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Airways Disease Technique Description Examples of lndications Airway inspection Msualization of the tracheobronchial tree to the level Hemoptysis of segmental airways Localized wheeze Persistent atelectasis Dia gnosis of tracheobronchomalacia lnhalational injury Bronchial washings Samples from large airways Diagnosis o{ infections Bronchoalveolar lavage Samples from small bronchi and alveoli Diagnosis of infections Cell counts in diagnosis of parenchymal lung disease Alveolar hemorrhage Cytology for mali g nancy Bronchial brushings Brushings of the endobronchial mucosa for cells Endobronchial lesions Endobronchial biopsy Biopsy within the ainvay lumen Endobronchial mass or lesion Transbronchial lung biopsy Biopsy of the lung parenchyma or lung nodules/ Diffuse lung disease masses using smallforceps; often aided by Persistent infiltrates guidance technology, including fluoroscopy, electromagnetic navigation, and radial Lung nodules/masses ultrasonography Posttra nspla nt rejection

Bronchoalveolar lavage Samples from small bronchi and alveoli Diagnosis of infections Cell counts in diagnosis of parenchymal lung disease Alveolar hemorrhage Cytology for mali g nancy Bronchial brushings Brushings of the endobronchial mucosa for cells Endobronchial lesions Endobronchial biopsy Biopsy within the ainvay lumen Endobronchial mass or lesion Transbronchial lung biopsy Biopsy of the lung parenchyma or lung nodules/ Diffuse lung disease masses using smallforceps; often aided by Persistent infiltrates guidance technology, including fluoroscopy, electromagnetic navigation, and radial Lung nodules/masses ultrasonography Posttra nspla nt rejection Transbronchial needle aspiration Aspiration of a lymph node or mass adjacent to the Lymphadenopathy airway Pulmonary mass Mediastinal mass Endobronchial ultrasonography Use of an ultrasound probe at the distal end of the Lymphadenopathy bronchoscope to guide transbronchial needle Pulmonary mass aspiration Mediastinal mass Electromag netic navigation lmages from a recent CT are "linked" with the Pulmonary mass or nodule bronchoscope; an electromagnetic guidance system atthe bronchoscope creates a map ofthe airways and ides the n to the area of interest

Transbronchial needle aspiration Aspiration of a lymph node or mass adjacent to the Lymphadenopathy airway Pulmonary mass Mediastinal mass Endobronchial ultrasonography Use of an ultrasound probe at the distal end of the Lymphadenopathy bronchoscope to guide transbronchial needle Pulmonary mass aspiration Mediastinal mass Electromag netic navigation lmages from a recent CT are "linked" with the Pulmonary mass or nodule bronchoscope; an electromagnetic guidance system atthe bronchoscope creates a map ofthe airways and ides the n to the area of interest TAgL[ 4. BronchoscopicTherapeutic Procedures Technique Description Examples of lndications Flexible bronchoscopy Large airway suctioning Lobar atelectasis from mucus plugs Basket and forceps extractions Foreign body Balloon tamponade of airway Bleeding Bronchial thermoplasty Radiofrequency energy ablation of proximal airway Severe asthma smooth muscle Endobronchial stent placement Bronchoscopic placement of silicon and metal Malignant obstruction prostheses to expand and support the airways Benign strictures Tracheomalacia or bronchomalacia Anastomotic dehiscence Airway ablative therapies Laser therapy Malignant airway obstruction Electrocautery Benign airway obstruction Argon plasma coagulation Airway tumor Cryotherapy Brachytherapy Endobronchial valve placement Airway placement of one-way valves Bronchopleu ral f istu la Emphysema Balloon dilation Targeted endobronchial balloon inflation Benign or malignant airway stricture

TAgL[ 4. BronchoscopicTherapeutic Procedures Technique Description Examples of lndications Flexible bronchoscopy Large airway suctioning Lobar atelectasis from mucus plugs Basket and forceps extractions Foreign body Balloon tamponade of airway Bleeding Bronchial thermoplasty Radiofrequency energy ablation of proximal airway Severe asthma smooth muscle Endobronchial stent placement Bronchoscopic placement of silicon and metal Malignant obstruction prostheses to expand and support the airways Benign strictures Tracheomalacia or bronchomalacia Anastomotic dehiscence Airway ablative therapies Laser therapy Malignant airway obstruction Electrocautery Benign airway obstruction Argon plasma coagulation Airway tumor Cryotherapy Brachytherapy Endobronchial valve placement Airway placement of one-way valves Bronchopleu ral f istu la Emphysema Balloon dilation Targeted endobronchial balloon inflation Benign or malignant airway stricture 6

Airways Disease (COPD, heart failure) and tl.re normal effects of aging on Symptoms and Clinical Evaluation pul n.ronary physiology. Common symptoms of asthma are cough, wheezing, chest XEY POIl{I tightness, and shortness of breath. They occur intermittently . Approximately 7 .9"/,, of the U.S. population has been and in response to various stimuli, including allergens, infec diagnosed with asthma, and prevalence is increased tions, dusts, fumes, and exercise. Symptoms often have a among patients older than 65 years, women, Black per diurnal variation, worsening in the evening and early morn sons. and persons living below the poverty level. ing. Viral respiratory inf'ections are a particularly robust trigqer fbr most patients. Variability ot symptr,rms (both improvement Pathogenesis and worsening of symptoms over time) is a key diagnostic 'l-he pathophysiologic mechanisms of asthma include f'eature of asthma.

(COPD, heart failure) and tl.re normal effects of aging on Symptoms and Clinical Evaluation pul n.ronary physiology. Common symptoms of asthma are cough, wheezing, chest XEY POIl{I tightness, and shortness of breath. They occur intermittently . Approximately 7 .9"/,, of the U.S. population has been and in response to various stimuli, including allergens, infec diagnosed with asthma, and prevalence is increased tions, dusts, fumes, and exercise. Symptoms often have a among patients older than 65 years, women, Black per diurnal variation, worsening in the evening and early morn sons. and persons living below the poverty level. ing. Viral respiratory inf'ections are a particularly robust trigqer fbr most patients. Variability ot symptr,rms (both improvement Pathogenesis and worsening of symptoms over time) is a key diagnostic 'l-he pathophysiologic mechanisms of asthma include f'eature of asthma. chronic airway inflanlnration, airway narro'n^,'ing due to History taking should establish whether the patient has edema, subepithelial fibrosis, smooth muscle hypertrophy, ever smoked tobacco or other products, has pets, or has hacl and mucus hypersecretion, in addition to airway smooth environmental exposures to dust, I'umes, or particulate matter muscle constriction causing bronchial hyperreactivity in known to cause bronchial hyperreactivity. A personal or fanr response to various stimuli. 'fhe airway cellular inflanrma ily history of atopy or allergic sinus disease may be present. In trlry profile is variable, persists even during the absence of particular, the presence of nasal polyps, sensitivity to aspirin, symptoms, and includes eosinophils, T lymphocytes, mast and wheezing is known as the "asthmatic triad." The physical cells, and neutrophils. Type 2 inflammation r,r,ith eosincr examination may demonstrate wheezing, reduced airflow or philia is commonly recognized in allergic asthma, but other a prolonged expiratory phase. However, patients may also have

chronic airway inflanlnration, airway narro'n^,'ing due to History taking should establish whether the patient has edema, subepithelial fibrosis, smooth muscle hypertrophy, ever smoked tobacco or other products, has pets, or has hacl and mucus hypersecretion, in addition to airway smooth environmental exposures to dust, I'umes, or particulate matter muscle constriction causing bronchial hyperreactivity in known to cause bronchial hyperreactivity. A personal or fanr response to various stimuli. 'fhe airway cellular inflanrma ily history of atopy or allergic sinus disease may be present. In trlry profile is variable, persists even during the absence of particular, the presence of nasal polyps, sensitivity to aspirin, symptoms, and includes eosinophils, T lymphocytes, mast and wheezing is known as the "asthmatic triad." The physical cells, and neutrophils. Type 2 inflammation r,r,ith eosincr examination may demonstrate wheezing, reduced airflow or philia is commonly recognized in allergic asthma, but other a prolonged expiratory phase. However, patients may also have cellular profiles exist, with neutrophilic inflammation a completely normal respiratory exam, particularly when they

chronic airway inflanlnration, airway narro'n^,'ing due to History taking should establish whether the patient has edema, subepithelial fibrosis, smooth muscle hypertrophy, ever smoked tobacco or other products, has pets, or has hacl and mucus hypersecretion, in addition to airway smooth environmental exposures to dust, I'umes, or particulate matter muscle constriction causing bronchial hyperreactivity in known to cause bronchial hyperreactivity. A personal or fanr response to various stimuli. 'fhe airway cellular inflanrma ily history of atopy or allergic sinus disease may be present. In trlry profile is variable, persists even during the absence of particular, the presence of nasal polyps, sensitivity to aspirin, symptoms, and includes eosinophils, T lymphocytes, mast and wheezing is known as the "asthmatic triad." The physical cells, and neutrophils. Type 2 inflammation r,r,ith eosincr examination may demonstrate wheezing, reduced airflow or philia is commonly recognized in allergic asthma, but other a prolonged expiratory phase. However, patients may also have cellular profiles exist, with neutrophilic inflammation a completely normal respiratory exam, particularly when they increasingly recognized in older patients. Bronchial hyper are symptom fiee. reactivity causing airway obstruction is typically episodic Confirmation of reversible airllow obstruction is a corner and triggered by stimuli that would not induce symptoms in stone of asthma diagnosis and can be assessed by spirometry healthy people. Common triggers include allergens, dusts, with measurement of FEV,, FVC, and the FEV'/FVC ratio- or by fumes, exercise, extremes of temperature, and viral respira serial measurement o{'peak expiratory flow rates. Airway torv infections. obstruction that improves with brcinchodilators, improves on subsequent measurements, or improves after 4 weeks of anti inflammatory treatment supports a diagnosis of asthma. Risk Factors For adults, a significant change in FEV' is an increase fiom Risk factors for asthma include both host and environ baseline of at least 12'X, and at least 200 mL. For some patients, mental factors. Genes predisposing to atopy, bronchial airflow obstruction is not present during the initial evalua hyperreactivity, and airway inf'lammation have been iden tion, and demonstration of bronchial hyperreactivity with ti(ied, but genetic predisposition is thought to interact bronchial challenge testing is indicated. This is usually per with additional factors, including exposure to indoor aller fbrmed with inhaled methacholine, although other stinruli gens (mites, furred animals, cockroaches, molds), outdoor (exercise, mannitol) have been validated. lf a bronchial chal allergens (pollens, molds), tobacco smoke, occupational lenge test is negative, it is untikely that a patient has asthma. sensitizers and allergens, viral respir;rtory infections, and A positive challenge test confirnts bronchial hyperreactivity air pollution. ln addition, obesity is an important risk fact<,rr but is not sufficient to confirm asthma because other disor fbr asthma. ders may also demonstrate this finding. Therefbre, clinical Asthma is heterogeneous. but distinct phenotypes are correlation of this finding with symptoms and other testing recognized and have implicatit-rns for underlying mechanisms, is needed. Fractional exhaled nitric oxide testing is condi treatment, and outcomes. Although specific phenotypes are tionally recommended as an adjunct in asthma evaluation tbr not yet broadly accepted, many are commonly described. These those aged 5 years and older. Specific recommendations fbr subsets tend to have diff'erent cellular compositions of airway use of nitric oxide testing are when the diagnosis of asthma inflammation and may respond variably to anti inflammatory is uncertain after standard evaluation or when spirometry therapies. cannot be performed (conditional recommendation)' as I(EY POII'T well as in persistent allergic asthma and uncertainty in choosing, monitoring, or adjusting medications (conditional o Genetic predisposition to asthma is thought to interact recommendation). with additional factors, including exposure to indoor A chest radiograph is helptul in many patients to rule out allergens (mites, furred animals, cockroaches, molds), other diagnoses. such as COPD, heart failure, parenchymal outdoor allergens (pollens, molds), tobacco smoke, lung disorders, central airway obstruction, and bronchiectasis. occupational sensitizers and allergens, viral respiratory This is especially important in older adults, in whom asthma infections, and air pollution. is often underrecognized and undertreated.

increasingly recognized in older patients. Bronchial hyper are symptom fiee. reactivity causing airway obstruction is typically episodic Confirmation of reversible airllow obstruction is a corner and triggered by stimuli that would not induce symptoms in stone of asthma diagnosis and can be assessed by spirometry healthy people. Common triggers include allergens, dusts, with measurement of FEV,, FVC, and the FEV'/FVC ratio- or by fumes, exercise, extremes of temperature, and viral respira serial measurement o{'peak expiratory flow rates. Airway torv infections. obstruction that improves with brcinchodilators, improves on subsequent measurements, or improves after 4 weeks of anti inflammatory treatment supports a diagnosis of asthma. Risk Factors For adults, a significant change in FEV' is an increase fiom Risk factors for asthma include both host and environ baseline of at least 12'X, and at least 200 mL. For some patients, mental factors. Genes predisposing to atopy, bronchial airflow obstruction is not present during the initial evalua hyperreactivity, and airway inf'lammation have been iden tion, and demonstration of bronchial hyperreactivity with ti(ied, but genetic predisposition is thought to interact bronchial challenge testing is indicated. This is usually per with additional factors, including exposure to indoor aller fbrmed with inhaled methacholine, although other stinruli gens (mites, furred animals, cockroaches, molds), outdoor (exercise, mannitol) have been validated. lf a bronchial chal allergens (pollens, molds), tobacco smoke, occupational lenge test is negative, it is untikely that a patient has asthma. sensitizers and allergens, viral respir;rtory infections, and A positive challenge test confirnts bronchial hyperreactivity air pollution. ln addition, obesity is an important risk fact<,rr but is not sufficient to confirm asthma because other disor fbr asthma. ders may also demonstrate this finding. Therefbre, clinical Asthma is heterogeneous. but distinct phenotypes are correlation of this finding with symptoms and other testing recognized and have implicatit-rns for underlying mechanisms, is needed. Fractional exhaled nitric oxide testing is condi treatment, and outcomes. Although specific phenotypes are tionally recommended as an adjunct in asthma evaluation tbr not yet broadly accepted, many are commonly described. These those aged 5 years and older. Specific recommendations fbr subsets tend to have diff'erent cellular compositions of airway use of nitric oxide testing are when the diagnosis of asthma inflammation and may respond variably to anti inflammatory is uncertain after standard evaluation or when spirometry therapies. cannot be performed (conditional recommendation)' as I(EY POII'T well as in persistent allergic asthma and uncertainty in choosing, monitoring, or adjusting medications (conditional o Genetic predisposition to asthma is thought to interact recommendation). with additional factors, including exposure to indoor A chest radiograph is helptul in many patients to rule out allergens (mites, furred animals, cockroaches, molds), other diagnoses. such as COPD, heart failure, parenchymal outdoor allergens (pollens, molds), tobacco smoke, lung disorders, central airway obstruction, and bronchiectasis. occupational sensitizers and allergens, viral respiratory This is especially important in older adults, in whom asthma infections, and air pollution. is often underrecognized and undertreated. 7

Airways Disease TEY POIXTS exercise. EIB is one of the most common triggers of symptoms . Common symptoms of asthma are cough, wheezing, in patients with known asthma, and it also occurs in patients without asthma, typically elite athletes, during periods of chest tightness, and shortness ofbreath; they are inter- high intensity exercise. Environmental factors play a key role mittent and occur in response to various stimuli, includ in precipitating symptoms. Exercise in cold. dry air, such as ing allergens, infections, dusts, fumes, and exercise. during winter or in indoor ice rinks; exposure to high levels of o Confirmation of reversible airflow obstruction with trichloramines in swimming pools; and inhalation of airborne bronchodilators is a cornerstone of asthma diagnosis particulates and ozone have all been implicated. and can be made by spirometry with measurement of Other disorders. such vocal cord dysfunction and cardiac FEV, or FVC showing an increase from baseline of >12% disorders, can mimic EIB; therefore. establishing the presence and >200 mL. of bronchial hyperreactivity is crucial to making an accurate . ln patients with clinical symptoms suggestive of asthma diagnosis. For most patients this entails bronchial challenge but with normal spirometry bronchial challenge testing testing with inhaled agents or, ideally, exercise. For safety. (such as with methacholine) may be helpful to evaluate guidelines from the Global Initiative lor Asthma no longer for asthma; a negative test excludes asthma, whereas a recommend treatment of asthma, including EIB. with a short positive test requires clinical correlation. acting p, agonist (SABA) alone. Recommended therapy is either an inhaled glucocorticoid plus SABA needed or "t'hen before exercise or low dose inhaled glucocorticoid-formoterol Asthma Syndromes as needed or before exercise. Nonpharmacologic measures Allergic Asthma include preexercise warm up and warming cold air before ldentiffing the presence of atopy can determine an allergic inhalation (for example, with a mask or scarf). asthma phenotype in a patient with respiratory symptoms. The key constituents of the atopic response (activated eosino I(EY POIilI phils and IgE) are generated by pathways involving cy,tokines o Initial pharmacologic therapy for exercise-induced bron- secreted mainly by Th2 cells, and this class of asthmatic airway choconstriction should consist of administration of an inflammation is referred to as type 2. It is estimated that at inhaled glucocorticoid plus a short-acting pr-agonist or least half of all patients with asthma have type 2 airway inflam low dose inhaled glucocorticoid formoterol when needed mation. Biomarker evaluation in these patients olten demon- or before exercise. strates serum or sputum eosinophilia or high IgE levels with elevated FeNO. Other common tests to identiff atopy include Occupational Asthma allergr skin prick tests, which may be administered in the A careful occupational history is an essential part of asthma outpatient setting by qualified personnel, and laboratory evaluation. as it is estimated that 15',?, of adult asthma is u'ork measurement of allergen specific IgE in serum. Results of each related. Occupational asthma include; both asthma that is directly method are generally concordant. Skin testing is more sensi caused by exposure to sensitizing or irritant substances in the tive but subject to errors related to administration, whereas workplace and preexisting asthma that is exacerbated by these serum tests are more specific but have higher costs. A normal same factors. Typical sensitizing agents are high molecular level oftotal serum IgE does not preclude clinical allergies. In weight substances, such as proteins, that induce an IgE mediated patients with severe disease, elevated levels of IgE and eosino- immunologic response. Examples include animal and plant phils are therapeutic targets for biologic therapies. allergens, latex, grains. and diisocyanates. Once sensitized, patients may subsequently react to lery lou, ler'els of exposure. Cough-Variant Asthma Those at risk include farmers and animal workers. health care Patients with asthma whose primary symptom manifestation workers, latex glove users. bakers. and manufacturers of polyu is chronic cough without other symptoms are considered to rethane products. A key clinical indicator is the relationship ol have cough variant asthma. Diagnosis requires documenta- symptoms to work exposures; patients often improve during tion of bronchial hyperreactivity, as most patients will have weekends and time away from work. Spirometry before and normal baseline spirometry. Recommended therapies are the after workplace exposure is a cost effective way to confirm same as those for other types of asthma. Other causes of a suspected diagrrosis of occupational asthma. Alternatively, chronic cough, including gastroesophageal reflux and upper demonstration of bronchial hyperreactivity through bronchial airway cough syndrome due to rhinitis, should be investigated. challenge testing or serial peak flow measurements can be used. Frequently, these etiologies coexist and require concomitant Treatment consists of reducing exposure to the offending agent therapy (see MKSAP 19 General Internal Medicine 1). through r,r,orkplace modifications or removing patients from the workplace entirely, in addition to pharmacologic therapy. The Exercise-Induced Bronchoconstriction overriding principle of treatment should be prevention. rt'hich Exercise induced bronchoconstriction (EIB) refers to acute, includes workplace interventions to avoid exposures and moni measurable airway obstruction that occurs in response to toring fbr early identification ofdisease.

