Kiran Sarikonda, Ajay Sheshadri, Mario Castro, and Jeffrey J. Atkinson
Chronic Obstructive Pulmonary Disease
GENERAL PRINCIPLES
Definition
Chronic obstructive pulmonary disease (COPD) is “a common preventable and treatable disease state characterized by persistent airflow limitation that is usually progressive and associated with enhanced chronic inflammatory response to noxious particles or gases.”1
Classification
COPD is a complex disease in which patients may have components of chronic bronchitis, emphysema, and airway hyperreactivity:
· Chronic bronchitis is defined as cough, productive of at least two tablespoons of sputum, for at least 3 months in 2 consecutive years.
· Emphysema is a pathologic definition referring to permanent enlargement of the airspaces distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis.
· Airway hyperreactivity is an enhanced constrictive response of airway smooth muscle resulting in increased obstruction; typically due to an external stimulus like antigens, chemicals, or infections. Although asthmatics that smoke can develop COPD, many nonasthmatic individuals with COPD demonstrate at least occasional airway hyperreactivity after fixed airflow obstruction has been established. Asthma differs from COPD in that the airflow limitation is largely reversible, although some patients with asthma develop poorly reversible airflow limitation over time. Asthma is a different disease entity with regard to pathogenesis, and therapeutic response and will be addressed separately.
Epidemiology
· COPD is currently the fourth leading cause of morbidity and mortality in the United States and is projected to be the third leading cause by 2020.2
· Women have exceeded men in mortality attributed to COPD since 2010.
· Approximately 4% to 6% of adult white males and 1% to 3% of adult white females have COPD. It is estimated that 20 million adults in the United States have COPD, the majority of whom do not carry a physician diagnosis of COPD.
· The predominant risk factor for COPD in the United States and other industrialized countries is cigarette smoking, but additional other environmental and likely genetic factors contribute to disease development (Table 16-1). Biomass fuels utilized for cooking in closed spaces may be a more important risk factor worldwide.
TABLE 16-1 Risk Factors for Chronic Obstructive Pulmonary Disease (COPD)
DIAGNOSIS
Clinical Presentation
· COPD is an insidious disease, with dyspnea being the predominant presenting symptom. However, dyspnea typically does not develop until the FEV1 (forced expiratory volume in 1 second) is ≤60% of predicted.
· The etiology of the dyspnea is multifactorial and includes the following:
o Expiratory airflow obstruction with air trapping3
o Hyperinflation that reduces diaphragm efficiency and results in abnormalities of chest wall and respiratory muscle function
o Mucus hypersecretion
o Bronchoconstriction
o Maldistribution of ventilation, resulting in ventilation-perfusion mismatching
o Physical deconditioning
o Nutritional abnormalities and weight loss
History
· Important symptoms of COPD include the following: dyspnea, chronic cough, sputum production, chest tightness, and wheezing (occasionally).
· Exacerbations of combinations of these symptoms, requiring antibiotic therapy or even hospitalization.
· Symptoms of weight loss, recurrent hemoptysis, or hoarseness should precipitate a thorough search for concurrent malignancy.
Physical Examination
· Signs on physical examination are often present only with more advanced disease and include the following: wheezing, prolonged expiration, barrel-shaped chest (hyperinflation), pursed lip breathing, accessory muscle use, and peripheral edema from cor pulmonale.
· Clubbing is not a physical exam finding that occurs in COPD and should prompt a search for additional or alternative etiologies.
Diagnostic Testing
Laboratories
· α1-Antitrypsin levels should be checked in patients with the following problems4:
o Premature onset of COPD or significant impairment before the age of 50
o Predominance of basilar emphysema
o A family history of α1-antitrypsin deficiency or early-onset emphysema
o Chronic bronchitis with airflow obstruction in a patient who never smoked
o Unexplained bronchiectasis or cirrhosis
· Genetic phenotyping should be performed if the α1-antitrypsin level is low.
Imaging
· Imaging studies, such as chest radiographs (CXR), are not sufficient to exclude lung cancer and offer little additional prognostic or therapeutic information.
· Routine chest computed tomography (CT) scanning is not indicated in the care of patients with COPD. However, annual low-dose CT protocols do detect early cancer, despite a high false-positive rate, and confer a survival advantage that is similar to routine mammography.5 These protocols are now indicated in smokers over 50 years old with a >30-pack-year history and within 15 years of the last cigarette. It is not known if coexistent COPD results in a greater survival advantage with screening, but given the increased lung cancer risk in individuals with COPD, routine screening in patients outside the guideline population will require future study.
Diagnostic Procedures
· The crucial step in the diagnosis and ongoing assessment of obstructive lung disease is formal pulmonary function testing (PFT).
· Spirometry is the only reliable means for diagnosing COPD and, importantly, also classifies the severity of the disease.6
· The sine qua non for making the diagnosis of obstructive lung disease is a reduced ratio of the FEV1 to the forced vital capacity (FVC).
· The grading of COPD severity by PFTs is presented in Table 16-2.
· A comprehensive pulmonary assessment often includes other testing of pulmonary function (Table 16-3). As disease severity increases, an oxygen evaluation becomes important.
TABLE 16-2 Grading the Severity of COPD
COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity.
Data from Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med2007;176:532–555.
TABLE 16-3 Pulmonary Function Testing in COPD
COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; DLCO, diffusing capacity of the lung for carbon monoxide.
TREATMENT
· An overview of the general management of COPD is given in Figure 16-1.6,7 Each component of this management plan will be discussed in detail below.
· General consideration should be given to comorbidities as most patients with COPD have a higher frequency of cardiac disease, osteoporosis, gastroesophageal reflux, depression, and lung cancer.
· Death from cardiac disease or lung cancer is more common than directly from COPD.
· Individuals with COPD benefit from cardiac treatments, such as β-blockers, even with severe disease.
Figure 16-1 Therapy at each stage of COPD, the GOLD guidelines. COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity. (Modified from Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med2007;176:532–555, with permission.)
Medications
Short-Acting Bronchodilators
· Metered-dose inhalers (MDIs) that contain a β2-agonist, an anticholinergic agent, or both can result in improvement of airflow obstruction and hyperinflation and therefore less dyspnea. Commonly used inhalers for COPD are detailed in Table 16-4.
· These agents are the mainstay of symptomatic therapy in COPD, and patients can use two to four puffs every 4 to 6 hours.8 Regular use of short-acting bronchodilators does not preserve lung function or alter mortality.9
· Combination therapy with both anticholinergic agents and β2-agonists is appropriate in patients with more severe disease.10
· Proper MDI technique should be verified at outpatient visits, and if patients have difficulty, a spacer device may prove beneficial. Nebulized agents may also be used in patients unable to acquire proper technique.
· Frequent MDI use can lead to failure of patients to recognize an MDI containing no active medication, as propellant quantity exceeds active drug. Patients need to be counseled; presence of propellant does not ensure active drug is also present.
TABLE 16-4 Commonly Used Inhalers in COPD and Cystic Fibrosis
COPD, chronic obstructive pulmonary disease; DPI, dry powder inhaler; HFA, hydrofluoroalkane; INH, inhalation; MDI, metered-dose inhaler; NEB, nebulizer solution or nebulized.
Long-Acting Bronchodilators
· Current guidelines endorse the regular use of long-acting agents to improve symptoms and quality of life. Reduction in exacerbations of COPD has been demonstrated for several of these medications.6,11,12Multiple formulations are available (Table 16-4).
· The long-acting β2-agonists (LABAs, Table 16-4) produce bronchodilation for 12 hours or more, potentially reducing nocturnal symptoms. Whether agents acting >12 hours offer greater efficacy, compliance, or simply convenience has not been addressed.
