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Editors: McPhee, Stephen J.; Papadakis, Maxine A.; Tierney, Lawrence M.

Title: Current Medical Diagnosis & Treatment, 46th Edition

Copyright ©2007 McGraw-Hill

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9

Lung

Mark S. Chesnutt MD

Thomas J. Prendergast MD

Common Manifestations of Lung Disease

Dyspnea

Dyspnea is a common symptom. It is analogous to hunger or nausea in that sensory input from multiple sites is integrated in the cerebral cortex. In general, dyspnea increases with the level of functional impairment as measured by spirometry. However, there is only a weak correlation between the severity of dyspnea and quantitative measures of airflow limitation or exercise tolerance.

Several pathophysiologic processes contribute to dyspnea. The most important is the increased respiratory effort that accompanies many different diseases: airflow obstruction (asthma; chronic obstructive pulmonary disease [COPD]), changes in pulmonary compliance (interstitial fibrosis, congestive heart failure) or chest wall compliance (obesity, pleural disease), intrinsic respiratory muscle weakness (inanition, neuromuscular disease, chronic respiratory failure), or the weakness conveyed by the mechanical disadvantage of hyperinflation (asthma or emphysema). Dyspnea is magnified by increased respiratory drive. Acute hypercapnia is therefore a potent stimulus to dyspnea, while hypoxemia is usually a weak one. Stimulation of irritant receptors in the airways intensifies dyspnea, while stimulation of pulmonary stretch receptors decreases it. In mechanically ventilated patients, failure to provide adequate inspiratory flow rates to patients with heightened respiratory drive commonly results in dyspnea that may present as agitation.

Clinical Findings

The history should focus on onset and timing of symptoms, the patient's position at onset of symptoms, the relationship of symptoms to activity, and any factors that may improve or exacerbate symptoms. The clinician can assess dyspnea and response to treatment with a numeric rating scale by asking the patient, “On a scale of zero to ten, with zero being no shortness of breath and ten being the worst shortness of breath you can imagine, how short of breath are you?” Exertional dyspnea should be quantified, but the absolute level of exertion that precipitates dyspnea is less important than acute changes in the threshold level of activity. Complete allergic, occupational, and smoking histories are essential.

Acute dyspnea has a short list of causes, most of which are readily identified: asthma, pulmonary infection, pulmonary edema, pneumothorax, pulmonary embolus, metabolic acidosis, or acute respiratory distress syndrome (ARDS). Panic attacks may present as a respiratory complaint. Orthopnea (dyspnea on recumbency) and nocturnal dyspnea suggest asthma, gastroesophageal reflux disease (GERD), left ventricular dysfunction, or obstructive sleep apnea. Rapid onset of severe dyspnea when supine suggests phrenic nerve impairment leading to diaphragmatic weakness or paralysis. Platypnea (dyspnea that worsens in the upright position) is a rare complaint associated with arteriovenous malformations at the lung bases or with hepatopulmonary syndrome, resulting in increased shunting and hypoxemia in the upright position (orthodeoxia).

Chronic dyspnea is invariably progressive. Symptoms often first appear during exertion; patients learn to limit their activity to accommodate their diminished pulmonary reserve until dyspnea occurs with minimal activity or at rest. Episodic dyspnea suggests congestive heart failure, asthma, acute or chronic bronchitis, or recurrent pulmonary emboli. Constant dyspnea is most commonly due to COPD but may indicate interstitial lung disease (eg, pulmonary fibrosis), pulmonary vascular disease, or fixed airflow obstruction from severe asthma.

Evaluation should include a complete blood count, renal function tests, chest radiograph, spirometry, and noninvasive oximetry. Patients over 40 years of age or with a family history of early coronary disease should have an electrocardiogram. Arterial blood gases, measurement of lung volumes, ventilation-perfusion ([V with dot above]/[Q with dot above]) scanning, echocardiography, and cardiopulmonary exercise testing are reserved for cases that elude diagnosis on initial evaluation.

Treatment

In patients with advanced lung disease, the responsible condition may be easily identified but treatment only partially effective. Oxygen improves survival in those who are hypoxemic and can improve the exercise tolerance of all patients. Its effect on dyspnea is variable.

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Opioids reduce respiratory drive and blunt dyspnea. They can be titrated safely even in patients with advanced lung disease. Anxiety can play an important role in the distress caused by dyspnea and may be relieved by judicious use of benzodiazepines such as lorazepam, 0.5–1 mg orally every 6–8 hours. Pulmonary rehabilitation can improve respiratory function and train patients in energy conservation and breathing techniques that help moderate their sense of respiratory effort. Finally, fresh air or a fan may offer additional relief. Smokers with progressive exertional dyspnea should know that they can limit future loss of function through smoking cessation.

Dyspnea is increasingly being recognized as a major issue in the care of dying patients, and clinicians typically undertreat this symptom. See Chapter 5.

Dyspnea. Mechanisms, assessment, and management: a consensus statement. American Thoracic Society. Am J Respir Crit Care Med 1999;159:321.

Karnani NG et al: Evaluation of chronic dyspnea. Am Fam Physician 2005;71:1529.

Luce JM et al: Management of dyspnea in patients with far-advanced lung disease: “once I lose it, it's kind of hard to catch it…” JAMA 2001;285:1331.

Cough

Cough is an important physiologic mechanism that defends against respiratory pathogens and helps clear the tracheobronchial tree of mucus, foreign particles, and noxious aerosols. Excessive cough is one of the most common symptoms for which patients seek medical care and may represent up to one-third of a pulmonologist's outpatient practice referrals. Persistent severe cough, seen in interstitial lung disease or bronchiectasis, may impair respiration as well as disrupt sleep and social functioning. Bronchospasm (brought on by repetitive forced exhalation), syncope, rib fractures, and urinary incontinence are all potential complications. A reduced or absent cough, seen in some postoperative patients or those with neuromuscular disease, will reduce clearance of secretions and may impair oxygenation.

Cough may be voluntary or involuntary. Involuntary cough is stimulated by vagal afferent receptors in the trachea, especially at the carina, and the larynx but also from others throughout the head and neck. Stimulation of cough receptors may be mechanical, as in cases of aspiration, or irritative.

Clinical Findings

It is important to distinguish acute (< 3 weeks) from subacute (3–8 weeks) and chronic (> 8 weeks) cough. Acute cough most commonly follows viral or bacterial upper respiratory tract infection. Within 2 days after onset of the common cold, 85% of untreated patients cough; 25% are still coughing 14 days later; in a few, cough will persist for 6–8 weeks. Many patients with persistent cough following upper respiratory tract infection have underlying asthma. Other causes of acute cough include aspiration, pneumonia, pulmonary embolism, and pulmonary edema.

The most common cause of chronic cough is a low-grade chronic bronchitis secondary to exposure to tobacco smoke, though smokers do not commonly seek medical attention for this problem. Over 90% of nonsmokers presenting for evaluation of chronic cough suffer from postnasal drip, GERD, or asthma (even without other symptoms). Angiotensin-converting enzyme (ACE) inhibitors have become another common cause. In primary care settings, single causes predominate.

The character and timing of chronic cough and the presence or absence of sputum production do not permit an etiologic diagnosis and should not be used as the sole basis for empiric therapy. The history and physical examination should attempt to identify anatomic locations of the afferent limb of the cough reflex in light of the common causes listed above. A nasal discharge, frequent need to clear the throat, and mucoid or mucopurulent secretions in the posterior pharynx suggest postnasal drip. Sinus radiographs may be diagnostic of acute or chronic sinusitis. Wheezing on chest auscultation or airflow obstruction on pulmonary function tests suggests asthma. In cough-variant asthma, methacholine bronchoprovocation testing may be positive in the absence of clinical findings of asthma. GERD is an important cause of chronic cough but is associated with the fewest clinical clues; cough, in the absence of heartburn, may be the only symptom. Barium swallow is specific but insensitive, and esophageal pH monitoring may be necessary for diagnosis. Chest radiographs are best reserved for evaluation of cough in smokers and patients with hemoptysis or constitutional symptoms such as fever and weight loss.

Treatment

The first step is to eliminate irritant exposures such as tobacco smoke (primary or secondary) and occupational agents and to discontinue medications such as ACE inhibitors or β-blockers, including eyedrops. Cough due to ACE inhibitors should subside within 1–4 days after discontinuing the medication, though it may take several weeks. Postnasal drip syndrome due to allergic rhinitis that does not respond to antihistamines should be treated with intranasal corticosteroids. Chronic sinusitis may require prolonged antibiotics directed against Haemophilus influenzae. Cough caused by asthma that does not respond after 2 weeks of bronchodilators and corticosteroids suggests another contributing condition. Cough due to GERD is difficult to treat and may require proton pump inhibitors since H2 blockers may be inadequate. Patients whose cough began after an upper respiratory tract infection usually respond to treatment with an antihistamine-decongestant combination or treatment for asthma.

Chang AB et al: Gastro-oesophageal reflux treatment for prolonged non-specific cough in children and adults. Cochrane Database Syst Rev 2005;(2):CD004823.

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Hewlett EL et al: Clinical practice. Pertussis—not just for kids. N Engl J Med 2005;352:1215.

Morice AH et al; ERS Task Force: The diagnosis and management of chronic cough. Eur Respir J 2004;24:481.

Pratter MR et al: An empiric integrative approach to the management of cough: ACCP evidence-based clinical practice guidelines. Chest 2006;129(1 Suppl):222S.

Hemoptysis

Hemoptysis is the expectoration of blood that originates below the vocal cords. It is commonly classified as trivial, mild, or massive—the latter defined as more than 200–600 mL in 24 hours. The dividing lines are arbitrary, since the amount of blood is rarely quantified with precision. Massive hemoptysis can be usefully defined as any amount that is hemodynamically significant or threatens ventilation, in which case the initial management goal is not diagnostic but therapeutic.

The lungs are supplied with a dual circulation. The pulmonary arteries arise from the right ventricle to supply the pulmonary parenchyma in a low-pressure circuit. The bronchial arteries arise from the aorta or intercostal arteries and carry blood under systemic pressure to the airways, blood vessels, hila, and visceral pleura. The bronchial arterial circulation is a high-pressure circuit that provides the blood supply to the airways and lesions within those airways. Although the bronchial circulation represents only 1–2% of total pulmonary blood flow, it can increase dramatically under conditions of chronic inflammation—eg, chronic bronchiectasis—and is frequently the source of hemoptysis.

The causes of hemoptysis can be classified anatomically. Blood may arise from the airways in chronic bronchitis, bronchiectasis, and bronchogenic carcinoma; from the pulmonary vasculature in left ventricular failure, mitral stenosis, pulmonary emboli, and arteriovenous malformations; or from the pulmonary parenchyma in pneumonia, inhalation of crack cocaine, or autoimmune diseases such as Goodpasture's disease or Wegener's granulomatosis. Iatrogenic hemorrhage may follow transbronchial lung biopsies, anticoagulation, or pulmonary artery rupture due to distal placement of a balloon-tipped catheter.

Clinical Findings

Blood-tinged sputum in the setting of acute bronchitis in an otherwise healthy nonsmoker does not warrant an extensive diagnostic evaluation if the hemoptysis subsides with resolution of the infection. However, hemoptysis is frequently a sign of serious disease, especially in patients with a high prior probability of underlying pulmonary pathology. The goal of the history is to identify patients at risk for one of the disorders listed above. Pertinent features include past or current tobacco use, duration of symptoms, or the presence of respiratory infection. Nonpulmonary sources of hemorrhage—from the nose or the gastrointestinal tract—should be excluded.

Laboratory evaluation should include a chest radiograph and complete blood count, including platelet count. Renal function tests, urinalysis, and coagulation studies are appropriate in specific circumstances. Flexible bronchoscopy reveals endobronchial cancer in 3–6% of patients with hemoptysis who have a normal (non-lateralizing) chest radiograph. Nearly all of these patients are smokers over the age of 40, and most will have had symptoms for more than a week. Bronchoscopy is indicated in such patients. High-resolution CT of the chest is complementary to bronchoscopy. It can diagnose unsuspected bronchiectasis and arteriovenous malformations and will show central endobronchial lesions in many cases. It is the test of choice for suspected small peripheral malignancies.

Treatment

The management of mild hemoptysis consists of identifying and treating the specific cause. Massive hemoptysis is life-threatening. The airway must be protected, ventilation ensured, and effective circulation maintained. If the location of the bleeding site is known, the patient should be placed in the decubitus position with the involved lung dependent. Uncontrollable hemorrhage warrants rigid bronchoscopy and surgical consultation. In stable patients, flexible bronchoscopy may localize the site of bleeding, and angiography can embolize the involved bronchial arteries. Embolization is effective initially in 85% of cases, though rebleeding may occur in up to 20% of patients over the following year. The anterior spinal artery arises from the bronchial artery in up to 5% of people, and paraplegia may result if it is inadvertently cannulated.

Bidwell JL et al: Hemoptysis: diagnosis and management. Am Fam Physician 2005;72:1253.

Flume PA et al: Massive hemoptysis in cystic fibrosis. Chest 2005;128:729.

Yoon YC et al: Hemoptysis: bronchial and nonbronchial systemic arteries at 16-detector row CT. Radiology 2005;234:292.

Approach to the Patient

Physical Examination

Examination of the patient with suspected pulmonary disease includes inspection, palpation, percussion, and auscultation of the chest. An efficient approach begins with observing the pattern of breathing, auscultation of the chest, and inspection for extrapulmonary signs of pulmonary disease. More detailed examination follows from initial findings.

The pattern of breathing refers to the respiratory rate and rhythm, the depth of breathing or tidal volume, and the relative amount of time spent in inspiration and expiration. Normal values are a rate of 12–14 breaths per minute, tidal volumes of 5 mL/kg, and a ratio of

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inspiratory to expiratory time of 2:3. Tachypnea is an increased rate of breathing and is commonly associated with a decrease in tidal volume. Respiratory rhythm is normally regular, with a sigh (1.5–2 times normal tidal volume) every 90 breaths or so to prevent collapse of alveoli and atelectasis. Alterations in the rhythm of breathing include rapid, shallow breathing, seen in restrictive lung disease and as a precursor to respiratory failure; Kussmaul breathing, rapid large-volume breathing indicating intense stimulation of the respiratory center, seen in metabolic acidosis; and Cheyne-Stokes respiration, a rhythmic waxing and waning of both rate and tidal volumes that includes regular periods of apnea. This last pattern is seen in patients with end-stage left ventricular failure or neurologic disease and in many normal persons at high altitude, especially during sleep.

During normal quiet breathing, the primary muscle of respiration is the diaphragm. Movement of the chest wall is minimal. The use of accessory muscles of respiration, the intercostal and sternocleidomastoid muscles, indicates high work of breathing. At rest, the use of accessory muscles is a sign of significant pulmonary impairment. As the diaphragm contracts, it pushes the abdominal contents down. Hence, the chest and abdominal wall normally expand simultaneously. Expansion of the chest but collapse of the abdomen on inspiration indicates weakness of the diaphragm. The chest normally expands symmetrically. Asymmetric expansion suggests unilateral volume loss, as in atelectasis or pleural effusion, unilateral airway obstruction, asymmetric pulmonary or pleural fibrosis, or splinting from chest pain.

The examiner may palpate as follows: the trachea at the suprasternal notch, to detect shifts in the mediastinum; on the posterior chest wall, to gauge fremitus and the transmission through the lungs of vibrations of spoken words; and on the anterior chest wall to assess the cardiac impulse. All these maneuvers are characterized by low interobserver agreement.

Chest percussion identifies dull areas that correspond to lung consolidation or pleural effusion or hyperresonant areas suggesting emphysema or pneumothorax. Percussion has a low sensitivity (10–20% in several studies) compared with chest radiographs to detect abnormalities. Specificity is high (85–99%). Since an insensitive test is a poor screening examination, percussion and palpation are not necessary in every patient. These techniques do serve as important confirmatory tests in specific patients when the prior probability of a finding is increased. For example, in a patient with a suspected tension pneumothorax, the finding of tracheal shift and hyperresonance can be lifesaving, permitting immediate decompression of the affected side.

Auscultation of the chest depends on a reliable and consistent classification of auditory findings. Normal lung sounds heard over the periphery of the lung are called vesicular. They have a gentle, rustling quality heard throughout inspiration that fades during expiration. Normal sounds heard over the suprasternal notch are called tracheal or bronchial lung sounds. They are louder, higher-pitched, and have a hollow quality that tends to be louder on expiration. Bronchial lung sounds heard over the periphery of the lung are abnormal and imply consolidation. Globally diminished lung sounds are an important finding predictive of significant airflow obstruction.

Abnormal lung sounds (“adventitious” breath sounds) may be continuous (> 80 ms in duration) or discontinuous (< 20 ms). Continuous lung sounds are divided into wheezes, which are high-pitched, musical, and have a distinct whistling quality; and rhonchi, which are lower-pitched, sonorous, and may have a gurgling quality. Wheezes occur in the setting of bronchospasm, mucosal edema, or excessive secretions. In each case, the airway is narrowed to the point where adjacent airway walls flutter as airflow is limited. Rhonchi originate in the larger airways when excessive secretions and abnormal airway collapsibility cause repetitive rupture of fluid films. Rhonchi frequently clear after cough.

Discontinuous lung sounds are called crackles—brief, discrete, nonmusical sounds with a popping quality. Fine crackles are soft, high-pitched, and crisp (< 10 ms in duration). They are formed by the explosive opening of small airways previously held closed by surface forces and are heard in interstitial diseases or early pulmonary edema. Coarse crackles are louder, lower-pitched, and slightly longer in duration (< 20 ms) and probably result from gas bubbling through fluid. Coarse crackles are heard in pneumonia, obstructive lung disease, and late pulmonary edema.

Interobserver agreement regarding auscultatory findings is good. The clinical usefulness of these findings is also well established. The presence of wheezes on physical examination is a powerful predictor of obstructive lung disease. The absence of wheezes is not helpful since patients may have significant airflow limitation without wheezing. Such patients will have globally diminished lung sounds as the clinical clue to their obstructive lung disease. Normal lung sounds exclude significant airway obstruction. The timing and character of crackles can reliably distinguish different pulmonary disorders. Fine, late inspiratory crackles suggest pulmonary fibrosis, while early coarse crackles suggest pneumonia or heart failure.

Extrapulmonary signs of intrinsic pulmonary disease include digital clubbing, cyanosis, elevation of central venous pressures, and lower extremity edema.

Digital clubbing refers to structural changes at the base of the nails that include softening of the nail bed and loss of the normal 150-degree angle between the nail and the cuticle. The distal phalanx is convex and enlarged: its thickness is equal to or greater than the thickness of the distal interphalangeal joint. Symmetric clubbing may be a normal variant but more commonly is a sign of underlying disease. Clubbing is seen in patients with chronic infections of the lungs and pleura (lung abscess, empyema, bronchiectasis, cystic fibrosis), malignancies of the lungs and pleura, chronic interstitial lung disease (idiopathic

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pulmonary fibrosis), and arteriovenous malformations. It does not normally accompany asthma or COPD; when seen in the latter, concomitant lung cancer should be suspected. It is observed less often in small-cell cancer than in other histologic types. Clubbing is not specific to pulmonary disorders; it is also seen in cyanotic congenital heart disease, infective endocarditis, cirrhosis, and inflammatory bowel disease. Hypertrophic pulmonary osteoarthropathy is a syndrome of digital clubbing, chronic proliferative periostitis of the long bones, and synovitis. It is seen in the same conditions as digital clubbing but is particularly common in bronchogenic carcinoma. The cause of clubbing and hypertrophic osteoarthropathy is not known with certainty, but the disorder may reflect platelet clumping and local release of platelet-derived growth factor at the nail bed. Both clubbing and osteoarthropathy may resolve with appropriate treatment of the underlying disease. Cyanosis is a blue or bluish-gray discoloration of the skin and mucous membranes caused by increased amounts (> 5 g/dL) of unsaturated hemoglobin in capillary blood. Since the oxygen saturation at which cyanosis becomes clinically apparent is a function of hemoglobin concentration, anemia may prevent cyanosis from appearing while polycythemia may lead to cyanosis in the setting of mild hypoxemia. Cyanosis is therefore not a reliable indicator of hypoxemia but should prompt direct measurement of arterial PO2 or of hemoglobin saturation.

Estimation of central venous pressure (CVP) and assessment of lower extremity edema are indirect measures of pulmonary hypertension, the major cardiovascular complication of chronic lung disease. Estimation of CVP can be done with precision in many patients. Elevated CVP is a pathologic finding associated with impaired ventricular function, pericardial effusion or restriction, valvular heart disease, and chronic obstructive or restrictive lung disease. Peripheral edema is a nonspecific finding that, in the setting of chronic lung disease, suggests right ventricular failure.

Bettencourt PE et al: Clinical utility of chest auscultation in common pulmonary diseases. Am J Respir Crit Care Med 1994;150(5 Pt 1):1291.

Lichtenstein D et al: Comparative diagnostic performances of auscultation, chest radiography, and lung ultrasonography in acute respiratory distress syndrome. Anesthesiology 2004; 100:9.

Myers KA et al: Does this patient have clubbing? JAMA 2001; 286:341.

Pulmonary Function Tests

Standard pulmonary function tests measure airflow rates, lung volumes, and the ability of the lung to transfer gas across the alveolar-capillary membrane. Indications for pulmonary function testing include assessment of the type and extent of lung dysfunction; diagnosis of causes of dyspnea and cough; detection of early evidence of lung dysfunction; longitudinal surveillance in occupational settings; follow-up of response to therapy; preoperative assessment; and disability evaluation.

Contraindications to pulmonary function testing include acute severe asthma, respiratory distress, angina aggravated by testing, pneumothorax, ongoing hemoptysis, and active tuberculosis. Many test results are effort-dependent, and some patients may be too impaired to make a maximal effort. Suboptimal effort limits validity and is a common cause of misinterpretation of results. All pulmonary function tests are measured against predicted values derived from large studies of healthy subjects. In general, these predictions vary with age, gender, height and, to a lesser extent, weight and ethnicity.

Spirometry (see box, p. 227) and measurement of lung volumes allow measurement of the presence and severity of obstructive and restrictive pulmonary dysfunction. Obstructive dysfunction is marked by a reduction in airflow rates judged by a fall in the ratio of FEV1 (forced expiratory volume in the first second) to FVC (forced vital capacity). Causes include asthma, COPD (chronic bronchitis and emphysema), bronchiectasis, bronchiolitis, and upper airway obstruction. Restrictive dysfunction is marked by a reduction in lung volumes with a normal to increased FEV1/FVC ratio. Severity is graded by the reduction in total lung capacity. A reduced FVC suggests pulmonary restriction but is not diagnostic. Causes include decreased lung compliance from infiltrative disorders such as pulmonary fibrosis; reduced muscle strength from phrenic nerve injury, diaphragm dysfunction, or neuromuscular disease; pleural disease, including large pleural effusion or marked pleural thickening; and prior lung resection. The flow-volume loop combines the maximal expiratory and inspiratory flow-volume curves and is especially helpful in determining the site of airway obstruction. (See Figure 9-1.)

Spirometry is adequate for evaluation of most patients with suspected respiratory disease. If airflow obstruction is evident, spirometry may be repeated 10–20 minutes after an inhaled bronchodilator is administered. This doubles the cost of the study. The absence of improvement in spirometry after inhaled bronchodilator in the pulmonary function laboratory does not preclude a successful clinical response to bronchodilator therapy. Measurements of lung volumes and diffusing capacity are useful in selected patients, but these tests are expensive and should not be ordered routinely with spirometry.

Measurement of the single-breath diffusing capacity for carbon monoxide (DLCO), which reflects the ability of the lung to transfer gas across the alveolar/capillary interface, is particularly helpful in evaluation of patients with diffuse infiltrative lung disease or emphysema. The total pulmonary diffusing capacity depends on the diffusion properties of the alveolar-capillary membrane and the amount of hemoglobin occupying the pulmonary capillaries. The diffusing capacity should therefore be corrected for the blood hemoglobin concentration.1

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Lung Volumes, Capacities, and the Normal Spirogram

The volume of gas in the lungs is divided into volumes and capacities as shown in the bars to the left of the figure below. Lung volumes are primary: they do not overlap each other. Tidal volume (Vt) is the amount of gas inhaled and exhaled with each resting breath. Residual volume (RV) is the amount of gas remaining in the lungs at the end of a maximal exhalation. The vital capacity (VC) is the total amount of gas that can be exhaled following a maximal inhalation. The vital capacity and the residual volume together constitute the total lung capacity (TLC), or the total amount of gas in the lungs at the end of a maximal inhalation. The functional residual capacity (FRC) is the amount of gas in the lungs at the end of a resting tidal breath. (IC = inspiratory capacity; IRV = inspiratory reserve volume; ERV = expiratory reserve volume; RV = residual volume.) The forced vital capacity (FVC) maneuver begins with an inhalation from FRC to TLC (lasting about 1 second) followed by a forceful exhalation from TLC to RV (lasting about 5 seconds). The amount of gas exhaled during the first second of this maneuver is the forced expiratory volume in the first second (FEV1). Normal subjects expel approximately 80% of the FVC in the first second. The ratio of the FEV1 to the FVC (often referred to as the FEV1%) is diminished in patients with obstructive lung disease. It may be increased in patients with restrictive physiology.

Figure. No caption available.

Modified, with permission, from Comroe JH et al: The Lung: Clinical Physiology and Pulmonary Function Tests, 2nd ed. Year Book Medical Publishers, 1962.

Elevated DLCO is observed in pulmonary hemorrhage and may be seen in acute congestive heart failure and asthma due to an increase in pulmonary capillary blood volume. A diffusing capacity of 6 mL CO/mm Hg or more below the predicted value in women or 8.1 mL CO/mm Hg in men is considered abnormally low (Intermountain Thoracic Society guidelines). Reporting the ratio of measured diffusing capacity to alveolar volume (DLCO/VA) is helpful, because a diminished diffusing capacity may only reflect a reduction in lung volume. In patients with emphysema, the diffusing capacity is characteristically low, the alveolar volume normal or increased, and the DLCO/VA ratio is low. In patients with diffuse infiltrative lung disease, both the diffusing capacity and the alveolar volume are characteristically reduced, and the DLCO/VA ratio is normal or low.

In patients with AIDS, DLCO is a highly sensitive screening test for the presence of pulmonary disease, especially Pneumocystis jiroveci (formerly P carinii) pneumonia, but it lacks specificity. A normal DLCO in an AIDS patient is strong evidence against Pneumocystis pneumonia. An abnormal result indicates the need for further diagnostic evaluation. Routine measurement of DLCO and other pulmonary function tests in AIDS patients with pulmonary disease is not advised, because of expense and lack of specificity.

Arterial blood gas analysis is indicated whenever a clinically important acid-base disturbance, hypoxemia, or hypercapnia is suspected. Oximetry provides an inexpensive, noninvasive alternative means of monitoring hemoglobin saturation with oxygen. Oximeters monitor hemoglobin saturation and not oxygen tension. Figure 9-2 displays the normal relationship between hemoglobin saturation and partial pressure of oxygen in blood. This relationship is not linear. The clinical accuracy of pulse oximeters is reduced in such conditions as severe anemia (< 5 g/dL hemoglobin), the presence of abnormal hemoglobin moieties (carboxyhemoglobin, methemoglobin, fetal hemoglobin), the presence of intravascular dyes, motion artifact, and lack of pulsatile arterial blood flow (hypotension, hypothermia, cardiac arrest, simultaneous use of a blood pressure cuff, and cardiopulmonary bypass). The normal arterial PO2 falls with increasing altitude (Table 9-1).

Nonspecific bronchial provocation testing may aid the evaluation of suspected asthma, when baseline spirometry is normal, and in unexplained cough. The subject inhales a nebulized solution containing methacholine

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or histamine. These agents cause bronchial smooth muscle constriction in asthmatic patients at much lower doses than in nonasthmatics. If the FEV1 falls by more than 20% at a dose of 16 mg/mL or less, the test is positive. Bronchial provocation testing is 95% sensitive for the diagnosis of asthma. A negative result therefore makes asthma unlikely. Specificity is lower—about 70%—since false positives may occur in several common conditions, including COPD, congestive heart failure, recent viral respiratory infection, cystic fibrosis, and sarcoidosis.

Figure 9-1. Representative spirograms (upper panel) and expiratory flow-volume curves (lower panel) for normal (A), obstructive (B), and restrictive (C) patterns.

Figure 9-2. Oxygen-hemoglobin dissociation curve, pH 7.40, temperature 38°C. (Reproduced, with permission, from

Comroe JH Jr et al: The Lung: Clinical Physiology and Pulmonary Function Tests, 2nd ed. Year Book Medical Publishers, 1962.

)

Evans SE et al: Current practice in pulmonary function testing. Mayo Clin Proc 2003;78:758.

Miller MR et al; ATS/ERS Task Force: General considerations for lung function testing. Eur Respir J 2005;26:153.

Cardiopulmonary Exercise Stress Testing

Cardiopulmonary exercise testing is usually performed to evaluate patients with unexplained exertional dyspnea. A bicycle ergometer or treadmill is used. Minute ventilation, expired oxygen and carbon dioxide tension, heart rate, blood pressure, and respiratory rate are monitored. The exercise protocol is determined by the indications for the test and the ability of the patient to exercise. Complications are rare.

American Thoracic Society; American College of Chest Physicians: ATS/ACCP statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med 2003;167:211.

Bronchoscopy

Flexible bronchoscopy is an essential tool in the diagnosis and management of many pulmonary diseases. Bronchoscopy

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is indicated for evaluation of the airway, diagnosis and staging of bronchogenic carcinoma, evaluation of hemoptysis, and diagnosis of pulmonary infections. It allows transbronchial lung biopsy, bronchoalveolar lavage, and removal of retained secretions and foreign bodies from the airway. The procedure is contraindicated in severe bronchospasm or a bleeding diathesis. Complications include hemorrhage, fever, and transient hypoxemia. The rate of major complications is less than 1% but increases to about 7% when transbronchial lung biopsy is performed. Deaths are rare. Hospitalization for flexible bronchoscopy is not necessary.

Table 9-1. The effect of altitude on PO2 in normal adults.

Altitude (feet) Barometric Pressure (mm Hg) Atmo-spheric1 PO2 (mm Hg) Tracheal2 PO2 (mm Hg) Arterial3 PO2 (mm Hg)
Sea level 760 159 149 99
2000 707 148 138 88
4000 656 137 127 77
6000 609 127 118 68
8000 564 118 108 58
10,000 523 109 100 50
15,000 426 90 80 30
1Dry gas.
2Saturated with water vapor.
3Actual values at altitude will be higher, depending on the degree of adaptation (ventilatory response to hypoxia).

Rigid bronchoscopy is performed for massive bleeding, extraction of large obstructing objects (foreign bodies, blood clots, tumor masses, broncholiths), biopsy of tracheal or main stem bronchus tumors and bronchial carcinoids, and facilitation of laser therapy. Unlike flexible bronchoscopy, which can usually be performed with only topical anesthesia and low-dose conscious sedation (an opioid or a benzodiazepine or both), rigid bronchoscopy usually requires general anesthesia.

Advances in techniques including endobronchial laser therapy, electrocautery, tracheobronchial stenting, and endobronchial ultrasound guidance to locate lymph nodes prior to transbronchial needle aspiration biopsy (“Wang” biopsy) promise to expand diagnostic and therapeutic avenues available to the bronchoscopist significantly. This is an area of rapid technological advancement and emerging clinical research study.

Footnote

where [Hb] is the measured hemoglobin concentration (g/dL).

Peikert T et al: Safety, diagnostic yield, and therapeutic implications of flexible bronchoscopy in patients with febrile neutropenia and pulmonary infiltrates. Mayo Clin Proc 2005; 80:1414.

Seijo LM et al: Interventional pulmonology. N Engl J Med 2001; 344:740.

Disorders of the Airways

Airway disorders have diverse causes but share certain common pathophysiologic and clinical features. Airflow limitation is characteristic and frequently causes dyspnea and cough. Other symptoms are common and typically disease-specific. Disorders of the airways can be classified as those that involve the upper airways—loosely defined as those above and including the vocal cords—and those that involve the lower airways.

Disorders of the upper Airways

Upper airway obstruction may occur acutely or present as a chronic condition. Acute upper airway obstruction can be immediately life-threatening and must be relieved promptly to avoid asphyxia. Causes of acute upper airway obstruction include foreign body aspiration, laryngospasm, laryngeal edema from airway burns, angioedema, trauma to the larynx or pharynx, infections (Ludwig's angina, pharyngeal or retropharyngeal abscess, acute epiglottis), and acute allergic laryngitis.

Chronic obstruction of the upper airway may be caused by carcinoma of the pharynx or larynx, laryngeal or subglottic stenosis, laryngeal granulomas or webs, or bilateral vocal cord paralysis. Laryngeal or subglottic stenosis may become evident weeks or months following a period of translaryngeal endotracheal intubation. Inspiratory stridor, intercostal retractions on inspiration, a palpable inspiratory thrill over the larynx, and wheezing localized to the neck or trachea on auscultation are characteristic findings. Flow-volume loops may show flow limitations characteristic of obstruction. Soft tissue radiographs of the neck may show supraglottic or infraglottic narrowing. CT and MRI scans can reveal exact sites of obstruction. Flexible endoscopy may be diagnostic, but caution is necessary to avoid exacerbating upper airway edema and precipitating critical airway narrowing.

