Vol 3 The Netter Collection of Medical - Terapia Respiratória (2025)

Prévia do material em texto

124 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONSPlate 4-14 Respiratory SystemBRONCHIAL ASTHMAAsthma affects between 5% and 15% of the population in most countries where this has been evaluated. Asthma is a clinical syndrome characterized by variable airfl ow obstruction, increased responsiveness of the airway to constriction induced by nonspecifi c inhaled stimuli (airway hyperresponsiveness), and cellular infl amma-tion. Asthmatic symptoms are characteristically epi-sodic and consist of dyspnea, wheezing, cough, and chest tightness caused by airfl ow obstruction because of airway smooth muscle constriction, airway wall edema, airway infl ammation, and hypersecretion by mucous glands. A major feature of the airfl ow obstruction of asthma is that it is partially or fully reversible either spontaneously or as a result of treatment.CLINICAL FORMS OF BRONCHIAL ASTHMAAsthma is a syndrome because, although the clinical presentation is often quite characteristic, its etiologic factors vary. Previous descriptors of asthma included the terms extrinsic asthma, implying that an external stimulus was responsible for causing the disease, and intrinsic asthma, in which no obvious external cause could be identifi ed. It is now recognized that likely all asthma is initiated by some external stimulus, the most commonly identifi ed of which are environmental allergens.Allergic AsthmaAllergic asthma most often affects children and young adults (Plate 4-14). A personal history of other allergic manifestations (atopy), such as allergic rhinitis, conjunctivitis, or eczema is common, as is a family history of atopy. Atopy is identifi ed by positive dermal responses to environmental and occupational allergens and elevated serum immunoglobulin E (IgE) levels.Nonallergic AsthmaNonallergic asthma is usually identifi ed in patients who develop asthma symptoms as adults (see Plate 4-15). The symptoms may develop after a respiratory tract infection, and occasionally infective agents such as Chlamydia pneumoniae or Mycoplasma spp. are impli-cated. Occupational sensitizers are other important causes of nonallergic asthma, and a detailed occupational history is a critical component of the evaluation of the patient. Nonallergic asthma is also commonly associated with comorbidities such as chronic sinusitis, obesity, or gastroesophageal refl ux.INDUCERS AND INCITERS OF ASTHMAAn important distinction needs to be made between stimuli that are inducers of asthma (cause the disease), such as environmental allergens and occupational sen-sitizers, and inciters of asthma, which are stimuli that cause exacerbations or transient symptoms (see Plate 4-16).Respiratory Viral InfectionsViral infections are important inducers of asthma and have been associated with a number of important clinical consequences in people with asthma, including ALLERGIC ASTHMA: CLINICAL FEATURESYoung patient: child or teenagerFamily history usually positiveAttacks related to specific antigensPollens FoodsDrugsDustsDandersSkin test resultsusually positiveHistory of eczema inchildhood“Allergic shiner” may be presentIgE associatedTHE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 125Plate 4-15 Diseases and Pathologythe development of wheezing-associated illnesses in infants and small children; the development of asthma in the fi rst decade of life; causing acute asthma exacerbations (particularly rhinovirus); and inducing changes in airway physiology, including increasing airway responsiveness.Environmental AllergensAllergens are known to both induce asthma and be inciters of asthma symptoms. Indeed, some people with asthma only experience seasonal symptoms when they are exposed to allergens. Patients with allergen sensitiv-ity can experience acute bronchoconstriction within 10 to 15 minutes after allergen inhalation, which usually resolves with 2 hours (the early asthmatic response); however, the bronchoconstriction can recur between 3 to 6 hours later (the late asthmatic response), which develops more slowly and is characterized by severe bronchoconstriction and dyspnea. The late response occurs because of progressively increasing infl ux of infl ammatory cells, particularly basophils and eosi-nophils, into the airways. The bronchoconstriction usually resolves within 24 hours, but patients are left with increased airway responsiveness, which may persist for more than 1 week.Occupational Sensitizing AgentsOccupational asthma is a common cause of adult-onset asthma. More than 200 agents have been iden-tifi ed in the workplace, including allergens such as animal dander, wheat fl our, psyllium, and enzymes, which cause airway narrowing through IgE-mediated responses, and chemicals (often small molecular weight, e.g., toluene diisocyanate), which cause asthma through non–IgE-mediated mechanisms. Work-related expo-sures and inhalation accidents are a signifi cant risk for new-onset asthma. When occupational chemical sensitizers are inhaled by a sensitized subject in the laboratory, an early asthmatic response can often be elicited, similar to that induced by allergen. This can be followed by a late asthmatic response. The airway infl ammatory responses caused by occupational sensitizers do not appear to differ substantially from other causes of asthma, such as environmental allergens.ExerciseExercise is a very commonly experienced asthma inciter. Bronchoconstriction occurs after exercise, becoming maximal 10 to 20 minutes after the end of exertion, and generally resolves within 1 hour. Bronchoconstriction very rarely occurs during exercise. Bronchoconstriction is caused by the cooling and drying of the airways because the large volumes of air inhaled during exercise are conditioned to body temperature and are fully saturated. Similar symptoms can be experienced by people with asthma who inhale very cold, dry air. Exercise-induced bronchoconstriction can usually be prevented by pretreatment with inhaled β2-agonists 5 to 10 minutes before exercise.Atmospheric PollutantsA variety of atmospheric pollutants are asthma inciters. These include nitrogen dioxide (NO2), sulfur dioxide NONALLERGIC ASTHMA: CLINICAL FEATURESAdult patient: age 35 years and olderFamilyhistoryusuallynegativeAttacksrelated toinfections,exercise,otherstimuliSkin test resultsusuallynegativeNo history of eczema in childhoodNot IgE associatedConsider occupationalasthma as a causeBRONCHIAL ASTHMA (Continued)126 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONSPlate 4-16 Respiratory System(SO2), ozone, and inhaled particles smaller than 10 μm in diameter (PM10). Other environmental irritants that can incite asthma symptoms include strong smells, such as perfume, car exhaust fumes, and secondhand tobacco smoke.Aspirin SensitivityA triad of aspirin sensitivity, asthma, and nasal polyposis (Samter triad) has been recognized in approximately 5% of individuals with asthma (although nasal polyposis is not invariably present in asthmatics with aspirin sensitivity). Symptoms of asthma develop within 20 minutes of ingestion of aspirin, which may be very severe and occasionally life threatening. This sensitivity exists to all drugs that are cyclo-oxygenase (COX-1) inhibitors and sometimes also to tartrazine. Acetami-nophen and COX-2 inhibitors appear to be safe to use in most aspirin-sensitive individuals with asthma.CLINICAL PRESENTATIONSymptoms and Clinical FindingsSymptoms and signs of asthma range from mild, dis-crete episodes of shortness of breath, wheezing, and cough, which are very intermittent, usually after expo-sure to an asthma trigger, followed by signifi cant remis-sion, to continuous, chronic symptoms that wax and wane in severity. For any patient, symptoms may be mild, moderate, or severe at any given time, and even patients with mild, intermittent asthma can have severethe pathologic changes in large airways. Although patients with chronic mucus hypersecretion with cough and sputum are more prone to respiratory infections and exacerbations of COPD, the presence of cough and sputum are not, by themselves, indicative of a poor prognosis in the absence of airfl ow obstruction. The magnitude of airfl ow obstruction is better corre-lated with the pathologic involvement of the small airways.Small Airways Disease (see Plate 4-33)COPD is also associated with changes in the small airways, those less than 2 mm and between the fourth and twelfth generation of airway branching in the lungs. The changes in the small airways may occur independ-ently of changes in the larger airways. Changes in the small airways occur across a spectrum and may range from bland intraluminal secretions to a more cellular infi ltrate, with polymorphonuclear neutrophils, macro-phages, CD4 cells and other lymphocyte subtypes. The presence of lymphoid follicles in the small airways dem-onstrates increased immune surveillance of the mucosal surface. In addition to cellular infl ammation, airway wall thickening, including changes in the epithelium, lamina propria, and adventitia, corresponds to disease progression. The diffuse changes in small airways con-tribute more to the obstruction and maldistribution of inspired gas than do the abnormalities in large airways. Obstruction of small airways with mucous plugs is asso-ciated with increased mortality.EMPHYSEMAThe several types of emphysema are classifi ed accord-ing to patterns of septal destruction and airspace enlargement within terminal respiratory units, or acini (see Plates 4-34 to 4-36). The normal acinus is supplied by a terminal bronchiole. The terminal bronchiole under-goes three orders of branching—fi rst into respiratory bronchioles with alveolated walls, into alveolar ducts, and fi nally into alveolar sacs.If the septal destruction and dilatation are limited to the central portion of the acinus in the region of the terminal bronchiole and respiratory bronchioles, the disorder is called centriacinar or centrilobular emphysema (see Plate 4-35). Because of septal destruction, there is free communication between all orders of respiratory bronchioles. Alveolar sacs at the periphery of the acinus lose volume as the central portions enlarge. Although centriacinar emphysema is often considered to be a diffuse disease process, there is considerable variation in severity from acinus to acinus within the same segment or lobe. In general, however, more of the acini are affected in the upper lung zones than in the lower zones. Extensive centriacinar emphysema is most often found in those with histories of heavy smoking and chronic bronchitis.In contrast to centriacinar emphysema, panacinar or panlobular emphysema affects the acinus more uniformly with less variability within an individual segment or lobe (see Plate 4-36). There is some tendency for the lower zones to be more severely affected. Panacinar emphysema is the characteristic lesion in α1-antitrypsin defi ciency, although smokers with α1-antitrypsin defi ciency may have centriacinar emphysema as well. Panacinar emphysema to a mild degree is a common fi nding after the fi fth decade of life and may be exten-sive in elderly nonsmoking patients who have age-related “senile” emphysema. In severe smoking-related chronic obstructive airway disease, both centriacinar and panacinar emphysema are ordinarily found along with chronic bronchitic changes in the airways.Radiograph showing typicalenlarged pulmonary arteryshadows and outflow tract of right ventricleHypertrophy and dilatation of right ventricle, leading to hypertrophy and dilatation of right atrium and to tricuspid insufficiency terminallyBulge of septum to leftmay impair left ventricularfilling (reverse Bernheimphenomenon)Enlargementof liver (passivecongestion)Electrocardiogram indicative of right ventricular hypertrophyPeripheral edemaElevation ofpulmonaryarterypressureCOR PULMONALE CAUSED BY COPDSystolicDiastolicNormalreadings VenousdistensionReduction of pulmonaryarterial bed (loss of vesselsplus reflex hypoxicvasoconstriction)6025circulating levels of TNF-α and soluble TNF-α receptors.CHRONIC OBSTRUCTIVE PULMONARY DISEASE BronchitisChronic bronchitisLarge cartilaginous airwaysMucous gland hyperplasia(elevated Reid index)Dilated duct of glandThickened basement membraneSquamous metaplasiaInflammatory infiltrateHyperemiaEdemaFibrosisProfuse exudate in lumenEpithelial desquamationCartilage intactSmall airwaysGoblet cell hyperplasiaThickened basement membraneHyperemiaInflammatory infiltrateExudate in lumenEdemaSquamous metaplasiaFibrosisCHRONIC OBSTRUCTIVE PULMONARY DISEASE (Continued)144 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONSPlate 4-34 Respiratory SystemThe fi nal common pathway of infl ammatory cytokines, protease-antiprotease imbalance, and oxida-tive stress is destruction of alveolar epithelial and capil-lary endothelial cells by a programmed sequence of cell death, or apoptosis. Because the lung requires replace-ment of its cellular scaffolding on a continuing basis, any process that leads to an imbalance of cell destruc-tion and cell growth can eventually lead to emphysema. Thus, insuffi ciency of growth factors is also postulated to contribute to the development of emphysema.The presence of CD8 cells and airway-associated lymphoid follicles in the lung parenchyma in smokers with COPD has raised the possibility that immunologic processes such as autoimmunity or response to chronic viral infection may also contribute to the pathogenesis of COPD.α1-ANTITRYPSINSerum levels of α1-antitrypsin are either defi cient or absent in some patients with early onset of emphysema associated with particular genotypes (see Plate 4-38). Most people in the normal population have α1-antitrypsin levels in excess of 250 mg/100 mL of serum along with two M genes, designated as Pi-type MM. Several genes are associated with alterations in serum α1-antitrypsin levels, but the most common ones associated with emphysema are the Z and S genes. Indi-viduals who are homozygous ZZ or SS have serum levels of α1-antitrypsin of less than 50 mg/100 mL and develop severe panacinar emphysema at an early age, particularly if they smoke or are exposed to occupa-tional dusts. The MZ and MS heterozygotes have inter-mediate levels of serum α1-antitrypsin. Although smokers with MZ or MS genotypes may have slightly increased decline in FEV1 if they smoke, the risk of developing COPD is not materially increased beyond other smokers.α1-Antitrypsin defi ciency is caused by a single amino acid substitution. The Z mutation is caused by a gluta-mate to lysine mutation at position 342, and the S mutation is caused by a glutamate to valine mutation at position 264. These mutations lead to misfolding of the protein preventing release from the liver, where it is mainly manufactured. The misfolded protein may be destroyed by proteosomal processes, or if it polymer-izes, may be stored in the endoplasmic reticulum and not released into the circulation. Excessive liver storage may lead to infl ammatory liver disease and cirrhosis, particularly in affected infants and children.The precise way that antitrypsin defi ciency produces emphysema is unclear. In addition to inhibiting trypsin, α1-antitrypsin effectively inhibits elastase and colla-genase, as well as several other enzymes. α1-Antitrypsin is an acute-phase reactant, and the serum levels increase in association with many infl ammatory reactions and with estrogen administration in all except homozy-gotes. It has been proposed, with some supporting experimental evidence, that the structural integrity of lung elastin and collagen depends on this antiprotease, which protects the lung from proteases released from leukocytes. Proteases released by lysed leukocytes in the alveoli may be uninhibited and consequently free to damage the alveolar walls themselves. Alternative theories suggest that the unopposed protease activity may lead to an ongoing immune-mediated infl amma-tory response or acceleration of natural programmed cell death.PATHOPHYSIOLOGYWhether bronchitis or emphysema predominates, by the time a patient with COPD begins to have Normal lung acinus (secondary lobule)ANATOMIC DISTRIBUTION OF EMPHYSEMACentriacinar (centrilobular) emphysemaPanacinar (panlobular) emphysemaTerminal bronchioleSeptum of acinus1st order2nd order3rd orderAlveolar ductsRespiratorybronchiolesAll airways and alveoliinvolved with breakdownof dividing wallsDistended respiratorybronchioles of allorders communicatingwith one anotherAlveolar sacsCHRONIC OBSTRUCTIVE PULMONARY DISEASE (Continued)THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 145Plate 4-35 Diseases and Pathologysymptoms, airfl ow limitation is readily demonstrable as an obstructive ventilatory defect. The most easily meas-ured indexes of obstruction are taken from the volume-time plot of a forced expiratory VC maneuver, classically measured with a spirometer coupled to a rotating drum kymograph. Although volume-measuring spirometers are stable, rugged, and linear instruments, most modern spirometry systems use fl ow-measuring devices (pneu-motachometers) interfaced with a microprocessor that integrates fl ow over time to produce a time-based record of forced expired volume (see Plate 4-39). The FEV1 is low both as a percentage of the value predicted for a given gender, age, and height category and as a percentage of the patient’s own FVC. Depending on the purpose of the pulmonary function test, an obstructive ventilatory defect is defi ned either as an FEV1/FVC ratio of less than 70% or less than the 95th percentile for the demographic category.With COPD, static lung volumes are often abnor-mal. Plate 4-39 depicts the normal lung volumes and those often found in COPD. The functional residual capacity (FRC) is the lung volume at the end of a quiet exhalation and, in normal subjects, is the volume at which the inward recoil of the lung is equal and oppo-site to the outward recoil of the relaxed chest wall. An elevated FRC in individuals with COPD results from the loss of the static elastic recoil properties of the lung as well as initiation of inspiration before the static balance volume is reached (so-called “dynamic hyper-infl ation”). TLC is determined by pressures exerted by the diaphragm and muscles of the chest wall in relation to the static elastic recoil properties of both the chest wall and lung. When TLC is elevated in COPD, a signifi cant degree of emphysema is present, although the TLC can also be elevated during acute episodes of asthma. RV is elevated early in the clinical course of COPD and is a sensitive sign of airfl ow limitation. Early in the course of the disease, elevation of RV is thought to be caused by closure of airways, but late in the disease, emphysematous bullae may also contribute to the elevation in RV. Because the TLC does not increase as much as the RV increases, the VC (i.e., TLC − RV) decreases with advancing COPD.The measurement of static lung volumes in COPD is subject to some technical issues (see Plate 2-3). Resi-dent gas methods using helium dilution or nitrogen may underestimate the true lung volumes because of incomplete gas mixing or washout in regions with impaired ventilation. Plethysmographic lung volumes that depend on Boyle’s law relying on the compressibil-ity of resident gas in the lung are more accurate but are subject to overestimation of the true lung volume if the panting frequency is too rapid to permit equilibration of the mouth and alveolar pressures. Because the differ-ence between the resident gas and plethysmographic measure is caused by regions of lung with little or no ventilation, the difference between the two methods has been called “trapped gas” and used as an indicator of COPD severity (see Section 2).In addition to the easily demonstrable obstructive abnormalities duringforced exhalation, there are sig-nifi cant alterations in the pressure-fl ow relationships during ordinary breathing in COPD. This contrasts with exhalation in normal subjects who can increase expiratory fl ow during tidal breathing (see Plate 4-39). Because of the slow emptying of the lung in COPD, the next breath is initiated before the respiratory system can return to the static FRC. This means that the individual breathes at higher lung volumes to maintain adequate expiratory airfl ow, a condition referred to as dynamic hyperinfl ation (see Plate 4-39). Although breathing at high lung volumes has the advantage of increasing airfl ow because of the increased lung elastic Microscopic section Distension of airspaceswith rupture ofalveolar wallsGross specimenInvolvement tends to be most marked in upper part of lungMagnified sectionDistended, inter-communicating,saclike spacesin central areaof aciniCENTRIACINAR (CENTRILOBULAR) EMPHYSEMACHRONIC OBSTRUCTIVE PULMONARY DISEASE (Continued)146 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONSPlate 4-36 Respiratory Systemrecoil, it requires an increase in the work of breathing and a decrease in the effi ciency of breathing. Increas-ing respiratory rate accentuates dynamic hyperinfl ation and can worsen the sensation of dyspnea. Pursed-lip breathing causes patients to slow their respiratory rate and can relieve dyspnea by diminishing dynamic hyperinfl ation.The physiologic hallmark of emphysema is a reduc-tion in lung elastic recoil caused by destruction of alveolar septal elements. This causes the pressure-volume curve of the lung to be shifted