InternalMed_Harrison

InternalMed_Harrison. Asbestos has largely been replaced in the developed world with synthetic mineral fibers such as fiberglass and refractory ceramic fibers, but it continues to be used in the developing world. The major health effects from exposure to asbestos are pleural and pulmonary fibrosis, cancers of the respiratory tract, and pleural and peritoneal mesothelioma. Asbestosis is a diffuse interstitial fibrosing disease of the lung that is directly related to the intensity and duration of exposure. The disease resembles other forms of diffuse interstitial fibrosis (Chap. 315). Usually, exposure has taken place for at least 10 years before the disease becomes manifest. The mechanisms by which asbestos fibers induce lung fibrosis are not completely understood but are known to involve oxidative injury due to the generation of reactive oxygen species by the transition metals on the surface of the fibers as well as from cells engaged in phagocytosis.


InternalMed_Harrison

InternalMed_Harrison. Past exposure to asbestos is specifically indicated by pleural plaques on chest radiographs, which are characterized by either thickening or calcification along the parietal pleura, particularly along the lower lung fields, the diaphragm, and the cardiac border. Without additional manifestations, pleural plaques imply only exposure, not pulmonary impairment. Benign pleural effusions also may occur. The fluid is typically a serous or bloody exudate. The effusion may be slowly progressive or may resolve spontaneously. Irregular or linear opacities that usually are first noted in the lower lung fields are the chest radiographic hallmark of asbestosis. An indistinct heart border or a “ground-glass” appearance in the lung fields may be seen. HRCT may show distinct changes of subpleural curvilinear lines 5–10 mm in length that appear to be parallel to the pleural surface (Fig. 311-1).


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InternalMed_Harrison. Pulmonary function testing in asbestosis reveals a restrictive pattern with a decrease in both lung volumes and diffusing capacity. There may also be evidence of mild airflow obstruction (due to peribronchiolar fibrosis). Because no specific therapy is available for asbestosis, supportive care is the same as that given to any patient with diffuse interstitial fibrosis of any cause. In general, newly diagnosed cases will have resulted from exposures that occurred many years before.


InternalMed_Harrison

InternalMed_Harrison. Lung cancer (Chap. 107) is the most common cancer associated with asbestos exposure. The excess frequency of lung cancer (all histologic types) in asbestos workers is associated with a minimum latency of 15–19 years between first exposure and development of the disease. Persons with more exposure are at greater risk of disease. In addition, there is a significant interactive effect of smoking and asbestos exposure that results in greater risk than what would be expected from the additive effect of each factor.


InternalMed_Harrison

InternalMed_Harrison. Mesotheliomas (Chap. 316), both pleural and peritoneal, are also associated with asbestos exposure. In contrast to lung cancers, these tumors do not appear to be associated with smoking. Relatively short-term asbestos exposures of ≤1–2 years, occurring up to 40 years in the past, have been associated with the development of mesotheliomas (an observation that emphasizes the importance of obtaining a complete environmental exposure history). Although the risk of mesothelioma is much less than that of lung cancer among asbestos-exposed workers, over 2000 cases were reported in the United States per year at the start of the twenty-first century. Because epidemiologic studies have shown that >80% of mesotheliomas may be associated with asbestos exposure, documented mesothelioma in a patient with occupational or environmental exposure to asbestos may be compensable.


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InternalMed_Harrison. FIGURE 311-1 Asbestosis. A. Frontal chest radiograph shows bilateral calcified pleural plaques consistent with asbestos-related pleural disease. Poorly defined linear and reticular abnormalities are seen in the lower lobes bilaterally. B. Axial high-resolution computed tomography of the thorax obtained through the lung bases shows bilateral, subpleural reticulation (black arrows), representing fibrotic lung disease due to asbestosis. Subpleural lines are also present (arrowheads), characteristic of, though not specific for, asbestosis. Calcified pleural plaques representing asbestos-related pleural disease (white arrows) are also evident.


InternalMed_Harrison

InternalMed_Harrison. Despite being one of the oldest known occupational pulmonary hazards, free silica (SiO2), or crystalline quartz, is still a major cause of disease. The major occupational exposures include mining; stonecutting; sand blasting; glass and cement manufacturing; foundry work; packing of silica flour; and quarrying, particularly of granite. Most often, pulmonary fibrosis due to silica exposure (silicosis) occurs in a dose-response fashion after many years of exposure. Workers heavily exposed through sandblasting in confined spaces, tunneling through rock with a high quartz content (15–25%), or the manufacture of abrasive soaps may develop acute silicosis with as little as 10 months of exposure. The clinical and pathologic features of acute silicosis are similar to those of pulmonary alveolar proteinosis


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InternalMed_Harrison. FIGURE 311-2 Acute silicosis. This high-resolution computed tomog-raphy scan shows multiple small nodules consistent with silicosis but also diffuse ground-glass densities with thickened intralobular and interlobular septa producing polygonal shapes. This has been referred to as “crazy paving.” (Chap. 315). The chest radiograph may show profuse miliary infiltration or consolidation, and there is a characteristic HRCT pattern known as “crazy paving” (Fig. 311-2). The disease may be quite severe and progressive despite the discontinuation of exposure. Whole-lung lavage may provide symptomatic relief and slow the progression.


InternalMed_Harrison

InternalMed_Harrison. With long-term, less intense exposure, small rounded opacities in the upper lobes may appear on the chest radiograph after 15–20 years of exposure, usually without associated impairment of lung function (simple silicosis). Calcification of hilar nodes may occur in as many as 20% of cases and produces a characteristic “eggshell” pattern. Silicotic nodules may be identified more readily by HRCT (Fig. 311-3). The nodular fibrosis may be progressive in the absence of further exposure, with coalescence and formation of nonsegmental conglomerates of irregular masses >1 cm in diameter (complicated silicosis). These masses can become quite large, and when this occurs, the term progressive massive fibrosis (PMF) is applied. Significant functional impairment with both restrictive and obstructive components may be associated with PMF.


InternalMed_Harrison

InternalMed_Harrison. Because silica is cytotoxic to alveolar macrophages, patients with silicosis are at greater risk of acquiring lung infections that involve these cells as a primary defense (Mycobacterium tuberculosis, atypical mycobacteria and fungi). Because of the increased risk of active tuberculosis, the recommended treatment of latent tuberculosis in these patients is longer. Another potential clinical complication of silicosis is autoimmune connective tissue disorders such as rheumatoid arthritis and scleroderma. In addition, there are sufficient epidemiologic data that the International Agency for Research on Cancer lists silica as a probable lung carcinogen.


InternalMed_Harrison

InternalMed_Harrison. Other, less hazardous silicates include fuller’s earth, kaolin, mica, diatomaceous earths, silica gel, soapstone, carbonate dusts, and cement dusts. The production of fibrosis in workers exposed to these agents is believed to be related either to the free silica content of these dusts or, for substances that contain no free silica, to the potentially large dust loads to which these workers may be exposed. Some silicates, including talc and vermiculite, may be contaminated with asbestos. Fibrosis of lung or pleura, lung cancer, and mesothelioma have been associated with chronic exposure to talc and vermiculite dusts.


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InternalMed_Harrison. FIGURE 311-3 Chronic silicosis. A. Frontal chest radiograph in a patient with silicosis shows variably sized, poorly defined nodules (arrows) predominating in the upper lobes. B. Axial thoracic com-puted tomography image through the lung apices shows numerous small nodules, more pronounced in the right upper lobe. A number of the nodules are subpleural in location (arrows). Occupational exposure to coal dust can lead to CWP, which has enormous social, economic, and medical significance in every nation in which coal mining is an important industry. Simple radiographically identified CWP is seen in ~10% of all coal miners and in as many as 50% of anthracite miners with more than 20 years of work on the coal face. The prevalence of disease is lower in workers in bituminous coal mines.


InternalMed_Harrison

InternalMed_Harrison. With prolonged exposure to coal dust (i.e., 15–20 years), small, rounded opacities similar to those of silicosis may develop. As in silicosis, the presence of these nodules (simple CWP) usually is not associated with pulmonary impairment. In addition to CWP, coal dust can cause chronic bronchitis and COPD (Chap. 314). The effects of coal dust are additive to those of cigarette smoking. Complicated CWP is manifested by the appearance on the chest radiograph of nodules ≥1 cm in diameter generally confined to the upper half of the lungs. As in silicosis, this condition can progress to PMF that is accompanied by severe lung function deficits and associated with premature mortality. Despite improvements in technology to protect coal miners, cases of PMF still occur in the United States at a disturbing rate.


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InternalMed_Harrison. Caplan syndrome (Chap. 380), first described in coal miners but subsequently in patients with silicosis, is the combination of pneumoconiotic nodules and seropositive rheumatoid arthritis. Silica has immunoadjuvant properties and is often present in anthracitic coal dust.


InternalMed_Harrison

InternalMed_Harrison. Beryllium is a lightweight metal with tensile strength, good electrical conductivity, and value in the control of nuclear reactions through its ability to quench neutrons. Although beryllium may produce an acute pneumonitis, it is far more commonly associated with a chronic granulomatous inflammatory disease that is similar to sarcoidosis (Chap. 390). Unless one inquires specifically about occupational exposures to beryllium in the manufacture of alloys, ceramics, or high-technology electronics in a patient with sarcoidosis, one may miss entirely the etiologic relationship to the occupational exposure. What distinguishes chronic beryllium disease (CBD) from sarcoidosis is evidence of a specific cell-mediated immune response (i.e., delayed hypersensitivity) to beryllium.


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InternalMed_Harrison. The test that usually provides this evidence is the beryllium lymphocyte proliferation test (BeLPT). The BeLPT compares the in vitro proliferation of lymphocytes from blood or bronchoalveolar lavage in the presence of beryllium salts with that of unstimulated cells. Proliferation is usually measured by lymphocyte uptake of radiolabeled thymidine.


InternalMed_Harrison

InternalMed_Harrison. Chest imaging findings are similar to those of sarcoidosis (nodules along septal lines) except that hilar adenopathy is somewhat less common. As with sarcoidosis, pulmonary function test results may show restrictive and/or obstructive ventilatory deficits and decreased diffusing capacity. With early disease, both chest imaging studies and pulmonary function tests may be normal. Fiberoptic bronchoscopy with transbronchial lung biopsy usually is required to make the diagnosis of CBD. In a beryllium-sensitized individual, the presence of noncaseating granulomas or monocytic infiltration in lung tissue establishes the diagnosis. Accumulation of beryllium-specific CD4+ T cells occurs in the granulomatous inflammation seen on lung biopsy. Susceptibility to CBD is highly associated with human leukocyte antigen DP (HLA-DP) alleles that have a glutamic acid in position 69 of the β chain.