Vocal cord dysfunction syndrome is a condition characterized by paradoxical vocal cord adduction, resulting in both acute and chronic upper airway obstruction. It can cause dyspnea and wheezing that may present as asthma; it may be distinguished from asthma by the lack of response to bronchodilator therapy, normal spirometry immediately after an attack, spirometric evidence of upper airway obstruction, a negative bronchial provocation test, or direct visualization of adduction of the vocal cords on both inspiration and expiration. Bronchodilators are of no therapeutic benefit. Treatment consists of speech therapy.

Ernst A et al: Central airway obstruction. Am J Respir Crit Care Med 2004;169:1278.

Gose JE: Acute workup of vocal cord dysfunction. Ann Allergy Asthma Immunol 2003;91:318.

Soli CG et al: Vocal cord dysfunction: An uncommon cause of stridor. J Emerg Med 2005;28:31.

Disorders of the Lower Airways

Tracheal obstruction may be intrathoracic (below the suprasternal notch) or extrathoracic. Fixed tracheal obstruction may be caused by acquired or congenital tracheal stenosis, primary or secondary tracheal neoplasms, extrinsic compression (tumors of the lung, thymus, or thyroid; lymphadenopathy; congenital vascular rings; aneurysms, etc), foreign body aspiration, tracheal granulomas and papillomas, and tracheal trauma.

Acquired tracheal stenosis is usually secondary to previous tracheotomy or endotracheal intubation. Dyspnea, cough, and inability to clear pulmonary secretions occur weeks to months after tracheal decannulation or extubation. Physical findings may be absent until tracheal diameter is reduced 50% or more, when wheezing, a palpable tracheal thrill, and harsh breath sounds may be detected. The diagnosis is usually confirmed by plain films or CT of the trachea. Complications include recurring pulmonary infection and life-threatening respiratory failure. Management is directed toward ensuring adequate

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ventilation and oxygenation and avoiding manipulative procedures that may increase edema of the tracheal mucosa. Surgical reconstruction, endotracheal stent placement, or laser photoresection may be required.

Bronchial obstruction may be caused by retained pulmonary secretions, aspiration, foreign bodies, bronchogenic carcinoma, compression by extrinsic masses, and tumors metastatic to the airway. Clinical and radiographic findings vary depending on the location of the obstruction and the degree of airway narrowing. Symptoms include dyspnea, cough, wheezing, and, if infection is present, fever and chills. A history of recurrent pneumonia in the same lobe or segment or slow resolution (> 3 months) of pneumonia on successive radiographs suggests the possibility of bronchial obstruction and the need for bronchoscopy. Complete obstruction of a main stem bronchus may be obvious on physical examination (asymmetric chest expansion, mediastinal shift, absence of breath sounds on the affected side, and dullness to percussion), but partial obstruction is often difficult or impossible to detect. Prolonged expiration and localized wheezing may be the only clues. Segmental or subsegmental bronchial obstruction may produce no abnormalities on physical examination.

Roentgenographic findings include atelectasis (local parenchymal collapse), postobstructive infiltrates, and air trapping caused by unidirectional expiratory obstruction. CT scanning may demonstrate the nature and the exact location of obstruction of the central bronchi. MRI may be superior to CT for delineating the extent of the underlying disease in the hilum, but it is usually reserved for cases in which CT findings are equivocal. Bronchoscopy is the definitive diagnostic study, particularly if tumor or foreign body aspiration is suspected. The finding of tubular breath sounds on physical examination or an air bronchogram on chest radiograph in an area of atelectasis rules out complete airway obstruction. Bronchoscopy is unlikely to be of therapeutic benefit in this situation.

Right middle lobe syndrome is recurrent or persistent atelectasis of the right middle lobe. This collapse is related to the relatively long length and narrow diameter of the right middle lobe bronchus and the oval (“fish mouth”) opening to the lobe, in the setting of impaired collateral ventilation. Fiberoptic bronchoscopy or CT scan is often necessary to rule out obstructing tumor. Foreign body or other benign causes are common.

Duggan M et al: Pulmonary atelectasis: a pathogenic perioperative entity. Anesthesiology 2005;102:838.

Kwon KY et al: Middle lobe syndrome: a clinicopathological study of 21 patients. Hum Pathol 1995;26:302.

Asthma

Essentials of Diagnosis

  • Episodic or chronic symptoms of airflow obstruction: breathlessness, cough, wheezing, and chest tightness.

  • Symptoms frequently worse at night or in the early morning.

  • Prolonged expiration and diffuse wheezes on physical examination.

  • Limitation of airflow on pulmonary function testing or positive bronchoprovocation challenge.

  • Complete or partial reversibility of airflow obstruction, either spontaneously or following bronchodilator therapy.

General Considerations

Asthma is a common disease, affecting approximately 5% of the population. Men and women appear to be equally affected. Each year, approximately 470,000 hospital admissions and 5000 deaths in the United States are attributed to asthma. Hospitalization rates have been highest among blacks and children, and death rates for asthma are consistently highest among blacks aged 15–24 years. Prevalence, hospitalizations, and fatal asthma have all increased in the United States over the past 20 years.

Definition & Pathogenesis

Asthma is a chronic inflammatory disorder of the airways. The histopathologic features include denudation of airway epithelium, collagen deposition beneath the basement membrane, airway edema, mast cell activation, and inflammatory cell infiltration with neutrophils, eosinophils, and lymphocytes (especially T lymphocytes). Hypertrophy of bronchial smooth muscle and hypertrophy of mucous glands with plugging of small airways with thick mucus can occur. This airway inflammation underlies disease chronicity and contributes to airway hyperresponsiveness, airflow limitation, and respiratory symptoms (including recurrent episodes of wheezing, breathlessness, chest tightness, and cough, particularly during the nighttime and early morning hours).

A genetic predisposition to asthma is recognized. The strongest identifiable predisposing factor for the development of asthma is atopy. Exposure of sensitive patients to inhaled allergens increases airway inflammation, airway hyperresponsiveness, and symptoms. Symptoms may develop immediately (immediate asthmatic response) or 4–6 hours after allergen exposure (late asthmatic response). Common aeroallergens include house dust mites (often found in pillows, mattresses, upholstered furniture, carpets, and drapes), cockroaches, cats, and seasonal pollens. Substantially reducing exposure reduces pathologic findings and clinical symptoms.

Nonspecific precipitants of asthma include exercise, upper respiratory tract infections, rhinitis, sinusitis, postnasal drip, aspiration, gastroesophageal reflux, changes in the weather, and stress. Exposure to environmental tobacco smoke increases asthma symptoms and the need for medications and reduces lung function. Increased

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air levels of respirable particles, ozone, SO2, and NO2 precipitate asthma symptoms and increase emergency department visits and hospitalizations. Selected individuals may experience asthma symptoms after exposure to aspirin, nonsteroidal anti-inflammatory drugs, or tartrazine dyes. Certain other medications may also precipitate asthma symptoms (Table 9-28). Occupational asthma is triggered by various agents in the workplace and may occur weeks to years after initial exposure and sensitization. Women may experience catamenial asthma at predictable times during the menstrual cycle. Exercise-induced bronchoconstriction usually begins within 3 minutes after the end of exercise, peaks within 10–15 minutes, and then resolves by 60 minutes. This phenomenon is thought to be a consequence of the airways' attempt to warm and humidify an increased volume of expired air during exercise. “Cardiac asthma” is wheezing precipitated by uncompensated congestive heart failure.

Table 9-2. Classification of severity of chronic stable asthma.

  Symptoms Nighttime Symptoms Lung Function
Mild intermittent Symptoms ≤ 2 times a week
Asymptomatic and normal PEF between exacerbations
Exacerbations brief (few hours to few days); intensity may vary
≤ 2 times a month FEV1 or PEF ≥ 80% predicted
PEF variability ≤ 20%
Mild persistent Symptoms > 2 times a week but < 1 time a day
Exacerbations may affect activity
> 2 times a month FEV1 or PEF > 80% predicted
PEF variability 20-30%
Moderate persistent Daily symptoms
Daily use of inhaled short-acting β2-agonist
Exacerbations affect activity
Exacerbations ≥ 2 times a week; may last days
> 1 time a week FEV1 or PEF > 60% to < 80% predicted
PEF variability > 30%
Severe persistent Continual symptoms
Limited physical activity
Frequent exacerbations
Frequent FEV1 or PEF ≤ 60% predicted
PEF variability > 30%
PEF = peak expiratory flow; FEV1 = forced expiratory volume in the first second.
Adapted from National Asthma Education and Prevention Program. Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma. National Institutes of Health Pub. No. 97-4051. Bethesda, MD, 1997.

Clinical Findings

Symptoms and signs vary widely from patient to patient as well as individually over time. General clinical findings in stable asthma patients are listed below (Table 9-2); findings seen during asthma exacerbations are listed in Table 9-3.

A. Symptoms and Signs

Asthma is characterized by episodic wheezing, difficulty in breathing, chest tightness, and cough. The frequency of asthma symptoms is highly variable. Some patients may have only a chronic dry cough and others a productive cough. Some patients have infrequent, brief attacks of asthma and others may suffer nearly continuous symptoms. Asthma symptoms may occur spontaneously or may be precipitated or exacerbated by many different triggers as discussed above. Asthma symptoms are frequently worse at night; circadian variations in bronchomotor tone and bronchial reactivity reach their nadir between 3 AM and 4 AM, increasing symptoms of bronchoconstriction.

Some physical findings increase the probability of asthma. Nasal mucosal swelling, increased nasal secretions, and nasal polyps are often seen in patients with allergic asthma. Eczema, atopic dermatitis, or other manifestations of allergic skin disorders may also be present. Hunched shoulders and use of accessory muscles of respiration suggest an increased work of breathing. Chest examination may be normal between exacerbations in patients with mild asthma. Wheezing during normal breathing or a prolonged forced expiratory phase correlates well with the presence of airflow obstruction. Wheezing during forced expiration does not. During severe asthma exacerbations, airflow may be too limited to produce wheezing, and the only diagnostic clue on auscultation may be globally reduced breath sounds with prolonged expiration.

B. Pulmonary Function Testing

Clinicians are able to identify airflow obstruction on examination, but they have limited ability to assess it

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or to predict whether it is reversible. The evaluation for asthma should therefore include spirometry (FEV1, FVC, FEV1/FVC) before and after the administration of a short-acting bronchodilator. These measurements help determine the presence and extent of airflow obstruction and whether it is immediately reversible. Airflow obstruction is indicated by a reduced FEV1/FVC ratio (< 75%). In severe airflow obstruction with significant air trapping, the FVC may also be reduced, resulting in a pattern that suggests a restrictive ventilatory defect. Significant reversibility of airflow obstruction is defined by an increase of ≥ 12% and 200 mL in FEV1 or ≥ 15% and 200 mL in FVC after inhaling a short-acting bronchodilator. However, the absence of improvement in airflow after administration of a bronchodilator is not proof of irreversible airflow obstruction.

Table 9-3. Classification of severity of asthma exacerbations.

  Mild Moderate Severe Impending Respiratory Failure
Symptoms
   Breathlessness With activity With talking At rest At rest
   Speech Sentences Phrases Words Mute
Signs
   Body position Able to recline Prefers sitting Unable to recline Unable to recline
   Respiratory rate Increased Increased Often > 30/min > 30/min
   Use of accessory respiratory muscles Usually not Commonly Usually Paradoxical thoracoabdominal movement
   Breath sounds Moderate wheezing at mid- to end-expiration Loud wheezes throughout expiration Loud inspiratory and expiratory wheezes Little air movement without wheezes
   Heart rate (beats/min) < 100 100–120 > 120 Relative bradycardia
   Pulsus paradoxus (mm Hg) < 10 10-25 Often > 25 Often absent
   Mental status May be agitated Usually agitated Usually agitated Confused or drowsy
Functional assessment
   PEF (% predicted or personal best) > 80 50-80 < 50 or response to therapy lasts < 2 hours < 50
   Sao2 (%, room air) > 95 91-95 < 91 < 91
   Pao2 (mm Hg, room air) Normal > 60 < 60 < 60
   Paco2 (mm Hg) < 42 < 42 ≥ 42 ≥ 42
PEF = peak expiratory flow.
Adapted from National Asthma Education and Prevention Program. Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma. National Institutes of Health Pub. No. 97-4051. Bethesda, MD, 1997.

Peak expiratory flow (PEF) meters are handheld devices designed as home monitoring tools. PEF monitoring can establish peak flow variability, quantify asthma severity, and provide both the patient and the clinician with objective measurements on which to base treatment decisions. There are conflicting data about whether measuring PEF improves asthma outcomes, but doing so is recommended as part of a comprehensive approach to asthma management in Expert Panel Report 2 of the National Asthma Education and Prevention Program (NAEPP) of the National Heart, Lung and Blood Institute.

Predicted values for PEF vary with age, height, and gender but are poorly standardized. Comparison with reference values is less helpful than comparison with the patient's best baseline. PEF shows diurnal variation. It is generally lowest on first awakening and highest several hours before the midpoint of the waking day. PEF should be measured in the morning before the administration of a bronchodilator and in the afternoon after taking a bronchodilator. A 20% change in PEF values from morning to afternoon or from day to day suggests inadequately controlled asthma. PEF values less than 200 L/min indicate severe airflow obstruction.

Bronchial provocation testing with histamine or methacholine—or exercise challenge testing—may be useful when asthma is suspected and spirometry is nondiagnostic. Bronchial provocation is not generally recommended if the FEV1 is less than 65% of predicted.

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A positive test is defined as a decrease in FEV1 of at least 20% at exposure to a dose of 16 mg/mL or less. A negative test has a negative predictive value for asthma of 95%.

Arterial blood gas measurements may be normal during a mild asthma exacerbation, but respiratory alkalosis and an increase in the alveolar-arterial oxygen difference (A-a-DO2) are common. During severe exacerbations, hypoxemia develops and the PaCO2 returns to normal. The combination of an increased PaCO2 and respiratory acidosis is a harbinger of respiratory failure and may indicate the need for mechanical ventilation.

C. Additional Testing

Routine chest radiographs in patients with asthma usually show only hyperinflation. Other findings may include bronchial wall thickening and diminished peripheral lung vascular shadows. Chest radiographs are indicated when pneumonia, another disorder mimicking asthma, or a complication of asthma such as pneumothorax is suspected. The diagnostic usefulness of measurements of biologic markers of inflammation such as cell counts and mediator titers in blood and sputum is being investigated. Skin testing or in vitro testing to assess sensitivity to relevant environmental allergens may be useful in patients with persistent asthma. Evaluations for paranasal sinus disease or gastroesophageal reflux should be considered in patients with pertinent symptoms and in those who have severe or refractory asthma.

Complications

Complications of asthma include exhaustion, dehydration, airway infection, cor pulmonale, and tussive syncope. Pneumothorax occurs but is rare. Acute hypercapnic and hypoxic respiratory failure occurs in severe disease.

Differential Diagnosis

Disorders that mimic asthma typically fall into one of three categories: upper and lower airway disorders, systemic vasculitides, and psychiatric disorders. It is prudent to consider these conditions in patients who have atypical asthma symptoms or response to therapy. Upper airway disorders that mimic asthma include vocal cord paralysis, vocal cord dysfunction syndrome, foreign body aspiration, laryngotracheal masses, tracheal narrowing, tracheomalacia, and airway edema as in the setting of angioedema or inhalation injury. Lower airway disorders include nonasthmatic COPD (chronic bronchitis or emphysema), bronchiectasis, allergic bronchopulmonary mycosis, cystic fibrosis, eosinophilic pneumonia, and bronchiolitis obliterans. Systemic vasculitides that often have an asthmatic component include Churg-Strauss syndrome and other systemic vasculitides with pulmonary involvement. Psychiatric causes include conversion disorders, which have been variably referred to as functional asthma, emotional laryngeal wheezing, vocal cord dysfunction, or episodic laryngeal dyskinesis. Munchausen syndrome or malingering may rarely explain the patient's complaints.

Classification of Asthma Severity

The Expert Panel of the NAEPP has developed asthma classification schemes that are useful in directing asthma therapy and identifying patients at high risk for developing life-threatening asthma attacks. Table 9-2 is used to classify the severity of chronic, stable asthma; Table 9-3 is used to classify the severity of asthma exacerbations. A patient's clinical features before treatment are used to classify the patient. The presence of only one of the severity features is sufficient to place a patient in that category; patients should be assigned to the most severe grade in which any feature occurs.

Approach to Long-Term Treatment

The goals of asthma therapy are to minimize chronic symptoms that impair normal activity (including exercise), to prevent recurrent exacerbations, to minimize the need for emergency department visits or hospitalizations, and to maintain near-normal pulmonary function. These goals should be met while providing optimal pharmacotherapy with the fewest adverse effects and while meeting patients' and families' expectations of satisfaction with asthma care.

Current approaches to persistent asthma focus on daily anti-inflammatory therapy with inhaled corticosteroids. Treatment algorithms are based on both the severity of a patient's baseline asthma and the severity of asthma exacerbations. Expert Panel Report 2 from the NAEPP recommends a stepwise approach to therapy (Table 9-4). The amount of medication and frequency of dosing are dictated by asthma severity and directed toward suppression of increasing airway inflammation. To establish prompt control, therapy should be initiated early at a higher intensity level than anticipated for long-term therapy. Pharmacotherapy can then be cautiously stepped down once asthma control is achieved and sustained; this allows for identification of the minimum medication necessary to maintain long-term control.

Pharmacologic Agents for Asthma

Asthma medications can be divided into two categories: agents that offer quick relief of symptoms and agents taken to promote long-term asthma control. Quick-relief medications are taken to promote prompt reversal of acute airflow obstruction and relieve accompanying symptoms by direct relaxation of bronchial smooth muscle. Long-term control medications are taken daily independent of symptoms to achieve and maintain control of persistent asthma. These agents—also known as maintenance, controller, or preventive medications—act primarily to attenuate airway inflammation.

Table 9-4. Stepwise approach for managing asthma.1

  Long-Term Control Quick Relief Education
Step 1:
   Mild intermittent No daily medication needed. Short-acting bronchodilator: inhaled β2-agonists as needed for symptoms.
Intensity of treatment will depend on severity of exacerbation.
Use of short-acting inhaled β2-agonists > 2 times a week may indicate the need for long-term control therapy.
Teach basic facts about asthma
Teach inhaler/inhalation chamber technique
Discuss roles of medications
Develop self-management and action plans
Discuss appropriate environmental control measures
Step 2:
   Mild persistent One daily medication:
   Anti-inflammatory: either inhaled corticosteroid (low doses) or cromolyn or nedocromil
Less desirable alternatives: sustained-release theophylline or leukotriene modifier
Step 1 actions plus:
   Use of short-acting inhaled β2-agonists on a daily basis, or increasing use, indicates the need for additional long-term control therapy.
Step 1 actions plus:
   Teach self-monitoring
   Refer to group education if available
   Review and update self-management plan
Step 3:
   Moderate persistent Daily medication:
         Either
   Anti-inflammatory: inhaled corticosteroid (medium dose)
         or
   Inhaled corticosteroid (low-medium dose) and a long-acting bronchodilator (long-acting inhaled β2-agonist, sustained-release theophylline or long-acting β2-agonist tablets)
         If needed:
   Anti-inflammatory: inhaled corticosteroid (medium-high dose)
         and
   Long-acting bronchodilator (long-acting inhaled β2-agonist, sustained-release theophylline or long-acting β2-agonist tablets)
As for step 2. Step 1 actions plus:
   Teach self-monitoring
   Refer to group education if available
   Review and update self-management plan
Step 4:
   Severe persistent Daily medication:
   Anti-inflammatory: inhaled corticosteroid (high dose)
         and
   Long-acting bronchodilator (long-acting inhaled β2-agonist, sustained release theophylline or long-acting inhaled β2-agonist tablets)
         and
Corticosteroid tablets or syrup (1-2 mg/kg/d, generally not to exceed 60 mg/d)
As for step 2. Step 2 and 3 actions plus:
   Refer to individual education, counseling
Step down: Review treatment every 1-6 months; a gradual stepwise reduction in treatment may be possible.
Step up: If asthma control is not maintained, consider step up to next treatment level after reviewing medication technique, adherence, and environmental control.
1Preferred treatments are in bold text; however, specific medication plans should be tailored to individual patients.
Modified from National Asthma Education and Prevention Program. Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma. National Institutes of Health Pub. No. 97-4051. Bethesda, MD, 1997.

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Many asthma medications are administered orally or by inhalation. Inhalation of an appropriate agent results in a more rapid onset of pulmonary effects as well as fewer systemic effects compared with oral administration of the same dose. Metered-dose inhalers (MDIs) propelled by chlorofluorocarbons (CFCs) have been the most widely used delivery system, but non-CFC propellant systems and dry powder inhalers are available. These alternatives are effective and well tolerated. Proper MDI technique and the use of an inhalation chamber improve drug delivery to the lung and decrease oropharyngeal deposition. Nebulizer therapy is reserved for acutely ill patients and those who cannot use MDIs because of difficulties with coordination or cooperation.

A. Long-Term Control Medications

Anti-inflammatory agents, long-acting bronchodilators, and leukotriene modifiers comprise the important medications in this group of agents (see Table 9-5). Other classes of agents are mentioned briefly below.

1. Anti-inflammatory agents

Corticosteroids are the most potent and consistently effective anti-inflammatory agents currently available. They reduce both acute and chronic inflammation, resulting in fewer asthma symptoms, improvement in airflow, decreased airway hyperresponsiveness, fewer asthma exacerbations, and less airway remodeling. These agents may also potentiate the action of β-adrenergic agonists.

Inhaled corticosteroids are preferred for the long-term control of asthma and are first-line agents for patients with persistent asthma. Patients with persistent symptoms or asthma exacerbations who are not taking inhaled corticosteroids should be started on an inhaled corticosteroid; symptomatic patients already taking an inhaled corticosteroid should have the dose increased. Dosages for inhaled corticosteroids vary depending on the specific agent and delivery device. The most important determinants of agent selection and appropriate dosing are the patient's status and response to treatment. For most patients, twice-daily dosing provides adequate control of asthma. Once-daily dosing may be sufficient in selected patients with mild persistent asthma. Maximum responses from inhaled corticosteroids may not be observed for months. The use of an inhalation chamber coupled with mouth washing after inhalation decreases local side effects (cough, dysphonia, oropharyngeal candidiasis) and systemic absorption. Systemic effects (adrenal suppression, osteoporosis, skin thinning, easy bruising, and cataracts) may occur with high-dose inhalation therapy.

Systemic corticosteroids (oral or parenteral) are most effective in achieving prompt control of asthma during exacerbations or when initiating long-term asthma therapy. In patients with severe persistent asthma, systemic corticosteroids are often required for the long-term suppression of symptoms. Repeated efforts should be made to reduce the dose to the minimum needed to control symptoms. Alternate-day treatment is preferred to daily treatment. Rapid discontinuation of systemic corticosteroids after chronic use may precipitate adrenal insufficiency. Concurrent treatment with calcium supplements and vitamin D should be initiated to prevent corticosteroid-induced bone mineral loss in long-term administration. Bisphosphonates may offer additional protection to these patients (see Table 26-18).

2. Long-acting bronchodilators

a. Mediator inhibitors

Cromolyn sodium and nedocromil are long-term control medications that prevent asthma symptoms and improve airway function in patients with mild persistent asthma or exercise-induced asthma. Both of these agents modulate mast cell mediator release and eosinophil recruitment and inhibit both early and late asthmatic responses to allergen challenge and exercise-induced bronchospasm. The clinical response to these agents is less predictable than the response to inhaled corticosteroids. Nedocromil may help reduce the dose requirements for inhaled corticosteroids. Both agents have excellent safety profiles.

b. β-Adrenergic agents

Long-acting β2-agonists provide bronchodilation for up to 12 hours after a single dose. However, because their onset of action is delayed, they are not effective—and should not be used—in the treatment of acute bronchoconstriction. Salmeterol and formoterol are the two agents in this class available in the United States. They are administered via dry powder delivery devices. They are indicated for long-term prevention of asthma symptoms, nocturnal symptoms, and for prevention of exercise-induced bronchospasm. They should not be used in place of anti-inflammatory therapy. When added to standard doses of inhaled corticosteroids, salmeterol provides control equivalent to what is achieved by doubling the inhaled corticosteroid dose. Side effects are minimal at standard doses.

c. Phosphodiesterase inhibitors

Theophylline provides mild bronchodilation in asthmatic patients. This drug may also have anti-inflammatory properties, enhance mucociliary clearance, and strengthen diaphragmatic contractility. Sustained-release theophylline preparations are effective in controlling nocturnal asthma and are usually reserved for use as adjuvant therapy in patients with moderate or severe persistent asthma. They can also be used as alternative long-term preventive therapy in patients with mild persistent asthma. Theophylline serum concentrations need to be monitored closely owing to the drug's narrow toxic-therapeutic range, individual differences in metabolism, and the effects of many factors on drug absorption and metabolism. Decreases in theophylline clearance accompany the use of cimetidine, macrolide and quinolone antibiotics, and oral contraceptives. Increases in theophylline clearance are caused by rifampin, phenytoin, barbiturates, and tobacco.

Adverse effects at therapeutic doses include insomnia, upset stomach, aggravation of dyspepsia and gastroesophageal reflux symptoms, and urination difficulties in elderly men with prostatism. Dose-related toxicities are common and include nausea, vomiting,

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tachyarrhythmias, headache, seizures, hyperglycemia, and hypokalemia.

Table 9-5. Long-term control medications for asthma.1

Drug Important Formulations Usual Adult Dosage Cost2 Comments
Inhaled corticosteroids3
   Beclomethasone dipropionate (QVAR) 40 mcg/puff
80 mcg/puff
Two or three puffs BID
One to two puffs BID
$61.54/7.30 g
$77.44/7.30 g
Chlorofluorocarbon-free; hydrofluoralkane propellant
   Budesonide (Pulmicort Turbuhaler) Dry powder delivery system: 200 mcg/puff; 200 puffs/inhaler One inhalation twice a day $158.15/inhaler Dry powder
   Flunisolide (AeroBid) MDI: 250 mcg/puff; 100 puffs/inhaler Two to four puffs twice a day $77.57/7 g Chlorofluorocarbon propellant
   Fluticasone (Flovent HFA) MDI: 44, 110, or 220 mcg/puff; 120 puffs/inhaler Two or three puffs (of 110 mcg) twice a day $103.98/13 g (110 µg) Chlorofluorocarbon propellant
   Fluticasone (Flovent Rotadisk) Dry powder delivery system: 44, 88, 220 mcg/blister; 4 blisters/Rotadisk, 15 Rotadisks per tube One or two puffs (of 88 mcg) twice a day Not available in the U.S. Dry powder
   Triamcinolone acetonide (Azmacort) MDI: 100 mcg/puff; 240 puffs/inhaler Two or three puffs four times a day, or four to six puffs twice daily $92.58/20 g Chlorofluorocarbon propellant
Systemic corticosteroids
   Methylprednisolone (many) Tablets: 4 mg 5-60 mg daily to every other day as needed $0.54/4 mg  
   Prednisolone (many) Tablets: 5 mg 5-60 mg daily to every other day as needed $0.04/5 mg  
   Prednisone (many) Tablets: 1, 2.5, 5, 10, 20, 50 mg 5-60 mg daily to every other day as needed $0.04/5 mg  
Combination inhaled corticosteroid and long-acting β2-agonist
   Fluticasone and salmeterol (Advair Diskus) Dry powder delivery system: 100, 250, or 500 mcg fluticasone per dose and 50 mcg salmeterol per dose One puff twice a day of 250/50; cannot use more than one puff twice a day due to salmeterol component $177.71/60 250/60 disks Dry powder
Cromolyn (Intal) MDI: 800 mcg per puff: 200 puffs/inhaler 2-4 puffs 4 times a day $102.12/14.2 g Chlorofluorocarbon propellant
Nebulizer solution: 20 mg/2 mL ampule 20 mg (2 mL) four times a day $1.26/2 mL Administer with powered nebulizer
Nedocromil (Tilade) MDI: 1.75 mg/puff; 112 puffs/inhaler Two puffs four times a day $79.68/16.2 g Chlorofluorocarbon propellant
Long-acting β2 agonists4
   Salmeterol (Serevent Diskus) Dry powder: 50 mcg/blister; 60 blisters per pack One blister every 12 hours $100.16/60 Dry powder
   Formoterol (Foradil Aerolizer) Dry powder: 12 mcg/capsule; 60 capsules/Aerolizer One capsule every 12 hours $79.83/60 Dry powder
   Sustained-release albuterol (Proventil Repetab) Sustained-release tablet, 4 mg One tablet every 12 hours $1.24/4 mg Usually reserved for nocturnal symptoms not improved with other therapies
Theophylline (many) Sustained-release tablets and capsules Initially 10 mg/kg/d up to 300 mg maximum; then 200-600 mg every 8-24 hours $0.33/200 mg Maintenance dose guided by serum drug level. Absorption and dosing vary with brand
Leukotriene modifiers
   Montelukast (Singulair) Tablet, 10 mg One tablet each evening $3.47/10 mg
$104.10/mo
 
   Zafirlukast (Accolate) Tablet, 20 mg One tablet twice a day $1.46/20 mg
$88.10/mo
Administration with meals decreases bioavailability; take at least 1 hour before or 2 hours after meals
   Zileuton (Zyflo) Tablet, 600 mg One tablet four times a day $2.28/600 mg
$273.75/mo
Monitor hepatic enzymes
1Only drugs available in the United States are listed.
2Average wholesale price (AWP, for AB-rated generic when available) for quantity listed. Source: Red Book Update, Vol. 25, No. 5. May 2006. AWP may not accurately represent actual pharmacy cost because wide contractual variations exist among institutions.
3Dosing should be individualized. See text.
4Not for acute relief of symptoms.
MDI = metered-dose inhaler.

3. Leukotriene modifiers

This is the newest class of medications for long-term control of asthma. Leukotrienes are potent biochemical mediators that contribute to airway obstruction and asthma symptoms by contracting airway smooth muscle, increasing vascular permeability and mucus secretion, and attracting and activating airway inflammatory cells. Zileuton is a 5-lipoxygenase inhibitor that decreases leukotriene production, and zafirlukast and montelukast are cysteinyl leukotriene receptor antagonists. They cause modest improvements in lung function and reductions in asthma symptoms and lessen the need for β-agonist rescue therapy. These agents may be considered as alternatives to low-dose inhaled corticosteroids in patients with mild persistent asthma. Zileuton can cause reversible elevations in plasma aminotransferase levels, and Churg-Strauss syndrome has been diagnosed in a small number of patients who have taken montelukast or zafirlukast.

4. Desensitization

Immunotherapy for specific allergens may be considered in selected asthma patients who have exacerbations of asthma symptoms when exposed to allergens to which they are sensitive and who do not respond to environmental control measures or other forms of conventional therapy. Studies show a reduction in asthma symptoms in patients treated with single-allergen immunotherapy. Because of the risk of immunotherapy-induced bronchoconstriction, it should be administered only in a setting where such complications can be treated.

5. Miscellaneous agents

Oral sustained-release β2-agonists are reserved for patients with bothersome nocturnal asthma symptoms or moderate to severe persistent asthma who do not respond to other therapies. Omalizumab is a recombinant antibody that binds IgE without activating mast cells. In clinical trials, it reduces the need for corticosteroids in moderate to severe asthmatic patients with elevated IgE levels. Corticosteroid-sparing anti-inflammatory agents such as troleandomycin, methotrexate, cyclosporine, intravenous immunoglobulin, and gold should be used only in selected severe asthmatic patients. These and other agents have variable benefit and worrisome toxicities.

B. Quick-Relief Medications

Short-acting bronchodilators and systemic corticosteroids comprise the important medications in this group of agents (Table 9-6).

1. β-Adrenergic agents

Short-acting inhaled β-adrenergic agonists are clearly the most effective bronchodilators during exacerbations. β-Adrenergic agonists should be used in all patients to treat acute symptoms. These agents relax airway smooth muscle and cause a prompt increase in airflow and reduction of symptoms. Administration before exercise effectively prevents exercise-induced bronchoconstriction. There is no convincing evidence to support the use of one agent over another. However, β2-selective agents produce less cardiac stimulation than those with mixed β1 and β2 activities. Currently available short-acting β2-selective adrenergic agonists include albuterol, bitolterol, pirbuterol, and terbutaline.

Inhaled β-adrenergic agonist therapy is as effective as oral or parenteral therapy in relaxing airway smooth muscle and improving acute asthma and offers the advantages of rapid onset of action (< 5 minutes) with fewer systemic side effects. Repetitive administration produces incremental bronchodilation. Intravenous and subcutaneous routes of administration should be reserved for patients who because of age or mechanical factors are unable to inhale medications.