. Common symptoms of asthma are cough, wheezing, in patients with known asthma, and it also occurs in patients without asthma, typically elite athletes, during periods of chest tightness, and shortness ofbreath; they are inter- high intensity exercise. Environmental factors play a key role mittent and occur in response to various stimuli, includ in precipitating symptoms. Exercise in cold. dry air, such as ing allergens, infections, dusts, fumes, and exercise. during winter or in indoor ice rinks; exposure to high levels of o Confirmation of reversible airflow obstruction with trichloramines in swimming pools; and inhalation of airborne bronchodilators is a cornerstone of asthma diagnosis particulates and ozone have all been implicated. and can be made by spirometry with measurement of Other disorders. such vocal cord dysfunction and cardiac FEV, or FVC showing an increase from baseline of >12% disorders, can mimic EIB; therefore. establishing the presence and >200 mL. of bronchial hyperreactivity is crucial to making an accurate . ln patients with clinical symptoms suggestive of asthma diagnosis. For most patients this entails bronchial challenge but with normal spirometry bronchial challenge testing testing with inhaled agents or, ideally, exercise. For safety. (such as with methacholine) may be helpful to evaluate guidelines from the Global Initiative lor Asthma no longer for asthma; a negative test excludes asthma, whereas a recommend treatment of asthma, including EIB. with a short positive test requires clinical correlation. acting p, agonist (SABA) alone. Recommended therapy is either an inhaled glucocorticoid plus SABA needed or "t'hen before exercise or low dose inhaled glucocorticoid-formoterol Asthma Syndromes as needed or before exercise. Nonpharmacologic measures Allergic Asthma include preexercise warm up and warming cold air before ldentiffing the presence of atopy can determine an allergic inhalation (for example, with a mask or scarf). asthma phenotype in a patient with respiratory symptoms. The key constituents of the atopic response (activated eosino I(EY POIilI phils and IgE) are generated by pathways involving cy,tokines o Initial pharmacologic therapy for exercise-induced bron- secreted mainly by Th2 cells, and this class of asthmatic airway choconstriction should consist of administration of an inflammation is referred to as type 2. It is estimated that at inhaled glucocorticoid plus a short-acting pr-agonist or least half of all patients with asthma have type 2 airway inflam low dose inhaled glucocorticoid formoterol when needed mation. Biomarker evaluation in these patients olten demon- or before exercise. strates serum or sputum eosinophilia or high IgE levels with elevated FeNO. Other common tests to identiff atopy include Occupational Asthma allergr skin prick tests, which may be administered in the A careful occupational history is an essential part of asthma outpatient setting by qualified personnel, and laboratory evaluation. as it is estimated that 15',?, of adult asthma is u'ork measurement of allergen specific IgE in serum. Results of each related. Occupational asthma include; both asthma that is directly method are generally concordant. Skin testing is more sensi caused by exposure to sensitizing or irritant substances in the tive but subject to errors related to administration, whereas workplace and preexisting asthma that is exacerbated by these serum tests are more specific but have higher costs. A normal same factors. Typical sensitizing agents are high molecular level oftotal serum IgE does not preclude clinical allergies. In weight substances, such as proteins, that induce an IgE mediated patients with severe disease, elevated levels of IgE and eosino- immunologic response. Examples include animal and plant phils are therapeutic targets for biologic therapies. allergens, latex, grains. and diisocyanates. Once sensitized, patients may subsequently react to lery lou, ler'els of exposure. Cough-Variant Asthma Those at risk include farmers and animal workers. health care Patients with asthma whose primary symptom manifestation workers, latex glove users. bakers. and manufacturers of polyu is chronic cough without other symptoms are considered to rethane products. A key clinical indicator is the relationship ol have cough variant asthma. Diagnosis requires documenta- symptoms to work exposures; patients often improve during tion of bronchial hyperreactivity, as most patients will have weekends and time away from work. Spirometry before and normal baseline spirometry. Recommended therapies are the after workplace exposure is a cost effective way to confirm same as those for other types of asthma. Other causes of a suspected diagrrosis of occupational asthma. Alternatively, chronic cough, including gastroesophageal reflux and upper demonstration of bronchial hyperreactivity through bronchial airway cough syndrome due to rhinitis, should be investigated. challenge testing or serial peak flow measurements can be used. Frequently, these etiologies coexist and require concomitant Treatment consists of reducing exposure to the offending agent therapy (see MKSAP 19 General Internal Medicine 1). through r,r,orkplace modifications or removing patients from the workplace entirely, in addition to pharmacologic therapy. The Exercise-Induced Bronchoconstriction overriding principle of treatment should be prevention. rt'hich Exercise induced bronchoconstriction (EIB) refers to acute, includes workplace interventions to avoid exposures and moni measurable airway obstruction that occurs in response to toring fbr early identification ofdisease. 8

Airways Disease rEY POIilT minimize risks of developing persistent airway obstruction. l{VC . A key clinical indicator of occupational asthma is symp- This should be accomplished by assessing asthma severity, tom improvement during weekends and time away controlling symptoms on an ongoing basis, and then modifying from work; spirometry before and after workplace therapies appropriately, using a stepwise approach (Figure 3). exposures is a cost-effective way to confirm a suspected There are three essential components to the management of asthma: diagnosis. 1. Assessment of symptom control and risk. Standardized,

rEY POIilT minimize risks of developing persistent airway obstruction. l{VC . A key clinical indicator of occupational asthma is symp- This should be accomplished by assessing asthma severity, tom improvement during weekends and time away controlling symptoms on an ongoing basis, and then modifying from work; spirometry before and after workplace therapies appropriately, using a stepwise approach (Figure 3). exposures is a cost-effective way to confirm a suspected There are three essential components to the management of asthma: diagnosis. 1. Assessment of symptom control and risk. Standardized, Reactive Airways Dysfunction Syndrome validated questionnaires that can discriminate between Reactive airways dysfunction syndrome is a well described well controlled and inadequately controlled asthma on subset of irritant induced occupational asthma. This syn, the basis of patient symptoms include the Asthma Con drome occurs in patients without preexisting asthma after a trol Test and the Asthma Control Questionnaire. Patients single, high level exposure to fumes, gases, or vapors; usually with daytime symptoms less than twice weekly and the exposure is severe enough to prompt immediate medical nocturnal symptoms less than twice monthly during the preceding 4 weeks are considered well controlled. Risk evaluation. The diagnosis requires evidence ofl asthmatic is based on measured lung tunction and the potential fbr symptoms for at least 3 months after the exposure and is con firmed by airway obstruction or bronchial hyperreactivity. future exacerbations, which is related to the presence of comorbidities (Table 5) and historical features known Aspirin-Exacerbated Respiratory Disease to predict future exacerbations. Comorbidities such as gastroesophageal reflux disease, sinus disease, obstruc- Aspirin exacerbated respiratory disease describes asthma and rhinosinusitis that are precipitated by exposure to aspirin or tive sleep apnea, vocal cord dysfunction, and obesity other NSAIDs that inhibit cyclooxygenase-I. Clinical charac- are common and should be considered and actively managed to reduce symptoms and potentially improve teristics include an onset in adulthood, airway and peripheral asthma control. eosinophilia, inflammatory sinusitis with polyposis, and per sistent, often severe asthma. Ingestion oftriggering substances 2. Treatment. Once symptoms and risk are established, can cause life threatening bronchospasm within minutes to therapy should be initiated. All patients with asthma hours, sometimes accompanied by rhinorrhea, conjunctival should be provided with rescue medication to use as injection, and flushing. Chronic management, in addition to needed for symptoms. Controller medications are used the usual stepped asthma care, includes discontinuing all aspi as maintenance therapy to control symptoms and pre rin and NSAIDs and use of leukotriene receptor antagonists vent exacerbations. A critical component ofthis therapy that target the increased leukotriene production implicated is teaching and assessing proper inhaler technique: pa in the mechanism of this particular asthma. Aspirin desensiti tients require skill and training to effectively use these zation can improve control in a significant percentage of devices. Use of a spacer can be helpful with compatible patients but requires specialized expertise. inhaler devices. 3. Review response and adjust therapy. Patients should be Allergic Bronchopulmonary Aspergillosis reassessed several months alter initiation of asthma ther Allergic bronchopulmonary aspergillosis is an ongoing immu- apies for their level of control and tolerance of medica nologic response to inhaled Aspergillus species that leads to tions. Controller medications can be stepped up or down persistent eosinophilic airway inflammation, increased IgE with the goal of'maintaining symptom control and mini levels (both total and Aspergillus specific), and eventually tis mizing medication exposure. sue damage with airway remodeling. Patients present with XEY POIilTS difflcult to control asthma, productive cough, and expectora tion ol mucus plugs. Radiographs may demonstrate pulmo- . Aspirin exacerbated respiratory disease describes nary infiltrates and bronchiectasis. The diagnostic criteria are asthma and rhinosinusitis that are precipitated by debated but include the presence of asthma, elevated IgE lev- exposure to aspirin or other NSAIDs that inhibit els, positive skin tests to Aspergillus antigens, increased cyclooxygenase-1. Aspergillus specific IgE and IgG levels, and either central r Control of asthma should be assessed with the use of bronchiectasis or infiltrates. Management is aimed at sup validated questionnaires. pressing the enhanced immunologic response with systemic o Inhaler skills training and adherence are essential for glucocorticoids and reducing the fungal antigenic burden with successful treatment. antifungal agents. Quick-Relief Medication Management of Chronic Asthma All patients with asthma should be provided with quick The goals of longitudinal asthma management are to con relief, or rescue, therapy. SABAs are the preferred medications trol chronic asthma symptoms, prevent exacerbations, and to quickly reverse bronchospasm and relieve acute asthma

Reactive Airways Dysfunction Syndrome validated questionnaires that can discriminate between Reactive airways dysfunction syndrome is a well described well controlled and inadequately controlled asthma on subset of irritant induced occupational asthma. This syn, the basis of patient symptoms include the Asthma Con drome occurs in patients without preexisting asthma after a trol Test and the Asthma Control Questionnaire. Patients single, high level exposure to fumes, gases, or vapors; usually with daytime symptoms less than twice weekly and the exposure is severe enough to prompt immediate medical nocturnal symptoms less than twice monthly during the preceding 4 weeks are considered well controlled. Risk evaluation. The diagnosis requires evidence ofl asthmatic is based on measured lung tunction and the potential fbr symptoms for at least 3 months after the exposure and is con firmed by airway obstruction or bronchial hyperreactivity. future exacerbations, which is related to the presence of comorbidities (Table 5) and historical features known Aspirin-Exacerbated Respiratory Disease to predict future exacerbations. Comorbidities such as gastroesophageal reflux disease, sinus disease, obstruc- Aspirin exacerbated respiratory disease describes asthma and rhinosinusitis that are precipitated by exposure to aspirin or tive sleep apnea, vocal cord dysfunction, and obesity other NSAIDs that inhibit cyclooxygenase-I. Clinical charac- are common and should be considered and actively managed to reduce symptoms and potentially improve teristics include an onset in adulthood, airway and peripheral asthma control. eosinophilia, inflammatory sinusitis with polyposis, and per sistent, often severe asthma. Ingestion oftriggering substances 2. Treatment. Once symptoms and risk are established, can cause life threatening bronchospasm within minutes to therapy should be initiated. All patients with asthma hours, sometimes accompanied by rhinorrhea, conjunctival should be provided with rescue medication to use as injection, and flushing. Chronic management, in addition to needed for symptoms. Controller medications are used the usual stepped asthma care, includes discontinuing all aspi as maintenance therapy to control symptoms and pre rin and NSAIDs and use of leukotriene receptor antagonists vent exacerbations. A critical component ofthis therapy that target the increased leukotriene production implicated is teaching and assessing proper inhaler technique: pa in the mechanism of this particular asthma. Aspirin desensiti tients require skill and training to effectively use these zation can improve control in a significant percentage of devices. Use of a spacer can be helpful with compatible patients but requires specialized expertise. inhaler devices. 3. Review response and adjust therapy. Patients should be Allergic Bronchopulmonary Aspergillosis reassessed several months alter initiation of asthma ther Allergic bronchopulmonary aspergillosis is an ongoing immu- apies for their level of control and tolerance of medica nologic response to inhaled Aspergillus species that leads to tions. Controller medications can be stepped up or down persistent eosinophilic airway inflammation, increased IgE with the goal of'maintaining symptom control and mini levels (both total and Aspergillus specific), and eventually tis mizing medication exposure. sue damage with airway remodeling. Patients present with XEY POIilTS difflcult to control asthma, productive cough, and expectora tion ol mucus plugs. Radiographs may demonstrate pulmo- . Aspirin exacerbated respiratory disease describes nary infiltrates and bronchiectasis. The diagnostic criteria are asthma and rhinosinusitis that are precipitated by debated but include the presence of asthma, elevated IgE lev- exposure to aspirin or other NSAIDs that inhibit els, positive skin tests to Aspergillus antigens, increased cyclooxygenase-1. Aspergillus specific IgE and IgG levels, and either central r Control of asthma should be assessed with the use of bronchiectasis or infiltrates. Management is aimed at sup validated questionnaires. pressing the enhanced immunologic response with systemic o Inhaler skills training and adherence are essential for glucocorticoids and reducing the fungal antigenic burden with successful treatment. antifungal agents. Quick-Relief Medication Management of Chronic Asthma All patients with asthma should be provided with quick The goals of longitudinal asthma management are to con relief, or rescue, therapy. SABAs are the preferred medications trol chronic asthma symptoms, prevent exacerbations, and to quickly reverse bronchospasm and relieve acute asthma I

Airways Disease lnllrrdibilt drm. Step 5 Step 6 Step 3 Step 4 Treatment Step 1 Step 2 SABA Daily Daily and Daily and Daily medium- Daily high-dose as needed' low-dose ICS as-needed as-needed to high-dose lC$l-ABA+ OR and SABA combination combination ICS.LABA + LAMA oral ICS and SABAb as needed low-dose medium-dose and SABA glucocorticoid + as needed OR lC5-formoterol ICS-formoterol as needed SABA as needed Concomitant ICS and SABA Consider as needed add-on anti-lgE, anti-lL-5, anti-lL-5R, anti-lL4/lL-13

SABA Daily Daily and Daily and Daily medium- Daily high-dose as needed' low-dose ICS as-needed as-needed to high-dose lC$l-ABA+ OR and SABA combination combination ICS.LABA + LAMA oral ICS and SABAb as needed low-dose medium-dose and SABA glucocorticoid + as needed OR lC5-formoterol ICS-formoterol as needed SABA as needed Concomitant ICS and SABA Consider as needed add-on anti-lgE, anti-lL-5, anti-lL-5R, anti-lL4/lL-13 Daily LTRA DailY Daily Daily + SABA as medium-dose medium-dose medium- to needed ICS + SABA ICS.LABA high-dose as needed or rcs-|-ABA OR rcs-l-AMA, and SABA Altomet{vc Daily low-dose and SABA as needed ICS.LABA as needed or ICS-LAMA, Consider and SABA add-on anti-lgE, as needed anti-lL-5, anti-lL-5R, anti-lL-4/lL-1 3

Daily LTRA DailY Daily Daily + SABA as medium-dose medium-dose medium- to needed ICS + SABA ICS.LABA high-dose as needed or rcs-|-ABA OR rcs-l-AMA, and SABA Altomet{vc Daily low-dose and SABA as needed ICS.LABA as needed or ICS-LAMA, Consider and SABA add-on anti-lgE, as needed anti-lL-5, anti-lL-5R, anti-lL-4/lL-1 3 Step up if needed (first check adherence, inhaler technique, environmental factors, and comorbidities) Step down if possible (and asthma is well controlled x 3 months) . At each step, include patient education, environmental control, and management of comorbidities. . For steps 2-4: Consider subcutaneous allergen immunotherapy for patients whose asthma is controlled at initiation, buildup, and maintenance phases. . lf step 4 care or higher is needed, consult with an asthma specialist.

Step up if needed (first check adherence, inhaler technique, environmental factors, and comorbidities) Step down if possible (and asthma is well controlled x 3 months) . At each step, include patient education, environmental control, and management of comorbidities. . For steps 2-4: Consider subcutaneous allergen immunotherapy for patients whose asthma is controlled at initiation, buildup, and maintenance phases. . lf step 4 care or higher is needed, consult with an asthma specialist. Ouick relief for all patients: . SABA as needed for symptoms: up to 3 treatments at 2O-minute intervals as needed . ln steps 3 and 4, ICS-formoterol 1-2 puffu as needed up to a maximum total daily dosage of 12 pufG (5a yg) . Use of SABA >2 days a week (not prevention of EIB) indicates inadequate control and the need to step up therapy tIGURE 3.Stepwiseapproachtoasthmatherapy.2020guidelinesfromtheNationalfuthmaEducationandPreventionProgram(NAEPP) recommendthatall adultsand adolescents with mild persistent asthma use a daily inhaled glucocorticoid with an as-needed SABA or use both on an as-needed basis. Those with moderate persistent asthma should use a single inhaler with glucocorticoids and formoterol daily plus additional doses ol the combination regimen as needed (known as single maintenance and I-AMA = long-acting muscarinic antagonist; I-TRA = leukotriene receptor antagonist; SABA = short-acting plagonist. 'National Anhma tducation and Prevention Pr0gram (NAtPP) re(ommendation. bGlobal lnitiative for 16lhma recommendation 10

Airways Disease TABLE 5. Common Asthma Comorbidities Comorbidity Symptoms Diagnosis and Treatment Gastroesophagea I Frequently coexists in patients with asthma Empirictrial of a proton pump inhibitorfor2 months reflux disease (GERDr,b May be an independent cause of respiratory Consider further testing such as endoscopy and symptoms such as cough and chest pain 24-hour esophageal pH monitoring if symptoms do not improve Sinus disease Allergic rhinitis: rhinorrhea, nasal obstruction, itching, lntranasal gl ucocorticoids and sneezing; symptoms can be seasonal, For severe cases, consider adding: intermittent, or perennial(usually caused by persistent exposure to indoor allergens such as dust lntranasal H1 -antihistamines mites) Oral antileukotrienes Chronic rhinosinusitis: additional symptoms of facial pain, sinus pressure, and sometimes anosmia Oral glucocorticoids lmmunotherapy Biologic targeting lgE or eosinophils Obstructive sleep Snoring, excessive daytime sleepiness, and Confirm with polysomnography or home sleep apneab witnessed apneas testing More common in patients with asthma than those Positive airway pressure: improves asthma without asthma symptoms, quality of life, bronchodilator use, and peak flow rates Worsens asth ma contro l, increases asthma-related health care use, and reduces quality of life Vocal cord dysfunction lnspiratory breathlessness, with throat tightness or Laryngoscopy demonstrating paradoxical vocal cord (VCD) voice dysfunction during attacks adduction during a symptomatic episode Caused by paradoxical adduction ofthe vocal cords Patients often asymptomatic when evaluated or unable during inspiration, causing functional upper airway to tolerate laryngoscopy during an acute episode obstruction Trial of treatment with speech therapy Often triggered by exercise, exposure to fumes or Also address {actors known to worsen VCD (GERD, irritants, and stress postnasal drip) May mimic or coexist with asthma Obesity' Symptoms BMI measurement and objective documentation of reversible airway obstruction in all patients Dyspnea, wheezing undergoing asthma evaluation Higher prevalence of asthma with poorer symptom Weight loss: improves asthma control and lung control compared with patients with asthma and function normal BMI; and not as responsive to standard controller therapies Bariatric surgery: greater amounts of weight loss correlate with better outcomes May confound asthma diagnosis because of overlapping symptoms of breathlessness and exertional wheezing

TABLE 5. Common Asthma Comorbidities Comorbidity Symptoms Diagnosis and Treatment Gastroesophagea I Frequently coexists in patients with asthma Empirictrial of a proton pump inhibitorfor2 months reflux disease (GERDr,b May be an independent cause of respiratory Consider further testing such as endoscopy and symptoms such as cough and chest pain 24-hour esophageal pH monitoring if symptoms do not improve Sinus disease Allergic rhinitis: rhinorrhea, nasal obstruction, itching, lntranasal gl ucocorticoids and sneezing; symptoms can be seasonal, For severe cases, consider adding: intermittent, or perennial(usually caused by persistent exposure to indoor allergens such as dust lntranasal H1 -antihistamines mites) Oral antileukotrienes Chronic rhinosinusitis: additional symptoms of facial pain, sinus pressure, and sometimes anosmia Oral glucocorticoids lmmunotherapy Biologic targeting lgE or eosinophils Obstructive sleep Snoring, excessive daytime sleepiness, and Confirm with polysomnography or home sleep apneab witnessed apneas testing More common in patients with asthma than those Positive airway pressure: improves asthma without asthma symptoms, quality of life, bronchodilator use, and peak flow rates Worsens asth ma contro l, increases asthma-related health care use, and reduces quality of life Vocal cord dysfunction lnspiratory breathlessness, with throat tightness or Laryngoscopy demonstrating paradoxical vocal cord (VCD) voice dysfunction during attacks adduction during a symptomatic episode Caused by paradoxical adduction ofthe vocal cords Patients often asymptomatic when evaluated or unable during inspiration, causing functional upper airway to tolerate laryngoscopy during an acute episode obstruction Trial of treatment with speech therapy Often triggered by exercise, exposure to fumes or Also address {actors known to worsen VCD (GERD, irritants, and stress postnasal drip) May mimic or coexist with asthma Obesity' Symptoms BMI measurement and objective documentation of reversible airway obstruction in all patients Dyspnea, wheezing undergoing asthma evaluation Higher prevalence of asthma with poorer symptom Weight loss: improves asthma control and lung control compared with patients with asthma and function normal BMI; and not as responsive to standard controller therapies Bariatric surgery: greater amounts of weight loss correlate with better outcomes May confound asthma diagnosis because of overlapping symptoms of breathlessness and exertional wheezing 'See MKSAP 1 9 Gastroenterology and Hepatology: Disorders of the Esophagus section LSee Sleep Medicine sect on.