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InternalMed_Harrison. Aluminum and titanium dioxide have been rarely associated with a sarcoid-like reaction in lung tissue. Exposure to dust containing tungsten carbide, also known as “hard metal,” may produce giant cell interstitial pneumonitis. Cobalt is a constituent of tungsten carbide and is the likely etiologic agent of both the interstitial pneumonitis and the occupational asthma that may occur. The most common exposures to tungsten carbide occur in tool and dye, saw blade, and drill bit manufacture. Diamond polishing may also involve exposure to cobalt dust. In patients with interstitial lung disease, one should always inquire about exposure to metal fumes and/or dusts. Especially when sarcoidosis appears to be the diagnosis, one should always consider possible CBD.


InternalMed_Harrison

InternalMed_Harrison. Most of the inorganic dusts discussed thus far are associated with the production of either dust macules or interstitial fibrotic changes in the lung. Other inorganic and organic dusts (see categories in Table 311-1), along with some of the dusts previously discussed, are associated with chronic mucus hypersecretion (chronic bronchitis), with or without reduction of expiratory flow rates. Cigarette smoking is the major cause of these conditions, and any effort to attribute some component of the disease to occupational and environmental exposures must take cigarette smoking into account. Most studies suggest an additive effect of dust exposure and smoking. The pattern of the irritant dust effect is similar to that of cigarette smoking, suggesting that small airway inflammation may be the initial site of pathologic response in those cases and continued exposure may lead to chronic bronchitis and COPD.


InternalMed_Harrison

InternalMed_Harrison. Some of the specific diseases associated with organic dusts are discussed in detail in the chapters on asthma (Chap. 309) and hypersensitivity pneumonitis (Chap. 310). Many of these diseases are named for the specific setting in which they are found, e.g., farmer’s lung, malt worker’s disease, and mushroom worker’s disease. Often the temporal relation of symptoms to exposure furnishes the best evidence for the diagnosis. Three occupational exposures are singled out for discussion 1691 here because they affect the largest proportions of workers.


InternalMed_Harrison

InternalMed_Harrison. Cotton Dust (Byssinosis) Workers occupationally exposed to cotton dust (but also to flax, hemp, or jute dust) in the production of yarns for textiles and rope making are at risk for an asthma-like syndrome known as byssinosis. Exposure occurs throughout the manufacturing process but is most pronounced in the portions of the factory involved with the treatment of the cotton before spinning, i.e., blowing, mixing, and carding (straightening of fibers). The risk of byssinosis is associated with both cotton dust and endotoxin levels in the workplace environment.


InternalMed_Harrison

InternalMed_Harrison. Byssinosis is characterized clinically as occasional (early-stage) and then regular (late-stage) chest tightness toward the end of the first day of the workweek (“Monday chest tightness”). Exposed workers may show a significant drop in FEV1 over the course of a Monday work-shift. Initially the symptoms do not recur on subsequent days of the week. However, in 10–25% of workers, the disease may be progressive, with chest tightness recurring or persisting throughout the workweek. After >10 years of exposure, workers with recurrent symptoms are more likely to have an obstructive pattern on pulmonary function testing. The highest grades of impairment generally are seen in smokers.


InternalMed_Harrison

InternalMed_Harrison. Dust exposure can be reduced by the use of exhaust hoods, general increases in ventilation, and wetting procedures, but respiratory protective equipment may be required during certain operations. Regular surveillance of pulmonary function in cotton dust–exposed workers using spirometry before and after the workshift is required by OSHA. All workers with persistent symptoms or significantly reduced levels of pulmonary function should be moved to areas of lower risk of exposure. Grain Dust Worldwide, many farmers and workers in grain storage facilities are exposed to grain dust. The presentation of obstructive airway disease in grain dust–exposed workers is virtually identical to the characteristic findings in cigarette smokers, i.e., persistent cough, mucus hypersecretion, wheeze and dyspnea on exertion, and reduced FEV1 and FEV1/FVC (forced vital capacity) ratio (Chap. 306e).


InternalMed_Harrison

InternalMed_Harrison. Dust concentrations in grain elevators vary greatly but can be >10,000 μg/m3 with many particles in the respirable size range. The effect of grain dust exposure is additive to that of cigarette smoking, with ~50% of workers who smoke having symptoms. Smoking grain dust–exposed workers are more likely to have obstructive ventilatory deficits on pulmonary function testing. As in byssinosis, endotoxin may play a role in grain dust–induced chronic bronchitis and COPD.


InternalMed_Harrison

InternalMed_Harrison. Farmer’s Lung This condition results from exposure to moldy hay containing spores of thermophilic actinomycetes that produce a hypersensitivity pneumonitis (Chap. 310). A patient with acute farmer’s lung presents 4–8 h after exposure with fever, chills, malaise, cough, and dyspnea without wheezing. The history of exposure is obviously essential to distinguish this disease from influenza or pneumonia with similar symptoms. In the chronic form of the disease, the history of repeated attacks after similar exposure is important in differentiating this syndrome from other causes of patchy fibrosis (e.g., sarcoidosis). A wide variety of other organic dusts are associated with the occurrence of hypersensitivity pneumonitis (Chap. 310). For patients who present with hypersensitivity pneumonitis, specific and careful inquiry about occupations, hobbies, and other home environmental exposures is necessary to uncover the source of the etiologic agent.


InternalMed_Harrison

InternalMed_Harrison. Exposure to toxic chemicals affecting the lung generally involves gases and vapors. A common accident is one in which the victim is trapped in a confined space where the chemicals have accumulated to harmful levels. In addition to the specific toxic effects of the chemical, the victim often sustains considerable anoxia, which can play a dominant role in determining whether the individual survives. Table 311-2 lists a variety of toxic agents that can produce acute and sometimes life-threatening reactions in the lung. All these agents in sufficient concentrations have been demonstrated, at least in animal studies, to affect the lower airways and disrupt alveolar architecture, either acutely or as a result of chronic exposure. Some of these agents may be generated acutely in the environment (see below).


InternalMed_Harrison

InternalMed_Harrison. Acid fumes: H2SO4, Manufacture of fertilizers, chlorinated organic Mucous membrane irritation, followed by Bronchitis and suggestion of mildly HNO3 compounds, dyes, explosives, rubber products, chemical pneumonitis 2–3 days later reduced pulmonary function in children metal etching, plastics with lifelong residential exposure to high levels Acrolein and other By-product of burning plastics, woods, tobacco Mucous membrane irritant, decrease in Upper respiratory tract irritation aldehydes smoke lung function Ammonia Refrigeration; petroleum refining; manufacture Same as for acid fumes, but bronchiectasis Upper respiratory tract irritation, chronic of fertilizers, explosives, plastics, and other also has been reported bronchitis chemicals Cadmium fumes Smelting, soldering, battery production Mucous membrane irritant, acute respira-Chronic obstructive pulmonary disease tory distress syndrome (ARDS) (COPD)


InternalMed_Harrison

InternalMed_Harrison. Cadmium fumes Smelting, soldering, battery production Mucous membrane irritant, acute respira-Chronic obstructive pulmonary disease tory distress syndrome (ARDS) (COPD) Formaldehyde Manufacture of resins, leathers, rubber, metals, Same as for acid fumes Nasopharyngeal cancer and woods; laboratory workers, embalmers; emission from urethane foam insulation Halides and acid Bleaching in pulp, paper, textile industry; manu-Mucous membrane irritation, pulmonary Upper respiratory tract irritation, epistaxis, salts (Cl, Br, F) facture of chemical compounds; synthetic rub-edema; possible reduced forced vital tracheobronchitis ber, plastics, disinfectant, rocket fuel, gasoline capacity (FVC) 1–2 years after exposure Hydrogen sulfide By-product of many industrial processes, oil, Increase in respiratory rate followed by Conjunctival irritation, chronic bronchitis, other petroleum processes and storage respiratory arrest, lactic acidosis, pulmo-recurrent pneumonitis nary edema, death


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InternalMed_Harrison. Isocyanates (TDI, Production of polyurethane foams, plastics, Mucous membrane irritation, dyspnea, Upper respiratory tract irritation, cough, HDI, MDI) adhesives, surface coatings cough, wheeze, pulmonary edema asthma, hypersensitivity pneumonitis, reduced lung function Nitrogen dioxide Silage, metal etching, explosives, rocket fuels, Cough, dyspnea, pulmonary edema may Emphysema in animals, ? chronic bronchi- welding, by-product of burning fossil fuels be delayed 4–12 h; possible result from tis, associated with reduced lung function acute exposure: bronchiolitis obliterans in in children with lifelong residential 2–6 weeks exposure Ozone Arc welding, flour bleaching, deodorizing, emis-Mucous membrane irritant, pulmonary Excess cardiopulmonary mortality rates sions from copying equipment, photochemical hemorrhage and edema, reduced pulmoair pollutant nary function transiently in children and adults, and increased hospitalization with exposure to summer haze


InternalMed_Harrison

InternalMed_Harrison. Phosgene Organic compound, metallurgy, volatilization of Delayed onset of bronchiolitis and pulmo-Chronic bronchitis chlorine-containing compounds nary edema Sulfur dioxide Manufacture of sulfuric acid, bleaches, coating Mucous membrane irritant, epistaxis, Chronic bronchitis of nonferrous metals, food processing, refriger-bronchospasm (especially in people with ant, burning of fossil fuels, wood pulp industry asthma) Abbreviations: HDI, hexamethylene diisocyanate; MDI, methylene diphenyl diisocyanate; TDI, toluene diisocyanate.