upward and to the left, resulting in decreased static recoil pressure at a specifi c lung volume and an increase in the compli-ance of the lung (see Plates 4-39 and 4-40).The surface area of the alveolar-capillary membrane is reduced as a consequence of emphysema. This results in decreased transfer of diffusion-limited gases such as carbon monoxide across the alveolar-capillary mem-brane. This is measured in the pulmonary function laboratory as the DLCO. The DLCO correlates roughly with the magnitude of reduction in maximum elastic recoil of the lung as well as the anatomic extent of emphysema assessed by imaging with computed tom-ography (CT). In chronic bronchitis, the DLCO may be preserved, and in asthma, the DLCO tends to be elevated.With the progression of COPD comes progressive exercise limitation. This is caused by the increased work of breathing as ventilation increases with exercise. With increased respiratory rate, patients develop dynamic hyperinfl ation, a condition in which the end-expiratory lung volume does not return to the static end-expiratory volume of FRC (see Plate 4-40). The hyper-infl ation that occurs causes an increased work of breathing and exacerbates dyspnea. An indicator of dynamic hyperinfl ation is the inspiratory capacity (IC), which progressively decreases with increasing ventila-tion. Measures that reduce dynamic hyperinfl ation, increasing IC, can improve exercise capacity. These include alterations in breathing pattern, oxygen sup-plementation, helium inhalation, and use of inhaled bronchodilators, particularly long-acting, and lung volume reduction surgery.RADIOGRAPHIC APPEARANCEChronic BronchitisOn plain chest radiographs, thickening of bronchial walls is often seen as parallel or tapering shadows, referred to as tram tracking or ring shadows of airways that are visualized in cross-section. A generalized increase in lung markings at the bases is also frequently seen and is referred to as dirty lungs. In patients who have been exposed to occupational dusts, these mark-ings may be accentuated but do not necessarily indicate the presence of pneumoconiosis.The CT may show airway wall thickening or mucoid impactions in patients with COPD even in the absence of emphysema. The magnitude of these abnormalities, however, does not necessarily correlate with the severity of airfl ow obstruction or the extent of emphysema, and it remains to be seen whether there are prognostic or therapeutic implications of these fi ndings.EmphysemaIn evaluating plain radiographs, a range of fi ndings can represent emphysema. These include attenuation of the pulmonary vasculature peripherally, irregular radiolu-cency of lung fi elds, fl attening or inversion of the dia-phragm as seen on both posteroanterior (PA) and lateral projections, and an increase in the retrosternal space on the lateral projection. The latter two fi ndings have PANACINAR (PANLOBULAR) EMPHYSEMAGross section of lung.Dilated, saccular air spaces.In cases of disease causedby 1-antitrypsin deficiency,lower part of lung tendsto be more affected Magnifiedsection.Diffuseinvolvementof all portionsof aciniCHRONIC OBSTRUCTIVE PULMONARY DISEASE (Continued)THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 147Plate 4-37 Diseases and Pathologycorrelated best with the severity of emphysema as assessed at subsequent postmortem examination.High-resolution CT examination of the chest is now considered the best indicator of the extent and distribution of emphysema (see Plate 4-41). Qualitative visual assessments can assess the presence of thin-walled bullae and regions of diminished vascularity. Quantitative assessments use the degree of attenuation of x-rays to estimate the air-tissue ratio as a measure of airspace enlargement. Regions of the lung on thin-section CT scans that approach the radiodensity of air (−1000 Hounsfi eld units [HU]) are considered to be emphysema. For example, the emphysema index is cal-culated as the percentage of image voxels in the lung regions that have a densitywho were randomly assigned to smoking intervention plus placebo, smoking intervention plus bronchodilator, or no intervention. Randomization to the smoking cessa-tion intervention was shown to reduce the rate of decline in FEV1 and to improve mortality, mainly related to cardiovascular disease and lung cancer. Throughout the study, some patients reverted from Cigarette smokeCOPD: INFLAMMATIONReactive oxygen speciesMacro-phageNeutrophil AlveoliEmphysemaCD8+ T cellIP-10I-TACMIGIL-8TNF-αMMPsMMPsα1-antitrypsinMMPsDestruction ofextracellularmatrixNeutrophilelastaseTIMPSIncreasedMMPproductionHistone deacetylase(HDAC)DNAacetylationNF-κBNF-κBIN-κBCHRONIC OBSTRUCTIVE PULMONARY DISEASE (Continued)148 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONSPlate 4-38 Respiratory Systembeing smokers to quitters and vice versa. When patients were followed for 11 years, those who successfully quit smoking had a small initial increase in FEV1 followed by a slow, normal rate of FEV1 decline. Quitters who reverted to cigarette smoking showed a more rapid FEV1 decline than those who were sustained quitters. At 14.5 years, those randomized to the 10-week smoking cessation had a reduced mortality rate compared with those randomized to usual care.Persons who quit smoking with earlier disease have better outcomes relative to those who continue to smoke than those who quit smoking later in the disease. When the disease is advanced, the infl ammatory response persists, and the rate of decline of lung func-tion tends to progress. Because there are many years of asymptomatic decline in lung function, it is possible to diagnose COPD with forced expiratory spirometry before the disease is apparent and to implement aggres-sive smoking intervention programs. There is no con-sensus whether it is necessary to screen for COPD among all cigarette smokers, but there is evidence that presentation of a person’s FEV1 in terms of “lung age” does assist in smoking cessation.Reduce Harmful Environmental ExposuresReduction of secondhand smoke and other environ-mental pollutants is important in preventing the pro-gression of COPD. Reducing exposure to indoor and outdoor pollutants requires a combination of public policy to defi ne and uphold air quality standards and steps taken at the individual level to minimize exposure to elevated concentrations of pollutants in the indoor or outdoor environments. Occupational exposures should be ascertained with attention to fumes and dusts, and vigorous measures should be taken to eliminate harmful exposures. Respiratory protective equipment should be worn by COPD patients exposed to heavy dust concentrations. Although there is no level of FEV1 that absolutely prohibits the use of respiratory protec-tive equipment, some COPD patients will need to change their work environment if they cannot tolerate protective devices.Minimize Infectious RisksAlthough it is not possible to completely eliminate exposure to the many infectious agents, patients should keep away from large crowds and persons with obvious respiratory infections, especially during infl uenza season. Handwashing or hand sanitization should be emphasized. Patients should be educated about early signs of exacerbations and treated promptly. Some patients may want to keep a prescription or supply of antibiotics or steroids available at home. Pneumococcal vaccination is recommended, although the evidence of its particular effi cacy in COPD is lacking. Annual infl u-enza immunization can prevent or attenuate this poten-tially fatal infection.Exercise and RehabilitationRegular, prudent, self-directed exercise is recom-mended for all individuals with COPD to prevent the muscle deconditioning that often accompanies the disorder. Individuals should be encouraged to perform at least 20 to 30 minutes of constant low-intensity aerobic exercise such as walking at least three times per week. This is usually feasible even in more severely impaired patients. It is important to instruct patients that they should exercise to a level of dyspnea that is tolerable for the entire exercise period. Supplemental oxygen for exercise is necessary for patients who Cigarette smokeEmphysema No emphysemaElastaseMMP 1, 9, 12CathepsinsTIMPsSLIPIα1 AntitrypsinPROTEASECOPD: PROTEASE-ANTIPROTEASE IMBALANCEANTIPROTEASENeutrophilMacrophageThe balance between proteases and antiproteasesis influenced by cigarette smoke, which inducesinflammatory cells to produce proteases. Cigarettesmoke also inhibits the activity of antiproteases.The net effect shifts the balance toward destructionof lung tissue and development of emphysema.CHRONIC OBSTRUCTIVE PULMONARY DISEASE (Continued)THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 149Plate 4-39 Diseases and Pathologydesaturate with exercise and may benefi t some patients without demonstrable oxygen desaturation in terms of exercise capacity and training effect.Formal rehabilitation programs are established as an effective component of COPD management and should be offered to patients who have substantial limitation in daily activities (see Plate 5-11). The goals of pulmo-nary rehabilitation are to improve quality of life, reduce symptoms, and increase physical and emotional partici-pation in daily activities. To achieve these goals, pulmo-nary rehabil itation programs use a multidisciplinary approach, including exercise training, nutrition, educa-tion, and psychological support. Smoking cessation programs are often linked to pulmonary rehabilitation programs. Exercise training typically consists of bicycle ergometry or treadmill exercise. Upper extremity weight training is often included as a component of strength training. Practical advice on energy conserva-tion and pacing during activities of daily living can be delivered individually or in group sessions. Proper use of inhalers, oxygen supplementation, and good nutri-tion are goals of education programs.TREATMENT OF STABLE CHRONIC OBSTRUCTIVE PULMONARY DISEASEThe goals of treatment of COPD are to prevent pro-gression and complications of the disease, relieve symp-toms, improve exercise capacity, improve quality of life, treat exacerbations, and improve survival. In addition to smoking intervention and treatment of hypoxemia with supplemental oxygen, pharmacologic therapy is available for treatment of patients with COPD. See the section on pharmacology (Plates 5-1 to 5-10) for a more detailed description of many of the drugs discussed below.The current goals of drug therapy are not only to improve lung function, but also to improve quality of life and exercise capacity and to prevent exacerba-tions. The recommended approach to drug treatment for COPD is to sequentially add agents using the minimum number of agents and the most convenient dosing schedule, starting with the agents having the greatest benefi t, best tolerance, and lowest cost (see Plate 4-42).Inhaled bronchodilators, including β-agonists and anticholinergic agents, are the foundation of treatment for patients with COPD. They are given on a regular basis to maintain bronchodilation and on an as-needed basis for relief of symptoms. Both β-agonist and anti-cholinergic classes are available in short-duration (4-6 hour) and long-duration (12-24 hour) forms. Evi-dence suggests that long-acting agents are more effective than short-acting agents, but the choice of medication should also account for cost considerations and patient preference. Combination of different classes of bronchodilators is often more effective than increas-ing the dose of a single agent, and combination inhalers can simplify treatment regimens. Individuals with fre-quent exacerbations or more severe COPD may benefi t from a combination inhaler of corticosteroids and long-acting bronchodilator. Long-acting oral theophyllinecan also be used as adjunctive therapy. Chronic use of systemic corticosteroids should be reserved for indi-viduals with very frequent or life-threatening exacerba-tions who cannot tolerate their discontinuation.Replacement therapy with α1-antitrypsin should be considered for individuals with severe defi ciency. Observational studies suggest that individuals with moderate degrees of impairment (FEV1 35%-65% pre-dicted) seem to benefi t most in terms of preservation of lung function and improved survival.Obstruction Normal 43 2 1 RVMaximal expiratory flow-volume curves. TLC may be increased in obstruction but expiratory flow rate decreased. In severe obstruction, tidal breathing may coincide with MEFV curve FEF25%–75%FEF25%–75%Automated spirometry testingPULMONARY FUNCTION IN OBSTRUCTIVE DISEASENormalTidalbreathingObstructionLung vol. (L)FEV, and FEF25%–75% reducedFRCVCObstructionInspiratoryreserve vol.(IRV)Inspiratoryreserve vol.(IRV)Tidal vol. (TV)Tidal vol. (TV)Expiratoryreservevol. (ERV)Expiratoryreservevol. (ERV)Residualvol. (RV)Residualvol. (RV)Totallungcapacity(TLC)(TLC) (TLC)88665 4432NormalTLCincreasedlargelybecauseof reducedlung elasticrecoilVitalcapacity(VC)Functionalresidualcapacity(FRC)TLC0 1 2 3 4 5 6 7 8 9Flow (L/sec)FEV1FEV1Vol.(L)Time (sec)CHRONIC OBSTRUCTIVE PULMONARY DISEASE (Continued)150 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONSPlate 4-40 Respiratory SystemPatient education about pharmacotherapy is impor-tant to ensure proper use of medications, as well as to enhance adherence. Inhaled agents are administered by metered-dose inhalers or dry powder inhalers or as a nebulized solution. The selection of route of adminis-tration is made by cost and convenience of the device because all are similarly effective if used properly. Proper use of inhaled medications is diffi cult for many patients to learn and retain. Adherence with inhaled medication, particularly when it does not provide immediate symptom relief, is poor. Typically, about half of patients do not take their medication in the dose or quantity prescribed. Reasons for this include a lack of understanding of the role of the medication, failure of the medication to provide meaningful benefi t, complex-ity of the treatment program, and expense of the treat-ment. Many patients do not want to confi de poor adherence to their physician, so it is important for the physician to ascertain this information in a way that does not interfere with the relationship with the patient. If nonadherence is a problem, the treating physician can undertake actions to improve adherence such as simpli-fi cation of the medication program, education about the benefi ts of treatment, linking drug use to estab-lished habits such as meals or tooth brushing, or pre-scribing less costly drugs.TREATMENT OF EXACERBATIONSCOPD exacerbations are characterized by worsening dyspnea, cough, and increased sputum production. There are several formal defi nitions of a COPD exacerbation, but a useful working defi nition is that a COPD exacerbation is a worsening of dyspnea, cough, or sputum production that exceeds day-to-day variability and that persists for more than 1 or 2 days. On average, patients with COPD have two to three exacerbations per year, but there is wide vari-ation, and the frequency of exacerbations is only roughly correlated with severity of airfl ow obstruction. The best predictor of future exacerbations is a history of frequent exacerbations, and these are more common in patients with chronic cough and sputum produc-tion. Precipitating events include respiratory and nonrespiratory infections; exposure to respiratory irri-tants and air pollution; and comorbid conditions such as heart failure, pulmonary embolism, myocardial ischemia, or pneumothorax.For patients treated at home, increasing the fre-quency and intensity of inhaled short-acting bron-chodilators for several days is effective in mild exacerbations. A nebulizer may be needed for those who have diffi culty using inhalers or in those with severe dyspnea. Increasing dyspnea accompanied by a change in the quantity or color of phlegm is usually an indication of bacterial infection and should prompt ini-tiation of antibiotics. A course of corticosteroids, equiv-alent to 30 to 60 mg of prednisone for 7 to 14 days, will shorten the duration of symptoms for patients with exacerbations managed as outpatients.For patients admitted to the hospital, intensifi cation of inhaled bronchodilator treatment, systemic corti-costeroids, and antibiotics should be administered. Controlled oxygen supplementation should be pro-vided at the lowest level needed to reverse hypoxemia and minimize the induction of hypercapnia. The selec-tion of the oral or intravenous route for antibiotics and corticosteroids is determined by the severity of the illness and the ability of the patient to tolerate oral medication.Treatment in an intensive care setting should be undertaken for patients with severe life-threatening Resistance to outflowat lips maintainsintrabronchialpressure andslows flow rateBronchi remain openbecause of positivepressure within lumenand slower flow rateTLC as % of that predictedElastic (recoil) pressure (Pel)100EmphysemaNormal500 10 20DVDVDPDP30 40TLCEELVIC IRVICIC ICIC ICEELV Air trappingduring exerciseDynamichyperinflationNormalHyperinflationPATHOPHYSIOLOGY OF EMPHYSEMA: LOSS OF ELASTIC RECOIL AND HYPERINFLATIONRVTLCCOPDRVCHRONIC OBSTRUCTIVE PULMONARY DISEASE (Continued)THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 151Plate 4-41 Diseases and Pathologyexacerbations and those who require more constant attention. For patients with respiratory failure, nonin-vasive mask ventilation has proven to be an effective strategy to avert endotracheal intubation, shorten the duration of illness, and improve outcomes. When non-invasive mask ventilation is not successful in sustaining ventilation or if the patient is too ill to use the mask, endotracheal intubation and mechanical ventilation are needed to treat respiratory failure. The mechanical ven-tilator should be set to provide a provide a prolonged duration of expiration to minimize dynamic hyper-infl ation (“intrinsic positive end-expiratory pressure”), which can lead to dyspnea, ventilator dyscoordination, and barotrauma. Care should be taken not to overven-tilate the patient and cause alkalemia, which may ulti-mately impede liberation from the ventilator. Survival after an episode of acute respiratory failure for COPD is about 50% at 2 years after discharge, with about 50% of the patients being readmitted to the hospital within 6 months.TREATMENT COMPLICATIONSPatients with advanced COPD are prone to developing secondary complications of the disease. The goals of treatment are to restore functional status as quickly and as much as possible and to alleviate distress and discomfort.PneumothoraxAcute worsening of dyspnea may result from a pneu-mothorax, which patients with bullous emphysema are prone to have. Treatment involves use of high-concentration oxygen and drainage with a catheter or chest tube connected to a valve or vacuum drainage system. Patients with recurrent, life-threatening, or bilateral pneumothorax are candidates for pleurodesis to prevent recurrence.Cor PulmonaleThe pulmonary vascular bed normally has an impres-sive reserve that accommodates large increases in cardiac output with minimal elevations of pulmonary artery pressures (see Plate 4-32). In COPD, there is a decrease in the total cross-sectional area of the pulmo-nary vascular bed caused by anatomic changes in the arteries; constriction of smooth muscle in response to alveolar hypoxia; and, to theextent that emphysema is present, a loss of pulmonary capillaries. Therefore, the pressures that must be generated by the right ventricle are elevated, and dilatation and hypertrophy of the right ventricle result. Overt right ventricular failure often occurs in association with endobronchial infections, which leads to worsening hypoxemia and hypercapnia. Such episodes are more frequent in patients in whom bronchitis is dominant.Patients with cor pulmonale are cyanotic and have distended neck veins that do not collapse with inspira-tion, hepatic engorgement with a tender and enlarged liver, and pitting edema of the extremities. The heart may or may not appear enlarged on a PA chest radio-graph, but pulmonary vessels are prominent. Physical examination may disclose a palpable right ventricular heave and an audible early diastolic gallop that is accen-tuated by inspiration. On occasion, there is dilatation of the tricuspid ring with secondary tricuspid insuffi -ciency; this disappears with effective treatment. The electrocardiogram may show changes of right ventricu-lar hypertrophy. Echocardiographic fi ndings may be inconsistent, especially because of diffi culty obtaining HIGH-RESOLUTION CT SCAN OF LUNGS IN COPDMiddle lobeUpper lobeLower lobeCT scans show severe panacinaremphysema of the upper (aboveand middle) and lower (below) lobes of the lungCHRONIC OBSTRUCTIVE PULMONARY DISEASE (Continued)152 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONSPlate 4-42 Respiratory Systemgood-quality views of the right ventricle because of overlying hyperinfl ation of the lungs. Thus, in patients suspected to have pulmonary hypertension, a right-sided heart catheterization is the most defi nitive means of making the diagnosis.Treatment of hypoxemia is the mainstay of preven-tion and treatment of cor pulmonale. Supplemental oxygen should be prescribed to maintain adequate oxygen saturations regardless of the development of hypercapnia (see Plates 5-12 to 5-14). The presence of sleep apnea