TABLE 5. Common Asthma Comorbidities Comorbidity Symptoms Diagnosis and Treatment Gastroesophagea I Frequently coexists in patients with asthma Empirictrial of a proton pump inhibitorfor2 months reflux disease (GERDr,b May be an independent cause of respiratory Consider further testing such as endoscopy and symptoms such as cough and chest pain 24-hour esophageal pH monitoring if symptoms do not improve Sinus disease Allergic rhinitis: rhinorrhea, nasal obstruction, itching, lntranasal gl ucocorticoids and sneezing; symptoms can be seasonal, For severe cases, consider adding: intermittent, or perennial(usually caused by persistent exposure to indoor allergens such as dust lntranasal H1 -antihistamines mites) Oral antileukotrienes Chronic rhinosinusitis: additional symptoms of facial pain, sinus pressure, and sometimes anosmia Oral glucocorticoids lmmunotherapy Biologic targeting lgE or eosinophils Obstructive sleep Snoring, excessive daytime sleepiness, and Confirm with polysomnography or home sleep apneab witnessed apneas testing More common in patients with asthma than those Positive airway pressure: improves asthma without asthma symptoms, quality of life, bronchodilator use, and peak flow rates Worsens asth ma contro l, increases asthma-related health care use, and reduces quality of life Vocal cord dysfunction lnspiratory breathlessness, with throat tightness or Laryngoscopy demonstrating paradoxical vocal cord (VCD) voice dysfunction during attacks adduction during a symptomatic episode Caused by paradoxical adduction ofthe vocal cords Patients often asymptomatic when evaluated or unable during inspiration, causing functional upper airway to tolerate laryngoscopy during an acute episode obstruction Trial of treatment with speech therapy Often triggered by exercise, exposure to fumes or Also address {actors known to worsen VCD (GERD, irritants, and stress postnasal drip) May mimic or coexist with asthma Obesity' Symptoms BMI measurement and objective documentation of reversible airway obstruction in all patients Dyspnea, wheezing undergoing asthma evaluation Higher prevalence of asthma with poorer symptom Weight loss: improves asthma control and lung control compared with patients with asthma and function normal BMI; and not as responsive to standard controller therapies Bariatric surgery: greater amounts of weight loss correlate with better outcomes May confound asthma diagnosis because of overlapping symptoms of breathlessness and exertional wheezing 'See MKSAP 1 9 Gastroenterology and Hepatology: Disorders of the Esophagus section LSee Sleep Medicine sect on. 'See MKSAP 1 9 General lnternal Medicine 2: Obesity section.

TABLE 5. Common Asthma Comorbidities Comorbidity Symptoms Diagnosis and Treatment Gastroesophagea I Frequently coexists in patients with asthma Empirictrial of a proton pump inhibitorfor2 months reflux disease (GERDr,b May be an independent cause of respiratory Consider further testing such as endoscopy and symptoms such as cough and chest pain 24-hour esophageal pH monitoring if symptoms do not improve Sinus disease Allergic rhinitis: rhinorrhea, nasal obstruction, itching, lntranasal gl ucocorticoids and sneezing; symptoms can be seasonal, For severe cases, consider adding: intermittent, or perennial(usually caused by persistent exposure to indoor allergens such as dust lntranasal H1 -antihistamines mites) Oral antileukotrienes Chronic rhinosinusitis: additional symptoms of facial pain, sinus pressure, and sometimes anosmia Oral glucocorticoids lmmunotherapy Biologic targeting lgE or eosinophils Obstructive sleep Snoring, excessive daytime sleepiness, and Confirm with polysomnography or home sleep apneab witnessed apneas testing More common in patients with asthma than those Positive airway pressure: improves asthma without asthma symptoms, quality of life, bronchodilator use, and peak flow rates Worsens asth ma contro l, increases asthma-related health care use, and reduces quality of life Vocal cord dysfunction lnspiratory breathlessness, with throat tightness or Laryngoscopy demonstrating paradoxical vocal cord (VCD) voice dysfunction during attacks adduction during a symptomatic episode Caused by paradoxical adduction ofthe vocal cords Patients often asymptomatic when evaluated or unable during inspiration, causing functional upper airway to tolerate laryngoscopy during an acute episode obstruction Trial of treatment with speech therapy Often triggered by exercise, exposure to fumes or Also address {actors known to worsen VCD (GERD, irritants, and stress postnasal drip) May mimic or coexist with asthma Obesity' Symptoms BMI measurement and objective documentation of reversible airway obstruction in all patients Dyspnea, wheezing undergoing asthma evaluation Higher prevalence of asthma with poorer symptom Weight loss: improves asthma control and lung control compared with patients with asthma and function normal BMI; and not as responsive to standard controller therapies Bariatric surgery: greater amounts of weight loss correlate with better outcomes May confound asthma diagnosis because of overlapping symptoms of breathlessness and exertional wheezing 'See MKSAP 1 9 Gastroenterology and Hepatology: Disorders of the Esophagus section LSee Sleep Medicine sect on. 'See MKSAP 1 9 General lnternal Medicine 2: Obesity section. symptoms; however, new saf'ety information suggests that one of three inhaled glucocorticoid combination regimens to they should only be used in combination with inhaled gluco reduce the risk for serious exacerbations and to control corticoids (Table 6). SABAs have a rapid onset of action and symptoms: deliver medications directly through the airways, reducing 1. For mild asthma, an inhaled glucocorticoid formoterol systemic adverse etl'ects. Their main mechanism of action is combination as needed or a low dose inhaled glucocorti- induction of airway smooth muscle relaxation using stimula- coid whenever a SABA is taken (note that both combina tion of pr-agonist receptors. SABAs are generally not adminis tions are off label use) tered on a scheduled basis nor as the sole agent. Albuterol 2. A regular inhaled glucocorticoid or inhaled glucocorti- is the most commonly used SABA in the United States. While coid plus an inhaled long acting B, agonist (LABA) daily, the National Asthma Education and Prevention Program plus an as needed SABA continues to recommend as needed SABA for intermittent asthma, the Global Initiative fbr Asthma now recommends 3. Maintenance and rescue treatment with inhaled low dose that all adults and adolescents with asthma should receive budesonide plus formoterol

symptoms; however, new saf'ety information suggests that one of three inhaled glucocorticoid combination regimens to they should only be used in combination with inhaled gluco reduce the risk for serious exacerbations and to control corticoids (Table 6). SABAs have a rapid onset of action and symptoms: deliver medications directly through the airways, reducing 1. For mild asthma, an inhaled glucocorticoid formoterol systemic adverse etl'ects. Their main mechanism of action is combination as needed or a low dose inhaled glucocorti- induction of airway smooth muscle relaxation using stimula- coid whenever a SABA is taken (note that both combina tion of pr-agonist receptors. SABAs are generally not adminis tions are off label use) tered on a scheduled basis nor as the sole agent. Albuterol 2. A regular inhaled glucocorticoid or inhaled glucocorti- is the most commonly used SABA in the United States. While coid plus an inhaled long acting B, agonist (LABA) daily, the National Asthma Education and Prevention Program plus an as needed SABA continues to recommend as needed SABA for intermittent asthma, the Global Initiative fbr Asthma now recommends 3. Maintenance and rescue treatment with inhaled low dose that all adults and adolescents with asthma should receive budesonide plus formoterol 11

Airways Disease TABLE 6. Asthma Medications Drug Formulations Adverce Effects Short-Acing fo -Agonists Albuterol HFA-MDI, nebulizer solution Tachycardia and hypokalemia Levalbuterol HFA-MDI, nebulizer solution Should not be used as monotherapy Short-Acting Anticholinergics ( Muscarini< Antagonists) lpratropium bromide HFA-MDI, nebulizer solution Dry mouth, tachycardia, acute narrow-angle glaucoma (rare) Albuterol/ipratropium bromide HFA-MDl, nebulizer solution Same and combined effects of both drug classes long-Acting pr-Agonists Formoterol" DPI Tremor, tachycardia; black box warning for use of long- acting p2-agonist monotherapy in asthma Salmeterol DPI Arformoterol" Nebulizer solution Formoterolfumarate" Nebulizer solution Olodaterol" SMI lndacaterol maleateu DPI Long-Acting Muscarinic Antagonists (Anticholinergics) Tiotropium DPl, SMI Dry mouth, tachycardia, urinary retention, acute narrow-angle glaucoma (rare) Aclidinium bromide DPI Umeclidinium DPI Glycopyrrolate DPI

Arformoterol" Nebulizer solution Formoterolfumarate" Nebulizer solution Olodaterol" SMI lndacaterol maleateu DPI Long-Acting Muscarinic Antagonists (Anticholinergics) Tiotropium DPl, SMI Dry mouth, tachycardia, urinary retention, acute narrow-angle glaucoma (rare) Aclidinium bromide DPI Umeclidinium DPI Glycopyrrolate DPI lnhaled Glucocorticoids Beclomethasone HFA-MDI Dysphonia, xerostomia, oral candidiasis, bruising, pneumonia; low incidence of oral glucocorticoid adverse effects Budesonide DPl, nebulizer solution Fluticasone propionate HFA, DPI Fluticasone furoate DPI Mometasone DPI Ciclesonide HFA-MDI Flunisolide HFA-MDI lnhaled Glucocorticoids and Long-Acting p2-Agonists Budesonide and formoterol" HFA Same as combined effects of both drug classes Fluticasone and salmeterol HFA, DPI Mometasone furoate and formoterol HFA fumarateu Fluticasone furoate and vilanterol" DPI

lnhaled Glucocorticoids Beclomethasone HFA-MDI Dysphonia, xerostomia, oral candidiasis, bruising, pneumonia; low incidence of oral glucocorticoid adverse effects Budesonide DPl, nebulizer solution Fluticasone propionate HFA, DPI Fluticasone furoate DPI Mometasone DPI Ciclesonide HFA-MDI Flunisolide HFA-MDI lnhaled Glucocorticoids and Long-Acting p2-Agonists Budesonide and formoterol" HFA Same as combined effects of both drug classes Fluticasone and salmeterol HFA, DPI Mometasone furoate and formoterol HFA fumarateu Fluticasone furoate and vilanterol" DPI Oral Glucocorticoids Prednisone Tablet, liquid Bruising, adrenal suppression, osteoporosis, glaucoma, diabetes mellitus, opportunistic infection, insomnia, Prednisolone Tablet, liquid cataracts, hypertension, weight gain, myopathy, acne Methylpred nisolone lV infusion, tablet [.eukotriene-Modifying Agents Montelukast Tablet Headache; rarely liver disease; neuropsychiatric events, including suicidal thoughts and actions Zafirl u kast Tablet Zileuton (5-lipoxygenase inhibitor) Tablet BiologicAgents Omalizumab (anti-lgE) Subcutaneous injection Anaphylaxis, increased risk for malignancy Mepolizumab (anti-lL-5) Subcutaneous injection Reslizumab (anti-lL-5) lV infusion Benralizumab (anti-lL-5) Subcuta neous injection Dupilumab (anti-lL-4 and lL-13) Subcutaneous injection Other Theophylline Tablet, capsule, liquid Tachycardia, nausea, overdose can be fatal

Oral Glucocorticoids Prednisone Tablet, liquid Bruising, adrenal suppression, osteoporosis, glaucoma, diabetes mellitus, opportunistic infection, insomnia, Prednisolone Tablet, liquid cataracts, hypertension, weight gain, myopathy, acne Methylpred nisolone lV infusion, tablet [.eukotriene-Modifying Agents Montelukast Tablet Headache; rarely liver disease; neuropsychiatric events, including suicidal thoughts and actions Zafirl u kast Tablet Zileuton (5-lipoxygenase inhibitor) Tablet BiologicAgents Omalizumab (anti-lgE) Subcutaneous injection Anaphylaxis, increased risk for malignancy Mepolizumab (anti-lL-5) Subcutaneous injection Reslizumab (anti-lL-5) lV infusion Benralizumab (anti-lL-5) Subcuta neous injection Dupilumab (anti-lL-4 and lL-13) Subcutaneous injection Other Theophylline Tablet, capsule, liquid Tachycardia, nausea, overdose can be fatal DPI=drypowderinhaler;HFA=hydro{luoroalkane;lL=interleukin;lV=intravenous;MDl=metereddoseinhaler;5Ml=softmistinhaler. 'Relief of acute bronchospasm is an off,label indication for this medication. 12 1

Airways Disease Short acting inhaled anticholinergics are less effective inhaled low dose glucocorticoid in a single inhaler device. than SABAs at relieving acute bronchospasm; however, they Administration in a single inhaler is preferred because ol may be used as adjunctive therapy to SABA treatment in the greater adherence and reduced cost compared with adminis management of acute exacerbations in the emergency depart tration of each drug in a separate inhaler. Single agent use of ment. This combination has been shown to reduce hospital LABAs is not recommended because of the demonstrated admission rates. increased risk fbr asthma related death when used without a simultaneous controller medication. However, five large clini l(tY P0rltIs cal trials showed that LABAs. when used with inhaled . All patients with asthma should be provided with glucocorticoids, did not significantly increase the risk fbr quick relief, or rescue, therapy. asthma related hospitalization, intubation, or death compared o The most recent Global lnitiative for Asthma guidelines with inhaled glucocorticoids alone, and resulted in signifi recommend one of three inhaled glucocorticoid combi cantly fewer asthma exacerbations. nation regimens: an inhaled glucocorticoid-formoterol Leukotriene receptor antagonists have a modest bron- combination as needed or low-dose inhaled glucocorti- chodilation efl'ect and treat upper airway conditions such as coid whenever a short-acting B, agonist (SABA) is allergic rhinitis. Patients with aspirin exacerbated respiratory taken; a daily inhaled glucocorticoid or inhaled gluco disease often respond well to these agents. corticoid plus inhaled long acting Br-agonist, plus an Oral glucocorticoids are a cornerstone of therapy fbr as-needed SABA: or maintenance and rescue treatment the treatment of acute asthma exacerbations, but Iong term with low dose budesonide-formoterol. use exposes patients to the well known adverse effects o{' these ugents (see Table o). Controller Medications Long acting muscarinic antagonists (LAMAs) provide Controller medications are used to provide ongoing symptom sustained airway dilation, and tiotropium has been shown to relief and to prevent asthma exacerbations. Ser,eral different improve lung function and reduce exacerbations when classes of controllers exist that target different mechanisms of added to therapy in patients not controlled with inhaled the asthmatic profile: therefbre, medications can be eflectively glucocorticoid LABA combination therapy. For patients combined to irchieve good control. The choice of therapy gen with excessive adverse efTects from LABAs, a LAMA can rea- erally depends on the assessment ofrisk and is adjusted on the sonably be substituted. However, there is not substantial basis of symptom response and patient tolerance (see Figure 3 evidence that LAMAs. instead ol LABAs. should be the first and Tirble 6). choice tbr long-acting airway dilation. lnhaled glucocorticoids are the most effective class of Newer antibody therapies directed against specific medi asthma controller medications. These agents alleviate several ators of the asthmatic response can be used in patients with pathologic processes that make up the asthmatic response, severe asthma not adequately controlled on standard therapy, including airway mucosal edema, mucus hypersecretion, and and they have significantly altered the treatment paradigm for airur:ry inflammation. Adverse effects are dose related and these patients. Several types of biologic therapies are now vary with the steroid formulation. They relate to local deposi' available, and more are in development. The currently availa tion (oral candidiasis, dysphonia) and can sometimes be gen ble agents are directed against lype 2 inflammation and target eralized as a result of some degree of systemic absorption. pathways involved in the activation of eosinophils and lgE Systemic adverse eflects such as adrenocortical suppression. production. lt is estimated that at least half of patients with reduced bone mineral density, and cataracts do not generally asthma have type 2 airway inflammation. In a process referred occur at doses belor.r, 400 [g of inhaled budesonide daily or to as phenotyping, clinically recognizable characteristics are equivalent doses of other inhaled glucocorlicoid formulations. combined with biomarkers to determine whether patients An increased rate ol pneumonia is found with high-dose and have type 2 inflammation that could benefit from specific bio high potency tbrmulations. Despite these risks, use of inhaled logic treatments. Clinical characteristics suggesting a type 2 glucocorticoids to prevent the need fbr oral glucocorticoids high phenotype include atopy, seasonal exacerbations, hay should outweigh the potential adverse effects. In active smok I'ever, and allergen sensitization. If patients have atopy, as ers, the effectiveness of these medications is diminished and documented by skin testing or elevated serum allergen higher dosing may be required. specific IgE with high total lgE levels, they can benefit from the Inhaled LABAs that provide sustained airway dilation anti lgE biologic omalizumab. Omalizumab is a monoclonal withjustonce ortwice dailydosingarean importanttool lor antibody that binds lgE and has been shown to reduce exacer asthma treatment. When added to an inhaled glucocorticoid, bations in patients with severe persistent asthma despite ther they provide improved control and decrease the risk for exac- apy with high dose inhaled glucocorticoid and LABA therapy erbation. Fbr patients whose asthma is not adequately con and, often, additional pharmacologic therapies. Patients with trolled by a low or medium strength inhaled glucocorticoid eosinophilia can be treated with inhibitors of interleukins and SABA as needed, the recommended next step is the addi involved in eosinophilic recruitment and maturation. These tion of formoterol (a LABA) as combined therapy with an include mepolizumab, reslizumab, and benralizumab, which

Short acting inhaled anticholinergics are less effective inhaled low dose glucocorticoid in a single inhaler device. than SABAs at relieving acute bronchospasm; however, they Administration in a single inhaler is preferred because ol may be used as adjunctive therapy to SABA treatment in the greater adherence and reduced cost compared with adminis management of acute exacerbations in the emergency depart tration of each drug in a separate inhaler. Single agent use of ment. This combination has been shown to reduce hospital LABAs is not recommended because of the demonstrated admission rates. increased risk fbr asthma related death when used without a simultaneous controller medication. However, five large clini l(tY P0rltIs cal trials showed that LABAs. when used with inhaled . All patients with asthma should be provided with glucocorticoids, did not significantly increase the risk fbr quick relief, or rescue, therapy. asthma related hospitalization, intubation, or death compared o The most recent Global lnitiative for Asthma guidelines with inhaled glucocorticoids alone, and resulted in signifi recommend one of three inhaled glucocorticoid combi cantly fewer asthma exacerbations. nation regimens: an inhaled glucocorticoid-formoterol Leukotriene receptor antagonists have a modest bron- combination as needed or low-dose inhaled glucocorti- chodilation efl'ect and treat upper airway conditions such as coid whenever a short-acting B, agonist (SABA) is allergic rhinitis. Patients with aspirin exacerbated respiratory taken; a daily inhaled glucocorticoid or inhaled gluco disease often respond well to these agents. corticoid plus inhaled long acting Br-agonist, plus an Oral glucocorticoids are a cornerstone of therapy fbr as-needed SABA: or maintenance and rescue treatment the treatment of acute asthma exacerbations, but Iong term with low dose budesonide-formoterol. use exposes patients to the well known adverse effects o{' these ugents (see Table o). Controller Medications Long acting muscarinic antagonists (LAMAs) provide Controller medications are used to provide ongoing symptom sustained airway dilation, and tiotropium has been shown to relief and to prevent asthma exacerbations. Ser,eral different improve lung function and reduce exacerbations when classes of controllers exist that target different mechanisms of added to therapy in patients not controlled with inhaled the asthmatic profile: therefbre, medications can be eflectively glucocorticoid LABA combination therapy. For patients combined to irchieve good control. The choice of therapy gen with excessive adverse efTects from LABAs, a LAMA can rea- erally depends on the assessment ofrisk and is adjusted on the sonably be substituted. However, there is not substantial basis of symptom response and patient tolerance (see Figure 3 evidence that LAMAs. instead ol LABAs. should be the first and Tirble 6). choice tbr long-acting airway dilation. lnhaled glucocorticoids are the most effective class of Newer antibody therapies directed against specific medi asthma controller medications. These agents alleviate several ators of the asthmatic response can be used in patients with pathologic processes that make up the asthmatic response, severe asthma not adequately controlled on standard therapy, including airway mucosal edema, mucus hypersecretion, and and they have significantly altered the treatment paradigm for airur:ry inflammation. Adverse effects are dose related and these patients. Several types of biologic therapies are now vary with the steroid formulation. They relate to local deposi' available, and more are in development. The currently availa tion (oral candidiasis, dysphonia) and can sometimes be gen ble agents are directed against lype 2 inflammation and target eralized as a result of some degree of systemic absorption. pathways involved in the activation of eosinophils and lgE Systemic adverse eflects such as adrenocortical suppression. production. lt is estimated that at least half of patients with reduced bone mineral density, and cataracts do not generally asthma have type 2 airway inflammation. In a process referred occur at doses belor.r, 400 [g of inhaled budesonide daily or to as phenotyping, clinically recognizable characteristics are equivalent doses of other inhaled glucocorlicoid formulations. combined with biomarkers to determine whether patients An increased rate ol pneumonia is found with high-dose and have type 2 inflammation that could benefit from specific bio high potency tbrmulations. Despite these risks, use of inhaled logic treatments. Clinical characteristics suggesting a type 2 glucocorticoids to prevent the need fbr oral glucocorticoids high phenotype include atopy, seasonal exacerbations, hay should outweigh the potential adverse effects. In active smok I'ever, and allergen sensitization. If patients have atopy, as ers, the effectiveness of these medications is diminished and documented by skin testing or elevated serum allergen higher dosing may be required. specific IgE with high total lgE levels, they can benefit from the Inhaled LABAs that provide sustained airway dilation anti lgE biologic omalizumab. Omalizumab is a monoclonal withjustonce ortwice dailydosingarean importanttool lor antibody that binds lgE and has been shown to reduce exacer asthma treatment. When added to an inhaled glucocorticoid, bations in patients with severe persistent asthma despite ther they provide improved control and decrease the risk for exac- apy with high dose inhaled glucocorticoid and LABA therapy erbation. Fbr patients whose asthma is not adequately con and, often, additional pharmacologic therapies. Patients with trolled by a low or medium strength inhaled glucocorticoid eosinophilia can be treated with inhibitors of interleukins and SABA as needed, the recommended next step is the addi involved in eosinophilic recruitment and maturation. These tion of formoterol (a LABA) as combined therapy with an include mepolizumab, reslizumab, and benralizumab, which 13