InternalMed_Harrison

InternalMed_Harrison. Firefighters and fire victims are at risk of smoke inhalation, an Two other agents have been associated with potentially severe lung important cause of acute cardiorespiratory failure. Smoke inhalation disease. Occupational exposure to nylon flock has been shown to kills more fire victims than does thermal injury. Carbon monoxide induce a lymphocytic bronchiolitis, and workers exposed to diacetyl, poisoning with resulting significant hypoxemia can be life-threatening which is used to provide “butter” flavor in the manufacture of micro(Chap. 473e). Synthetic materials (plastic, polyurethanes), when wave popcorn and other foods, have developed bronchiolitis obliterans burned, may release a variety of other toxic agents (such as cyanide and (Chap. 315). hydrochloric acid), and this must be considered in evaluating smoke inhalation victims. Exposed victims may have some degree of lower World Trade Center Disaster A consequence of the attack on the World respiratory tract inflammation


InternalMed_Harrison

InternalMed_Harrison. be considered in evaluating smoke inhalation victims. Exposed victims may have some degree of lower World Trade Center Disaster A consequence of the attack on the World respiratory tract inflammation and/or pulmonary edema. Trade Center (WTC) on September 11, 2001, was relatively heavy Exposure to certain highly reactive, low-molecular-weight agents exposure of a large number of firefighters and other rescue workers used in the manufacture of synthetic polymers, paints, and coatings to the dust generated by the collapse of the buildings. Environmental (diisocyanates in polyurethanes, aromatic amines and acid anhydrides monitoring and chemical characterization of WTC dust has revealed in epoxies) is associated with a high risk of occupational asthma. a wide variety of potentially toxic constituents, although much of the Although this occupational asthma manifests clinically as if sensitiza-dust was pulverized cement. Possibly because of the high alkalinity tion has occurred, an IgE


InternalMed_Harrison

InternalMed_Harrison. constituents, although much of the Although this occupational asthma manifests clinically as if sensitiza-dust was pulverized cement. Possibly because of the high alkalinity tion has occurred, an IgE antibody–mediated mechanism is not neces-of WTC dust, significant cough, wheeze, and phlegm production sarily involved. Hypersensitivity pneumonitis–like reactions also have occurred among firefighters and cleanup crews. New cough and been described in diisocyanate and acid anhydride–exposed workers. wheeze syndromes also occurred among local residents. Heavier expo-


InternalMed_Harrison

InternalMed_Harrison. Fluoropolymers such as Teflon, which at normal temperatures sure to WTC dust among New York City firefighters was associated produce no reaction, become volatilized upon heating. The inhaled with accelerated decline of lung function over the first year after the agents cause a characteristic syndrome of fever, chills, malaise, and disaster. More recently, concerns have been raised about risk of inter- occasionally mild wheezing, leading to the diagnosis of polymer fume stitial lung disease, especially of a granulomatous nature. fever. A similar self-limited, influenza-like syndrome—metal fume fever—results from acute exposure to fumes containing zinc oxide, OCCUPATIONAL RESPIRATORY CARCINOGENS typically from welding of galvanized steel. These inhalational fever Exposures at work have been estimated to contribute to 10% of all syndromes may begin several hours after work and resolve within lung cancer cases. In addition to asbestos, other agents either proven 24 h, only to return on


InternalMed_Harrison

InternalMed_Harrison. estimated to contribute to 10% of all syndromes may begin several hours after work and resolve within lung cancer cases. In addition to asbestos, other agents either proven 24 h, only to return on repeated exposure. or suspected to be respiratory carcinogens include acrylonitrile, arsenic compounds, beryllium, bis(chloromethyl) ether, chromium (hexavalent), formaldehyde (nasal), isopropanol (nasal sinuses), mustard gas, nickel carbonyl (nickel smelting), polycyclic aromatic hydrocarbons (coke oven emissions and diesel exhaust), secondhand tobacco smoke, silica (both mining and processing), talc (possible asbestos contamination in both mining and milling), vinyl chloride (sarcomas), wood (nasal cancer only), and uranium. Workers at risk of radiation-related lung cancer include not only those involved in mining or processing uranium but also those exposed in underground mining operations of other ores where radon daughters may be emitted from rock formations.


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InternalMed_Harrison. Disability is the term used to describe the decreased ability to work due to the effects of a medical condition. Physicians are generally able to assess physiologic dysfunction, or impairment, but the rating of disability for compensation of loss of income also involves nonmedical factors such as the education and employability of the individual. The disability rating scheme differs with the compensation-granting agency. For example, the U.S. Social Security Administration requires that an individual be unable to do any work (i.e., total disability) before he or she will receive income replacement payments. Many state workers’ compensation systems allow for payments for partial disability. In the Social Security scheme, no determination of cause is done, whereas work-relatedness must be established in workers’ compensation systems.


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InternalMed_Harrison. For respiratory impairment rating, resting pulmonary function tests (spirometry and diffusing capacity) are used as the initial assessment tool, with cardiopulmonary exercise testing (to assess maximal oxygen consumption) used if the results of the resting tests do not correlate with the patient’s symptoms. Methacholine challenge (to assess airway reactivity) can also be useful in patients with asthma who have normal spirometry when evaluated. Some compensation agencies (e.g., Social Security) have proscribed disability classification schemes based on pulmonary function test results. When no specific scheme is proscribed, the Guidelines of the American Medical Association should be used.


InternalMed_Harrison

InternalMed_Harrison. In 1971, the U.S. government established national air quality standards for several pollutants believed to be responsible for excess cardiorespiratory diseases. Primary standards regulated by the U.S. Environmental Protection Agency (EPA) designed to protect the public health with an adequate margin of safety exist for sulfur dioxide, particulates matter, nitrogen dioxide, ozone, lead, and carbon monoxide. Standards for each of these pollutants are updated regularly through an extensive review process conducted by the EPA. (For details on current standards, go to http://www.epa.gov/air/criteria.html.)


InternalMed_Harrison

InternalMed_Harrison. Pollutants are generated from both stationary sources (power plants and industrial complexes) and mobile sources (motor vehicles), and none of the regulated pollutants occurs in isolation. Furthermore, pollutants may be changed by chemical reactions after being emitted. For example, sulfur dioxide and particulate matter emissions from a coal-fired power plant may react in air to produce acid sulfates and aerosols, which can be transported long distances in the atmosphere. Oxides of nitrogen and volatile organic compounds from automobile exhaust react with sunlight to produce ozone. Although originally thought to be confined to Los Angeles, photochemically derived pollution (“smog”) is now known to be a problem throughout the United States and in many other countries. Both acute and chronic effects of these exposures have been documented in large population studies.


InternalMed_Harrison

InternalMed_Harrison. The symptoms and diseases associated with air pollution are the same as conditions commonly associated with cigarette smoking. In addition, decreased growth of lung function and asthma have been associated with chronic exposure to only modestly elevated levels of traffic-related gases and respirable particles. Multiple population-based time-series studies within cities have demonstrated excess health care utilization for asthma and other cardiopulmonary conditions as well as increased mortality rates. Cohort studies comparing cities that have relatively high levels of particulate exposures with less polluted 1693 communities suggest excess morbidity and mortality rates from cardiopulmonary conditions in long-term residents of the former. The strong epidemiologic evidence that fine particulate matter is a risk factor for cardiovascular morbidity and mortality has prompted toxicologic investigations into the underlying mechanisms. The inhalation of fine particles from combustion sources


InternalMed_Harrison

InternalMed_Harrison. matter is a risk factor for cardiovascular morbidity and mortality has prompted toxicologic investigations into the underlying mechanisms. The inhalation of fine particles from combustion sources probably generates oxidative stress followed by local injury and inflammation in the lungs that in turn lead to autonomic and systemic inflammatory responses that can induce endothelial dysfunction and/or injury. Recent research findings on the health effects of air pollutants has led to stricter U.S. ambient air quality standards for ozone, oxides of nitrogen, and particulate matter as well as greater emphasis on publicizing pollution alerts to encourage individuals with significant cardiopulmonary impairment to stay indoors during high-pollution episodes.


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InternalMed_Harrison. Secondhand tobacco smoke (Chap. 470), radon gas, wood smoke, and other biologic agents generated indoors must be considered. Several studies have shown that the respirable particulate load in any household is directly proportional to the number of cigarette smokers living in that home. Increases in prevalence of respiratory illnesses, especially asthma, and reduced levels of pulmonary function measured with simple spirometry have been found in the children of smoking parents in a number of studies. Recent meta-analyses for lung cancer and cardiopulmonary diseases, combining data from multiple secondhand tobacco smoke epidemiologic studies, suggest an ~25% increase in relative risk for each condition, even after adjustment for major potential confounders.


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InternalMed_Harrison. Exposure to radon gas in homes is a risk factor for lung cancer. The main radon product (radon-222) is a gas that results from the decay series of uranium-238, with the immediate precursor being radium-226. The amount of radium in earth materials determines how much radon gas will be emitted. Levels associated with excess lung cancer risk may be present in as many as 10% of the houses in the United States. When smokers reside in the home, the problem is potentially greater, because the molecular size of radon particles allows them to attach readily to smoke particles that are inhaled. Fortunately, technology is available for assessing and reducing the level of exposure.


InternalMed_Harrison

InternalMed_Harrison. Other indoor exposures of concern are bioaerosols that contain antigenic material (fungi, cockroaches, dust mites, and pet danders) associated with an increased risk of atopy and asthma. Indoor chemical agents include strong cleaning agents (bleach, ammonia), formaldehyde, perfumes, pesticides, and oxides of nitrogen from gas appliances. Nonspecific responses associated with “tight-building syndrome,” perhaps better termed “building-associated illness,” in which no particular agent has been implicated, have included a wide variety of complaints, among them respiratory symptoms that are relieved only by avoiding exposure in the building in question. The degree to which “smells” and other sensory stimuli are involved in the triggering of potentially incapacitating psychological or physical responses has yet to be determined, and the long-term consequences of such environmental exposures are unknown.


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InternalMed_Harrison. Indoor exposure to biomass smoke (wood, dung, crop resi dues, charcoal) is estimated to be responsible for >4% of worldwide disability-adjusted life-years (DALYs) lost, due to acute lower respiratory infections in children, COPD and lung cancer in women, and cardiovascular disease among men. This burden of disease places indoor exposure to biomass smoke as the leading environmental hazard for poor health and the third most important risk factor overall. Almost one-half of the world’s population uses biomass fuel for cooking, heating, or baking. This occurs predominantly in the rural areas of developing countries. Because many families burn biomass fuels in open stoves, which are highly inefficient, and inside homes with poor ventilation, women and young children are exposed on a daily basis to high levels of smoke. In these homes, 24-h mean levels


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InternalMed_Harrison. FIGURE 311-4 Histopathologic features of biomass smoke–induced interstitial lung disease. A. Anthracitic pigment is seen accumulating along alveolar septae (arrowheads) and within a pigmented dust macule (single arrow). B. A high-power photomicrograph contains a mixture of fibroblasts and carbon-laden macrophages. of fine particulate matter, a component of biomass smoke, have been reported to be 2–30 times higher than the National Ambient Air Quality Standards set by the U.S. EPA.