is common in patients with COPD and pul-monary hypertension. Thus, evaluation with a sleep study is often helpful to determine the need for noctur-nal oxygen or continuous positive airway pressure (see Plates 4-165 to 4-166). In occasional patients who have severe pulmonary hypertension with minimal COPD, pulmonary thromboembolism should be ruled out. Rarely, pulmonary vasodilators may be used when the magnitude of pulmonary hypertension seems dispro-portionate to the severity of the COPD and hypoxemia.SURGICAL TREATMENTLung Volume Reduction Surgery (see Plate 5-32)Lung volume reduction surgery (LVRS) is a surgical procedure that involves stapled resection of 20% to 30% of the lung bilaterally, usually from the apices (see section on LVRS). Although some patients show sub-stantial physiologic and symptomatic improvement after LVRS, many do not. The group of patients that fares best with LVRS is those who have emphysema predominantly in the upper lung zones and who have low exercise capacity despite pulmonary rehabilitation. These patients have improved survival after LVRS and show improved functional status and quality of life. Conversely, patients without upper lobe predominance (i.e., lower lobe emphysema or homogeneous emphy-sema) and who have adequate exercise capacity after rehabilitation have worse outcomes after LVRS.Surgical resection of a single large bulla is rarely indicated for treatment of COPD. Isolated giant bullae are usually the result of an expanding congenital cyst. The generally accepted indication for resection of a single large bulla is that it occupies more than one-third of the hemithorax and causes compression of normal lung. Some believe that a preserved DLCO is an indica-tor of those most likely to improve after bullectomy.Lung Transplantation (see Plate 5-33)In younger patients with advanced disease, lung trans-plantation should be a treatment consideration (see Plate 5-33). Criteria for lung transplantation referral in patients with COPD is an FEV1 below 25% pre-dicted, severe hypercapnia, or severe pulmonary hyper-tension in patients younger than age 60 to 65 years. The traditional recommendation is that patients should be referred for transplantation when their life expect-ancy is less than 2 years because this is the average waiting time on a transplant recipient list. In recent years, the waiting time has lengthened to closer to 4 years, so this may infl uence physicians to make earlier referrals. Other comorbid conditions, such as poor nutritional status, obesity, chronic mycobacterial infection, or severe osteoporosis, as well as suboptimal psychosocial support, are considered relative contrain-dications. Current smoking, recent malignant disease, major organ system failure (particularly renal or chronic hepatitis B or C infections) are considered absolute contraindications. Lung transplantation may be either unilateral or bilateral depending on the availability of donor organs and the preference of the transplant surgeon. Generally, younger patients and those with accompanying bronchiectasis are con-sidered more suitable candidates for bilateral lung transplantation.In the past, COPD has been the most common indi-cation for lung transplantation, accounting for nearly 40% of all lung transplants and about 50% of single lung transplants. This is accounted for by the high prevalence of COPD as well as the better survival rate for patients with COPD than those with other trans-plant indications while awaiting donor organs. However, current criteria for prioritization of transplant recipi-ents based on diagnosis rather than waiting time alone are likely to diminish the likelihood that COPD patients will receive donor organs. Early survival for patients with COPD after lung transplant is slightly better than that of other diagnostic groups in the fi rst few years. Overall, 30-day survival is 93%, 3-year survival is 61%, and 5-year survival is 45%.MILDFEV1/FVC > 70%FEV1 ≥ 80% predictedFEV1/FVCrecurrent otitis media and sinusitis, neonatal respiratory distress, chronic cough, and situs inversus (in ∼50%). Nasal nitric oxide measurements are a valuable screen-ing tool, with low concentrations seen almost uniformly in patients with PCD. Evaluation of ciliary ultrastruc-ture from a nasal scrape remains the best method of diagnosis. Most PCD patients (∼90%) have ultrastruc-tural defects of cilia involving the outer dynein arm (ODA), inner dynein arm (IDA), or both. Genetic diagnosis is becoming increasingly possible. Mutations in DHAI1 and DNAH5 (encoding ODA proteins) are found in about 40% of PCD patients with ODA defects.α1-Antitrypsin disease is increasingly recognized as a cause of bronchiectasis. Although emphysema remains the most common pulmonary feature, 27% of patients in one series had clinically important bronchiectasis.Immune defi ciencies may contribute to bronchiecta-sis, including IgG subclass defi ciencies; hypogamma-globulinemia; or, more rarely, chronic granulomatous disease or other causes of abnormal neutrophil adhe-sion, respiratory burst, and chemotaxis. HIV/AIDS is also a risk factor for bronchiectasis.Autoimmune or immune-related diseases such as allergic bronchopulmonary aspergillosis (ABPA), col-lagen vascular diseases (particularly Sjögren syndrome and rheumatoid arthritis) and infl ammatory bowel dis-eases may be associated with bronchiectasis.Anatomic AbnormalityPatients with chronic obstructive pulmonary disease may have associated bronchiectasis, affecting up to 50% of those with severe but stable disease in one series. Other anatomic lung diseases associated with diffuse bronchiectasis include tracheobronchomegaly (Mounier-Kuhn disease), congenital cartilage defi -ciency (Williams-Campbell syndrome), and yellow nail syndrome. Obstructive airway lesions, such as endo-bronchial tumors, granulomatous disease, or foreign bodies, may lead to focal bronchiectasis distal to the obstruction. Other processes, such as unilateral hyper-lucent lung (Swyer-James syndrome) and pulmonary sequestration, may also lead to focal bronchiectasis.Postinfectious BronchiectasisThe prevalence of postinfectious bronchiectasis plum-meted in the developed world with the introduction of antibiotic therapy for lower respiratory infections and routine childhood immunizations. However, it remains the most common cause in the developing world. Although any lower respiratory tract infection can potentially lead to bronchiectasis, infections that place individuals at greatest risk include adenovirus, pertussis, measles, and tuberculosis, as well as Klebsiella pneumoniae, Staphylococcus aureus, and Haemophilus infl uenzae.Nontuberculous mycobacteria (NTM), particularly Mycobacterium avium complex (MAC), are associated with and may cause nodular bronchiectasis. MAC may present with bronchiectasis, particularly of the lingula and right middle lobe, in immunocompetent individu-als without preexisting lung disease. The typical patient is an elderly, thin, white woman. A joint statement on NTM disease by the American Thoracic Society and the Infectious Disease Society of America emphasized the role of NTM in bronchiectasis.DIAGNOSISThe diagnosis of bronchiectasis should be considered in individuals presenting with chronic cough and sputum production. Other symptoms may include dyspnea, hemoptysis, and systemic symptoms such as fatigue or malaise. Among adults, bronchiectasis is more common in women than men. Idiopathic bron-chiectasis occurs most frequently in middle-aged women who are lifelong nonsmokers. HRCT is the BILATERAL SEVERE BRONCHIECTASISExtensive bronch-iectasis in a patientwith rheumatoidarthritisDilated and inflamedairways throughout thelungs, which are filled with pus and retained secretions.154 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONSPlate 4-44 Respiratory Systemgold standard for diagnosis of bronchiectasis. Plain radiography is insuffi ciently sensitive, and contrast bronchography no longer plays a role. The extent of disease on HRCT has been correlated with functional change and clinical outcomes.An underlying cause of bronchiectasis is more fre-quently identifi ed in children than in adults. In two series from the United Kingdom, among 136 children, the cause of bronchiectasis was identifi ed as an immu-nodefi ciency in 34%, aspiration in 18%, PCD in 16%, and idiopathic in 25%. In two adult series from the United Kingdom, idiopathic bronchiectasis was diag-nosed in 25% to 47% of individuals.Examinations to consider in patients with HRCT-diagnosed bronchiectasis may include a sweat chloride test and CF genetic analysis to evaluate for CF, nasal nitric oxide and nasal scrape for PCD, immuno-defi ciency evaluation (quantitative immunoglobulins with IgG subclasses, antibody response to vaccines with tetanus, H. infl uenzae), barium esophagram for gastro-esophageal refl ux, α1-antitrypsin levels, sputum culture, and acid-fast baeilli (AFB). In focal bronchiectasis, evaluation for an airway lesion should be considered.CLINICAL COURSEThe clinical course of non-CF bronchiectasis is highly variable, depending on the underlying cause and man-agement. Some individuals have daily symptoms, fre-quent exacerbations, and progressive loss of lung function, but others have minimal daily symptoms and relative preservation of lung function. Factors associated with more rapid decline in lung function include colonization with Pseudomonas aeruginosa, more frequent exacerbations, and evidence of systemic infl ammation.MANAGEMENTThere have been few randomized, controlled trials of therapies in individuals with bronchiectasis, partly because of the heterogeneity of the disease. Although the rationale for therapy may be similar in CF and non-CF bronchiectasis, therapies must be tested spe-cifi cally in this population. For example, because in general, lung function and mortality are less impacted in non-CF bronchiectasis, therapies may be best directed to decreasing exacerbation rates rather than slowing lung function decline. Whereas rhDNase is a mainstay of therapy in CF, it has been demonstrated to have an adverse safety profi le in adults with bronchiectasis.Airway ClearanceAlthough airway clearance techniques are a mainstay of treatment in non-CF bronchiectasis patients, there are no long-term trials in this population. There is also interest in inhaled hyperosmolar agents such as 7% saline and mannitol to rehydrate airway surface liquid. Mechanical clearance techniques, such as chest physi-otherapy and fl utter valves, are useful but less proven in non-CF bronchiectasis as important methods of airway clearance.Antibiotic TherapyTreatment of exacerbations should be undertaken with antibiotics tailored to the most recent sputum culture. The most common organisms isolated from patients with bronchiectasis include nonenteric gram-negative rods, S. aureus, and nontuberculous mycobacteria. About one-third of adults with bronchiectasis are chronically colonized with P. aeruginosa. For patients with chronic P. aeruginosa colonization, agents include intravenous antibiotics and oral ciprofl oxacin. A recent study showed modest microbial benefi t but no clinical benefi t to the addition of inhaled tobramycin to oral ciprofl oxacin for the treatment of acute exacerbations caused by infection with P. aeruginosa.The role of maintenance or prophylactic antibiotics is unclear. Several small pilot studies with agents, including inhaled tobramycin, inhaled colistin, and rotating oral antibiotics, have suggested potential for microbiologic and clinical stability, but longer term studies with more attention to acquisition of resistant organisms are needed.Antiinfl ammatory TherapyInhaled corticosteroids may reduce airway infl amma-tion and improve clinical outcomes in adults with bron-chiectasis, but the long-termsafety profi le is unclear. In small pilot studies, oral macrolides (erythromycin and azithromycin) may improve lung function and reduce exacerbations, but larger scale trials are needed. Caution must be taken to avoid improper treatment of unrecog-nized NTM infection, thus causing the emergence of resistant organisms.SurgerySurgery may be indicated for resection of areas of focal bronchiectasis that have led to uncontrolled infection or hemoptysis.Section through dilated bronchus.Epithelium is hyperplastic and lumencontains cellular exudate. Peribronchialarea shows replacement by looseconnective tissue with many lymphocytes,both disseminated and aggregatedinto folliclesFocal bronchiectasis. Saccular dilatations of bronchi, confined to left lower lobe. Such limited pathology may be amenable to surgeryLOCALIZED BRONCHIECTASISBRONCHIECTASIS (Continued)THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 155Plate 4-45 Diseases and PathologyCYSTIC FIBROSISCystic fi brosis (CF) is the most common autosomal recessive life-shortening disease among whites but also affects all races. There are approximately 30,000 individuals in the United States with diagnosed CF. Progress in the understanding of the underlying genetic defect and pathophysiology and the impact of this knowledge on CF care have been rapid over the past 20 years, resulting in remarkable improvements in quality of life and survival. These gains have converted CF from a respiratory and digestive disease of young chil-dren to a complex, multisystem disorder extending into adulthood.GENETICSCF is caused by mutations in the CF transmembrane conductance regulator (CFTR), a 230-kb gene on chro-mosome 7 encoding a chloride channel expressed in epithelial cells in the sweat duct, airway, pancreatic duct, intestine, biliary tree, and vas deferens. More than 1000 mutations in CFTR have been described, although far fewer have been clearly identifi ed as causing disease. These mutations can be grouped into six classes based on their function (Plate 4-45). The level of functional CFTR is important in determining the manifestations of CF, and the broad spectrum of disease related to CFTR dysfunction is increasingly being recognized (Plate 4-45). Attempts to predict the severity of lung disease, the major cause of morbidity and mortality in CF, from the CFTR genotype have been unsuccessful. It is likely that environmental factors and modifi er genes play important roles in determining the pheno-type of patients with CF.DIAGNOSISUpdated guidelines for the diagnosis of CF have recently been published. Although symptoms sugges-tive of CF include poor weight gain, steatorrhea, rectal prolapse, chronic cough, and recurrent sinusitis, CF is increasingly diagnosed via prenatal or newborn screen-ing. Until the advent of widespread newborn screening for CF, suspicion for CF arose only from the appearance of symptoms or a family history of the disease. But by 2010, newborn screening for CF will be universal throughout the United States, and most indi-viduals will enter the diagnostic algorithm because of a positive newborn screen result. The primary test for establishing the diagnosis of CF remains the sweat chloride test, which is performed by the pilocarpine iontophoresis method. The identifi cation of two CF disease-causing mutations can also establish the diagnosis.CLINICAL MANIFESTATIONSManifestations of CF may include chronic sinusitis, recurrent nasal polyposis, progressive obstructive pulmonary disease, exocrine pancreatic insuffi ciency, Class IIClass IIIClass IVClass VIClass I Absent protein synthesis due to defective transcription; Class II Defective protein maturation and degradation;Class III Defective regulation; Class IV Defective chloride conductance; Class V Reduced protein synthesis due toreduced transcription; Class VI Defective chloride channel stabilityCFTR mutation classesPATHOPHYSIOLOGY AND CLINICAL MANIFESTATIONS OF CYSTIC FIBROSISCFTR activityPathogenesisClinical manifestationsNo symptomsChronic sinusitisFocal biliarycirrhosisPortalhypertensionCholestasisRectal prolapseNasal polyposisRisk forpancreatitis,sinusitis,lungdisease,and ABPACongenital bilateralabsence of vasdeferens50%(heterozygote)10%Abnormalsweat chloride,lung disease5%Classic CF withpancreaticinsufficiencyDefectiveCFTRgene1%Endoplasmic reticulum Golgi complexProteasomeRegulationInflam-mationImpairedmucociliaryclearanceBacterial infectionCl–Cl–Cl–CFTRSweat glands NaClChronic obstructive lung diseaseBronchiectasisExocrine pancreatic insufficiencyCF-related diabetes mellitusMeconium ileusReduced fertility: Aspermia (in males) Cervicitis (in females)Defective ordeficientCFTRproteinAbnormalchloridetransportDepletionof airwaysurface liquidImpairedmucociliaryclearanceInfectionsInflammationBronchiectasisLung insufficencyMucusobstructionClass INucleusClass V156 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONSPlate 4-46 Respiratory Systembiliary disease, CF-related diabetes, and male infertility. Given the chronic, complex, multisystem nature of the illness, patients with CF should be followed in a special-ized CF center, such as those accredited in the United States by the Cystic Fibrosis Foundation.PULMONARY DISEASELung disease is the primary cause of morbidity and mortality in people with CF. It is characterized by a vicious cycle of endobronchial bacterial infection and a vigorous host neutrophilic infl ammatory response, resulting in progressive structural damage (bron-chiectasis) and obstructive lung disease (see Plate 4-46). The airways of CF patients become infected with a distinctive spectrum of bacterial pathogens, generally acquired in an age-dependent fashion. Common patho-gens at an early age include Staphylococcus aureus and Haemophilus infl uenzae. Later, infection with Pseu-domonas aeruginosa becomes increasingly prevalent. At fi rst, P. aeruginosa infection is intermittent and non-mucoid, but it eventually becomes chronic and mucoid in phenotype. Acquisition of P. aeruginosa, particularly mucoid strains, is associated with more rapid clinical deterioration.Respiratory treatments vary by age and disease sever-ity; guidelines have recently been published. These treatments, although dramatically improving pulmo-nary outcomes over the past 2 decades, also represent the greatest challenge to patients and families. The inhaled therapies and airway clearance can take more than 1 hour each day and can cause fi nancial hardships. Chronic treatments may include airway clearance tech-niques; mucolytics such as inhaled rhDNase and hyper-tonic saline; and in patients chronically infected with P. aeruginosa, oral macrolides and alternate-month inhaled antibiotics.Individuals with CF intermittently experience epi-sodes of increased cough, increased sputum production, and decline in lung function, often in conjunction with anorexia and fatigue, termed a pulmonary exacerbation. Milder exacerbations are typically treated with oral or inhaled antibiotics coupled with increased airway clear-ance. Severe exacerbations or those that fail to resolve with outpatient therapy require treatment with intrave-nous antibiotics, generally in the inpatient setting. In an effort to slow or avoid the decline in lung function associated with chronic Pseudomonas infection, fi rst acquisition of Pseudomonas spp. is treated with an eradi-cation protocol, which may include oral, inhaled, or intravenous antibiotics, often in combination.Complications include hemoptysis and pneumotho-races. Bilateral lung transplantation is an option for some CF patients with end-stage lung disease.GASTROINTESTINAL DISEASEApproximately 20% of infants with CF present acute intestinal obstruction caused by meconiumileus in the neonatal period. Exocrine pancreatic insuffi ciency occurs in approximately 90% of individuals affected with CF. Patients with two severe CFTR mutations (class 1, 2, or 3) present with pancreatic insuffi ciency, Gross lung section.Dilated bronchi filled withpus and foci of consolidationBilateral, severe bronchiectasisseen on chest CT in a youngpatient with cystic fibrosisPus-filledbronchiRADIOGRAPHIC AND GROSS ANATOMIC FINDINGS OF THE LUNG IN CYSTIC FIBROSISCYSTIC FIBROSIS (Continued)THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 157Plate 4-47 Diseases and Pathologyand those with one or more mild mutations (class 4 or 5) may be pancreatic suffi cient. Pancreatic insuffi ciency places CF patients at risk for fat malabsorption, sub-optimal nutrition, and inadequate circulating levels of fat-soluble vitamins. CF patients with pancreatic insuf-fi ciency are treated with a high-fat, high-calorie diet and pancreatic enzyme replacement therapy in the form of capsules taken with each meal. Patients with pancreatic suffi ciency are at increased risk of acute or chronic pancreatitis.Some level of liver disease is common in CF patients, with the prevalence increasing with advancing age. Abnormalities may include elevated transaminases, hepatosteatosis, or biliary tract disease. Cholelithiasis is also common. A small number of patients develop frank biliary cirrhosis with portal hypertension. Man-agement of CF liver disease often includes ursodeoxy-cholic acid.ENDOCRINE DISEASEThe prevalence of CF-related diabetes also increases with advancing age. The prevalence is 9% at ages 5 to 9 years, increasing to 43% for age older than 30 years. CF-related diabetes is a risk factor for more accelerated decline in lung function and higher mortality. There-fore, routine screening is recommended. Treatment generally involves maintenance of a high-fat, high-calorie diet plus insulin therapy.Osteopenia is also an