One or two inhalations of a short-acting inhaled β2-agonist from an MDI are usually sufficient for mild to moderate symptoms. Severe exacerbations frequently require higher doses: equivalent bronchodilation can be achieved by high doses (6–12 puffs every 30–60 minutes) of a β2-agonist by MDI with an inhalation chamber or by nebulizer therapy. Administration by wet nebulization does not offer more effective delivery than MDIs but it is given in higher doses. With most β2-agonists, the recommended dose by nebulizer for acute asthma (albuterol, 2.5 mg) is 25–30 times that delivered by a single activation of the MDI (albuterol, 0.09 mg). This difference suggests that the standard use of inhalations from an MDI will often be insufficient in the setting of an acute exacerbation. Independent of dose, nebulizer therapy may be more effective in patients who are unable to coordinate inhalation of medication from an MDI because of age, agitation, or severity of the exacerbation.

Scheduled daily use of short-acting β2-agonists is not generally recommended. Increased use (more than one canister a month) or lack of expected effect indicates diminished asthma control and dictates the need for additional long-term control therapy.

2. Anticholinergics

Anticholinergic agents reverse vagally mediated bronchospasm but not allergen- or exercise-induced bronchospasm. They may decrease mucus gland hypersecretion seen in asthma. Ipratropium bromide, a quaternary derivative of atropine free of atropine's side effects, reverses acute bronchospasm and is the inhaled alternative for patients with intolerance to β2-agonists. Ipratropium bromide may be a useful adjunct to inhaled short-acting β2-agonists and considered in patients with moderate to severe asthma exacerbations. High doses of inhaled ipratropium bromide (0.5 mg) cause additional bronchodilation in some patients with severe airway obstruction, but the role in long-term management of asthma has not been clarified. It is the drug of choice for bronchospasm due to β-blocker medications.

3. Phosphodiesterase inhibitors

Methylxanthines are not recommended for therapy of asthma exacerbations. Aminophylline has clearly been shown to be less

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effective than β2-agonists when used as single-drug therapy for acute asthma and adds little except toxicity to the acute bronchodilator effects achieved by nebulized metaproterenol alone. Patients with exacerbations who are currently taking a theophylline-containing preparation should have their serum theophylline concentration measured to exclude theophylline toxicity.

Table 9-6. Quick-relief medications for asthma.1

Drug Important Formulations Usual Adult Dosage Cost2 Comments
Short-acting Inhaled β2-agonists
   Albuterol (Proventil, Ventolin) MDI: 90 mcg/puff, 200 puffs/canister Two puffs 5 minutes before exercise $29.79/17 g Preferred formulation in most cases.
  Two puffs every 4-6 hours as needed   Chlorofluorocarbon propellant.
Nebulizer solutions: 5 mg/mL (0.5%) 1.25-5 mg (0.25-1 mL) in 2-3 mL of normal saline every 4-8 hours as needed $16.50/20 mL Administer with powered nebulizer. More frequent dosing is acceptable for acute or severe exacerbations.
Unit dose: 0.083%, 3 mL One dose every 4-8 hours as needed $1.24/unit May mix with cromolyn or ipratropium nebulizer solutions.
Tablets: 2 mg, 4 mg 2-4 mg orally every 6-8 hours $31.14/100 2-mg tablets Extended-release 4-mg tablet (Proventil Repetab) available for use every 12 hours.
   Albuterol HFA (Proventil HFA) MDI: 90 mcg/puff, 200 puffs/canister Two puffs 5 minutes before exercise
Two puffs every 4-6 hours as needed
$42.20/6.7 g Nonchlorofluorocarbon propellant.
   Pirbuterol (Maxair Autoinhaler) MDI 200 mcg/puff, 400 puffs/canister Two puffs every 4-6 hours as needed $96.78/14 g Breath-activated MDI system. Chlorofluorocarbon propellant.
   Terbutaline (Brethine) Tablets: 2.5 mg, 5 mg 2.5-5 mg orally three times a day $62.21/100 5-mg tablets Tremor, nervousness, palpitations common; therefore not recommended.
Injection solution, 1 mg/mL 0.25 mg (0.25 mL) subcutaneously; may be repeated once in 30 minutes $22.49/1 mg Onset of action 30 minutes. Not limited to β2-agonist effects.
Anticholinergics
   Ipratropium bromide (Atrovent HFA) MDI: 18 mcg/puff, 200 puffs/canister Two to four puffs every 6 hours $84.60/14 g Non-chlorofluorocarbon propellant.
Unit dose nebulizer solution, 0.2 mg/mL (0.02%), 2.5 mL (0.5 mg) 0.25-0.5 mg (1-2 mL) every 6 hours $1.76/unit  
Systemic corticosteroids
   Methylprednisolone (many) Tablets: 4 mg 40-60 mg/d as single dose or in two divided doses for 3-10 days $11.00/4-mg dose-pack  
   Methylprednisolone sodium succinate (many) Intravenous injection solution vials: 40, 125, 500 mg 0.5-1 mg/kg every 6 hours $3.75/125-mg vial  
   Prednisolone (many) Tablets: 5 mg 40-60 mg/d as single dose or in two divided doses for 3-10 days $0.04/5-mg tablet  
Syrup: 15 mg/5 mL $6.21/240 mL syrup  
Prednisone (many) Tablets: 1, 2.5, 5, 10, 20, 50 mg 40-60 mg/d as single dose or in two divided doses for 3-10 days $0.04/5 mg  
1Only drugs available in the United States are listed.
2Average wholesale price (AWP, for AB-rated generic when available) for quantity listed. Source: Red Book Update, Vol. 25., No. 5, May 2006. AWP may not accurately represent the actual pharmacy cost because wide contractual variations exist among institutions.
MDI = metered-dose inhaler.

4. Corticosteroids

Systemic corticosteroids are effective primary treatment for patients with moderate to severe exacerbations or for patients who do not respond promptly and completely to inhaled β2-agonist therapy. Systemic corticosteroids are one of the mainstays of the treatment of patients with severe asthma. These medications speed the resolution of airflow obstruction and reduce the rate of relapse. Delays in administering corticosteroids may result in delayed benefits from these important agents. Therefore, oral corticosteroids should be available for early administration at home in many patients with moderate to severe asthma.

It may be prudent to administer corticosteroids to critically ill patients via the intravenous route in order to avoid concerns about altered gastrointestinal absorption. The minimal effective dose of systemic corticosteroids for asthma patients has not been identified. Outpatient prednisone “burst” therapy is 0.5–1 mg/kg/d (typically 40–60 mg) as a single or in two divided doses for 3–10 days. Severe exacerbations requiring hospitalization typically require 1 mg/kg of prednisone equivalent every 6–12 hours for 48 hours or until the FEV1 (or PEF rate) returns to 50% of predicted (or 50% of baseline). The dose is then decreased to 60–80 mg/d until the PEF reaches 70% of predicted or personal best. No clear advantage has been found for higher doses of corticosteroids in severe exacerbations.

5. Antimicrobials

Antibiotics have no role in routine asthma exacerbations. They may be useful if bacterial respiratory tract infections are thought to contribute. Thus, patients with fever and purulent sputum and evidence of pneumonia or bacterial sinusitis are reasonable candidates.

Approach to Treatment of Asthma Exacerbations

The principal goals in the treatment of asthma exacerbations are correction of hypoxemia, reversal of airflow obstruction, and reduction of the likelihood of recurrence of obstruction. Early intervention may lessen the severity and duration of an exacerbation. Of paramount importance is correction of hypoxemia through the use of supplemental oxygen. At the same time, rapid reversal of airflow obstruction should be attempted by repetitive or continuous administration of an inhaled short-acting β2-agonist and the early administration of systemic corticosteroids to patients with moderate to severe asthma exacerbations or to patients who do not respond promptly and completely to an inhaled short-acting β2-agonist.

Serial measurements of lung function to quantify the severity of airflow obstruction and its response to treatment are especially useful. The improvement in FEV1 after 30 minutes of treatment correlates significantly with a broad range of indices of the severity of asthma exacerbations. Serial measurement of airflow in the emergency department is an important factor in disposition and may reduce the rate of hospital admissions for asthma exacerbations.

The postexacerbation care plan is an important aspect of management. Regardless of the severity, all patients should be provided with necessary medications and education in how to use them, instruction in self-assessment, a follow-up appointment, and instruction in an action plan for managing recurrence.

Approach to Treatment of Mild Asthma Exacerbations

Mild asthma exacerbations are characterized by only minor changes in airway function (PEF > 80%) and minimal symptoms and signs of airway dysfunction (Table 9-3). The majority of exacerbations can be managed with home-based therapies. Most patients respond quickly and fully to an inhaled short-acting β2-agonist alone. However, an inhaled short-acting β2-agonist may need to be continued every 3–4 hours for 24–48 hours. For mild exacerbations in patients already taking an inhaled corticosteroid, the dose is doubled until peak flow returns to predicted or personal best. In patients not already taking an inhaled corticosteroid, initiation of this agent should be considered. A 3- to 10-day course of oral corticosteroids may be necessary for mild exacerbations that persist despite an increase in the dose of inhaled corticosteroids. See Table 9-6.

Approach to Treatment of Moderate & Severe Asthma Exacerbations

Some patients with moderate asthma exacerbations can be managed at home with the telephone assistance of a clinician. However, most such patients require a more comprehensive evaluation and treatment program such as that outlined below for severe asthma exacerbations. A course of oral corticosteroids is usually necessary.

Owing to the life-threatening nature of severe exacerbations of asthma, treatment should be started immediately once the exacerbation is recognized. All patients with a severe exacerbation should immediately receive oxygen, high doses of an inhaled short-acting β2-agonist, and systemic corticosteroids. A brief history pertinent to the exacerbation can be completed while treatment is given. More detailed assessments, including laboratory studies, usually add little in the early phase of evaluation and management and should be delayed until after initial therapy has been completed.

Asphyxia is a common cause of death, and oxygen therapy is therefore very important. Supplemental oxygen

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should be given to maintain an SaO2 > 90% or a PaO2 > 60 mm Hg. Oxygen-induced hypoventilation is extremely rare, and concern for hypercapnia should never delay correction of hypoxemia.

Frequent high-dose delivery of an inhaled short-acting β2-agonist is indicated and is usually well tolerated in the setting of severe airway obstruction. Some studies suggest that continuous therapy is more efficacious than intermittent administration of these agents, but there is no clear consensus as long as similar doses are administered. At least three MDI or nebulizer treatments should be given in the first hour of therapy. Thereafter, the frequency of administration varies according to the improvement in airflow and associated symptoms and the occurrence of side effects.

Systemic corticosteroids are administered as detailed above. Mucolytic agents (eg, acetylcysteine, potassium iodide) may worsen cough or airflow obstruction. Anxiolytic and hypnotic drugs are contraindicated in critically ill asthma patients because of their respiratory depressant effects.

Repeat assessment of patients with severe exacerbations should be made after the initial dose of inhaled bronchodilator and after three doses of inhaled bronchodilators (60–90 minutes after initiating treatment). The response to initial treatment is a better predictor of the need for hospitalization than is the severity of an exacerbation on presentation. The decision to hospitalize a patient should be based on the duration and severity of symptoms, severity of airflow obstruction, course and severity of prior exacerbations, medication use at the time of the exacerbation, access to medical care and medications, adequacy of social support and home conditions, and presence of psychiatric illness. In general, discharge to home is appropriate if the PEF or FEV1 has returned to ≥ 70% of predicted or personal best and symptoms are minimal or absent. Patients with a rapid response to treatment should be observed for 30 minutes after the most recent dose of bronchodilator to ensure stability of response before discharge to home.

A small minority of patients will not respond well to treatment and will show signs of impending respiratory failure due to a combination of worsening airflow obstruction and respiratory muscle fatigue (Table 9-3). Such patients can deteriorate rapidly and thus should be monitored in a critical care setting. Intubation of an acutely ill asthma patient is technically difficult and is best done semielectively, before the crisis of a respiratory arrest. At the time of intubation, close attention should be given to maintaining intravascular volume because hypotension commonly accompanies the administration of sedation and the initiation of positive-pressure ventilation in patients dehydrated due to poor recent oral intake and high insensible losses.

The main goals of mechanical ventilation are to ensure adequate oxygen and to avoid barotrauma. Controlled hypoventilation with permissive hypercapnia is often required to limit airway pressures. Frequent high-dose delivery of inhaled short-acting β2-agonists should be continued along with anti-inflammatory agents as discussed above. Many questions remain regarding the optimal delivery of inhaled β2-agonists to intubated, mechanically ventilated patients. Further studies are needed to determine the comparative efficacy of MDIs and nebulizers, optimal ventilator settings to use during drug delivery, ideal site along the ventilator circuit for introduction of the delivery system, and maximal acceptable drug doses. In acute severe asthma (FEV1 < 25% of predicted), intravenous magnesium sulfate produces a detectable but clinically insignificant improvement in airflow. Unconventional therapies such as helium-oxygen mixtures and inhalational anesthetic agents are of unclear benefit but may be appropriate in selected patients.

Assessment, Monitoring, & Prevention

Periodic assessments and ongoing monitoring of asthma are essential to determine if the goals of therapy are being met. Clinical assessment and patient self-assessment are the primary methods for monitoring asthma. Patients should be given a written action plan based on signs and symptoms or expiratory flow rates. An action plan is especially important for patients with moderate to severe asthma or those with a history of severe exacerbations. Patients should be taught to recognize symptoms—especially patterns indicating inadequate asthma control or predicting the need for additional therapy. The written asthma action plan should direct the asthma patient to adjust medications in response to particular signs, symptoms, and peak flow measurements and should state when to seek medical help.

Spirometry is recommended at the time of initial assessment, once treatment is initiated and symptoms and peak flows have stabilized, and at least every 1–2 years thereafter. Regular follow-up visits (at least every 6 months, or more frequently based on patient status) are essential to help maintain asthma control and to reevaluate medication requirements. Patients with asthma should receive the pneumococcal vaccine (Pneumovax) and annual influenza vaccinations.

Barnes PJ et al: How do corticosteroids work in asthma? Ann Intern Med 2003;139:359.

Busse WW et al: Asthma. N Engl J Med 2001;344:350.

Kallstrom TJ: Evidence-based asthma management. Respir Care 2004;49:783.

National Asthma Education and Prevention Program: Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma Update on Selected Topics—2002. J Allergy Clin Immunol 2002;110(5 Suppl):S141.

Sin DD et al: Pharmacological management to reduce exacerbations in adults with asthma: a systematic review and meta-analysis. JAMA 2004;292:367.

Walker S et al: Anti-IgE for chronic asthma in adults and children. Cochrane Database Syst Rev 2004;3:CD003559.

Wenzel S: Severe asthma in adults. Am J Respir Crit Care Med 2005;172:149.

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Chronic Obstructive Pulmonary Disease

Essentials of Diagnosis

  • History of cigarette smoking.

  • Chronic cough and sputum production (in chronic bronchitis) and dyspnea (in emphysema).

  • Rhonchi, decreased intensity of breath sounds, and prolonged expiration on physical examination.

  • Airflow limitation on pulmonary function testing that is not fully reversible and most often progressive.

General Considerations

COPD is a disease state characterized by the presence of airflow obstruction due to chronic bronchitis or emphysema; the airflow obstruction is generally progressive, may be accompanied by airway hyperreactivity, and may be partially reversible (American Thoracic Society). The National Heart, Lung, and Blood Institute estimates that 14 million Americans have been diagnosed with COPD; an equal number are thought to be afflicted but remain undiagnosed. Grouped together, COPD and asthma now represent the fourth leading cause of death in the United States, with over 120,000 deaths reported annually. The death rate from COPD is increasing rapidly, especially among elderly men.

Most patients with COPD have features of both emphysema and chronic bronchitis. Chronic bronchitis is a clinical diagnosis defined by excessive secretion of bronchial mucus and is manifested by daily productive cough for 3 months or more in at least 2 consecutive years. Emphysema is a pathologic diagnosis that denotes abnormal permanent enlargement of air spaces distal to the terminal bronchiole, with destruction of their walls and without obvious fibrosis.

Cigarette smoking is clearly the most important cause of COPD. Nearly all smokers suffer an accelerated decline in lung function that is dose- and duration-dependent. Fifteen percent develop progressively disabling symptoms in their 40s and 50s. It is estimated that 80% of patients seen for COPD have significant exposure to tobacco smoke. The remaining 20% frequently have a combination of exposures to environmental tobacco smoke, occupational dusts and chemicals, and indoor air pollution from biomass fuel used for cooking and heating in poorly ventilated buildings. Outdoor air pollution, airway infection, familial factors, and allergy have also been implicated in chronic bronchitis, and hereditary factors (deficiency of α1-antiprotease) have been implicated in COPD. The pathogenesis of emphysema may involve excessive lysis of elastin and other structural proteins in the lung matrix by elastase and other proteases derived from lung neutrophils, macrophages, and mononuclear cells. Atopy and the tendency for bronchoconstriction to develop in response to nonspecific airway stimuli may be important risks for COPD.

Clinical Findings

A. Symptoms and Signs

Patients with COPD characteristically present in the fifth or sixth decade of life complaining of excessive cough, sputum production, and shortness of breath. Symptoms have often been present for 10 years or more. Dyspnea is noted initially only on heavy exertion, but as the condition progresses it occurs with mild activity. In severe disease, dyspnea occurs at rest. A hallmark of COPD is frequent exacerbations of illness that result in absence from work and eventual disability. Pneumonia, pulmonary hypertension, cor pulmonale, and chronic respiratory failure characterize the late stage of COPD. Death usually occurs during an exacerbation of illness in association with acute respiratory failure.

Clinical findings may be completely absent early in the course of COPD. As the disease progresses, two symptom patterns tend to emerge, historically referred to as “pink puffers” and “blue bloaters” (Table 9-7). These patterns have been thought to represent pure forms of emphysema and bronchitis, respectively, but this is a simplification of the anatomy and pathophysiology. Most COPD patients have pathologic evidence of both disorders, and their clinical course may reflect other factors such as central control of ventilation and concomitant sleep-disordered breathing.

B. Laboratory Findings

Spirometry provides objective information about pulmonary function and assesses the results of therapy. Pulmonary function tests early in the course of COPD reveal only evidence of abnormal closing volume and reduced midexpiratory flow rate. Reductions in FEV1 and in the ratio of forced expiratory volume to vital capacity (FEV1% or FEV1/FVC ratio) occur later. In severe disease, the FVC is markedly reduced. Lung volume measurements reveal a marked increase in residual volume (RV), an increase in total lung capacity (TLC), and an elevation of the RV/TLC ratio, indicative of air trapping, particularly in emphysema.

Arterial blood gas measurements characteristically show no abnormalities early in COPD other than an increased A-a-DO2. Indeed, they are unnecessary unless (1) hypoxemia or hypercapnia is suspected, (2) the FEV1 is < 40% of predicted, or (3) there are clinical signs of right heart failure. Hypoxemia occurs in advanced disease, particularly when chronic bronchitis predominates. Compensated respiratory acidosis occurs in patients with chronic respiratory failure, particularly in chronic bronchitis, with worsening of acidemia during acute exacerbations.

Table 9-7. Patterns of disease in advanced COPD.

  Type A: Pink Puffer (Emphysema Predominant) Type B: Blue Bloater (Bronchitis Predominant)
History and physical examination Major complaint is dyspnea, often severe, usually presenting after age 50. Cough is rare, with scant clear, mucoid sputum. Patients are thin, with recent weight loss common. They appear uncomfortable, with evident use of accessory muscles of respiration. Chest is very quiet without adventitious sounds. No peripheral edema. Major complaint is chronic cough, productive of mucopurulent sputum, with frequent exacerbations due to chest infections. Often presents in late 30s and 40s. Dyspnea usually mild, though patients may note limitations to exercise. Patients frequently overweight and cyanotic but seem comfortable at rest. Peripheral edema is common. Chest is noisy, with rhonchi invariably present; wheezes are common.
Laboratory studies Hemoglobin usually normal (12-15 g/dL). Pao2 normal to slightly reduced (65-75 mm Hg) but SaO2 normal at rest. PaCO2 normal to slightly reduced (35-40 mm Hg). Chest radiograph shows hyperinflation with flattened diaphragms. Vascular markings are diminished, particularly at the apices. Hemoglobin usually elevated (15-18 g/dL). Pao2 reduced (45-60 mm Hg) and PaCO2 slightly to markedly elevated (50-60 mm Hg). Chest radiograph shows increased interstitial markings (“dirty lungs”), especially at bases. Diaphragms are not flattened.
Pulmonary function tests Airflow obstruction ubiquitous. Total lung capacity increased, sometimes markedly so. DLCO reduced. Static lung compliance increased. Airflow obstruction ubiquitous. Total lung capacity generally normal but may be slightly increased. DLCO normal. Static lung compliance normal.
Special evaluations
   [V with dot above]/[Q with dot above] matching Increased ventilation to high [V with dot above]/[Q with dot above] areas, ie, high dead space ventilation Increased perfusion to low [V with dot above]/[Q with dot above] areas.
Hemodynamics Cardiac output normal to slightly low. Pulmonary artery pressures mildly elevated and increase with exercise. Cardiac output normal. Pulmonary artery pressures elevated, sometimes markedly so, and worsen with exercise.
Nocturnal ventilation Mild to moderate degree of oxygen desaturation not usually associated with obstructive sleep apnea. Severe oxygen desaturation, frequently associated with obstructive sleep apnea.
Exercise ventilation Increased minute ventilation for level of oxygen consumption. Pao2 tends to fall, PaCO2 rises slightly. Decreased minute ventilation for level of oxygen consumption. Pao2 may rise; PaCO2 may rise significantly.
DLCO = single-breath diffusing capacity for carbon monoxide; [V with dot above]/[Q with dot above] = ventilation-perfusion.

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Examination of the sputum may reveal Streptococcus pneumoniae, H influenzae, or Moraxella catarrhalis. Positive sputum cultures are poorly correlated with acute exacerbations, and research techniques demonstrate evidence of preceding viral infection in a majority of patients with exacerbations. The ECG may show sinus tachycardia, and in advanced disease, chronic pulmonary hypertension may produce electrocardiographic abnormalities typical of cor pulmonale. Supraventricular arrhythmias (multifocal atrial tachycardia, atrial flutter, and atrial fibrillation) and ventricular irritability also occur.

C. Imaging

Radiographs of patients with chronic bronchitis typically show only nonspecific peribronchial and perivascular markings. Plain radiographs are insensitive for the diagnosis of emphysema; they show hyperinflation with flattening of the diaphragm or peripheral arterial deficiency in about half of cases. Parenchymal bullae in the setting of either of these findings are diagnostic of emphysema. Pulmonary hypertension becomes evident as enlargement of central pulmonary arteries in advanced disease. Doppler echocardiography is an effective way to estimate pulmonary artery pressure if pulmonary hypertension is suspected.

Differential Diagnosis

Clinical, roentgenographic, and laboratory findings should enable the clinician to distinguish COPD from other obstructive pulmonary disorders such as bronchial asthma, bronchiectasis, cystic fibrosis, bronchopulmonary mycosis, and central airflow obstruction. Simple asthma is characterized by complete or near-complete

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reversibility of airflow obstruction. Bronchiectasis is distinguished from COPD by features such as recurrent pneumonia and hemoptysis, digital clubbing, and radiographic abnormalities. Patients with severe α1-antiprotease deficiency are recognized by the appearance of panacinar, bibasilar emphysema early in life, usually in the third or fourth decade, and hepatic cirrhosis and hepatocellular carcinoma may occur. Cystic fibrosis occurs in children and younger adults. Rarely, mechanical obstruction of the central airways simulates COPD. Flow-volume loops may help separate patients with central airway obstruction from those with diffuse intrathoracic airway obstruction characteristic of COPD.

Complications

Acute bronchitis, pneumonia, pulmonary thromboembolism, and concomitant left ventricular failure may worsen otherwise stable COPD. Pulmonary hypertension, cor pulmonale, and chronic respiratory failure are common in advanced COPD. Spontaneous pneumothorax occurs in a small fraction of patients with emphysema. Hemoptysis may result from chronic bronchitis or may signal bronchogenic carcinoma.

Prevention

COPD is largely preventable through elimination of long-term exposure to tobacco smoke. Smokers with early evidence of airflow limitation can alter their disease by smoking cessation. Smoking cessation slows the decline in FEV1 in middle-aged smokers with mild airways obstruction. Vaccination against influenza and pneumococcal infection may also be of benefit.

Treatment

Standards for the management of patients with COPD have been published by the American Thoracic Society and the Global Initiative for Obstructive Lung Disease (GOLD), a joint expert committee of the National Heart, Lung, and Blood Institute and the World Health Organization. See Chapter 38 for a discussion of air travel in patients with lung disease.

A. Ambulatory Patients

1. Smoking cessation

The single most important intervention in smokers with COPD is to encourage smoking cessation. Simply telling a patient to quit succeeds 5% of the time. The Lung Health Study reported 22% sustained abstinence at 5 years in their intervention group (behavior modification plus nicotine gum). Nicotine transdermal patch, nicotine gum, and bupropion increase cessation rates in motivated smokers (see Chapter 1).

2. Oxygen therapy

The only drug therapy that is documented to improve the natural history of COPD is supplemental oxygen in those patients with resting hypoxemia. Proved benefits of home oxygen therapy in advanced COPD include longer survival, reduced hospitalization needs, and better quality of life. Survival in hypoxemic patients with COPD treated with supplemental oxygen therapy is directly proportionate to the number of hours per day oxygen is administered: in patients treated with continuous oxygen, the survival after 36 months is about 65%—significantly better than the survival rate of about 45% in those who are treated with only nocturnal oxygen. Oxygen by nasal prongs must be given at least 15 hours a day unless therapy is intended only for exercise or sleep.

Requirements for Medicare coverage for a patient's home use of oxygen and oxygen equipment are listed in Table 9-8. Arterial blood gas analysis is preferred over oximetry to guide initial oxygen therapy. Hypoxemic patients with pulmonary hypertension, chronic cor pulmonale, erythrocytosis, impaired cognitive function, exercise intolerance, nocturnal restlessness, or morning headache are particularly likely to benefit from home oxygen therapy.

Home oxygen may be supplied by liquid oxygen systems (LOX), compressed gas cylinders, or oxygen concentrators. Most patients benefit from having both stationary and portable systems. For most patients, a flow rate of 1–3 L/min achieves a PaO2 greater than 55 mm Hg. The monthly cost of home oxygen therapy ranges from $300.00 to $500.00 or more, being higher for liquid oxygen systems. Medicare covers approximately 80% of home oxygen expenses. Transtracheal oxygen is an alternative method of delivery and may be useful for patients who require higher flows of oxygen than can be delivered via the nose or who are experiencing troublesome side effects from nasal delivery such as nasal drying or epistaxis. Reservoir nasal cannulas or “pendants” and demand (pulse) oxygen delivery systems are also available to conserve oxygen.

3. Bronchodilators

Bronchodilators are the most important agents in the pharmacologic management of patients with COPD. Bronchodilators do not alter the inexorable decline in lung function that is a hallmark of the disease, but they offer some patients improvement in symptoms, exercise tolerance, and overall health status. Aggressiveness of bronchodilator therapy should be matched to the severity of the patient's disease. In patients who experience no symptomatic improvement, bronchodilators should be discontinued.

The two most commonly prescribed bronchodilators are the anticholinergic ipratropium bromide and short-acting β2-agonists (eg, albuterol, metaproterenol), delivered by MDI or as an inhalation solution by nebulizer. Ipratropium bromide is generally preferred to the short-acting β2-agonists as a first-line agent because of its longer duration of action and absence of sympathomimetic side effects. Some studies have suggested that ipratropium achieves superior bronchodilation in COPD patients. Typical doses are two to four puffs (36–72 mcg) every 6 hours. There is a dose response above this level without additional side effects. Short-acting β2-agonists are less expensive and have a more rapid onset of action, commonly leading to

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greater patient satisfaction. At maximal doses, β2-agonists have bronchodilator action equivalent to that of ipratropium but may cause tachycardia, tremor, or hypokalemia. There does not appear to be any advantage of scheduled use of short-acting β2-agonists compared with as-needed administration. Use of both short-acting β2-agonists and anticholinergics at submaximal doses leads to improved bronchodilation compared with either agent alone but does not improve dyspnea.

Table 9-8. Home oxygen therapy: requirements for Medicare coverage.1

Group I (any of the following):
  1. Pao2 ≤ 55 mm Hg or SaO2 ≤ 88% taken at rest breathing room air, while awake.
  2. During sleep (prescription for nocturnal oxygen use only):
    1. Pao2 ≤ 55 mm Hg or SaO2 ≤ 88% for a patient whose awake, resting, room air PaO2 is ≥ 56 mm Hg or SaO2 ≥ 89%,
                  or
    2. Decrease in Pao2 > 10 mm Hg or decrease in SaO2 > 5% associated with symptoms or signs reasonably attributed to hypoxemia (eg, impaired cognitive processes, nocturnal restlessness, insomnia).
  3. During exercise (prescription for oxygen use only during exercise):
    1. Pao2 ≤ 55 mg Hg or SaO2 ≤ 88% taken during exercise for a patient whose awake, resting, room air PaO2 is ≥ 56 mm Hg or SaO2 ≥ 89%,
                  and
    2. There is evidence that the use of supplemental oxygen during exercise improves the hypoxemia that was demonstrated during exercise while breathing room air.
Group II2:
Pao2 = 56-59 mm Hg or SaO2 = 89% if there is evidence of any of the following:
  1. Dependent edema suggesting congestive heart failure.
  2. P pulmonale on ECG (P wave > 3 mm in standard leads II, III, or aVF).
  3. Hematocrit > 56%.
1Health Care Financing Administration, 1989.
2Patients in this group must have a second oxygen test 3 months after the initial oxygen set-up.

Long-acting β2-agonists (eg, formoterol, salmeterol) and anticholinergics (tiotropium) appear to achieve bronchodilation that is equivalent or superior to what is experienced with ipratropium in addition to similar improvements on health status. They are currently more expensive than short-acting agents. Their role in management of stable COPD is an area of active research.

Oral theophylline is a third-line agent in COPD patients who fail to achieve adequate symptom control with anticholinergics and β2-agonists. Sustained-release theophylline improves arterial oxygen hemoglobin saturation during sleep in COPD patients and is a first-line agent for those with sleep-related breathing disorders. Theophylline has fallen out of favor because of its narrow toxic therapeutic window and the availability of potent inhaled bronchodilators. Nonetheless, theophylline does improve dyspnea, exercise performance, and pulmonary function in many stable COPD patients. Its benefits may result from anti-inflammatory properties and extrapulmonary effects on diaphragm strength, myocardial contractility, and renal function.

4. Corticosteroids

Apart from acute exacerbations, COPD is not generally a corticosteroid-responsive disease. Only 10% of stable outpatients with COPD given oral corticosteroids will have a greater than 20% increase in FEV1 compared with patients receiving placebo. Since there are no clear predictors of which patients will respond, empiric trials of oral (equivalent to 0.5 mg/kg/d of prednisone for 14–21 days) and inhaled (6–12 weeks of therapy) corticosteroids are common. Such trials should be guided by the following principles: The baseline FEV1 should be stable, ie, not measured during an exacerbation, and documented on maximal bronchodilator therapy. The postbronchodilator FEV1 value is considered the appropriate baseline. The drug should be discontinued unless there is a 20% or greater increase in FEV1 after the trial of therapy. Patients who feel better without spirometric evidence of improvement are nonresponders. Responders to oral agents are usually switched to inhaled corticosteroids, but there are few data to guide this practice.

Several large clinical trials have reported no effect of inhaled corticosteroids on the characteristic decline in lung function experienced by COPD patients. Some clinical trials have reported a small reduction in the frequency of COPD exacerbations and an increase in self-reported functional status in patients treated with inhaled agents. Typically, these effects are small and occur with long-term, high-dose inhaled therapy.

5. Antibiotics

Antibiotics are commonly prescribed to outpatients with COPD for the following indications: (1) to treat an acute exacerbation, (2) to treat acute bronchitis, and (3) to prevent acute exacerbations of chronic bronchitis (prophylactic antibiotics). There is evidence from clinical studies that antibiotics improve outcomes slightly in the first two situations. There is no convincing evidence to support the use of prophylactic antibiotics in patients with COPD. Patients with a flare of COPD associated with dyspnea and a change in the quantity or character of sputum benefit the most from antibiotic therapy. Common agents include trimethoprim-sulfamethoxazole (160/800 mg every 12 hours), amoxicillin or amoxicillin-clavulanate (500 mg every 8 hours), or doxycycline (100 mg every 12 hours) given for 7–10 days. Broader-spectrum therapy may be indicated in patients with more severe baseline airflow obstruction. There are few controlled trials of antibiotics in severe COPD exacerbations; prompt administration of parenteral antibiotics seems reasonable as long as the decision is reevaluated frequently.