InternalMed_Harrison

InternalMed_Harrison. of fine particulate matter, a component of biomass smoke, have been reported to be 2–30 times higher than the National Ambient Air Quality Standards set by the U.S. EPA. Epidemiologic studies have consistently shown associations between exposure to biomass smoke and both chronic bronchitis and COPD, with odds ratios ranging between 3 and 10 and increasing with longer exposures. In addition to the common occupational exposure to biomass smoke of women in developing countries, men from such countries may be occupationally exposed. Because of increased migration to the United States from developing countries, clinicians need to be aware of the chronic respiratory effects of exposure to biomass smoke, which can include interstitial lung disease (Fig. 311-4). Evidence is beginning to emerge that improved stoves with chimneys can reduce


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InternalMed_Harrison. Disorders of the Respiratory System biomass smoke–induced respiratory illness in both children and women. Bronchiectasis Rebecca M. Baron, Miriam Baron Barshak Bronchiectasis refers to an irreversible airway dilation that involves the lung in either a focal or a diffuse manner and that classically has been categorized as cylindrical or tubular (the most common form), varicose, or cystic. 312


InternalMed_Harrison

InternalMed_Harrison. Bronchiectasis can arise from infectious or noninfectious causes (Table 312-1). Clues to the underlying etiology are often provided by the pattern of lung involvement. Focal bronchiectasis refers to bronchiectatic changes in a localized area of the lung and can be a consequence of obstruction of the airway—either extrinsic (e.g., due to compression by adjacent lymphadenopathy or parenchymal tumor mass) or intrinsic (e.g., due to an airway tumor or aspirated foreign body, a scarred/stenotic airway, or bronchial atresia from congenital underdevelopment of the airway). Diffuse bronchiectasis is characterized by widespread bronchiectatic changes throughout the lung and often arises from an underlying systemic or infectious disease process.


InternalMed_Harrison

InternalMed_Harrison. More pronounced involvement of the upper lung fields is most common in cystic fibrosis (CF) and is also observed in postradiation fibrosis, corresponding to the lung region encompassed by the radiation port. Bronchiectasis with predominant involvement of the lower lung fields usually has its source in chronic recurrent aspiration (e.g., due to esophageal motility disorders like those in scleroderma), end-stage fibrotic lung disease (e.g., traction bronchiectasis from idiopathic Pattern of Lung Etiology by Category Involvement (Examples) Workup Focal Obstruction (aspirated foreign body, tumor mass) Diffuse Infection (bacterial, nontuberculous mycobacterial) Immunodeficiency (hypogammaglobulinemia, HIV infection, bronchiolitis obliterans after lung transplantation) Genetic causes (cystic fibrosis, Kartagener’s syndrome, α1 antitrypsin deficiency)


InternalMed_Harrison

InternalMed_Harrison. Immunodeficiency (hypogammaglobulinemia, HIV infection, bronchiolitis obliterans after lung transplantation) Genetic causes (cystic fibrosis, Kartagener’s syndrome, α1 antitrypsin deficiency) Autoimmune or rheumatologic causes (rheumatoid arthritis, Sjögren’s syndrome, inflammatory bowel disease); immune-mediated disease (allergic bronchopulmonary aspergillosis) Miscellaneous (yellow nail syndrome, traction bronchiectasis from postradiation fibrosis or idiopathic pulmonary fibrosis) Sputum Gram’s stain/culture; stains/cultures for acid-fast bacilli and fungi. If no pathogen is identified, consider bronchoscopy with bronchoalveolar lavage. Complete blood count with differential; immunoglobulin measurement; HIV testing Measurement of chloride levels in sweat (for cystic fibrosis), α1 antitrypsin levels; nasal or respiratory tract brush/biopsy (for dyskinetic/ immotile cilia syndrome); genetic testing


InternalMed_Harrison

InternalMed_Harrison. Measurement of chloride levels in sweat (for cystic fibrosis), α1 antitrypsin levels; nasal or respiratory tract brush/biopsy (for dyskinetic/ immotile cilia syndrome); genetic testing Clinical examination with careful joint exam, serologic testing (e.g., for rheumatoid factor). Consider workup for allergic bronchopulmonary aspergillosis, especially in patients with refractory asthma.a Test of swallowing function and general neuromuscular strength Exclusion of other causes aSkin testing for Aspergillus reactivity; measurement of serum precipitins for Aspergillus, serum IgE levels, serum eosinophils, etc.


InternalMed_Harrison

InternalMed_Harrison. Exclusion of other causes aSkin testing for Aspergillus reactivity; measurement of serum precipitins for Aspergillus, serum IgE levels, serum eosinophils, etc. pulmonary fibrosis), or recurrent immunodeficiency-associated infections (e.g., hypogammaglobulinemia). Bronchiectasis resulting from infection by nontuberculous mycobacteria (NTM), most commonly the Mycobacterium avium-intracellulare complex (MAC), often preferentially affects the midlung fields. Congenital causes of bronchiectasis with predominant midlung field involvement include the dyskinetic/ immotile cilia syndrome. Finally, predominant involvement of the central airways is reported in association with allergic bronchopulmonary aspergillosis (ABPA), in which an immune-mediated reaction to Aspergillus damages the bronchial wall. Congenital causes of central airway–predominant bronchiectasis resulting from cartilage deficiency include tracheobronchomegaly (Mounier-Kuhn syndrome) and Williams-Campbell syndrome.


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InternalMed_Harrison. In many cases, the etiology of bronchiectasis is not determined. In case series, as many as 25–50% of patients referred for bronchiectasis have idiopathic disease. The overall reported prevalence of bronchiectasis in the United States has recently increased, but the epidemiology of bronchiectasis varies greatly with the underlying etiology. For example, patients born with CF often develop significant clinical bronchiectasis in late adolescence or early adulthood, although atypical presentations of CF in adults in their thirties and forties are also possible. In contrast, bronchiectasis resulting from MAC infection classically affects nonsmoking women >50 years of age. In general, the incidence of bronchiectasis increases with age. Bronchiectasis is more common among women than among men. In areas where tuberculosis is prevalent, bronchiectasis more frequently occurs as a sequela of granulomatous infection.


InternalMed_Harrison

InternalMed_Harrison. In areas where tuberculosis is prevalent, bronchiectasis more frequently occurs as a sequela of granulomatous infection. Focal bronchiectasis can arise from extrinsic compression of the airway by enlarged granulomatous lymph nodes and/or from development of intrinsic obstruction as a result of erosion of a calcified lymph node through the airway wall (e.g., broncholithiasis). Especially in reactivated tuberculosis, parenchymal destruction from infection can result in areas of more diffuse bronchiectasis. Apart from cases associated with tuberculosis, an increased incidence of non-CF bronchiectasis with an unclear underlying mechanism has been reported as a significant problem in developing nations. It has been suggested that the high incidence of malnutrition in certain areas may predispose to immune dysfunction and development of bronchiectasis.


InternalMed_Harrison

InternalMed_Harrison. The most widely cited mechanism of infectious bronchiectasis is the “vicious cycle hypothesis,” in which susceptibility to infection and poor mucociliary clearance result in microbial colonization of the bronchial tree. Some organisms, such as Pseudomonas aeruginosa, exhibit a particular propensity for colonizing damaged airways and evading host defense mechanisms. Impaired mucociliary clearance can result from inherited conditions such as CF or dyskinetic cilia syndrome, and it has been proposed that a single severe infection (e.g., pneumonia caused by Bordetella pertussis or Mycoplasma pneumoniae) can result in significant airway damage and poor secretion clearance. The presence of the microbes incites continued chronic inflammation, with consequent damage to the airway wall, continued impairment of secretion and microbial clearance, and ongoing propagation of the infectious/inflammatory cycle. Moreover, it has been proposed that mediators released directly from bacteria can


InternalMed_Harrison

InternalMed_Harrison. impairment of secretion and microbial clearance, and ongoing propagation of the infectious/inflammatory cycle. Moreover, it has been proposed that mediators released directly from bacteria can interfere with mucociliary clearance.


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InternalMed_Harrison. Classic studies of the pathology of bronchiectasis from the 1950s demonstrated significant small-airway wall inflammation and larger-airway wall destruction as well as dilation, with loss of elastin, smooth muscle, and cartilage. It has been proposed that inflammatory cells in the small airways release proteases and other mediators, such as reactive oxygen species and proinflammatory cytokines, that damage the larger-airway walls. Furthermore, the ongoing inflammatory process in the smaller airways results in airflow obstruction. It is thought that antiproteases, such as α1 antitrypsin, play an important role in neutralizing the damaging effects of neutrophil elastase and in enhancing bacterial killing. Bronchiectasis and emphysema have been observed in patients with α1 antitrypsin deficiency.


InternalMed_Harrison

InternalMed_Harrison. Proposed mechanisms for noninfectious bronchiectasis include immune-mediated reactions that damage the bronchial wall (e.g., those associated with systemic autoimmune conditions such as Sjögren’s syndrome and rheumatoid arthritis). Traction bronchiectasis refers to 1695 dilated airways arising from parenchymal distortion as a result of lung fibrosis (e.g., postradiation fibrosis or idiopathic pulmonary fibrosis).


InternalMed_Harrison

InternalMed_Harrison. The most common clinical presentation is a persistent productive cough with ongoing production of thick, tenacious sputum. Physical findings often include crackles and wheezing on lung auscultation, and some patients with bronchiectasis exhibit clubbing of the digits. Mild to moderate airflow obstruction is often detected on pulmonary function tests, overlapping with that seen at presentation with other conditions, such as chronic obstructive pulmonary disease (COPD). Acute exacerbations of bronchiectasis are usually characterized by changes in the nature of sputum production, with increased volume and purulence. However, typical signs and symptoms of lung infection, such as fever and new infiltrates, may not be present.


InternalMed_Harrison

InternalMed_Harrison. The diagnosis is usually based on presentation with a persistent chronic cough and sputum production accompanied by consistent radiographic features. Although chest radiographs lack sensitivity, the presence of “tram tracks” indicating dilated airways is consistent with bronchiectasis. Chest computed tomography (CT) is more specific for bronchiectasis and is the imaging modality of choice for confirming the diagnosis. CT findings include airway dilation (detected as parallel “tram tracks” or as the “signet-ring sign”—a cross-sectional area of the airway with a diameter at least 1.5 times that of the adjacent vessel), lack of bronchial tapering (including the presence of tubular structures within 1 cm from the pleural surface), bronchial wall thickening in dilated airways, inspissated secretions (e.g., the “tree-in-bud” pattern), or cysts emanating from the bronchial wall (especially pronounced in cystic bronchiectasis; Fig. 312-1). APPROACH TO THE PATIENT:


InternalMed_Harrison

InternalMed_Harrison. APPROACH TO THE PATIENT: The evaluation of a patient with bronchiectasis entails elicitation of a clinical history, chest imaging, and a workup to determine the underlying etiology. Evaluation of focal bronchiectasis almost always requires bronchoscopy to exclude airway obstruction by an underlying mass or foreign body. A workup for diffuse bronchiectasis includes analysis for the major etiologies (Table 312-1), with an initial focus on excluding CF. Pulmonary function testing is an important component of a functional assessment of the patient. FIGURE 312-1 Representative chest computed tomography (CT) image of severe bronchiectasis. This patient’s CT demonstrates many severely dilated airways, seen both longitudinally (arrowhead) and in cross-section (arrow).