increasingly recognized com-plication of CF. The cause is likely related to poor nutritional status, malabsorption of vitamins K and D, delayed pubertal maturation, steroid exposure, inactiv-ity, and chronic pulmonary infl ammation. Routine screening is recommended, and prevention via aggres-sive nutritional interventions, fat-soluble vitamins, and maximization of pulmonary health is critical.FERTILITYAt least 98% of men with CF are infertile because of absence or atresia of the vas deferens and absent or dilated seminal vesicles. Men with CF can become fathers with artifi cial insemination procedures. Female reproduction is normal, and an increasing number of women with CF are becoming mothers.PROGNOSISSurvival of patients with CF has made continuous, sustained improvements over the past 50 years, with median survival in the United States improving from 8 years in 1969 to more than 37 years today (see Plate 4-47). Female survival has been lower than male, but this “gender gap” appears to be closing. Potential contributors to improved survival include CF center care, aggressive nutritional support, and the intro-duction of new pulmonary therapies. Major quality improvement initiatives, the widespread uptake of newborn screening, and new therapies aimed at restor-ing CFTR function and combating chronic infl amma-tion are sure to result in continued improvements in quality of life and survival for individuals with CF.CYSTIC FIBROSIS: CLINICAL ASPECTSChest physiotherapyAerosol treatment4036322824'86 '88 '90 '92YearMedian survival age (years)'94 '96 '98 '00 '02 '04 '06 '08Median predicted survival age, 1986–2008Sweat testThe median predicted survival is 37.4 years for 2008. This represents the age by which half of the currentCF Registry population would be expected to be dead, given the ages of the patients in the Registry andthe mortality distribution of the deaths in 2008. The whiskers represent the 95 percent confidence boundsfor the survival estimates, indicating that the 2008 median survival is between 35.0 and 40.1.Data from Cystic Fibrosis Foundation, 2009. Annual data report to the center directors. Bethesda, MD: Cystic Fibrosis Foundation 2009.CYSTIC FIBROSIS (Continued)158 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONSPlate 4-48 Respiratory SystemLUNG CANCER OVERVIEWLung cancer is the most common cause of cancer death in the world, with estimated total deaths of 1.18 million by GLOBOCAN of the International Agency for Research on Cancer (IARC). In the United States, there will be an estimated 222,000 new diagnoses and 157,000 deaths in 2010. Lung cancer is a lethal disease, with only 6% of all new cases surviving 5 years in the United States. The average 5-year survival rate in Europe is 10% and is 8.9% in developing countries. Lung cancer causes more deaths than the four next most common cancers combined (colorectal, breast, prostate, and pan-creas). These numbers are staggering, especially because it was a rare disease in the early 1900s.Cigarette smoking has been identifi ed as the single most common etiologic agent and is estimated to cause 85% to 90% of all cases. Radon is reported to cause 10% of lung cancers. Other etiologic agents are of less frequency and are primarily occupational exposures (e.g., arsenic, asbestos, chromium, nickel, coal, tar). For a complete list of carcinogens to humans, refer to the IARC (http://monographs.iarc.fr). Secondhand smoke increases the risk of lung cancer by 30% or a relative risk of 1.3 versus a never smoker with no secondhand exposure. Lung cancer risk increases with age. Less than 5% of lung cancer occurs before the age of 40 years, and the average age at diagnosis in the United States is 68 years. Family history (genetics) is a risk factor and responsible for a two- to threefold relative risk increase if lung cancer has been diagnosed in a fi rst-degree relative, especially if he or she was at a younger age at diagnosis. The genetic predisposition of lung cancer is a subject of intense research, but to date, a lung cancer gene has not been identifi ed. The gene 15q 24-25 encompasses the nicotinic acetylcholine receptor gene that has a role in nicotine addiction and has been associated with lung cancer risk, but it is cur-rently uncertain if this gene is directly related to lung cancer, independent of nicotine use.Overwhelming evidence suggests that cigarette smoking is the major cause of lung cancer. The lung cancer epidemic in Western countries parallels the inci-dence of smoking but lags by about 20 to 30 years. The relative risk among smokers compared with people who have never smoked is 10 to 15 times higher and is dependent on the age of onset of smoking, dose, and duration (pack-years). Stopping smoking has been shown to decrease the relative risk, but the risk does not return to that of someone who has never smoked unless one quits at an early age. Tobacco smoking increases the risk of all major histologic cell types, but the strong-est association is with small cell and squamous cell and less strongly with adenocarcinoma. The most common histology in a never smoker is adenocarcinoma.The frequency of lung cancer in women has risen dramatically in most Western countries over the past 4 to 5 decades. Globally, it is still a male-predominant disease (male : female ratio, 2-3 : 1). However, in the United States, women constitute 45% of all new lung cancer diagnoses. Lung cancer has surpassed breast cancer as the most common cause of cancer death, which occurred in the United States in the mid 1980s. Currently, 72,000 women die of lung cancer versus 40,000 deaths from breast cancer per year. Although there has been some controversy, recent studies have not shown a difference in risk between men and women who have smoked a similar amount. There is no clear evidence of ethnic differences in susceptibility to this disease.The signs and symptoms of lung cancer are myriad, but the most common are new cough, dyspnea, hemo-ptysis, chest pain, or weight loss. Paraneoplastic symp-toms of lung cancer are discussed later. Symptomatic lung cancer usually results in an abnormal chest radio-graph. Approximately 15% to 20% of lung cancers are asymptomatic when they are detected by an incidental chest radiograph or computed tomography scan done for other reasons. Methods of diagnosis include sputum cytology, thoracentesis if pleural fl uid is present, bron-choscopy, transthoracic needle aspiration, or needle aspiration and biopsy of distant metastatic sites. In some cases, the diagnosis is made at the time of surgical resection.The World Health Organization histologic classifi -cation of lung tumors is the generally accepted stand-ard. Lung cancer is classifi ed as small cell and non–small cell. Non–small cell lung cancer includes squamous cell, adenocarcinoma, large cell, adenosquamous carcinoma, and sarcomatoid carcinoma. Small cell histology gener-ally has the fastest growth rate, but tumor doubling times can vary tremendously within the same cell type. The slowest growing types have been bronchioloalveo-lar carcinoma (subtype of adenocarcinoma) and super-fi cial squamous carcinoma (in situ), but again, the variability in growth rate can be enormous.BreastLung and bronchusPer capita cigaretteconsumptionMale lung cancerdeath rateFemale lung cancerdeath rateStomachUterusPancreasOvary StomachLung and bronchusColon and rectumColon and rectumProstatePancreasLiverLeukemiaSquamous cell Small cell Adenocarcinoma19301008040200*Age-adjusted to 2000 US standard population.Source: US Mortality Data 1960–2004,US Mortality Volumes 1930–1959, National Centerfor Health Statistics, Centers for Disease Controland Prevention, 2006.60Rate per 100,000Cancer death rates* among men, US, 1930–20041935194019451950195519601965197019751980198519901995200019301008040200*Age-adjusted to 2000 US standard population.Source: US Mortality Data 1960–2004,US Mortality Volumes 1930–1959, National Centerfor Health Statistics, Centers for Disease Controland Prevention, 2006.*Age-adjusted to 2000 US standard population.Source: Death rates: US Mortality Data,1960–2004, US Mortality Volumes, 1930–1959,National Center for Health Statistics, Centers forDisease Control and Prevention, 2006. Cigaretteconsumption: US Department of Agriculture,1900–2004.60Rate per 100,000Cancer death rates* among women, US, 1930–20041935194019451950195519601965197019751980198519901995200019005000400045002000250010001500500030003500Per capita cigarette consumptionAge-adjusted lung cancer death rates*Tobacco use in the US, 1900–2004190519101915192019251930193519401945195019551960196519701980197519851990199520000102030405060708090100Large cellCLASSIFICATION OF BRONCHOGENIC CARCINOMA THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 159Plate 4-49 Diseases and PathologyLUNG CANCER STAGINGIn 2010, the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC) published the revised seventh edition of the TNM (tumor, node, metastasis) staging system. This seventh edition was developed on the basis of the Inter-national Association for the Study of Lung Cancer (IASLC) and proposed changes to the classifi cation from analysis of more than 67,000 cases of non–small cell lung cancer from around the world. This was the largest data set ever analyzed for the purpose of devel-oping and validating a new staging system. The pro-posed new TNM staging system has also been validated for small cell carcinoma and bronchial carcinoid tumors. The primary determinant of each T, N, and M descrip-tor, as well as the overall stage grouping, was based on survival. Detailed algorithms were used to identify unique stages in the simplest way with the least overlap. Stages were internally and externally validated for out-comes across the various databases and geographic regions from which the data were gathered.There were a number of substantial changes made to the former (sixth) staging system:• T1 tumors were divided into T1a (tumors ≤2 cm in greatest diameter) and T1b (tumors >2 cm but ≤3 cm in greatest dimension).• T2 tumors were divided into T2a (tumors >3 cm but ≤5 cm in greatest diameter) and T2b (tumors >5 cm but ≤7 cm in greatest dimension).• Tumors more than 7 cm in greatest dimension are classifi ed as T3.• Tumors with additional nodule(s) in the same lobe are classifi ed as T3.• Tumors with additional nodule(s) in another ipsi-lateral lobe are classifi ed as T4.• Pleural dissemination (malignant pleural or peri-cardial effusions, pleural nodules) is classifi ed as M1a.• The lymph node classifi cation remained the same, with N1 as intrapulmonary or ipsilateral hilar, N2 as ipsilateral mediastinal or subcarinal, and N3 as contralateral mediastinal or supraclavicular.• Incorporated proposed changes to T and M (affects T2, T3, T4, and M1 categories).• Reclassify T2aN1 tumors (≤5 cm) as stage IIA (from IIB).• Reclassify T2bN0 tumors (>5 cm to 7 cm) as stage IIA (from IB).• Reclassify T3 (tumor >7 cm) N0M0 as stage IIB (from IB).• Reclassify T4N0 and T4N1 as stage IIIA (from IIIB).• Reclassify pleural dissemination (malignant pleural or pericardial effusions, pleural nodules) from T4 to M1a.• Subclassify M1 by additional nodules in contra-lateral lung as M1a.• Subclassify M1 by distant metastases (outside the lung/pleura) as M1b.Because of the addition of new T and M descriptors, the staging defi nitions have clearly become more complex. However, the new system now provides a more validated system for defi ning prognosis. In addi-tion, the system also allows common terminology to be used across the world to describe similar patients, which is critical for accurate communication across the medical community and the conduct of worldwide clinical trials. A future goal is the further refi nement of the classifi cation system to include the biologic behavior of lung tumors, not just anatomic location, which should promote understanding of tumor biology and provide guidance toward more specifi c therapies.Brachiocephalic (innominate) arterySuperior mediastinal nodesInferior mediastinal nodesN1 nodesBrachiocephalic(innominate) veinAortic archTracheaLigamentum arteriosumMediastinal pleural envelopeMediastinal pleural envelopeCarinaEsophagusPulmonary ligamentMain bronchusLobar bronchiRight pulmonary arteryRight primary bronchusLeft pulmonary arterySegmental bronchiLeft primary bronchusBrachiocephalic(innominate) arteryAortic archLigamentum arteriosumMediastinal pleural envelopeRight pulmonary arteryAnatomy of lymph node stations relevant to lung cancer staging. The IASLC proposes grouping the lymphnodes into the zones shown in bold and circled to assist with prognosis.Aortic nodesLeft pulmonary arteryBrachiocephalic(innominate) vein160 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONSPlate 4-50 Respiratory SystemSQUAMOUS CELL CARCINOMA OF THE LUNGSquamous cell carcinoma (SCC) is defi ned as a malig-nant epithelial tumor showing keratinization or intra-cellular bridges (or both) arising from bronchial epithelium. Previously, SCC, sometimes called epider-moid carcinoma, was the most common cell type, but that has changed in the past 1 or 2 decades in the United States, parts of Western Europe, and Japan. Currently, SCCs account for 20% of all lung cancers in the United States (http://seer.cancer.gov). The vast majoritylife-threatening exacerbations. An asthmatic exacer-bation can be a terrifying experience, especially for patients who are aware of its potentially progressive nature.Symptoms of an asthmatic exacerbation most often develop gradually but occasionally can be sudden in onset. Most often asthma exacerbations are preceded by viral upper respiratory tract infections. Many patients complain of a sensation of retrosternal chest tightness. Expiratory and often inspiratory wheezing is audible and is associated with variable degrees of dyspnea. Cough is likely to be present and may be productive of purulent sputum.In severe asthma exacerbations, the patient prefers to sit upright; visible nasal alar fl aring and use of the acces-sory respiratory muscles refl ect the increased work of breathing. Anxiety and apprehension generally relate to the intensity of the exacerbation. Tachypnea may be the result of fear, airway obstruction, or changes in blood and tissue gas tensions or pH. Hypertension and tachy-cardia both refl ect increased catecholamine output, although a pulse rate greater than 110 to 130 beats/min may indicate signifi cant hypoxemia (PaO2 60 L/min) after inhalation of a β2-agonist or diurnal variation in PEF of more than 20% over 2 weeks of measurements also confi rms variable airfl ow obstruction.AIRWAY HYPERRESPONSIVENESSFor patients with symptoms consistent with asthma but normal lung function, measurements of airway responsiveness to direct airway challenges (e.g., inhaled methacholine and histamine) or indirect airway chal-lenges (e.g., inhaled mannitol or exercise challenge) may help establish a diagnosis of asthma (Plate 4-17). Measurements of airway responsiveness refl ect the “sensitivity” of the airways to factors that can cause asthma symptoms, and the test results are usually expressed as the provocative concentration (or dose) of the agonist causing a given decrease in FEV1. These tests are sensitive for a diagnosis of asthma but have limited specifi city. This means that a negative test result can be useful to exclude a diagnosis of persistent asthma in a patient who is not taking inhaled glucocorticoster-oid treatment, but a positive test result does not always mean that a patient has asthma. This is because airway hyperresponsiveness has been described in patients with allergic rhinitis and in those with airfl ow limitation VARIABLE AIRFLOW OBSTRUCTION AND AIRWAY HYPERRESPONSIVENESSMethacholine and exercise challengesMethacholine (mg/mL)Baseline BronchoconstrictionExercise at 85% of predicted maximal heart rate or 80% of MVV for 6-8 minutes. Spirometry measured at baseline and at 5-minute intervalsafter exercise. Positive challenge is a fall inFEV1 by �15% from baselineInhalation of nebulized methacholine atincreasing doses. Each dose is followed byspirometry. Fall in FEV1 by �20% frombaseline at a concentration of �8mg/mLis a positive response12�10� 8� 6� 4� 222 3 4 5 614681012Flow (L/S)Volume (L)02 3 4 5 6124Volume (L)PredictedPredictedActualActualPEFFVCFEV1Time (sec)5060801002 4 8 161% Baseline FEV1 NormalAsthmaTime (min)1 3 5 10 150FEV1 (L/S)NormalExercise6-8 minAsthmaBRONCHIAL ASTHMA (Continued)128 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONSPlate 4-18 Respiratory Systemcaused by conditions other than asthma, such as cystic fi brosis, bronchiectasis, and chronic obstructive pulmo-nary disease (COPD).INVESTIGATIONS THAT MAY BE CONSIDERED TO ESTABLISH A DIAGNOSISRadiographyThe primary value of radiography is to exclude other diseases and to determine whether pneumonia, atel-ectasis, pneumothorax, pneumomediastinum, or bron-chiectasis exists. In mild asthma, the chest radiograph shows no abnormalities. With severe obstruction, however, a characteristic reversible hyperlucency of the lung is evident, with widening of costal interspaces, depressed diaphragms, and increased retrosternal air. In contrast to pulmonary emphysema, in which vascular branching is attenuated and distorted, vascular caliber and distribution in asthma are generally undisturbed.Focal atelectasis, a complication of asthma, is caused by impaction of mucus. In children, even complete col-lapse of a lobe may be observed. Atelectatic shadows may be transient as mucus impaction shifts from one lung zone to another. When sputum is mobilized, these patterns resolve.Radiography is also useful in evaluating coexisting sinusitis. An upper gastrointestinal series may be indi-cated if gastroesophageal refl ux is suspected. A lung ventilation-perfusion scan or computed tomography angiogram may be required if pulmonary emboli are believed to mimic asthma.SputumSpontaneously produced as well as induced sputum can beof SCC occurs in smokers. Recent Surveil-lance, Epidemiology and End Results (SEER) data report that SCC accounts for 24% of all cancers in men versus 16% in women. The recent decrease in SCC and increase in adenocarcinoma histology has been attributed to the change in the cigarette, from nonfi lter to fi lter, and the decrease in tar. About 60% to 80% of these cancers arise centrally in mainstem, lobar, or seg-mental bronchi, but they may present as a peripheral lung lesion.SCC arises from the bronchial epithelium, and it is thought that the airway abnormality progresses through a series of changes from hyperplasia to dysplasia to carcinoma in situ, which is classifi ed by World Health Organization as preinvasive and a precursor to SCC. Varying degrees of dysplasia have been associated with cumulative genetic alterations, but the critical genetic change(s) before developing frank cancer is still uncertain.Because of the tendency to occur centrally in the airway, SCC presents more commonly with hemopty-sis, new or change in cough, chest pain, or pneumonia caused by bronchial obstruction. The usual radio-graphic presentation is a central mass or obstructing pneumonia with or without lobar collapse. About 10% to 20% of SCCs present as peripheral lesions. Cavita-tion may occur in 10% to 15% of all SCCs and is the most common histology associated with cavitation. The cavities are usually thick walled. Cavitation in the lung may also be caused by obstructive pneumonia and abscess formation.Sputum cytology has the highest diagnostic yield with this cell type because of the predominant central location. Bronchoscopy with brushings and biopsy are diagnostic in more than 90% of SCCs when the cancer is visible endoscopically. The yield for peripheral lesions that are endoscopically negative is signifi cantly less and depends on the size of the tumor. For lesions smaller than 2 cm in diameter, transthoracic needle aspiration has the highest diagnostic yield if a tissue diagnosis is required before surgical resection.SCC in situ (pre invasive lesion) has an unpredictable course, and the treatment is a topic of current debate. Surgery is the treatment of choice for early-stage disease (stage I or II). Combination chemotherapy and radiotherapy are recommended for good performance score patients with unresectable stage III A or B disease. Stage IV (metastatic disease) is generally treated with systemic chemotherapy, but treatment is noncurative (palliative).It was previously believed that SCC was more slow-growing than other cell types, but recent analysis of a large international database that controlled for stage of disease does not demonstrate defi nite survival benefi t of SCC versus other non–small cell histolo-gies. In the past, SCCs have been treated the same as all other non–small cell histologies, but recent data show that optimal treatment depends on specifi c typing.Tumortypicallylocatednear hilus,projectinginto bronchiBronchoscopic viewCarcinoma in peripheral zone ofright upper lobe with cavitationBronchoscopic viewCombined CT/PET image showing a squamouscell carcinoma (bright area) of the left lung.Tumor typically located nearhilum, projecting into bronchi THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 161Plate 4-51 Diseases and PathologyADENOCARCINOMA OF THE LUNGAtypical adenomatous hyperplasia is classifi ed by the World Health Organization (WHO) as a putative pre-cursor of adenocarcinoma (ACA), especially bron-chioloalveolar carcinoma (BAC). ACA