contrast, chest radiographs are routinely recommended when evaluating severe or "difficult-to-control" asthma and when co-morbid conditions (eg, allergic bronchopulmonary aspergillosis, eosinophilic pneumonia, or atelectasis due to mucus plugging) are suspected based on history, physical examination, and/or other laboratory data. 

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In addition, chest radiography is indicated in patients presenting with features that are atypical for asthma, including any of the following: > Fever >Chronic purulent sputum production >Persistently localized wheezing >» Hemoptysis Weight loss >Clubbing * Inspiratory crackles * Significant hypoxemia (eg, pulse oxygen saturation less than approximately 94 percent) in the absence of an acute asthmatic attack _ Moderate or severe air flow obstruction that does not reverse with bronchodilators Table 

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FACTORS FOR __ ASTHMA __ 

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PRE- AND PERINATAL FACTORS Genetics and familial history Maternal age Maternal diet during pregnancy Maternal asthma Prenatal exposure to maternal smoking Prenatal medication exposure Perinatal factors 

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CHILDHOOD Sex Early abnormalities in pulmonary function Atopy and allergens Respiratory infections Medication use in infancy Air pollution Obesity Early puberty 

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ADULTHOOD Obesity Tobacco smoke Occupational exposures Postmenopausal hormone replacement therapy ۱ Table 

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[|_| MANAGEMENT AND TREATMENT 

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GOALS OF ASTHMA TREATMENT Optimizing control of asthma symptoms > Freedom from frequent or troublesome symptoms of asthma (cough, chest tightness, wheezing, or shortness of breath) > Few night-time awakenings (<2 nights per month) due to asthma > Minimal need (<2 days per week) for medication for acute relief of asthma symptoms ۲ Optimized lung function ۲ Maintenance of normal daily activities, including work or school attendance and participation in athletics and exercise > Satisfaction with asthma care on the part of patients and caregivers. Reducing future risk > Prevention of recurrent exacerbations and need for emergency department or hospital care > Prevention of reduced lung growth in children and loss of lung function in adults (due to poor asthma control) > Optimization of pharmacotherapy with minimal or no adverse effects 

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Intermittent >Daytime asthma symptoms occurring two or fewer days per week >Two or fewer nocturnal awakenings per month >Use of short-acting beta agonists (SABAs) to relieve symptoms two or fewer days per week No interference with normal activities between exacerbations >FEV1 measurements between exacerbations that are consistently within the normal range (ie, 280 percent of predicted) >FEVI/FVC ratio between exacerbations that is normal (based on age-adjusted values) >One or no exacerbations requiring oral glucocorticoids per year 

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National Asthma Education and Prevention Program: Expert Panel 8 Global Initiative for Asthma (GINA; 2020) Working Group (NAEPP 2020) Asthma symptoms/lung function Therapy” Asthma symptoms ‘Therapy Intermittent asthma/step 1 Step 1 Daytime symptoms =2 days/week | ® SABA, as needed Infrequent asthma symptoms (eg, | * Low-dose ICS with rapid onset Nocturnal awakenings <2/month <2 times/week) LABA (eg, budesonide-formoterol = Normal FEV combination MDI 160. meg-45 meg/inhalation or DPI 200 meg-6 imeg/inhalation) 1 inhalation, as needed Exacerbations = 1/year = Low-dose ICS whenever SABA used. 

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Mild persistent >Symptoms more than twice weekly (although less than daily) > Approximately three to four nocturnal awakenings per month due to asthma (but fewer than every week) >Use of SABAs to relieve symptoms more than two days out of the week (but not daily) » Minor interference with normal activities >FEV1 measurements within normal range (280 percent of predicted) A patient with symptoms and lung function suggesting intermittent asthma but with two or more exacerbations per year requiring oral glucocorticoids is considered to have mild persistent asthma. 