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InternalMed_Harrison. Treatment of infectious bronchiectasis is directed at the control of active infection and improvements in secretion clearance and bronchial hygiene so as to decrease the microbial load within the airways and minimize the risk of repeated infections.


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InternalMed_Harrison. Antibiotics targeting the causative or presumptive pathogen (with Haemophilus influenzae and P. aeruginosa isolated commonly) should be administered in acute exacerbations, usually for a minimum of 7–10 days and perhaps for as long as 14 days. Decisions about treatment of NTM infection can be difficult, given that these organisms can be colonizers as well as pathogens and the prolonged treatment course often is not well tolerated. Consensus guidelines have advised that diagnostic criteria for true clinical infection with NTM should be considered in patients with symptoms and radiographic findings of lung disease who have at least two sputum samples positive on culture; at least one bronchoalveolar lavage (BAL) fluid sample positive on culture; a biopsy sample displaying histopathologic features of NTM infection (e.g., granuloma or a positive stain for acid-fast bacilli) along with one positive sputum culture; or a pleural fluid sample (or a sample from another sterile extrapulmonary


InternalMed_Harrison

InternalMed_Harrison. of NTM infection (e.g., granuloma or a positive stain for acid-fast bacilli) along with one positive sputum culture; or a pleural fluid sample (or a sample from another sterile extrapulmonary site) positive on culture. MAC strains are the most common NTM pathogens, and the recommended regimen for HIV-negative patients includes a macrolide combined with rifampin and ethambutol. Consensus guidelines also recommend macrolide susceptibility testing for clinically significant MAC isolates.


InternalMed_Harrison

InternalMed_Harrison. The numerous approaches used to enhance secretion clearance in bronchiectasis include hydration and mucolytic administration, aerosolization of bronchodilators and hyperosmolar agents (e.g., hypertonic saline), and chest physiotherapy (e.g., postural drainage, traditional mechanical chest percussion via hand clapping to the chest, or use of devices such as an oscillatory positive expiratory pressure flutter valve or a high-frequency chest wall oscillation vest). Pulmonary rehabilitation and a regular exercise program may assist with secretion clearance as well as with other aspects of bronchiectasis, including improved exercise capacity and quality of life. The mucolytic dornase (DNase) is recommended routinely in CF-related bronchiectasis but not in non-CF bronchiectasis, given concerns about lack of efficacy and potential harm in the non-CF population.


InternalMed_Harrison

InternalMed_Harrison. It has been proposed that control of the inflammatory response may be of benefit in bronchiectasis, and relatively small-scale trials have yielded evidence of alleviated dyspnea, decreased need for inhaled β-agonists, and reduced sputum production with inhaled glucocorticoids. However, no significant differences in lung function or bronchiectasis exacerbation rates have been observed. Risks of immunosuppression and adrenal suppression must be carefully considered with use of anti-inflammatory therapy in infectious bronchiectasis. Nevertheless, administration of oral/systemic glucocorticoids may be important in treatment of bronchiectasis due to certain etiologies, such as ABPA, or of noninfectious bronchiectasis due to underlying conditions, especially that in which an autoimmune condition is believed to be active (e.g., rheumatoid arthritis or Sjögren’s syndrome). Patients with ABPA may also benefit from a prolonged course of treatment with the oral antifungal agent itraconazole.


InternalMed_Harrison

InternalMed_Harrison. In select cases, surgery can be considered, with resection of a focal area of suppuration. In advanced cases, lung transplantation can be considered. In more severe cases of infectious bronchiectasis, recurrent infections and repeated courses of antibiotics can lead to microbial resistance to antibiotics. In certain cases, combinations of antibiotics that have their own independent toxicity profiles may be necessary to treat resistant organisms. Recurrent infections can result in injury to superficial mucosal vessels, with bleeding and, in severe cases, life-threatening hemoptysis. Management of massive hemoptysis usually requires intubation to stabilize the patient, identification of the source of bleeding, and protection of the nonbleeding lung. Control of bleeding often necessitates bronchial artery embolization and, in severe cases, surgery.


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InternalMed_Harrison. Outcomes of bronchiectasis can vary widely with the underlying etiology and may also be influenced by the frequency of exacerbations and (in infectious cases) the specific pathogens involved. In one study, the decline of lung function in patients with non-CF bronchiectasis was similar to that in patients with COPD, with the forced expiratory volume in 1 s (FEV1) declining by 50–55 mL per year as opposed to 20–30 mL per year for healthy controls. Reversal of an underlying immunodeficient state (e.g., by administration of gamma globulin for immunoglobulin-deficient patients) and vaccination of patients with chronic respiratory conditions (e.g., influenza and pneumococcal vaccines) can decrease the risk of recurrent infections. Patients who smoke should be counseled about smoking cessation.


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InternalMed_Harrison. After resolution of an acute infection in patients with recurrences (e.g., ≥3 episodes per year), the use of suppressive antibiotics to minimize the microbial load and reduce the frequency of exacerbations has been proposed, although there is less consensus with regard to this approach in non-CF-associated bronchiectasis than in patients with CF-related bronchiectasis. Possible suppressive treatments include (1) administration of an oral antibiotic (e.g., ciprofloxacin) daily for 1–2 weeks per month; (2) use of a rotating schedule of oral antibiotics (to minimize the risk of development of drug resistance); (3) administration of a macrolide antibiotic (see below) daily or three times per week (with mechanisms of possible benefit related to non-antimicrobial properties, such as anti-inflammatory effects and reduction of gram-negative bacillary biofilms); (4) inhalation of aerosolized antibiotics (e.g., tobramycin inhalation solution) by select patients on a rotating schedule (e.g., 30


InternalMed_Harrison

InternalMed_Harrison. effects and reduction of gram-negative bacillary biofilms); (4) inhalation of aerosolized antibiotics (e.g., tobramycin inhalation solution) by select patients on a rotating schedule (e.g., 30 days on, 30 days off ), with the goal of decreasing the microbial load without eliciting the side effects of systemic drug administration; and (5) intermittent administration of IV antibiotics (e.g., “clean-outs”) for patients with more severe bronchiectasis and/or resistant pathogens. In relation to macrolide therapy (point 3 above), a number of double-blind, placebo-controlled, randomized trials have recently been published in non-CF bronchiectasis and support a benefit of long-term macrolides (6–12 months of azithromycin or erythromycin) in decreasing rates of bronchiectasis exacerbation, mucus production, and decline in lung function. However, two of these studies also reported increased macrolide resistance in commensal pathogens, dampening enthusiasm for universal use of macrolides in this


InternalMed_Harrison

InternalMed_Harrison. and decline in lung function. However, two of these studies also reported increased macrolide resistance in commensal pathogens, dampening enthusiasm for universal use of macrolides in this setting and raising the question of whether there might be select non-CF bronchiectasis patients with higher morbidity for whom benefits of long-term macrolides might outweigh the risks of emergence of antibiotic resistance. In particular, development of macrolide-resistant NTM is a significant concern, making treatment of that pathogen much more difficult. Therefore, it is advised to rule out NTM infection before chronic macrolide therapy is considered.


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InternalMed_Harrison. In addition, ongoing consistent attention to bronchial hygiene can promote secretion clearance and decrease the microbial load in the airways. Cystic fibrosis Eric J. Sorscher CLINICAL FEATURES Cystic fibrosis (CF) is an autosomal recessive exocrinopathy affecting multiple epithelial tissues. The gene product responsible for CF (the cystic fibrosis transmembrane conductance regulator [CFTR]) 313 serves as an anion channel in the apical (luminal) plasma membranes of epithelial cells and regulates volume and composition of exocrine secretion. An increasingly sophisticated understanding of CFTR molecular genetics and membrane protein biochemistry has facilitated CF drug discovery, with a number of new agents advancing through the clinical testing phase.


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InternalMed_Harrison. Respiratory Manifestations The major morbidity and mortality associated with CF is attributable to respiratory compromise, characterized by copious hyperviscous and adherent pulmonary secretions that obstruct small and medium-sized airways. CF airway secretions are exceedingly difficult to clear, and a complex bacterial flora that includes Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa (among other pathogens) is routinely cultured from CF sputum. Robust pulmonary inflammation in the setting of inspissated mucus and chronic bacterial infection leads to collateral tissue injury and further aggravates respiratory decline. Organisms such as P. aeruginosa exhibit a stereotypic mode of pathogenesis; a sentinel and early colonization event often engenders lifelong pulmonary infection by the same genetic strain. Over the course of many years,


InternalMed_Harrison

InternalMed_Harrison. P. aeruginosa evolves in CF lungs to adopt a mucoid phenotype (attributable to release of alginate exoproduct) that confers selective advantage for the pathogen and poor prognosis for the host. Infection with other bacterial organisms such as Burkholderia cepacia also indicates a less favorable pulmonary outlook. Strategies to eradicate organisms such as P. aeruginosa early in the pathogenesis cascade have been successful and are thought to improve prognosis significantly if sustained.


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InternalMed_Harrison. Pancreatic Findings The complete name of the disease, cystic fibrosis of the pancreas, refers to profound tissue destruction of the exocrine pancreas, with fibrotic scarring and/or fatty replacement, cyst proliferation, loss of acinar tissue, and ablation of normal pancreatic architecture. As in the lung, tenacious exocrine secretions (sometimes termed concretions) obstruct pancreatic ducts and impair production and flow of digestive enzymes to the duodenum. The sequelae of exocrine pancreatic insufficiency include chronic malabsorption, poor growth, fat-soluble vitamin insufficiency, high levels of serum immunoreactive trypsinogen (a diagnostic test used in newborn screening), and loss of pancreatic islet cell mass. CF-related diabetes mellitus is a manifestation in over 30% of adults with the disease and is likely multifactorial in nature (attributable to progressive destruction of the endocrine pancreas, insulin resistance due to stress hormones, and other factors).