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6. Other measures

In patients with chronic bronchitis, increased mobilization of secretions may be accomplished through the use of adequate systemic hydration, effective cough training methods, or use of a hand-held flutter device and postural drainage, sometimes with chest percussion or vibration. Postural drainage and chest percussion should be used only in selected patients with excessive amounts of retained secretions that cannot be cleared by coughing and other methods; these measures are of no benefit in pure emphysema. Expectorant-mucolytic therapy has generally been regarded as unhelpful in patients with chronic bronchitis. Cough suppressants and sedatives should be avoided as routine measures.

Human α1-antitrypsin is available for replacement therapy in emphysema due to congenital deficiency of α1-antitrypsin. Patients over 18 years of age with airflow obstruction by spirometry and levels less than 11 mcmol/L are potential candidates for replacement therapy. α1-Antitrypsin is administered intravenously in a dose of 60 mg/kg body weight once weekly.

Graded aerobic physical exercise programs (eg, walking 20 minutes three times weekly, or bicycling) are helpful to prevent deterioration of physical condition and to improve the patient's ability to carry out daily activities. Training of inspiratory muscles by inspiring against progressively larger resistive loads improves exercise tolerance in some but not all patients. Pursed-lip breathing to slow the rate of breathing and abdominal breathing exercises to relieve fatigue of accessory muscles of respiration may reduce dyspnea in some patients.

Severe dyspnea in spite of optimal medical management may warrant a clinical trial of an opioid. Sedative-hypnotic drugs (eg, diazepam, 5 mg three times daily) are controversial in intractable dyspnea but may benefit very anxious patients. Intermittent negative-pressure (cuirass) ventilation and transnasal positive-pressure ventilation at home to rest the respiratory muscles are promising approaches to improve respiratory muscle function and reduce dyspnea in patients with severe COPD. A bilevel transnasal ventilation system has been reported to reduce dyspnea in ambulatory patients with severe COPD, but the long-term benefits of this approach and compliance with it have not been defined.

B. Hospitalized Patients

Hospitalization is indicated for acute worsening of COPD that fails to respond to measures for ambulatory patients. Patients with acute respiratory failure or complications such as cor pulmonale and pneumothorax should also be hospitalized.

Management of the hospitalized patient with an acute exacerbation of COPD includes supplemental oxygen, inhaled ipratropium bromide and inhaled β2-agonists, and broad-spectrum antibiotics, corticosteroids and, in selected cases, chest physiotherapy. Theophylline should not be initiated in the acute setting, but patients taking theophylline prior to acute hospitalization should have their theophylline serum levels measured and maintained in the therapeutic range. Oxygen therapy should not be withheld for fear of worsening respiratory acidemia; hypoxemia is more detrimental than hypercapnia. Cor pulmonale usually responds to measures that reduce pulmonary artery pressure, such as supplemental oxygen and correction of acidemia; bed rest, salt restriction, and diuretics may add some benefit. Cardiac arrhythmias, particularly multifocal atrial tachycardia, usually respond to aggressive treatment of COPD itself. Atrial flutter may require DC cardioversion after initiation of the above therapy. If progressive respiratory failure ensues, tracheal intubation and mechanical ventilation are necessary. In clinical trials of COPD patients with hypercapnic acute respiratory failure, noninvasive positive- pressure ventilation (NPPV) delivered via face mask reduced the need for intubation and shortened lengths of stay in the intensive care unit (ICU). Other studies have suggested a lower risk of nosocomial infections and less use of antibiotics in COPD patients treated with NPPV. These benefits do not appear to extend to hypoxemic respiratory failure or to patients with acute lung injury or ARDS.

C. Surgery for COPD

1. Lung transplantation

Experience with both single and bilateral sequential lung transplantation for severe COPD is extensive. Requirements for lung transplantation are severe lung disease, limited activities of daily living, exhaustion of medical therapy, ambulatory status, potential for pulmonary rehabilitation, limited life expectancy without transplantation, adequate function of other organ systems, and a good social support system. Average total charges for lung transplantation through the end of the first postoperative year exceed $250,000. The two-year survival rate after lung transplantation for COPD is 75%. Complications include acute rejection, opportunistic infection, and obliterative bronchiolitis. Substantial improvements in pulmonary function and exercise performance have been noted after transplantation.

2. Lung volume reduction surgery

Lung volume reduction surgery (LVRS), or reduction pneumoplasty, is a surgical approach to relieve dyspnea and improve exercise tolerance in patients with advanced diffuse emphysema and lung hyperinflation. Bilateral resection of 20–30% of lung volume in selected patients results in modest improvements in pulmonary function, exercise performance, and dyspnea. The duration of any improvement as well as any mortality benefit remains uncertain. Prolonged air leaks occur in up to 50% of patients postoperatively. Mortality rates in centers with the largest experience with LVRS range from 4% to 10%.

The National Emphysema Treatment Trial compared LVRS with medical treatment in a randomized, multicenter clinical trial of 1218 patients with severe emphysema.

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Overall, surgery improved exercise capacity but not mortality when compared with medical therapy. The persistence of this benefit remains to be defined. Subgroup analysis suggested that certain patient groups might have improved survival while other groups suffered excess mortality when randomized to surgery.

3. Bullectomy

Bullectomy is an older surgical procedure for palliation of severe dyspnea in patients with severe bullous emphysema. In this procedure, the surgeon removes a very large emphysematous bulla that demonstrates no ventilation or perfusion on lung scanning and compresses adjacent lung that has preserved function. Bullectomy can now be performed with a CO2 laser via thoracoscopy.

Prognosis

The outlook for patients with clinically significant COPD is poor. The median survival of patients with severe COPD (FEV1 ≤ 1 L) is about 4 years. The degree of pulmonary dysfunction (as measured by FEV1) at the time the patient is first seen is probably the most important predictor of survival. Comprehensive care programs, cessation of smoking, and supplemental oxygen may reduce the rate of decline of pulmonary function, but therapy with bronchodilators and other approaches probably has little, if any, impact on the natural course of COPD.

Dyspnea at the end of life can be extremely uncomfortable and distressing to the patient and family. Dyspnea can be effectively managed with a combination of medications and mechanical interventions (see Dyspnea, Treatment, above). As patients near the end of life, meticulous attention to palliative care is essential. (See Chapter 5.)

Bach PB et al: Management of acute exacerbations of chronic obstructive pulmonary disease: a summary and appraisal of published evidence. Ann Intern Med 2001;134:600.

Cote CG et al: New treatment strategies for COPD. Pairing the new with the tried and true. Postgrad Med 2005;117:27.

Gluck O et al: Recognizing and treating glucocorticoid-induced osteoporosis in patients with pulmonary diseases. Chest 2004; 125:1859.

Hersh CP et al: Predictors of survival in severe, early onset COPD. Chest 2004;126:1443.

Hogg JC et al: The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004;350:2645.

Pauwels RA et al: Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 2001;163:1256.

Shapiro SD: COPD unwound. N Engl J Med 2005;352:2016.

Sin DD et al: Contemporary management of chronic obstructive pulmonary disease: scientific review. JAMA 2003;290:2301.

Wouters EF: Management of severe COPD. Lancet 2004;364:883.

Bronchiectasis

Essentials of Diagnosis

  • Chronic productive cough with dyspnea and wheezing.

  • Recurrent pulmonary infections requiring antibiotics.

  • A preceding history of recurrent pulmonary infections or inflammation, or a predisposing condition.

  • Radiographic findings of dilated, thickened airways and scattered, irregular opacities.

General Considerations

Bronchiectasis is a congenital or acquired disorder of the large bronchi characterized by permanent, abnormal dilation and destruction of bronchial walls. It may be caused by recurrent inflammation or infection of the airways and may be localized or diffuse. Cystic fibrosis causes about half of all cases of bronchiectasis. Other causes include lung infection (tuberculosis, fungal infections, lung abscess, pneumonia), abnormal lung defense mechanisms (humoral immunodeficiency, α1-antiprotease deficiency with cigarette smoking, mucociliary clearance disorders, rheumatic diseases), and localized airway obstruction (foreign body, tumor, mucoid impaction). Immunodeficiency states that may lead to bronchiectasis include congenital or acquired panhypogammaglobulinemia; common variable immunodeficiency; selective IgA, IgM, and IgG subclass deficiencies; and acquired immunodeficiency from cytotoxic therapy, AIDS, lymphoma, multiple myeloma, leukemia, and chronic renal and hepatic diseases. However, most patients with bronchiectasis have panhypergammaglobulinemia, presumably reflecting an immune system response to chronic airway infection. Acquired primary bronchiectasis is now uncommon in the United States because of improved control of bronchopulmonary infections.

Clinical Findings

A. Symptoms and Signs

Symptoms of bronchiectasis include chronic cough with production of copious amounts of purulent sputum, hemoptysis, and pleuritic chest pain. Dyspnea and wheezing occur in 75% of patients. Weight loss, anemia, and other systemic manifestations are common. Physical findings are nonspecific, but persistent crackles at the lung bases are common. Clubbing is infrequent in mild cases but is common in severe disease. Copious, foul-smelling, purulent sputum is characteristic. Obstructive pulmonary dysfunction with hypoxemia is seen in moderate or severe disease.

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B. Imaging

Radiographic abnormalities include dilated and thickened bronchi that may appear as “tram-tracks” or as ring-like markings. Scattered irregular opacities, atelectasis, and focal consolidation may be present. High-resolution CT is the diagnostic study of choice.

Treatment

Treatment of acute exacerbations consists of antibiotics (selected on the basis of sputum smears and cultures), daily chest physiotherapy with postural drainage and chest percussion, and inhaled bronchodilators. Hand-held flutter valve devices may be as effective as chest physiotherapy in clearing secretions. Empiric oral antibiotic therapy for 10–14 days with amoxicillin or amoxicillin-clavulanate (500 mg every 8 hours), ampicillin or tetracycline (250–500 mg four times daily), or trimethoprim-sulfamethoxazole (160/800 mg every 12 hours) is reasonable therapy in an acute exacerbation if a specific bacterial pathogen cannot be isolated. Preventive or suppressive treatment is sometimes given to stable outpatients with bronchiectasis who have copious purulent sputum. Clinical trial data to guide this practice are scant. Common regimens include macrolides (azithromycin, 500 mg three times a week; erythromycin, 500 mg twice daily), high-dose (3 g/d) amoxicillin or alternating cycles of the antibiotics listed above given orally for 2–4 weeks. Inhaled aerosolized aminoglycosides reduce colonization by Pseudomonas species. In patients with underlying cystic fibrosis, inhaled antibiotics improve FEV1 and reduce hospitalizations, but these benefits are not consistently seen in the non-cystic fibrosis population. Complications of bronchiectasis include hemoptysis, cor pulmonale, amyloidosis, and secondary visceral abscesses at distant sites (eg, brain). Bronchoscopy is sometimes necessary to evaluate hemoptysis, remove retained secretions, and rule out obstructing airway lesions. Massive hemoptysis may require embolization of bronchial arteries or surgical resection. Surgical resection is otherwise reserved for the few patients with localized bronchiectasis and adequate pulmonary function in whom conservative management fails.

Barker AF: Bronchiectasis. N Engl J Med 2002;346:1383.

Evans DJ et al: Prolonged antibiotics for purulent bronchiectasis. Cochrane Database Syst Rev 2003;(4):CD001392.

Noone PG et al: Primary ciliary dyskinesia: diagnostic and phenotypic features. Am J Respir Crit Care Med 2004;169: 459.

Allergic Bronchopulmonary Mycosis

Allergic bronchopulmonary mycosis is a pulmonary hypersensitivity disorder caused by allergy to fungal antigens that colonize the tracheobronchial tree. It usually occurs in atopic asthmatic individuals who are 20–40 years of age, in response to antigens of Aspergillus species. For this reason, the disorder is commonly referred to as allergic bronchopulmonary aspergillosis (ABPA). Primary criteria for the diagnosis of ABPA include (1) a clinical history of asthma, (2) peripheral eosinophilia, (3) immediate skin reactivity to Aspergillus antigen, (4) precipitating antibodies to Aspergillus antigen, (5) elevated serum IgE levels, (6) pulmonary infiltrates (transient or fixed), and (7) central bronchiectasis. If the first six of these seven primary criteria are present, the diagnosis is almost certain. Secondary diagnostic criteria include identification of Aspergillus in sputum, a history of brown-flecked sputum, and late skin reactivity to Aspergillus antigen. High-dose prednisone (0.5–1 mg/kg orally per day) for at least 2 months is the treatment of choice, and the response in early disease is usually excellent. Depending on the overall clinical situation, prednisone can then be cautiously tapered. Relapses are frequent, and protracted or repeated treatment with corticosteroids is not uncommon. Patients with corticosteroid-dependent disease may benefit from itraconazole (200 mg orally once or twice daily) without added toxicity. Bronchodilators (Table 9-6) are also helpful. Complications include hemoptysis, severe bronchiectasis, and pulmonary fibrosis.

Greenberger PA: Allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol 2002;110:685.

Wark P: Pathogenesis of allergic bronchopulmonary aspergillosis and an evidence-based review of azoles in treatment. Respir Med 2004;98:915.

Cystic Fibrosis

Essentials of Diagnosis

  • Chronic or recurrent cough, sputum production, dyspnea, and wheezing.

  • Recurrent infections or chronic colonization of the airways with nontypeable H influenzae, mucoid and nonmucoid Pseudomonas aeruginosa, Staphylococcus aureus, or Burkholderia cepacia.

  • Pancreatic insufficiency, recurrent pancreatitis, distal intestinal obstruction syndrome, chronic hepatic disease, nutritional deficiencies, or male urogenital abnormalities.

  • Bronchiectasis and scarring on chest radiographs.

  • Airflow obstruction on spirometry.

  • Sweat chloride concentration above 60 mEq/L on two occasions or gene mutation known to cause cystic fibrosis.

General Considerations

Cystic fibrosis is the most common cause of severe chronic lung disease in young adults and the most

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common fatal hereditary disorder of whites in the United States. It is an autosomal recessive disorder affecting about 1 in 3200 whites; 1 in 25 is a carrier. Cystic fibrosis is caused by abnormalities in a membrane chloride channel (the cystic fibrosis transmembrane conductance regulator [CFTR] protein) that results in altered chloride transport and water flux across the apical surface of epithelial cells. Almost all exocrine glands produce an abnormal mucus that obstructs glands and ducts. Obstruction results in glandular dilation and damage to tissue. In the respiratory tract, inadequate hydration of the tracheobronchial epithelium impairs mucociliary function. High concentration of DNA in airway secretions (due to chronic airway inflammation and autolysis of neutrophils) increases sputum viscosity. Over 1000 mutations in the gene that encodes CFTR have been described, and at least 230 mutations are known to be associated with clinical abnormalities. The mutation referred to as ΔF508 accounts for about 60% of cases of cystic fibrosis.

Over one-third of the nearly 30,000 cystic fibrosis patients in the United States are adults. Because of the wide range of alterations seen in the CFTR protein structure and function, cystic fibrosis in adults may present with a variety of pulmonary and nonpulmonary manifestations. Pulmonary manifestations in adults include acute and chronic bronchitis, bronchiectasis, pneumonia, atelectasis, and peribronchial and parenchymal scarring. Pneumothorax and hemoptysis are common. Hypoxemia, hypercapnia, and cor pulmonale occur in advanced cases. Biliary cirrhosis and gallstones may occur. Nearly all men with cystic fibrosis have congenital bilateral absence of the vas deferens with azoospermia. Patients with cystic fibrosis have an increased risk of malignancies of the gastrointestinal tract, osteopenia, and arthropathies.

Clinical Findings

A. Symptoms and Signs

Cystic fibrosis should be suspected in a young adult with a history of chronic lung disease (especially bronchiectasis), pancreatitis, or infertility. Cough, sputum production, decreased exercise tolerance, and recurrent hemoptysis are typical complaints. Patients also often complain of facial (sinus) pain or pressure and purulent nasal discharge. Steatorrhea, diarrhea, and abdominal pain are also common. Digital clubbing, increased anteroposterior chest diameter, hyperresonance to percussion, and apical crackles are noted on physical examination. Sinus tenderness, purulent nasal secretions, and nasal polyps may also be seen.

B. Laboratory Findings

Arterial blood gas studies often reveal hypoxemia and, in advanced disease, a chronic, compensated respiratory acidosis. Pulmonary function studies show a mixed obstructive and restrictive pattern. There is a reduction in FVC, airflow rates, and TLC. Air trapping (high ratio of RV to TLC) and reduction in pulmonary diffusing capacity are common.

C. Imaging

Hyperinflation is seen early in the disease process. Peribronchial cuffing, mucus plugging, bronchiectasis (ring shadows and cysts), increased interstitial markings, small rounded peripheral opacities, and focal atelectasis may be seen separately or in various combinations. Pneumothorax can also be seen. Thin-section CT scanning may confirm the presence of bronchiectasis.

D. Diagnosis

The quantitative pilocarpine iontophoresis sweat test reveals elevated sodium and chloride levels (> 60 mEq/L) in the sweat of patients with cystic fibrosis. Two tests on different days are required for accurate diagnosis. Facilities must perform enough tests to maintain laboratory proficiency and quality. A normal sweat chloride test does not exclude the diagnosis. Genotyping or other alternative diagnostic studies (such as measurement of nasal membrane potential difference, semen analysis, or assessment of pancreatic function) should be pursued if the test is repeatedly negative but there is a high clinical suspicion of cystic fibrosis. Standard genotyping is a limited diagnostic tool because it screens for only a fraction of the known cystic fibrosis mutations.

Treatment

Early recognition and comprehensive multidisciplinary therapy improve symptom control and the chances of survival. Referral to a regional cystic fibrosis center is strongly recommended. Conventional treatment programs focus on the following areas: clearance and reduction of lower airway secretions, reversal of bronchoconstriction, treatment of respiratory tract infections and airway bacterial burden, pancreatic enzyme replacement, and nutritional and psychosocial support (including genetic and occupational counseling).

Clearance of lower airway secretions can be promoted by postural drainage, chest percussion or vibration techniques, positive expiratory pressure (PEP) or flutter valve breathing devices, directed cough, and other breathing techniques; these approaches require detailed patient instruction by experienced personnel. Sputum viscosity in cystic fibrosis is increased by the large quantities of extracellular DNA that result from chronic airway inflammation and autolysis of neutrophils. Inhaled recombinant human deoxyribonuclease (rhDNase) cleaves extracellular DNA in sputum; when administered long-term at a daily nebulized dose of 2.5 mg, this therapy leads to improved FEV1 and reduces the risk of cystic fibrosis-related respiratory exacerbations and the need for intravenous antibiotics. Pharyngitis, laryngitis, and voice alterations are common adverse effects. Antibiotics are used to treat active airway infections based on results of culture and susceptibility testing of sputum. S aureus (including

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methicillin-resistant strains) and a mucoid variant of Pseudomonas aeruginosa are commonly present. H influenzae, Stenotrophomonas maltophilia, and B cepacia (which is a highly drug-resistant organism) are occasionally isolated. Azithromycin (500 mg orally three times a week) may slow progression of disease in patients with P aeruginosa. The use of aerosolized antibiotics (inhalation tobramycin solution and others) for prophylaxis or treatment of lower respiratory tract infections is sometimes helpful. Although some studies of inhaled antibiotics demonstrate reduced exacerbations and increased FEV1 in patients chronically infected with P aeruginosa, there is concern about the emergence of drug-resistant organisms, equipment contamination with B cepacia, and side effects such as bronchospasm.

Inhaled bronchodilators (eg, albuterol, two puffs every 4 hours as needed) should be considered in patients who demonstrate an increase of at least 12% in FEV1 after an inhaled bronchodilator. Vaccination against pneumococcal infection and annual influenza vaccination are advised. Screening of family members and genetic counseling are suggested.

Lung transplantation is currently the only definitive treatment for advanced cystic fibrosis. Double-lung or heart-lung transplantation is required. A few transplant centers offer living lobar lung transplantation to selected patients. The 3-year survival rate following transplantation for cystic fibrosis is about 55%.

Investigational therapies for cystic fibrosis include anti-inflammatory agents (eg, ibuprofen, pentoxifylline, antiproteases), protein modification agents (eg, milrinone, phenylbutyrate), ion transport agents (eg, amiloride), and gene therapy.

Prognosis

The longevity of patients with cystic fibrosis is increasing, and the median survival age is over 30 years. Death occurs from pulmonary complications (eg, pneumonia, pneumothorax, or hemoptysis) or as a result of terminal chronic respiratory failure and cor pulmonale.

Elkins MR et al; National Hypertonic Saline in Cystic Fibrosis (NHSCF) Study Group: A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N Engl J Med 2006;354:229.

Ellaffi M et al: One-year outcome after severe pulmonary exacerbation in adults with cystic fibrosis. Am J Respir Crit Care Med 2005;171:158.

Gibson RL et al: Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med 2003;168:918.

Rowe SM et al: Cystic fibrosis. N Engl J Med 2005;352:1992.

Yankaskas JR et al: Cystic fibrosis adult care: consensus conference report. Chest 2004;125(1 Suppl):1S.

Bronchiolitis

Bronchiolitis is nonspecific inflammation of terminal and respiratory bronchioles. In infants and children, bronchiolitis is a common and often severe acute respiratory illness, usually caused by respiratory syncytial virus or adenovirus. Acute infectious bronchiolitis is rare in adults. In adults, bronchiolitis is a chronic, frequently progressive nonspecific response of the distal small airways to injury.

Bronchiolitis has two pathologic variants, either of which may be associated with obliteration of bronchioles. Constrictive bronchiolitis (formerly referred to as bronchiolitis obliterans) is characterized by chronic inflammation, concentric scarring, and smooth muscle hypertrophy causing luminal obstruction. These patients have airflow obstruction on spirometry, minimal radiographic abnormalities, and a progressive clinical course unresponsive to corticosteroids. Proliferative bronchiolitis occurs when intraluminal polyps consisting of fibroblasts, foamy macrophages, and lymphocytes partially or completely obstruct the bronchioles. When this exudate extends to the alveolar space, the pattern is referred to as bronchiolitis obliterans with organizing pneumonia (see below). The most common clinical patterns are described below.

Toxic fume bronchiolitis obliterans follows 1–3 weeks after exposure to oxides of nitrogen, phosgene, and other noxious gases. The chest radiograph shows diffuse nonspecific alveolar or “ground-glass” densities.

Postinfectious bronchiolitis obliterans is a late response to mycoplasmal or viral lung infection in adults and has a highly variable radiographic appearance.

Constrictive bronchiolitis may occur in association with rheumatoid arthritis, polymyositis, and dermatomyositis. Penicillamine therapy has been implicated as a possible cause in patients with rheumatoid arthritis. Constrictive bronchiolitis also occurs in up to 70% of patients following lung transplantation and 10% of patients undergoing allogeneic bone marrow transplantation, the latter occurring in the setting of chronic graft-versus-host disease.

Bronchiolitis obliterans with organizing pneumonia (BOOP), now more commonly referred to as cryptogenic organizing pneumonitis (COP), affects men and women equally. Most patients are between the ages of 50 and 70. Dry cough, dyspnea, and a flu-like illness, ranging in duration from a few days to several months, are typical. Fever and weight loss are common. Physical examination demonstrates crackles in most patients, and wheezing is present in about a third. Clubbing is uncommon. Pulmonary function studies demonstrate restrictive dysfunction and hypoxemia. The chest radiograph typically shows patchy, bilateral, ground glass or alveolar infiltrates. Solitary pneumonia-like infiltrates and a diffuse interstitial pattern have also been described (see Table 9-19).

COP is usually a difficult diagnosis to make on clinical grounds alone. The presence of fever and weight loss, abrupt onset of symptoms (often following an upper respiratory tract infection), a relatively short duration of symptoms, the absence of clubbing, and the presence of alveolar infiltrates help the clinician distinguish this entity from idiopathic interstitial pneumonia. Surgical lung biopsy may be necessary.

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Buds of loose connective tissue and inflammatory cells fill alveoli and distal bronchioles. Corticosteroid therapy is effective in two-thirds of cases, often abruptly. Relapses are common if corticosteroids are stopped prematurely, and most patients require at least 6 months of therapy. Prednisone is usually given initially in doses of 1 mg/kg/d for 2–3 months. The dose is then tapered slowly to 20–40 mg/d, depending on response, and eventually to an alternate-day regimen.

Two other well-described disorders are not usually associated with obliteration of bronchioles. Respiratory bronchiolitis is a disorder of small airways in cigarette smokers. Clinically and radiographically, this disorder resembles desquamative interstitial pneumonia (DIP). (See Table 9-19.) Cough, dyspnea, and crackles on chest auscultation are typical. However, the reduction in lung compliance seen in pulmonary fibrosis is not found in this disorder. The condition may be recognized only on surgical lung biopsy, which demonstrates characteristic metaplasia of terminal and respiratory bronchioles and filling of respiratory and terminal bronchioles, alveolar ducts, and alveoli by pigmented alveolar macrophages. The prognosis is good if the patient stops smoking.

Diffuse panbronchiolitis is an idiopathic disorder of respiratory bronchioles frequently diagnosed in Japan. The condition appears to be less common in the United States or Europe. Men are affected about twice as often as women and are usually between ages 20 and 80. About two-thirds of patients are nonsmokers. The large majority have a history of chronic pansinusitis. Marked dyspnea, cough, and sputum production are cardinal features. Crackles and rhonchi are noted on physical examination. Pulmonary function tests reveal obstructive abnormalities. The chest radiograph shows a distinct pattern of diffuse small nodular shadows and hyperinflation. Surgical lung biopsy is necessary for diagnosis.

Boehler A et al: Post-transplant bronchiolitis obliterans. Eur Respir J 2003;22:1007.

Cordier JF: Cryptogenic organizing pneumonia. Clin Chest Med 2004;25:727.

Oymak FS et al: Bronchiolitis obliterans organizing pneumonia. Clinical and roentgenological features in 26 cases. Respiration 2005;72:254.

Ryu JH et al: Bronchiolar disorders. Am J Respir Crit Care Med 2003;168:1277.

Pulmonary Infections

Pneumonia

Lower respiratory tract infections continue to be a major health problem despite advances in the identification of etiologic organisms and the availability of potent antimicrobial drugs. In addition, there is still much controversy regarding diagnostic approaches and treatment choices for pneumonia.

Characteristics of pneumonia caused by specific agents and appropriate antimicrobial therapy are presented in Table 9-9. Pneumonias are typically classified as being either community-acquired or hospital-acquired (nosocomial). Anaerobic pneumonias and lung abscess can occur in both settings and warrant separate consideration.

This section sets forth the evaluation and management of immunocompetent hosts separately from the approach to the evaluation and management of pulmonary infiltrates in immunocompromised hosts—defined as patients with HIV disease, absolute neutrophil counts < 1000/mcL, current or recent exposure to myelosuppressive or immunosuppressive drugs, or those currently taking prednisone in a dosage of over 5 mg/d.

1. Community-Acquired Pneumonia

Essentials of Diagnosis

  • Symptoms and signs of an acute lung infection: fever or hypothermia, cough with or without sputum, dyspnea, chest discomfort, sweats, or rigors.

  • Bronchial breath sounds or rales are frequent auscultatory findings.

  • Parenchymal infiltrate on chest radiograph.

  • Occurs outside of the hospital or less than 48 hours after admission in a patient who is not hospitalized or residing in a long-term care facility for more than 14 days before the onset of symptoms.

General Considerations

Community-acquired pneumonia is a common disorder, with approximately 2–3 million cases diagnosed each year in the United States. It is the most deadly infectious disease in the United States and the sixth leading cause of death. Mortality is estimated to be approximately 14% among hospitalized patients and less than 1% for patients who do not require hospitalization. Important risk factors for increased morbidity and mortality from community-acquired pneumonia include advanced age, alcoholism, comorbid medical conditions, altered mental status, respiratory rate ≥ 30 breaths/min, hypotension (defined by systolic blood pressure < 90 mm Hg or diastolic blood pressure < 60 mm Hg), and blood urea nitrogen (BUN) > 30 mg/dL.

A predictor of patient risk and mortality from community-acquired pneumonia has been developed and validated by the Pneumonia Patient Outcomes Research Team (PORT). The PORT prediction scheme uses 19 clinical variables to stratify patients into five

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mortality risk classes. (See Table 9-10.) Patients under 50 years of age without those comorbid conditions and specific physical examination abnormalities listed in Table 9-10 are assigned to risk class I. All other patients are assigned to risk categories based on the scoring system in Table 9-11. Thirty-day mortality by category is listed in Table 9-11. The PORT model can be used along with clinical judgment in the initial decision about whether to hospitalize a patient with community-acquired pneumonia.

Table 9-9. Characteristics and treatment of selected pneumonias.

Organism; Appearance on Smear of Sputum Clinical Setting Complications Laboratory Studies Antimicrobial Therapy1,2
Streptococcus pneumoniae (pneumococcus). Gram-positive diplococci. Chronic cardiopulmonary disease; follows upper respiratory tract infection Bacteremia, meningitis, endocarditis, pericarditis, empyema Gram stain and culture of sputum, blood, pleural fluid Preferred3: Penicillin G, amoxicillin.
Alternative: Macrolides, cephalosporins, doxycycline, fluoroquinolones, clindamycin, vancomycin, TMP-SMZ, linezolid.
Haemophilus influenzae. Pleomorphic gram-negative coccobacilli. Chronic cardiopulmonary disease; follows upper respiratory tract infection Empyema, endocarditis Gram stain and culture of sputum, blood, pleural fluid Preferred3: Cefotaxime, ceftriaxone, cefuroxime, doxycycline, azithromycin, TMP-SMZ.
Alternative: Fluoroquinolones, clarithromycin.
Staphylococcus aureus. Plump gram-positive cocci in clumps. Residence in chronic care facility, nosocomial, influenza epidemics; cystic fibrosis, bronchiectasis, injection drug use Empyema, cavitation Gram stain and culture of sputum, blood, pleural fluid For methicillin-susceptible strains: Preferred: A penicillinase-resistant penicillin with or without rifampin, or gentamicin.
Alternative: A cephalosporin; clindamycin, TMP-SMZ, vancomycin, a fluoroquinolone.
For methicillin-resistant strains: Vancomycin with or without gentamicin or rifampin, linezolid.
Klebsiella pneumoniae. Plump gram-negative encapsulated rods. Alcohol abuse, diabetes mellitus; nosocomial. Cavitation, empyema Gram stain and culture of sputum, blood, pleural fluid Preferred: Third-generation cephalosporin. For severe infections, add an aminoglycoside.
Alternative: Aztreonam, imipenem, meropenem, β-lactam/β-lactamase inhibitor, an aminoglycoside, or a fluoroquinolone.
Escherichia coli. Gram-negative rods. Nosocomial; rarely, community-acquired Empyema Gram stain and culture of sputum, blood, pleural fluid Same as for Klebsiella pneumoniae.
Pseudomonas aeruginosa. Gram-negative rods. Nosocomial; cystic fibrosis, bronchiectasis Cavitation Gram stain and culture of sputum, blood Preferred: An antipseudomonal β-lactam plus an aminoglycoside.
Alternative: Ciprofloxacin plus an aminoglycoside or an antipseudomonal β-lactam.
Anaerobes. Mixed flora. Aspiration, poor dental hygiene Necrotizing pneumonia, abscess, empyema Culture of pleural fluid or of material obtained by transtracheal or transthoracic aspiration Preferred: Clindamycin, β-lactam/β-lactamase inhibitor, imipenem.
Mycoplasma pneumoniae. PMNs and monocytes; no bacteria. Young adults; summer and fall Skin rashes, bullous myringitis; hemolytic anemia PCR. Culture.4 Complement fixation titer.5 Cold agglutinin serum titers are not helpful as they lack sensitivity and specificity. Preferred: Doxycycline or erythromycin.
Alternative: Clarithromycin; azithromycin, or a fluoroquinolone.
Legionella species. Few PMNs; no bacteria. Summer and fall; exposure to contaminated construction site, water source, air conditioner; community-acquired or nosocomial Empyema, cavitation, endocarditis, pericarditis Direct immunofluorescent examination or PCR of sputum or tissue; culture of sputum or tissue.4Urinary antigen assay for L pneumophila serogroup 1. Preferred: A macrolide with or without rifampin; a fluoroquinolone.
Alternative: Doxycycline with or without rifampin, TMP-SMZ.
Chlamydia pneumoniae. Nonspecific. Clinically similar to M pneumoniae, but prodromal symptoms last longer (up to 2 weeks). Sore throat with hoarseness common. Mild pneumonia in teenagers and young adults. Reinfection in older adults with underlying COPD or heart failure may be severe or even fatal Isolation of the organism is very difficult. Serologic studies include microimmunofluorescence with TWAR antigen. PCR at selected laboratories. Preferred: Doxycycline. Alternative: Erythromycin, clarithromycin, azithromycin, or a fluoroquinolone.
Moraxella catarrhalis. Gram-negative diplococci. Preexisting lung disease; elderly; corticosteroid or immunosuppressive therapy Rarely, pleural effusions and bacteremia Gram stain and culture of sputum, blood, pleural fluid Preferred: A second- or third-generation cephalosporin; a fluoroquinolone.
Alternative: TMP-SMZ, amoxicillin-clavulanic acid, or a macrolide.
Pneumocystis jiroveci. Nonspecific. AIDS, immunosuppressive or cytotoxic drug therapy, cancer Pneumothorax, respiratory failure, ARDS, death Methenamine silver, Giemsa, or DFA stains of sputum or bronchoalveolar lavage fluid Preferred: TMP-SMZ or pentamidine isethionate plus prednisone.
Alternative: Dapsone plus trimethoprim; clindamycin plus primaquine; trimetrexate plus folinic acid.
1Antimicrobial sensitivities should guide therapy when available. (Modified from: The choice of antibacterial drugs. Med Lett Drugs Ther 2004;43:69, and from Bartlett JG et al: Practice guidelines for the management of community-acquired pneumonia in adults. Clin Infect Dis 2000;31:347.)
2For additional antimicrobial therapy information, see Infectious Disease: Antimicrobial Therapy: Tables 37-1 (drugs of choice), 37-5 and 37-7 (doses per day), and 37-4, 37-8, and 37-9 (pharmacology and dosage adjustment for renal dysfunction).
3Consider penicillin resistance when choosing therapy. See text.
4Selective media are required.
5Fourfold rise in titer is diagnostic.
TMP-SMZ = trimethoprim-sulfamethoxazole; PCR = polymerase chain reaction; COPD = chronic obstructive pulmonary disease; ARDS = acute respiratory distress syndrome.