· Long-acting antimuscarinic (anticholinergic) agents (LAMA, Table 16-4) can improve airflow over a 24-hour period.
o A large trial compared LAMA with LABA therapy in predominantly GOLD 2 and 3 diseases and demonstrated a slight therapeutic advantage of anticholinergics. However, this trial and several large anticholinergic trials have excluded subjects with higher-risk cardiac disease.12
o Increased potential cardiac risk with anticholinergic agent use in clinical practice may outweigh the marginal benefit in subjects with advanced coronary disease.
· Many patients with significant dyspnea are managed with combinations of short-acting and long-acting bronchodilators. Use of both LABA and LAMA medications simultaneously likely has an additive symptomatic effect, but whether this also results in further exacerbation reduction is not known. Symptomatic dyspnea relief with simultaneous therapy is an option for some patients but may be cost prohibitive.
Inhaled Corticosteroids
· Inhaled corticosteroids (ICS) combined with LABAs have a role in reducing exacerbation frequency of patients with more than one exacerbation per year and GOLD 3+ disease.11
· There is an increased risk of pneumonia, so caution should be taken to utilize these medications in combination with LABAs and for the outcome of exacerbation reduction and not symptomatic relief alone.
· ICS as a monotherapy do not confer the same level of benefit. Use as part of a combined inhaler (Table 16-4) is preferred to improve compliance.
· Oral thrush is a common side effect, and mouth rinse or using medication prior to brushing teeth typically prevents this complication.
Macrolides
· One randomized placebo-controlled trial that included subjects with greater than one annual exacerbation and GOLD 2+ COPD demonstrated a significant reduction in COPD exacerbations.13
· Subset analysis may suggest that current smokers and older subjects received less benefit.
· Thought should be given to the possibility of atypical mycobacterial disease before chronic therapy is initiated, as later eradication is complicated if the mycobacteria develop resistance to macrolide antibiotics.
· Higher than expected levels of hearing loss were observed in the trial and likely warrant audiometry testing in older patients selected for chronic use.
Phosphodiesterase-4 (PDE4) Inhibitors
· Currently, one PDE4 inhibitor is available for use in COPD (Table 16-4).
· This medication has the narrow indication of reduction of exacerbation frequency in GOLD 3+ subjects with chronic bronchitis.14
· Similar to macrolides, the benefit in current smokers is less clear.
· GI distress is relatively common with this class of medications and may be a relative contraindication in patients with low BMI at the outset.
Methylxanthines
· Theophylline use has declined steadily due to its potential toxicity; however, this long-acting oral bronchodilator can be used as add-on therapy in patients who are still dyspneic despite maximal inhaled bronchodilator use.15
· Theophylline has multiple drug interactions, and drug levels need to be monitored routinely and whenever potentially interacting medications are added to a patient’s regimen. Therapeutic range is between 6 and 12 mg/L.
· Common side effects include anxiety, tremor, nausea, and vomiting.
· Toxicity is manifested as tachyarrhythmias and seizures.
Oral Corticosteroids
· ICS are used in COPD, but the use of chronic oral corticosteroids has less supportive clinical evidence.
· A brief trial of oral corticosteroids may benefit as many as 30% of patients with COPD with wheezing, frequent exacerbations, or severe impairment. An objective improvement in FEV1 should be evident to justify maintenance therapy with an oral steroid. Doses in the range of 40 mg/day for 1 to 2 weeks are generally initiated and then tapered off as soon as possible.
· Chronic use of oral steroids is discouraged because of the systemic side effects including osteoporosis, hyperglycemia, risk of peptic ulcer disease, immunosuppression, and cataracts.
Replacement Therapy
· Augmentation therapy with α1-antitrypsin is available and is indicated in patients with α1-antitrypsin deficiency and obstructive lung disease who have quit smoking.16
· Hepatitis vaccination should be performed prior to starting therapy.
· The efficacy of this therapy has been supported by radiographic measurement of emphysema progression but not rate of change in FEV1.
· The therapy is very expensive and is given intravenously at weekly or monthly intervals to achieve trough levels equivalent to a heterozygote (80 mg/dL).
Other Nonpharmacologic Therapy
· Oxygen therapy has been shown to reduce mortality in hypoxemic patients with COPD and also improve physical and mental function.17,18
· Arterial blood gases (ABGs) should be obtained to document whether hypoxemia is present when breathing room air in individuals with more severe disease. Pulse oximetry can be used for oxygen titration after an arterial oxyhemoglobin saturation is obtained. It should be noted that in current smokers lower oxygen saturation can be present as carboxyhemoglobin levels can reach >10% but do not result in reduced noninvasive saturation measurements.
· The indications for oxygen therapy as derived from the Nocturnal Oxygen Therapy Trial Group (NOTT) are as follows17:
o PaO2 < 55 mm Hg or SpO2 < 88% at rest
o PaO2 < 56 to 59 mm Hg or SpO2 < 89% if there is P pulmonale, cor pulmonale, or hematocrit >55%
o With exercise if accompanied by desaturation to levels listed above
o With sleep if accompanied by desaturation to levels listed above
· Desaturation is common during sleep in patients with COPD, so formal overnight oximetry with oxygen titration may be helpful. If this is not available, patients are generally told to increase their resting oxygen setting by 1 L during sleep.
· Many patients develop worsening hypoxemia during acute exacerbations of COPD. These supplemental requirements may decrease after treatment of the exacerbation, so a follow-up oxygen evaluation should be performed 1 to 3 months later.
· Prescriptions for oxygen should specify the oxygen dose (L/minute) for rest, exercise, and sleep as well as the delivery system.
· There are three main forms of oxygen delivery for patients:
o Oxygen concentrators: These are large devices, which are normally placed in the patient’s home for home use. Patients need an additional portable mode of delivery, which is discussed below. Concentrators require power, and the portable tanks also function as a reserve if power failures occur.
o Compressed gas: A portable form of therapy that can occasionally be difficult to carry or push around because of the size and weight of the gas canisters.
o Liquid oxygen: This is the most expensive but most mobile form of therapy for patients. A large reservoir is typically present at home with refillable smaller portable tanks. Therefore, no concentrator pairing is need with liquid.
· The oxygen is normally delivered to the patient via a continuous-flow, dual-prong nasal cannula.
· Patients with COPD rarely require very high concentrations of oxygen, as the predominant cause of hypoxemia is ventilation-perfusion mismatch. However, higher requirements necessitate the use of a reservoir system like an Oxymizer device.
· Demand pulse systems that deliver oxygen only during inspiration are also available and can extend tank life for individuals with higher flow requirements.
Surgical Management
· Bullectomy can be performed in patients with dyspnea in whom a bulla or bullae occupy at least 50% of a hemithorax and compress the normal lung.
· Lung volume reduction surgery (LVRS) can have excellent spirometric and functional outcomes in highly selected patients with severe emphysema (FEV1 <35%) and apical target areas, which consist of poorly functioning and volume-occupying lung, which can be surgically resected.19 Individuals with low diffusing capacities and therefore little residual functioning compressed lung do not achieve improvement with LVRS and, in fact, have increased mortality.
· Lung transplantation can be performed in patients who have severe obstruction (FEV1 <25%), hypercapnia, pulmonary hypertension, and marked limitation of activities of daily living (ADLs), but who are young without significant comorbidities.20
Lifestyle/Risk Modification
Smoking Cessation
· The beneficial effect of smoking cessation is well demonstrated by the Lung Health Study.9 Subjects with COPD who continued to smoke experience higher yearly declines in lung function than sustained quitters.
· The Framingham offspring cohort has given additional data on smoking cessation, as cessation after 40 years had less of an impact in normalizing annual decline.21 This cohort included lung function in young women, demonstrating early smoking may also cause harm via suppressing maximal lung function.
· It is well recognized that in addition to rate of decline, continued smoking also increases the risk of subsequent exacerbations and symptom severity, such as sputum production. Therefore, smoking cessation has the potential to preserve lung function, reduce symptoms, and decrease morbidity and mortality.