Airways Disease target interleukin-5 (lL 5), or dupilumab, an inhibitor ol IL 4 TABLE 7. Severe Asthma Exacerbation Risk Factors and lL 13. The level olblood eosinophilia that predicts efficacy and Signs varies for each agent and ranges from an absolute eosinophil Risk Factors for Asthma-Related Death count of 150 cells/pl (o.ts x 109/L) to 400 cells,pL (0.4 x History of near-fatal asthma attack or intubation 109/L). regardless of lgE level. Emergency department or hospitalvisit in the last 12 months Both anti IgE and anti interleukin therapies reduce symptoms, need tbr oral glucocorticoids, and exacerbations in Poor asthma medication adherence or not using inhaled glucocorticoid eligible patients with moderate or severe persistent asthma. Current or recent treatment with oral glucocorticoid These treatments are expensive and should only be considered after veriffing patient adherence with asthma medications. Psychosocial stressors or psychiatric disease assessing inhaler technique, and addressing any comorbid Food allergy conditions. Nonetheless, omalizumab reduces emergency Overuse of short-acting n ist

target interleukin-5 (lL 5), or dupilumab, an inhibitor ol IL 4 TABLE 7. Severe Asthma Exacerbation Risk Factors and lL 13. The level olblood eosinophilia that predicts efficacy and Signs varies for each agent and ranges from an absolute eosinophil Risk Factors for Asthma-Related Death count of 150 cells/pl (o.ts x 109/L) to 400 cells,pL (0.4 x History of near-fatal asthma attack or intubation 109/L). regardless of lgE level. Emergency department or hospitalvisit in the last 12 months Both anti IgE and anti interleukin therapies reduce symptoms, need tbr oral glucocorticoids, and exacerbations in Poor asthma medication adherence or not using inhaled glucocorticoid eligible patients with moderate or severe persistent asthma. Current or recent treatment with oral glucocorticoid These treatments are expensive and should only be considered after veriffing patient adherence with asthma medications. Psychosocial stressors or psychiatric disease assessing inhaler technique, and addressing any comorbid Food allergy conditions. Nonetheless, omalizumab reduces emergency Overuse of short-acting n ist department visits and may be cost e|'ective in eligible patients Signs of a Severe Asthma Exacerbation with moderate to severe atopic asthma that is not well con Unable to speak in full sentences trolled with other therapies. Use of accessory muscles of respiration t(Er Potilrs Respiration rate >30/min, heart rate >1 2Olmin . Inhaled glucocorticoids are the most effective class ol SpOz <90% on ambient air asthma controller medications. Agitation, confusion, or drowsiness . For patients whose asthma is not adequately controlled SpO- = oxygen saturation as measured b,y PUlse oximetry. by a moderate strength inhaled glucocorticoid, the addition of a long acting pr-agonist as combined ther apy with an inhaled low-dose glucocorticoid in a single Clinicians should screen for patient factors that contribute to inhaler device is the recommended next step. an increased risk fbr death fiom asthma and counsel patients . Single agent use oflong-acting p, agonists is not rec- appropriately (Table 7). Self treatment ofan exacerbation con sists of frequent use of reliever medications; increasing the ommended because of the demonstrated increased risk dose, frequency, or both ofcontroller medications; and adding for asthma-related death when used without another a short course ol oral glucocorticoids (typically 5 7 days of controller medication. prednisone 10 50 mg/d). Patients do not improve with . Targeting elevated IgE or eosinophil levels with antibody "t'ho self-care or r.r,ho have signs that indicate a severe attack should therapies in eligible patients with severe persistent aller be evaluated in an acute care facility. Management there gic asthma despite standard therapy reduces symptoms, should include close monitoring of dyspnea, work of'breath- need for oral glucocorticoids, and exacerbations. ing, and vital signs; treatment should include trequent inhaled SABA administration. prompt glucocorticoid therapy, and Nonpharmacologic Therapy administration of supplemental oxygen to maintain oxygen Comprehensive asthma care strategies include avoidance of saturation above 93'1,. For further discussion of severe asthma triggers with allergen management (mold abatement, pest con exacerbations. see Common ICU Conditions. trol, air filters), reduced exposure to environmental tobacco rtY Potilr smoke, and a healthy diet and exercise program to promote weight loss. . All patients with asthma should have a written asthma Bronchial thermoplasty is a radiofrequency ain^ay treat- management plan that helps them recognize the symp ment administered using bronchoscopy that can reduce exac toms of an exacerbation and begin self treatment. erbations and improve quality ol lif'e. Candidates are patients with an FEV, higher than 607, and severe asthma that is poorly Severe Refractory Asthma controlled despite high dose inhaled glucocorlicoid LABA Severe refractory asthma is present in patients who require combination tl.rerapy. high doses of'an inhaled glucocorticoid plus a second control Ier or oral glucocorticoids to prevent worsening. or who expe Management of Asthma Exacerbations rience two or more exacerbations within 1 year that require Asthma exacerbation refers to an acute worsening of symp an emergency department visit or hospitalization. This group toms or lung fur.rction fiom baseline that necessitates a step up of patients consumes the most asthma-related health care in therapy (see Figure 3). Prompt recognition and treatment o1' resources. [t is important to verify the diagnosis in these asthma exacerbations are needed to relieve symptoms and patients and to document medication compliance and correct prevent hospitalizations. All patients with asthma should have inhaler technique before considering additional therapies. In a written asthma management plan that helps them recognize addition, comorbidities should be aggressively n.ranaged. the symptoms of an exacerbation and begin self treatn-rent. Treatment guided by specific phenotypes can be helpful in

department visits and may be cost e|'ective in eligible patients Signs of a Severe Asthma Exacerbation with moderate to severe atopic asthma that is not well con Unable to speak in full sentences trolled with other therapies. Use of accessory muscles of respiration t(Er Potilrs Respiration rate >30/min, heart rate >1 2Olmin . Inhaled glucocorticoids are the most effective class ol SpOz <90% on ambient air asthma controller medications. Agitation, confusion, or drowsiness . For patients whose asthma is not adequately controlled SpO- = oxygen saturation as measured b,y PUlse oximetry. by a moderate strength inhaled glucocorticoid, the addition of a long acting pr-agonist as combined ther apy with an inhaled low-dose glucocorticoid in a single Clinicians should screen for patient factors that contribute to inhaler device is the recommended next step. an increased risk fbr death fiom asthma and counsel patients . Single agent use oflong-acting p, agonists is not rec- appropriately (Table 7). Self treatment ofan exacerbation con sists of frequent use of reliever medications; increasing the ommended because of the demonstrated increased risk dose, frequency, or both ofcontroller medications; and adding for asthma-related death when used without another a short course ol oral glucocorticoids (typically 5 7 days of controller medication. prednisone 10 50 mg/d). Patients do not improve with . Targeting elevated IgE or eosinophil levels with antibody "t'ho self-care or r.r,ho have signs that indicate a severe attack should therapies in eligible patients with severe persistent aller be evaluated in an acute care facility. Management there gic asthma despite standard therapy reduces symptoms, should include close monitoring of dyspnea, work of'breath- need for oral glucocorticoids, and exacerbations. ing, and vital signs; treatment should include trequent inhaled SABA administration. prompt glucocorticoid therapy, and Nonpharmacologic Therapy administration of supplemental oxygen to maintain oxygen Comprehensive asthma care strategies include avoidance of saturation above 93'1,. For further discussion of severe asthma triggers with allergen management (mold abatement, pest con exacerbations. see Common ICU Conditions. trol, air filters), reduced exposure to environmental tobacco rtY Potilr smoke, and a healthy diet and exercise program to promote weight loss. . All patients with asthma should have a written asthma Bronchial thermoplasty is a radiofrequency ain^ay treat- management plan that helps them recognize the symp ment administered using bronchoscopy that can reduce exac toms of an exacerbation and begin self treatment. erbations and improve quality ol lif'e. Candidates are patients with an FEV, higher than 607, and severe asthma that is poorly Severe Refractory Asthma controlled despite high dose inhaled glucocorlicoid LABA Severe refractory asthma is present in patients who require combination tl.rerapy. high doses of'an inhaled glucocorticoid plus a second control Ier or oral glucocorticoids to prevent worsening. or who expe Management of Asthma Exacerbations rience two or more exacerbations within 1 year that require Asthma exacerbation refers to an acute worsening of symp an emergency department visit or hospitalization. This group toms or lung fur.rction fiom baseline that necessitates a step up of patients consumes the most asthma-related health care in therapy (see Figure 3). Prompt recognition and treatment o1' resources. [t is important to verify the diagnosis in these asthma exacerbations are needed to relieve symptoms and patients and to document medication compliance and correct prevent hospitalizations. All patients with asthma should have inhaler technique before considering additional therapies. In a written asthma management plan that helps them recognize addition, comorbidities should be aggressively n.ranaged. the symptoms of an exacerbation and begin self treatn-rent. Treatment guided by specific phenotypes can be helpful in 14

Airways Disease this group, such as biologic agents for patients with high IgE or volume during exeftion. Compensatory use of accessory mus eosinophil levels and leukotriene receptor antagonists fbr cles to increase tidal volume and increased respiration rate patients with aspirin sensitivity. Referral to a team of subspe augnrent minute ventilation. These changes increase the work cialists is often indicated. of breathing and contribute to the sensation of dyspnea in patients with COPD. Asthma in Pregnancy Pregnant patients should be advised that the advantages of Risk Factors asthma treatnlent are significantly greater than the potential Exposure to cigarette smoke (both first and secondhand risk to the tetus fiom asthma therapies. Pregnancy can affect exposure) is the most important risk factor for COPD. Ger.retic asthma control, leading to either worsening or improvement, predisposition seems to explain some of the variation in sus and patients should be closely monitored lor signs of exacer ceptibility to developing COPD when exposed to cigarette bation, which occurs most trequently during the second tri smoke. Long ternr exposure to other irritants can also result in mester. Inhaled glucocorticoids, oral glucocorticoids, SABAs, COPD. This includes exposure to air pollution (both indoor leukotriene receptor antagonists (montelukast, zafirlukast), and outdoor) and occupational chemicals and dusts. An and LABAs have all been used extensively during pregnancy important ex:rmple of indoor air pollution is the use of bio without data to suggest t'etal harm. mass fuel for cooking inside the home, which is a comrnon risk factor for COPD in the developing world. A family history of COPD is also considered a risk factor for the disease. as is Chronic Obstructive rx, antitrypsin deficiency. Pulmonary Disease I(EY POITI Definition o Exposure to cigarette smoke is the most important risk COPD is a chronic lung disease defined by persistent respira factor fbr COPD. tory symptoms and airflow limitation or obstmction that is not fullv reversible. Heterogeneity of COPD COPD is a heterogeneous condition. Some patients present Epidemiology predominately with a chronic productive cough due to mucus COPD is a comnlon disorder that currently affects more than hypersecretion, whereas others present predominately with 6')1, of the U.S. population. The worldwide prevalence contin progressive dyspnea secondary to hyperinflation. The hetero ues to rise, and the World Health Organization predicts that by geneity extends beyond clinical symptoms. Phenotypic het 2030 COPD will become the world's flfth most prevalent dis erogeneity has been characterized on the basis of clinical, order and the third leading cause ofdeath. COPD is associated physiologic, molecular, and radiographic variables. For with high morbidity and mortality and is the fourth leading example, eosinophilia has been associated with increased cause ofdeath in the United States. responsiveness to glucocorticoids. There also appears to be a subgroup of'patients who are more prone to developing acute Pathophysiology exacerbations. Understanding such variables could poten COPD is an inf'lammatory condition. Cigarette smoke and tially improve the accurate assessment of prognosis and indi other irritants activate both macrophages and epithelial cells vidualize patient care. Because of the heterogeneity of the within the respiratory tract. The epithelial cells then release disease and its presentation, tools have been developed to aid several neutrophil chemotactic factors. Macrophages and neu in determining prognosis and best treatment strategies. trophils release proteases that cause destruction of lung Several staging assessments exist. For example, the Global parenchyma. Proteases are typically inactivated by antipro lnitiative tbr Chronic Obstructive Lung Disease (GOLD) sys teases, such as a, antitrypsin, which may also be reduced in tem combines the degree of airflow obstruction obtained COPD. Oxidative stress front irritants and inflammatory cells from spirometry with the number of previous exacerbations may lead to aclditional inflan.rn.ration and tissue destruction. as well as symptoms to help determine treatment. The BODE Ultimately, patients develop fibrosis of the small airways and index uses the variables of body mass index (B), airflow reduced elastic recoil of the lungs leading to static hyperinfla obstruction (O), dyspnea (D), and exercise capacity (E) to tioni in addition, mucin concentrations are abnormally predict outconles and response to therapy. Airflow obstmc elevated. As the degree ol inflammation increases, airflow tion is determined using the postbronchodilator FEV, per obstruction worsens and the ability to fully exhale decreases. centage of preclicted value for age, sex, height, and race. The Inhalation is initiated be[ore exhal:rtion is completed, resulting BODE index uses the Modified British Medical Research in dynamic hyperinflation termed air trapping which is Council (mMRC) dyspnea scale questionnaire to grade per seen as an increased anteroposterior diameter ofthe chest and ceived dyspnea ranging ltom dyspnea only with strenuotls flattening of the diaphragm on chest radiographs. The dia exercise kr dyspnea even when getting dressed. The exercise phragmatic flattening limits the ability to increase breath capacity is cletermined by the walking distance on a 6 minute

this group, such as biologic agents for patients with high IgE or volume during exeftion. Compensatory use of accessory mus eosinophil levels and leukotriene receptor antagonists fbr cles to increase tidal volume and increased respiration rate patients with aspirin sensitivity. Referral to a team of subspe augnrent minute ventilation. These changes increase the work cialists is often indicated. of breathing and contribute to the sensation of dyspnea in patients with COPD. Asthma in Pregnancy Pregnant patients should be advised that the advantages of Risk Factors asthma treatnlent are significantly greater than the potential Exposure to cigarette smoke (both first and secondhand risk to the tetus fiom asthma therapies. Pregnancy can affect exposure) is the most important risk factor for COPD. Ger.retic asthma control, leading to either worsening or improvement, predisposition seems to explain some of the variation in sus and patients should be closely monitored lor signs of exacer ceptibility to developing COPD when exposed to cigarette bation, which occurs most trequently during the second tri smoke. Long ternr exposure to other irritants can also result in mester. Inhaled glucocorticoids, oral glucocorticoids, SABAs, COPD. This includes exposure to air pollution (both indoor leukotriene receptor antagonists (montelukast, zafirlukast), and outdoor) and occupational chemicals and dusts. An and LABAs have all been used extensively during pregnancy important ex:rmple of indoor air pollution is the use of bio without data to suggest t'etal harm. mass fuel for cooking inside the home, which is a comrnon risk factor for COPD in the developing world. A family history of COPD is also considered a risk factor for the disease. as is Chronic Obstructive rx, antitrypsin deficiency. Pulmonary Disease I(EY POITI Definition o Exposure to cigarette smoke is the most important risk COPD is a chronic lung disease defined by persistent respira factor fbr COPD. tory symptoms and airflow limitation or obstmction that is not fullv reversible. Heterogeneity of COPD COPD is a heterogeneous condition. Some patients present Epidemiology predominately with a chronic productive cough due to mucus COPD is a comnlon disorder that currently affects more than hypersecretion, whereas others present predominately with 6')1, of the U.S. population. The worldwide prevalence contin progressive dyspnea secondary to hyperinflation. The hetero ues to rise, and the World Health Organization predicts that by geneity extends beyond clinical symptoms. Phenotypic het 2030 COPD will become the world's flfth most prevalent dis erogeneity has been characterized on the basis of clinical, order and the third leading cause ofdeath. COPD is associated physiologic, molecular, and radiographic variables. For with high morbidity and mortality and is the fourth leading example, eosinophilia has been associated with increased cause ofdeath in the United States. responsiveness to glucocorticoids. There also appears to be a subgroup of'patients who are more prone to developing acute Pathophysiology exacerbations. Understanding such variables could poten COPD is an inf'lammatory condition. Cigarette smoke and tially improve the accurate assessment of prognosis and indi other irritants activate both macrophages and epithelial cells vidualize patient care. Because of the heterogeneity of the within the respiratory tract. The epithelial cells then release disease and its presentation, tools have been developed to aid several neutrophil chemotactic factors. Macrophages and neu in determining prognosis and best treatment strategies. trophils release proteases that cause destruction of lung Several staging assessments exist. For example, the Global parenchyma. Proteases are typically inactivated by antipro lnitiative tbr Chronic Obstructive Lung Disease (GOLD) sys teases, such as a, antitrypsin, which may also be reduced in tem combines the degree of airflow obstruction obtained COPD. Oxidative stress front irritants and inflammatory cells from spirometry with the number of previous exacerbations may lead to aclditional inflan.rn.ration and tissue destruction. as well as symptoms to help determine treatment. The BODE Ultimately, patients develop fibrosis of the small airways and index uses the variables of body mass index (B), airflow reduced elastic recoil of the lungs leading to static hyperinfla obstruction (O), dyspnea (D), and exercise capacity (E) to tioni in addition, mucin concentrations are abnormally predict outconles and response to therapy. Airflow obstmc elevated. As the degree ol inflammation increases, airflow tion is determined using the postbronchodilator FEV, per obstruction worsens and the ability to fully exhale decreases. centage of preclicted value for age, sex, height, and race. The Inhalation is initiated be[ore exhal:rtion is completed, resulting BODE index uses the Modified British Medical Research in dynamic hyperinflation termed air trapping which is Council (mMRC) dyspnea scale questionnaire to grade per seen as an increased anteroposterior diameter ofthe chest and ceived dyspnea ranging ltom dyspnea only with strenuotls flattening of the diaphragm on chest radiographs. The dia exercise kr dyspnea even when getting dressed. The exercise phragmatic flattening limits the ability to increase breath capacity is cletermined by the walking distance on a 6 minute 15

Airways Disease lvalk test. This index provides better prognostic information TABLE 8. Modified Medical Research Council than the FEV, alone and has been used to approximate 4 year Dyspnea Scale survival and risk fbr hospitalization for COPD. Score Description of Dyspnea Severity 0 I get breathless only with None Comorbid Conditions strenuous exercise. Patients with COPD often sulfer from comorbid conditions I get short of breath when Mild that further increase nrorbidiry and mortality. Some condi hurrying on level ground or tions. such as cardiovascular disease, share common risk walking up a slight hill. factors. but others seem to be independently associated with 2 On level ground, lwalk slower Moderate than other people my age COPD or a consequence oftreatment ofCOPD. These include because of breathlessness, or I muscle loss with associated weakness and weight loss, osteo have to stop for breath when porosis, and depression. walking at my own pace. 3 I stop for breath after walking Severe I(EY POIilI approximately 100 yards or after . COPD is a heterogeneous condition and patients present a few minutes on level ground. with variable symptoms, including cough, sputum pro- 4 I am too breathless to leave the Very severe duction, and dyspnea. house or breathless when d ressing.