InternalMed_Harrison

InternalMed_Harrison. Other Organ System Damage As in CF lung and pancreas, thick and tenacious secretions compromise numerous other exocrine tissues. Obstruction of intrahepatic bile ducts and parenchymal fibrosis are commonly observed in pathologic specimens, with multilobular cirrhosis in 4–15% of patients with CF and significant hepatic insufficiency as a resulting manifestation among adults. Contents of the intestinal lumen are often difficult to excrete, leading to meconium ileus (a presentation in approximately 10–20% of newborns with CF) or distal intestinal obstructive syndrome in older individuals. Men typically exhibit complete involution of the vas deferens and infertility (despite functioning spermatogenesis), and approximately 99% of males with CF are infertile. The etiology of this dramatic anatomic defect in the male genitourinary system is not understood but may represent a developmental abnormality secondary to secretory obstruction of the vas. Abnormalities of female reproductive tract


InternalMed_Harrison

InternalMed_Harrison. defect in the male genitourinary system is not understood but may represent a developmental abnormality secondary to secretory obstruction of the vas. Abnormalities of female reproductive tract secretions are likely contributors to an increased incidence of infertility among women with CF. Radiographic evidence of sinusitis occurs in most CF patients and is associated with pathogens similar to those recovered from lower airways, suggesting that the sinus may serve as a reservoir 1697 for bacterial seeding.


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InternalMed_Harrison. PATHOGENESIS Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) CFTR is an integral membrane protein that functions as an epithelial anion channel. The ~1480-amino-acid molecule encodes a passive conduit for chloride and bicarbonate transport across plasma membranes of epithelial tissues, with direction of ion flow dependent on the electrochemical driving force. Gating of CFTR involves conformational cycling between an open and closed configuration and is augmented by hydrolysis of adenosine triphosphate (ATP). Anion flux mediated by CFTR does not involve active transport against a concentration gradient but utilizes the energy provided from ATP hydrolysis as a central feature of ion channel mechanochemistry and gating.


InternalMed_Harrison

InternalMed_Harrison. CFTR is situated in the apical plasma membranes of acinar and other epithelial cells where it regulates the amount and composition of secretion by exocrine glands. In numerous epithelia, chloride and bicarbonate release is followed passively by the flow of water, allowing for mobilization and clearance of exocrine products. Along respiratory mucosa, CFTR is necessary to provide sufficient depth of the periciliary fluid layer (PCL), allowing normal ciliary extension and mucociliary transport. CFTR-deficient airway cells exhibit depleted PCL, causing ciliary collapse and failure to clear overlying mucus (Video 313-1). In airway submucosal glands, CFTR is highly expressed in acini and may participate both in the formation of mucus and extrusion of glandular secretion onto the airway surface (Fig. 313-1). In other exocrine glands characterized by abrogated mucus transport (e.g., pancreatic acini and ducts, bile canaliculi, intestinal lumen), similar pathogenic mechanisms have been


InternalMed_Harrison

InternalMed_Harrison. (Fig. 313-1). In other exocrine glands characterized by abrogated mucus transport (e.g., pancreatic acini and ducts, bile canaliculi, intestinal lumen), similar pathogenic mechanisms have been implicated. In these tissues, a driving force for apical chloride and/or bicarbonate secretion is believed to promote CFTR-mediated fluid and electrolyte release into the lumen, which confers proper rheology of mucins and other exocrine products. Failure of this mechanism disrupts normal hydration and transport of glandular secretion and is widely viewed as a proximate cause of ductular obstruction, with concomitant tissue injury.


InternalMed_Harrison

InternalMed_Harrison. Pulmonary Inflammation and Remodeling The CF airway is characterized by an aggressive, unrelenting, neutrophilic inflammatory response with release of proteases and oxidants leading to airway remodeling and bronchiectasis. Intense pulmonary inflammation is largely driven by chronic respiratory infection. Macrophages resident in CF lungs augment elaboration of proinflammatory cytokines, which contribute to innate and adaptive immune reactivity. CFTR-dependent abnormalities of airway surface fluid composition (e.g., pH) have been reported as contributors to impaired bacterial killing in CF lungs. The role of CFTR as a direct mediator of inflammatory responsiveness and/or pulmonary remodeling represents an important and topical area of investigation.


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InternalMed_Harrison. DNA sequencing of CFTR from patients (and others) worldwide has revealed almost 2000 allelic variants; however, only about 10% of these have been well-characterized as disease-causing mutations. Distinguishing the single nucleotide transversions or other polymorphisms with causal relevance often presents a significant challenge. The CFTR2 resource (www.cftr2.org/) delineates gene variants with a clear etiologic role.


InternalMed_Harrison

InternalMed_Harrison. CFTR defects known to elicit disease are often categorized based on molecular mechanism. For example, the common F508del mutation (nomenclature denotes omission of a single phenylalanine residue [F] at CFTR position 508) leads to a folding abnormality recognized by cellular quality control pathways. CFTR encoding F508del retains partial ion channel function, but protein maturation is arrested in the endoplasmic reticulum, and CFTR fails to arrive at the plasma membrane. Instead, F508del CFTR is misrouted and undergoes endoplasmic reticulum–associated degradation via the proteasome. CFTR mutations that disrupt protein maturation are termed class II defects and are by far the most common genetic abnormalities. F508del alone accounts for ~70% of defective CFTR alleles in the United States, where 1698 approximately 90% of individuals with CF carry at least one F508del mutation.


InternalMed_Harrison

InternalMed_Harrison. Other gene defects include CFTR ion channels properly trafficked to the apical cell surface but unable to open and/or gate. Such channel proteins include G551D (a glycine to aspartic acid replacement at CFTR position 551), which leads to an inability to transport Cl– or


InternalMed_Harrison

InternalMed_Harrison. HCO3 in the presence of ATP (a class III abnormality). Individuals with at least one G551D allele represent 4–5% of CF patients in North America. CFTR nonsense alleles such as G542X, R553X, and W1282X (premature termination codon replaces glycine, arginine, or tryptophan at positions 542, 553, or 1282, respectively) are among the common class I defects, in addition to large deletions or other major disruptions of the gene. The W1282X mutation, for example, is prevalent among individuals of Ashkenazi descent and is a predominant CF genotype in Israel. Additional categories of CFTR mutation include defects in the ion channel pore (class IV), RNA splicing (class V), and increased plasma membrane turnover (class VI) (Fig. 313-2).


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InternalMed_Harrison. The diagnosis of CF is based in part on clinical symptoms, family history, or positive newborn screening. CFTR mutation analysis together with sweat electrolyte measurements represent cardinal diagnostic tests. DNA-based evaluation typically surveys numerous disease-associated mutations; panels that identify 20–80 gene defects are FIGURE 313-1 Extrusion of mucus secretion onto the epithelial surface of airways in cystic fibrosis. A. Schematic of the surface epithelium and supporting glandular structure of the human airway.


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InternalMed_Harrison. B. The submucosal glands of a patient with cystic fibrosis are filled with mucus, and mucopurulent debris overlies the airway surfaces, essentially burying the epithelium. C. A higher magnification view of a mucus plug tightly adhering to the airway surface, with arrows indicating the interface between infected and inflamed secretions and the underlying epithelium to which the secretions adhere. (Both B and C were stained with hematoxylin and eosin, with the colors modified to highlight structures.) Infected secretions obstruct airways and, over time, dramatically disrupt the normal architecture of the lung. D. CFTR is expressed in surface epithelium and serous cells at the base of submucosal glands in a porcine lung sample, as shown by the dark staining, signifying binding by CFTR antibodies to epithelial structures (aminoethylcarbazole detection of horseradish peroxidase with hematoxylin counterstain). (From SM Rowe, S Miller, EJ Sorscher: N Engl J Med 352:1992, 2005.)


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InternalMed_Harrison. FIGURE 313-2 Categories of CFTR mutations. Classes of defects in the CFTR gene include the absence of synthesis (class I); defective protein maturation and premature degradation (class II); disordered gating/regulation, such as diminished adenosine triphosphate (ATP) binding and hydrolysis (class III); defective conductance through the ion channel pore (class IV); a reduced number of CFTR transcripts due to a promoter or splicing abnormality (class V); and accelerated turnover from the cell surface (class VI). (From SM Rowe, S Miller, EJ Sorscher: N Engl J Med 352:1992, 2005.) available through commercial sources. For difficult cases, complete CFTR exonic sequencing together with analysis of splice junctions and key regulatory elements can be obtained. Sweat electrolytes following pilocarpine iontophoresis comprise an invaluable diagnostic measurement, with levels of chloride markedly elevated in CF compared to non-CF individuals. The sweat test result is highly specific and served as


InternalMed_Harrison

InternalMed_Harrison. iontophoresis comprise an invaluable diagnostic measurement, with levels of chloride markedly elevated in CF compared to non-CF individuals. The sweat test result is highly specific and served as the mainstay of diagnosis for many decades prior to availability of CFTR genotyping. Notably, hyperviscosity of eccrine sweat is not a clinical feature of the disease. Sweat ducts function to reabsorb chloride from a primary sweat secretion produced by the glandular coil. Malfunction of CFTR leads to diminished chloride uptake from the ductular lumen, and sweat emerges on the skin with markedly elevated levels of chloride. For the unusual situation in which both CFTR genotype and sweat electrolytes are inconclusive, in vivo measurement of ion transport across the nasal airways can serve as a specific test for CF and is used by a number of referral centers. For example, elevated (sodium-dependent) transepithelial charge separation across airway epithelial tissue and failure of


InternalMed_Harrison

InternalMed_Harrison. serve as a specific test for CF and is used by a number of referral centers. For example, elevated (sodium-dependent) transepithelial charge separation across airway epithelial tissue and failure of isoproterenol-dependent chloride secretion (via CFTR) represent bioelectric findings highly specific for the disease. Measurements of CFTR activity in excised rectal mucosal biopsies can also be obtained.


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InternalMed_Harrison. CF classically presents in childhood with chronic productive cough, malabsorption including steatorrhea, and failure to thrive. The disease is most common among whites (~1 in 3300 live births) and much less frequent among African-American (~1 in 15,000) or Asian populations (~1 in 33,000). Several “severe” defects that impair CFTR activity (including F508del, G551D, and truncation alleles) are predictive of pancreatic insufficiency, which is clinically evident in 80–90% of individuals with CF. These few specific genotype-phenotype correlations notwithstanding, genotype is, in general, a poor predictor of overall respiratory prognosis.