· Nicotine addiction causes a state of dependence; therefore, effective smoking cessation requires a multidisciplinary approach that includes consideration of pharmacologic treatment of addiction.22Smoking cessation is discussed in detail in Chapter 45.
Pulmonary Rehabilitation
· Dyspnea significantly impairs quality of life in COPD; pulmonary rehabilitation comprises a multidimensional continuum of services aimed at improving functional status both physically and psychologically. Rehabilitation programs can reduce exacerbation frequencies and significantly improve quality of life and ability to perform ADLs.23 Insurance benefits are important to evaluate as coverage can vary significantly.
· Any patient with moderate COPD should be considered for referral to a comprehensive pulmonary rehabilitation program, particularly those with persistent dyspnea on maximal pharmacologic therapy, frequent exacerbations and hospital admissions, and impaired functional status and quality of life.
· These programs consist of the following24:
o Nutrition and psychosocial support and counseling
o Graded exercise programs to enhance functionality
§ Typically, sessions are three times a week with a goal of 30 minutes of continuous aerobic activity. Patients are exercised on tracks, treadmills, and bicycles and also perform arm ergometry and light weight lifting to promote upper body strength. Attention is also paid to increasing flexibility.
§ Patients are monitored with pulse oximetry, and oxygen is titrated during the exercise program. The workload is gradually increased until patients reach 80% of their maximum heart rate or breathlessness.
§ Often, coverage is for a single initiation period with continued lifelong exercise to be performed by the patient independently. Reinitiation of previous independent exercise often relies on the discharging physician after hospitalizations for COPD exacerbations.
· Oxygen assessments and potentially noninvasive cardiac stress testing should be performed prior to initiation of a rehabilitation program in patients at risk for significant coronary artery disease.
Patient Education
It is important that patients understand the nature, chronicity, treatment options, and prognosis of COPD. Educational materials are available from the American Lung Association (http://www.lung.org, last accessed January 20, 2015).
Health Maintenance
Yearly influenza vaccination is recommended for all patients, as well as a pneumococcal vaccine every 5 years. Yearly CT screening is indicated in the previously discussed high-risk population.
OUTCOMES/PROGNOSIS
· The BODE index is a multidimensional grading system to provide a better assessment of mortality risk and includes parameters that can be obtained at routine outpatient visits25:
o Body mass index (BMI)
o FEV1 (obstruction)
o Dyspnea, graded by the Medical Research Council dyspnea scale (Table 16-5)
o Exercise tolerance (6-minute walk distance)
· The highest possible score is 10 points, with lower scores indicating a lower risk of death (Table 16-6).
TABLE 16-5 The Medical Research Council (MRC) Dyspnea Scale
Adapted from Fletcher CM, Elmes PC, Fairbairn MB, et al. The significance of respiratory symptoms and the diagnosis of chronic bronchitis in a working population. BMJ 1959;2:257–266.
TABLE 16-6 The BODE Index
BMI, body mass index; FEV1, forced expiratory volume in 1 second; MRC, Medical Research Council.
Adapted from Celli BR, Cote CG, Marin JM, et al. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med 2004;350:1005–1012.
Acute Exacerbations of COPD
GENERAL PRINCIPLES
· Acute exacerbations are a common occurrence in patients with COPD and tend to occur more frequently in those patients who continue to smoke.
· These episodes are characterized by a change in the patient’s baseline dyspnea, cough and/or sputum production beyond day-to-day variability, and sufficient to warrant a change in management.
· Exacerbations are often precipitated by viral or bacterial respiratory infections but can be precipitated by other noxious stimuli like air pollution. Exacerbations account for a significant portion of the costs of managing COPD due to frequent physician visits, hospitalization, and time away from work.26
DIAGNOSIS
· Patients who are experiencing exacerbations often have worsening of their hypoxemia and hypercapnia during these episodes; evaluation is indicated to identify patients who may require hospitalization.
· Evaluation should focus on the severity of the dyspnea; the patients’ ability to sleep, eat, and care for themselves; and underlying comorbidities.
· Physical exam findings of altered mental status, hemodynamic abnormalities, increased accessory muscle use, and significant comorbidities should prompt hospitalization.
· A CXR should also be performed in these patients.
TREATMENT
· Management, whether pursued as an outpatient or as an inpatient, consists of maximizing bronchodilator therapy, corticosteroids (oral prednisone at a dose of 40 mg/day for 7 to 10 days), and antibiotics if there is evidence of purulent sputum.27
· The antibiotic chosen can be narrow spectrum to cover Haemophilus influenzae, Moraxella spp., or Streptococcus pneumoniae in patients who do not have recent nosocomial risk factors. Reasonable choices include azithromycin, amoxicillin-clavulanate, an oral second-generation cephalosporin, or moxifloxacin.
· Gram-negative organisms (including Pseudomonas aeruginosa) are not unusual in patients with severe COPD, comorbid illnesses, and recurrent exacerbations, so coverage should be broadened in patients with these risk factors. For outpatients, ciprofloxacin or levofloxacin is acceptable. For inpatients, more aggressive treatment is warranted, such as piperacillin-tazobactam, cefepime, or levofloxacin.
Asthma
GENERAL PRINCIPLES
· Asthma is a chronic inflammatory disorder of the airways characterized by airway hyperresponsiveness and variable airflow obstruction in response to a wide variety of stimuli that is at least partially reversible either spontaneously or with treatment.28
· Many cell types play a role in the inflammation, in particular, mast cells, eosinophils, and Th2 lymphocytes.
· In susceptible individuals, this inflammation causes paroxysms of wheezing, chest tightness, dyspnea, and cough.
· Asthma is a chronic disease with episodic acute exacerbations that are interspersed with symptom-free periods.
· Exacerbations are characterized by a progressive increase in asthma symptoms that can last minutes to hours. They are triggered by viral infections, allergens, and occupational exposures and occur when airway reactivity is increased and lung function becomes unstable.
Classification
· Asthma severity should be classified based on both level of impairment (symptoms, activity limitation, lung function, and rescue medication use) and risk (exacerbations, lung function decline, medication side effects). At the initial evaluation, this assessment will determine level of severity in patients not on controller medications (Table 16-7). The level of severity is based upon the most severe category in which any feature appears. On subsequent visits or if the patient is on a controller medication, this assessment is based on the lowest step of therapy to maintain clinical control (Table 16-8).
· Patients who have had two or more exacerbations requiring systemic corticosteroids in the past year may be considered in the same category as those who have persistent asthma, regardless of level of impairment.
TABLE 16-7 Classification of Asthma Severity on Initial Assessment
OCS, oral corticosteroids; FEV1, forced expiratory volume over 1 second; PEF, peak expiratory flow.
GINA Report, Global Strategy for Asthma Management and Prevention, 2011—www.ginasthma.org and National Asthma Education and Prevention Program-Expert Panel Report 3, 2007—http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf
TABLE 16-8 Assessment of Asthma Control
FEV1, forced expiratory volume over 1 second; PEF, peak expiratory flow; ACT, Asthma Control Test; ACQ, Asthma Control Questionnaire; OCS, oral corticosteroids.
Epidemiology
· In the United States, asthma is the leading cause of chronic illness among children (20% to 30%).
· The prevalence of asthma and asthma-related mortality had been increasing from 1980 to the mid-1990s, but since the 2000s, mortality has decreased.29
· African Americans are more likely than whites to be hospitalized and have a higher rate of mortality due to asthma.