Table 9-10. Scoring system for risk class assignment for PORT prediction rule.

Patient Characteristic Points Assigned1
Demographic factor
   Age: men Number of years
   Age: women Number of years minus 10
   Nursing home resident 10
Comorbid illnesses
   Neoplastic disease2 30
   Liver disease3 20
   Congestive heart failure4 10
   Cerebrovascular disease5 10
   Renal disease6 10
Physical examination finding
   Altered mental status7 20
   Respiratory rate ≥ 30 breaths/min 20
   Systolic blood pressure < 90 mm Hg 20
   Temperature ≤ 35°C or ≥ 40°C 15
   Pulse ≥ 125 beats/min 10
Laboratory or radiographic finding
   Arterial pH < 7.35 30
   Blood urea nitrogen ≥ 30 mg/dL 20
   Sodium < 130 mEq/L 20
   Glucose > 250 mg/dL 10
   Hematocrit < 30% 10
   Arterial Po2 < 60 mm Hg 10
   Pleural effusion 10
1A total point score for a given patient is obtained by summing the patient's age in years (age minus 10 for women) and the points for each applicable characteristic.
2Any cancer except basal or squamous cell of the skin that was active at the time of presentation or diagnosed within 1 year before presentation.
3Clinical or histologic diagnosis of cirrhosis or another form of chronic liver disease.
4Systolic or diastolic dysfunction documented by history, physical examination and chest radiograph, echocardiogram, MUGA scan, or left ventriculogram.
5Clinical diagnosis of stroke or transient ischemic attack or stroke documented by MRI or CT scan.
6History of chronic renal disease or abnormal blood urea nitrogen and creatinine concentration documented in the medical record.
7Disorientation (to person, place, or time, not known to be chronic), stupor, or coma.
Modified and reproduced, with permission, from Fine MJ et al: A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 1997;336:243. Copyright © 1997 Massachusetts Medical Society. All rights reserved.

In immunocompetent patients, the history, physical examination, radiographs, and sputum examination are neither sensitive nor specific for identifying the microbiologic cause of community-acquired pneumonia. While helpful in selected patients, these modalities do not consistently differentiate bacterial from viral causes or distinguish “typical” from “atypical” causes. As a result, the American Thoracic Society recommends empiric treatment based on epidemiologic data. In contrast, practice guidelines proposed by the Infectious Disease Society of America advocate systematic use of the microbiology laboratory in an attempt to administer pathogen-directed antimicrobial therapy whenever possible, especially in hospitalized patients.

Definition & Pathogenesis

Community-acquired pneumonia begins outside of the hospital or is diagnosed within 48 hours after admission to the hospital in a patient who has not resided in a long-term care facility for 14 days or more before the onset of symptoms.

Pulmonary defense mechanisms (cough reflex, mucociliary clearance system, immune responses) normally prevent the development of lower respiratory tract infections following aspiration of oropharyngeal

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secretions containing bacteria or inhalation of infected aerosols. Community-acquired pneumonia occurs when there is a defect in one or more of the normal host defense mechanisms or when a very large infectious inoculum or a highly virulent pathogen overwhelms the host.

Table 9-11. PORT risk class 30-day mortality rates and recommendations for site of care.

Number of Points Risk Class Mortality at 30 days (%) Recommended Site of Care
Absence of predictors I 0.1-0.4 Outpatient
≤ 70 II 0.6-0.7 Outpatient
71-90 III 0.9-2.8 Outpatient or brief inpatient
91-130 IV 8.2-9.3 Inpatient
≥ 130 V 27.0-31.1 Inpatient
Data from Fine MJ et al: A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 1997;336:243. Copyright © 1997 Massachusetts Medical Society. All rights reserved.

Prospective studies have failed to identify the cause of community-acquired pneumonia in 40–60% of cases; two or more causes are identified in up to 5% of cases. Bacteria are more commonly identified than viruses. The most common bacterial pathogen identified in most studies of community-acquired pneumonia is S pneumoniae, accounting for approximately two-thirds of bacterial isolates. Other common bacterial pathogens include H influenzae, Mycoplasma pneumoniae, Chlamydia pneumoniae, S aureus, Neisseria meningitidis, M catarrhalis, Klebsiella pneumoniae, other gram-negative rods, and Legionella species. Common viral causes of community-acquired pneumonia include influenza virus, respiratory syncytial virus, adenovirus, and parainfluenza virus. A detailed assessment of epidemiologic risk factors may aid in diagnosing pneumonias due to the following causes: Chlamydia psittaci (psittacosis), Coxiella burnetii (Q fever), Francisella tularensis (tularemia), endemic fungi (Blastomyces, Coccidioides, Histoplasma), and sin nombre virus (hantavirus pulmonary syndrome).

Clinical Findings

A. Symptoms and Signs

Most patients with community-acquired pneumonia experience an acute or subacute onset of fever, cough with or without sputum production, and dyspnea. Other common symptoms include rigors, sweats, chills, chest discomfort, pleurisy, hemoptysis, fatigue, myalgias, anorexia, headache, and abdominal pain.

Common physical findings include fever or hypothermia, tachypnea, tachycardia, and mild arterial oxygen desaturation. Many patients will appear acutely ill. Chest examination is often remarkable for altered breath sounds and rales. Dullness to percussion may be present if a parapneumonic pleural effusion is present.

The differential diagnosis of lower respiratory tract symptoms and signs is extensive and includes upper respiratory tract infections, reactive airway diseases, congestive heart failure, BOOP, lung cancer, pulmonary vasculitis, pulmonary thromboembolic disease, and atelectasis.

B. Laboratory Findings

Controversy surrounds the role of Gram stain and culture analysis of expectorated sputum in patients with community-acquired pneumonia. Most reports suggest that these tests have poor positive and negative predictive value in most patients. Some argue, however, that the tests should still be performed to try to identify etiologic organisms in the hope of reducing microbial resistance to drugs, unnecessary drug costs, and avoidable side effects of empiric antibiotic therapy. Expert panel guidelines suggest that sputum Gram stain should be attempted in all patients with community-acquired pneumonia and that sputum culture should be obtained for all patients who require hospitalization. Sputum should be obtained before antibiotics are initiated except in a case of suspected antibiotic failure. The specimen is obtained by deep cough and should be grossly purulent. Culture should be performed only if the specimen meets strict cytologic criteria, eg, more than 25 neutrophils and fewer than 10 squamous epithelial cells per low power field. These criteria do not apply to cultures of legionella or mycobacteria.

Additional testing is generally recommended for patients who require hospitalization: preantibiotic blood cultures (at least two sets with needle sticks at separate sites), arterial blood gases, complete blood count with differential, and a chemistry panel (including serum glucose, electrolytes, urea nitrogen, creatinine, bilirubin, and liver enzymes). The results of these tests help assess the severity of the disease and guide evaluation and therapy. HIV serology should be obtained from all hospitalized patients.

C. Imaging

Chest radiography may confirm the diagnosis and detect associated lung diseases. It can also be used to help assess severity and response to therapy over time. Radiographic findings can range from patchy airspace infiltrates to lobar consolidation with air bronchograms to diffuse alveolar or interstitial infiltrates. Additional findings can include pleural effusions and cavitation. No pattern of radiographic abnormalities is pathognomonic of a specific cause of pneumonia.

Progression of pulmonary infiltrates during antibiotic therapy or lack of radiographic improvement over time are poor prognostic signs and also raise concerns about secondary or alternative pulmonary processes. Clearing of pulmonary infiltrates in patients with community-acquired pneumonia can take 6 weeks or longer and is usually fastest in young patients, nonsmokers, and those with only single lobe involvement.

D. Special Examinations

Sputum induction is reserved for patients who cannot provide expectorated sputum samples or who may have P jiroveci or Mycobacterium tuberculosis pneumonia. Transtracheal aspiration, fiberoptic bronchoscopy, and transthoracic needle aspiration techniques to obtain samples of lower respiratory secretions or tissues are reserved for selected patients.

Thoracentesis with pleural fluid analysis (Gram stain and cultures; glucose, lactate dehydrogenase (LDH), and total protein levels; leukocyte count with differential; pH determination) should be performed on most patients with pleural effusions to assist in diagnosis of the etiologic agent and assess for empyema or complicated parapneumonic process. Serologic assays, polymerase chain reaction tests, specialized culture

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tests, and other new diagnostic tests for organisms such as Legionella, M pneumoniae, and C pneumoniae are performed when these diagnoses are suspected. Limitations of many of these tests include delay in obtaining test results and poor sensitivity and specificity.

Treatment

Antimicrobial therapy should be initiated promptly after the diagnosis of pneumonia is established and appropriate specimens are obtained, especially in patients who require hospitalization. Delays in obtaining diagnostic specimens or the results of testing should not preclude the early administration of antibiotics to acutely ill patients. Decisions regarding hospitalization should be based on prognostic criteria as outlined above in the section on general considerations. Treatment recommendations can be divided into those for patients who can be treated as outpatients and those for patients who require hospitalization.

Special consideration must be given to penicillin-resistant strains of S pneumoniae. Intermediate resistance to penicillin is defined as a minimum inhibitory concentration (MIC) of 0.1–1 mcg/mL. Strains with high-level resistance usually require an MIC ≥ 2 mcg/mL for penicillin. Resistance to other antibiotics (β-lactams, trimethoprim-sulfamethoxazole, macrolides, others) often accompanies resistance to penicillin. The prevalence of resistance varies by patient group, geographic region, and over time. Local resistance pattern data should therefore guide empiric therapy of suspected or documented S pneumoniae infections until specific susceptibility test results are available.

A. Treatment of Outpatients

Empiric antibiotic options for patients with community-acquired pneumonia who do not require hospitalization include the following: (1) Macrolides (clarithromycin, 500 mg orally twice a day, or azithromycin, 500 mg orally as a first dose and then 250 mg once a day for 4 days). (2) Doxycycline (100 mg orally twice a day). (3) Fluoroquinolones (with enhanced activity against S pneumoniae, such as gatifloxacin 400 mg orally once a day, levofloxacin 500 mg orally once a day, or moxifloxacin 400 mg orally once a day). Some experts prefer doxycycline or macrolides for patients under 50 years of age without comorbidities and a fluoroquinolone for patients with comorbidities or who are older than 50 years of age. Alternatives include erythromycin (250–500 mg orally four times daily), amoxicillin-potassium clavulanate—especially for suspected aspiration pneumonia—500 mg orally three times a day or 875 mg orally twice a day, and some second- and third-generation cephalosporins such as cefuroxime axetil (250–500 mg orally twice a day), cefpodoxime proxetil (100–200 mg orally twice a day), or cefprozil (250–500 mg orally twice a day).

There are limited data to guide recommendations for duration of treatment. The decision is influenced by the severity of illness, the etiologic agent, response to therapy, other medical problems, and complications. Therapy until the patient is afebrile for at least 72 hours is usually sufficient for pneumonia due to S pneumoniae. A minimum of 2 weeks of therapy is appropriate for pneumonia due to S aureus, P aeruginosa, Klebsiella, anaerobes, M pneumoniae, C pneumoniae, or Legionella species.

B. Treatment of Hospitalized Patients

Empiric antibiotic options for patients with community-acquired pneumonia who require hospitalization can be divided into those for patients who can be cared for on a general medical ward and those for patients who require care in an ICU. Patients who only require general medical ward care usually respond to an extended-spectrum β-lactam (such as ceftriaxone or cefotaxime) with a macrolide (clarithromycin or azithromycin is preferred if H influenzae infection is suspected) or a fluoroquinolone (with enhanced activity against S pneumoniae) such as gatifloxacin, levofloxacin, or moxifloxacin. Alternatives include a β-lactam/β-lactamase inhibitor (ampicillin-sulbactam or piperacillin-tazobactam) with a macrolide.

Patients requiring admission to the ICU require a macrolide or a fluoroquinolone (with enhanced activity against S pneumoniae) plus an extended-spectrum cephalosporin (ceftriaxone, cefotaxime) or a β-lactam/β-lactamase inhibitor (ampicillin-sulbactam or piperacillin-tazobactam). Patients with penicillin allergies can be treated with a fluoroquinolone (with enhanced activity against S pneumoniae) with or without clindamycin. Patients with suspected aspiration pneumonia should receive a fluoroquinolone (with enhanced activity against S pneumoniae) with or without clindamycin, metronidazole, or a β-lactam/β-lactamase inhibitor. Patients with structural lung diseases such as bronchiectasis or cystic fibrosis benefit from empiric therapy with an antipseudomonal penicillin, carbapenem, or cefepime plus a fluoroquinolone (including high-dose ciprofloxacin) until sputum culture and sensitivity results are available. Expanded discussions of specific antibiotics are provided in Chapter 37.

Almost all patients who are admitted to a hospital for therapy of community-acquired pneumonia receive intravenous antibiotics. Despite this preference, no studies demonstrate superior outcomes when hospitalized patients are treated intravenously instead of orally if patients can tolerate oral therapy and the drug is well absorbed. Duration of antibiotic treatment is the same as for outpatients with community-acquired pneumonia.

Prevention

Polyvalent pneumococcal vaccine (containing capsular polysaccharide antigens of 23 common strains of S pneumoniae) has the potential to prevent or lessen the severity of the majority of pneumococcal infections in immunocompetent patients. Indications for pneumococcal vaccination include the following: age ≥ 65 years or any chronic illness that increases the risk of

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community-acquired pneumonia (see Chapter 30). Immunocompromised patients and those at highest risk of fatal pneumococcal infections should receive a single revaccination 6 years after the first vaccination. Immunocompetent persons 65 years of age or older should receive a second dose of vaccine if the patient first received the vaccine 6 or more years previously and was under 65 years old at the time of vaccination.

The influenza vaccine is effective in preventing severe disease due to influenza virus with a resulting positive impact on both primary influenza pneumonia and secondary bacterial pneumonias. The influenza vaccine is administered annually to persons at risk for complications of influenza infection (age ≥ 65 years, residents of long-term care facilities, patients with pulmonary or cardiovascular disorders, patients recently hospitalized with chronic metabolic disorders) as well as health care workers and others who are able to transmit influenza to high-risk patients.

Hospitalized patients who would benefit from pneumococcal and influenza vaccines should be vaccinated during hospitalization. The vaccines can be given simultaneously, and there are no contraindications to use immediately after an episode of pneumonia.

Bodi M et al; Community-Acquired Pneumonia Intensive Care Units (CAPUCI) Study Investigators: Antibiotic prescription for community-acquired pneumonia in the intensive care unit: impact of adherence to IDSA guidelines on survival. Clin Infect Dis 2005;41:1709.

File TM Jr et al: Guidelines for empiric antimicrobial prescribing in community-acquired pneumonia. Chest 2004;125:1888.

Metlay JP et al: Testing strategies in the initial management of patients with community-acquired pneumonia. Ann Intern Med 2003;138:109.

Niederman MS et al: Guidelines for the management of adults with community-acquired pneumonia. Diagnosis, assessment of severity, antimicrobial therapy, and prevention. Am J Respir Crit Care Med 2001;163:1730.

Wunderink RG et al: Community-acquired pneumonia: pathophysiology and host factors with focus on possible new approaches to management of lower respiratory tract infections. Infect Dis Clin North Am 2004;18:743.

2. Hospital-Acquired Pneumonia

Essentials of Diagnosis

  • Occurs more than 48 hours after admission to the hospital and excludes any infection present at the time of admission.

  • At least two of the following: fever, cough, leukocytosis, purulent sputum.

  • New or progressive parenchymal infiltrate on chest radiograph.

  • Especially common in patients requiring intensive care or mechanical ventilation.

General Considerations

Hospital-acquired (nosocomial) pneumonia is an important cause of morbidity and mortality despite widespread use of preventive measures, advances in diagnostic testing, and potent new antimicrobial agents. Nosocomial pneumonia is the second most common cause of hospital-acquired infection and is the leading cause of death due to nosocomial infection with mortality rates ranging from 20% to 50%. While the majority of cases occur in patients who are not in the ICU, the highest-risk patients are those in such units or who are being mechanically ventilated; these patients also experience higher morbidity and mortality from nosocomial pneumonias.

Definition & Pathogenesis

Hospital-acquired pneumonia is defined as pneumonia developing more than 48 hours after admission to the hospital. Ventilator-associated pneumonia develops in a mechanically ventilated patient more than 48 hours after intubation.

Colonization of the pharynx and possibly the stomach with bacteria is the most important step in the pathogenesis of nosocomial pneumonia. Pharyngeal colonization is promoted by exogenous factors (instrumentation of the upper airway with nasogastric and endotracheal tubes, contamination by dirty hands and equipment, and treatment with broad-spectrum antibiotics that promote the emergence of drug-resistant organisms) and patient factors (malnutrition, advanced age, altered consciousness, swallowing disorders, and underlying pulmonary and systemic diseases). Aspiration of infected pharyngeal or gastric secretions delivers bacteria directly to the lower airway. Impaired cellular and mechanical defense mechanisms in the lungs of hospitalized patients raise the risk of infection after aspiration has occurred. Tracheal intubation increases the risk of lower respiratory infection by mechanical obstruction of the trachea, impairment of mucociliary clearance, trauma to the mucociliary escalator system, and interference with coughing. Tight adherence of bacteria such as Pseudomonas to the tracheal epithelium and the biofilm that lines the endotracheal tube makes clearance of these organisms from the lower airway difficult. Less important pathogenetic mechanisms of nosocomial pneumonia include inhalation of contaminated aerosols and hematogenous dissemination of microorganisms.

The role of the stomach in the pathogenesis of nosocomial pneumonia remains controversial. Observational studies have suggested that elevations of gastric pH due to antacids, H2-receptor antagonists, or enteral feeding is associated with gastric microbial overgrowth, tracheobronchial colonization, and nosocomial pneumonia. Sucralfate, a cytoprotective agent that does not alter gastric pH, is associated with a trend toward a lower incidence of ventilator-associated pneumonia.

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The most common organisms responsible for nosocomial pneumonia are P aeruginosa, S aureus, Enterobacter, K pneumoniae, and Escherichia coli. Proteus, Serratia marcescens, H influenzae, and streptococci account for most of the remaining cases. Infection by P aeruginosa and Acinetobacter tend to cause pneumonia in the most debilitated patients, those with previous antibiotic therapy, and those requiring mechanical ventilation. Anaerobic organisms (bacteroides, anaerobic streptococci, fusobacterium) may also cause pneumonia in the hospitalized patient; when isolated, they are commonly part of a polymicrobial flora. Mycobacteria, fungi, chlamydiae, viruses, rickettsiae, and protozoal organisms are uncommon causes of nosocomial pneumonia.

Clinical Findings

A. Symptoms and Signs

The signs and symptoms associated with nosocomial pneumonia are nonspecific; however, one or more clinical findings (fever, leukocytosis, purulent sputum, and a new or progressive pulmonary infiltrate on chest radiograph) are present in most patients. Other findings associated with nosocomial pneumonia include those listed above for community-acquired pneumonia.

The differential diagnosis of new lower respiratory tract symptoms and signs in hospitalized patients includes congestive heart failure, atelectasis, aspiration, ARDS, pulmonary thromboembolism, pulmonary hemorrhage, and drug reactions.

B. Laboratory Findings

The minimum evaluation for suspected nosocomial pneumonia includes blood cultures from two different sites and an arterial blood gas or pulse oximetry determination. Blood cultures can identify the pathogen in up to 20% of all patients with nosocomial pneumonia; positivity is associated with increased risk for complications and other sites of infection. The assessment of oxygenation helps define the severity of illness and determines the need for supplemental oxygen. Blood counts and clinical chemistry tests are not helpful in establishing a specific diagnosis of nosocomial pneumonia; however, they can help define the severity of illness and identify complications. Thoracentesis for pleural fluid analysis (stains, cultures; glucose, LDH, and total protein levels; leukocyte count with differential; pH determination) should be performed in patients with pleural effusions.

Examination of sputum is attended by the same disadvantages as in community-acquired pneumonia. Gram stains and cultures of sputum are neither sensitive nor specific in the diagnosis of nosocomial pneumonia. The identification of a bacterial organism by culture of sputum does not prove that the organism is a lower respiratory tract pathogen. However, it can be used to help identify antibiotic sensitivity patterns of bacteria and as a guide to therapy. If nosocomial pneumonia from Legionella pneumophila is suspected, direct fluorescent antibody staining can be performed. Sputum stains and cultures for mycobacteria and certain fungi may be diagnostic.

C. Imaging

Radiographic findings are nonspecific and can range from patchy airspace infiltrates to lobar consolidation with air bronchograms to diffuse alveolar or interstitial infiltrates. Additional findings can include pleural effusions and cavitation. Progression of pulmonary infiltrates during antibiotic therapy and lack of radiographic improvement over time are poor prognostic signs and also raise concerns about secondary or alternative pulmonary processes. Clearing of pulmonary infiltrates can take 6 weeks or longer.

D. Special Examinations

Endotracheal aspiration using a sterile suction catheter and fiberoptic bronchoscopy with bronchoalveolar lavage or a protected specimen brush can be used to obtain lower respiratory tract secretions for analysis, most commonly in patients with ventilator-associated pneumonias. Endotracheal aspiration cultures have significant negative predictive value but limited positive predictive value in the diagnosis of specific etiologic agents in patients with nosocomial pneumonia. An invasive diagnostic approach using quantitative culture of bronchoalveolar lavage samples or protected specimen brush samples in patients suspected of having ventilator-associated pneumonia leads to significantly less antibiotic use, earlier attenuation of organ dysfunction, and fewer deaths at 14 days.

Treatment

Treatment of nosocomial pneumonia, like treatment of community-acquired pneumonia, is usually empiric. Because of the high mortality rate, therapy should be started as soon as pneumonia is suspected. Initial regimens must be broad in spectrum and tailored to the specific clinical setting. There is no uniform consensus on the best regimens.

Recommendations for the treatment of hospital-acquired pneumonia have been proposed by many organizations, including the American Thoracic Society. Initial empiric therapy with antibiotics is determined by the severity of illness, risk factors, and the length of hospitalization. Empiric therapy for mild to moderate nosocomial pneumonia in a patient without unusual risk factors or a patient with severe early-onset (within 5 days after hospitalization) hospital-acquired pneumonia may consist of a second-generation cephalosporin, a nonantipseudomonal third-generation cephalosporin, or a combination of a β-lactam and β-lactamase inhibitor.

Empiric therapy for patients with severe, late-onset (≥ 5 days after hospitalization) hospital-acquired pneumonia or with ICU- or ventilator-associated pneumonia should include a combination of antibiotics directed against the most virulent organisms, particularly P aeruginosa,

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Acinetobacter species, and Enterobacter species. The antibiotic regimen should include an aminoglycoside or fluoroquinolone plus one of the following: an antipseudomonal penicillin, an antipseudomonal cephalosporin, a carbapenem, or aztreonam—aztreonam alone with an aminoglycoside will be inadequate if coverage for gram-positive organisms or H influenzae is required. Vancomycin is added if infection with methicillin-resistant S aureus is of concern (especially in patients with coma, head trauma, diabetes mellitus, or renal failure, or who are in the ICU). Anaerobic coverage with clindamycin or a β-lactam/β-lactamase inhibitor combination may be added for patients who have risk factors for anaerobic pneumonia, including aspiration, recent thoracoabdominal surgery, or an obstructing airway lesion. A macrolide is added when patients are at risk for Legionella infection, such as those receiving high-dose corticosteroids. After results of sputum, blood, and pleural fluid cultures have been obtained, it may be possible to switch to a regimen with a narrower spectrum. Duration of antibiotic therapy should be individualized based on the pathogen, severity of illness, response to therapy, and comorbid conditions. Therapy for gram-negative bacterial pneumonia should continue for at least 14–21 days.

Expanded discussions of specific antibiotics are provided in Chapter 37. Antibiotic dosage suggestions are provided in Chapter 37.

Fagon JY et al: Antimicrobial treatment of hospital-acquired pneumonia. Clin Chest Med 2005;26:97.

Mehta RM et al: Nosocomial pneumonia in the intensive care unit: controversies and dilemmas. J Inten Care Med 2003; 18:175.

Sopena N et al: Multicenter study of hospital-acquired pneumonia in non-ICU patients. Chest 2005;127:213.

3. Anaerobic Pneumonia & Lung Abscess

Essentials of Diagnosis

  • History of or predisposition to aspiration.

  • Indolent symptoms, including fever, weight loss, malaise.

  • Poor dentition.

  • Foul-smelling purulent sputum (in many patients).

  • Infiltrate in dependent lung zone, with single or multiple areas of cavitation or pleural effusion.

General Considerations

Aspiration of small amounts of oropharyngeal secretions occurs during sleep in normal individuals but rarely causes disease. Sequelae of aspiration of larger amounts of material include nocturnal asthma, chemical pneumonitis, mechanical obstruction of airways by particulate matter, bronchiectasis, and pleuropulmonary infection. Individuals predisposed to disease induced by aspiration include those with depressed levels of consciousness due to drug or alcohol use, seizures, general anesthesia, or central nervous system disease; those with impaired deglutition due to esophageal disease or neurologic disorders; and those with tracheal or nasogastric tubes, which disrupt the mechanical defenses of the airways.

Periodontal disease and poor dental hygiene, which increase the number of anaerobic bacteria in aspirated material, are associated with a greater likelihood of anaerobic pleuropulmonary infection. Aspiration of infected oropharyngeal contents initially leads to pneumonia in dependent lung zones, such as the posterior segments of the upper lobes and superior and basilar segments of the lower lobes. Body position at the time of aspiration determines which lung zones are dependent. The onset of symptoms is insidious. By the time the patient seeks medical attention, necrotizing pneumonia, lung abscess, or empyema may be apparent.

Most aspiration patients with necrotizing pneumonia, lung abscess, and empyema are found to be infected with multiple species of anaerobic bacteria. Most of the remainder are infected with both anaerobic and aerobic bacteria. Prevotella melaninogenica, Peptostreptococcus, Fusobacterium nucleatum, and Bacteroides species are commonly isolated anaerobic bacteria.

Clinical Findings

A. Symptoms and Signs

Patients with anaerobic pleuropulmonary infection usually present with constitutional symptoms such as fever, weight loss, and malaise. Cough with expectoration of foul-smelling purulent sputum suggests anaerobic infection, though the absence of productive cough does not rule out such an infection. Dentition is often poor. Patients are rarely edentulous; if so, an obstructing bronchial lesion is usually present.

B. Laboratory Findings

Expectorated sputum is inappropriate for culture of anaerobic organisms because of contaminating mouth flora. Representative material for culture can be obtained only by transthoracic aspiration, thoracentesis, or bronchoscopy with a protected brush. Transthoracic aspiration is rarely indicated, because drainage occurs via the bronchus and anaerobic pleuropulmonary infections usually respond well to empiric therapy.

C. Imaging

The different types of anaerobic pleuropulmonary infection are distinguished on the basis of their radiographic appearance. Lung abscess appears as a thick-walled solitary cavity surrounded by consolidation. An air-fluid level is usually present. Other causes of cavitary lung disease (tuberculosis, mycosis, cancer, infarction, Wegener's granulomatosis) should be excluded. Necrotizing pneumonia is distinguished by multiple areas of

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cavitation within an area of consolidation. Empyema is characterized by the presence of purulent pleural fluid and may accompany either of the other two radiographic findings. Ultrasonography is of value in locating fluid and may also reveal pleural loculations.

Treatment

Penicillins have been the standard treatment for anaerobic pleuropulmonary infections. However, an increasing number of anaerobic organisms produce β-lactamases, and up to 20% of patients do not respond to penicillins. Improved responses have been documented with clindamycin (600 mg intravenously every 8 hours until improvement, then 300 mg orally every 6 hours) or amoxicillin-clavulanate (875 mg orally every 12 hours). Penicillin (amoxicillin, 500 mg every 8 hours, or penicillin G, 1–2 million units intravenously every 4–6 hours) plus metronidazole (500 mg orally or intravenously every 8–12 hours) is another option. Antibiotic therapy should be continued until the chest radiograph improves, a process that may take a month or more; patients with lung abscesses should be treated until radiographic resolution of the abscess cavity is demonstrated. Anaerobic pleuropulmonary disease requires adequate drainage with tube thoracostomy for the treatment of empyema. Open pleural drainage is sometimes necessary because of the propensity of these infections to produce loculations in the pleural space.

Marik PE: Aspiration pneumonitis and aspiration pneumonia. N Engl J Med 2001;344:665.

Pulmonary Infiltrates in the Immunocompromised Host

Pulmonary infiltrates in immunocompromised patients may arise from infectious or noninfectious causes. Infection may be due to bacterial, mycobacterial, fungal, protozoal, helminthic, or viral pathogens. Noninfectious processes such as pulmonary edema, alveolar hemorrhage, drug reactions, pulmonary thromboembolic disease, malignancy, and radiation pneumonitis may mimic infection.

Although almost any pathogen can cause pneumonia in a compromised host, two clinical tools help the clinician narrow the differential diagnosis. The first is knowledge of the underlying immunologic defect. Specific immunologic defects are associated with particular infections. Defects in humoral immunity predispose to bacterial infections; defects in cellular immunity lead to infections with viruses, fungi, mycobacteria, and protozoa. Neutropenia and impaired granulocyte function predispose to infections from S aureus, Aspergillus, gram-negative bacilli, and Candida. Second, the time course of infection also provides clues to the etiology of pneumonia in immunocompromised patients. A fulminant pneumonia is often caused by bacterial infection, whereas an insidious pneumonia is more apt to be caused by viral, fungal, protozoal, or mycobacterial infection. Pneumonia occurring within 2–4 weeks after organ transplantation is usually bacterial, whereas several months or more after transplantation P jiroveci, viruses (eg, cytomegalovirus), and fungi (eg, Aspergillus) are encountered more often.

Chest radiography is rarely helpful in narrowing the differential diagnosis. Examination of expectorated sputum for bacteria, fungi, mycobacteria, Legionella, and P jiroveci is important and may preclude the need for expensive, invasive diagnostic procedures. Sputum induction is often necessary for diagnosis. The sensitivity of induced sputum for detection of P jiroveci depends on institutional expertise, number of specimens analyzed, and detection methods.

Routine evaluation frequently fails to identify a causative organism. The clinician may begin empiric antimicrobial therapy and proceed to invasive procedures such as bronchoscopy, transthoracic needle aspiration, or open lung biopsy. The approach to management must be based on the severity of the pulmonary infection, the underlying disease, the risks of empiric therapy, and local expertise and experience with diagnostic procedures. Bronchoalveolar lavage using the flexible bronchoscope is a safe and effective method for obtaining representative pulmonary secretions for microbiologic studies. It involves less risk of bleeding and other complications than bronchial brushing and transbronchial biopsy. Bronchoalveolar lavage is especially suitable for the diagnosis of P jiroveci pneumonia in patients with AIDS when induced sputum analysis is negative. Open lung biopsy, now often performed by video-assisted thoracoscopy, provides the best opportunity for diagnosis of pulmonary infiltrates in the immunocompromised host. However, a specific diagnosis is obtained in only about two-thirds of cases, and the information obtained rarely affects the outcome. Therefore, empiric treatment is often preferred.

Hohenthal U et al: Bronchoalveolar lavage in immunocompromised patients with haematological malignancy—value of new microbiological methods. Eur J Hematol 2005;74:203.

Jain P et al: Role of flexible bronchoscopy in immunocompromised patients with lung infiltrates. Chest 2004;125:712.

Shorr AF et al: Pulmonary infiltrates in the non-HIV-infected immunocompromised patient: etiologies, diagnostic strategies, and outcomes. Chest 2004;125:260.