InternalMed_Harrison

InternalMed_Harrison. A spectrum of CFTR-related diseases with features resembling classic CF has been well described. In addition to multiorgan involvement, forme frustes, such as isolated congenital bilateral absence of the vas deferens or pancreatitis (without other organ system findings), are strongly associated with CFTR mutations in at least one allele. Although CF is a classic monogenic disease, the importance of non-CFTR gene modifiers and proteins that regulate ion flux, inflammatory pathways, and airway remodeling has been increasingly appreciated as influencing clinical course. For example, the magnitude of transepithelial sodium reabsorption in CF airways, which helps control periciliary fluid depth and composition, is strongly influenced by CFTR and represents a molecular target for disease intervention.


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InternalMed_Harrison. Standard care for outpatients with CF is intensive, with regimens that include exogenous pancreatic enzymes taken with meals, nutritional supplementation, anti-inflammatory medication, bronchodilators, and chronic or periodic administration of oral or aerosolized antibiotics (e.g., as maintenance therapy for patients with P. aeruginosa). Recombinant DNAse aerosols (degraded DNA strands that contribute to mucus viscosity) and nebulized hypertonic saline (serves to augment PCL depth, activate mucociliary clearance, and mobilize inspissated airway secretions) are administered routinely. Chest physiotherapy several times each day is a standard means to promote clearance of airway mucus. Among older individuals with CF, malabsorption, chronic inflammation, and endocrine abnormalities can lead to poor bone mineralization, requiring treatment with vitamin D, calcium, and other measures. The time, complexity, and expense of home care are considerable and take a significant toll on patients


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InternalMed_Harrison. to poor bone mineralization, requiring treatment with vitamin D, calcium, and other measures. The time, complexity, and expense of home care are considerable and take a significant toll on patients and their families.


InternalMed_Harrison

InternalMed_Harrison. Severe respiratory exacerbation is commonly managed by hospital admission for frequent chest physiotherapy and parenteral antibiotics directed against serious (and often multiply resistant) bacterial pathogens. Aggressive intervention in this setting can restore a large component of lung function, but ongoing and cumulative loss of pulmonary reserve reflects the natural history of the disease. Poor prognostic indicators such as sputum culture containing B. cepacia, mucoid P. aeruginosa, or atypical mycobacteria are rigorously monitored in the 1699 CF patient population. An increasing incidence of methicillin-resistant


InternalMed_Harrison

InternalMed_Harrison. S. aureus has also been observed, although the clinical significance of this finding has not been fully elucidated. Typical inpatient antibiotic coverage includes combination drug therapy with an aminoglycoside and β-lactam for up to 14 days. Maximal improvement in lung function is often achieved by 8–10 days in this setting. Many families elect parenteral antibiotic treatment at home, and additional studies are needed to evaluate specific drug combinations, duration of therapy, and home versus inpatient management. Other CF respiratory sequelae that may require hospitalization include hemoptysis and pneumothorax. Hypersensitivity to Aspergillus (allergic bronchopulmonary aspergillosis) occurs in approximately 5% of individuals with the disease and should be suspected in the absence of a response to conventional treatment.


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InternalMed_Harrison. Lung transplantation remains a viable therapeutic option in the setting of end-stage CF pulmonary failure, with 5-year postoperative survival rates on the order of 50–60%. Determining the optimal tim ing for surgery presents a substantial challenge, particularly because overall prognosis for individuals with severe lung disease is sometimes difficult to predict, and mortality associated with transplantation is significant (1-year survival rates of approximately 80%). Forced expiratory volume in 1 s (FEV1) measurements less than 30% predicted, together with an assortment of other clinical features, are often used as thresholds for entry onto transplantation lists, although waiting periods for healthy donor lungs can be quite protracted. Based on clinical outcome and limited access to healthy donor lungs, many CF patients and their families do not pursue this option.


InternalMed_Harrison

InternalMed_Harrison. CFTR MODULATION Potentiation of Mutant CFTR Gating A massive effort directed toward high-throughput drug analysis of large compound libraries (containing millions of individual agents) has identified novel and promising approaches to CF therapy. The approved compound ivacaftor, for example, robustly potentiates CFTR channel opening and stimulates ion transport. Ivacaftor overcomes the G551D CFTR gating defect, and individuals carrying this mutation exhibit dramatic improvement in lung function, weight gain, and other clinical parameters after only a few weeks of oral therapy. Remarkably, sweat chloride values are significantly improved with this treatment in patients with G551D CFTR. No clinical intervention of any sort has previously been shown to normalize the CF sweat chloride abnormality. Long-term studies of the drug in patients with G551D CFTR are ongoing. Ivacaftor has been viewed as the harbinger of a new era for CF therapeutics directed at treating the most fundamental causes


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InternalMed_Harrison. Long-term studies of the drug in patients with G551D CFTR are ongoing. Ivacaftor has been viewed as the harbinger of a new era for CF therapeutics directed at treating the most fundamental causes of the disease.


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InternalMed_Harrison. Correction of the F508del Processing Abnormality Advancement of new drugs that address specific CFTR defects in protein folding and maturation has been bolstered by clinical studies of F508del rescue in combination with ivacaftor. So-called “corrector” molecules (as distinct from CFTR gating “potentiators” such as ivacaftor) discovered through compound library screening are suitable for promoting cell surface localization of the F508del protein. Significant improvement in pulmonary function of F508del homozygous individuals has been achieved with potentiator/corrector combination therapy in early clinical trials, and several candidate molecules are under evaluation.


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InternalMed_Harrison. Personalized Molecular Therapies The advent of modulators with robust clinical impact has engendered new optimism regarding care of patients with CF. It is clear that future interventions will be tailored to specific genotypic abnormalities. Drug screening campaigns and other research programs have identified agents capable of suppressing CFTR nonsense alleles, augmenting potentiator activity, and promoting F508del correction. Efforts to apply these compounds in a fashion that will benefit CF subjects carrying a single copy of F508del (i.e., with a distinct or unusual CFTR mutation on the second allele) comprise an essential priority for the future. Progress in CF drug discovery is emblematic of what might be accomplished in other refractory genetic diseases using an approach grounded in molecular mechanism and unbiased compound library screening.


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InternalMed_Harrison. Chronic obstructive pulmonary Disease John J. Reilly, Jr., Edwin K. Silverman, Steven D. Shapiro Chronic obstructive pulmonary disease (COPD) is defined as a disease state characterized by airflow limitation that is not fully reversible 314 1700 CF QUALITY IMPROVEMENT, INCLUDING ASPECTS OF GLOBAL HEALTH As a direct result of advances in basic research, new therapies have transformed CF from a disease typically leading to death in early childhood to a condition with frequent survival well into the fourth decade of life. It has also become increasingly clear that specified approaches to patient management can have an impact on overall prognosis. For example, standardization of clinical intervention throughout the United States has led to remarkable benefit among the CF population. Well-defined measures for outpatient care are now established, including thresholds for hospital admission, antibiotic regimens, nutritional guidelines, periodicity of diagnostic tests, and other clinical


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InternalMed_Harrison. measures for outpatient care are now established, including thresholds for hospital admission, antibiotic regimens, nutritional guidelines, periodicity of diagnostic tests, and other clinical parameters. These therapeutic recommendations have become standardized throughout approximately 110 specialized CF care centers and 55 affiliated programs. The initiative has improved endpoints such as weight gain, body mass index, and pulmonary function. Information regarding standardized protocols for CF therapy can be accessed at (www.cff.org/treatments/cfcareguidelines/) or through a number of excellent reviews. Newborn screening for CF is now universal throughout the United States, most of the Canadian provinces, Australia, New Zealand, and much of Europe, and will facilitate early CF intervention. Based on data indicating that early nutritional and other therapies can be beneficial, newborn diagnosis is expected to significantly promote health in the CF population. Export of quality control


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InternalMed_Harrison. Based on data indicating that early nutritional and other therapies can be beneficial, newborn diagnosis is expected to significantly promote health in the CF population. Export of quality control measures and novel therapeutics worldwide has become an increasing imperative. For example, median survival of individuals with CF is less than 20 years in much of Central and South America (compared to ~40 years in the United States and Canada), and efforts to apply state-of-the-art management to underdiagnosed and underserved CF patient populations are expected to improve outcome and mitigate CF health disparities in the future.


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InternalMed_Harrison. VIDEO 313-1 Initial video sequences describe establishment of the normal periciliary fluid layer bathing the surface airway epithelium, with spheres representing chloride and bicarbonate ions secreted through CFTR and across the apical (mucosal) respiratory surface. Later video sequences depict failure of CFTR anion transport and resulting depletion of the periciliary layer, “plastering” of cilia against the mucosal surface, and accumulation of mucus in the airway with resulting bacterial infection. (Video courtesy of the Cystic Fibrosis Foundation.) (http://www.goldcopd.com/). COPD includes emphysema, an anatomically defined condition characterized by destruction and enlargement of the lung alveoli; chronic bronchitis, a clinically defined condition with chronic cough and phlegm; and small airways disease, a condition in which small bronchioles are narrowed. COPD is present only if chronic airflow obstruction occurs; chronic bronchitis without chronic airflow obstruction is not


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InternalMed_Harrison. small airways disease, a condition in which small bronchioles are narrowed. COPD is present only if chronic airflow obstruction occurs; chronic bronchitis without chronic airflow obstruction is not included within COPD.


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InternalMed_Harrison. COPD is the third leading cause of death and affects >10 million persons in the United States. COPD is also a disease of increasing public health importance around the world. Estimates suggest that COPD will rise from the sixth to the third most common cause of death worldwide by 2020. Airflow limitation, the major physiologic change in COPD, can result from both small airway obstruction and emphysema. As described below, small airways may become narrowed by cells (hyperplasia and accumulation), mucus, and fibrosis. Of note, activation of transforming growth factor β (TGF-β) contributes to airway fibrosis, while lack of TGF-β may contribute to parenchymal inflammation and emphysema. Largely due to greater similarity of animal air spaces than airways to humans, we know more about mechanisms involved in emphysema than small airway obstruction.