Pathophysiology
Asthma is characterized by airway obstruction, hyperinflation, and airflow limitation resulting from multiple processes:
· Acute and chronic airway inflammation characterized by infiltration of the airway wall, mucosa, and lumen by activated eosinophils, mast cells, macrophages, and T lymphocytes
· Bronchial smooth muscle contraction resulting from mediators released by a variety of cell types including inflammatory, local neural, and epithelial cells
· Epithelial damage manifested by denudation and desquamation of the epithelium leading to mucous plugs that obstruct the airway
· Airway remodeling characterized by the following findings:
o Subepithelial fibrosis, specifically thickening of the lamina reticularis from collagen deposition
o Smooth muscle hypertrophy and hyperplasia
o Goblet cell and submucosal gland hypertrophy and hyperplasia resulting in mucus hypersecretion
o Airway angiogenesis
o Airway wall thickening due to edema and cellular infiltration
DIAGNOSIS
Clinical Presentation
History
· The patient’s medical history is of critical importance in establishing the diagnosis of asthma and also identifying characteristic triggers for exacerbations of the patient’s symptoms. Asthma may have its onset in infancy through adulthood, and the symptoms may be intermittent or persistent.30 Asthma is less likely to be the sole cause of respiratory symptoms in patients presenting for the first time after 50 years of age or who have >20-pack-year history of smoking.
· The history at the initial visit and all subsequent visits should focus on the following features:
o Presence of cough, which can occasionally be productive of yellow sputum and classically is worse at night or in the early morning31
o Presence of wheezing
o Shortness of breath
o A feeling of chest tightness
o Nocturnal awakenings
o A history of episodic symptoms and/or seasonal variation
o Triggers of asthma: exercise, allergen exposure (mold, pollen, dust mites, pet dander, cockroaches), changes in weather, and occupational allergens and irritants such as perfumes, cleaners, or detergents
o Symptoms suggestive of gastroesophageal reflux disease
o History of sinusitis/allergic rhinitis and postnasal drip
o History of missed work/school days
o Prior history of hospitalization and intubation
o Presence of tobacco abuse
o History of aspirin sensitivity
o Personal or family history of atopy
o Prior therapeutic response to asthma medications
Physical Examination
· Wheezing and prolonged expiratory phase can be noted, but a normal lung examination does not exclude asthma.
· Signs of atopy, such as eczema, rhinitis (pale, boggy nasal mucous membranes), or nasal polyps often coexist with asthma.
· Patients with more severe airflow obstruction may exhibit tachypnea or accessory muscle use but may not have any wheezing due to poor air movement and can ultimately develop a pulsus paradoxus.
Differential Diagnosis
Other conditions may present with wheezing and need to be considered, especially in patients with refractory asthma. Many of the conditions in Table 16-9 can be differentiated from asthma by the absence of reversibility with bronchodilators, review of the flow volume loop, and consideration of the onset and temporal course of the symptoms.
TABLE 16-9 Common Mimics of Asthma
Diagnostic Testing
· Routine laboratory tests are not indicated for the diagnosis of asthma, but a complete blood count with differential may reveal eosinophilia in some patients. Serum IgE level should be checked in patients with difficult to control asthma to evaluate for allergic bronchopulmonary aspergillosis and use of anti-IgE therapy.
· Allergy skin testing and in vitro testing for allergen specific IgE can be useful in management of asthma, to provide guidance for environmental modification.
· CXR and/or CT of the chest are not routinely indicated and are performed only if a complicating pulmonary process such as pneumonia or pneumothorax is suspected or to rule out other causes of respiratory symptoms in patients being evaluated for asthma.
· An objective measurement of airflow obstruction with PFTs is essential to the diagnosis of asthma.
· In patients with asthma, PFTs demonstrate an obstructive pattern, the hallmark of which is a decrease in expiratory flow rates:
o A reduction in FEV1 and a proportionally smaller reduction in the FVC occurs. This produces a decreased FEV1/FVC ratio (generally <0.7). With mild obstructive disease that involves only the small airways, the FEV1/FVC ratio may be normal, with the only abnormality being a decrease in airflow at midlung volumes (forced expiratory flow 25% to 75%).
o The clinical diagnosis of asthma is supported by an obstructive pattern that improves after bronchodilator therapy. Improvement is defined as an increase in FEV1 of >12% and 200 mL after two to four puffs of a short-acting bronchodilator. Most patients will not demonstrate reversibility at each assessment.
o In patients with chronic, severe asthma, the airflow obstruction may no longer be completely reversible. In these patients, the most effective way to establish the maximal degree of airway reversibility is to repeat PFTs after a course of oral corticosteroids (usually 40 mg/day for 10 to 14 days).
· Lack of demonstrable obstruction or reactivity does not rule out a diagnosis of asthma. If spirometry is normal, bronchoprovocation testing with methacholine or mannitol may identify patients with airway hyperresponsiveness.32 This test is not specific for asthma; however, a negative test makes the diagnosis less likely.
· Measurement of peak expiratory flow rate (PEFR), with handheld peak flow meters, can be a useful indicator of airflow obstruction and is helpful in outpatient management of the disease.33
o The clinician should be aware of the limitations of PEFR measurement. PEFR is very effort and technique dependent.
o Reduced peak flows are not synonymous with obstruction, and complete PFT is needed to distinguish an obstructive from restrictive abnormality.
o Thus, PEFR monitoring is best used in patients in whom the diagnosis of asthma has already been established. Patients can identify their personal bests and can be educated on the appropriate management when their PEFR starts decreasing.
TREATMENT
· The current NIH/NHLBI guidelines updated in 2007 are a very useful resource for clinicians to guide asthma management28 (Tables 16-7, 16-8, and 16-10).
· The major goals of asthma therapy are to avoid impairment and to minimize risk.
o Freedom from symptoms (including nocturnal symptoms)
o No limitation of daily activities including exercise
o Optimization of lung function
o Minimize acute exacerbations and emergency visits
o Minimize medication side effects and tailor medications to individual patient profiles
· To attain these goals, periodic patient visits are necessary; patient and caregiver education is critical to prevent clinical deterioration. Visits should be an opportunity to assess for symptoms, medication usage, especially short-acting bronchodilators, obtain an objective assessment of lung function, and to educate the patient on appropriate self-management.
· Medical management involves chronic management and a plan for acute exacerbations (asthma action plan). Most often it includes the daily use of an anti-inflammatory medication (long-term control medications) and as-needed use of a short-acting bronchodilator (quick-relief medications).
· The stepwise approach to increasing severity of asthma provides general guidelines to assist clinical decision making, and clinicians should tailor medications to the needs of individual patients.
o When initiating therapy for a patient not already on controller medicine, one should assess patient’s severity and assign the patient to the highest level in which any one feature has occurred over the previous 2 to 4 weeks (Table 16-7).
o Assessment of control on subsequent visits is used to modify therapy when following patients already on controller medication (Table 16-8).
TABLE 16-10 Stepwise Approach for Managing Asthma in Adults
Modified from National Asthma Education and Prevention Program Expert Panel Report 3 (EPR3): Guidelines for the Diagnosis and Management of Asthma. Full Report 2007. National Institutes of Health, National Heart, Lung, and Blood Institute, Publication No. 08-4051, 2007.
Medications
· The goal of the stepwise approach is to gain control of symptoms as quickly as possible. Either start with aggressive therapy (e.g., add a course of oral steroids or a higher dose of inhaled steroids to the therapy) or start at the step that corresponds to the patient’s initial severity and step up treatment, if necessary.
· At the same time, level of control varies over time, and consequently, medication requirements vary as well, so therapy should be reviewed every 3 months to check whether stepwise reduction is possible.
· Medications commonly used for asthma are detailed in Table 16-11.
· Inadequate control is indicated by increased use of short-acting β2-agonists.
· Patients with exercise-induced bronchospasm should take two to four puffs of an inhaled β2-agonist 10 to 30 minutes before exercise.
· Inhaled corticosteroids (ICS) are the agents of choice for patients with persistent asthma.28 Dosing is based on the severity and control of asthma. Systemic corticosteroid absorption can occur with high-dose ICS, and thus, high-dose ICS should be reserved for patients with severe disease or for those who otherwise require oral corticosteroids.
· Long-acting bronchodilators (LABA) should not be used as monotherapy in persistent asthma.34 However, when used with ICS, salmeterol and formoterol have consistently been shown to improve lung function, both day and nighttime symptoms, reduce exacerbations, and minimize the required dose of ICS.