with variable symptoms, including cough, sputum pro- 4 I am too breathless to leave the Very severe duction, and dyspnea. house or breathless when d ressing. Based on the 1 959 wRC Breathlessness Scale, as modified and published in Diagnosis Global lnltiative for Chronic Obstructive Lung Disease, Global strategy for the d agnosis, management, and prevention of chronic obstructive pulmonary The possibility of COPD should be considered and spirom- disease: 2020 report; 28. Accessed September 27, 2020. hftps://goldcopd.orgl etry should be performed in patients aged 40 years or older gold reports/. Used with the permission of the lr,ledical Research Council. with progressive dyspnea, chronic cough, chronic sputum production, or recurrent Iower respiratory tract infections, particularly in the presence ol known risk factors for the spirometry. history of acute exacerbations, and presence of disease, especially smoking. The role of screening spirom comorbid conditions. Several validated tools are available to etry in asymptomatic individuals with risk factors is assess patients' symptoms, including the COPD Assessment

with progressive dyspnea, chronic cough, chronic sputum production, or recurrent Iower respiratory tract infections, particularly in the presence ol known risk factors for the spirometry. history of acute exacerbations, and presence of disease, especially smoking. The role of screening spirom comorbid conditions. Several validated tools are available to etry in asymptomatic individuals with risk factors is assess patients' symptoms, including the COPD Assessment controversial. The U.S. Preventive Services Task Force Test. the Clinical COPD Questionnaire, and the mMRC scale (Table 8). The GOLD criteria use the COPD Assessment Test or guideline recommends against screening for COPD in asymptomatic adults, whereas the GOLD advocates per mMRC scale to determine symptom severity, and the BODE lorming screening spirometry in individuals with risk index (Table 9) requires the use of the mMRC scale. The f'actors fbr COPD. Clinical COPD Questionnaire is often used to screen patients In the appropriate clinical context, the diagnosis of for symptoms of COPD. Symptoms are then combined with COPD is made using spirometric measurement to document the results from spirometry (Table 10) to determine disease airflow obstruction. COPD is confirmed by a postbroncho severity (Table fl). dilator FEVr/FVC ratio o1' less than 0.70. This differs from Patients who have had two or more acute exacerbations the finding in patients with asthma, whose airflow obstruc within the last year, who have an FEV' of less than 507, of tion is reversible with bronchodilator therapy. Measuring predicted, or who have ever been hospitalized for an acute lung volumes and diffusing capacity is not required to diag exacerbation are at high risk lor recurrent acute exacerbations. nose COPD but may help in determining the severity of Clinicians should determine whether the patient suffers from disease. Clinicians should rule out other causes of chronic any of the common comorbid conditions associated with respiratory symptoms, including heart failure, bronchiecta COPD that indicate a higher morbidity and mortality and treat

controversial. The U.S. Preventive Services Task Force Test. the Clinical COPD Questionnaire, and the mMRC scale (Table 8). The GOLD criteria use the COPD Assessment Test or guideline recommends against screening for COPD in asymptomatic adults, whereas the GOLD advocates per mMRC scale to determine symptom severity, and the BODE lorming screening spirometry in individuals with risk index (Table 9) requires the use of the mMRC scale. The f'actors fbr COPD. Clinical COPD Questionnaire is often used to screen patients In the appropriate clinical context, the diagnosis of for symptoms of COPD. Symptoms are then combined with COPD is made using spirometric measurement to document the results from spirometry (Table 10) to determine disease airflow obstruction. COPD is confirmed by a postbroncho severity (Table fl). dilator FEVr/FVC ratio o1' less than 0.70. This differs from Patients who have had two or more acute exacerbations the finding in patients with asthma, whose airflow obstruc within the last year, who have an FEV' of less than 507, of tion is reversible with bronchodilator therapy. Measuring predicted, or who have ever been hospitalized for an acute lung volumes and diffusing capacity is not required to diag exacerbation are at high risk lor recurrent acute exacerbations. nose COPD but may help in determining the severity of Clinicians should determine whether the patient suffers from disease. Clinicians should rule out other causes of chronic any of the common comorbid conditions associated with respiratory symptoms, including heart failure, bronchiecta COPD that indicate a higher morbidity and mortality and treat sis, obliterative bronchiolitis, tuberculosis, and diffuse appropriately. panbronchiolitis. Pulse oximetry at rest and at exertion should be used to determine the need for supplemental oxygen. Arterial r(EY P0rr{Ts blood gases should be measured to assess for underlying r The U.S. Preventive Services Task Force guideline does hypercapnia in patients with a low FEV,, change in mental not recommend spirometric screening for COPD in status. acute exacerbation. elevated level ofserum bicarbo' asymptomatic individuals. nate, or oxygen saturation of less than 92'1, on pulse . In the appropriate clinical context, COPD is diagnosed by oximetry. a postbronchodilator FEV,/FVC ratio of less than 0.70. An cr.r antitrypsin level should be obtained once in all patients with COPD. A pattern of basilar emphysema. associ Disease Assessment ated liver disease or panniculitis, or a strong family history of After a diagnosis of COPD has been established, the initial assess emphysema in patients with COPD suggests possible o, ment focuses on disease severity, which is determined using a antitrypsin deficiency, but none of these features is sufficiently combination of symptoms, degree of airflow obstruction on sensitive fbr the condition.

sis, obliterative bronchiolitis, tuberculosis, and diffuse appropriately. panbronchiolitis. Pulse oximetry at rest and at exertion should be used to determine the need for supplemental oxygen. Arterial r(EY P0rr{Ts blood gases should be measured to assess for underlying r The U.S. Preventive Services Task Force guideline does hypercapnia in patients with a low FEV,, change in mental not recommend spirometric screening for COPD in status. acute exacerbation. elevated level ofserum bicarbo' asymptomatic individuals. nate, or oxygen saturation of less than 92'1, on pulse . In the appropriate clinical context, COPD is diagnosed by oximetry. a postbronchodilator FEV,/FVC ratio of less than 0.70. An cr.r antitrypsin level should be obtained once in all patients with COPD. A pattern of basilar emphysema. associ Disease Assessment ated liver disease or panniculitis, or a strong family history of After a diagnosis of COPD has been established, the initial assess emphysema in patients with COPD suggests possible o, ment focuses on disease severity, which is determined using a antitrypsin deficiency, but none of these features is sufficiently combination of symptoms, degree of airflow obstruction on sensitive fbr the condition. 16

Airways Disease TABLE 9. BODE lndex to Estimate Prognosis o{ COPD TABLE 1 0. Classification of Airflow Limitation Severity in Parameter Points Assigned COPD by 5pirometry",b Category Severity Spirometry >21 GOLD 1 Mild FEV1 >80% predicted 0 <21 GOLD 2 Moderate 50% < FEV1 < B0% predicted 1 Obstruction of Airflow: FEV, ( Postbronchodilator GOLD 3 Severe 30% < FEV1 < 50% predicted Percentage Predicted) GOLD 4 Very severe FEV1 <30% predicted >65"/" 0 GOLD = Global lnitrative for Chronic Obstructive Lung Disease. 50Yo-640/0 1 "ln patienrs with FEV1/FVC less than 0.7. I 3670-49"/" 2 Based on postbroncnodtldtor FFVr.

50Yo-640/0 1 "ln patienrs with FEV1/FVC less than 0.7. I 3670-49"/" 2 Based on postbroncnodtldtor FFVr. <35"/" ) Reproduced with permission, {rom Global strategy for the diagnosis, management, and prevention of chronic obstructive pu lmonary disea se: 2020 repon; 27 . Dyspnea: mMRC Score Copyright 2020, Global lnitiative for Chronic Obstructive Lung Disease, available from www.goldcopd.org, published in Fontana, Wl, USA. 0-l 0 2 1 Management of COPD ) 2 A management plan for COPD should include the identifica 4 3 tion and reversal of risk factors, especially ongoing exposure Exercise Capacity: 6-Minute Walking Distance to cigarette smoke. The severity of a patient's COPD should I >350 m 0 guide the choice of therapy (Table 12). No currently available treatments can prevent long term decline in lung function, so 250-349 m 1 patients should be monitored for evidence ofdisease progres- 150-249 m 2 sion that may guide additional therapy. The goals of therapy <149m 3 are to reduce symptoms and improve exercise tolerance and BODE = body mass, airf ow obstruction, dyspnea, and exercise; mMRC = Modified quality ol life, as well as to prevent and treat exacerbations, British Medical Research Council dyspnea scale. Approximate 4 year suruival: 0-2 points: 807o; 3 4 points: 67%; 5 6 points: 57%;7 10 points: 1 8%. prevent disease progression, and decrease mortality. From Celli BR, Cote CG, Marin JM, et al. The body mass index, airflow obstruction, ronic obstructive pulmonary disease. N Engl Smoking Cessation Copyright O 2004 N.4assachusetts Medical the Massachusetts Medical Society. Smoking cessation is essential in the management of COPD, as it can slow the decline of FEVr. Clinicians should encour- I(EY POIilIS age patients to quit smoking and be aware that the success . After a diagnosis of COPD has been established, the ini- rates fbr smoking cessation increase when counseling is tial assessment focuses on disease severity, which is combined with medication therapy. All smokers without determined using a combination of symptoms, degree contraindications should additionally receive at least one of of airflow obstruction on spirometry history of acute the seven FDA approved treatments for smoking cessation. exacerbations, and presence of comorbid conditions. The approved medications include nicotine replacement therapies, varenicline, and bupropion (see MKSAP 19 General . Patients who have had two or more acute exacerbations Internal Medicine 1). within the last year, who have an FEV, of less than 50% of predicted, or who have ever been hospitalized for an t(tY P0t ilr acute exacerbation are considered to be at high risk for . Smoking cessation is essential in the management of recurrent acute exacerbations. COPD, as it can slow the decline of FEV,.

<35"/" ) Reproduced with permission, {rom Global strategy for the diagnosis, management, and prevention of chronic obstructive pu lmonary disea se: 2020 repon; 27 . Dyspnea: mMRC Score Copyright 2020, Global lnitiative for Chronic Obstructive Lung Disease, available from www.goldcopd.org, published in Fontana, Wl, USA. 0-l 0 2 1 Management of COPD ) 2 A management plan for COPD should include the identifica 4 3 tion and reversal of risk factors, especially ongoing exposure Exercise Capacity: 6-Minute Walking Distance to cigarette smoke. The severity of a patient's COPD should I >350 m 0 guide the choice of therapy (Table 12). No currently available treatments can prevent long term decline in lung function, so 250-349 m 1 patients should be monitored for evidence ofdisease progres- 150-249 m 2 sion that may guide additional therapy. The goals of therapy <149m 3 are to reduce symptoms and improve exercise tolerance and BODE = body mass, airf ow obstruction, dyspnea, and exercise; mMRC = Modified quality ol life, as well as to prevent and treat exacerbations, British Medical Research Council dyspnea scale. Approximate 4 year suruival: 0-2 points: 807o; 3 4 points: 67%; 5 6 points: 57%;7 10 points: 1 8%. prevent disease progression, and decrease mortality. From Celli BR, Cote CG, Marin JM, et al. The body mass index, airflow obstruction, ronic obstructive pulmonary disease. N Engl Smoking Cessation Copyright O 2004 N.4assachusetts Medical the Massachusetts Medical Society. Smoking cessation is essential in the management of COPD, as it can slow the decline of FEVr. Clinicians should encour- I(EY POIilIS age patients to quit smoking and be aware that the success . After a diagnosis of COPD has been established, the ini- rates fbr smoking cessation increase when counseling is tial assessment focuses on disease severity, which is combined with medication therapy. All smokers without determined using a combination of symptoms, degree contraindications should additionally receive at least one of of airflow obstruction on spirometry history of acute the seven FDA approved treatments for smoking cessation. exacerbations, and presence of comorbid conditions. The approved medications include nicotine replacement therapies, varenicline, and bupropion (see MKSAP 19 General . Patients who have had two or more acute exacerbations Internal Medicine 1). within the last year, who have an FEV, of less than 50% of predicted, or who have ever been hospitalized for an t(tY P0t ilr acute exacerbation are considered to be at high risk for . Smoking cessation is essential in the management of recurrent acute exacerbations. COPD, as it can slow the decline of FEV,. TABLE 1 1 . GOLD Model for Classifying Severity of Disease in COPD" PatientCategory Characteristics Exacerbations PerYear CAT Score mMRC Score A Low risk, fewer symptoms <1, no hospitalization <1 0 0-1

TABLE 1 1 . GOLD Model for Classifying Severity of Disease in COPD" PatientCategory Characteristics Exacerbations PerYear CAT Score mMRC Score A Low risk, fewer symptoms <1, no hospitalization <1 0 0-1 B Low risk, more symptoms <1, no hospitalization >1 0 >2 c High risk, fewer symptoms >2or>1 with hospital admission <10 0-1 D High risk, more symptoms >2 or 21 with hospital admission >10 >_2 CAT = COPD Assessment Test; GOLD = Global lnitiative for Chronic Obstructive Lung Disease; mMRC = Modified Medical Research Council dyspnea scale. "See Table 1 0 for definitions of spirometric classifrcations. 2020 report. Accessed September 27,2020. https://goldcopd.orglgold-reports/ 17

Airways Disease TABLE 1 2. Recommended Pharmacologic Management of COPD by GOLD Classi{ication Patient Group Recommended Therapy Alternative Therapy Other Considerations Short-acti ng bronchodi lator Evaluate effect oftherapy and All patients in group A should receive continue, stop, or try alternative bronchodilator therapy based on its effect on or bronchodilator as appropriate dyspnea; therapy should be continued if Lon g-acting bronchodi lator symptomatic benefit is documented. B Long-acting bronchodilator lf symptoms persist after one Long-acting inhaled bronchodilators are (LABA or LAMA) long-acting bronchodilator, try superior to short-acting bronchodilators combined therapy with LABA received as needed. or and LAMA There is no evidence to support use of one Combination therapy with two class of long-acting bronchodilators over bronchodilators may be another for initial relief of symptoms for considered for patients with patients in group B. ln the individual patient, severe dyspnea the choice should depend on the patient's perception of symptom relief. Patients in group B are likely to have comorbidities that affect symptoms and prognosis, and these should be investigated.

TABLE 1 2. Recommended Pharmacologic Management of COPD by GOLD Classi{ication Patient Group Recommended Therapy Alternative Therapy Other Considerations Short-acti ng bronchodi lator Evaluate effect oftherapy and All patients in group A should receive continue, stop, or try alternative bronchodilator therapy based on its effect on or bronchodilator as appropriate dyspnea; therapy should be continued if Lon g-acting bronchodi lator symptomatic benefit is documented. B Long-acting bronchodilator lf symptoms persist after one Long-acting inhaled bronchodilators are (LABA or LAMA) long-acting bronchodilator, try superior to short-acting bronchodilators combined therapy with LABA received as needed. or and LAMA There is no evidence to support use of one Combination therapy with two class of long-acting bronchodilators over bronchodilators may be another for initial relief of symptoms for considered for patients with patients in group B. ln the individual patient, severe dyspnea the choice should depend on the patient's perception of symptom relief. Patients in group B are likely to have comorbidities that affect symptoms and prognosis, and these should be investigated. c LAMA; if further exacerbations, LABA and inhaled LABA and LAMA is preferred to LABA and LAMAand LABA glucocorticoids inhaled glucocorticoids because inhaled glucocorticoids increase the risk of developing pneumonia in some patients. D LAMAoT lf exacerbations continue, lnitialtherapy with LABA and inhaled consider: glucocorticoids may be appropriate in some LAMA and LABA" patients, including those with a history or Roflumilast (patients with an or findings suggestive of asthma. FEV1 <50% of predicted and lnhaled glucocorticoids and chronic bronchitis, particularly if LABAb they have experienced at least one hospitalization for an exacerbation in the previous year) or Macrolide therapy (the best available evidence exists for the use of azithromycin)

c LAMA; if further exacerbations, LABA and inhaled LABA and LAMA is preferred to LABA and LAMAand LABA glucocorticoids inhaled glucocorticoids because inhaled glucocorticoids increase the risk of developing pneumonia in some patients. D LAMAoT lf exacerbations continue, lnitialtherapy with LABA and inhaled consider: glucocorticoids may be appropriate in some LAMA and LABA" patients, including those with a history or Roflumilast (patients with an or findings suggestive of asthma. FEV1 <50% of predicted and lnhaled glucocorticoids and chronic bronchitis, particularly if LABAb they have experienced at least one hospitalization for an exacerbation in the previous year) or Macrolide therapy (the best available evidence exists for the use of azithromycin) I GOLO=GtobatlnitiativeforChronicObstructiveLungDisease;LABA=long-actingp2-agonist;LAMA=longactingmuscarinicagent "Consider if highly symptomatic. bConsider if eosinophils >300/!L (0.30 x 1 oell).

c LAMA; if further exacerbations, LABA and inhaled LABA and LAMA is preferred to LABA and LAMAand LABA glucocorticoids inhaled glucocorticoids because inhaled glucocorticoids increase the risk of developing pneumonia in some patients. D LAMAoT lf exacerbations continue, lnitialtherapy with LABA and inhaled consider: glucocorticoids may be appropriate in some LAMA and LABA" patients, including those with a history or Roflumilast (patients with an or findings suggestive of asthma. FEV1 <50% of predicted and lnhaled glucocorticoids and chronic bronchitis, particularly if LABAb they have experienced at least one hospitalization for an exacerbation in the previous year) or Macrolide therapy (the best available evidence exists for the use of azithromycin) I GOLO=GtobatlnitiativeforChronicObstructiveLungDisease;LABA=long-actingp2-agonist;LAMA=longactingmuscarinicagent "Consider if highly symptomatic. bConsider if eosinophils >300/!L (0.30 x 1 oell). 2020 report. Accessed September 27, 2020. https://goldcopd.org/9old reports/

c LAMA; if further exacerbations, LABA and inhaled LABA and LAMA is preferred to LABA and LAMAand LABA glucocorticoids inhaled glucocorticoids because inhaled glucocorticoids increase the risk of developing pneumonia in some patients. D LAMAoT lf exacerbations continue, lnitialtherapy with LABA and inhaled consider: glucocorticoids may be appropriate in some LAMA and LABA" patients, including those with a history or Roflumilast (patients with an or findings suggestive of asthma. FEV1 <50% of predicted and lnhaled glucocorticoids and chronic bronchitis, particularly if LABAb they have experienced at least one hospitalization for an exacerbation in the previous year) or Macrolide therapy (the best available evidence exists for the use of azithromycin) I GOLO=GtobatlnitiativeforChronicObstructiveLungDisease;LABA=long-actingp2-agonist;LAMA=longactingmuscarinicagent "Consider if highly symptomatic. bConsider if eosinophils >300/!L (0.30 x 1 oell). 2020 report. Accessed September 27, 2020. https://goldcopd.org/9old reports/ Pharmacologic Therapy However, dual treatment results in a greater degree ol bron Pharmacologic therapies in COPD are used to reduce symp chodilation and expiratory airflow which may lead to symp toms, improve quality of life, and reduce the frequency and tom benefit in select patients. severity of exacerbations (Table 13). Bronchodilators are main- If short acting bronchodilators are insufficient to control stays of therapy for COPD irrespective of the severity of the symptoms in patients with more severe disease, a long acting disease. Any time bronchodilators or other inhalers are pre bronchodilator-either a LABA or a LAMA can be added. scribed, the clinician should ensure that the patient receives Choosing the appropriate long-acting bronchodilator inhaler education on proper inhaler technique. Recommended initial requires consideration of patient and physician preference, management is outlined in Table 12. potential adverse effects, and cost. If symptoms persist on mon otherapy, the addition of a second long-acting bronchodilator Bronchodilators from the alternate bronchodilator class may result in clinical Inhaled bronchodilators include B, agonists and anticholiner- improvement. Long acting bronchodilators alone should not be gics/antimuscarinic agents. Both are available as short-acting used in patients with a history or diagnosis of asthma unless an and long-acting inhalers and improve symptoms and expira inhaled glucocorticoid is also prescribed because ofthe poten tory airflow. SABAs and muscarinic antagonists result in simi- tial for increased risk for mortality in this patient population lar bronchodilation, and either can be used as monotherapy. when a LABA is used without an inhaled glucocorticoid.