is defi ned as a malignant epithelial tumor with glandular differentia-tion or mucin production. ACA is the most common cell type in the United States and many developed countries. It accounts for 37% of all lung cancers in the Surveillance, Epidemiology and End Results (SEER) database (40% in women; 33% in men; http://seer.cancer.gov). ACA histology is associated with cigarette smoking, but the association is not as strong as it is for squamous cell and small cell carcinoma. ACA is the most common histology of lung cancer in never smokers, especially women.Bronchioloalveolar cell, also called alveolar cell, is classifi ed by the WHO as a subtype of ACA. BACs are mostly moderate or well-differentiated tumors and grow along preexisting alveolar structures (lepidic growth) without evidence of invasion. If there is evi-dence of invasion, then the tumor is classifi ed as ACA mixed type. Pure BAC by the current classifi cation is a rare tumor; most are ACA mixed type. It is anticipated that pure BAC will be renamed as adenocarcinoma in situ in the new classifi cation.ACAs are usually peripherally located in the lungs. Because of the peripheral location, more of the patients are asymptomatic, and the lesion is detected on an inci-dental chest radiograph. Patients may present with a new cough, chest pain, or less commonly hemoptysis. Presenting symptoms caused by distant metastases to the bone, brain, or liver are common with all cell types, especially ACA and large cell carcinoma. Individuals with BAC may present with an asymptomatic solitary pulmonary nodule, pneumonia such as consolidation of the lung, or rarely with a profound bronchorrhea. Bronchorrhea is usually seen in those with extensive bilateral lung involvement.The most common radiographic presentation is a peripheral lung nodule or mass (mass defi ned as ≥3 cm) in maximum diameter. It may infrequently present as a central mass and rarely cavitates. ACA is the most common cell type to present with a malignant pleural effusion.Sputum cytology results are rarely positive. Diagnos-tic yields with bronchoscopy are less than with squa-mous cell or small cell carcinoma because of the peripheral location. For lesions that are 2 cm in diam-eter or larger, the diagnostic yields are approximately 60% to 70%. Transthoracic needle aspirations (TTNAs) are diagnostic in 85% to 90% of all lesions and are the preferred diagnostic test for lesions smaller than 2 cm in diameter. The benefi ts of TTNA should be balanced against the risk of pneumothorax, especially in patients with chronic obstructive pulmonary disease or emphy-sema. Thoracentesis and pleural fl uid cytology is the preferred diagnostic test in individuals with pleural effusion.The treatment of choice for patients with stage I, II, or IIIA/B is generally the same as for all non–small cell lung cancers. Patients with stage IV (metastatic) disease have generally been treated with systemic chemother-apy as palliative treatment. In recent years, a number of genetic alterations have been identifi ed in the tumor that are changing the treatment approach. Some ACAs have been identifi ed to have a mutation in the intracel-lular domain of the epidermal growth factor receptor (EGFR) gene. The predominant mutations include in frame deletions of exon 19 and missense mutation in exon 21. These mutations have been associated with a high response rate to treatment with the EGFR tyro-sine kinase inhibitors (TKIs) gefi tinib and erlotinib. For reasons that are currently unknown, the frequency of the EGFR tyrosine kinase mutations vary in different ethnic populations. The frequency of mutation in North America and Europe is approximately 15% of all ACA versus 30% of ACA in East Asians. These mutations are almost exclusively limited to the ACA cell type.Recent reports have documented better survival in individuals when these EGFR mutations are treated initially with EGFR TKIs versus conventional chemo-therapy. Other studies have shown that KRAS muta-tions, which occur in 20% to 30% of patients with ACA, confer resistance to treatment with the EGFR inhibitors. Mutations in KRAS and EGFR are almost always mutually exclusive. It is very likely that future identifi cation of genetic mutations or identifi cation of predominant intracellular pathways of malignant cells will infl uence thechoice of treatment of ACA and other histologies. Most recently a mutation of anaplastic lym-phoma kinase (ALK) has been identifi ed in 3% to 5% of ACA, and promising new treatment with the tyrosine kinase inhibitor crizotinib has been reported.Small, peripherally placed tumorHistology of adenocarcinoma. Tumor cells form glandlike structureswith or without mucin secretionPeripheral adenocarcinoma with mediastinalnodal metastases seen on combined CT andPET imaging (bright areas)Different histologic types of bronchogenic carcinoma cannot be distin-guished by gross specimens or radiography alone. However, a peri-pherally located tumor 4 cm in diameter is most likely to beadenocarcinoma162 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONSPlate 4-52 Respiratory SystemLARGE CELL CARCINOMAS OF THE LUNGLarge cell carcinoma is a malignant epithelial undif-ferentiated neoplasm lacking glandular or squamous differentiation and features of small cell carcinoma. It is a diagnosis of exclusion and includes many poorly differentiated non–small cell carcinomas. Several variants are recognized, including neuroendocrine differentiation (large cell neuroendocrine carcinoma [LCNEC]) and basaloid carcinoma), but it is uncertain if this differentiation is of prognostic or therapeutic importance. Large cell carcinoma and its variants can only be diagnosed reliably on surgical material; cytol-ogy samples are not generally suffi cient. LCNEC is differentiated from atypical carcinoid tumor by having more mitotic fi gures, usually 11 or more per 2 mm2 of viable tumor, and large areas of necrosis are common. Neuroendocrine differentiation is confi rmed using immunohistochemical markers such as chromogranin, synaptophysin, or CD56. Patients with LCNEC have a worse prognosis than those with atypical carcinoid tumors. Large cell carcinoma is associated with ciga-rette smoking. This cell type accounted for 4% of all lung cancers in the Surveillance, Epidemiology and End Results (SEER) database. The SEER database listed the cell type of 24% of all lung cancers as “other non–small cell.” These other cancers include non–small cell cancers that pathologists specify as NOS (not otherwise specifi ed). As treatment moves toward spe-cifi c treatment for specifi c cell types, it will be impor-tant for pathologists to classify the histology as accurately as possible and to decrease the percentages of cases reported as NOS.The signs and symptoms of this cell type are similar to those of other non–small cell carcinomas. The most common radiographic fi nding is a large peripheral lung mass. Because of the peripheral location, these cancers may be asymptomatic and detected on an incidental chest radiograph. Because of the rapid growth of this cell type, the radiographic lesion may appear rather suddenly (within a few months) or enlarge rapidly.Diagnostic procedures are similar to those of other histologic types. Sputum cytology is not generally helpful because of the peripheral location, and bron-choscopic diagnostic yields are similar to those for peripheral adenocarcinomas and squamous cell carcino-mas (∼60%-70%). Transthoracic needle aspiration is diagnostic in the majority of cases. These cancers are usually aggressive tumors with a strong tendency for early metastases. Nevertheless, surgery is still the treat-ment of choice for patients with early-stage disease. Currently, there is no convincing evidence that patients with LCNEC should be treated differently than those with any other large cell carcinoma. Patients with stage III and IV disease are treated the same as those with other non–small cell types. Patients with stage III are treated with combined chemotherapy and thoracic radiotherapy. Survival is similar to that of patients with other non–small cell lung cancers, and patients with stage IV are treated with chemotherapy with palliative intent.Tumors are variable in locationTumor composed of large multinucleated cellwithout evidence of differentiation toward glandformation or squamous epithelium. These cellsproduce mucin (stained red). Some tumors may becomposed of large clear cells containing glycogenLarge cell carcinoma in middle of right upper lobe with extensiveinvolvement of hilar and carinalnodes. Distortion of tracheaand widening of carinaTHE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 163Plate 4-53 Diseases and PathologySMALL CELL CARCINOMAS OF THE LUNGSmall cell carcinoma is defi ned as a malignant epithelial tumor consisting of small cells with scant cytoplasm. If other histologic types of non–small cell carcinoma are also present, then it is classifi ed as combined small cell carcinoma. The cells contain neuroendocrine granules, and it is usually considered as a neuroendocrine tumor at the most malignant end of the neuroendocrine spec-trum. It usually stains positive for the neuroendocrine markers CD56, chromogranin, and synaptophysin. This cell type has the strongest association with ciga-rette smoking and rarely occurs in people who have never smoked. Small cell histology accounts for 14% of all lung cancers (13% in men; 15% in women) in the Surveillance, Epidemiology and End Results database (http://seer.cancer.gov). This cell type generally has the fastest growth rate and a tendency to early spread.Small cell carcinoma is centrally located in the large majority of cases and therefore present with symptoms of cough, hemoptysis, chest pain, or obstructive pneu-monia. Because of the tendency for early spread, many individuals present with signs and symptoms of regional or distant metastasis. Mediastinal lymph node spread may result in hoarseness or a change in voice caused by vocal cord paralysis, dysphagia caused by esophageal compression, or superior vena cava syndrome (dis-cussed later). Symptoms caused by brain, bone, or liver metastases may be the fi rst signs of the disease. Small cell carcinoma is the most common cell type associated with paraneoplastic syndromes (discussed later).Ten percent or fewer of small cell carcinomas present as a peripheral mass or solitary pulmonary nodule. Supraclavicular lymph node metastases may be present and are an easy source for tissue diagnosis. Sputum cytology is rarely positive. Bronchoscopy is the most common method of diagnosis. The tumor is frequently located submucosally, and bronchoscopic biopsies may not yield a diagnosis if deep submucosal samples are not obtained. Pleural fl uid cytology may be diagnostic; however, in many cases, the pleural fl uid is due to a parapneumonic effusion and not caused by malignant seeding of the pleural space.Small cell carcinoma is usually staged as limited or extensive stage disease. Limited disease is defi ned as disease confi ned to one hemithorax and mediastinal lymph nodes with or without ipsilateral supraclavicular nodes. It is generally disease that can be safely confi ned within a thoracic radiotherapy fi eld of treatment. Extensive stage is defi ned as spread of disease beyond the hemithorax with distant metastases. Malignant pleural effusion, cytologically documented, is consid-ered to be extensive stage.The treatment of limited stage disease is combined concurrent chemotherapy and thoracic radiotherapy in patients with a good performance score and minimal weight loss. Recent cooperative group trials of concurrent treatment have resulted in median survival times of 18 to 20 months and 5-year survival rates of 20% to 25%. For patients with extensive stage disease, the usual treatment is chemotherapy for four to six cycles with a platinum based doublet. The median sur-vival time is 8 to 10 months with 10% or less 2-year survival and virtually no 5-year survivors. Chemother-apy treatment for small cell carcinoma has plateaued with no major advances for the past 2 decades.Tumor withmetastasis to hilar andcarinal nodesand collapse ofright upperlobeIntrapulmonary lymphatic spread of neoplasmSmall cellcarcinoma seen by chest CTillustratingextensive hilarinvolvement andcollapse at leftupper lobeMasses of small cellswith hyperchromaticround to oval nucleiand scant cytoplasmBiopsy specimen.Cells elongated164 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONSPlate 4-54 Respiratory SystemSUPERIOR VENA CAVA SYNDROMESuperior vena cava (SVC) syndrome is caused by extrin-sic compression or internal thrombosis of the SVC, which compromises the venous drainage from the head and upper extremities. Lung cancer is responsible for the large majority of SVC syndrome in adults older than age 40 years. Lymphoma is the most common cause in younger individuals. Patients complain of a sensation of fullness in the head, cough, or dyspnea. They may experience lightheadedness, especially when bending over, or have edema and swelling in the head, neck, and arms. Edema of the larynx or pharynx may result in stridor, and cerebral edema may result in head-aches or confusion.Physical fi ndings include dilated neck veins and sub-cutaneous veins of the chest that persist with the patient in an upright position. Facial edema and a plethoric appearance may be present. Computed tomography chest scans with contrast injected through the arm veins show the mass with narrowing or obstruction of the SVC and the extensive venous collateral circulation of subcutaneous and mediastinal veins. If the SVC syn-drome is caused by a benign condition such as fi brosing mediastinitis, then a lung mass will not be identifi ed.Small cell carcinoma is the classic histology to cause SVC syndrome, but any histologic type may do so. Although SVC syndrome is a serious condition, it is not generally an emergency situation. Accordingly, a tissue diagnosis should be obtained before treatment begins. It is important to know if it is caused by lymphoma, small cell carcinoma, or non–small cell lung cancer before the appropriate treatment is instituted. SVC syndrome may occasionally be caused by other tumors (e.g., breast cancer, germ cell tumor), fi brosing medias-tinitis, or an infectious process (rarely). Bronchoscopy has a high diagnostic rate when SVC syndrome is caused by lung cancer. If bronchoscopy results are negative, then mediastinoscopy is the next logical pro-cedure in most cases.Treatment of patients with SVC syndrome should include stenting of the SVC early on in the process. This treatment quickly relieves the obstruction in more than 90% of cases. Chemotherapy alone as initial treat-ment is indicated for cases caused by small cell carci-noma or lymphoma, and radiotherapy or combined chemoradiotherapy is used for non–small cell lung cancer. Treatment should rarely be given without a tissue diagnosis. In patients with SVC syndrome caused by lung cancer, the long-term prognosis is related to the histologic type and stage of the disease at the time of initial diagnosis.Obstruction of superior venacava by cancerous invasion ofmediastinal lymph nodes withdistension of brachiocephalic(innominate), jugular, andsubclavian veins and tributariesEdema and rubor offace, neck, and upper chest. Arm veins fail to empty on elevationTHE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 165Plate 4-55 Diseases and PathologyPANCOAST TUMOR AND SYNDROMESuperior sulcus tumors are located at the apical pleuro-pulmonary groove adjacent to the subclavian vessels. Superior sulcus tumors received notoriety in reports by Henry Pancoast and are commonly referred to as Pan-coast tumors. Lung cancer is by far the most common cause of Pancoast and superior sulcus tumors. It is more commonly associated with adenocarcinoma but may be caused by any histologic type. A variety of other rare tumors or infectious diseases have occasionally been reported to cause a Pancoast tumor.Tumors of the superior sulcus may cause shoulder and arm pain (in the distribution of the C8, T1, and T2 dermatomes), Horner syndrome, and weakness of the muscles of the hand. This complex is referred to as Pancoast syndrome. Shoulder pain is the usual presenting symptom and is caused by tumor invasion of the tumor into the chest wall, fi rst and second ribs, vertebral body, and possibly the brachial plexus. Pain may radiate up to the head and neck or to the axilla and arm in the dis-tribution of the ulnar nerve. The cause of the pain is frequently misdiagnosed for months as osteoarthritis or bursitis of the shoulder. Horner syndrome consists of ipsilateral ptosis, miosis, enophthalmos, and anhidrosis of half of the face and head and is caused by involve-ment of the paravertebral sympathetic chain and the inferior cervical (stellate) ganglion. Contralateral facial sweating and fl ushing have been reported.Tumor involvement of the C8 and T1 nerve roots may result in weakness and atrophy of the intrinsic muscles of the hand or pain or paresthesias of the fourth and fi fth digits and medial aspect of the arm and forearm. Abnormal sensation or pain in the axilla and medial aspect of the upper arm caused by T2 nerve root involvement may be an early symptom. As these tumors progress, they may invade the intervertebral foramina and cause spinal cord compression and paraplegia. This may especially be a problem for patients with progres-sive disease who have failed local treatment. Tumors with progressive mediastinal involvement may result in phrenic nerve or laryngeal nerve paralysis.The classic radiographic fi nding is that of an apical mass or unilateral apical cap. Occasionally, the abnormality will not be obvious on a chest radiograph; therefore if the diagnosis is suspected, a computed tomography (CT) scan of the chest is required. The CT will demonstrate greater detail and is more likely to elucidate the extent of the tumor locally. Magnetic resonance imaging (MRI) is better at demonstrating brachial plexus involvement and evaluating the spinal canal for tumor extension. MR angiography is better for demonstrating subclavian vessel involvement. Bron-choscopy may be diagnostic for larger tumors, but transthoracic needle aspiration is the most common method of diagnosis of these apical tumors. The usual staging tests include a positron emission computed tomography (PET) scan and MRI of the brain because of the propensity for brain metastases.The treatment of patients with superior sulcus tumors caused by non–small cell lung cancer with no evidence of mediastinal nodal metastases is initial con-current chemotherapy and radiotherapy followed by surgical resection 3 to 5 weeks after induction therapy. The 5-year survival with this trimodality treatment is approximately 40%. Patients with documented medias-tinal lymph node involvement at initial presentation are treated with defi nitive chemoradiotherapy alone with somewhat inferior long-term survival. Patients with stage IV or metastatic disease at presentation are treated with palliative radiotherapy and systemic chemotherapy similar to other patients with stage IV disease.Vagus nerveSympathetic trunkBrachial plexusRecurrent nerveTumorSubclavian artery and veinPancoast syndrome. Horner syndrome, pluspain, paresthesias, and paresis ofarm and handCombined CT/PET images of Pancoast tumor(bright area) seen in coronal and axial viewsAxial CoronalPancoast tumor166 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONSPlate 4-56 Respiratory SystemPARANEOPLASTIC MANIFESTATIONS OF LUNG CANCERParaneoplastic effects of tumors are remote effects that are not related to direct invasion, obstruction, or metas-tases. Paraneoplastic syndromes occur in 10% to 15% of all lung cancers. The following are some of the most common.The syndrome of inappropriate antidiuretic hormone secretion (SIADH) may be caused by pulmonary infec-tions, central nervous system (CNS) disease or trauma, drugs, or lung tumors. Small celllung cancer is the most common malignancy to cause SIADH. The tumor secretes ectopic antidiuretic hormone (ADH; vaso-pressin), which exerts its action on the kidneys and enhances the fl ow of water from the lumen of the renal collecting ducts to the medullary interstitium with resulting concentration of the urine. Patients present with hyponatremia that is associated with low plasma osmolality and elevated urine sodium and osmolality. To make the diagnosis of SIADH, patients must also have normal renal, adrenal, and thyroid function. The symptoms of hyponatremia may include anorexia, nausea, vomiting, irritability, restlessness, confusion, coma, or seizures. The severity of symptoms is related to the degree of hyponatremia and the rapidity of the decrease in serum sodium. The treatment for mildly symptomatic patients is to restrict fl uid intake to 500 to 1000 mL/24 hours. For more severe or life-threatening symptoms, treatment consists of intravenous fl uids with normal saline and loop diuretics. For severe symptoms, some experts recommend 300 mL of 3% saline intra-venously, but extreme caution must be used because too rapid correction of serum sodium may be associated with central pontine myelinolysis, which is a devastat-ing CNS process that is often fatal. For patients with less severe symptoms from hyponatremia but requiring more than fl uid restriction, oral demeclocycline can be used. The onset of action may take from a few hours to a few weeks, and