· Leukotriene-modifying agents (montelukast, zafirlukast, and zileuton) can be used as add-on therapy in patients with persistent asthma to improve asthma control and potentially reduce the dose of inhaled corticosteroid.35However, in comparison to ICS + LABA, they are not as effective in improving asthma outcomes.
· Omalizumab, a monoclonal anti-IgE antibody, has been shown to reduce asthma exacerbations and improve asthma control symptoms in poorly controlled, moderate-to-severe persistent allergic asthma.36Potential candidates for omalizumab must have allergy testing to document sensitization to a perennial allergen. The therapy is expensive, and the drug is dosed based on patient weight and baseline IgE levels.
TABLE 16-11 Medications Commonly Used for Asthma
MDI, metered-dose inhaler; HFA, hydrofluoroalkane; NEB, nebulizer solution or nebulized; DPI, dry powder inhaler; INH, inhalation.
Other Nonpharmacologic Therapies
Bronchial thermoplasty is a novel therapy for severe asthma in which a specialized radiofrequency catheter is introduced through a bronchoscope to deliver thermal energy to airways in order to reduce smooth muscle mass surrounding the airways. Though asthma symptoms may worsen immediately after the procedure, long-term asthma-related quality of life and health care utilization have been shown to improve with bronchial thermoplasty.37
SPECIAL CONSIDERATIONS
· During pregnancy, patients should have more frequent follow-up as the severity often changes and requires medication adjustment. There is more potential risk to the fetus with poorly controlled asthma compared to asthma medication exposure, most of which are generally considered safe.38
· Occupational asthma requires a detailed history of occupational exposure to a sensitizing agent, lack of asthma symptoms prior to exposure, and a documented relationship between symptoms and the workplace. Beyond standard asthma medical treatment, exposure avoidance is crucial.
· Acute exacerbations of asthma are common.
o Patients experiencing severe asthma exacerbations (PEF or FEV1 <40%) should receive systemic corticosteroids.
o Oxygen should be administered to keep the oxygen saturation >90%.
o The response to initial treatment (60 to 90 minutes, three treatments every 20 minutes with a short-acting bronchodilator) can be a better predictor of the need for hospitalization than the severity of an exacerbation.
o A low threshold for hospital admission is appropriate for patients who do not respond to initial therapy, have history of recent hospitalization, or have a previous life-threatening exacerbation.
o In addition, presence of a pulsus paradoxus >12 mm Hg, hypoxemia, and normocapnia despite tachypnea or hypercapnia (PaCO2 >42 mm Hg) should trigger hospital admission.
o The management of the hospitalized patient with an asthma exacerbation will not be discussed here, except to highlight the need for patient education prior to discharge, a written patient action plan, PEFR meter use reinforcement, and planning for outpatient follow-up.39
PATIENT EDUCATION
· One of the primary intents of asthma education is to develop a partnership with the patient and family.
· Information about asthma should be provided including
o Chronicity of the disease and common triggers of exacerbations
o Role of short-acting β2-agonists and long-term controllers
o Importance of communication
· Teach and discuss inhaler and spacer techniques.
· Discuss environmental control measures.
· Address misconceptions, fears, and financial concerns.
· Develop an action plan for exacerbations.
Cystic Fibrosis
GENERAL PRINCIPLES
Epidemiology
· Cystic fibrosis (CF) is the most common lethal genetic disease in Caucasians, with an incidence of 1 in 2,500 live births.40
· Although it is less common in non-Caucasians, the diagnosis needs to be considered in patients of diverse backgrounds.
· The diagnosis of CF is typically made during childhood, and most states implemented newborn screening programs by 2008, but historically, 8% of patients are diagnosed during adolescence or adulthood.
· The median survival has been extended to approximately 37 years, and within the next 5 to 10 years, it is expected that over half of CF patients will be adults.
Pathophysiology
· CF is an autosomal recessive disorder that is caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, located on chromosome 7.41 CFTR protein normally regulates and participates in the transport of electrolytes across epithelial cell membranes.42
· There is considerable phenotypic variation in disease expression with the greatest modifier being the specific genetic mutation. More than 1,500 CFTR domain mutations have been identified and can result in defective protein synthesis, processing, regulation, and activity.
· The primary clinical manifestations of the disease are related to abnormal electrolyte transport in exocrine organs resulting in thickened secretions.
· The abnormal airway secretions in patients with CF predispose them to chronic infection and chronic colonization with organisms such as S. aureus and mucoid strains of gram-negative organisms such as P. aeruginosa. The chronic infection results in chronic airway inflammation and ultimately bronchiectasis.
DIAGNOSIS
· The diagnosis of CF in previously undiagnosed adults is based on clinical and family history in combination with persistently elevated concentrations of sweat chloride (the main laboratory confirmation used) or genetic confirmation revealing two known disease-causing CF mutations.43
· Atypical patients may lack classic symptoms and signs or have normal to indeterminant sweat tests. Although genotyping may assist in the diagnosis, it alone cannot establish or rule out the diagnosis of CF. Evidence of functional changes must be present.
· Although often overlooked, in males with an indeterminant diagnostic workup a testicular ultrasound demonstrating the presence of bilateral vas deferens can rule out cystic fibrosis, as the formation of a normal vas deferens is most sensitive to CFTR dysfunction.
· Newborn screening has identified a new subgroup of patients who do not have disease but have an abnormal sweat test or genetic testing showing a mutation that could cause CFTR-related organ dysfunction.44 Although these patients will carry a diagnosis of CFTR-related metabolic syndrome (CRMS), whether this will represent a milder spectrum of disease in adults or merely a laboratory entity is not known.
Clinical Presentation
Pulmonary Manifestations
· Pulmonary symptoms lead to the consideration of the diagnosis of CF in 50% of cases.
· Symptoms typically include cough and purulent sputum production with dyspnea ensuing as the disease progresses. Almost all patients eventually develop chronic sinopulmonary disease, bronchiectasis, and obstructive lung disease.
· Acute pulmonary exacerbations, characterized by cough, increased sputum volume and purulence, malaise, and weight loss, typically in the absence of fevers, may lead to significant deterioration and subsequent hospitalization.
· Endobronchial infection occurs early in life, and the flora tends to change with time.45
o S. aureus and H. influenza tend to be found in younger patients, and in older individuals, it is replaced by mucoid strains of P. aeruginosa.
o Recurrent isolation of unusual gram-negative organisms like Burkholderia spp. or nontuberculous mycobacteria are more common in CF patients but often require special specimen processing due to P. aeruginosaovergrowth.
· Additional respiratory problems include episodes of hemoptysis, pneumothorax, and allergic bronchopulmonary aspergillosis.46,47
Extrapulmonary Manifestations
· Extrapulmonary manifestations of CF include exocrine pancreatic insufficiency, seen in 90% of patients, resulting in fat malabsorption; deficiency of fat-soluble vitamins A, D, E, and K; and malnutrition.
· CF involvement of the gastrointestinal (GI) tract causes considerable problems including steatorrhea, constipation, impaction, distal ileal obstruction syndrome, volvulus, intussusception, rectal prolapse, and increased risk of GI cancers.
· CF also affects the endocrine pancreas causing diabetes mellitus and pancreatitis. Significant hepatobiliary complications include the development of cirrhosis with portal hypertension, cholelithiasis, and cholecystitis.
· Male patients with CF tend to be infertile due to an absence of the vas deferens, whereas female patients may have fertility problems due to amenorrhea and abnormally thick cervical mucus production.48
· Many individuals with CF suffer from growth retardation, osteopenia, and osteoporosis related to nutritional deficiencies.49
· A CF-associated arthropathy as well as leukocytoclastic vasculitis with lower extremity palpable purpura can develop and may coincide with exacerbations.