Yen KT et al: Pulmonary complications in bone marrow transplantation: a practical approach to diagnosis and treatment. Clin Chest Med 2004;25:189.

Pulmonary Tuberculosis

Essentials of Diagnosis

  • Fatigue, weight loss, fever, night sweats, and cough.

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  • Pulmonary infiltrates on chest radiograph, most often apical.

  • Positive tuberculin skin test reaction (most cases).

  • Acid-fast bacilli on smear of sputum or sputum culture positive for M tuberculosis.

General Considerations

Tuberculosis is one of the world's most widespread and deadly illnesses. M tuberculosis, the organism that causes tuberculosis infection and disease, infects an estimated 20–43% of the world's population. Each year, 3 million people worldwide die of the disease. In the United States, it is estimated that 15 million people are infected with M tuberculosis. Tuberculosis occurs disproportionately among disadvantaged populations such as the malnourished, homeless, and those living in overcrowded and substandard housing. There is an increased occurrence of tuberculosis among HIV-positive individuals.

Infection with M tuberculosis begins when a susceptible person inhales airborne droplet nuclei containing viable organisms. Tubercle bacilli that reach the alveoli are ingested by alveolar macrophages. Infection follows if the inoculum escapes alveolar macrophage microbicidal activity. Once infection is established, lymphatic and hematogenous dissemination of tuberculosis typically occurs before the development of an effective immune response. This stage of infection, primary tuberculosis, is usually clinically and radiographically silent. In most persons with intact cell-mediated immunity, T cells and macrophages surround the organisms in granulomas that limit their multiplication and spread. The infection is contained but not eradicated, since viable organisms may lie dormant within granulomas for years to decades.

Individuals with this latent tuberculosis infection do not have active disease and cannot transmit the organism to others. However, reactivation of disease may occur if the host's immune defenses are impaired. Active tuberculosis will develop in approximately 10% of individuals with latent tuberculosis infection who are not given preventive therapy; half of these cases occur in the 2 years following primary infection. Up to 50% of HIV-infected patients will develop active tuberculosis within 2 years after infection with tuberculosis. Diverse conditions such as gastrectomy, silicosis, and diabetes mellitus and disorders associated with immunosuppression (eg, HIV infection or therapy with corticosteroids or other immunosuppressive drugs) are associated with an increased risk of reactivation.

In approximately 5% of cases, the immune response is inadequate and the host develops progressive primary tuberculosis, accompanied by both pulmonary and constitutional symptoms that are described below. Standard teaching has held that 90% of tuberculosis in adults represents activation of latent disease. New diagnostic technologies such as DNA fingerprinting suggest that as many as one-third of new cases of tuberculosis in urban populations are primary infections resulting from person-to-person transmission.

The percentage of patients with atypical presentations—particularly elderly patients, patients with HIV infection, and those in nursing homes—has increased. Extrapulmonary tuberculosis is especially common in patients with HIV infection, who often display lymphadenitis or miliary disease.

Strains of M tuberculosis resistant to one or more first-line antituberculous drugs are being encountered with increasing frequency. Risk factors for drug resistance include immigration from parts of the world with a high prevalence of drug-resistant tuberculosis, close and prolonged contact with individuals with drug-resistant tuberculosis, unsuccessful previous therapy, and patient noncompliance. Resistance to one or more antituberculous drugs has been found in 15% of tuberculosis patients in the United States. Outbreaks of multidrug-resistant tuberculosis in hospitals and correctional facilities in Florida and New York have been associated with mortality rates of 70–90% and median survival rates of 4–16 weeks.

Clinical Findings

A. Symptoms and Signs

The patient with pulmonary tuberculosis typically presents with slowly progressive constitutional symptoms of malaise, anorexia, weight loss, fever, and night sweats. Chronic cough is the most common pulmonary symptom. It may be dry at first but typically becomes productive of purulent sputum as the disease progresses. Blood-streaked sputum is common, but significant hemoptysis is rarely a presenting symptom; life-threatening hemoptysis may occur in advanced disease. Dyspnea is unusual unless there is extensive disease. Rarely, the patient is asymptomatic. On physical examination, the patient appears chronically ill and malnourished. On chest examination, there are no physical findings specific for tuberculosis infection. The examination may be normal or may reveal classic findings such as posttussive apical rales.

B. Laboratory Findings

Definitive diagnosis depends on recovery of M tuberculosis from cultures or identification of the organism by DNA or RNA amplification techniques. Three consecutive morning sputum specimens are advised. Sputum induction may be helpful in patients who cannot voluntarily produce satisfactory specimens. Fluorochrome staining with rhodamine-auramine of concentrated, digested sputum specimens is performed initially as a screening method, with confirmation by the Kinyoun or Ziehl-Neelsen stains. Demonstration of acid-fast bacilli on sputum smear does not confirm

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a diagnosis of tuberculosis, since saprophytic nontuberculous mycobacteria may colonize the airways and rarely may cause pulmonary disease.

In patients thought to have tuberculosis despite negative sputum smears, fiberoptic bronchoscopy can be considered. Bronchial washings are helpful; however, transbronchial lung biopsies increase the diagnostic yield. Postbronchoscopy expectorated sputum specimens may also be useful. Early morning aspiration of gastric contents after an overnight fast is an alternative to bronchoscopy but is suitable only for culture and not for stained smear, because nontuberculous mycobacteria may be present in the stomach in the absence of tuberculous infection. M tuberculosis may be cultured from blood in up to 15% of patients with tuberculosis.

Cultures on solid media to identify M tuberculosis may require 12 weeks. Liquid medium culture systems allow detection of mycobacterial growth in several days. Once mycobacteria have been grown in culture, nucleic acid probes or high-performance liquid chromatography can be used to identify the species within hours. The results of nucleic acid (DNA and RNA) amplification tests for tuberculosis should be interpreted in the clinical context and on the basis of local laboratory performance. Drug susceptibility testing of culture isolates is considered routine for the first isolate of M tuberculosis, when a treatment regimen is failing, and when sputum cultures remain positive after 2 months of therapy.

DNA fingerprinting using the restriction fragment length polymorphism analysis is available to identify individual strains of M tuberculosis, thereby revealing if infection has been transmitted from person to person. In addition, this method can be used to detect laboratory cross-contamination.

Needle biopsy of the pleura reveals granulomatous inflammation in approximately 60% of patients with pleural effusions caused by M tuberculosis. Pleural fluid cultures for M tuberculosis are positive in less than 25% of cases of pleural tuberculosis. Culture of three pleural biopsy specimens combined with microscopic examination of a pleural biopsy yields a diagnosis in up to 90% of patients with pleural tuberculosis.

C. Imaging

Radiographic abnormalities in primary tuberculosis include small homogeneous infiltrates, hilar and paratracheal lymph node enlargement, and segmental atelectasis. Pleural effusion may be present, especially in adults, sometimes as the sole radiographic abnormality. Cavitation may be seen with progressive primary tuberculosis. Ghon (calcified primary focus) and Ranke (calcified primary focus and calcified hilar lymph node) complexes are seen in a minority of patients and represent residual evidence of healed primary tuberculosis.

Reactivation tuberculosis is associated with various radiographic manifestations, including fibrocavitary apical disease, nodules, and pneumonic infiltrates. The usual location is in the apical or posterior segments of the upper lobes or in the superior segments of the lower lobes; up to 30% of patients may present with radiographic evidence of disease in other locations. This is especially true in elderly patients, in whom lower lobe infiltrates with or without pleural effusion are encountered with increasing frequency. Lower lung tuberculosis may masquerade as pneumonia or lung cancer. A “miliary” pattern (diffuse small nodular densities) can be seen with hematologic or lymphatic dissemination of the organism. Resolution of reactivation tuberculosis leaves characteristic radiographic findings. Dense nodules in the pulmonary hila, with or without obvious calcification, upper lobe fibronodular scarring, and bronchiectasis with volume loss are common findings.

In patients with early HIV infection, the radiographic features of tuberculosis resemble those in patients without HIV infection. In contrast, atypical radiographic features predominate in patients with late stage HIV infection. These patients often display lower lung zone, diffuse, or miliary infiltrates, pleural effusions, and involvement of hilar and, in particular, mediastinal lymph nodes.

D. Special Examinations

The tuberculin skin test identifies individuals who have been infected with M tuberculosis but does not distinguish between active and latent infection. The test is used to evaluate a person who has symptoms of tuberculosis, an asymptomatic person who may be infected with M tuberculosis (eg, after contact exposure), or to establish the prevalence of tuberculous infection in a population. Routine testing of individuals at low risk for tuberculosis is not recommended. The Mantoux test is the preferred method: 0.1 mL of purified protein derivative (PPD) containing 5 tuberculin units is injected intradermally on the volar surface of the forearm using a 27-gauge needle on a tuberculin syringe. The transverse width in millimeters of induration at the skin test site should be measured after 48–72 hours. Table 9-12 summarizes the criteria established by the Centers for Disease Control and Prevention (CDC) for interpretation of the Mantoux tuberculin skin test. In patients who have serial testing, a tuberculin skin test conversion is defined as an increase of ≥ 10 mm of induration within a 2-year period regardless of patient age.

In general, it takes 2–10 weeks after tuberculosis infection for an immune response to PPD to develop. Both false-positive and false-negative results occur. False-positive tuberculin skin test reactions occur in persons previously vaccinated against M tuberculosis with bacillus Calmette-Guérin (BCG) (extract of Mycobacterium bovis) and in those infected with nontuberculous mycobacteria. False-negative tuberculin skin test reactions may result from improper testing technique, concurrent infections, malnutrition, advanced age, immunologic disorders, lymphoreticular malignancies,

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corticosteroid therapy, chronic renal failure, HIV infection, and fulminant tuberculosis. Some individuals with latent tuberculosis infection may have a negative skin test reaction when tested many years after exposure.

Table 9-12. Classification of positive tuberculin skin test reactions.1

Reaction Size Group
≥ 5 mm
  1. HIV-positive persons.
  2. Recent contacts of individuals with active tuberculosis.
  3. Persons with fibrotic changes on chest x-rays suggestive of prior tuberculosis.
  4. Patients with organ transplants and other immunosuppressed patients (receiving the equivalent of > 15 mg/d of prednisone for 1 month or more).
≥ 10 mm
  1. Recent immigrants (< 5 years) from countries with a high prevalence of tuberculosis (eg, Asia, Africa, Latin America).
  2. HIV-negative injection drug users.
  3. Mycobacteriology laboratory personnel.
  4. Residents of and employees2 in the following high-risk congregate settings: correctional institutions; nursing homes and other long-term facilities for the elderly; hospitals and other health care facilities; residential facilities for AIDS patients; and homeless shelters.
  5. Persons with the following medical conditions that increase the risk of tuberculosis: gastrectomy, ≥ 10% below ideal body weight, jejunoileal bypass, diabetes mellitus, silicosis, chronic renal failure, some hematologic disorders, (eg, leukemias, lymphomas), and other specific malignancies (eg, carcinoma of the head or neck and lung).
  6. Children < 4 years of age or infants, children, and adolescents exposed to adults at high risk.
≥ 15 mm
  1. Persons with no risk factors for tuberculosis.
1A tuberculin skin test reaction is considered positive if the transverse diameter of the indurated area reaches the size required for the specific group. All other reactions are considered negative.
2For persons who are otherwise at low risk and are tested at entry into employment, a reaction of > 15 mm induration is considered positive.
Adapted from: Screening for tuberculosis and tuberculosis infection in high-risk populations: recommendations of the Advisory Council for the Elimination of Tuberculosis. MMWR Morb Mortal Wkly Rep 1995;44(RR-11):19.

Serial testing may create a false impression of skin test conversion. Dormant mycobacterial sensitivity is sometimes restored by the antigenic challenge of the initial skin test. This phenomenon is called “boosting.” A two-step testing procedure is used to reduce the likelihood that a boosted tuberculin reaction will be misinterpreted as a recent infection. Following a negative tuberculin skin test, the person is retested in 1–3 weeks. If the second test is negative, the person is uninfected or anergic; if positive, a boosted reaction is likely. Two-step testing should be used for the initial tuberculin skin testing of individuals who will be tested repeatedly, such as health care workers. Anergy testing is not recommended for routine use to distinguish a true-negative result from anergy. Poor anergy test standardization and lack of outcome data limit the evaluation of its effectiveness. Interpretation of the tuberculin skin test in persons who have previously received BCG vaccination is the same as in those who have not had BCG.

Novel in vitro methods promise significant changes in the identification of persons with latent M tuberculosis infection. Potential advantages of in vitro testing include reduced variability and subjectivity associated with placing and reading the PPD, fewer false-positive results from prior BCG vaccination, and better discrimination of positive responses due to nontuberculous mycobacteria.

Persons with concomitant HIV and tuberculosis infection usually respond best when the HIV infection is treated concurrently. In some cases, prolonged antituberculous therapy may be warranted. Therefore, all patients with tuberculosis infection should be tested for HIV within 2 months after diagnosis.

Treatment

A. General Measures

The goals of therapy are to eliminate all tubercle bacilli from an infected individual while avoiding the emergence of clinically significant drug resistance. The basic principles of antituberculous treatment are (1) to administer multiple drugs to which the organisms are susceptible; (2) to add at least two new antituberculous agents to a regimen when treatment failure is suspected; (3) to provide the safest, most effective therapy in the shortest period of time; and (4) to ensure adherence to therapy.

All suspected and confirmed cases of tuberculosis should be reported promptly to local and state public health authorities. Public health departments will perform case investigations on sources and patient contacts to determine if other individuals with untreated, infectious tuberculosis are present in the community. They can identify infected contacts eligible for treatment of latent tuberculous infection, and ensure that a plan for monitoring adherence to therapy is established for each patient with tuberculosis. Patients with tuberculosis should be treated by physicians who are

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skilled in the management of this infection. Clinical expertise is especially important in cases of drug-resistant tuberculosis.

Table 9-13. Characteristics of antituberculous drugs.1

Drug Most Common Side Effects Tests for Side Effects Drug Interactions Remarks
Isoniazid Peripheral neuropathy, hepatitis, rash, mild CNS effects. AST and ALT; neurologic examination. Phenytoin (synergistic); disulfiram. Bactericidal to both extracellular and intracellular organisms. Pyridoxine, 10 mg orally daily as prophylaxis for neuritis; 50-100 mg orally daily as treatment.
Rifampin Hepatitis, fever, rash, flu-like illness, gastrointestinal upset, bleeding problems, renal failure. CBC, platelets, AST and ALT. Rifampin inhibits the effect of oral contraceptives, quinidine, corticosteroids, warfarin, methadone, digoxin, oral hypoglycemics; aminosalicyclic acid may interfere with absorption of rifampin. Significant interactions with protease inhibitors and nonnucleoside reverse transcriptase inhibitors. Bactericidal to all populations of organisms. Colors urine and other body secretions orange. Discoloring of contact lenses.
Pyrazinamide Hyperuricemia, hepatotoxicity, rash, gastrointestinal upset, joint aches. Uric acid, AST, ALT. Rare. Bactericidal to intracellular organisms.
Ethambutol Optic neuritis (reversible with discontinuance of drug; rare at 15 mg/kg); rash. Red-green color discrimination and visual acuity (difficult to test in children under 3 years of age). Rare. Bacteriostatic to both intracellular and extracellular organisms. Mainly used to inhibit development of resistant mutants. Use with caution in renal disease or when ophthalmologic testing is not feasible.
Streptomycin Eighth nerve damage, nephrotoxicity. Vestibular function (audiograms); BUN and creatinine. Neuromuscular blocking agents may be potentiated and cause prolonged paralysis. Bactericidal to extracellular organisms. Use with caution in older patients or those with renal disease.
1See also Chapter 37.
Key: AST = aspartate aminotransferase; ALT = alanine aminotransferase; CBC = complete blood count; BUN = blood urea nitrogen.

Nonadherence to antituberculous treatment is a major cause of treatment failure, continued transmission of tuberculosis, and the development of drug resistance. Adherence to treatment can be improved by providing detailed patient education about tuberculosis and its treatment in addition to a case manager who oversees all aspects of an individual patient's care. Directly observed therapy (DOT), which requires that a health care worker physically observe the patient ingest antituberculous medications in the home, clinic, hospital, or elsewhere, also improves adherence to treatment. The importance of direct observation of therapy cannot be overemphasized. The CDC recommends DOT for all patients with drug-resistant tuberculosis and for those receiving intermittent (twice- or thrice-weekly) therapy.

Hospitalization for initial therapy of tuberculosis is not necessary for most patients. It should be considered if a patient is incapable of self-care or is likely to expose new, susceptible individuals to tuberculosis. Hospitalized patients with active disease require a private room with appropriate ventilation until tubercle bacilli are no longer found in their sputum (“smear-negative”) on three consecutive smears taken on separate days.

Additional treatment considerations can be found in Chapter 33. Characteristics of antituberculous drugs are provided in Table 9-13 and in Chapter 37. More complete information can be obtained from the CDC's Division of Tuberculosis Elimination Web site at http://www.cdc.gov/nchstp/tb/.

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B. Treatment of Tuberculosis in HIV-Negative Persons

Most patients with previously untreated pulmonary tuberculosis can be effectively treated with either a 6-month or a 9-month regimen, though the 6-month regimen is preferred. The initial phase of a 6-month regimen consists of 2 months of daily isoniazid, rifampin, pyrazinamide, and ethambutol. Once the isolate is determined to be isoniazid-sensitive, ethambutol may be discontinued. If the M tuberculosis isolate is susceptible to isoniazid and rifampin, the second phase of therapy consists of isoniazid and rifampin for a minimum of 4 additional months, with treatment to extend at least 3 months beyond documentation of conversion of sputum cultures to negative for M tuberculosis. If DOT is used, medications may be given intermittently using one of three regimens: (1) Daily isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by isoniazid and rifampin two or three times each week for 4 months if susceptibility to isoniazid and rifampin is demonstrated. (2) Daily isoniazid, rifampin, pyrazinamide, and ethambutol for 2 weeks, then administration of the same agents twice weekly for 6 weeks followed by administration of isoniazid and rifampin twice each week for 4 months if susceptibility to isoniazid and rifampin is demonstrated. (3) Thrice-weekly administration of isoniazid, rifampin, pyrazinamide, and ethambutol for 6 months.

Patients who cannot or should not (eg, pregnant women) take pyrazinamide should receive daily isoniazid and rifampin along with ethambutol for 4–8 weeks. If susceptibility to isoniazid and rifampin is demonstrated or drug resistance is unlikely, ethambutol can be discontinued and isoniazid and rifampin may be given twice a week for a total of 9 months of therapy. If drug resistance is a concern, patients should receive isoniazid, rifampin, and ethambutol for 9 months. Patients with smear- and culture-negative disease (eg, pulmonary tuberculosis diagnosed on clinical grounds) and patients for whom drug susceptibility testing is not available can be treated with 6 months of isoniazid and rifampin combined with pyrazinamide for the first 2 months. This regimen assumes low prevalence of drug resistance. Previous guidelines have used streptomycin interchangeably with ethambutol. Increasing worldwide streptomycin resistance has made this drug less useful as empiric therapy.

When a twice-weekly or thrice-weekly regimen is used instead of a daily regimen, the dosages of isoniazid, pyrazinamide, and ethambutol or streptomycin must be increased. Recommended dosages for the initial treatment of tuberculosis are listed in Table 9-14. Fixed-dose combinations of isoniazid and rifampin (Rifamate) and of isoniazid, rifampin, and pyrazinamide (Rifater) are available to simplify treatment. Single tablets improve compliance but are more expensive than the individual drugs purchased separately.

C. Treatment of Tuberculosis in HIV-Positive Persons

Management of tuberculosis is rendered even more complex in patients with concomitant HIV disease. Experts in the management of both tuberculosis and HIV disease should be involved in the care of such patients. The CDC has published detailed recommendations for the treatment of tuberculosis in HIV-positive patients. These documents can be obtained by accessing the CDC Division of Tuberculosis Elimination Web site at http://www.cdc.gov/nchstp/tb/pubs/mmwrhtm/Maj_guide/HIV_AIDS.htm

The basic approach to HIV-positive patients with tuberculosis is similar to that detailed above for patients without HIV disease. Additional considerations in HIV-positive patients include (1) longer duration of therapy and (2) drug interactions between rifamycin derivatives

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such as rifampin and rifabutin, used to treat tuberculosis, and some of the protease inhibitors and nonnucleoside reverse transcriptase inhibitors (NNRTIs), used to treat HIV (see above Web site). DOT should be used for all HIV-positive tuberculosis patients. Pyridoxine (vitamin B6), 25–50 mg orally each day, should be administered to all HIV-positive patients being treated with isoniazid to reduce central and peripheral nervous system side effects.

Table 9-14. Recommended dosages for the initial treatment of tuberculosis.

Drugs Daily Cost1 Twice a Week2 Cost1/wk Three Times a Week2 Cost1/wk
Isoniazid 5 mg/kgMax: 300 mg/dose $0.13/300 mg 15 mg/kgMax: 900 mg/dose $0.78 15 mg/kgMax: 900 mg/dose $1.17
Rifampin 10 mg/kgMax: 600 mg/dose $3.80/600 mg 10 mg/kgMax: 600 mg/dose $7.60 10 mg/kgMax: 600 mg/dose $11.40
Pyrazinamide 15-30 mg/kgMax: 2 g/dose $4.40/2 g 50-70 mg/kgMax: 4 g/dose $17.60 50-70 mg/kgMax: 3 g/dose $19.80
Ethambutol 5-25 mg/kgMax: 2.5 g/dose $11.27/2.5 g 50 mg/kgMax: 2.5 g/dose $22.54 25-30 mg/kgMax: 2.5 g/dose $33.81
Streptomycin 15 mg/kgMax: 1 g/dose $9.75/1 g 25-30 mg/kgMax: 1.5 g/dose $39.00 25-30 mg/kgMax: 1.5 g/dose $58.50
1Average wholesale price (AWP, for AB-rated generic when available) for quantity listed. Source: Red Book Update, Vol. 25, No. 5, May 2006. AWP may not accurately represent the actual pharmacy cost because wide contractual variations exist among institutions.
2All intermittent dosing regimens should be used with directly observed therapy.

D. Treatment of Drug-Resistant Tuberculosis

Patients with drug-resistant M tuberculosis infection require careful supervision and management. Clinicians who are unfamiliar with the treatment of drug-resistant tuberculosis should seek expert advice. Tuberculosis resistant only to isoniazid can be successfully treated with a 6-month regimen of rifampin, pyrazinamide, and ethambutol or streptomycin or a 12-month regimen of rifampin and ethambutol. When isoniazid resistance is documented during a 9-month regimen without pyrazinamide, isoniazid should be discontinued. If ethambutol was part of the initial regimen, rifampin and ethambutol should be continued for a minimum of 12 months. If ethambutol was not part of the initial regimen, susceptibility tests should be repeated and two other drugs to which the organism is susceptible should be added. Treatment of M tuberculosis isolates resistant to agents other than isoniazid and treatment of drug resistance in HIV-infected patients require expert consultation.

Multidrug-resistant tuberculosis (MDRTB) calls for an individualized daily directly observed treatment plan under the supervision of a clinician experienced in the management of this entity. Treatment regimens are based on the patient's overall status and the results of susceptibility studies. Most MDRTB isolates are resistant to at least isoniazid and rifampin and require a minimum of three drugs to which the organism is susceptible. These regimens are continued until culture conversion is documented, and then a two-drug regimen is then continued for at least another 12 months. Some experts recommend at least 18–24 months of a three-drug regimen.

E. Treatment of Extrapulmonary Tuberculosis

In most cases, regimens that are effective for treating pulmonary tuberculosis are also effective for treating extrapulmonary disease. However, many experts recommend 9 months of therapy when miliary, meningeal, or bone and joint disease is present. Treatment of skeletal tuberculosis is enhanced by early surgical drainage and debridement of necrotic bone. Corticosteroid therapy has been shown to help prevent cardiac constriction from tuberculous pericarditis and to reduce neurologic complications from tuberculous meningitis.

F. Treatment of Pregnant or Lactating Women

Tuberculosis in pregnancy is usually treated with isoniazid, rifampin, and ethambutol. Ethambutol can be excluded if isoniazid resistance is unlikely. Therapy is continued for 9 months. Since the risk of teratogenicity with pyrazinamide has not been clearly defined, pyrazinamide should be used only if resistance to other drugs is documented and susceptibility to pyrazinamide is likely. Streptomycin is contraindicated in pregnancy because it may cause congenital deafness. Pregnant women taking isoniazid should receive pyridoxine (vitamin B6), 10–25 mg orally once a day, to prevent peripheral neuropathy.

Small concentrations of antituberculous drugs are present in breast milk and are not known to be harmful to nursing newborns. Therefore, breastfeeding is not contraindicated while receiving antituberculous therapy.

G. Treatment Monitoring

Adults should have measurements of serum bilirubin, hepatic enzymes, urea nitrogen, creatinine, and a complete blood count (including platelets) before starting chemotherapy for tuberculosis. Visual acuity and red-green color vision tests are recommended before initiation of ethambutol and serum uric acid before starting pyrazinamide. Audiometry should be performed if streptomycin therapy is initiated.

Routine monitoring of laboratory tests for evidence of drug toxicity during therapy is not recommended. Monthly questioning for symptoms of drug toxicity is advised. Patients should be educated about common side effects of antituberculous medications and instructed to seek medical attention should these symptoms occur. Monthly follow-up of outpatients is recommended, including sputum smear and culture for M tuberculosis until cultures convert to negative. Patients with negative sputum cultures after 2 months of treatment should have at least one additional sputum smear and culture performed at the end of therapy. Patients with MDRTB should have sputum cultures performed monthly during the entire course of treatment. A chest radiograph at the end of therapy provides a useful baseline for any future films.

Patients whose cultures do not become negative or whose symptoms do not resolve despite 3 months of therapy should be evaluated for drug-resistant organisms and for nonadherence to the treatment regimen. DOT is required for the remainder of the treatment regimen, and the addition of at least two drugs not previously given should be considered pending repeat drug susceptibility testing. The clinician should seek expert assistance if drug resistance is newly found, if the patient remains symptomatic, or if smears or cultures remain positive.

Patients with only a clinical diagnosis of pulmonary tuberculosis (smears and cultures negative for M tuberculosis) whose symptoms and radiographic abnormalities are unchanged after 3 months of treatment usually either have another process or have had tuberculosis in the past.

H. Treatment of Latent Tuberculosis

Treatment of latent tuberculous infection is essential to controlling and eliminating tuberculosis in the

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United States. Treatment of latent tuberculous infection substantially reduces the risk that infection will progress to active disease. Targeted testing is used to identify persons who are at high risk for tuberculosis and who stand to benefit from treatment of latent infection. Table 9-12 defines high-risk groups and gives the tuberculin skin test criteria for treatment of latent tuberculous infection. It is essential that each person who meets the criteria for treatment of latent tuberculous infection undergo a careful assessment to exclude active disease. A history of past treatment for tuberculosis and contraindications to treatment should be sought. All patients at risk for HIV infection should be tested for HIV. Patients suspected of having tuberculosis should receive one of the recommended multidrug regimens for active disease until the diagnosis is confirmed or excluded.

Some close contacts of persons with active tuberculosis should be evaluated for treatment of latent tuberculous infection despite a negative tuberculin skin test reaction (< 5 mm induration). These include immunosuppressed persons and those who may develop disease quickly after tuberculous infection. Close contacts who have a negative tuberculin skin test reaction on initial testing should be retested 10–12 weeks later.

Several treatment regimens for both HIV-negative and HIV-positive persons are available for the treatment of latent tuberculous infection: (1) Isoniazid: A 9-month regimen (minimum of 270 doses administered within 12 months) is considered optimal. Dosing options include a daily dose of 300 mg or twice-weekly doses of 15 mg/kg. Persons at risk for developing isoniazid-associated peripheral neuropathy (diabetes mellitus, uremia, malnutrition, alcoholism, HIV infection, pregnancy, seizure disorder) may be given supplemental pyridoxine (vitamin B6), 10–50 mg/d. (2) Rifampin and pyrazinamide: A 2-month regimen (60 doses administered within 3 months) of daily rifampin (10 mg/kg up to a maximum dose of 600 mg) and pyrazinamide (15–20 mg/kg up to a maximum dose of 2 g) is recommended. (3) Rifampin: Patients who cannot tolerate isoniazid or pyrazinamide can be considered for a 4-month regimen (minimum of 120 doses administered within 6 months) of rifampin. HIV-positive patients given rifampin who are receiving protease inhibitors or NNRTIs require management by experts in both tuberculosis and HIV disease (see Treatment of Tuberculosis in HIV-Positive Persons, above).

Contacts of persons with isoniazid-resistant, rifampin-sensitive tuberculosis should receive a 2-month regimen of rifampin and pyrazinamide or a 4-month regimen of daily rifampin alone. Contacts of persons with MDRTB should receive two drugs to which the infecting organism has demonstrated susceptibility. Tuberculin skin test-negative and HIV-negative contacts may be observed without treatment or treated for 6 months. HIV-positive contacts should be treated for 12 months. All contacts of persons with MDRTB should have 2 years of follow-up regardless of treatment.

Persons with a positive tuberculin skin test (≥ 5 mm of induration) and fibrotic lesions suggestive of old tuberculosis on chest radiographs who have no evidence of active disease and no history of treatment for tuberculosis should receive 9 months of isoniazid, or 2 months of rifampin and pyrazinamide, or 4 months of rifampin (with or without isoniazid). Pregnant or breastfeeding women with latent tuberculosis should receive either daily or twice-weekly isoniazid with pyridoxine (vitamin B6).

Baseline laboratory testing is indicated for patients at risk for liver disease, patients with HIV infection, women who are pregnant or within 3 months of delivery, and persons who use alcohol regularly. Patients receiving treatment for latent tuberculous infection should be evaluated once a month to assess for signs and symptoms of active tuberculosis and hepatitis and for adherence to their treatment regimen. Routine laboratory testing during treatment is indicated for those with abnormal baseline laboratory tests and for those at risk for developing liver disease.

Vaccine BCG is an antimycobacterial vaccine developed from an attenuated strain of M bovis. Millions of individuals worldwide have been vaccinated with BCG. However, it is not generally recommended in the United States because of the low prevalence of tuberculous infection, the vaccine's interference with the ability to determine latent tuberculous infection using tuberculin skin test reactivity, and its variable effectiveness against pulmonary tuberculosis. BCG vaccination in the United States should only be undertaken after consultation with local health officials and experts in the management of tuberculosis. Vaccination of health care workers should be considered on an individual basis in settings in which a high percentage of tuberculosis patients are infected with strains resistant to both isoniazid and rifampin, in which transmission of such drug-resistant M tuberculosis and subsequent infection are likely, and in which comprehensive tuberculous infection-control precautions have been implemented but have not been successful. The BCG vaccine is contraindicated in persons with impaired immune responses due to disease or medications.

Prognosis

Almost all properly treated patients with tuberculosis can be cured. Relapse rates are less than 5% with current regimens. The main cause of treatment failure is nonadherence to therapy.

American Thoracic Society; Centers for Disease Control and Prevention; Infectious Diseases Society of America: controlling tuberculosis in the United States. Am J Respir Crit Care Med 2005;172:1169.

Blumberg HM et al: American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care Med 2003;167:603.

Blumberg HM et al: Update on the treatment of tuberculosis and latent tuberculosis infection. JAMA 2005;293:2776.

Brodie D et al: The diagnosis of tuberculosis. Clin Chest Med 2005;26:247.

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Burman WJ: Issues in the management of HIV-related tuberculosis. Clin Chest Med 2005;26:283.

Diagnostic Standards and Classification of Tuberculosis in Adults and Children. American Thoracic Society and Centers for Disease Control and Prevention. Am J Respir Crit Care Med 2000;161(4 Part 1):1376.

Frieden TR et al: Tuberculosis. Lancet 2003;362:887.

Pulmonary Disease Caused by Nontuberculous Mycobacteria

Essentials of Diagnosis

  • Chronic cough, sputum production, and fatigue; less commonly: malaise, dyspnea, fever, hemoptysis, and weight loss.

  • Parenchymal infiltrates on chest radiograph, often with thin-walled cavities, that spread contiguously and often involve overlying pleura.

  • Isolation of nontuberculous mycobacteria in a sputum culture.

General Considerations

Mycobacteria other than M tuberculosis—nontuberculous mycobacteria (NTM), sometimes referred to as “atypical” mycobacteria—are ubiquitous in water and soil and have been isolated from tap water. There appears to be a continuing increase in the number and prevalence of NTM species. Marked geographic variability exists, both in the NTM species responsible for disease and in the prevalence of disease. These organisms are not considered communicable from person to person, have distinct laboratory characteristics, and are often resistant to most antituberculous drugs. See Chapter 33 for further information.

Definition & Pathogenesis

The diagnosis of lung disease caused by NTM is based on a combination of clinical, radiographic, and bacteriologic criteria and the exclusion of other diseases that can resemble the condition. Specific diagnostic criteria are discussed below. Complementary data are important for diagnosis because NTM organisms can reside in or colonize the airways without causing clinical disease, especially in patients with AIDS, and many patients have preexisting lung disease that may make their chest radiographs abnormal.