renal function should be monitored. The best treatment for SIADH, if the patient is stable, is to treat the small cell lung cancer with systemic chemotherapy. Regression of the tumor results in nor-malization of the sodium in most cases.Cushing syndrome may be related to ectopic produc-tion of corticotropin (adrenocorticotropic hormone) or corticotropin-releasing hormone by small cell carci-noma. It has also been reported with bronchial carci-noid tumors or carcinoid tumors of the thymus or pancreas. Small cell lung cancer accounts for 75% of all cases of Cushing syndrome caused by ectopic hormone secretion. Because of the rapid growth of small cell lung cancer, patients are more likely to present with edema, hypertension, and hyperglycemia with or without muscle weakness. This is in contrast to the classic fea-tures of Cushing syndrome that include truncal obesity, rounded (moon) facies, buffalo hump (dorsocervical fat pad), and diabetes mellitus. The best screen for Cushing syndrome caused by ectopic hormone secretion is the 24-hour urine free cortisol measurement. Marked ele-vation of cortisol production and plasma corticotropin levels are highly suggestive of ectopic corticotropin as the cause of Cushing syndrome.Treatment of patients with ectopic corticotropin production includes metyrapone, aminoglutethimide, mitotane, or ketoconazole given alone or in combina-tion. Ketoconazole is the most commonly used agent. If the patient is stable with no superimposed infection, then systemic chemotherapy is the best treatment for histologically confi rmed small cell lung cancer. If the Cushing syndrome is caused by carcinoid tumor, then surgical resection, if possible, is the treatment of choice.Hypercalcemia in relation to lung cancer may be caused by bone metastases, or less commonly, secretion of parathyroid hormone–related protein (PTHrP) or other cytokines. The most common cancers to cause paraneoplastic hypercalcemia are kidney, lung, breast, myeloma, and lymphoma. For lung cancers, squamous cell carcinoma is the most common cell type associated with hypercalcemia. Symptoms of hypercalcemia include anorexia, nausea, vomiting, constipation, leth-argy, polyuria, polydipsia, and dehydration. Confusion and coma are late manifestations. A shortened QT interval on electrocardiography, ventricular arrhyth-mia, heart block, and asystole may occur. Renal failure and nephrocalcinosis are also possible. Elevated PTHrP levels may be detected in the serum of about half of patients with hypercalcemia of malignancy that is not caused by bony metastasis. Patients with mild elevation of calcium do not require treatment. Treatment is determined by symptoms and includes intravenous fl uids to correct dehydration caused by polyuria and vomiting. Intravenous treatment with bisphosphonates inhibits osteoclast activity, and one dose achieves a normal calcium level in 4 to 10 days in most individuals. If rapid partial correction of hypercalcemia is needed, calcitonin will rapidly lower the calcium level by 1 to 2 mg/dL, but the effects are short lived. If the lung cancer is localized, then the treatment of choice, after the patient has been stabilized, is surgical resection. However, the usual situation is that the patient has metastatic disease. For these individuals with hypercal-cemia, the average life expectancy, even with treatment, is 1 month.Paraneoplastic neurologic syndromes (PNSs) are most commonly associated with small cell lung cancer ENDOCRINE MANIFESTATIONS OF LUNG CANCERCorticotropic effectsAntidiuretic hormone (ADH) effectsParathyroid hormone–like effectsSmall cell carcinomaof lungCorticotropic substance elaboratedCortical hormonesAtypical Cushing syndrome with edema hypertensionand hyperglycemiaHypokalemic alkalosisHypercalcemia Lethargy Polyuria Polydipsia Constipation Abdominal pain Coma if extremeSmall cell carcinoma of lungHigh urine osmolalityHyponatremiaIrritability Confusion Weakness Seizures if extremeParathyroidhormone–likesubstanceSquamous cell carcinomaADHAdrenal cortex hyperplasiaLow serum osmolalityTHE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 167Plate 4-57 Diseases and Pathologyand are quite variable. They include Lambert-Eaton myasthenic syndrome (LEMS), sensory neuropathy, encephalomyelopathy, cerebellar degeneration, auto-nomic neuropathy, retinal degeneration, and opso-clonus. Limbic encephalitis (dementia with or without seizures) has frequently been observed. The neurologic syndromes may precede the diagnosis of lung cancer by months to years.PNSs are thought to be immune mediated on the basis of identifying autoantibodies. The antineuronal nuclear antibody (ANNA-1), also known as anti-Hu antibody, has been associated with small cell carcinoma and various neurologic syndromes. ANNA-2 (anti-Ri antibody) and CRMP-5 antibody have also been associ-ated with various PNSs. These antibodies predict the patients’ neoplasm but not a specifi c neurologic syn-drome. The ANNA-1 binds to the nucleus of all neurons in the central and peripheral nervous system, including the sensory and autonomic ganglia and mye-nteric plexus.Proximal muscle weakness, hyporefl exia, and auto-nomic dysfunction characterize LEMS. Cranial nerve involvement may be present and does not differentiate LEMS from myasthenia gravis. There is a strong asso-ciation of LEMS with antibodies against P/Q type presynaptic voltage-gated calcium channels of the peripheral cholinergic nerve terminals. These antibod-ies have also been identifi ed in 25% of patients with small cell lung cancers with no neurologic syndrome. Myasthenia gravis, in contrast to LEMS, is associated with antiacetylcholine receptor antibodies. Malignancy is identifi ed in approximately 50% of patients with LEMS, and small cell lung cancer is by far the most common type. The diagnosis of LEMS is based on the characteristic electromyographic (EMG) fi nding that shows a small amplitude of the resting compound muscle action potential and facilitation with rapid, repetitive, and supramaximal nerve stimulation. A single-fi ber EMG is optimal for making the diagnosis. Careful radiographic evaluation of the lungs and mediastinum is indicated, especially in current or former smokers who have a suspected PNS. In many cases, the radio-graphic fi ndings are very subtle. If the patient has a positive paraneoplasticautoantibody blood test result and the computed tomography (CT) chest scan does not reveal an abnormality, then current guidelines rec-ommend that a positron emission computed tomogra-phy (PET) scan be performed to look for an occult malignancy. Strong consideration should be given to biopsy of even subtle abnormalities because without diagnosis and treatment the PNS will progress, fre-quently with devastating consequences.The best treatment for patients with PNS caused by small cell lung cancer is to treat with chemotherapy with or without thoracic radiotherapy, depending on the stage of disease. LEMS may improve with treat-ment, but not always. The other PNSs rarely improve with treatment, but the goal is to treat the lung cancer as soon as possible to try to prevent progressive neuro-logic disease.Skeletal muscular paraneoplastic syndromes include digital clubbing, hypertrophic pulmonary osteoar-thropathy (HPO), and dermatomyositis or polymyosi-tis. Clubbing may involve the fi ngers and toes and consist of selective enlargement of the connective tissue in the terminal phalanges with loss of the angle between the base of the nail bed and cuticle, rounded nails, and enlarged fi ngertips. There are nonmalignant causes of clubbing such as pulmonary fi brosis or congenital heart disease. HPO is uncommon in association with lung cancer and is characterized by painful joints that usually involve the ankles, knees, wrists, and elbows and is most often symmetric. Some patients may complain of pain or tenderness along the shins. The pain and arthropa-thy is caused by a proliferative periostitis that involves the long bones but may involve metacarpal, metatarsal, and phalangeal bones. Clubbing may be present along with HPO. Large cell and adenocarcinoma are the most common types to cause HPO. The cause of HPO is uncertain but is thought to be attributable to a humeral agent. A radiograph of the long bones (tibia and fi bula or radius and ulna) may show the characteristic perio-steal new bone formation. An isotype bone scan or PET scan typically demonstrates diffuse uptake in the long bones. Symptoms of HPO may resolve with thoracot-omy with or without resection of the malignancy. For inoperable patients, treatment with nonsteroidal anti-infl ammatory agents is often of benefi t. Recently, the use of intravenous bisphosphonates has been reported to alleviate the symptoms of HPO.There have been reports of the association of lung cancer with dermatomyositis-polymyositis (DM-PM), but the relationship is uncertain. Patients may present with painful muscles and weakness. Blood tests for the muscle enzymes creatine kinase or aldolase will demon-strate elevated levels. An EMG or muscle biopsy is diagnostic. A CT scan of the chest is warranted in a patient with DM-PM who is at high risk for lung cancer. The treatment of patients with malignancy-related DM-PM is the same as for nonmalignancy-related disease plus appropriate treatment of the underlying lung cancer.Neuromuscular manifestationsConnective tissue manifestationsEdema and/or painful swelling of feet, legs,or handsSubacutecerebellardegeneration;vertigo, ataxiaElectromyographic abnormalityin Lambert-Eaton Myasthenicsyndrome (readings fromhypothenar muscles withstimulation of ulnar nerveat wrist). Note low amplitudeand initial decline.(Normal � 5 mv or morewith no initial decline)30 stim/sec10 stim/sec3 stim/secmv42024mvmv4 4 sec1 sec0.4 sec20242101Lambert-Eaton syndrome; weaknessof proximal muscle groups (oftenmanifested by difficulty in risingfrom chair)Peripheral neuropathy;paresthesias, pain,loss of functionHypertrophicpulmonaryosteoarthropathyClubbing of fingers Subperiosteal new bone formationDementia (may predateonset of pulmonarysymptoms)Swellingof knee joint(synovialeffusionmay bepresent)NEUROMUSCULAR AND CONNECTIVE TISSUE MANIFESTATIONSPARANEOPLASTIC MANIFESTATIONS OF LUNG CANCER (Continued)helpful in confi rming the diagnosis of asthma and in deciding treatment requirements (Plate 4-18). Spon-taneously produced sputum may be mucoid, purulent, or a mixture of both. Importantly, purulent sputum does not always indicate the presence of a bacterial infection in asthmatic patients.Thin spiral bronchiolar casts (Curschmann spirals) in sputum, measuring up to several centimeters in length, are strongly indicative of asthma. Ciliated columnar bronchial epithelial cells are frequently found. Creola bodies are clumps of such bronchial epithelial cells with moving cilia and are seen in severe asthma.In asthma, both sputum eosinophils and neutrophils may be increased or the cellular infi ltrate may be pre-dominantly eosinophilic or neutrophilic or occasionally paucigranulocytic. The importance of a sputum eosi-nophilia is that it indicates inadequate treatment with or poor adherence to inhaled corticosteroids (ICS). Acute exacerbations of asthma are usually associated with an increase in eosinophil or neutrophil cell numbers in sputum.Skin Prick TestsIt is important to establish the presence of atopy in asthmatic subjects, particularly, whether environmental SPUTUM IN BRONCHIAL ASTHMAUnstained smear of asthmatic sputum; schematic (low power)MacrophageCharcot-Leyden crystalsPolymorphonuclearneutrophilCurschmann spiralsEosinophilsCluster of bronchialepithelial cells(Creola bodies)Bronchial cast (gross)Eosinophils in stained smearCarcot-Leyden crystals, eosinophils,and epithelial cell under high powerBRONCHIAL ASTHMA (Continued)THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 129Plate 4-19 Diseases and Pathologyallergens are important triggers of asthma symptoms. Preferably, skin tests are performed by a skin prick using aqueous extracts of common antigens, such as molds, pollens, fungi, house dusts, feathers, foods, or animal dander technique (Plate 4-19). If skin-sensitizing antibodies to the antigen are present, a wheal-and-fl are reaction develops within 15 to 30 minutes; a control test with saline diluent should show little or no reaction.Optimally, both the history and dermal reactivity will give corresponding results. However, some patients have positive histories but negative skin test results. In other patients, negative histories and positive skin test results indicate immunologic reactivity that is clinically insignifi cant.Blood TestsBlood tests are rarely of value in the diagnosis of asthma, but radioallergosorbent tests (RASTs) are used to identify the presence of allergy to specifi c allergens. Also, blood eosinophil counts may be increased in asth-matic patients, but they are neither sensitive nor spe-cifi c for a diagnosis.Exhaled Nitric OxideElevated levels of exhaled nitric oxide (eNO) may indi-cate eosinophilic infl ammation associated with asthma in the right clinical setting, but the clinical utility of this test is still uncertain.DIFFERENTIAL DIAGNOSISDiseases to be considered in the differential evalua-tion are depicted in Plate 4-20. In children, diseases that may be misdiagnosed as asthma also include chronic rhinosinusitis, gastroesophageal refl ux, cystic fi brosis, bronchopulmonary dysplasia, congenital mal-formation causing narrowing of the intrathoracic airways, foreign body aspiration, primary ciliary dys-kinesia syndrome, immune defi ciency, and congenital heart disease. In adult patients, pulmonary disorders, other than those illustrated in Plate 4-20, include cystic fi brosis, pneumoconiosis, and systemic vasculitis involving the lungs.PHYSIOLOGIC ABNORMALITIES IN ASTHMASpirometry and Ventilatory Function in AsthmaIn asthma, the prime physiologic disturbance is obstruc-tion to airfl ow, which is more marked in expiration. This obstruction is variable in severity and in its site of involvement and is, by defi nition, reversible to some degree. Various combinations of smooth muscle con-striction, infl ammation, edema, and mucus hypersecre-tion produce this airfl ow impediment. In addition, low lung volumes with terminal airspace collapse may com-pound the airway obstruction. In the larger airways, the rigid cartilaginous rings help maintain patency. In the peripheral airways, however, there is little opposition SKIN TESTING FOR ALLERGYA. Scratch test:1. Single dropsof control andsuspected antigensapplied to volarsurface offorearm (or othernonhirsute skinsurface)2. Small prick or scratch madethrough each droplet; cleanstylet used for eachErythema butno wheal��Erythema and whealwithout pseudopodia����Negative(or control)Erythema plus 15-mm wheal with pseudopodia����B. Intradermal test: Method moresensitive but more likely to producesystemic reactionC. InterpretationSyringe of epinephrineTourniquetArray of commerciallyavailable test antigensBRONCHIAL ASTHMA (Continued)130 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONSPlate 4-20 Respiratory Systemto the smooth muscle action because of the paucity of cartilage. Instead, the patency of these airways is infl u-enced by lung volume because they are imbedded in and partially supported by the lung parenchyma.At the onset of an asthmatic attack, or in mild cases, obstruction is not extensive. As asthma progresses, airways resistance signifi cantly increases. Although inspiratory resistance also increases, the abnormality is more pronounced during expiration because of narrow-ing or closure of the airways as the lung empties. At this point, further expiratory effort does not produce any increase in expiratory fl ow rate and may even intensify airway collapse.Because of these mechanical resistances, the respira-tory muscles must produce a greater degree of chest expansion. More important, the elastic recoil of the lungs is insuffi cient for “passive” expiration. The respi-ratory muscles, therefore, must now play an active role in expiration. If obstruction is severe, air trapping will occur, with an increase in residual volume (RV) and functional residual capacity (FRC).Airway obstruction is uneven and results in unequal distribution of gases to alveoli. This and other stimuli result in tachypnea and a consequently shortened res-piratory cycle even though the bronchial obstruction requires a lengthened respiratory time for adequate ventilation. These confl icting demands cannot be rec-onciled while the asthmatic attack continues.The severity of the obstruction is refl ected in the spirometric measurements of expiratory volume and airfl ow. The FEV1, FVC, and inspiratory capacity (IC) are all reduced during an acute attack.The peripheral airways have a proportionately large total cross-sectional area. For this reason, the resistance of the peripheral airways normally accounts for only 20% of the total airway resistance. Thus, extensive obstruction in these smaller airways may go undetected if the physician relies only on clinical fi ndings. The reduction in FVC and FEV1 shows a good correlation with the decrease in PaO2, although carbon dioxide retention does not occur until the FEV1 is about 1 L or 25% of the level predicted.With progressive obstruction, expiration becomes increasingly prolonged. Increases in RV and FRC occur (see Plate 4-39). These volume changes may represent an inherent physiologic response by the patient because breathing at higher lung volumes prevents the closure of terminal airways. The overall effect of these events is alveolar hyperinfl ation, which tends to further increase the diameter of the airways by exerting a greater lateral force on their walls. This hyperinfl ation may partially preserve gas exchange. It is disadvanta-geous because much more work is required, resulting in an increase in O2 consumption. Moreover, such a state compromises IC and vital capacity (VC). The symptoms of dyspnea and fatigue may also arise in part from this process. Finally,the effectiveness of cough is impaired because the velocity of respiratory airfl ow is seriously reduced.As a result of the nonhomogeneous airway obstruc-tion in asthma, the distribution of inspired air to the terminal respiratory units is not uniform through-out the lungs. Alveoli that are hypoventilated because they are supplied by obstructed airways are interspersed with normal or hyperventilated alveoli; hence, the REPRESENTATIVE DIFFERENTIAL DIAGNOSIS OF BRONCHIAL ASTHMABronchitis orbronchiolitis(acute orchronic)Bronchiectasis or otherpulmonary disease(infective, neoplastic,or granulomatous)Congestive heart failure(cardiac asthma)AnaphylaxisPulmonaryembolismIrritant inhalants(industrial or home)Aspiration (food or foreign body)Farmer’s lung(allergic alveolitiswith dualasthmatic reaction)Congenitalconstrictivevascular ringsHiatalherniawith refluxTracheobronchialtumorsMediastinalmasses(tumors,lymph nodes)Aortic aneurysmVocal cord dysfunctionLaryngeal tumor or cyst(may be ball-valve type)Laryngeal edema (croup)BRONCHIAL ASTHMA (Continued)THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 131Plate 4-21 Diseases and Pathologyseverity of asthma is directly related to the ratio of poorly ventilated to well-ventilated alveolar groups. Arterial hypoxemia, which is the primary defect in gas exchange in asthma, is caused by this � �V QA C nonho-mogeneity (Plate 4-21). As the population of alveolar units with a low � �V QA C ratio increases (because of advancing obstruction), the degree of arterial hypox-emia also intensifi es. The � �V QA C disturbance is com-pounded if some airways are completely obstructed. The right-to-left intrapulmonary shunt effect results in arterial hypoxemia.Carbon dioxide elimination is not impaired when the number of alveolar-capillary units with normal � �V QA C ratios remains large relative to the number of those with low � �V QA C ratios. As airway obstruction progresses, there are more and more hypoventilated alveoli. Simul-taneously, appropriate increases in respiratory work, rate, and depth occur. Such a response initially mini-mizes the increase in physiologic dead space but even-tually becomes limited, and alveolar ventilation fi nally fails to support the metabolic needs of the body. Carbon dioxide retention now occurs together with increasing hypoxemia. This is a state of ventilatory failure, and it commonly arises when the FEV1 is less than 25% predicted.PATHOGENESIS OF ASTHMAGeneticsGenetic and environmental factors interact in a complex manner to produce both asthma susceptibility and asthma expression. Several genes on chromosome 5q31-33 may be important in the development or pro-gression of the infl ammation associated with asthma and atopy, including the cytokines interleukin-3 (IL-3), IL-4, IL-5, IL-9, IL-12, IL-13, and granulocyte-macrophage colony-stimulating factor (GM-CSF). In addition, a number of other genes may play a role in the development of asthma or its pathogenesis, includ-ing the corticosteroid receptor and the β2-adrenergic receptor. Chromosome 5q32 contains the gene for the β2-adrenoceptor, which is highly polymorphic, and a number of variants of this gene have been discovered that alter receptor functioning and response to β-agonists.Other chromosome regions linked to the develop-ment of allergy or asthma include chromosome 11q, which contains the gene for the β chain of the high-affi nity IgE receptor (FcεRIβ). Chromosome 