· Digital clubbing appears in childhood in virtually all patients with significant bronchiectasis.
Differential Diagnosis
· All adult patients with unexplained bronchiectasis should be considered as possible cases of undiagnosed CF and should have sweat testing performed.50
· Primary ciliary dyskinesia or immunoglobulin deficiency may lead to bronchiectasis, sinusitis, and infertility, but few GI symptoms and no sweat electrolyte abnormalities are present.
· Men with Young syndrome have bronchiectasis, sinusitis, and azoospermia, but the respiratory disease is usually mild, and GI symptoms or sweat manifestations are not present.
· Shwachman syndrome, consisting of pancreatic insufficiency and cyclic neutropenia, may also lead to lung disease, but sweat chloride concentrations are normal, and the neutropenia is distinguishing.
· Idiopathic bronchiectasis with or without nontuberculous mycobacterial infection can present similarly to milder CF mutations but needs to be differentiated as treatments are not identical.
Diagnostic Testing
Skin Sweat Testing
· Standardized quantitative pilocarpine iontophoresis remains the gold standard for the diagnosis of CF and is best performed at a laboratory with experience.
· A sweat chloride concentration of >60 mmol/L is consistent with the diagnosis of CF.50
· The diagnosis should be made only if there is an elevated sweat chloride concentration on two separate occasions in a patient with a typical phenotype or with a history of CF in a sibling.
· Borderline sweat test results (40 to 60 mmol/L sweat chloride) or nondiagnostic test results in the setting of high clinical suspicion should also lead to repeat sweat testing, nasal potential difference testing, testicular ultrasound, or genetic testing.51
· Abnormal sweat chloride concentrations are rarely detected in non-CF patients (e.g., significant malnutrition, Addison disease, or untreated hypothyroidism).
Genetic Testing
· Genetic tests have detected >1,200 CF mutations on chromosome 7. The most common CFTR mutation in patients is ΔF508.
· Most commercially available probes are quite sensitive but test for only a minority of the known CF mutations, although they are able to identify >90% of the abnormal CF genes in Ashkenazi Jews.
· For patients to have clinical disease, two of the recessive genes must be abnormal. Care should be taken in interpreting the presence of mutations and polymorphisms in the absence of symptoms. Identified abnormalities do not always result in disease as they may be on the same allele or simply do not alter protein function or localization. The Clinical and Functional Translation of CFTR website (www.cftr2.org, last accessed January 21, 2015) is a good resource for information related to clinical phenotype of genetic variants.
Nasal Potential Difference
Nasal potential difference measurements can be performed at experienced centers and are able to detect the abnormal epithelial chloride secretion that is typical of CF.51
Other Tests
· CXR may show hyperinflation and upper lobe predominant bronchiectasis.
· PFTs typically show expiratory airflow obstruction with air trapping and hyperinflation. Impairments of gas exchange also occur and can progress to hypoxemia and hypercapnia.
· Sputum cultures typically identify P. aeruginosa and S. aureus, or both. Most laboratories require labeling specimens as a CF patient so plating on special media occurs.
· Testing for malabsorption is often not formally performed, because clinical evidence of steatorrhea, low fat-soluble vitamin levels (A, D, and E), and a prolonged prothrombin time (vitamin K) as well as a clear response to pancreatic enzyme treatment are usually considered sufficient for diagnosing exocrine insufficiency.
· Testing for sinusitis or infertility, especially obstructive azoospermia in males, would also be supportive of the diagnosis of CF.
TREATMENT
· The goals of CF therapy include maintenance of a normal nutritional status, improving quality of life, decreasing the number of exacerbations, and decreasing mortality.52 The major focus of therapy is on clearance of airway secretions and controlling infections.
· Care at a comprehensive CF core center is recommended. These centers are designed to address the multiple organ system involvement typical of the disease and are typically staffed by pulmonary specialists who lead teams of nurses, nutritionists, and social workers to help the patients live with a chronic illness.
· Specialty consultation with gastroenterologists, endocrinologists, and occasionally interventional radiologists may be required during the course of care of each individual patient.
Medications
· Refer to Tables 16-4 and 16-12 for an overview of pharmacologic therapies for CF.
· Bronchodilators such as β2-agonists (Table 16-4) are used to treat the reversible components of airflow obstruction and help facilitate mucus clearance. Many patients with CF have acute improvements in FEV1 as well as symptomatic improvement with bronchodilators.53 Anticholinergics have not been demonstrated to provide benefit in CF.
· Recombinant human deoxyribonuclease (“DNase,” dornase alfa) digests extracellular DNA, decreasing the viscoelasticity of the sputum.
o Dornase alfa improves pulmonary function and decreases the incidence of respiratory tract infections that require parenteral antibiotics.54
o The recommended dose of dornase alfa is 2.5 mg/day inhaled using a jet nebulizer.
o Adverse effects may include pharyngitis, laryngitis, rash, chest pain, and conjunctivitis.
· Hypertonic saline, inhaled twice to four times a day, can be used as an additional regimen in patients already using bronchodilators and dornase alfa. Clinical trials have shown improved mucus clearance, small improvements in lung function, and fewer exacerbations requiring antibiotic therapy.55 Four milliliters of a 7% saline is used and should be preceded by an inhaled bronchodilator to offset the bronchospasm that can occur from this therapy. This is a relatively time-consuming therapy and must utilize a sterile endotoxin-free solution, which may not be covered by prescription plans.
· Antibiotic therapy forms an integral component of the care of patients with CF. The airways become infected in most patients with CF, and the typical pathogens in adulthood include P. aeruginosa and S. aureus.
o Sputum cultures provide the clinician with an idea which antibiotics are effective against the colonizers/pathogens during acute exacerbations. However, antibiotic therapy should never be withheld due to lack of in vitro efficacy given treatment with IV antibiotics was equally successful when regimens utilized two antibiotics of different classes despite lack of in vitro susceptibility.
o Routine sputum cultures are also useful in identifying new infecting organisms, which can impact treatment, isolation procedures, and outcomes in patients with CF, including the following: P. aeruginosa in previously negative patients, Burkholderia cepacia, Achromobacter xylosoxidans, Stenotrophomonas maltophilia, Aspergillus spp., methicillin-resistant S. aureus (MRSA), and nontuberculous mycobacteria (Mycobacterium avium complex or Mycobacterium abscessus).
o Aerosolized antibiotics are frequently used in patients with CF. Inhaling aerosolized tobramycin (300 mg nebulized bid for 28 days on, alternating with 28 days off) using an appropriate nebulizer and compressor improves pulmonary function, decreases the density of P. aeruginosa, and decreases the risk of hospitalization.56 Aztreonam lysinate (75 mg tid on alternating 28-day cycles) demonstrated similar benefits to tobramycin solution despite enrollment of a more aggressively treated cohort.57
o Macrolide antibiotic therapy with azithromycin (500 mg, PO), used chronically three times per week in patients without concurrent nontuberculous mycobacterial infection, has been shown to improve lung function and reduce exacerbations in individuals with chronic P. aeruginosa.58
· Systemic glucocorticoids are indicated only for refractory lung disease that has demonstrated subjective (less dyspnea) and objective (decreased airflow obstruction, improved exercise tolerance, or both) benefit during a trial period. Short courses of glucocorticoid therapy may be helpful to some patients, but long-term therapy should be avoided to minimize the side effects, which include glucose intolerance, osteopenia, and growth retardation. There is very little data to support the use of ICS in patients with CF, unless they have concomitant asthma.
· Pancreatic enzyme supplementation should be instituted after pancreatic insufficiency, and malabsorption have been demonstrated. Enzyme dose is titrated to achieve one to two semisolid stools per day. Enzymes are taken immediately before meals and snacks.
o Dosing of pancreatic enzymes should be initiated at 500 units lipase/kg/meal and should not exceed 2,500 units lipase/kg/meal.
o High doses (>6,000 units lipase/kg/meal) may be associated with chronic intestinal strictures.