Mycobacterium avium complex (MAC) is the most frequent cause of NTM pulmonary disease in humans in the United States. Mycobacterium kansasii is the next most frequent pulmonary pathogen. Other NTM causes of pulmonary disease include Mycobacterium abscessus, Mycobacterium xenopi, and Mycobacterium malmoense; the list of more unusual etiologic NTM species is long. Most NTM cause a chronic, slowly progressive pulmonary infection that resembles tuberculosis but tends to progress more slowly. Disseminated disease is rare in immunocompetent hosts; however, disseminated MAC disease is common in patients with AIDS.

Clinical Findings

A. Symptoms and Signs

Most patients with NTM infection experience a chronic cough, sputum production, and fatigue. Less common symptoms include malaise, dyspnea, fever, hemoptysis, and weight loss. Symptoms from coexisting lung disease (commonly COPD, bronchiectasis, previous mycobacterial disease, cystic fibrosis, and pneumoconiosis) may confound the evaluation.

Common physical findings include fever and altered breath sounds, including rales or rhonchi.

B. Laboratory Findings

The diagnosis of NTM infection rests on recovery of the pathogen from cultures. Sputum cultures positive for atypical mycobacteria do not in themselves prove infection because NTM may exist as saprophytes colonizing the airways or may be environmental contaminants. Bronchial washings are considered to be more sensitive than expectorated sputum samples; however, their specificity for clinical disease is not known.

Bacteriologic criteria have been proposed based on studies of patients with cavitary disease with MAC or M kansasii. Diagnostic criteria in HIV-seronegative or immunocompetent hosts include the following: (1) at least three sputum or bronchial wash samples within a 1-year period with the following findings: three positive cultures with negative acid-fast bacilli (AFB) smears or two positive cultures and one positive AFB smear; (2) if expectorated sputum samples are not available, a single bronchial wash culture with 2+ to 4+ growth or any positive culture plus a 2+ to 4+ AFB smear. The diagnosis can also be established by demonstrating NTM in a lung biopsy or bronchial wash plus histopathologic changes such as granulomatous inflammation in a lung biopsy. Rapid species identification of some NTM is possible using DNA probes or high-pressure liquid chromatography.

Diagnostic criteria are less stringent for patients with severe immune suppression. HIV-infected patients may show significant MAC growth on culture of bronchial washings without clinical infection, and, therefore, HIV patients being evaluated for MAC infection must be considered individually.

In general, drug susceptibility testing on cultures of NTM is not recommended except for the following NTM: (1) M kansasii and rifampin; (2) rapid growers (such as Mycobacterium fortuitum, Mycobacterium chelonei, M abscessus) and amikacin, doxycycline, imipenem, fluoroquinolones, clarithromycin, cefoxitin, and a sulfonamide.

C. Imaging

Chest radiographic findings include infiltrates that are progressive or persist for at least 2 months, cavitary lesions, and multiple nodular densities. The cavities are

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often thin-walled and have less surrounding parenchymal infiltrate than is commonly seen with MTB infections. Evidence of contiguous spread and pleural involvement is often present. High-resolution CT of the chest may show multiple small nodules with or without multifocal bronchiectasis. Progression of pulmonary infiltrates during therapy or lack of radiographic improvement over time are poor prognostic signs and also raise concerns about secondary or alternative pulmonary processes. Clearing of pulmonary infiltrates due to NTM is slow.

Treatment

Treatment regimens and responses vary with the species of NTM. Disease caused by M kansasii responds well to drug therapy. A daily regimen of rifampin, isoniazid, and ethambutol for at least 18 months with a minimum of 12 months of negative cultures is usually successful.

The treatment of the immunocompetent patient with MAC infection is controversial and largely empiric. Traditional chemotherapeutic regimens have taken an aggressive approach using a combination of agents, but these have been associated with a high incidence of drug-induced side effects. Adherence to such regimens is also difficult. Non-HIV-infected patients with MAC pulmonary disease usually receive a combination of daily clarithromycin or azithromycin, rifampin or rifabutin, and ethambutol. Streptomycin is considered for the first 2 months as tolerated. The optimal duration of treatment is unknown, but therapy should be continued for 12 months after sputum conversion. Medical treatment is initially successful in about two-thirds of cases, but relapses after treatment are common; long-term benefit is demonstrated in about half of all patients. Those who do not respond favorably generally have active but stable disease. Surgical resection is an alternative for the patient with progressive disease that responds poorly to chemotherapy; the success rate with surgical therapy is good.

Field SK et al: Mycobacterium avium complex pulmonary disease in patients without HIV infection. Chest 2004;126:566.

Kim JS et al: Nontuberculous mycobacterial infection: CT scan findings, genotype, and treatment responsiveness. Chest 2005;128:3863.

Wagner D et al: Nontuberculous mycobacterial infections: a clinical review. Infection 2004;32:257.

Pulmonary Neoplasms

Screening for Lung Cancer

Periodic evaluation of asymptomatic people at high risk for lung cancer is an attractive strategy without demonstrated benefit. Available evidence from the Mayo Lung Project suggests that serial chest radiographs can identify a significant number of early stage malignancies but that neither disease-specific mortality from lung cancer nor all-cause mortality is affected by screening. The illusory benefits of screening have been attributed to lead time, length time, and overdiagnosis biases. Since three large randomized clinical trials published between 1984 and 1986 came to similar conclusions, screening for lung cancer has not been recommended by any major advisory group.

The availability of rapid-acquisition, low-dose helical computed tomography (LDCT) has rekindled enthusiasm for lung cancer screening. LDCT is a very sensitive test. Compared with chest radiography, LDCT identifies between four and ten times the number of asymptomatic lung malignancies. LDCT may also increase the number of false-positive tests, unnecessary diagnostic procedures, and overdiagnosis. A mortality benefit remains to be proved. The National Lung Cancer Screening Trial is an ongoing NCI-funded multicenter trial to determine whether using LDCT to screen current or former heavy smokers for lung cancer will improve mortality in this population. Information is available at http://www.cancer.gov/NLST/.

Humphrey LL et al: Lung cancer screening with sputum cytologic examination, chest radiography, and computed tomography: an update for the U.S. Preventive Services Task Force. Ann Intern Med 2004;140:740.

Mulshine JL et al: Clinical practice. Lung cancer screening. N Engl J Med 2005;352:2714.

Solitary Pulmonary Nodule

A solitary pulmonary nodule, sometimes referred to as a “coin lesion,” is a < 3 cm isolated, rounded opacity on the chest radiograph outlined by normal lung and not associated with infiltrate, atelectasis, or adenopathy. Most are asymptomatic and represent an unexpected finding on chest radiography. The finding is important because it carries a significant risk of malignancy. The frequency of malignancy in surgical series ranges from 10% to 68% depending on patient population. Most benign nodules are infectious granulomas. Benign neoplasms such as hamartomas account for less than 5% of solitary nodules.

The goals of evaluation are to identify and resect malignant tumors in patients who stand to benefit from resection while avoiding invasive procedures in benign disease. The task is to identify nodules with a sufficiently high probability of malignancy to warrant biopsy or resection or a sufficiently low probability of malignancy to justify observation.

Symptoms alone rarely establish the cause, but clinical and radiographic data can be used to assess the probability of malignancy. The patient's age is important. Malignant nodules are rare in persons under age 30. Above age 30, the likelihood of malignancy increases with age. Smokers are at increased risk, and the likelihood of malignancy increases with the number of cigarettes smoked daily. Patients with a prior malignancy

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have a higher likelihood of having a malignant solitary nodule.

The first and most important step in the radiographic evaluation is to review old radiographs. Comparison with prior studies allows estimation of doubling time, which is an important marker for malignancy. Rapid progression (doubling time less than 30 days) suggests infection; long-term stability (doubling time over 465 days) suggests benignity. Certain radiographic features help in estimating the probability of malignancy. Increasing size is correlated with malignancy. A recent study of solitary nodules identified by CT scan showed a 1% malignancy rate in those measuring 2–5 mm, 24% in 6–10 mm, 33% in 11–20 mm, and 80% in 21–45 mm. The appearance of a smooth, well-defined edge is characteristic of a benign process. Ill-defined margins or a lobular appearance suggest malignancy. A high-resolution CT finding of spiculated margins and a peripheral halo are both highly associated with malignancy. Calcification and its pattern are also helpful clues. Benign lesions tend to have dense calcification in a central or laminated pattern. Malignant lesions are associated with sparser calcification that is typically stippled or eccentric. Cavitary lesions with thick (> 16 mm) walls are much more likely to be malignant. High-resolution CT offers better resolution of these characteristics than chest radiography and is more likely to detect lymphadenopathy or the presence of multiple lesions. High-resolution CT is indicated in any suspicious solitary pulmonary nodule.

Treatment

Based on clinical and radiologic data, the clinician should assign a specific probability of malignancy to the lesion. The decision whether and how to obtain a diagnostic biopsy depends on the interpretation of this probability in light of the patient's unique clinical situation. The probabilities in parentheses below represent guidelines only and should not be interpreted as prescriptive.

In the case of solitary pulmonary nodules, a continuous probability function may be grouped into three categories. In patients with a low probability (< 8%) of malignancy (eg, age under 30, lesions stable for more than 2 years, characteristic pattern of benign calcification), watchful waiting is appropriate. Management consists of serial radiographs every 3 months for 1 year and then every 6 months for a second year. Three-dimensional reconstruction of high-resolution CT images may provide a more sensitive test for growth. These techniques are in research trials.

Patients with a high probability (> 70%) of malignancy should proceed directly to resection following staging, provided there are no contraindications to surgery. Biopsies rarely yield a specific benign diagnosis and are not indicated.

Optimal management of patients with an intermediate probability of malignancy (8–70%) remains controversial. The traditional approach is to obtain a diagnostic biopsy either through transthoracic needle aspiration (TTNA) or bronchoscopy. Bronchoscopy yields a diagnosis in 10–80% of procedures depending on the size of the nodule and its location. Complications are generally rare. TTNA has a higher diagnostic yield, reported to be between 50% and 97%. The yield is strongly operator-dependent, however, and is affected by the location and size of the lesion. Complications are higher than bronchoscopy, with pneumothorax occurring in up to 30% of patients.

Disappointing diagnostic yields and a high false-negative rate (up to 25–30% in TTNA) have prompted alternative approaches. Several new imaging techniques may help improve the specificity of high-resolution CT in excluding malignancy. Malignant nodules tend to be more highly vascularized and therefore show increased enhancement on high-resolution CT following the intravenous infusion of iodine-containing contrast media. Sensitivity and specificity appear promising but await validation. Positron emission tomography (PET) detects increased glucose metabolism within malignant lesions with high sensitivity (85–97%) and specificity (70–85%). Many diagnostic algorithms have incorporated PET into the assessment of patients with inconclusive high-resolution CT findings. PET has several drawbacks, however: resolution below 1 cm is poor, the test is expensive, and availability remains limited. Sputum cytology is highly specific but lacks sensitivity. It is used in central lesions and in patients who are poor candidates for invasive diagnostic procedures. Researchers have attempted to improve the sensitivity of sputum cytology through the use of monoclonal antibodies to proteins that are up-regulated in pulmonary malignancies. Such tests offer promise but remain research tools at this time.

Video-assisted thoracoscopic surgery (VATS) offers a more aggressive approach to diagnosis. VATS is more invasive than bronchoscopy or TTNA but is associated with less postoperative pain, shorter hospital stays, and more rapid return to function than traditional thoracotomy. These advantages have led some centers to recommend VATS resection of all solitary pulmonary nodules with intermediate probability of malignancy. In some cases, surgeons will remove the nodule and evaluate it in the operating room with frozen section. If the nodule is malignant, they will proceed to lobectomy and lymph node sampling, either thoracoscopically or through conversion to standard thoracotomy.

Gurney JW: Determining the likelihood of malignancy in solitary pulmonary nodules with Bayesian analysis. Part I. Theory. Radiology 1993;186:405.

MacMahon H et al: Guidelines for management of small pulmonary nodules detected on CT scans: a statement from the Fleischner Society. Radiology 2005;237:395.

Ost D et al: Clinical practice. The solitary pulmonary nodule. N Engl J Med 2003;348:2535.

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Bronchogenic Carcinoma

Essentials of Diagnosis

  • New cough, or change in chronic cough.

  • Dyspnea, hemoptysis, anorexia, weight loss.

  • Enlarging nodule or mass; persistent infiltrate, atelectasis, or pleural effusion on chest radiograph or CT scan.

  • Cytologic or histologic findings of lung cancer in sputum, pleural fluid, or biopsy specimen.

General Considerations

Lung cancer is the leading cause of cancer deaths in both men and women. The American Cancer Society estimates 172,570 new diagnoses and 163,510 deaths from lung cancer in the United States in 2005, accounting for approximately 13% of new cancer diagnoses and 28% of all cancer deaths. More Americans now die of lung cancer than of colorectal, breast, and prostate cancers combined. This dramatic increase in a previously reportable disease is causally related to exposure to carcinogens through inhalation of tobacco smoke. The causal connection between cigarettes and lung cancer is now established not only epidemiologically but also through identification of carcinogens in tobacco smoke and analysis of the effect of these carcinogens on specific oncogenes expressed in lung cancer. Even cigarette manufacturers no longer dispute the role of tobacco in this epidemic.

Cigarette smoking causes more than 80% of cases of lung cancer. Through the 1990s, mortality from lung cancer fell among men while it increased among women, reflecting changing patterns of tobacco use over the past 30 years (see Chapter 1). Other environmental risk factors for the development of lung cancer include exposure to environmental tobacco smoke, radon gas (among uranium miners and in areas where radium in the soil causes significant indoor air contamination), asbestos (60- to 100-fold increased risk in smokers with asbestos exposure), metals (arsenic, chromium, nickel, iron oxide), and industrial carcinogens (bis-chloromethyl ether). A familial predisposition to lung cancer is recognized. Certain diseases are associated with an increased risk of lung cancer, including pulmonary fibrosis, COPD, and sarcoidosis. Second primary lung cancers are more frequent in patients who survive their initial lung cancer.

The mean age at diagnosis of lung cancer is 60; it is unusual under the age of 40. After the diagnosis of lung cancer is made, approximately 40% of patients survive 1 year. The combined 5-year survival rate for all stages of lung cancer is now approximately 15%, improved from 12% in 1974–1976.

Four histologic types of bronchogenic carcinoma account for more than 90% of cases of primary lung cancer. Squamous cell carcinoma (25–35% of cases) arises from the bronchial epithelium, typically as a centrally located, intraluminal sessile or polypoid mass. Squamous cell tumors are more likely to present with hemoptysis and more frequently are diagnosed by sputum cytology. They spread locally and may be associated with hilar adenopathy and mediastinal widening on chest radiography. Adenocarcinoma (35–40% of cases) arises from mucus glands or, in the case of the bronchioloalveolar cell carcinoma (2% of cases), from any epithelial cell within or distal to the terminal bronchioles. Adenocarcinomas usually present as peripheral nodules or masses. Bronchioloalveolar cell carcinoma spreads intra-alveolarly and may present as an infiltrate or as single or multiple pulmonary nodules. Large cell carcinoma (5–10% of cases) is a heterogeneous group of relatively undifferentiated tumors that share large cells and do not fit into other categories. Large cell carcinomas typically have rapid doubling times and an aggressive clinical course. They present as central or peripheral masses. Small cell carcinoma (15–20% of cases) is a tumor of bronchial origin that typically begins centrally, infiltrating submucosally to cause narrowing or obstruction of the bronchus without a discrete luminal mass. Hilar and mediastinal abnormalities are common on chest radiography.

For purposes of staging and treatment, bronchogenic carcinoma is divided into small cell lung cancer (SCLC) and the other three types, conveniently labeled non-small cell lung cancer (NSCLC). This practical classification reflects different natural histories and different treatment. SCLC is prone to early hematogenous spread. It is rarely amenable to surgical resection and has a very aggressive course with a median survival (untreated) of 6–18 weeks. The three histologic categories comprising NSCLC spread more slowly. They may be cured in the early stages following resection, and they respond similarly to chemotherapy.

Clinical Findings

Lung cancer is symptomatic at diagnosis in 75–90% of patients. The clinical presentation depends on the type and location of the primary tumor, the extent of local spread, and the presence of distant metastases and any paraneoplastic syndromes.

A. Symptoms and Signs

Anorexia, weight loss, or asthenia occurs in 55–90% of patients presenting with a new diagnosis of lung cancer. Up to 60% of patients have a new cough or a change in a chronic cough; 6–31% have hemoptysis; and 25–40% complain of pain, sometimes nonspecific chest pain but often referable to bony metastases to the vertebrae, ribs, or pelvis. Local spread may cause endobronchial obstruction with atelectasis and postobstructive pneumonia, pleural effusion (12–33%), change in voice (compromise of the recurrent laryngeal nerve), superior vena cava syndrome (obstruction of the superior vena cava

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with supraclavicular venous engorgement), and Horner's syndrome (ipsilateral ptosis, miosis, and anhidrosis from involvement of the inferior cervical ganglion and the paravertebral sympathetic chain). Distant metastases to the liver are associated with asthenia and weight loss. Brain metastases (10%; more common in adenocarcinoma) may present with headache, nausea, vomiting, seizures, or altered mental status.

Paraneoplastic syndromes are incompletely understood patterns of organ dysfunction related to immune-mediated or secretory effects of neoplasms (see Chapter 40). These syndromes occur in 10–20% of lung cancer patients. They may precede, accompany, or follow the diagnosis of lung cancer. They do not necessarily indicate metastatic disease. Fifteen percent of patients with small cell carcinoma will develop syndrome of inappropriate antidiuretic hormone (SIADH); 10% of patients with squamous cell carcinoma will develop hypercalcemia. Digital clubbing is seen in up to 20% of patients at diagnosis. Other common paraneoplastic syndromes include increased ACTH production, anemia, hypercoagulability, peripheral neuropathy, and the Eaton-Lambert myasthenia syndrome. Their recognition is important because treatment of the primary tumor may improve or resolve symptoms even when the cancer is not curable.

B. Laboratory Findings

The diagnosis of lung cancer rests on examination of a tissue or cytology specimen. Sputum cytology is highly specific but insensitive; the yield is highest when there are lesions in the central airways. Thoracentesis (sensitivity 50–65%) can be used to establish a diagnosis of lung cancer in patients with malignant pleural effusions. If cytologic examination of an adequate sample (50–100 mL) of pleural fluid is nondiagnostic, the procedure should be repeated once. If results remain negative, thoracoscopy is preferred to blind pleural biopsy. Fine-needle aspiration of palpable supraclavicular or cervical lymph nodes is frequently diagnostic. Serum tumor markers are neither sensitive nor specific enough to aid in diagnosis.

Fiberoptic bronchoscopy allows visualization of the major airways, cytology brushing of visible lesions or lavage of lung segments with cytologic evaluation of specimens, direct biopsy of endobronchial abnormalities, blind transbronchial biopsy of the pulmonary parenchyma or peripheral nodules, and fine-needle aspiration biopsy of mediastinal lymph nodes. Diagnostic yield varies widely (10–90%) depending on the size of the lesion and its location. Recent advances include fluorescence bronchoscopy, which improves the ability to identify early endobronchial lesions; and endoscopic ultrasound, which permits more accurate direction of fine-needle aspiration. TTNA has a sensitivity between 50% and 97%. Mediastinoscopy, VATS, and thoracotomy are necessary in cases where less invasive techniques fail to yield a diagnosis.

C. Imaging

Nearly all patients with lung cancer have abnormal findings on chest radiography or CT scan. These findings are rarely specific for a particular diagnosis. Interpretation of characteristic findings in isolated nodules is described above (see Solitary Pulmonary Nodule).

D. Special Examinations

1. Staging

Accurate staging (Table 9-15) is crucial (1) to provide the clinician with information to guide treatment, (2) to provide the patient with accurate information regarding prognosis, and (3) to standardize entry criteria for clinical trials to allow interpretation of results.

There are two essential principles of staging NSCLC. First, the more extensive the disease, the worse the prognosis; second, surgical resection offers the best and perhaps the only realistic hope for cure. Staging of NSCLC uses two integrated systems. The TNM international staging system attempts a physical description of the neoplasm: T describes the size and location of the primary tumor; N describes the presence and location of nodal metastases; and M refers to the presence or absence of distant metastases. These TNM stages are grouped into prognostic categories (stages I-IV) using the results of clinical trials. This classification is used to guide therapy. Many patients with stage I and stage II disease are cured through surgery. Patients with stage IIIB and stage IV disease do not benefit from surgery. Patients with stage IIIA disease have locally invasive disease that may benefit from surgery in certain circumstances.

SCLC is not staged using the TNM system because micrometastases are assumed to be present on diagnosis. SCLC is divided into two categories: limited disease (30%), when the tumor is limited to the unilateral hemithorax (including contralateral mediastinal nodes); or extensive disease (70%), when the tumor extends beyond the hemithorax (including pleural effusion). This scheme also guides therapy. Patients with limited SCLC benefit from thoracic radiation therapy in addition to chemotherapy and may benefit from prophylactic cranial radiation therapy.

For both SCLC and NSCLC, staging begins with a thorough history and physical examination. A complete examination is essential to exclude obvious metastatic disease to lymph nodes, skin, and bone. A detailed history is essential because the patient's performance status is a powerful predictor of disease course. All patients should have measurement of a complete blood count, electrolytes including calcium, creatinine, liver tests including LDH and alkaline phosphatase, and a chest radiograph. Further evaluation will follow the results of these tests. In general, screening asymptomatic lung cancer patients with CT and MRI imaging of the brain, radionuclide bone imaging, and abdominal CT imaging does not change patient outcomes. These tests should be targeted to specific symptoms and signs (see Table 9-16).

NSCLC patients being considered for surgery require meticulous evaluation to identify those with resectable disease. CT imaging is the most important modality for staging candidates for resection. A chest CT scan precisely defines the size of parenchymal lesions

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and identifies atelectatic lung or pleural effusions. However, CT imaging is less accurate at determining invasion of the chest wall (sensitivity 62%) or mediastinum (sensitivity 60–75%). The sensitivity and specificity of CT imaging for identifying lung cancer metastatic to the mediastinal lymph nodes are 57% (49–66%) and 82% (77–86%), respectively. Therefore, chest CT imaging does not provide definitive information on staging. CT imaging does help in making the decision about whether to proceed to resection of the primary tumor and sample the mediastinum at thoracotomy (common if there are no lymph nodes > 1 cm) or to use TTNA, mediastinoscopy, esophageal ultrasound with transesophageal needle aspiration, or limited thoracotomy to biopsy suspected metastatic disease (common where there are lymph nodes > 1–2 cm).

Table 9-15. TNM staging for lung cancer.

Stage T N M Description
0 Tis     Carcinoma in situ
IA T1 N0 M0 Limited local disease without nodal or distant metastases
IB T2 N0 M0  
IIA
IIB
T1
T2
T3
N1
N1
N0
M0
M0
M0
Limited local disease with ipsilateral hilar or peribronchial nodal involvement but not distant metastases or

Locally invasive disease without nodal or distant metastases
IIIA T3 N1 M0 Locally invasive disease with ipsilateral or peribronchial nodal involvement but not distant metastases or
  T1-3 N2 M0 Limited or locally invasive disease with ipsilateral mediastinal or subcarinal nodal involvement but not distant metastases
IIIB Any T N3 M0 Any primary with contralateral mediastinal or hilar nodes, or ipsilateral scalene or supraclavicular nodes or
  T4 Any N M0 Unresectable local invasion with any degree of adenopathy but no distant metatases; malignant pleural effusion
IV Any T Any N M1 Distant metastases
Primary Tumor (T)
TX Primary tumor cannot be assessed; or tumor proved by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy.
T0 No evidence of primary tumor.
Tis Carcinoma in situ.
T1 A tumor ≤ 3 cm in greatest dimension, surrounded by lung or visceral pleura, and without evidence of invasion proximal to a lobar bronchus at bronchoscopy.
T2 A tumor > 3.0 cm in greatest dimension, or a tumor of any size that either involves a main bronchus (but is ≥ 2 cm distal to the carina), invades the visceral pleura, or has associated atelectasis or obstructive pneumonitis extending to the hilar region. Any associated atelectasis or obstructive pneumonitis must involve less than an entire lung.
T3 A tumor of any size with direct extension into the chest wall (including superior sulcus tumors), the diaphragm, the mediastinal pleura, or the parietal pericardium; or a tumor in the main bronchus < 2 cm distal to the carina without involving the carina; or associated atelectasis or obstructive pneumonitis of the entire lung.
T4 A tumor of any size with invasion of the mediastinum, heart, great vessels, trachea, esophagus, vertebral body, or carina; or with a malignant pleural or pericardial effusion; or with satellite tumor nodules within the ipsilateral lobe of the lung containing the primary tumor.
Regional Lymph Nodes (N)
NX Regional lymph nodes cannot be assessed.
N0 No demonstrable metastasis to regional lymph nodes.
N1 Metastasis to lymph nodes in the peribronchial or the ipsilateral hilar region, or both, including direct extension.
N2 Metastasis to ipsilateral mediastinal lymph nodes and/or subcarinal lymph nodes.
N3 Metastasis to contralateral mediastinal lymph nodes, contralateral hilar lymph nodes, ipsilateral or contralateral scalene or supraclavicular lymph nodes.
Distant Metastases (M)
MX Presence of distant metastasis cannot be assessed.
M0 No (known) distant metastasis.
M1 Distant metastasis present.
Adapted from Mountain CF: Revisions in the international system for staging lung cancer. Chest 1997;111:1710.

Table 9-16. Approach to staging of patients with lung cancer.

Part A: Recommended tests for all patients
   Complete blood count
   Electrolytes, calcium, alkaline phosphatase, albumin, AST, ALT, total bilirubin, creatinine
   Chest radiograph
   CT of chest through the adrenal glands1,2
   Pathologic confirmation of malignancy3
Part B: Recommended tests for selected but not all patients
Test Indication
CT with contrast of liver or liver ultrasound Elevated liver function tests; abnormal non-contrast-enhanced CT of liver or abnormal clinical evaluation
CT with contrast of brain or MRI of brain CNS symptoms or abnormal clinical evaluation
Whole body 18F-fluoro-deoyx-D-glucose positron emission tomography scan (FDG-PET) To evaluate the mediastinum in patients who are candidates for surgery
Radionuclide bone scan Elevated alkaline phosphatase (bony fraction), elevated calcium, bone pain, or abnormal clinical evaluation
Pulmonary function tests If lung resection or thoracic radiotherapy planned
Quantitative radionuclide perfusion lung scan or exercise testing to evaluate maximum oxygen consumption Patients with borderline resectability due to limited cardiovascular status
1May not be necessary if patient has obvious M1 disease on chest x-ray or physical examination.
2Intravenous iodine contrast enhancement is not essential but is recommended in probable mediastinal invasion.
3While optimal in most cases, tissue diagnosis may not be necessary prior to surgery in some cases where the lesion is enlarging or the patient will undergo surgical resection regardless of the outcome of a biopsy.
Modified and reproduced, with permission, from: Pretreatment evaluation of non-small cell lung cancer. Consensus Statement of the American Thoracic Society and the European Respiratory Society. Am J Respir Crit Care Med 1997;156:320.

PET using 2-[18F]fluoro-2-deoxyglucose (FDG) is a noninvasive alternative for identifying metastatic foci in the mediastinum or distant sites. The sensitivity and specificity of PET for detecting mediastinal spread of primary lung cancer depend on the size of mediastinal nodes or masses. When only normal-sized (< 1 cm) mediastinal lymph nodes are present, the sensitivity and specificity of PET for tumor involvement of nodes are 74% and 96%, respectively. When CT shows enlarged (> 1 cm) lymph nodes, the sensitivity and specificity are 95% and 76%, respectively.

PET imaging is being incorporated into diagnostic algorithms that take advantage of both its positive and negative predictive values. Many lung cancer specialists find PET most useful to confirm lack of metastatic disease in NSCLC patients who are candidates for surgical resection. There is also evidence that PET imaging reduces futile thoracotomies by identifying mediastinal and distant metastases in patients with NSCLC. Disadvantages of PET imaging include limited resolution below 1 cm; the expense of FDG; limited availability; and false-positive scans due to sarcoidosis, tuberculosis, or fungal infections.

2. Preoperative assessment

See Chapter 3.

3. Pulmonary function testing

Many patients with NSCLC have moderate to severe chronic lung disease that increases the risk of perioperative complications as well as long-term pulmonary insufficiency following lung resection. All patients considered for surgery require spirometry. In the absence of other comorbidities, patients with good lung function (preoperative FEV1 > 2 L) are at low risk for complications from lobectomy or pneumonectomy. If the FEV1 is less than 2 L, then an estimated postoperative FEV1 should be calculated. The postresection FEV1 may be estimated from considering preoperative spirometry and the amount of lung to be resected; in severe obstructive disease, a quantitative lung

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perfusion scan may improve the estimate. A predicted post-lung resection FEV1 > 800 mL (or > 40% of predicted FEV1) is associated with a low incidence of perioperative complications. High-risk patients include those with a predicted postoperative FEV1 < 700 mL (or < 40% of predicted FEV1). In these patients—and in those with borderline spirometry—cardiopulmonary exercise testing may be helpful. A maximal oxygen uptake ([V with dot above]O2) of > 15 mL/kg/min identifies patients with an acceptable incidence of complications and mortality. Patients with an [V with dot above]O2 of < 10 mL/kg/min have a very high mortality rate at thoracotomy. Hypoxemia and hypercapnia are not independent predictors of outcome.

Treatment

A. Non-Small Cell Carcinoma

Cure of NSCLC is unlikely without resection. Therefore, the initial approach to the patient is determined by the answers to two questions: (1) Is complete surgical resection technically feasible? (2) If yes, is the patient able to tolerate the surgery with acceptable morbidity and mortality? Clinical features that preclude complete resection include extrathoracic metastases or a malignant pleural effusion; or tumor involving the heart, pericardium, great vessels, esophagus, recurrent laryngeal or phrenic nerves, trachea, main carina, or contralateral mediastinal lymph nodes. Accordingly, stage I and stage II patients are treated with surgical resection where possible. Stage IIIA patients have poor outcomes when treated with resection alone. They should be referred to multimodality protocols, including chemotherapy and radiotherapy. Stage IIIB patients treated with combined chemotherapy and radiation therapy have improved survival. Selected stage IIIB patients taken to resection following multimodality therapy have shown long-term survival and may be cured. Stage IV patients are treated with symptom-based palliative therapy, which may include outpatient chemotherapy (see below).

Surgical approach affects outcome. In a prospective trial of stage I patients randomized to lobectomy versus limited resection, there was a threefold increased rate of local recurrence in the limited resection group and a trend toward mortality benefit at 5 years in the lobectomy patients (56% versus 73% mortality, P = .09). There are inadequate outcome data on which to base a comparison of VATS with standard thoracotomy. Radiation therapy following surgery improves local control but does not improve survival.

Neoadjuvant chemotherapy consists of giving antineoplastic drugs in advance of surgery or radiation therapy. There is no consensus on the impact of neoadjuvant therapy on survival in stage I and stage II NSCLC. Such therapy is not recommended outside of ongoing clinical trials. Neoadjuvant therapy is more widely used in selected patients with stage IIIA or stage IIIB disease. Some studies suggest a survival advantage. This remains an area of active research.

Adjuvant chemotherapy consists of administering antineoplastic drugs following surgery or radiation therapy. Adjuvant chemotherapy with alkylating agents such as cyclophosphamide increases mortality. In stage I and N0 stage II disease, patients treated with multidrug platinum-based chemotherapy show a trend toward improved survival—on the order of 3 months at 5 years. Toxicity may be significant, however, and such therapy is not recommended. Newer antineoplastic agents with less toxicity are in clinical trials in these patients. In patients with stage IIIA disease and node positive stage II disease, the data are conflicting whether chemotherapy following surgery improves survival. Patients with locally advanced disease (stages IIIA and IIIB) who are not surgical candidates have improved survival when treated with combination chemotherapy and radiation therapy compared with no therapy or radiation alone.

Multidrug platinum-based chemotherapy is associated with an increase in survival equivalent to a mean gain of 6 weeks at 1 year in patients with advanced disease (stage IIIB and stage IV) but good performance status (Karnofsky performance status ≥ 60, < 5% weight loss in the past 6 months; see Chapter 40). There is no evidence of a survival benefit in patients with poor performance status.

Multiple clinical trials evaluating quality of life suggest that there is better overall performance status and symptom control in patients with stage IIIB and stage IV NSCLC receiving chemotherapy plus good supportive care versus supportive care alone. Several trials suggest an increase in median survival of from 5 months to 7 months. These trials compare small numbers of patients; they are unblinded; they are supported by the pharmaceutical companies that make the drugs used—all of which suggests caution in interpreting the results. Nonetheless, the reported findings are consistent. Furthermore, newer antineoplastic agents show increased effectiveness in advanced NSCLC along with favorable side effect profiles. It remains to be seen which patients stand to benefit most from what combination of agents. At this time, outpatient chemotherapy for advanced NSCLC should be offered on protocol to patients with good performance status.