Pharmacologic Therapy However, dual treatment results in a greater degree ol bron Pharmacologic therapies in COPD are used to reduce symp chodilation and expiratory airflow which may lead to symp toms, improve quality of life, and reduce the frequency and tom benefit in select patients. severity of exacerbations (Table 13). Bronchodilators are main- If short acting bronchodilators are insufficient to control stays of therapy for COPD irrespective of the severity of the symptoms in patients with more severe disease, a long acting disease. Any time bronchodilators or other inhalers are pre bronchodilator-either a LABA or a LAMA can be added. scribed, the clinician should ensure that the patient receives Choosing the appropriate long-acting bronchodilator inhaler education on proper inhaler technique. Recommended initial requires consideration of patient and physician preference, management is outlined in Table 12. potential adverse effects, and cost. If symptoms persist on mon otherapy, the addition of a second long-acting bronchodilator Bronchodilators from the alternate bronchodilator class may result in clinical Inhaled bronchodilators include B, agonists and anticholiner- improvement. Long acting bronchodilators alone should not be gics/antimuscarinic agents. Both are available as short-acting used in patients with a history or diagnosis of asthma unless an and long-acting inhalers and improve symptoms and expira inhaled glucocorticoid is also prescribed because ofthe poten tory airflow. SABAs and muscarinic antagonists result in simi- tial for increased risk for mortality in this patient population lar bronchodilation, and either can be used as monotherapy. when a LABA is used without an inhaled glucocorticoid. 18

Airways Disease Agent Adverse Effects Notes Bronchodilators lnhaled short-acting p2-agonists Tachycardia and hypokalemia (usually Generally used as needed for mild disease with few (albuterol, fenoterol, levalbuterol, dose dependent), but generally well symptoms metaproterenol, pirbuterol, terbutaline) tolerated by most patients lnhaled short-acting anticholinergic Dry mouth, mydriasis on contactwith eye, Generally used as needed for mild disease with few agents (ipratropium) tachycardia, tremors; rarely acute narrow- symptoms; avoid using both short- and long-acting angle glaucoma; this drug class has been a nticholinergics shown to be safe in a wide range of doses and clinical settings lnhaled long-acting anticholinergic Dry mouth, mydriasis on contact with Not to be used with ipratropium; use when short-acting agents (tiotropium, aclidinium, eye, tachycardia, tremors; rarely acute bronchodilators provide insufficient control of symptoms umeclidinium, glycopyrrolate) narrow-angle glaucoma lnhaled long-acting p2-agonists Sympathomimetic symptoms such as Use as maintenance therapy when short-acting (sal meterol, {ormoterol, arformoterol, tremor and tachycardia; overdose can bronchodilators provide insufficient control of indacaterol, olodaterol) be fatal symptoms; not intended to be used fortreatment of exacerbations of COPD or acute bronchospasm Methylxanthines (theophylline, Tachycardia, nausea, vomiting, and Used as maintenance therapy; generally used only after aminophylline; sustained and disturbed sleep; narrow therapeutic long-acting bronchodilator treatment to provide short-acting) index; overdose can be fatal with additional symptomatic relief of exacerbations; may also seizures and arrhythmias improve respiratory muscle function Oral p2-agonists (albuterol, Sympathomimetic symptoms such as Used as maintenance therapy; rarely used because of meta proterenol, terbutal ine) tremor and tachycardia adverse effects but may be bene{icial {or patients who cannot use inhalers Oral Phosophodiesterase-4 lnhibitor Roflumilast Diarrhea, nausea, backache, decreased Used to reduce risk for exacerbations in patients with appetite, dizziness severe COPD with chronic bronchitis and history of exacerbations; roflumilast should not be used with methylxanthines because of potential toxicity Anti-lnfl ammatory Aqents lnhaled glucocorticoids (fl uticasone, Dysphonia, skin bruising, oral Most effective in patients with a history of frequent budesonide, mometasone, ciclesonide, candidiasis; rarely adverse effects of exacerbations and when used in conjunction with long- beclomethasone, fl unisolide) oral glucocorticoids (see below) aaing bronchodilators Oral glucocorticoids (prednisone, Skin bruising, adrenal suppression, Use for significant exacerbations of COPD; avoid, i{ prednisolone) glaucoma, osteoporosis, diabetes possible, in stable COPD to limit glucocorticoid toxicity; mellitus, systemic hypertension, consider inhaled glucocorticoids to facilitate weaning of pneu monia, cataracts, opportunistic systemic glucocorticoids infection, insomnia, mood disturbance Combination Agents Combined inhaled long-acting p2-agonist Same/combined effeas of both drug and inhaled glucocorticoid in a single classes inhaler (fluticasone/salmeterol, budesonide/formoterol, mometasonel formoterol) Combined short-acting B2-agonist plus Same/combined effeas of both drug Generally used as needed for mild disease with few short-acting anticholinergic in a single classes symptoms; avoid using both short- and long-acting inhaler (fenoterol/ipratropi u m, anticholinergics; this combination therapy may be used for albuterol/ipratropium) maintenance therapy only if patients have well-controlled disease on this combination treatment and do not require t rescue therapy iflwhen expense is a determining factor

Agent Adverse Effects Notes Bronchodilators lnhaled short-acting p2-agonists Tachycardia and hypokalemia (usually Generally used as needed for mild disease with few (albuterol, fenoterol, levalbuterol, dose dependent), but generally well symptoms metaproterenol, pirbuterol, terbutaline) tolerated by most patients lnhaled short-acting anticholinergic Dry mouth, mydriasis on contactwith eye, Generally used as needed for mild disease with few agents (ipratropium) tachycardia, tremors; rarely acute narrow- symptoms; avoid using both short- and long-acting angle glaucoma; this drug class has been a nticholinergics shown to be safe in a wide range of doses and clinical settings lnhaled long-acting anticholinergic Dry mouth, mydriasis on contact with Not to be used with ipratropium; use when short-acting agents (tiotropium, aclidinium, eye, tachycardia, tremors; rarely acute bronchodilators provide insufficient control of symptoms umeclidinium, glycopyrrolate) narrow-angle glaucoma lnhaled long-acting p2-agonists Sympathomimetic symptoms such as Use as maintenance therapy when short-acting (sal meterol, {ormoterol, arformoterol, tremor and tachycardia; overdose can bronchodilators provide insufficient control of indacaterol, olodaterol) be fatal symptoms; not intended to be used fortreatment of exacerbations of COPD or acute bronchospasm Methylxanthines (theophylline, Tachycardia, nausea, vomiting, and Used as maintenance therapy; generally used only after aminophylline; sustained and disturbed sleep; narrow therapeutic long-acting bronchodilator treatment to provide short-acting) index; overdose can be fatal with additional symptomatic relief of exacerbations; may also seizures and arrhythmias improve respiratory muscle function Oral p2-agonists (albuterol, Sympathomimetic symptoms such as Used as maintenance therapy; rarely used because of meta proterenol, terbutal ine) tremor and tachycardia adverse effects but may be bene{icial {or patients who cannot use inhalers Oral Phosophodiesterase-4 lnhibitor Roflumilast Diarrhea, nausea, backache, decreased Used to reduce risk for exacerbations in patients with appetite, dizziness severe COPD with chronic bronchitis and history of exacerbations; roflumilast should not be used with methylxanthines because of potential toxicity Anti-lnfl ammatory Aqents lnhaled glucocorticoids (fl uticasone, Dysphonia, skin bruising, oral Most effective in patients with a history of frequent budesonide, mometasone, ciclesonide, candidiasis; rarely adverse effects of exacerbations and when used in conjunction with long- beclomethasone, fl unisolide) oral glucocorticoids (see below) aaing bronchodilators Oral glucocorticoids (prednisone, Skin bruising, adrenal suppression, Use for significant exacerbations of COPD; avoid, i{ prednisolone) glaucoma, osteoporosis, diabetes possible, in stable COPD to limit glucocorticoid toxicity; mellitus, systemic hypertension, consider inhaled glucocorticoids to facilitate weaning of pneu monia, cataracts, opportunistic systemic glucocorticoids infection, insomnia, mood disturbance Combination Agents Combined inhaled long-acting p2-agonist Same/combined effeas of both drug and inhaled glucocorticoid in a single classes inhaler (fluticasone/salmeterol, budesonide/formoterol, mometasonel formoterol) Combined short-acting B2-agonist plus Same/combined effeas of both drug Generally used as needed for mild disease with few short-acting anticholinergic in a single classes symptoms; avoid using both short- and long-acting inhaler (fenoterol/ipratropi u m, anticholinergics; this combination therapy may be used for albuterol/ipratropium) maintenance therapy only if patients have well-controlled disease on this combination treatment and do not require t rescue therapy iflwhen expense is a determining factor Combined inhaled glucocorticoid and Same/combined effeas of both drug Not to be used for treatment of acute bronchospasm ultra-long-acting p2-agonist in a single classes inhaler (fluticasone/vilanterol) Combined long-acting anticholinergic Same/combined effects of both drug Not to be used for treatment of acute bronchospasm; plus ultra-long-acting p2-agonist in a classes avoid using both short- and long-acting anticholinergics t single inhaler (umeclidinium/vilanterol) r Combined long-acting anticholinergic plus Same/combined effects of both drug Not to be used for treatment of acute bronchospasm; long-acting p2-agonist in a single inhaler classes avoid using both short- and long-acting anticholinergics (olodaterol/g lycopyrrolate, ndacaterol/ I i

Combined inhaled glucocorticoid and Same/combined effeas of both drug Not to be used for treatment of acute bronchospasm ultra-long-acting p2-agonist in a single classes inhaler (fluticasone/vilanterol) Combined long-acting anticholinergic Same/combined effects of both drug Not to be used for treatment of acute bronchospasm; plus ultra-long-acting p2-agonist in a classes avoid using both short- and long-acting anticholinergics t single inhaler (umeclidinium/vilanterol) r Combined long-acting anticholinergic plus Same/combined effects of both drug Not to be used for treatment of acute bronchospasm; long-acting p2-agonist in a single inhaler classes avoid using both short- and long-acting anticholinergics (olodaterol/g lycopyrrolate, ndacaterol/ I i g lycopyrrolate, g lycopyrrolate/formoterol, I olodaterol/tiotropium ) b Combined long-acting anticholinergic Same/combined effects of both drug Not to be used for treatment of acute bronchospasm; I t plus long-acting p2-agonist plus inhaled c I asses avoid using both short- and long-acting anticholinergics corticosteroid in a single inhaler I (fluticasone/umeclidinium/vilanterol) : : : 19 i I

Airways Disease I nhale d Gluc o c ort ic o ids Other Agents Inhaled glucocorticoids are typically used only in combination Macrolide antibiotics have inflammatory and antimicrobial with a long-acting bronchodilator for treatment of COPD (see effects. Long term macrolide therapy may reduce the frequency Table 12). Inhaled glucocorticoids are not used alone unless a of exacerbations when prescribed for patients with severe patient is not able to use long acting bronchodilators (see COPD and a history of frequent exacerbations. Mucolytics and Table 13). Inhaled glucocorticoids used alone and in combina antitussives are not routinely used in the management of COPD tion with long-acting bronchodilators improve lung function but may provide some symptomatic relief in patients with sig and reduce symptoms and exacerbations in patients with nificant sputum production. moderate to severe COPD, but they are associated with an increased risk for pneumonia. In patients with severe COPD, Immunization triple inhaler therapy with a LABA, a LAMA, and an inhaled Immunizations can prevent infections in patients with COPD. glucocorticoid may provide additional symptom benefit and Because infections are the most common trigger of acute exac reduced exacerbations. erbations. routine immunizations are recommended for all patients with COPD. Patients should receive the pneumococ rEY POIIITS cal polysaccharide vaccine (PPSV23) and an annual influenza . Bronchodilators are the mainstay of therapy for COPD immunization. Immunocompetent patients aged 65 years and irrespective of the severity of the COPD. older should be engaged in shared decision making regarding . Any time bronchodilators or other inhalers are prescribed, vaccination with the pneumococcal conjugate vaccine (PCV13). the clinician should ensure that the patient receives (See MKSAP 19 General Internal Medicine 2: Routine Care of education on proper inhaler technique. the Healthy Patient/Immunization section.)

I nhale d Gluc o c ort ic o ids Other Agents Inhaled glucocorticoids are typically used only in combination Macrolide antibiotics have inflammatory and antimicrobial with a long-acting bronchodilator for treatment of COPD (see effects. Long term macrolide therapy may reduce the frequency Table 12). Inhaled glucocorticoids are not used alone unless a of exacerbations when prescribed for patients with severe patient is not able to use long acting bronchodilators (see COPD and a history of frequent exacerbations. Mucolytics and Table 13). Inhaled glucocorticoids used alone and in combina antitussives are not routinely used in the management of COPD tion with long-acting bronchodilators improve lung function but may provide some symptomatic relief in patients with sig and reduce symptoms and exacerbations in patients with nificant sputum production. moderate to severe COPD, but they are associated with an increased risk for pneumonia. In patients with severe COPD, Immunization triple inhaler therapy with a LABA, a LAMA, and an inhaled Immunizations can prevent infections in patients with COPD. glucocorticoid may provide additional symptom benefit and Because infections are the most common trigger of acute exac reduced exacerbations. erbations. routine immunizations are recommended for all patients with COPD. Patients should receive the pneumococ rEY POIIITS cal polysaccharide vaccine (PPSV23) and an annual influenza . Bronchodilators are the mainstay of therapy for COPD immunization. Immunocompetent patients aged 65 years and irrespective of the severity of the COPD. older should be engaged in shared decision making regarding . Any time bronchodilators or other inhalers are prescribed, vaccination with the pneumococcal conjugate vaccine (PCV13). the clinician should ensure that the patient receives (See MKSAP 19 General Internal Medicine 2: Routine Care of education on proper inhaler technique. the Healthy Patient/Immunization section.) I(EY POII{TT Oral Glucocorticoids Oral glucocorticoids are recommended for short duration treat . Oral glucocorticoids are recommended for short duration ment ofacute exacerbations ofCOPD (see Acute Exacerbations: treatment of acute exacerbations of COPD; Iong term Goals and Therapeutic Management section). However, long use of oral glucocorticoids should be avoided.

I(EY POII{TT Oral Glucocorticoids Oral glucocorticoids are recommended for short duration treat . Oral glucocorticoids are recommended for short duration ment ofacute exacerbations ofCOPD (see Acute Exacerbations: treatment of acute exacerbations of COPD; Iong term Goals and Therapeutic Management section). However, long use of oral glucocorticoids should be avoided. term use oforal glucocorticoids should be avoided because of o All patients with COPD should have the pneumococcal the risk for significant adverse eflfects, including diabetes and polysaccharide vaccine and an annual influenza immu osteoporosis. nization.

term use oforal glucocorticoids should be avoided because of o All patients with COPD should have the pneumococcal the risk for significant adverse eflfects, including diabetes and polysaccharide vaccine and an annual influenza immu osteoporosis. nization. Methylxanthines Nonpharmacologic Therapy The methylxanthines (aminophylline and theophylline) are P ul mo nar y Re hab ilitat io n now rarely used to treat COPD. Theophylline has been shown Pulmonary rehabilitation is a comprehensive program that to improve functional capacity and reduce the number of combines exercise training, nutritional support, education, exacerbations. However. it has a narrow window between and social support for patients with chronic lung conditions. It therapeutic and toxic dosages and is therefore only used for has been shown to relieve symptoms, improve qualiry of life, patients with advanced COPD who have refractory symptoms and decrease frequency of hospitalizations in patients with not controlled by standard therapy. Studies ofthe use ofeither COPD. Clinicians should consider adding this to appropriate aminophylline or theophylline during acute exacerbations medicai therapy in patients with a GOLD severity group of B, have shown no benefit. C, or D, and particularly in those recently hospitalized after an exacerbation. Roflumilast Roflumilast is a selective phosphodiesterase 4 inhibitor that is OxygenTherapy used to reduce the frequency ofexacerbations in patients with The use of supplemental oxygen has been shown to improve severe COPD who have primarily symptoms of chronic quality of life and decrease mortality in patients with COPD bronchitis. and resting hypoxemia with an arterial Po, of 55 mm Hg or less or an oxygen saturation (as measured by pulse oxime a, - Antitry psin Augmentation Therapy try) of 88%, or less. Patients with cor pulmonale, heart Antiproteases, including cr,-antitrypsin, typically inactivate failure, or erythrocytosis should be offered the use of sup proteases that may lead to permanent lung injury. In patients plemental oxygen if their Po2 is 59 mm Hg or less or their with cr, antitrypsin deficiency, replacing this enzyme with oxygen saturation is 89% or less. Some patients may not augmentation therapy may slow the progression of related qualify for oxygen at rest but may desaturate during sleep, emphysema. However, it is costly, has not been shown to exertion, or air travel. Supplemental orygen is typically decrease exacerbations or the rate ofFEV, decline, and is not prescribed if the oxygen saturation as measured by pulse effective for the treatment of patients whose COPD is not oximetry falls below 89% in these situations, but the ben- caused by o, antitrypsin deficiency. efits are Iess defined.

Methylxanthines Nonpharmacologic Therapy The methylxanthines (aminophylline and theophylline) are P ul mo nar y Re hab ilitat io n now rarely used to treat COPD. Theophylline has been shown Pulmonary rehabilitation is a comprehensive program that to improve functional capacity and reduce the number of combines exercise training, nutritional support, education, exacerbations. However. it has a narrow window between and social support for patients with chronic lung conditions. It therapeutic and toxic dosages and is therefore only used for has been shown to relieve symptoms, improve qualiry of life, patients with advanced COPD who have refractory symptoms and decrease frequency of hospitalizations in patients with not controlled by standard therapy. Studies ofthe use ofeither COPD. Clinicians should consider adding this to appropriate aminophylline or theophylline during acute exacerbations medicai therapy in patients with a GOLD severity group of B, have shown no benefit. C, or D, and particularly in those recently hospitalized after an exacerbation. Roflumilast Roflumilast is a selective phosphodiesterase 4 inhibitor that is OxygenTherapy used to reduce the frequency ofexacerbations in patients with The use of supplemental oxygen has been shown to improve severe COPD who have primarily symptoms of chronic quality of life and decrease mortality in patients with COPD bronchitis. and resting hypoxemia with an arterial Po, of 55 mm Hg or less or an oxygen saturation (as measured by pulse oxime a, - Antitry psin Augmentation Therapy try) of 88%, or less. Patients with cor pulmonale, heart Antiproteases, including cr,-antitrypsin, typically inactivate failure, or erythrocytosis should be offered the use of sup proteases that may lead to permanent lung injury. In patients plemental oxygen if their Po2 is 59 mm Hg or less or their with cr, antitrypsin deficiency, replacing this enzyme with oxygen saturation is 89% or less. Some patients may not augmentation therapy may slow the progression of related qualify for oxygen at rest but may desaturate during sleep, emphysema. However, it is costly, has not been shown to exertion, or air travel. Supplemental orygen is typically decrease exacerbations or the rate ofFEV, decline, and is not prescribed if the oxygen saturation as measured by pulse effective for the treatment of patients whose COPD is not oximetry falls below 89% in these situations, but the ben- caused by o, antitrypsin deficiency. efits are Iess defined. 20