· Pancreatic endocrine dysfunction, specifically diabetes mellitus, is best treated with meal carbohydrate-based insulin as the typical diabetic dietary restrictions are liberalized (high-calorie diet with unrestricted fat) to encourage appropriate growth and weight maintenance. Occasionally, mild or early disease responds to metformin.
· Constipation or distal intestinal obstruction can be life threatening, but surgical intervention can frequently be prevented by a combination of treatments similar to preparation for a colonoscopy. Frequently, chronic use of polyethylene glycol laxatives is necessary to prevent recurrence.
· Vitamin supplementation is recommended, especially the fat-soluble vitamins that are not well absorbed in the setting of pancreatic insufficiency. Vitamins A, D, E, and K should all be supplemented orally on a regular basis. Iron deficiency anemia requires iron supplementation and occasionally intravenous replacement in refractory cases.
· Osteopenia should be aggressively treated.
· Sinus regimens including nasal irrigation limit sinusitis, but symptomatic chronic sinus symptoms are common even in adults with mild pulmonary disease.
· Vaccinations including a yearly influenza vaccine and a pneumococcal vaccine every 5 years are recommended.
TABLE 16-12 Additional Medications Commonly Used for Cystic Fibrosis
Other Nonpharmacologic Treatment
· Mucus mobilization/airway clearance can be accomplished using various airway clearance techniques, including postural drainage with chest percussion and vibration, with or without mechanical devices (flutter valves, high-frequency chest oscillation vests, and low and high positive expiratory pressure devices), and breathing and coughing exercises.59
· Pulmonary rehabilitation and exercise is recommended as it improves secretion mobilization and functional status.
· Oxygen therapy is indicated in patients with CF, based on the same criteria as in patients with COPD. Rest and exercise oxygen assessments should be performed as clinically indicated. Although there will likely never be a trial confirming enhanced survival, the presence of secondary pulmonary hypertension at the time of transplant evaluation of many CF patients suggests benefits similar to COPD should occur.
Surgical Management
· Most patients with CF die from pulmonary disease, and lung transplantation may be an option.
· An FEV1 <20% of the predicted normal value, alveolar gas exchange abnormalities (resting hypoxemia or hypercapnia), evidence of pulmonary hypertension, or increased frequency or severity of pulmonary exacerbations should lead to consideration of lung transplantation as a treatment option.60
· Bilateral transplantation is always performed due to chronic endobronchial infection.
· Survival rates of 40% to 60% at 5 years are standard.
SPECIAL CONSIDERATIONS
· Acute exacerbations of CF pulmonary disease are marked by dyspnea, increasing cough, increased mucus production, worsening of spirometry, but rarely fevers.61
o Mild exacerbations can be treated with oral antibiotics. Typical drugs for staphylococcal species include cephalexin, dicloxacillin, trimethoprim-sulfamethoxazole, or doxycycline. Most patients infected with P. aeruginosa will require ciprofloxacin (750 mg bid). Typical treatment intervals are 2 to 3 weeks with reassessment to ensure adequate clinical and spirometric improvement.
o Many patients with exacerbations will eventually require initiation of IV antibiotics. Choice of these agents is dictated by the sputum sensitivities, if available. Combination therapy with a semisynthetic penicillin, a third- or fourth-generation cephalosporin, a carbapenem or a quinolone, and an aminoglycoside is the typical therapy recommended during acute exacerbations.62
o The presence of MRSA on sputum culture testing often necessitates addition of vancomycin or linezolid.
o Treatment is typically 2 weeks and can be completed outside of the hospital.
o Drug dosing tends to be higher due to altered pharmacokinetics probably due to more rapid metabolism of larger charged molecules in CF patients.
o Once-daily IV tobramycin dosing is as effective and simpler than multiple daily-dose regimens but still requires monitoring of peak and trough levels given toxicity.63 Patients need to be monitored chronically for side effects, including ototoxicity given frequency of use in a disease with recurrent exacerbations.
o Home IV antibiotic therapy is common, administered through a peripherally inserted central catheter (PICC) line, subclavian Hohn catheter, or an established Port-A-Cath.
o Initial hospitalization is recommended to allow access to comprehensive therapy and diagnostic testing as well as establishment of appropriate dosing and monitoring of the aminoglycoside.
· B. cepacia complex: Acquisition of this organism is associated with accelerated decline of lung function and shortened survival in patients with CF. In addition, colonization with this organism is a contraindication to lung transplantation at some centers because of the resistance patterns of this pathogen.64 Patients colonized by Burkholderia spp. should be kept separated from other patients with CF (different clinic days, different floors in the hospital).
· Allergic bronchopulmonary aspergillosis can occur in patients with CF.47
· Nontuberculous mycobacteria, normally Mycobacterium avium-intracellulare (MAI) and rarely M. abscessus, can infect patients with CF. Treatment decisions depend on symptoms, radiographic appearance, and pulmonary function. In general, the same therapies are required as in patients with non-CF bronchiectasis.
· Hemoptysis in CF is common, especially small amounts of blood during pulmonary exacerbations. Massive hemoptysis is usually treated with IV antibiotics, airway control and ventilatory support if needed, and radiographic embolization of the bronchial arteries feeding the site of hemoptysis. Embolization may need to be repeated because of the extensive bronchial collaterals seen with CF. Limited pulmonary resection is a last resort.46
· Pneumothorax in patients with CF tends to occur as lung function worsens. Treatment consists of chest tube drainage. For persistent air leaks, pleurodesis may be required.46
· Women with CF who become pregnant normally tolerate the pregnant state well as long as their lung function is not severely impaired with associated pulmonary hypertension.65 Close monitoring of lung function and glycemic control is needed.
MONITORING/FOLLOW-UP
· Spirometry is the best objective measurement of lung function in CF, and routine spirometric monitoring is recommended. A significant decline in spirometry, even in the absence of increased symptoms, mandates intensification of therapy.
· Sputum cultures and sensitivity testing should also be sent from outpatient visits.
· A1C monitoring of diabetic patients is advised.
· Yearly vitamin levels (vitamins A, E) as well as bone densitometry are recommended.
REFERENCES
1.Celli BR, MacNee W. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004;23: 932–946.
2.Raherison C, Girodet PO. Epidemiology of COPD. Eur Respir Rev 2009;18:213–221.
3.Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004;350:2645–2653.
4.Stoller JK, Aboussouan LS. Alpha1-antitrypsin deficiency. Lancet 2005;365:2225–2236.
5.Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395–409.
6.Vestbo J, Hurd SS, Agusti AG, et al. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med2013;187(4):347–365.
7.Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med2007;176:532–555.
8.Ram FS, Sestini P. Regular inhaled short acting beta2 agonists for the management of stable chronic obstructive pulmonary disease: Cochrane systematic review and meta-analysis. Thorax 2003;58:580–584.
9.Anthonisen NR, Connett JE, Kiley JP, et al. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA1994;272:1497–1505.
10.COMBIVENT Inhalation Aerosol Study Group. In chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone. An 85-day multicenter trial. Chest 1994;105:1411–1419.
11.Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775–789.
12.Vogelmeier C, Hederer B, Glaab T, et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med 2011;364:1093–1103.
13.Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011;365:689–698.
14.Wedzicha JA, Rabe KF, Martinez FJ, et al. Efficacy of roflumilast in the chronic obstructive pulmonary disease frequent exacerbator phenotype. Chest 2013;143:1302–1311.
15.Ram FS, Jardin JR, Atallah A, et al. Efficacy of theophylline in people with stable chronic obstructive pulmonary disease: a systematic review and meta-analysis. Respir Med 2005;99:135–144.
16.Stoller JK, Aboussouan LS. alpha1-Antitrypsin deficiency. 5: intravenous augmentation therapy: current understanding. Thorax 2004;59:708–712.
17.Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Ann Intern Med 1980; 93:391–398.