12 also contains several candidate genes, including interferon-γ (INF-γ), stem cell factor (SCF), IGF-1, and the consti-tutive form of nitric oxide synthase (cNOS). The ADAM 33 gene (a disintegrin and metalloproteinase 33) on chromosome 20p13 has been signifi cantly asso-ciated with asthma. ADAM proteins are membrane-anchored proteolytic enzymes. The restricted expression of ADAM 33 to mesenchymal cells and its close assoc-iation with airways hyperresponsiveness (AHR) sug-gests it may be operating in airway smooth muscle or in events linked to airway remodeling.Cellular Infl ammationPersistent airway infl ammation is considered the char-acteristic feature of severe, mild, and even asympto-matic asthma. The characteristic features include infi ltration of the airways by infl ammatory cells, hyper-trophy of the airway smooth muscle, and thickening of the lamina reticularis just below the basement mem-brane (see Plate 4-22).An important feature of the airway infl ammatory infi ltrate in asthma is its multicellular nature, which is mainly composed of eosinophils but also includes neutrophils, lymphocytes, and other cells in varying degrees. Whereas neutrophils, eosinophils, and T O2CO2O2CO2pHPaCO2PaO2pHPaCO2PaO2Number of poorlyventilated alveoliversuswell-ventilatedalveoliNumber of poorlyventilated alveoliversuswell-ventilatedalveoli1. Bronchial obstruction leads todecreased blood oxygenation2. Hypoxia, anxiety, and increasedrespiratory work cause hyperventilation3. Hyperventilation results inincreased CO2 elimination (hypocapnia)4. Hypocapnia causes respiratory alkalosis1. Greater degree of bronchial obstruction causesgreatly decreased blood oxygenation2. Ventilatory responses become ineffective3. Because of advanced obstruction andinadequate respiration, ventilation fails withCO2 retention (hypercapnia)4. Hypercapnia causes respiratory acidosis,respiratory failureRespiratorycentersRespiratorycenters Blood gas and pH relationships in severe asthma and status asthmaticusBlood gas and pH relationships in mild asthmaBLOOD GAS AND PH RELATIONSHIPSBRONCHIAL ASTHMA (Continued)132 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONSPlate 4-22 Respiratory Systemlymphocytes are recruited from the circulation, mast cells are resident cells of the airways. Histologic evi-dence of mast cell degranulation and eosinophil vacu-olation reveals that the infl ammatory cells are activated. The mucosal mast cells are not increased but show signs of granule secretion in asthmatic patients. Postmortem studies have shown an apparent reduction in the number of mast cells in the asthmatic bronchi as well as in the lung parenchyma, which refl ects mast cell degranula-tion rather than a true reduction in their numbers.Eosinophils are considered to be the predominant and most characteristic cells in asthma, as observed from both bronchoalveolar lavage (BAL) and bronchial biopsy studies. The bronchial epithelium is infi ltrated by eosinophils, which is evident in both large and small airways, with a greater intensity in the proximal airways in acute severe asthma. However, some studies report the virtual absence of eosinophils in severe or fatal asthma, suggesting some heterogeneity in this process. Alveolar macrophages are the most prevalent cells in the human lungs, both in normal subjects and in asth-matic patients and, when activated, secrete a wide array of mediators. Lymphocytes are critical for the develop-ment of asthma and are found in the airways of asth-matic subjects in relationship to disease severity. The function and contribution of lymphocytes in asthma are multifactorial and center on their ability to secrete cytokines. Activated T cells are a source of Th2 cytokines (e.g., IL-4, IL-13), which may induce the activated B cell to produce IgE and enhance expression of cellular adhesion molecules, in particular vascular cell adhesion molecule-1 (VCAM-1) and IL-5, which is essential for eosinophil development and survival in tissues.IMMUNOLOGIC ABNORMALITIESAllergic asthma and other allergic diseases, such as allergic rhinitis and anaphylaxis, develop as a result of sensitization to environmental allergens and subse-quent immunologically mediated responses when the allergens are encountered. These allergic reactions take place in specifi c target organs, such as the lungs, gas-trointestinaltract, or skin. These immune processes leading to allergic reactions represent the disease state referred to clinically as “atopy.” The immune sequence consists of the sensitization phase followed by a chal-lenge reaction, which produces the clinical syndrome concerned (see Plate 4-23).Sensitization to an allergen occurs when the other-wise innocuous allergen is encountered for the fi rst time. Professional antigen-presenting cells (APCs) such as monocytes, macrophages, and immature dendritic cells capture the antigen and degrade it into short immunogenic peptides. Cleaved antigenic fragments are presented to naïve CD4+ T-helper (Th) cells on MHC class II molecules. Depending on a multitude of factors, particularly the cytokine microenvironment, these naïve T-helper cells are subsequently polarized into Th1 or Th2 lymphocytes. Th1 lymphocytes pre-dominantly secrete IL-2, INF-γ, and tumor necrosis factor (TNF)-β to induce a cellular immune response. In contrast, Th2 lymphocytes secrete IL-4, IL-5, IL-9, Late asthmatic responseAIRWAY PATHOPHYSIOLOGY IN ASTHMACytokineupregulationof adhesionmoleculesInflammatory cell migrationDisruption of epithelium byeosinophil-derived proteins,with loss of epithelial mediatorsAllergen penetrationinto submucosa viadesquamated areaActivatedmast cellTH2cellCytokines/chemokinesBasophil Proteins EosinophilCytokine and chemokinerecruitment and activationof inflammatory cellsSmoothmusclecontractionLate asthmatic response characterized by inflammatory changes mediated by cytokinesand chemokines, and epithelial disruption mediated by eosinophils and basophilsChronic asthmaThickened basement membraneChronic inflammationChronic inflammationresults in airwayhyperreactivityto allergens or irritantsChronic asthma exhibits chroniclow-grade inflammation, which extendsbeyond the muscularis, where it is lesssusceptible to inhaled medications.Thickening of basement membraneoccurs secondary to inflammationBRONCHIAL ASTHMA (Continued)THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 133Plate 4-23 Diseases and Pathologyand IL-13 cytokines to induce a humoral immune response, particularly the B-cell class switch to allergen-specifi c immunoglobulin E (IgE) production. In allergic asthma, an imbalance exists between Th1 and Th2 lymphocytes, with a shift in immunity from a Th1 pattern toward a Th2 profi le. Accordingly, allergic asthma is often referred to a Th2-mediated disorder, with a persistent Th2-skewed immune response to inhaled allergens (Plate 4-23).IgE is a γ-l-glycoprotein and is the least abundant antibody in serum, with a concentration of 150 ng/mL compared with 10 mg/mL for IgG in normal individu-als. However, IgE concentrations in the circulation may reach more than 10 times the normal level in “atopic” individuals. IgE levels are also increased in patients with parasitic infestations and hyper-IgE-syndrome. Increased serum concentration is not necessarily a spe-cifi c indicator of the extent or severity of allergy in the individual concerned. The IgE molecules attach to the surfaces of the mast cells or other cells such as basophils. The mast cells containing IgE are distributed in the mucosa of the upper and lower respiratory tract and perivascular connective tissues of the lung.After sensitization to an allergen has occurred, reex-posure of the patient to the allergen may result in an acute allergic reaction, also known as an imme-diate hypersensitivity reaction (Plate 4-23). IgE-sensitized mast cells in contact with the specifi c antigen secrete preformed and newly synthesized mediators, including histamine, cysteinyl leukotrienes, kinins, prostaglandins and thromboxane, and platelet activating factor. Also, mast cells are sources of proin-fl ammatory cytokines. Each antigen molecule has to bridge at least two of the IgE molecules bound to the surface of the cell. The subsequent airway smooth muscle contraction, vasoconstriction, and hypersecre-tion of mucus, together with an infl ammatory response of increased capillary permeability and cellular infi ltra-tion with eosinophils and neutrophils follows, produc-ing asthma symptoms.PATHOLOGIC CHANGES IN ASTHMAThe initial knowledge of the pathology of asthma came from postmortem studies of fatal asthma or airways of patients with asthma who have died of other causes or who had undergone lung resections. All showed similar, although variably severe, pathologic changes and pro-vided key directives as to the causes and consequences of the infl ammatory reactions in the airway (see Plate 4-24).The characteristic mucus plugs in asthmatic airways can cause airway obstruction, leading to ventilation-perfusion mismatch and contributing to hypoxemia. Mucus plugs are composed of mucus, serum proteins, infl ammatory cells, and cellular debris, which include desquamated epithelial cells and macrophages often arranged in a spiral pattern (Curschmann spirals). The excessive mucus production in fatal asthma is attributed to hypertrophy and hyperplasia of the submucosal glands. The mucus also contains increased quantities of nucleic acids, glycoproteins, and albumin, making it more viscous. This altered mucous rheology, coupled SensitizationAllergic reactionProstaglandinsInflammatorycytokinesCysteinylleukotrienesHistamineSmooth musclecontractionMucous glandhypersecretionIncreased capillarypermeability andinflammatory reactionEosinophilattractionD. Reexposure to same antigenE. Antigen reacts with antibody (IgE)on membrane ofsensitized mast cellsand/or basophils,which respond bysecreting pharmacologicmediatorsCa2+ Mg2+B. Plasma cells inlymphoid tissueof respiratorymucosa releaseimmuneglobulin E (IgE)C. Mast cellsand basophilssensitized byattachmentof IgE to cellmembraneFab fragmentFc fragmentDisulfide bondsHeavy chainLight chainAntigenA. Genetically atopic patient exposed to specific antigen (ragweed pollen illustrated)PollenLeukocytes in the asthmatic responseAntigenAntigen-presentingdendriticcell CD4+T cellHelperT cellsB cells Plasma cellsIgE antibodiesIL-9IL-4, IL-13IL-5Recruitment of eosinophils Mast cellsAfter sensitization to allergen,T-helper cells are skewed towarda TH2 cytokine profile, resulting ina humoral immune response(production of IgE) and activationof eosinophils and mast cells and mucussecretion, all of which result inairway inflammation andairway narrowing Degranulation(release of histamine,heparin, serotonin)T TH0TH1TH2 BBF. End-organ (airway) response MECHANISM OF TYPE 1 (IMMEDIATE) HYPERSENSITIVITYBRONCHIAL ASTHMA (Continued)134 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONSPlate 4-24 Respiratory Systemwith the loss of ciliated epithelium, impairs mucociliary clearance.The airway wall thickness is increased in asthma and is related to disease severity. Compared with non-asthmatic subjects, the airway wall thickness is increased from 50% to 300% in patients with fatal asthma and from 10% to 100% in nonfatal asthma. The greater thickness results from an increase in most tissue compartments, including smooth muscle, epithelium, submucosa, adventitia, and mucosal glands. The infl am-matory edema involves the whole airway, particularly the submucosal layer, with marked hypertrophy and hyperplasia of the submucosal glands and goblet cell hyperplasia. Goblet cell hyperplasia and hypertrophy accompany the loss of epithelial cells. There is hyper-plasia of the muscularis layer and microvascular vasodi-lation in the adventitial layers of the airways. Also, morphometric studies have shown that the bronchial lamina propria of asthmatic subjects had a larger number of vessels occupying a larger percentage area than in nonasthmatic subjects and in some circum-stances correlated withthe severity of disease.LONG-TERM MANAGEMENT OF ASTHMAAsthma treatment guidelines have been remarkably consistent in identifying the goals and objectives of asthma treatment. These are to (1) minimize or elimi-nate asthma symptoms, (2) achieve the best possible lung function, (3) prevent asthma exacerbations, (4) do the above with the fewest possible medications, (5) minimize short- and long-term adverse effects, and (6) educate the patient about the disease and the goals of management. One other important objective should be the prevention of the decline in lung function and the development of fi xed airfl ow obstruction, which occur in some asthmatic patients. In addition to these goals and objectives, each of these documents has described what is meant by the term asthma control. This includes the above objectives but also includes minimizing the need for rescue medications, such as inhaled β2-agonists, to less than daily use; minimizing the variabil-ity of fl ow rates that is characteristic of asthma; and having normal activities of daily living. Achieving this level of asthma control should be an objective from the very fi rst visit of the patient to the treating physician. The pharmacologic treatment of patients with asthma must only be considered in the context of asthma edu-cation and avoidance of inducers of the disease (see Plate 4-25).Mild Persistent AsthmaLow doses of inhaled corticosteroids (ICS) can often provide ideal asthma control and reduce the risks of severe asthma exacerbations in both children and adults with mild persistent asthma, and they should be the treatment of choice. ICS are the most effective anti-infl ammatory medications for asthma treatment. The mechanisms of action of asthma medications are depicted in Plate 4-26. There is no convincing evidence that regular use of combination therapy with ICS and inhaled long-acting β2-agonists (LABA) provides any PATHOLOGY OF SEVERE ASTHMATenacious, viscidmucous plugsin airways Foci ofatelectasisRegional or diffusehyperinflationPAS-positive matrixPolymorphonuclearneutrophilsEosinophilsCharcot-LeydencrystalsCurschmann’sspiralsCluster ofepithelial cells(Creola body)MucousplugEpithelial denudationHyaline thickening of basement membraneHypertrophy of smooth muscle,mucous glands, and goblet cellsInflammatory exudate with eosinophils and edemaEngorged blood vesselsMicroscopicGrossObstructed asthmatic airway*LumenEpitheliumBasementmembraneBlocked airway–”mucus plug”Muscle hypertrophyThickenedbasement membraneAA B BPATHOLOGY OF SEVERE ASTHMATenacious, viscidmucous plugsin airways Foci ofatelectasisRegional or diffusehyperinflationPAS-positive matrixPolymorphonuclearneutrophilsEosinophilsCharcot-LeydencrystalsCurschmannspiralsCluster ofepithelial cells(Creola body)MucousplugEpithelial denudationHyaline thickening of basement membraneHypertrophy of smooth muscle,mucous glands, and goblet cellsInflammatory exudate with eosinophils and edemaEngorged blood vesselsMicroscopicGrossMicroscopy of airwayObstructed asthmatic airway*LumenEpitheliumBasementmembrane(A) Normal airway. (B) Asthmatic airway before therapy with high-dose inhaled steroids demonstrating remodeling.Blocked airway–”mucus plug”Muscle hypertrophyThickenedbasement membraneAA BBRONCHIAL ASTHMA (Continued)THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 135Plate 4-25 Diseases and Pathologyadditional benefi t. Leukotriene receptor antagonists (LTRAs) are another treatment option in this popula-tion, but they are also less effective than low-dose ICS. There are considerable inter- and intraindividual dif-ferences in responses to any therapy. This is also true for response to treatment with ICS and LTRAs in both adults and in children. Although on average, ICS improve almost all asthma outcomes more than LTRAs some patients may show a greater response to LTRAs. Currently, it is not possible to accurately identify these responders based on their clinical, physiologic, or phar-macogenomic characteristics.The other issue that needs to be considered when making a decision to start ICS treatment in patients with mild asthma is the potential for side effects. ICS are not metabolized in the lungs, and every molecule of ICS that is administered into the lungs is absorbed into the systemic circulation. All of the studies in patients with mild persistent asthma have used low doses of ICS (maximal doses, 400 μg/d). A wealth of data are avail-able demonstrating the safety of these low doses, even used long term, in adults. However, a signifi cant reduc-tion in growth velocity has been demonstrated with low doses of ICS in children. This is unlikely to have any effect on the fi nal height of these children because the one study that has followed children treated with ICS to fi nal height did not show any detrimental effect even with a moderate daily ICS doses.Moderate Persistent AsthmaThese patients have asthma that is not well controlled on low doses of ICS. Asthma treatment guidelines rec-ommend that combination therapy with ICS and a LABA is the preferred treatment option in these patients. This is because the use of combination treat-ment of ICS and LABA for moderate persistent asthma has also been demonstrated to improve all indicators of asthma control compared with ICS alone. It is impor-tant to note that the evidence of the enhanced benefi t of combination therapy with ICS and LABA in moder-ate persistent asthma exists mainly in adults with asthma. Another recently described treatment approach for the management of patients with moderate asthma is the use of an inhaler containing the combination of the ICS budesonide and the LABA formoterol, both as maintenance and as relief therapy, which has been shown to reduce the risk of severe asthma exacerbations compared with the other approaches studied with an associated reduction in oral corticosteroid use.Several studies have compared the clinical benefi t when LTRAs are added to ICS in patients with moder-ate persistent asthma in both adults and children. The addition of LTRAs to ICS may modestly improve asthma control compared with ICS alone, but this strategy cannot be recommended as a substitute for increasing the dose of ICS. In addition, LTRAs have been shown to be less effective than LABAs when combined with ICS. Low-dose theophylline has also been evaluated as an add-on therapy to ICS. The magnitude of benefi t achieved is less than for LABAs. Another potential treatment option for patients with moderate asthma is omalizumab, which is a Good health measuresGastro-esophagealrefluxSinus infection,nasal polypsElimination or control of precipitating causesDust mitecontrolPetsProvocative drugsWool blanketsFeather pillowsDustsStuffed toysCarpets and rugsDraperiesPollens and all other offending allergensWashinglinens at 130� F, useHEPA filtervacuum,and cover-ing for mattressesand pillowEnviron-mental factors to be avoidedOccupational hazardsMoldy basementsCrowds and individuals with head or chest coldsExtremes of temperatureTobacco fumesVolatile chemicalsGeneral factors to be avoidedGENERAL MANAGEMENT PRINCIPLES FOR ALLERGIC ASTHMAReasonable physical activity and exerciseAdherenceto therapyAdequate rest and sleepBRONCHIAL ASTHMA (Continued)136 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONSPlate 4-26 Respiratory Systemrecombinant humanized monoclonal antibody against IgE. This anti-IgE antibody forms complexes with free IgE, thus blocking the interaction between IgE and effector cells and reducing serum concentrations of free IgE. Compared with placebo in patients on moder-ate to high doses of ICS, omalizumab reduces asthma exacerbations and enables a small but statistically sig-nifi cant reductionin the dose of ICS. However, this treatment has not been compared with proven additive therapies such as LABAs that are less expensive. There-fore, this therapy is currently recommended in inter-national guidelines for patients with moderate to severe asthma.Severe Persistent AsthmaPatients with severe asthma are those who do not respond adequately to even high doses of ICS and LABAs. This population disproportionately consumes health care resources related to asthma. Physiologically, these patients often have air trapping, airway collapsi-bility, and a high degree of AHR. Patients with severe diffi cult-to-treat asthma are most often adult patients with signifi cant comorbidities, including severe rhinosi-nusitis, gastroesophageal refl ux, obesity, and anxiety disorders. Often this population requires oral corticos-teroids in addition to ICS in an effort to achieve asthma control.TREATMENT OF SEVERE ASTHMA EXACERBATIONSEpisodes of acute severe asthma (asthma exacerbations) are episodes of progressive increase in shortness of breath, cough, wheezing, chest tightness, or some com-bination and are characterized by airfl ow obstruction that can be quantifi ed by measurement of PEF or FEV1. These measurements are more reliable indicators of the severity of airfl ow limitation than is the degree of symptoms. Severe exacerbations are potentially life threatening, and their treatment requires close super-vision. Patients with severe exacerbations should be encouraged to see their physicians promptly or to proceed to the nearest hospital that provides emergency access for patients with acute asthma. Close objective monitoring of the response to therapy is essential.The primary therapies for severe asthma exacerba-tions include