Airways Disease tYon i nuos iue Positiu e P ressure Ve ntilation exercise tolerance, pulmonary function, and survival with Noninvasive positive pressure ventilation (NPPV), also lung volume reduction surgery. A key finding from the termed noninvasive mechanical ventilation, can be used for National Emphysema Treatment Trial was that patient selec acute and chronic respiratory failure. For patients with a tion was critical to success and that patients with an FEV, of I COPD exacerbation and acute hypercapnic respiratory failure less than 2OoL of predicted, a diffusing capacity of less than with acidosis, NPPV improves symptoms and reduces intuba- 20"/,, of predicted, or non upper lobe predominant disease tion rates, lengths of hospital stay, and mortality. It may also had a high operative mortality and should not be offered lung be beneficial in patients with COPD who have pneumonia to volume reduction surgery. Nonsurgical lung volume reduction help with discontinuing mechanical ventilation and for pal- procedures, including bronchoscopic placement of endobron liative care. It does not replace intubation and mechanical chial valves or plugs and thermal ablation of the airway, are ventilation in critically ill patients, comatose patients, or being studied for treatment of emphysematous changes in patients who have sustained a cardiac arrest. NPPV is gener- patients with COPD. Early results suggest that patients with ally well tolerated, and improvement of the pH and Pco, severe air trapping and hyperinflation may get the most ben within 1 to 2 hours predicts success. Adding home NPPV to efit from these new techniques. Patient selection criteria for oxygen therapy in patients with persistent hypercapnia after surgical lung volume reduction also apply to nonsurgical an acute exacerbation of COPD prolongs the time to readmis- techniques. sion and death. Lung Transplantation Prognosis and Goals ofCare Referral for lung transplantation can be considered in patients 'l'he current GOLD initiative recommends combining the with severe COPD. The decision to refer should depend on the degree of airflow limitation using the postbronchodilator FEV, patient's life expectancy, quality of life, and preferences. In with the number of exacerbations and the patient's symptoms general, patients at high risk of dying in less than 2 years who to classiff the severity of disease. This will allow the clinician have a high probability of 90 day postoperative survival are to guide escalation or deescalation of medical therapies as candidates. Patients with an elevated BODE index (5 or 6), appropriate (see Tables 10, 11, and 12). resting hypoxemia, hypercapnia, an FEV, of less than 25"/,, of I The BODE index (see Table 9) can be used as a prognostic predicted, or significant exercise limitation despite medical ir.rdicator for patients with COPD to approximate 4 year therapy, smoking cessation, and participation in a pulmonary survival. rehabilitation program may be referred for evaluation for lung In patients with severe disease with an overall poor prog- transplantation. Transplantation improves quality of life, and nosis, referral for palliative care or hospice can provide signifi- the median Iife expectancy is 5.5 years. cant improvements in symptom burden. Palliative care can significantly aid in symptom management in patients with COPD at any stage of disease. Patients experience not only Acute Exacerbations dyspnea but also anxiety and depression, which may also be Definition addressed. Opioids are commonly used to treat dyspnea that An acute exacerbation of COPD is a worsening of a patient's persists despite medical therapy. Guidelines suggest a patient typical symptoms that leads to a change in medical therapy with severe COPD defined by disabling symptoms despite or requires hospitalization. Most commonly, exacerbations are manifested by an increase in the severity or frequency of medical therapy, progression of disease as evidenced by cough, worsening dyspnea, and an increase in the amount increasing emergency department evaluations or hospitaliza tions, and hypoxemia or hypercapnia should be considered or change in the character of sputum produced. Most exac erbations are triggered by a respiratory infection (either viral for hospice care. or bacterial), smoking, and environmental exposures. An I(EY POI l{T exacerbation can be triggered by other causes, and in some : o Guidelines suggest that a patient with severe COPD cases no trigger is identified. Studies suggest that exacerba (defined by disabling symptoms despite medical ther- tions are underreported by patients and result in adverse apy, progression of disease as evidenced by increasing outcomes. emergency department evaluations or hospitalizations, I(EY POII{T and hypoxemia or hypercapnia) should be considered o An acute exacerbation of COPD is a change in a patient's lor hospice care. typical symptoms that leads to a change in medical therapy or hospitalizationi the most common symp Lung Volume Reduction Therapy toms of exacerbations are an increase in the severity The National Emphysema Treatment Trial demonstrated that or frequency ofcough, worsening dyspnea, and an patients with upper lobe predominant emphysema and sig increase in the amount or change in the character of nificant exercise limitations even after participation in a pul sputum produced. monary rehabilitation program had improved quality of life,

tYon i nuos iue Positiu e P ressure Ve ntilation exercise tolerance, pulmonary function, and survival with Noninvasive positive pressure ventilation (NPPV), also lung volume reduction surgery. A key finding from the termed noninvasive mechanical ventilation, can be used for National Emphysema Treatment Trial was that patient selec acute and chronic respiratory failure. For patients with a tion was critical to success and that patients with an FEV, of I COPD exacerbation and acute hypercapnic respiratory failure less than 2OoL of predicted, a diffusing capacity of less than with acidosis, NPPV improves symptoms and reduces intuba- 20"/,, of predicted, or non upper lobe predominant disease tion rates, lengths of hospital stay, and mortality. It may also had a high operative mortality and should not be offered lung be beneficial in patients with COPD who have pneumonia to volume reduction surgery. Nonsurgical lung volume reduction help with discontinuing mechanical ventilation and for pal- procedures, including bronchoscopic placement of endobron liative care. It does not replace intubation and mechanical chial valves or plugs and thermal ablation of the airway, are ventilation in critically ill patients, comatose patients, or being studied for treatment of emphysematous changes in patients who have sustained a cardiac arrest. NPPV is gener- patients with COPD. Early results suggest that patients with ally well tolerated, and improvement of the pH and Pco, severe air trapping and hyperinflation may get the most ben within 1 to 2 hours predicts success. Adding home NPPV to efit from these new techniques. Patient selection criteria for oxygen therapy in patients with persistent hypercapnia after surgical lung volume reduction also apply to nonsurgical an acute exacerbation of COPD prolongs the time to readmis- techniques. sion and death. Lung Transplantation Prognosis and Goals ofCare Referral for lung transplantation can be considered in patients 'l'he current GOLD initiative recommends combining the with severe COPD. The decision to refer should depend on the degree of airflow limitation using the postbronchodilator FEV, patient's life expectancy, quality of life, and preferences. In with the number of exacerbations and the patient's symptoms general, patients at high risk of dying in less than 2 years who to classiff the severity of disease. This will allow the clinician have a high probability of 90 day postoperative survival are to guide escalation or deescalation of medical therapies as candidates. Patients with an elevated BODE index (5 or 6), appropriate (see Tables 10, 11, and 12). resting hypoxemia, hypercapnia, an FEV, of less than 25"/,, of I The BODE index (see Table 9) can be used as a prognostic predicted, or significant exercise limitation despite medical ir.rdicator for patients with COPD to approximate 4 year therapy, smoking cessation, and participation in a pulmonary survival. rehabilitation program may be referred for evaluation for lung In patients with severe disease with an overall poor prog- transplantation. Transplantation improves quality of life, and nosis, referral for palliative care or hospice can provide signifi- the median Iife expectancy is 5.5 years. cant improvements in symptom burden. Palliative care can significantly aid in symptom management in patients with COPD at any stage of disease. Patients experience not only Acute Exacerbations dyspnea but also anxiety and depression, which may also be Definition addressed. Opioids are commonly used to treat dyspnea that An acute exacerbation of COPD is a worsening of a patient's persists despite medical therapy. Guidelines suggest a patient typical symptoms that leads to a change in medical therapy with severe COPD defined by disabling symptoms despite or requires hospitalization. Most commonly, exacerbations are manifested by an increase in the severity or frequency of medical therapy, progression of disease as evidenced by cough, worsening dyspnea, and an increase in the amount increasing emergency department evaluations or hospitaliza tions, and hypoxemia or hypercapnia should be considered or change in the character of sputum produced. Most exac erbations are triggered by a respiratory infection (either viral for hospice care. or bacterial), smoking, and environmental exposures. An I(EY POI l{T exacerbation can be triggered by other causes, and in some : o Guidelines suggest that a patient with severe COPD cases no trigger is identified. Studies suggest that exacerba (defined by disabling symptoms despite medical ther- tions are underreported by patients and result in adverse apy, progression of disease as evidenced by increasing outcomes. emergency department evaluations or hospitalizations, I(EY POII{T and hypoxemia or hypercapnia) should be considered o An acute exacerbation of COPD is a change in a patient's lor hospice care. typical symptoms that leads to a change in medical therapy or hospitalizationi the most common symp Lung Volume Reduction Therapy toms of exacerbations are an increase in the severity The National Emphysema Treatment Trial demonstrated that or frequency ofcough, worsening dyspnea, and an patients with upper lobe predominant emphysema and sig increase in the amount or change in the character of nificant exercise limitations even after participation in a pul sputum produced. monary rehabilitation program had improved quality of life, 21

Airways Disease Prevention Supplemental oxygen should be used to maintain oxygen satu Acute exacerbations of COPD can have substantial effects on ration between 88% and 92',1,. Noninvasive positive pressure quality of life and health care costs, and they may accelerate ventilation may be required if oxygenation or ventilation can the decline in lung function and increase mortality. It is there not be maintained. Patients may require intubation and fore important to prevent exacerbations whenever possible. mechanical ventilation if they cannot tolerate NPPV. have an Strategies to prevent exacerbations include smoking cessation, altered mental status, or have rnorsening hypercapnic or participating in pulmonary rehabilitation programs when hypoxemic respiratory failure despite the use of NPPV. SABAs appropriate, receiving recommended immunizations, and 'a,ith or lr.ithout anticholinergic agents should be used to relieve ensuring proper inhaler technique and use of medications. acute symptoms. The use of oral glucocorticoids during acute Long term use of azithromycin or roflumilast has also been exacerbations has been shown to decrease the frequencl' of shown to prevent future exacerbations in patients who have a treatment failures, Iength of stay, and time to subsequent exac history of frequent exacerbations. erbations while improving FEV, and hypoxemia. Glucocorticoids have also been shown to decrease the need for hospitalization if I(EY POIlII used early. Randomized trials have demonstrated that short o Strategies to prevent COPD exacerbations include courses of lower dose oral prednisone (+o mg for 5 days) are smoking cessation, participating in pulmonary rehabili usually equiralent to longer courses, higher doses. and intrave- tation programs when appropriate, receiving recom nous administration. mended immunizations, and ensuring proper inhaler Antibiotics should be prescribed for 5 to 7 day's in cases of technique and use of medications. moderate or severe exacerbations or for patients lvith mild exacerbations who have noted an increase or change in spu Initial Assessment and Setting of Care tum production. A 2020 systemic revier,r, and meta-analysis The first steps in managing a patient r.r,ith a presumed COPD showed that for mild to severe COPD exacerbations. antibio exacerbation are to conflrm the diagnosis and determine the tics and oral glucocorticoids reduced treatment failure. The severity of the exacerbation. A mild exacerbation is one that most common infectious tri$lers are viruses. but bacterial can be managed solely by short acting bronchodilators. A causes include Streprococcu s pneumoniae. Hoemophibs influ moderate exacerbation requires treatment with antibiotics, enme. Moraxella catarrhalis, and Mycoplasma pneumoniae. glucocorticoids, or both. A severe exacerbation is defined by If the patient is still smoking, treatment should also focus the need for an evaluation in the emergency department or on smoking cessation because this can prevent future exacer hospitalization. Patients with respiratory distress ona,ho are at bations. Because the prevalence of pulmonary embolism is risk ofdeveloping respiratory distress should be hospitalized; higher in patients with COPD. a thromboembolic event should additional testing, including a chest radiograph. electrocardio- be considered as a potential trigger if patients do not improve gram, complete blood count, and basic metabolic panel, with rypical therapies for a COPD exacerbation. and appropri should be obtained to rule out other causes or comorbidities ate testing should be performed. contributing to the acute presentation. Oxygen saturation should be measured by pulse oximetry. Arterial blood gas Bronchiectasis measurement is recommended for patients with a severe exac- erbation to determine the presence of hypercapnia or hypox- Definition emia. A sputum culture is not routinely used to assess COPD Bronchiectasis is a chronic suppurative lung disease associated exacerbations as it rarely affects management. Patients with with irreversible enlargement of the ain^,ays due to destruc mild symptoms may not require any additional testing. tion of airway architecture. An injury to the lung typicall)' results in prolonged airway inflammation. rvhich leads to XEY POII{T5 localized injury with subsequent mucus stasis. r,r.hich can lead . Patients who have COPD and respiratory distress or to further airway obstruction. chronic infection. and inflam who are at risk of developing respiratory distress should mation r.l,ith worsening bronchiectasis. be hospitalized and evaluated with a chest radiograph, electrocardiogram, complete blood count, basic metabolic Causes panel, and oxygen saturation; arterial blood gas measure In many cases of bronchiectasis, an underlying cause is not ments can determine the presence of hypercapnia or identified. The most common causes olbronchiectasis include hypoxemia. cystic fibrosis. aspiration. immunodeficiencies. and connec HVC . A sputum culture is not routinely used to assess COPD tive tissue diseases (Table 14). exacerbations, as it rarely affects management. Presentation Goals and Therapeutic Management Bronchiectasis should be considered in the differential diagno The management goals during an acute COPD exacerbation are sis of any patient with a chronic cough, especially if the patient to relieve acute symptoms and to prevent future exacerbations. has a history of frequent respiratory infections or if the cough

Prevention Supplemental oxygen should be used to maintain oxygen satu Acute exacerbations of COPD can have substantial effects on ration between 88% and 92',1,. Noninvasive positive pressure quality of life and health care costs, and they may accelerate ventilation may be required if oxygenation or ventilation can the decline in lung function and increase mortality. It is there not be maintained. Patients may require intubation and fore important to prevent exacerbations whenever possible. mechanical ventilation if they cannot tolerate NPPV. have an Strategies to prevent exacerbations include smoking cessation, altered mental status, or have rnorsening hypercapnic or participating in pulmonary rehabilitation programs when hypoxemic respiratory failure despite the use of NPPV. SABAs appropriate, receiving recommended immunizations, and 'a,ith or lr.ithout anticholinergic agents should be used to relieve ensuring proper inhaler technique and use of medications. acute symptoms. The use of oral glucocorticoids during acute Long term use of azithromycin or roflumilast has also been exacerbations has been shown to decrease the frequencl' of shown to prevent future exacerbations in patients who have a treatment failures, Iength of stay, and time to subsequent exac history of frequent exacerbations. erbations while improving FEV, and hypoxemia. Glucocorticoids have also been shown to decrease the need for hospitalization if I(EY POIlII used early. Randomized trials have demonstrated that short o Strategies to prevent COPD exacerbations include courses of lower dose oral prednisone (+o mg for 5 days) are smoking cessation, participating in pulmonary rehabili usually equiralent to longer courses, higher doses. and intrave- tation programs when appropriate, receiving recom nous administration. mended immunizations, and ensuring proper inhaler Antibiotics should be prescribed for 5 to 7 day's in cases of technique and use of medications. moderate or severe exacerbations or for patients lvith mild exacerbations who have noted an increase or change in spu Initial Assessment and Setting of Care tum production. A 2020 systemic revier,r, and meta-analysis The first steps in managing a patient r.r,ith a presumed COPD showed that for mild to severe COPD exacerbations. antibio exacerbation are to conflrm the diagnosis and determine the tics and oral glucocorticoids reduced treatment failure. The severity of the exacerbation. A mild exacerbation is one that most common infectious tri$lers are viruses. but bacterial can be managed solely by short acting bronchodilators. A causes include Streprococcu s pneumoniae. Hoemophibs influ moderate exacerbation requires treatment with antibiotics, enme. Moraxella catarrhalis, and Mycoplasma pneumoniae. glucocorticoids, or both. A severe exacerbation is defined by If the patient is still smoking, treatment should also focus the need for an evaluation in the emergency department or on smoking cessation because this can prevent future exacer hospitalization. Patients with respiratory distress ona,ho are at bations. Because the prevalence of pulmonary embolism is risk ofdeveloping respiratory distress should be hospitalized; higher in patients with COPD. a thromboembolic event should additional testing, including a chest radiograph. electrocardio- be considered as a potential trigger if patients do not improve gram, complete blood count, and basic metabolic panel, with rypical therapies for a COPD exacerbation. and appropri should be obtained to rule out other causes or comorbidities ate testing should be performed. contributing to the acute presentation. Oxygen saturation should be measured by pulse oximetry. Arterial blood gas Bronchiectasis measurement is recommended for patients with a severe exac- erbation to determine the presence of hypercapnia or hypox- Definition emia. A sputum culture is not routinely used to assess COPD Bronchiectasis is a chronic suppurative lung disease associated exacerbations as it rarely affects management. Patients with with irreversible enlargement of the ain^,ays due to destruc mild symptoms may not require any additional testing. tion of airway architecture. An injury to the lung typicall)' results in prolonged airway inflammation. rvhich leads to XEY POII{T5 localized injury with subsequent mucus stasis. r,r.hich can lead . Patients who have COPD and respiratory distress or to further airway obstruction. chronic infection. and inflam who are at risk of developing respiratory distress should mation r.l,ith worsening bronchiectasis. be hospitalized and evaluated with a chest radiograph, electrocardiogram, complete blood count, basic metabolic Causes panel, and oxygen saturation; arterial blood gas measure In many cases of bronchiectasis, an underlying cause is not ments can determine the presence of hypercapnia or identified. The most common causes olbronchiectasis include hypoxemia. cystic fibrosis. aspiration. immunodeficiencies. and connec HVC . A sputum culture is not routinely used to assess COPD tive tissue diseases (Table 14). exacerbations, as it rarely affects management. Presentation Goals and Therapeutic Management Bronchiectasis should be considered in the differential diagno The management goals during an acute COPD exacerbation are sis of any patient with a chronic cough, especially if the patient to relieve acute symptoms and to prevent future exacerbations. has a history of frequent respiratory infections or if the cough 22

Airways Disease TABLE 14. Common Causes of Bronchiectasis Airway obstruction Tumor Foreign body Aspiration COPD Congenital Mounier Kuhn syndrome (congenital tracheobronchomegaly) Autoimmune disorders Rheumatoid arthritis Sjogren's syndrome lnflammatory bowel disease Hype rsensitivity Allergic bronchopulmonary aspergillosis lm m u nodeficiency Common variable immunode{iciency tIGURE 4. BronchiectasisonchestCT.Theairwayislargerthanitsaccompanying blood vessel lthick blue arrow) and the airway {ails t0 taper distally (thin red arrows). HIV Mucoci liary dysfunction presence of cor-rnective tissue disease and immune function. ln Cystic fibrosis selected patients, testing fbr cystic tibrosis. ciliary dysfuncti<-rtt. Primary ciliary dyskinesia or Gr antitrypsin deficiency may be appropriate. However, Young syndrome ( bronchiectasis, sinusitis, and obstructive even with rigrirous evaluation, more than half ol all cases are azoospermia and no evidence of cystic fibrosis) Iabelecl icliopatl.ric. lnfection - re lated t(EY POtl{rS Tuberculosis . In acute COPD exacerbations, 40 mg prednisone for 5 days Nontuberculous mycobacteria has been shown to decrease the frequency of treatment Pneumonia, especially recurrent failures, length of stay, and time to subsequent exacer bations while improving FEV, and hypoxemia. is productive. Other prissible symptoms include hemoptysis, . Bronchiectasis is diagnosed by high resolution chest wheezing, and chest pain. Features that should alert the clini CT; diagnostic criteria include airway diameter greater

Mucoci liary dysfunction presence of cor-rnective tissue disease and immune function. ln Cystic fibrosis selected patients, testing fbr cystic tibrosis. ciliary dysfuncti<-rtt. Primary ciliary dyskinesia or Gr antitrypsin deficiency may be appropriate. However, Young syndrome ( bronchiectasis, sinusitis, and obstructive even with rigrirous evaluation, more than half ol all cases are azoospermia and no evidence of cystic fibrosis) Iabelecl icliopatl.ric. lnfection - re lated t(EY POtl{rS Tuberculosis . In acute COPD exacerbations, 40 mg prednisone for 5 days Nontuberculous mycobacteria has been shown to decrease the frequency of treatment Pneumonia, especially recurrent failures, length of stay, and time to subsequent exacer bations while improving FEV, and hypoxemia. is productive. Other prissible symptoms include hemoptysis, . Bronchiectasis is diagnosed by high resolution chest wheezing, and chest pain. Features that should alert the clini CT; diagnostic criteria include airway diameter greater cian to consider bronchiectasis, especialiy without significant than that of its accompanying vessel and lack of distal smoking history, include clubbing and previous sputum cul airway tapering. tures growing uncommon pathogens such as Pseudomonos . For every patient diagnosed with bronchiectasis, it aeruginosa. Aspergillus, or nontuberculous mycobacteria. should be determined whether there is an underlying Patients with bronchiectasis may also present with cause that can be treated. extrirpulmonary sylnptoms, especially fatigue. Treatment Diagnosis The presencc of chronic symptoms of cough and sputum Initial evaluatiur.r sl.rould include a comprehensive medical production typically indicates irreversible airway dilation. histor1,. ir.rclucling childhood diseases. family history and ctlre 'lherefbre, treitment of tl.re underlying cause may not lead to lul evrluation to exclucle knou,n causes of bronchiectasis. improver.nent in current symptoms but could prevent further Bronchiectasis is diagnosed by high resolution chest CT. progrcssion. Otl.rer'"r,ise. treatment of bronchiectasis fbcuses Diagnostic criteria include an air$,ay diameter that is greater t.rn clearing the airu,a!,. treating infections, and preventing than that of its lccomp:rnying vessel and lack of distal airway eracerbltions. 'l-he goal ol irirway clearance is to improve tapering (Figure 4). llronchial wall thickening or cysts may be mucous clear:rnce and tl-rereby prevent chronic or recurrent present. For every cliagnosecl patient. it should be determined infectirlns. Broncl.roclilators, ir.rhaled glucocorticoids, and lvhethcr thcrc is an r.rnclerlying ciruse that can be treated. This combinatior-r ir-rhalers have been shown to decrease symptonls mtry involve testing tbr chronic bacterial or mycobacterial but havc no ellect on the clecline of lung function or frequency infbctions. 'l'hese tests can iclentify causes of disease progres of'exacerbltitins. Studies suggest that long-term use clf mac- sion and l.relp cleterrnine targeted antimicrobial therapy rolide ar.rtibiotics may prevent future exacerbations as a result lbr exacerbations. Patients sh<-ruld also be evaluated fbr the of their anti inflarnmatory effects. When deciding whether to

cian to consider bronchiectasis, especialiy without significant than that of its accompanying vessel and lack of distal smoking history, include clubbing and previous sputum cul airway tapering. tures growing uncommon pathogens such as Pseudomonos . For every patient diagnosed with bronchiectasis, it aeruginosa. Aspergillus, or nontuberculous mycobacteria. should be determined whether there is an underlying Patients with bronchiectasis may also present with cause that can be treated. extrirpulmonary sylnptoms, especially fatigue. Treatment Diagnosis The presencc of chronic symptoms of cough and sputum Initial evaluatiur.r sl.rould include a comprehensive medical production typically indicates irreversible airway dilation. histor1,. ir.rclucling childhood diseases. family history and ctlre 'lherefbre, treitment of tl.re underlying cause may not lead to lul evrluation to exclucle knou,n causes of bronchiectasis. improver.nent in current symptoms but could prevent further Bronchiectasis is diagnosed by high resolution chest CT. progrcssion. Otl.rer'"r,ise. treatment of bronchiectasis fbcuses Diagnostic criteria include an air$,ay diameter that is greater t.rn clearing the airu,a!,. treating infections, and preventing than that of its lccomp:rnying vessel and lack of distal airway eracerbltions. 'l-he goal ol irirway clearance is to improve tapering (Figure 4). llronchial wall thickening or cysts may be mucous clear:rnce and tl-rereby prevent chronic or recurrent present. For every cliagnosecl patient. it should be determined infectirlns. Broncl.roclilators, ir.rhaled glucocorticoids, and lvhethcr thcrc is an r.rnclerlying ciruse that can be treated. This combinatior-r ir-rhalers have been shown to decrease symptonls mtry involve testing tbr chronic bacterial or mycobacterial but havc no ellect on the clecline of lung function or frequency infbctions. 'l'hese tests can iclentify causes of disease progres of'exacerbltitins. Studies suggest that long-term use clf mac- sion and l.relp cleterrnine targeted antimicrobial therapy rolide ar.rtibiotics may prevent future exacerbations as a result lbr exacerbations. Patients sh<-ruld also be evaluated fbr the of their anti inflarnmatory effects. When deciding whether to 23