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Therap) # Low-dose ICS daily, with SABA as needed (preferred) # Low dose ICS-formoterol as needed (preferred) Other options "= Low-dose ICS pls SABA, concomitantly administered, as needed or (less preferred) = LTRA daily and SABA as needed Global Initiative for Asthma (GINA; 2020) Asthma symptoms Step 2 "Asthma symptoms or need for reliever inhaler > 2 times/week National Asthma Education and Prevention Program: Expert Panel Working Group (NAEPP 2020) Asthma symptoms/lung function Therapy" Mild persistent asthma/step 2 © Daytime symptoms >2 but <7 | = Low-dose ICS daily with SABA as days/week needed * Nocturnal awakenings 3 t0 4 or hights/month " Low.dose ICS plus SABA, © Minor interference with activities concomitantly administered, as ‎FEV, within the normal range needed‏ م ‎Exacerbations 22/year‏ * ‎Alternative option(s)‏ كه ‎Daily LTRA* and SABA‏ = ‎needed‏ ‎ ‎ ‎ ‎ ‎ ‎ ‎ 

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Moderate ۲ » Daily symptoms of asthma >» Nocturnal awakenings as often as once per week » Daily need for SABAs for symptom relief »Some limitation in normal activity »FEV1 =60 and <80 percent of predicted and FEV1/FVC below normal 

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Global Initiative for Asthma (GINA; 2020) 93 ICSLABA as maintenance and reliever therapy (ie, budesonie-formoterol) (preferred) = Low-dose or ® Low-dose ICS-LABA combination daily, with SABA as needed Other options = Medium-dose ICS daily, with SABA as needed © Low-dose ICS plus LTRA daily, with SABA as needed Asthma symptoms Ste Troublesome asthma symptoms most days, nocturnal awakening due to asthma 21 time/month, risk factors for exacerbations * Working Group (NAEPP 2020) ‘Therapy* ‘Moderate persistent asthma/step 3 ® Combination low-dose ICS- 16 2 halations as needed up to 2 inhalations/day (preferred option) Daily symptoms Noctural awakenings >1 week formoterol daily and Daily need for SABA Some activity limitation FEV , 60 to 80% predicted Alternative option(s) Exacerbations = 2/vear es oneal) ‎Medium-dose ICS daily and‏ ع ‎SABA as needed‏ ‎or‏ ‎Low-dose ICS-LABA combination‏ ® ‎daily or 166 plus‏ ‎LAMA daily or low-dose ICS‏ ‎plus LTRA daily and SABA as‏ ‎needed‏ ‎low-dose ‎or ‎Low-dose ICS daily plus zileuton and SABA as needed* ‎National Asthma Education and Prevention Program: Expert Panel ‎Asthma symptoms/lung function ‎ ‎ ‎ ‎ ‎ ‎ ‎ ‎ ‎ 

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Severe persistent Severe persistent asthma is manifest by : » presence of asthma symptoms throughout the day >nocturnal awakening due to asthma nightly »reliever medication needed for symptoms several times/day > activity limitation due to asthma 

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وح ‎T‏ وی سم Steps 410 5 = Medium-dose ICS-LABA daily and SABA as needed Severely uncontrolled asthma with =3 of the following: daytime asthma symptoms ~2 times/week; noctumal awakening due to asthma; reliever needed for | other options symptoms =2 times/week, oF = High-dose ICS daily — May need activity limitation due to asthma short course of oral or _shicocorticoids An acute exacerbation = Possible add-on tiotropium, صم سس مده تس لا Severe persistent asthma/steps 4 to 6 ‘= Combination medium dose ICS- ‘Symptoms all day Nocturnal awakenings nightly Need for SABA several times/day formoterol daily and 1 to 2 Extreme limitation in aetivity inhalations as needed to 12 inhalations/day (preferred FEV, =60% predicted Exacerbations =2/year ‏لدت‎ Alternative option(s) = Medium-dose ICS-LABA daily or medium-dose ICS plus LAMA daily and SABA as needed = Mediumdose ICS daily plus LTRA or zileuton and SABA as needed 

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