repetitive administration of rapid-acting inhaled β2-agonists, 2 to 4 puffs every 20 minutes for the fi rst hour (see Plate 4-27). After the fi rst hour, the dose of β2-agonists required depends on the severity of the exacerbation and the response of the previously administered inhaled β2-agonists. A combination of inhaled β2-agonist with an anticholin-ergic (ipratropium bromide) may produce better bron-chodilation than either drug alone. Oxygen should be administered by nasal cannula or by mask and should be titrated against pulse oximetry to maintain a satisfactory oxygen saturation of 90% or above (≥95% in children).Corticosteroids decreaserecruitment and activationof eosinophilsCorticosteroidssuppress cytokinegenerationEosinophilCytokinesHistamine/prostaglandinsLeukotrienesAntileukotrienesblock leukotrieneproduction and receptorsCorticosteroids depresseosinophil mediator releaseBronchodilationBronchoconstrictionAllergenAntigen-presentingcell (APC)Mast cellB cellIL–4,6, 10, 13Cytokines (IL–3,–4,–5,–6,–9,–10,–13, GM-CSF)IgECorticosteroids decrease mast cell migrationCorticosteroids and cromolynand nedocromil suppress mastcell mediator releaseCorticosteroids inhibitT-cell activationTH2 cell THo cell Smooth muscle relaxationATP cAMP�2-Adrenergicreceptor activation�2-Agonists causesmooth musclerelaxation, relievingbronchoconstrictionMECHANISMS OF ASTHMA MEDICATIONSAntiinflammatory drugsBronchodilator agentsAdenyl cyclaseBRONCHIAL ASTHMA (Continued)THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 137Plate 4-27 Diseases and PathologySystemic glucocorticosteroids speed resolution of exacerbations and should be used in all but the mildest exacerbations, especially if the initial rapid-acting inhaled β2-agonist therapy fails to achieve lasting improvement. Oral glucocorticosteroids are usually as effective as those administered intravenously and are preferred because this route of delivery is less invasive. The aims of treatment are to relieve airfl ow obstruction and hypoxemia as quickly as possible and to plan the prevention of future relapses. Sedation should be strictly avoided during exacerbations of asthma because of the respiratory depressant effect of anxiolytic and hypnotic drugs.Patients at high risk of asthma-related death should be encouraged to seek urgent care early in the course of their exacerbations. These patients include those with a previous history of near-fatal asthma requiring intubation and mechanical ventilation, who have had a hospitalization or emergency care visit for asthma in the past year, who are currently using or have recently stopped using oral glucocorticosteroids, who are over-dependent on rapid-acting inhaled β2-agonists, who have a history of psychiatric disease or psychosocial problems, and who have a history of noncompliance with an asthma medication plan.The response to treatment may take time, and patients should be closely monitored using clinical as well as objective measurements. The increased treat-ment should continue until measurements of lung function return to their previous best level or there is a plateau in the response to the inhaled β2-agonists, at which time a decision to admit or discharge the patient can be made based on these values. Patients who can be safely discharged will have responded within the fi rst 2 hours, at which time decisions regard-ing patient disposition can be made. Patients with a pretreatment FEV1 or peak expiratory fl ow (PEF) below 25% percent predicted or those with a post-treatment FEV1 or PEF below 40% percent predicted usually require hospitalization. Patients with posttreat-ment lung function of 40% to 60% predicted can often be discharged from the emergency setting provided that adequate follow-up is available in the community and their compliance with treatment is assured.For patients discharged from the emergency depart-ment, a minimum of a 7-day course of oral glucocorti-costeroids for adults and a shorter course (3-5 days) for children should be prescribed along with continuation of bronchodilator therapy. The bronchodilator can be used on an as-needed basis, based on both symptomatic and objective improvement. Patients should initiate or continue inhaled glucocorticosteroids. The patient’s inhaler technique and use of peak fl ow meter to monitor therapy at home should be reviewed. The factors that precipitated the exacerbation should be identifi ed and strategies for their future avoidance implemented. The patient’s response to the exacerbation should be evalu-ated, and an asthma action plan should be reviewed and written guidance provided.Pulmonary function (FEV1 or PEF)assessed before and after medicationto monitor treatment or determineneed for additional testsBronchodilator therapy(�2-agonist) startedimmediately and maintainedintermittently or continuouslyuntil pulmonary functionwithin desired limitsPatient response to initialtherapy better indicatorof need for further therapyor hospitalization thanseverity of exacerbation1 hourSystemiccorticosteroidtherapy (oralor parenteral)for all asthmaemergenciesO2 asindicatedPulseoximetryArterialblood gasesNormal physical examination, nosymptoms, and FEV1 �70% for atleast 1 hour since last treatmentOral corticosteroids, inhaled corticosteroids, long- and short-acting bronchodilators, pluswritten asthma action planEMERGENCY DEPARTMENT MANAGEMENT OF ASTHMADischarge criteriaFEV1Volume (L)Time (sec)�30%�50%Predicted orbest FEV10112233667789104455FEV1Volume (L)Time (sec)Pretreatment FEV1Predicted or best FEV1 PosttreatmentFEV1 �70%011223366774455BRONCHIAL ASTHMA (Continued)138 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONSPlate 4-28 Respiratory SystemCHRONIC OBSTRUCTIVE PULMONARY DISEASEChronic obstructive pulmonary disease (COPD) is a chronic disease that is defi ned by progressive airfl ow obstruction that is not completely reversible. COPD is caused by chronic infl ammation of the airwaysand lung parenchyma that develops in response to environmental insults, including cigarette smoke, and manifests clini-cally with symptoms of cough, dyspnea on exertion, and wheezing. Patients with COPD usually live a number of years with progressive disability and multiple acute exacerbations. Thus, the physician is likely to become involved for many years in the assessment, treatment, and education of a patient with COPD.SUBTYPESCOPD is a disorder that is characterized by slow emp-tying of the lung during a forced expiration (see Plate 4-39). In practice, this is measured as the ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC), and the arbitrary defi nition of airfl ow obstruction is generally taken to be an FEV1/FVC ratio lower than 0.70. Because the rate of emptying of the lung decreases with advancing age, many elderly indi-viduals demonstrate airfl ow obstruction even in the absence of a clinical diagnosis of COPD. The diagnosis of COPD usually describes individuals who have chronic airfl ow obstruction associated with tobacco smoke or some other environmental insult, although aging of the lung has many features that are similar to those of COPD.COPD encompasses several clinical subtypes, includ-ing chronic bronchitis, emphysema, and some forms of long-standing asthma. Chronic bronchitis is defi ned by cough and sputum production for at least 3 months of the year for more than 2 consecutive years in the absence of other kinds of endobronchial disease such as bronchiectasis. In practice, though, most patients with chronic bronchitis have perennial chronic productive coughs that are dismissed as “smokers’ cough.” Emphy-sema is defi ned as enlargement of the distal airspaces as a consequence of destruction of alveolar septa. The resultant loss of elasticity of the lung (i.e., increased distensibility) causes slowing of maximal airfl ow, hyper-infl ation, and air trapping that are the pathophysiologic hallmarks of COPD. Asthma is defi ned by completely reversible airfl ow obstruction and airway hyperrespon-siveness. Chronic persistent asthma may lead to irre-versible airfl ow obstruction and a subset of those with asthma smoke and have incompletely reversible airfl ow obstruction, resulting in a population that meets the defi nition of COPD. Because most patients have features of more than one subtype and because the treatment approaches are similar, physicians and epide-miologists usually do not distinguish among the various subcategories of COPD. In the future, however, as molecular and imaging methods permit fi ner distinc-tion of COPD subgroups, it may be possible to more precisely tailor treatments and defi ne prognosis for individual patients.Patients with COPD often seek medical attention after their disease is already severe. Typically, patients have incurred several decades of damage caused by ciga-rette smoking before they experience dyspnea limiting their functional capacity. Patients may be treated for recurrent lower respiratory tract infections before a diagnosis of COPD is considered. Clinical presenta-tions vary in the severity of the underlying lung disease, EmphysemaIrreversible orpartially reversibleairflow obstructionReversible airflow obstructionAsthmaChronic bronchitis70,000MaleU.S. COPD Deaths, 1980–2000INTERRELATIONSHIPS OF CHRONIC BRONCHITIS AND EMPHYSEMAFEV1 DeclineFemaleDeaths60,00050,00040,00030,00020,00010,000FEV1 (% of value at age 25)100755025025 50Age (years)DeathDisabilitySusceptiblesmokerQuit smokingNever smoked or notsusceptible to smoke750198019811982198319841985198619871988198919901991199219931994199519961997199819992000ChronicobstructivepulmonarydiseaseTHE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 139Plate 4-29 Diseases and Pathologythe rate of progression of disease, and the frequency of exacerbations.EPIDEMIOLOGYCOPD is the fourth leading cause of death in the United States, and mortality related to COPD is pro-jected to increase as cigarette smoking increases in developing countries. COPD is also among the leading causes of chronic medical disability and health care costs in the United States. Morbidity and mortality attributable to COPD have continued to increase, in contrast with other chronic diseases. COPD accounts for a great burden of health care costs, including direct costs of health care and indirect costs related to missed work and caregiver support. Historically, COPD was described as a disease that predominantly affected white men. However, the prevalence of COPD among women and minorities has grown in recent decades as the rate of increase in white men has leveled off. In the United States, morbidity and mortality from COPD in women now exceeds in men, which is largely attribut-able to increases in the prevalence of cigarette smoking among women. The most rapid increase in COPD mortality is among elderly women. In developing nations, indoor burning of biomass fuel has been an important risk factor for COPD among women. As tobacco use has become more widespread in the devel-oping world, the prevalence of COPD has risen among both men and women (see Plate 4-28).RISK FACTORSCOPD is caused by a combination of environmental exposures and genetic susceptibility. α1-Antitrypsin defi ciency is the best documented genetic risk factor for COPD and demonstrates the interaction between genetic predisposition and environmental exposures that results in clinical manifestations of COPD. Other genetic associations have been suggested but are not as well substantiated. Inhalational exposures are the major environmental risk factor for COPD, and cigarette smoking is by far the most common risk factor world-wide. Other inhalational exposures include outdoor atmospheric pollution and indoor air pollution from heating and cooking, especially with the use of biomass fuels in developing countries. Occupational exposures and recurrent bronchial infections have also been impli-cated as pathogenic factors. Socioeconomic status and poor nutrition are other factors that may predispose individuals to developing COPD, and individuals with reduced maximal lung function in early life are more likely to develop COPD later in life.NATURAL HISTORYCOPD is a heterogeneous disorder with the unifying feature of incompletely reversible airfl ow obstruction, demonstrated by slow emptying of the lungs during a forced expiration. The natural history of the decline in FEV1 in patients with COPD was described by Fletcher and Peto (see Plate 4-28). These investigators reported that most cigarette smokers have a relatively normal rate of decline in FEV1 with aging, but a certain subset of smokers is especially susceptible to cigarette smoke, as demonstrated by an accelerated rate of FEV1 decline. More recent studies have confi rmed that normal EMPHYSEMACHRONIC OBSTRUCTIVE PULMONARY DISEASE (Continued)140 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONSPlate 4-30 Respiratory Systemnonsmoking adults lose FEV1 at a rate of 30 mL per year, a consequence of aging-related loss of elastic recoil of the lung. Studies of patients with COPD show an average annual decline of FEV1 of 45 to 69 mL per year. Smokers that quit may revert to the normal state of decline (Plate 4-28). Persons who develop COPD may start early adulthood with lower levels of lung function and have increased rates of decline. The decline in lung function is asymptomatic for a period of years, and patients adjust their activities to limit strenuous exercise. In middle age, the onset of an inter-current respiratory infection, ascent to altitude, or pro-gression of the disease beyond a critical threshold may lead to impairment of routine daily activities or even acute respiratoryfailure. These events lead the patients with COPD to seek medical attention. Thus, the onset of COPD may appear precipitous even though it is the cumulative result of decades of progression.CLINICAL FEATURESCOPD is a heterogeneous disease that presents with a spectrum of clinical manifestations. Although end-stage COPD has classically been described as having features typical of emphysema or chronic bronchitis, most patients have features of both (see Plates 4-28 to 4-31). Although COPD represents a spectrum of clinical pres-entations, the presence of airfl ow limitation is a unify-ing feature, and spirometry serves as a diagnostic tool and a means of assessing disease severity (see Plates 4-39 and 4-42). Patients typically have some degree of dyspnea and may also experience cough and wheezing. COPD is progressive, and symptoms and clinical fea-tures worsen over time despite available treatments.PREDOMINANCE OF EMPHYSEMAThe classic representation of a patient with a predomi-nance of emphysema is an asthenic patient with a long history of exertional dyspnea and minimal cough pro-ductive of only scant amounts of mucoid sputum (see Plate 4-29). Weight loss is common, and the clinical course is characterized by marked, progressive dyspnea.On physical examination, the patient appears dis-tressed and is using accessory muscles of respiration, which serve to lift the sternum in an anterior-superior direction with each inspiration. The sternomastoid muscles are well-developed, but the limbs show evi-dence of muscle atrophy. The patient has tachypnea, with relatively prolonged expiration through pursed lips, or expiration is begun with a grunting sound. Patients who have active grunting expiration may exhibit well-developed, tense abdominal musculature. The hyperinfl ation of the chest leads to widening of the costal angle of the lower ribcage and elevation of the lateral clavicles. The fl attened diaphragm causes the lateral ribcage to move inward with each breath. While sitting, the patient often leans forward, extend-ing the arms to brace him- or herself in the so-called “tripod” position. Patients who brace themselves on their thighs may develop hyperkeratosis of the upper thighs. The neck veins may be distended during expiration, yet they collapse with inspiration. The lower intercostal spaces and sternal notch retract with each inspiration. The percussion note is hyperresonant, and the breath sounds on auscultation are diminished, with faint, high-pitched crackles early in inspiration, and wheezes heard in expiration. The cardiac impulse, if visible, is seen in the subxiphoid regions, and cardiac dullness is either absent or severely narrowed. The cardiac impulse is best palpated in the subxiphoid region. If pulmonary hypertension is present, a murmur of tricuspid insuffi ciency may be heard in the subxi-phoid region.The minute ventilation is maintained, the arterial Po2 is often above 60 mm Hg, and the Pco2 is low to normal. Pulmonary function testing demonstrates an increased total lung capacity (TLC) and residual volume (RV), with a decreased vital capacity. The DLCO (diffus-ing capacity for carbon monoxide) is decreased, refl ect-ing the destruction of the alveolar septa causing CHRONIC BRONCHITISCHRONIC OBSTRUCTIVE PULMONARY DISEASE (Continued)THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 141Plate 4-31 Diseases and Pathologyreduction of capillary surface area. When the DLCO decreases below 50% predicted, many patients with emphysema have arterial oxygen desaturation with exercise.PREDOMINANCE OF CHRONIC BRONCHITISPatients with a predominance of chronic bronchitis typically have a history of cough and sputum produc-tion for many years along with a history of heavy ciga-rette smoking (see Plate 4-30). Initially, the cough may be present only in the winter months, and the patient may seek medical attention only during the more severe of his or her repeated attacks of purulent bronchitis. Over the years, the cough becomes continuous, and episodes of illness increase in frequency, duration, and severity. After the patient begins to experience exer-tional dyspnea, he or she often seeks medical help and is found to have a severe degree of obstruction. Fre-quently, such patients do not seek out a physician until the onset of acute or chronic respiratory failure. Many of these patients report nocturnal snoring and daytime hypersomnolence and demonstrate sleep apnea syndrome, which may contribute to the clinical manifestations.Patients with a predominance of bronchitis are often overweight and cyanotic. There is often no apparent distress at rest; the respiratory rate is normal or only slightly increased. Accessory muscle usage is not appar-ent. The chest percussion note is normally resonant and, on auscultation, one can usually hear coarse rattles and rhonchi, which change in location and intensity after a deep breath and productive cough. Wheezing may be present during resting breathing or may be elicited with a forced expiration.The minute ventilation is either normal or only slightly increased. Failure to increase minute ventila-tion in the face of ventilation-perfusion mismatch leads to hypoxemia. Because of impaired chemosensitivity, such patients do not compensate properly and permit hypercapnia to develop with Paco2 levels above 45 mm Hg. The low Pao2 produces desaturation of hemoglobin, which causes hypoxic pulmonary vasocon-striction and eventually irreversible pulmonary hyper-tension. Desaturation may lead to visible cyanosis, and hypoxic pulmonary vasoconstriction leads to right-sided heart failure (see Plate 4-32). Because of the chronic systemic infl ammatory response that occurs with COPD, these patients often do not have a normal erythrocytic response to hypoxemia, so the serum hemoglobin may be normal, elevated, or even decreased.The TLC is often normal, and the RV is moderately elevated. The vital capacity (VC) is mildly diminished. Maximal expiratory fl ow rates are invariably low. Lung elastic recoil properties are normal or only slightly impaired; the DLCO is either normal or minimally decreased.PATHOLOGYLarge Airways Disease (see Plate 4-33)Chronic bronchitis is associated with hyperplasia and hypertrophy of the mucus-secreting glands found in the submucosa of the large cartilaginous airways. Because the mass of the submucous glands is approximately 40 times greater than that of the intraepithelial goblet cells, it is thought that these glands produce most airway mucus. The degree of hyperplasia is quantita-tively assessed as the ratio of the submucosal gland thickness to the overall thickness of the bronchial wall from the cartilage to the airway lumen. This ratio is known as the Reid index. Although the Reid index is often low in the bronchi of patients who do not have symptoms of COPD during life and is frequently high in those with chronic bronchitis, there is suffi cient overlap of Reid index values to suggest that a gradual change in the submucous glands may take place. Thus, the sharp distinction of the clinical defi nition of chronic bronchitis cannot correlate completely with MIXED CHRONIC BRONCHITIS AND EMPHYSEMAThe typical patient with COPD has clinical, physiological, and radiographic features of both chronic bronchitis and emphysema. She may have chronic cough and sputum production, and need accessory muscles and pursed lips to help her breathe. Pulmonary function testing may reveal variable degrees of airflow limitation, hyperinflation, and reduction in the diffusing capacity, and arterial blood gases may show variable decreases in PO2 and increases in PCO2. Radiographic imaging often shows components of airway wall thickening, excessive mucus, and emphysema.CHRONIC OBSTRUCTIVE PULMONARY DISEASE (Continued)142 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONSPlate 4-32 Respiratory System