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InternalMed_Harrison. The dominant paradigm of the pathogenesis of emphysema comprises four interrelated events (Fig. 314-1): (1) Chronic exposure to cigarette smoke leads to inflammatory and immune cell recruitment within the terminal air spaces of the lung. (2) These inflammatory cells release elastolytic and other proteinases that damage the extracellular matrix of the lung. (3) Structural cell death (endothelial and epithelial cells) occurs directly through oxidant-induced cigarette smoke damage and senescence as well as indirectly via proteolytic loss of matrix attachment. (4) Ineffective repair of elastin and other extracellular matrix components result in air space enlargement that defines pulmonary emphysema. THE ELASTASE:ANTIELASTASE HYPOTHESIS


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InternalMed_Harrison. THE ELASTASE:ANTIELASTASE HYPOTHESIS Elastin, the principal component of elastic fibers, is a highly stable component of the extracellular matrix that is critical to the integrity of the lung. The elastase:antielastase hypothesis proposed in the mid1960s states that the balance of elastin-degrading enzymes and their inhibitors determines the susceptibility of the lung to destruction resulting in air space enlargement. This hypothesis was based on the clinical observation that patients with genetic deficiency in α1 antitrypsin (α1AT), the inhibitor of the serine proteinase neutrophil elastase, were at increased risk of emphysema, and that instillation of elastases, including neutrophil elastase, into experimental animals results in emphysema. The elastase:antielastase hypothesis remains a prevailing mechanism for the development of emphysema. However, a complex


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InternalMed_Harrison. FIGURE 314-1 Pathogenesis of emphysema. Upon long-term exposure to cigarette smoke, inflammatory cells are recruited to the lung; they release proteinases in excess of inhibitors, and if repair is abnormal, this leads to air space destruction and enlargement or emphysema. ECM, extracellular matrix; MMP, matrix metalloproteinase. network of immune and inflammatory cells and additional proteinases that contribute to emphysema have subsequently been identified.


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InternalMed_Harrison. Upon exposure to oxidants from cigarette smoke, macrophages and epithelial cells become activated, producing proteinases and chemokines that attract other inflammatory and immune cells. One mechanism of macrophage activation occurs via oxidant-induced inactivation of histone deacetylase-2, shifting the balance toward acetylated or loose chromatin, exposing nuclear factor-κB sites, and resulting in transcription of matrix metalloproteinases, proinflammatory cytokines such as interleukin 8 (IL-8), and tumor necrosis factor α (TNF-α); this leads to neutrophil recruitment. CD8+ T cells are also recruited in response to cigarette smoke and release interferon-inducible protein-10 (IP-10, CXCL-7), which in turn leads to macrophage production of macrophage elastase (matrix metalloproteinase-12 [MMP-12]). Matrix metalloproteinases and serine proteinases, most notably neutrophil elastase, work together by degrading the inhibitor of the other, leading to lung destruction. Proteolytic cleavage


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InternalMed_Harrison. [MMP-12]). Matrix metalloproteinases and serine proteinases, most notably neutrophil elastase, work together by degrading the inhibitor of the other, leading to lung destruction. Proteolytic cleavage products of elastin also serve as a macrophage chemokine, fueling this destructive positive feedback loop.


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InternalMed_Harrison. Autoimmune mechanisms may promote the progression of disease. Increased B cells and lymphoid follicles are present in patients, particularly those with advanced disease. Antibodies have been found against elastin fragments as well; IgG autoantibodies with avidity for pulmonary epithelium and the potential to mediate cytotoxicity have been detected. Concomitant cigarette smoke–induced loss of cilia in the airway epithelium and impaired macrophage phagocytosis predispose to bacterial infection with neutrophilia. In end-stage lung disease, long after smoking cessation, there remains an exuberant inflammatory response, suggesting that mechanisms of cigarette smoke–induced inflammation that initiate the disease differ from mechanisms that sustain inflammation after smoking cessation.


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InternalMed_Harrison. Cell Death Cigarette smoke oxidant-mediated structural cell death occurs via a variety of mechanisms including rt801 inhibition of mammalian target of rapamycin (mTOR), leading to cell death as well as inflammation and proteolysis. Involvement of mTOR and other senescence markers has led to the recent concept that emphysema resembles premature aging of the lung. Uptake of apoptotic cells by macrophages results in production of growth factors and dampens inflammation, promoting lung repair. Cigarette smoke impairs macrophage uptake of apoptotic cells, limiting repair.


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InternalMed_Harrison. Ineffective Repair The ability of the adult lung to repair damaged alveoli appears limited. It is unlikely that the process of septation that is responsible for alveologenesis during lung development can be reinitiated. The capacity of stem cells to repopulate the lung is under active investigation. It appears difficult for an adult human to completely restore an appropriate extracellular matrix, particularly functional elastic fibers. Cigarette smoke exposure may affect the large airways, small airways (≤2 mm diameter), and alveoli. Changes in large airways cause cough and sputum, while changes in small airways and alveoli are responsible for physiologic alterations. Emphysema and small airway pathology are both present in most persons with COPD; however, they do not appear to be mechanistically related to each other, and their relative contributions to obstruction vary from one person to another.


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InternalMed_Harrison. Cigarette smoking often results in mucus gland enlargement and goblet cell hyperplasia, leading to cough and mucus production that define chronic bronchitis, but these abnormalities are not related to airflow limitation. Goblet cells not only increase in number but in extent through the bronchial tree. Bronchi also undergo squamous metaplasia, predisposing to carcinogenesis and disrupting mucociliary clearance. Although not as prominent as in asthma, patients may have smooth-muscle hypertrophy and bronchial hyperreactivity leading to airflow limitation. Neutrophil influx has been associ-1701 ated with purulent sputum of upper respiratory tract infections. Independent of its proteolytic activity, neutrophil elastase is among the most potent secretagogues identified.


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InternalMed_Harrison. The major site of increased resistance in most individuals with COPD is in airways ≤2 mm diameter. Characteristic cellular changes include goblet cell metaplasia, with these mucus-secreting cells replacing surfactant-secreting Clara cells. Smooth-muscle hypertrophy may also be present. These abnormalities may cause luminal narrowing by fibrosis, excess mucus, edema, and cellular infiltration. Reduced surfactant may increase surface tension at the air-tissue interface, predisposing to airway narrowing or collapse. Respiratory bronchiolitis with mononuclear inflammatory cells collecting in distal airway tissues may cause proteolytic destruction of elastic fibers in the respiratory bronchioles and alveolar ducts where the fibers are concentrated as rings around alveolar entrances. Narrowing and drop-out of small airways precede the onset of emphysematous destruction.


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InternalMed_Harrison. Emphysema is characterized by destruction of gas-exchanging air spaces, i.e., the respiratory bronchioles, alveolar ducts, and alveoli. Their walls become perforated and later obliterated with coalescence of small distinct air spaces into abnormal and much larger air spaces. Macrophages accumulate in respiratory bronchioles of essentially all young smokers. Bronchoalveolar lavage fluid from such individuals contains roughly five times as many macrophages as lavage from non smokers. In smokers’ lavage fluid, macrophages comprise >95% of the total cell count, and neutrophils, nearly absent in nonsmokers’ lavage, account for 1–2% of the cells. T lymphocytes, particularly CD8+ cells, are also increased in the alveolar space of smokers.


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InternalMed_Harrison. Emphysema is classified into distinct pathologic types, the most important being centriacinar and panacinar. Centriacinar emphysema, the type most frequently associated with cigarette smoking, is characterized by enlarged air spaces found (initially) in association with respiratory bronchioles. Centriacinar emphysema is usually most prominent in the upper lobes and superior segments of lower lobes and is often quite focal. Panacinar emphysema refers to abnormally large air spaces evenly distributed within and across acinar units. Panacinar emphysema is usually observed in patients with α1AT deficiency, which has a predilection for the lower lobes. Persistent reduction in forced expiratory flow rates is the most typical finding in COPD. Increases in the residual volume and the residual volume/total lung capacity ratio, nonuniform distribution of ventilation, and ventilation-perfusion mismatching also occur.


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InternalMed_Harrison. Airflow limitation, also known as airflow obstruction, is typically determined by spirometry, which involves forced expiratory maneuvers after the subject has inhaled to total lung capacity. Key parameters obtained from spirometry include the volume of air exhaled within the first second of the forced expiratory maneuver (FEV1) and the total volume of air exhaled during the entire spirometric maneuver (forced vital capacity [FVC]). Patients with airflow obstruction related to COPD have a chronically reduced ratio of FEV1/FVC. In contrast to asthma, the reduced FEV1 in COPD seldom shows large responses to inhaled bronchodilators, although improvements up to 15% are common. Asthma patients can also develop chronic (not fully reversible) airflow obstruction.


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InternalMed_Harrison. Airflow during forced exhalation is the result of the balance between the elastic recoil of the lungs promoting flow and the resistance of the airways limiting flow. In normal lungs, as well as in lungs affected by COPD, maximal expiratory flow diminishes as the lungs empty because the lung parenchyma provides progressively less elastic recoil and because the cross-sectional area of the airways falls, raising the resistance to airflow. The decrease in flow coincident with decreased lung 1702 volume is readily apparent on the expiratory limb of a flow-volume curve. In the early stages of COPD, the abnormality in airflow is only evident at lung volumes at or below the functional residual capacity (closer to residual volume), appearing as a scooped-out lower part of the descending limb of the flow-volume curve. In more advanced disease, the entire curve has decreased expiratory flow compared to normal.


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InternalMed_Harrison. Lung volumes are also routinely assessed in pulmonary function testing. In COPD there is often “air trapping” (increased residual volume and increased ratio of residual volume to total lung capacity) and progressive hyperinflation (increased total lung capacity) late in the disease. Hyperinflation of the thorax during tidal breathing preserves maximum expiratory airflow, because as lung volume increases, elastic recoil pressure increases, and airways enlarge so that airway resistance decreases.


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InternalMed_Harrison. Despite compensating for airway obstruction, hyperinflation can push the diaphragm into a flattened position with a number of adverse effects. First, by decreasing the zone of apposition between the diaphragm and the abdominal wall, positive abdominal pressure during inspiration is not applied as effectively to the chest wall, hindering rib cage movement and impairing inspiration. Second, because the muscle fibers of the flattened diaphragm are shorter than those of a more normally curved diaphragm, they are less capable of generating inspiratory pressures than normal. Third, the flattened diaphragm (with increased radius of curvature, r) must generate greater tension (t) to develop the transpulmonary pressure (p) required to produce tidal breathing. This follows from Laplace’s law, p = 2t/r. Also, because the thoracic cage is distended beyond its normal resting volume, during tidal breathing the inspiratory muscles must do work to overcome the resistance of the thoracic cage to


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InternalMed_Harrison. p = 2t/r. Also, because the thoracic cage is distended beyond its normal resting volume, during tidal breathing the inspiratory muscles must do work to overcome the resistance of the thoracic cage to further inflation instead of gaining the normal assistance from the chest wall recoiling outward toward its resting volume.