18.Crockett AJ, Cranston JM, Moss JR, et al. Domiciliary oxygen for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2005;(4):CD001744.
19.Fishman A, Martinez F, Naunheim K, et al. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med 2003;348:2059–2073.
20.Thabut G, Ravaud P, Christie JD, et al. Determinants of the survival benefit of lung transplantation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008;177:1156–1163.
21.Kohansal R, Martinez-Camblor P, Agusti A, et al. The natural history of chronic airflow obstruction revisited: an analysis of the Framingham offspring cohort. Am J Respir Crit Care Med 2009;180:3–10.
22.Treating tobacco use and dependence: 2008 update U.S. Public Health Service Clinical Practice Guideline executive summary. Respir Care 2008;53:1217–1222.
23.Parshall MB, Schwartzstein RM, Adams L, et al. An official American Thoracic Society statement: update on the mechanisms, assessment, and management of dyspnea. Am J Respir Crit Care Med2012;185:435–452.
24.American Thoracic Society. Pulmonary rehabilitation-1999. Am J Respir Crit Care Med 1999;159:1666–1682.
25.Celli BR, Cote CG, Marin JM, et al. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med 2004;350:1005–1012.
26.Connors AF Jr, Dawson NV, Thomas C, et al. Outcomes following acute exacerbation of severe chronic obstructive lung disease. The SUPPORT investigators (Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments). Am J Respir Crit Care Med 1996;154:959–967.
27.Niewoehner DE, Erbland ML, Deupree RH, et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group. N Engl J Med1999;340:1941–1947.
28.National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma. Full Report 2007. Bethesda, MD: National Institutes of Health, National Heart, Lung, and Blood Institute, Publication No. 08-4051; 2007. Available at: http://www.nhlbi.nih.gov/guidelines/asthma/index.htm (last accessed February 21, 2014).
29.Moorman JE, Rudd RA, Johnson CA, et al. National surveillance for asthma—United States, 1980–2004. MMWR Surveill Summ 2007;56(8):1–54.
30.Yunginger JW, Reed CE, O’Connell EJ, et al. A community-based study of the epidemiology of asthma. Incidence rates, 1964–1983. Am Rev Respir Dis 1992;146:888–894.
31.Irwin RS, Curley FJ, French CL. Chronic cough: the spectrum and frequency of causes, key components of the diagnostic evaluation, and outcome of specific therapy. Am Rev Respir Dis 1990;141:640–647.
32.Crapo RO, Casaburi R, Coates AL, et al. Guidelines for methacholine and exercise challenge testing-1999. Am J Respir Crit Care Med 2000;161:309–329.
33.Cowie RL, Revitt SG, Underwood MF, Field SK. The effect of a peak flow-based action plan in the prevention of exacerbations of asthma. Chest 1997;112:1534–1538.
34.Nelson HS, Weiss ST, Bleecker ER, et al. The salmeterol multicenter asthma research trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest2006;129:15–26.
35.Phipatanakul W, Greene C, Downes SJ, et al. Montelukast improves asthma control in asthmatic children maintained on inhaled corticosteroids. Ann Allergy Asthma Immunol 2003;91:49–54.
36.Soler M, Matz J, Townley R, et al. The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics. Eur Respir J 2001;18: 254–261.
37.Castro M, Rubin AS, Laviolette M, et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am J Respir Crit Care Med2010;181(2):116–124.
38.Källén B, Rydhstroem H, Aberg A. Congenital malformations after the use of inhaled budesonide in early pregnancy. Obstet Gynecol 1999;93:392–395.
39.Rodrigo GJ, Rodrigo C, Hall JB. Acute asthma in adults: a review. Chest 2004; 125:1081–1102.
40.Cohen-Cymberknoh M, Shoseyov D, Kerem E. Managing cystic fibrosis: strategies that increase life expectancy and improve quality of life. Am J Respir Crit Care Med 2011;183:1463–1471.
41.Rommens JM, Iannuzzi MC, Kerem B, et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 1989;245:1059–1065.
42.Denning GM, Ostedgaard LS, Cheng SH, et al. Localization of cystic fibrosis transmembrane conductance regulator in chloride secretory epithelia. J Clin Invest 1992;89:339–349.
43.Stern RC. The diagnosis of cystic fibrosis. N Engl J Med 1997;336:487–491.
44.Wagener JS, Zemanick ET, Sontag MK. Newborn screening for cystic fibrosis. Curr Opin Pediatr 2012;24:329–335.
45.Conrad D, Haynes M, Salamon P, et al. Cystic fibrosis therapy: a community ecology perspective. Am J Respir Cell Mol Biol 2013;48:150–156.
46.Flume PA, Mogayzel PJ Jr, Robinson KA, et al. Cystic fibrosis pulmonary guidelines: pulmonary complications: hemoptysis and pneumothorax. Am J Respir Crit Care Med 2010;182:298–306.
47.Stevens DA, Moss RB, Kurup VP, et al. Allergic bronchopulmonary aspergillosis in cystic fibrosis—state of the art: Cystic Fibrosis Foundation Consensus Conference. Clin Infect Dis 2003;37(suppl 3):S225–S264.
48.Dodge JA. Male fertility in cystic fibrosis. Lancet 1995;346:587–588.
49.Haworth CS, Selby PL, Webb AK, et al. Low bone mineral density in adults with cystic fibrosis. Thorax 1999;54:961–967.
50.Davis PB, Del Rio S, Muntz JA, et al. Sweat chloride concentration in adults with pulmonary diseases. Am Rev Respir Dis 1983;128:34–37.
51.Alton EW, Currie D, Logan-Sinclair R, et al. Nasal potential difference: a clinical diagnostic test for cystic fibrosis. Eur Respir J 1990;3:922–926.
52.Flume PA, O’Sullivan BP, Robinson KA, et al. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med 2007;176:957–969.
53.Cropp GJ. Effectiveness of bronchodilators in cystic fibrosis. Am J Med 1996; 100:19S–29S.
54.Fuchs HJ, Borowitz DS, Christiansen DH, et al. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group. N Engl J Med 1994;331:637–642.
55.Elkins MR, Robinson M, Rose BR, et al. A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N Engl J Med 2006;354:229–240.
56.Ramsey BW, Pepe MS, Quan JM, et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group. N Engl J Med 1999;340:23–30.
57.McCoy KS, Quittner AL, Oermann CM, et al. Inhaled aztreonam lysine for chronic airway Pseudomonas aeruginosa in cystic fibrosis. Am J Respir Crit Care Med 2008;178:921–928.
58.Saiman L, Marshall BC, Mayer-Hamblett N, et al. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA 2003;290:1749–1756.
59.Flume PA, Robinson KA, O’Sullivan BP, et al. Cystic fibrosis pulmonary guidelines: airway clearance therapies. Respir Care 2009;54:522–537.
60.Kreider M, Kotloff RM. Selection of candidates for lung transplantation. Proc Am Thorac Soc 2009;6:20–27.
61.Flume PA, Mogayzel PJ Jr, Robinson KA, et al. Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. Am J Respir Crit Care Med 2009;180:802–808.
62.Zobell JT, Waters CD, Young DC, et al. Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: II. Cephalosporins and penicillins. Pediatr Pulmonol 2013;48:107–122.
63.Smyth A, Tan KH, Hyman-Taylor P, et al. Once versus three-times daily regimens of tobramycin treatment for pulmonary exacerbations of cystic fibrosis—the TOPIC study: a randomised controlled trial. Lancet 2005;365:573–578.
64.Chaparro C, Maurer J, Gutierrez C, et al. Infection with Burkholderia cepacia in cystic fibrosis: outcome following lung transplantation. Am J Respir Crit Care Med 2001;163:43–48.
65.Goss CH, Rubenfeld GD, Otto K, et al. The effect of pregnancy on survival in women with cystic fibrosis. Chest 2003;124:1460–1468.