Airways Disease use macrolide antibiotics, the risk for future exacerbations areas of tissue destruction, which further drives increased should be weighed against the possibility of developing mac- viscosity of lung secretions. rolide resistance. Antibiotics may also be used in the manage Thickened secretions in the gastrointestinal tract impair ment of chronic non cystic-fibrosis bronchiectasis to eradicate flow of bile and pancreatic secretions, leading to pancreatic organisms such as P. oeruginosa or methicillin-resistant exocrine and endocrine deficiency, liver disease. and the Staphylococcus oureus. If eradication of bacterial colonization development of malabsorption and maldigestion. The secre is not successful, there may be some symptomatic benefit from tions increase the risk for bowel obstruction (distal ileal suppressive therapy with inhaled antibiotics. Patients should obstructive syndrome, intussusception, and rectal prolapse). also be encouraged to exercise, which can improve airway As a consequence, individuals with CF often present r,r,ith clearance and symptoms. Surgical resection should be consid malnutrition and weight loss. ered in patients who have localized disease with persistent symptoms despite therapy. Diagnosis Most patients with CF are diagnosed as children. Adults diag xtY P0ttls nosed with CF most often present with pulmonary or gastro- o Identification and treatment of underlying causes of intestinal symptoms. Pulmonary manifestations often include bronchiectasis should be initiated if possible. chronic productive cough, recurrent sinusitis, and recurrent . Treatment of bronchiectasis focuses on clearing the air- pulmonary infections requiring several courses of antibiotics. way, treating infections, and preventing exacerbations. For those with gastrointestinal symptoms, loose and frequent stools with abdominal pain are the most common. Pancreatic Treatment of Exacerbations insufficiency (either endocrine or exocrine) may occur but is Exacerbations of bronchiectasis may be difficult to differenti- less common. Chronic, persistent pulmonary or gastrointesti ate from baseline symptoms. However, changes in sputum nal symptoms requiring repetitive treatment should raise sus- volume, viscosity, or purulence; increased cough; wheezing; picion for CF, Radiographic findings include hyperinflation shortness of breath; hemoptysis; or declines in lung function followed by bronchiectasis and cyst formation with disease are considered evidence of an exacerbation. Therapy for an progression, often beginning in the upper lobes. exacerbation is ideally guided by routine sputum and acid- Often the greatest challenge in diagnosing CF is failing to fast bacilli culture results to identify a possible predominant include it in the differential diagnosis. A family history of CF organism for treatment. Empiric antibiotic therapy is recom- can be quite helpful in this regard. Sweat chloride testing is the mended and may be based on previous culture data until the initial test for CE, although it is less sensitive in adults. results of the current sputum culture become available. If Abnormal results on repeat testing are diagnostic of CF. Genetic previous data are not available, a fluoroquinolone can be testing confirms the diagnosis and helps with prognosis. A started to ensure Pseudomonos coverage until sputum culture negative sweat chloride test in an adult patient does not rule results are available. out disease. Therefore, if the clinical suspicion remains high after negative repeat sweat chloride testing, consideration lor referral to a center with expertise in CF or genetic testing is Cystic Fibrosis appropriate. Cystic fibrosis (CF) is an autosomal recessive disease affecting TEY POIilIS the CF transmembrane conductance regulator (CFTR) gene. It is diagnosed in approximately 1 of 2000 to 3000 live births r Adults diagnosed with cystic fibrosis most often present with a predilection for disease in those of European descent. with pulmonary or gastrointestinal symptoms; pulmo- \ The most common genetic variant resulting in disease is nary manifestations often include chronic productive AF50B, but there are at least 1500 other genetic mutations. cough, recurrent sinusitis, and recurrent pulmonary The pathogenesis for clinical manifestations of CF remains infections requiring several courses of antibiotics. incompletely understood; however, the abnormal homozy . A negative sweat chloride test in a patient who presents gous CFTR genotype results in abnormally thick secretions as an adult should not rule out cystic fibrosis. that are difficult to clear. There is an increased concentration of chloride in sweat gland secretions, and sweat chloride test Treatment ing is a primary diagnostic tool for CF. The changes in res The pillars of CF management are airway clearance. antibiotic piratory secretions lead to bacterial colonization of airways therapy, nutritional support, and psychosocial support. The and chronic bacterial infection, resulting in chronic inflam primary objectives of CF treatment are maintaining lung mation and, ultimately, bronchiectasis. Further tissue health and controlling/minimizing the effect of CF-affected destruction results from insufficient lung antiproteases to organ disease. The Cystic Fibrosis Foundation practice guide counteract the effect of elastase released from neutrophils. lines recommend use of chronic medications to improve This ongoing inflammatory process also results in large lung function and reduce exacerbations. These medications amounts of free DNA and matrix protein deposition within include mucolltics, hydrating agents, inhaled antibiotics, oral

use macrolide antibiotics, the risk for future exacerbations areas of tissue destruction, which further drives increased should be weighed against the possibility of developing mac- viscosity of lung secretions. rolide resistance. Antibiotics may also be used in the manage Thickened secretions in the gastrointestinal tract impair ment of chronic non cystic-fibrosis bronchiectasis to eradicate flow of bile and pancreatic secretions, leading to pancreatic organisms such as P. oeruginosa or methicillin-resistant exocrine and endocrine deficiency, liver disease. and the Staphylococcus oureus. If eradication of bacterial colonization development of malabsorption and maldigestion. The secre is not successful, there may be some symptomatic benefit from tions increase the risk for bowel obstruction (distal ileal suppressive therapy with inhaled antibiotics. Patients should obstructive syndrome, intussusception, and rectal prolapse). also be encouraged to exercise, which can improve airway As a consequence, individuals with CF often present r,r,ith clearance and symptoms. Surgical resection should be consid malnutrition and weight loss. ered in patients who have localized disease with persistent symptoms despite therapy. Diagnosis Most patients with CF are diagnosed as children. Adults diag xtY P0ttls nosed with CF most often present with pulmonary or gastro- o Identification and treatment of underlying causes of intestinal symptoms. Pulmonary manifestations often include bronchiectasis should be initiated if possible. chronic productive cough, recurrent sinusitis, and recurrent . Treatment of bronchiectasis focuses on clearing the air- pulmonary infections requiring several courses of antibiotics. way, treating infections, and preventing exacerbations. For those with gastrointestinal symptoms, loose and frequent stools with abdominal pain are the most common. Pancreatic Treatment of Exacerbations insufficiency (either endocrine or exocrine) may occur but is Exacerbations of bronchiectasis may be difficult to differenti- less common. Chronic, persistent pulmonary or gastrointesti ate from baseline symptoms. However, changes in sputum nal symptoms requiring repetitive treatment should raise sus- volume, viscosity, or purulence; increased cough; wheezing; picion for CF, Radiographic findings include hyperinflation shortness of breath; hemoptysis; or declines in lung function followed by bronchiectasis and cyst formation with disease are considered evidence of an exacerbation. Therapy for an progression, often beginning in the upper lobes. exacerbation is ideally guided by routine sputum and acid- Often the greatest challenge in diagnosing CF is failing to fast bacilli culture results to identify a possible predominant include it in the differential diagnosis. A family history of CF organism for treatment. Empiric antibiotic therapy is recom- can be quite helpful in this regard. Sweat chloride testing is the mended and may be based on previous culture data until the initial test for CE, although it is less sensitive in adults. results of the current sputum culture become available. If Abnormal results on repeat testing are diagnostic of CF. Genetic previous data are not available, a fluoroquinolone can be testing confirms the diagnosis and helps with prognosis. A started to ensure Pseudomonos coverage until sputum culture negative sweat chloride test in an adult patient does not rule results are available. out disease. Therefore, if the clinical suspicion remains high after negative repeat sweat chloride testing, consideration lor referral to a center with expertise in CF or genetic testing is Cystic Fibrosis appropriate. Cystic fibrosis (CF) is an autosomal recessive disease affecting TEY POIilIS the CF transmembrane conductance regulator (CFTR) gene. It is diagnosed in approximately 1 of 2000 to 3000 live births r Adults diagnosed with cystic fibrosis most often present with a predilection for disease in those of European descent. with pulmonary or gastrointestinal symptoms; pulmo- \ The most common genetic variant resulting in disease is nary manifestations often include chronic productive AF50B, but there are at least 1500 other genetic mutations. cough, recurrent sinusitis, and recurrent pulmonary The pathogenesis for clinical manifestations of CF remains infections requiring several courses of antibiotics. incompletely understood; however, the abnormal homozy . A negative sweat chloride test in a patient who presents gous CFTR genotype results in abnormally thick secretions as an adult should not rule out cystic fibrosis. that are difficult to clear. There is an increased concentration of chloride in sweat gland secretions, and sweat chloride test Treatment ing is a primary diagnostic tool for CF. The changes in res The pillars of CF management are airway clearance. antibiotic piratory secretions lead to bacterial colonization of airways therapy, nutritional support, and psychosocial support. The and chronic bacterial infection, resulting in chronic inflam primary objectives of CF treatment are maintaining lung mation and, ultimately, bronchiectasis. Further tissue health and controlling/minimizing the effect of CF-affected destruction results from insufficient lung antiproteases to organ disease. The Cystic Fibrosis Foundation practice guide counteract the effect of elastase released from neutrophils. lines recommend use of chronic medications to improve This ongoing inflammatory process also results in large lung function and reduce exacerbations. These medications amounts of free DNA and matrix protein deposition within include mucolltics, hydrating agents, inhaled antibiotics, oral 24

Diffuse Parenchymal Lung Disease macrolide antibiotics, and CFIR potentiators. The treatment of CF lung disease is experiencing a period of rapid evolution, Classification and Epidemiology Typically, DPLDs are classified into those with a known cause and management involves a multidisciplinary approach best provided at a CF care center. and those that are idiopathic (Table 1S). This classification has implications for management strategies and prognosis. The prevalence of DPLDs is estimated to be approximately 70 per 100,000 persons. Diffuse Parenchymal Lung Disease Diagnostic Approach Diffuse parenchymal lung diseases (DPLDs) are a diverse and Evaluation group of nonmalignant disorders resulting in the inflamma The most common presentation of a DPLD is subacute to tion and scarring of alveolar structures. These disorders tend chronic exertional dyspnea and nonproductive cough. History to mimic each other clinically and radiographically. should include a thorough review of potential exposures,

macrolide antibiotics, and CFIR potentiators. The treatment of CF lung disease is experiencing a period of rapid evolution, Classification and Epidemiology Typically, DPLDs are classified into those with a known cause and management involves a multidisciplinary approach best provided at a CF care center. and those that are idiopathic (Table 1S). This classification has implications for management strategies and prognosis. The prevalence of DPLDs is estimated to be approximately 70 per 100,000 persons. Diffuse Parenchymal Lung Disease Diagnostic Approach Diffuse parenchymal lung diseases (DPLDs) are a diverse and Evaluation group of nonmalignant disorders resulting in the inflamma The most common presentation of a DPLD is subacute to tion and scarring of alveolar structures. These disorders tend chronic exertional dyspnea and nonproductive cough. History to mimic each other clinically and radiographically. should include a thorough review of potential exposures, TABTE 15. Classification of Diffuse Parenchymal Lung Disease Known Causes Comments Drug-induced Examples: amiodarone, methotrexate, nitrofurantoin, chemotherapeutic agents (see www.pneumotox.com/drug/index for a complete listing) Smoking-related Respiratory bronchiolitis-associated lLD, desquamative interstitial pneumonia, smoking- related pulmonary fibrosis, combined emphysema with pulmonary fibrosis, pulmonary Langerhans cell histiocytosis Radiation Radiation-induced lung injury, radiation pneumonitis/radiation fibrosis; may occur weeks to months after radiation therapy Chronic aspiration Aspiration is often subclinical and may exacerbate otherforms of DPLD, mainly in the lower lobes; focal consolidation on CT scan of the chest, usually predominantly the right side Pneumoconioses Asbestosis, silicosis, berylliosis, coal workers' pneumoconiosis Connective tissue diseases (RA, systemic Nonspecific interstitial pneumonia, organizing pneumonia, usual interstitial pneumonia, sclerosis, dermatomyositis, polymyositis, lymphocytic interstitial pneumonia MCTD, SLE, Sjogren syndrome) pneumonitis Acute, subacute, or chronic Unknown Causes Comments ldiopathic interstitial pneumonias ldiopathic pulmonary fibrosis Chronic, insidious onset of cough and dyspnea, usually in a patient aged >50 years; usual interstitial pneumonia pathology (honeycombing, bibasilar infiltrates with fibrosis); diagnosis of exclusion ldiopathic nonspecific interstitial Affects a younger population than IPF; honeycombing is uncommon on HRCT pneumonia Cryptogenic organizing pneumonia Subacute presentation, patchy opacities that mimic infectious pneumonia Acute interstitial pneumonia Rapid progression to respiratory failure; high mortality Sarcoidosis Variable clinical presentation, ranging from asymptomatic to multiorgan involvement: stage 1 hilar lymphadenopathy; stage 2, hilar lymphadenopathy plus interstitial lung disease; stage 3, interstitial lung disease; stage 4, fibrosis. Noncaseating granulomas are hallmark. Rare DPLD With Well-Defined Comments Features Lymphangioleiomyomatosis Affects women, usually in their 30s and 40s. Associated with spontaneous pneumothorax and chylous effusions. Chest CT scan shows cystic disease that is diffuse in distribution. Chronic eosinophilic pneumonia Chest radiograph shows "radiographic negative" heart failure, with peripheral alveolar infiltrates predominating. Other findings may include peripheral blood eosinophilia and eosinophilia on bronchoalveolar lavage >25%. Pulmonary alveolar proteinosis Median age 39 years. Males predominate among smokers, but not nonsmokers. Diagnosed using bronchoalveolar lavage, which shows proteinaceous material in and around alveolar macrophages (periodic acid-Schiff stain positive). Chest CT scan shows "crazy paving" pattern

TABTE 15. Classification of Diffuse Parenchymal Lung Disease Known Causes Comments Drug-induced Examples: amiodarone, methotrexate, nitrofurantoin, chemotherapeutic agents (see www.pneumotox.com/drug/index for a complete listing) Smoking-related Respiratory bronchiolitis-associated lLD, desquamative interstitial pneumonia, smoking- related pulmonary fibrosis, combined emphysema with pulmonary fibrosis, pulmonary Langerhans cell histiocytosis Radiation Radiation-induced lung injury, radiation pneumonitis/radiation fibrosis; may occur weeks to months after radiation therapy Chronic aspiration Aspiration is often subclinical and may exacerbate otherforms of DPLD, mainly in the lower lobes; focal consolidation on CT scan of the chest, usually predominantly the right side Pneumoconioses Asbestosis, silicosis, berylliosis, coal workers' pneumoconiosis Connective tissue diseases (RA, systemic Nonspecific interstitial pneumonia, organizing pneumonia, usual interstitial pneumonia, sclerosis, dermatomyositis, polymyositis, lymphocytic interstitial pneumonia MCTD, SLE, Sjogren syndrome) pneumonitis Acute, subacute, or chronic Unknown Causes Comments ldiopathic interstitial pneumonias ldiopathic pulmonary fibrosis Chronic, insidious onset of cough and dyspnea, usually in a patient aged >50 years; usual interstitial pneumonia pathology (honeycombing, bibasilar infiltrates with fibrosis); diagnosis of exclusion ldiopathic nonspecific interstitial Affects a younger population than IPF; honeycombing is uncommon on HRCT pneumonia Cryptogenic organizing pneumonia Subacute presentation, patchy opacities that mimic infectious pneumonia Acute interstitial pneumonia Rapid progression to respiratory failure; high mortality Sarcoidosis Variable clinical presentation, ranging from asymptomatic to multiorgan involvement: stage 1 hilar lymphadenopathy; stage 2, hilar lymphadenopathy plus interstitial lung disease; stage 3, interstitial lung disease; stage 4, fibrosis. Noncaseating granulomas are hallmark. Rare DPLD With Well-Defined Comments Features Lymphangioleiomyomatosis Affects women, usually in their 30s and 40s. Associated with spontaneous pneumothorax and chylous effusions. Chest CT scan shows cystic disease that is diffuse in distribution. Chronic eosinophilic pneumonia Chest radiograph shows "radiographic negative" heart failure, with peripheral alveolar infiltrates predominating. Other findings may include peripheral blood eosinophilia and eosinophilia on bronchoalveolar lavage >25%. Pulmonary alveolar proteinosis Median age 39 years. Males predominate among smokers, but not nonsmokers. Diagnosed using bronchoalveolar lavage, which shows proteinaceous material in and around alveolar macrophages (periodic acid-Schiff stain positive). Chest CT scan shows "crazy paving" pattern RA = rheumatoid arthritis; 5LE = systemic lupus erlthematosus.

TABTE 15. Classification of Diffuse Parenchymal Lung Disease Known Causes Comments Drug-induced Examples: amiodarone, methotrexate, nitrofurantoin, chemotherapeutic agents (see www.pneumotox.com/drug/index for a complete listing) Smoking-related Respiratory bronchiolitis-associated lLD, desquamative interstitial pneumonia, smoking- related pulmonary fibrosis, combined emphysema with pulmonary fibrosis, pulmonary Langerhans cell histiocytosis Radiation Radiation-induced lung injury, radiation pneumonitis/radiation fibrosis; may occur weeks to months after radiation therapy Chronic aspiration Aspiration is often subclinical and may exacerbate otherforms of DPLD, mainly in the lower lobes; focal consolidation on CT scan of the chest, usually predominantly the right side Pneumoconioses Asbestosis, silicosis, berylliosis, coal workers' pneumoconiosis Connective tissue diseases (RA, systemic Nonspecific interstitial pneumonia, organizing pneumonia, usual interstitial pneumonia, sclerosis, dermatomyositis, polymyositis, lymphocytic interstitial pneumonia MCTD, SLE, Sjogren syndrome) pneumonitis Acute, subacute, or chronic Unknown Causes Comments ldiopathic interstitial pneumonias ldiopathic pulmonary fibrosis Chronic, insidious onset of cough and dyspnea, usually in a patient aged >50 years; usual interstitial pneumonia pathology (honeycombing, bibasilar infiltrates with fibrosis); diagnosis of exclusion ldiopathic nonspecific interstitial Affects a younger population than IPF; honeycombing is uncommon on HRCT pneumonia Cryptogenic organizing pneumonia Subacute presentation, patchy opacities that mimic infectious pneumonia Acute interstitial pneumonia Rapid progression to respiratory failure; high mortality Sarcoidosis Variable clinical presentation, ranging from asymptomatic to multiorgan involvement: stage 1 hilar lymphadenopathy; stage 2, hilar lymphadenopathy plus interstitial lung disease; stage 3, interstitial lung disease; stage 4, fibrosis. Noncaseating granulomas are hallmark. Rare DPLD With Well-Defined Comments Features Lymphangioleiomyomatosis Affects women, usually in their 30s and 40s. Associated with spontaneous pneumothorax and chylous effusions. Chest CT scan shows cystic disease that is diffuse in distribution. Chronic eosinophilic pneumonia Chest radiograph shows "radiographic negative" heart failure, with peripheral alveolar infiltrates predominating. Other findings may include peripheral blood eosinophilia and eosinophilia on bronchoalveolar lavage >25%. Pulmonary alveolar proteinosis Median age 39 years. Males predominate among smokers, but not nonsmokers. Diagnosed using bronchoalveolar lavage, which shows proteinaceous material in and around alveolar macrophages (periodic acid-Schiff stain positive). Chest CT scan shows "crazy paving" pattern RA = rheumatoid arthritis; 5LE = systemic lupus erlthematosus. 25