B. Small Cell Carcinoma

Response rates of SCLC to cisplatin and etoposide are excellent: 80–100% response in limited-stage disease (50–70% complete response), and 60–80% response in extensive stage disease (15–40% complete response). However, remissions tend to be short-lived with a median duration of 6–8 months. Once the disease has recurred, median survival is 3–4 months. Overall 2-year survival is 20% in limited-stage disease and 5% in extensive-stage disease. Thoracic radiation therapy improves survival in patients with limited SCLC but not those with extensive disease. Whole brain radiation therapy decreases the incidence of central nervous system disease but does not affect survival. Its effect on symptoms is controversial.

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Occasionally, a patient may have a peripheral nodule resected that turns out to be SCLC. Five-year survival following resection of the equivalent of stage I and stage II SCLC is higher than in patients treated with chemotherapy.

C. Palliative therapy

Photoresection with the Nd:YAG laser is sometimes performed on central tumors to relieve endobronchial obstruction, improve dyspnea, and control hemoptysis. External beam radiation therapy is also used to control dyspnea and hemoptysis, pain from bony metastases, obstruction from superior vena cava syndrome, and symptomatic brain metastases. Resection of solitary brain metastases does not affect survival but may improve quality of life when combined with radiation therapy. Intraluminal radiation (brachytherapy) is an alternative approach to endobronchial disease. Pain syndromes are very common in advanced disease. As patients approach the end of life, meticulous efforts at pain control are essential (see Chapter 5). Consultation with or referral to a palliative care specialist is recommended in advanced disease to aid in symptom management and to facilitate referrals to hospice programs.

Prognosis

The overall 5-year survival rate for lung cancer is 15%. Predictors of survival are the type of tumor (SCLC versus NSCLC), the stage of the tumor, and the patient's performance status, including weight loss in the past 6 months. These are independent predictors in both early and late stage disease. Most data suggest that there is no difference among non-small cell carcinomas when adjusted for stage and performance status. However, squamous cell carcinoma may have a better prognosis than adenocarcinoma or large cell carcinoma at the same TNM stage. (See Table 9-17.)

Table 9-17. Approximate survival rates following treatment for lung cancer.

Non-Small Cell Lung Cancer: Mean 5-Year Survival Following Resection
Stage Clinical Staging Surgical Staging
IA (T1N0M0) 60% 74%
IB (T2N0M0) 38% 61%
IIA (T1N1M0) 34% 55%
IIB (T2N1M0, T3N0M0) 23% 39%
IIIA 9-13% 22%
IIIB1 3-12%  
IV1 4%  
Small Cell Lung Cancer: Survival Following Chemotherapy
Mean 2-Year
Stage Survival Median Survival
Limited 15-20% 14-20 months
Extensive < 3% 8-13 months
1Independent of therapy, generally not surgical patients.
Data from multiple sources. Modified and reproduced, with permission, from Reif MS et al: Evidence-based medicine in the treatment of non-small cell cancer. Clin Chest Med 2000;21:107.

American College of Chest Physicians; Health and Science Policy Committee: Diagnosis and management of lung cancer: ACCP evidence-based guidelines. Chest 2003;123(1 Suppl): 1S.

Barnes DJ: The changing face of lung cancer. Chest 2004;126:1718.

Hamilton W et al: Diagnosis of lung cancer in primary care: a structured review. Fam Pract 2004;21:605.

Jackman DM et al: Small-cell lung cancer. Lancet 2005;366:1385.

Macbeth F et al: Palliative treatment for advanced non-small cell lung cancer. Hematol Oncol Clin North Am 2004;18: 115.

Mazzone PJ et al: Lung cancer: Preoperative pulmonary evaluation of the lung resection candidate. Am J Med 2005; 118:578.

Patel JD et al: Lung cancer in US women: a contemporary epidemic. JAMA 2004;291:1763.

Spira A et al: Multidisciplinary management of lung cancer. N Engl J Med 2004;350:379.

Yang P et al: Clinical features of 5,628 primary lung cancer patients: experience at Mayo Clinic from 1997 to 2003. Chest 2005;128:452.

Bronchial Carcinoid Tumors

Carcinoid and bronchial gland tumors are sometimes termed “bronchial adenomas.” This term should be avoided because it implies that the lesions are benign, when in fact carcinoid tumors and bronchial gland carcinomas are low-grade malignant neoplasms.

Carcinoid tumors are about six times more common than bronchial gland carcinomas, and most of them occur as pedunculated or sessile growths in central bronchi. Men and women are equally affected. Most patients are under 60 years of age. Common symptoms of bronchial carcinoid tumors are hemoptysis, cough, focal wheezing, and recurrent pneumonia. Peripherally located bronchial carcinoid tumors are rare and present as asymptomatic solitary pulmonary nodules. Carcinoid syndrome (flushing, diarrhea, wheezing, hypotension) is rare. Fiberoptic bronchoscopy may reveal a pink or purple tumor in a central airway. These lesions have a well-vascularized stroma, and biopsy may be complicated by significant bleeding. CT scanning is helpful to localize the lesion and to follow its growth over time. Octreotide scintigraphy is also available for localization of these tumors.

Bronchial carcinoid tumors grow slowly and rarely metastasize. Complications involve bleeding and airway obstruction rather than invasion by tumor and

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metastases. Surgical excision is necessary in some cases, and the prognosis is generally favorable. Most bronchial carcinoid tumors are resistant to radiation and chemotherapy.

Fink G et al: Pulmonary carcinoid: presentation, diagnosis, and outcome in 142 cases in Israel and review of 640 cases from the literature. Chest 2001;119:1647.

Hage R et al: Update in pulmonary carcinoid tumors: a review article. Ann Surg Onc 2003;10:697.

Schnirer II et al: Carcinoid—a comprehensive review. Acta Oncolog 2003;42:672.

Secondary Lung Cancer

Secondary lung cancers represent metastases from extrapulmonary malignant neoplasms that spread to the lungs through vascular or lymphatic channels or by direct extension. Almost any cancer can metastasize to the lung. Metastases usually occur via the pulmonary artery and typically present as multiple nodules or masses on chest radiography. The radiographic differential diagnosis of multiple pulmonary nodules also includes pulmonary arteriovenous malformation, pulmonary abscesses, granulomatous infection, sarcoidosis, rheumatoid nodules, and Wegener's granulomatosis. Metastases to the lungs are found in 20–55% of patients dying of various malignancies. Most are intraparenchymal. Endobronchial metastases occur in fewer than 5% of patients dying of nonpulmonary cancer; carcinoma of the kidney, breast, colon, and cervix and malignant melanoma are the most likely primary tumors.

Lymphangitic carcinomatosis denotes diffuse involvement of the pulmonary lymphatic network by primary or secondary lung cancer, probably a result of extension of tumor from lung capillaries to the lymphatics. Tumor embolization from extrapulmonary cancer (renal cell carcinoma, hepatocellular carcinoma, choriocarcinoma) is an uncommon route for tumor spread to the lungs. Secondary lung cancer may also present as malignant pleural effusion (see below).

Clinical Findings

A. Symptoms and Signs

Symptoms are uncommon but include cough, hemoptysis and, in advanced cases, dyspnea and hypoxemia. Symptoms are more often referable to the site of the primary tumor.

B. Laboratory Findings

The diagnosis of secondary lung cancer is usually established by identifying a primary tumor. Appropriate studies should be ordered if there is a suspicion of any primary cancer, such as breast, thyroid, testis, or prostate, for which specific treatment is available. Mammography should be considered unless one has been performed recently. If the history and physical examination fail to reveal the site of the primary tumor, attention is better focused on the lung, where tissue samples obtained by bronchoscopy, percutaneous needle biopsy, or thoracotomy may establish the histologic diagnosis and suggest the most likely primary. Occasionally, cytologic studies of pleural fluid or pleural biopsy reveal the diagnosis. Sputum cytology is rarely helpful.

C. Imaging

Chest radiographs usually show multiple spherical densities with sharp margins. The size of metastatic lesions varies from a few millimeters (miliary densities) to large masses. Nearly all are less than 5 cm in diameter. The lesions are usually bilateral, pleural or subpleural in location, and more common in lower lung zones. Cavitation suggests primary squamous cell tumor; calcification suggests osteosarcoma. Lymphangitic spread and solitary pulmonary nodule are less common radiographic presentations of secondary lung cancer. Conventional chest radiography is less sensitive than CT scan in detecting pulmonary metastases.

Treatment

Once the diagnosis has been established, management consists of treatment of the primary neoplasm and any pulmonary complications. Surgical resection of a solitary pulmonary nodule is often prudent in the patient with known current or previous extrapulmonary cancer. Local resection of one or more pulmonary metastases is feasible in a few carefully selected patients with various sarcomas and carcinomas (breast, testis, colon, kidney, and head and neck). Surgical resection should be considered only if the primary tumor is under control, if the patient is a good surgical risk, if all of the metastatic tumor can be resected, if nonsurgical approaches are not available, and if there are no metastases elsewhere in the body. Relative contraindications to resection of pulmonary metastases include (1) malignant melanoma primary, (2) requirement for pneumonectomy, (3) pleural involvement, and (4) simultaneous appearance of two or more metastases. The overall 5-year survival rate in secondary lung cancer treated surgically is 20–35%. For patients with progressive disease, diligent attention to palliative care is essential (see Chapter 5).

Avdalovic M et al: Thoracic manifestations of common nonpulmonary malignancies of women. Clin Chest Med 2004;25:379.

Greelish JP et al: Secondary pulmonary malignancy. Surg Clin North Am 2000;80:633.

Mesothelioma

Essentials of Diagnosis

  • Unilateral, nonpleuritic chest pain and dyspnea.

  • Distant (> 20 years earlier) history of exposure to asbestos.

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  • Pleural effusion or pleural thickening or both on chest radiographs.

  • Malignant cells in pleural fluid or tissue biopsy.

General Considerations

Mesotheliomas are primary tumors arising from the surface lining of the pleura (80% of cases) or peritoneum (20% of cases). About three-fourths of pleural mesotheliomas are diffuse (usually malignant) tumors, and the remaining one-fourth are localized (usually benign). Men outnumber women by a 3:1 ratio. Numerous studies have confirmed the association of malignant pleural mesothelioma with exposure to asbestos (particularly the crocidolite form). The lifetime risk to asbestos workers of developing malignant pleural mesothelioma is about 8%. Sixty to 80 percent of patients with malignant mesothelioma report a history of asbestos exposure. The latent period between exposure and onset of symptoms ranges from 20 to 40 years. The clinician should inquire about asbestos exposure through mining, milling, manufacturing, shipyard work, insulation, brake linings, building construction and demolition, roofing materials, and a variety of asbestos products (pipe, textiles, paint, tile, gaskets, panels). Although cigarette smoking significantly increases the risk of bronchogenic carcinoma in asbestos workers and aggravates asbestosis, there is no association between smoking and mesothelioma.

Clinical Findings

A. Symptoms and Signs

The mean age at onset of symptoms of malignant pleural mesothelioma is about 60 years. Symptoms include the insidious onset of shortness of breath, nonpleuritic chest pain, and weight loss. Physical findings include dullness to percussion, diminished breath sounds and, in some cases, digital clubbing.

B. Laboratory Findings

Pleural fluid is exudative and often hemorrhagic. VATS biopsy is usually necessary to obtain an adequate specimen for histologic diagnosis; even then, distinction from benign inflammatory conditions and from metastatic adenocarcinoma may be difficult. The histologic variants of malignant pleural mesothelioma are epithelial and fibrous (sarcomatous). Special stains and electron microscopy may be needed to confirm the diagnosis.

C. Imaging

Radiographic abnormalities consist of nodular, irregular, unilateral pleural thickening and varying degrees of unilateral pleural effusion. There may be scoliosis toward the side of the lesion. CT scan helps demonstrate the extent of pleural involvement.

Complications

Malignant pleural mesothelioma progresses rapidly as the tumor spreads along the pleural surface to involve the pericardium, mediastinum, and contralateral pleura. The tumor may eventually extend beyond the thorax to involve abdominal lymph nodes and organs. Progressive pain and dyspnea are characteristic. Local invasion of thoracic structures may cause superior vena cava syndrome, hoarseness, Horner's syndrome, and dysphagia. Paraneoplastic syndromes associated with mesothelioma include thrombocytosis, hemolytic anemia, disseminated intravascular coagulopathy, and migratory thrombophlebitis.

Treatment

Treatment with surgery, radiotherapy, chemotherapy, and a combination of methods has been attempted but is generally unsuccessful. Some surgeons believe that extrapleural pneumonectomy is the preferred surgical approach for patients with early stage disease. Drainage of pleural effusions, pleurodesis, radiation therapy, and even surgical resection may offer palliative benefit in some patients.

Prognosis

Most patients die of respiratory failure and complications of local extension. Median survival time from onset of symptoms ranges from 4 months in extensive disease to 16 months in localized disease. Five-year survival is less than 5%.

Robinson BW et al: Advances in malignant mesothelioma. N Engl J Med 2005;353:1591.

van Ruth S et al: Surgical treatment of malignant pleural mesothelioma: a review. Chest 2003;123:551.

Mediastinal Masses

Various developmental, neoplastic, infectious, traumatic, and cardiovascular disorders may cause masses that appear in the mediastinum on chest radiograph. A useful convention arbitrarily divides the mediastinum into three compartments—anterior, middle, and posterior—in order to classify mediastinal masses and assist in differential diagnosis. Specific mediastinal masses have a predilection for one or more of these compartments; most are located in the anterior or middle compartment. The differential diagnosis of an anterior mediastinal mass includes thymoma, teratoma, thyroid lesions, lymphoma, and mesenchymal tumors (lipoma, fibroma). The differential diagnosis of a middle mediastinal mass includes lymphadenopathy, pulmonary artery enlargement, aneurysm of the aorta or innominate artery, developmental cyst (bronchogenic, enteric, pleuropericardial), dilated azygous or hemiazygous vein, and foramen of Morgagni hernia. The differential diagnosis of a posterior mediastinal mass includes hiatus hernia, neurogenic tumor,

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meningocele, esophageal tumor, foramen of Bochdalek hernia, thoracic spine disease, and extramedullary hematopoiesis. The neurogenic tumor group includes neurilemmoma, neurofibroma, neurosarcoma, ganglioneuroma, and pheochromocytoma.

Symptoms and signs of mediastinal masses are nonspecific and are usually caused by the effects of the mass on surrounding structures. Insidious onset of retrosternal chest pain, dysphagia, or dyspnea is often an important clue to the presence of a mediastinal mass. In about half of cases, symptoms are absent, and the mass is detected on routine chest radiograph. Physical findings vary depending on the nature and location of the mass.

CT scanning is helpful in management; additional radiographic studies of benefit include barium swallow if esophageal disease is suspected, Doppler sonography or venography of brachiocephalic veins and the superior vena cava, and arteriography. MRI is useful; its advantages include better delineation of hilar structures and distinction between vessels and masses. MRI also allows imaging in multiple planes, whereas CT permits only axial imaging. Tissue diagnosis is necessary if a neoplastic disorder is suspected. Treatment and prognosis depend on the underlying cause of the mediastinal mass.

Aquino SL et al: Reconciliation of the anatomic, surgical, and radiographic classifications of the mediastinum. J Comp Assist Tomogr 2001;25:489.

Duwe BV et al: Tumors of the mediastinum. Chest 2005; 128:2893.

Interstitial Lung Disease (Diffuse Parenchymal Lung Disease)

Interstitial lung disease, or diffuse parenchymal lung disease, comprises a heterogeneous group of disorders that share a common response of the lung to injury: alveolitis, or inflammation, and fibrosis of the interalveolar septum. The term “interstitial” is misleading since the pathologic process usually begins with injury to the alveolar epithelial or capillary endothelial cells. Persistent alveolitis may lead to obliteration of alveolar capillaries and reorganization of the lung parenchyma, accompanied by irreversible fibrosis. The process does not affect the airways proximal to the respiratory bronchioles. At least 180 disease entities may present as interstitial lung disease (Table 9-18). In most patients, no specific cause can be identified. In the remainder, drugs and a variety of organic and inorganic dusts are the principal causes.

The clinical consequence of widespread lung fibrosis is diminished lung compliance, which presents as restrictive lung disease. Patients usually describe an insidious onset of exertional dyspnea and cough. Sputum production is minimal. Chest examination reveals fine, late inspiratory crackles at the lung bases. Digital clubbing is seen in 25–50% of patients at diagnosis.

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Pulmonary function testing shows a loss of lung volume with normal to increased airflow rates. The diffusing capacity for carbon monoxide is decreased, and hypoxemia with exercise is common. In advanced cases, resting hypoxemia may be present. The chest radiograph is normal on presentation in up to 10% of patients. More typically, it shows patchy distribution of ground-glass, reticular, or reticulonodular infiltrates. In advanced disease, there are multiple small, thick-walled cystic spaces in the lung periphery (“honeycomb” lung). Honeycombing indicates the presence of locally advanced fibrosis with destruction of normal lung architecture. Conventional CT and high-resolution CT imaging reveal in greater detail the findings described on chest radiograph. In some cases, high-resolution CT may be strongly suggestive of a specific pathologic process.

Table 9-18. Differential diagnosis of interstitial lung disease.

Drug-related
   Antiarrhythmic agents (amiodarone)
   Antibacterial agents (nitrofurantoin, sulfonamides)
   Antineoplastic agents (bleomycin, cyclophosphamide, methotrexate, nitrosoureas)
   Antirheumatic agents (gold salts, penicillamine)
   Phenytoin
Environmental and occupational (inhalation exposures)
   Dust, inorganic (asbestos, silica, hard metals, beryllium)
   Dust, organic (thermophilic actinomycetes, avian antigens, Aspergillus species)
   Gases, fumes, and vapors (chlorine, isocyanates, paraquat, sulfur dioxide)
   Ionizing radiation
   Talc (injection drug users)
Infections
   Fungus, disseminated (Coccidioides immitis, Blastomyces dermatitidis, Histoplasma capsulatum)
   Mycobacteria, disseminated
Pneumocystis jiroveci
   Viruses
Primary pulmonary disorders
   Cryptogenic organizing pneumonitis (COP)
   Idiopathic fibrosing interstitial pneumonia: Acute interstitial pneumonitis, desquamative interstitial pneumonitis, nonspecific interstitial pneumonitis, usual interstitial pneumonitis, respiratory bronchiolitis-associated interstitial lung disease
   Pulmonary alveolar proteinosis
Systemic disorders
   Acute respiratory distress syndrome
   Amyloidosis
   Ankylosing spondylitis
   Autoimmune disease: Dermatomyositis, polymyositis, rheumatoid arthritis, systemic sclerosis (scleroderma), systemic lupus erythematosus
   Chronic eosinophilic pneumonia
   Goodpasture's syndrome
   Idiopathic pulmonary hemosiderosis
   Inflammatory bowel disease
   Langerhans cell histiocytosis (eosinophilic granuloma)
   Lymphangitic spread of cancer (lymphangitic carcinomatosis)
   Lymphangioleiomyomatosis
   Pulmonary edema
   Pulmonary venous hypertension, chronic
   Sarcoidosis
   Wegener's granulomatosis

The history—particularly the occupational and medication history—may provide evidence of a specific cause. Serologic tests for antinuclear antibodies and rheumatoid factor are positive in 20–40% of patients but are rarely diagnostic. Antineutrophil cytoplasmic antibodies (ANCAs) may be diagnostic in some clinical settings. Invasive diagnostic testing is frequently necessary to make a specific diagnosis. Three diagnostic techniques are in common use: bronchoalveolar lavage, transbronchial biopsy, and surgical lung biopsy, either through an open procedure or using VATS.

Bronchoalveolar lavage may provide a specific diagnosis in cases of infection, particularly with P jiroveci or mycobacteria, or when cytologic examination reveals the presence of malignant cells. The findings may be suggestive if not diagnostic of eosinophilic pneumonia, Langerhans cell histiocytosis, and alveolar proteinosis. Analysis of the cellular constituents of lavage fluid may suggest a specific disease, but these findings are not diagnostic.

Transbronchial biopsy through the flexible bronchoscope is easily performed in most patients. The risks of pneumothorax (5%) and hemorrhage (1–10%) are low. However, the tissue specimens recovered are small, sampling error is common, and crush artifact may complicate diagnosis. Transbronchial biopsy can make a definitive diagnosis of sarcoidosis, lymphangitic spread of carcinoma, pulmonary alveolar proteinosis, miliary tuberculosis, and Langerhans cell histiocytosis. Transbronchial biopsy cannot establish a specific diagnosis of idiopathic interstitial pneumonia. These patients generally require surgical lung biopsy.

Surgical lung biopsy is the standard for diagnosis of interstitial lung disease. Two or three biopsies taken from multiple sites in the same lung, including apparently normal tissue, may yield a specific diagnosis as well as prognostic information regarding the extent of fibrosis versus active inflammation. Patients under age 60 without a specific diagnosis generally should undergo surgical lung biopsy. In older and sicker patients, the risks and benefits must be weighed carefully for three reasons: (1) the morbidity of the procedure can be significant; (2) a definitive diagnosis may not be possible even with surgical lung biopsy; and (3) when a specific diagnosis is made, there may be no effective treatment. Empiric therapy or no treatment may be preferable to surgical lung biopsy in some patients.

Known causes of interstitial lung disease are dealt with in their specific sections. The important idiopathic forms are discussed below.

Idiopathic Fibrosing Interstitial Pneumonia (Formerly: Idiopathic Pulmonary Fibrosis)

The most common diagnosis among patients presenting with interstitial lung disease is idiopathic pulmonary fibrosis, known in Britain as cryptogenic fibrosing alveolitis. Historically, this diagnosis was based on clinical and radiographic criteria with only a minority of patients undergoing surgical lung biopsy. When biopsies were obtained, the common element of fibrosis led to the grouping together of several histologic patterns under the category of idiopathic pulmonary fibrosis. We now recognize that these distinct histopathologic features are associated with different natural histories and responses to therapy (see Table 9-19). Therefore, in the evaluation of patients with idiopathic interstitial lung disease, clinicians should attempt to identify specific disorders and reserve the terms “idiopathic pulmonary fibrosis” or “cryptogenic fibrosing alveolitis” to denote only the histologic pattern of usual interstitial pneumonitis (UIP).

Patients with idiopathic fibrosing interstitial pneumonia may present with any of the histologic patterns described in Table 9-19. The first step in evaluation is to identify patients whose disease is truly idiopathic. As indicated in Table 9-18, most identifiable causes of interstitial lung disease are infectious, drug-related, or environmental or occupational agents. Interstitial lung diseases associated with other medical conditions (pulmonary-renal syndromes, collagen-vascular disease) may be identified through a careful medical history. Apart from acute interstitial pneumonia, the clinical presentations of the idiopathic interstitial pneumonias are sufficiently similar to preclude a specific diagnosis. Chest radiographs and high-resolution CT scans are occasionally diagnostic. Ultimately, many patients with apparently idiopathic disease require surgical lung biopsy to make a definitive diagnosis. The importance of accurate diagnosis is twofold. First, it allows the clinician to provide accurate information about the cause and natural history of the illness. Second, accurate diagnosis helps distinguish patients most likely to benefit from therapy. Surgical lung biopsy may spare patients with UIP treatment with potentially morbid therapies.

The diagnosis of UIP can be made on clinical grounds alone in selected patients. A diagnosis of UIP can be made with 90% confidence in patients over 65 years of age who have idiopathic disease by history and who demonstrate inspiratory crackles on physical examination;

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restrictive physiology on pulmonary function testing; characteristic radiographic evidence of progressive fibrosis over several years; and diffuse, patchy fibrosis with pleural-based honeycombing on high-resolution CT scan. Such patients do not need surgical lung biopsy. Note that the diagnosis of UIP cannot be confirmed on transbronchial lung biopsy since the histologic diagnosis requires a pattern of changes rather than a single pathognomonic finding. Transbronchial biopsy may exclude UIP by confirming a specific alternative diagnosis.

Table 9-19. Idiopathic fibrosing interstitial pneumonias.

Name and Clinical Presentation Histopathology Radiographic Pattern Response to Therapy and Prognosis
Usual interstitial pneumonia (UIP)
   Age 55-60, slight male predominance. Insidious dry cough and dyspnea lasting months to years. Clubbing present at diagnosis in 25-50%. Diffuse fine late inspiratory crackles on lung auscultation. Restrictive ventilatory defect and reduced diffusing capacity on pulmonary function tests. ANA and RF positive in 25% in the absence of documented collagen-vascular disease.
Patchy, temporally and geographically nonuniform distribution of fibrosis, honeycomb change, and normal lung. Type I pneumocytes are lost, and there is proliferation of alveolar type II cells. “Fibroblast foci” of actively proliferating fibroblasts and myofibroblasts. Inflammation is generally mild and consists of small lymphocytes. Intra-alveolar macrophage accumulation is present but is not a prominent feature. Diminished lung volume. Increased linear or reticular bibasilar and subpleural opacities. Unilateral disease is rare. High-resolution CT scanning shows minimal ground-glass and variable honeycomb change. Areas of normal lung may be adjacent to areas of advanced fibrosis. Between 2% and 10% have normal chest radiographs and high-resolution CT scans on diagnosis. No randomized study has demonstrated improved survival compared with untreated patients. Inexorably progressive. Response to corticosteroids and cytotoxic agents at best 15%, and these probably represent misclassification of histopathology. Median survival approximately 3 years, depending on stage at presentation. Current interest in antifibrotic agents.
Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD)1
   Age 40-45. Presentation similar to that of UIP though in younger patients. Similar results on pulmonary function tests, but less severe abnormalities. Patients with respiratory bronchiolitis are invariably heavy smokers.
Increased numbers of macrophages evenly dispersed within the alveolar spaces. Rare fibroblast foci, little fibrosis, minimal honeycomb change. In RB-ILD the accumulation of macrophages is localized within the peribronchiolar air spaces; in DIP,1 it is diffuse. Alveolar architecture is preserved. May be indistinguishable from UIP. More often presents with a nodular or reticulonodular pattern. Honeycombing rare. High-resolution CT more likely to reveal diffuse ground-glass opacities and upper lobe emphysema. Spontaneous remission occurs in up to 20% of patients, so natural history unclear. Smoking cessation is essential. Prognosis clearly better than that of UIP: median survival greater than 10 years. Corticosteroids thought to be effective, but there are no randomized clinical trials to support this view.
Acute interstitial pneumonitis (AIP)
   Clinically known as Hamman-Rich syndrome. Wide age range, many young patients. Acute onset of dyspnea followed by rapid development of respiratory failure. Half of patients report a viral syndrome preceding lung disease. Clinical course indistinguishable from that of idiopathic ARDS.
Pathologic changes reflect acute response to injury within days to weeks. Resembles organizing phase of diffuse alveolar damage. Fibrosis and minimal collagen deposition. May appear similar to UIP but more homogeneous and there is no honeycomb change–though this may appear if the process persists for more than a month in a patient on mechanical ventilation. Diffuse bilateral airspace consolidation with areas of ground-glass attenuation on high-resolution CT scan. Supportive care (mechanical ventilation) critical but effect of specific therapies unclear. High initial mortality: Fifty to 90 percent die within 2 months after diagnosis. Not progressive if patient survives. Lung function may return to normal or may be permanently impaired.
Nonspecific interstitial pneumonitis (NSIP)
   Age 45-55. Slight female predominance. Similar to UIP but onset of cough and dyspnea over months, not years.
Nonspecific in that histopathology does not fit into better-established categories. Varying degrees of inflammation and fibrosis, patchy in distribution but uniform in time, suggesting response to single injury. Most have lymphocytic and plasma cell inflammation without fibrosis. Honeycombing present but scant. Some have advocated division into cellular and fibrotic subtypes. May be indistinguishable from UIP. Most typical picture is bilateral areas of ground-glass attenuation and fibrosis on high-resolution CT. Honeycombing is rare. Treatment thought to be effective, but no prospective clinical studies have been published. Prognosis overall good but depends on the extent of fibrosis at diagnosis. Median survival greater than 10 years.
Cryptogenic organizing pneumonitis (formerly bronchiolitis obliterans organizing pneumonia [BOOP])
   Typically age 50-60 but wide variation. Abrupt onset, frequently weeks to a few months following a flu-like illness. Dyspnea and dry cough prominent, but constitutional symptoms are common: fatigue, fever, and weight loss. Pulmonary function tests usually show restriction, but up to 25% show concomitant obstruction.
Included in the idiopathic interstitial pneumonias on clinical grounds. Buds of loose connective tissue (Masson bodies) and inflammatory cells fill alveoli and distal bronchioles. Lung volumes normal. Chest radiograph typically shows interstitial and parenchymal disease with discrete, peripheral alveolar and ground-glass infiltrates. Nodular opacities common. High-resolution CT shows subpleural consolidation and bronchial wall thickening and dilation. Rapid response to corticosteroids in two-thirds of patients. Long-term prognosis generally good for those who respond. Relapses are common.
1Includes desquamative interstitial pneumonia (DIP).
ANA = antinuclear antibody; RF = rheumatoid factor; UIP = usual interstitial pneumonia; ARDS = acute respiratory distress syndrome.

Treatment of idiopathic fibrosing interstitial pneumonia is controversial. No randomized study has demonstrated that any treatment improves survival or quality of life compared with no treatment. Clinical experience suggests that patients with desquamative interstitial pneumonia (DIP; or respiratory bronchiolitis-associated interstitial lung disease, RB-ILD), nonspecific interstitial pneumonia (NSIP), or COP (see Table 9-19) frequently respond to corticosteroids and should be given a trial of therapy—typically prednisone, 1–2 mg/kg/d for a minimum of 2 months. The same therapy is almost uniformly ineffective in patients with UIP. Since this therapy carries significant morbidity, the pulmonary community does not recommend routine use of corticosteroids in patients with UIP. Antifibrotic therapy is an area of intense research. A clinical trial of interferon gamma-1b in UIP did not demonstrate statistically significant improvement in the primary end point of progression-free survival. No significant treatment effect was observed on measures of lung function, gas exchange, or quality of life. Subgroup analysis suggested improved survival in patients with mild to moderate disease.

American Thoracic Society; European Respiratory Society: American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med 2002;165:277.

Collard HR et al: Demystifying idiopathic interstitial pneumonia. Arch Intern Med 2003;163:17.

King TE Jr: Clinical advances in the diagnosis and therapy of the interstitial lung diseases. Am J Respir Crit Care Med 2005; 172:268.

Leslie KO: Pathology of interstitial lung disease. Clin Chest Med 2004;25:657.

Lynch DA et al: Idiopathic interstitial pneumonias: CT features. Radiology 2005;236:10.

Swigris JJ et al: Idiopathic pulmonary fibrosis: challenges and opportunities for the clinician and investigator. Chest 2005; 127:275.

Sarcoidosis

Essentials of Diagnosis

  • Symptoms related to the lung, skin, eyes, peripheral nerves, liver, kidney, heart, and other tissues.

  • Demonstration of noncaseating granulomas in a biopsy specimen.

  • Exclusion of other granulomatous disorders.

General Considerations

Sarcoidosis is a systemic disease of unknown etiology characterized in about 90% of patients by granulomatous

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inflammation of the lung. The incidence is highest in North American blacks and northern European whites; among blacks, women are more frequently affected than men. Onset of disease is usually in the third or fourth decade.

Clinical Findings

A. Symptoms and Signs

Patients may present with malaise, fever, and dyspnea of insidious onset. Symptoms referable to the skin, eyes, peripheral nerves, liver, kidney, or heart may also cause the patient to seek care. Some individuals are asymptomatic and come to medical attention after abnormal findings (typically bilateral hilar and right paratracheal lymphadenopathy) on chest radiographs. Physical findings are atypical of interstitial lung disease: crackles are uncommon on chest examination. Other findings may include erythema nodosum, parotid gland enlargement, hepatosplenomegaly, and lymphadenopathy.

B. Laboratory Findings

Laboratory tests may show leukopenia, an elevated erythrocyte sedimentation rate, and hypercalcemia (about 5% of patients) or hypercalciuria (20%). Angiotensin-converting enzyme (ACE) levels are elevated in 40–80% of patients with active disease. This finding is neither sensitive nor specific enough to have diagnostic significance. Physiologic testing may reveal evidence of airflow obstruction, but restrictive changes with decreased lung volumes and diffusing capacity are more common. Skin test anergy is present in 70%. ECG may show conduction disturbances and dysrhythmias.

C. Imaging

Radiographic findings are variable and include bilateral hilar adenopathy alone (radiographic stage I), hilar adenopathy and parenchymal involvement (radiographic stage II), or parenchymal involvement alone (radiographic stage III). Parenchymal involvement is usually manifested radiographically by diffuse reticular infiltrates, but focal infiltrates, acinar shadows, nodules and, rarely, cavitation may be seen. Pleural effusion is noted in fewer than 10% of patients.

D. Special Examinations

The diagnosis of sarcoidosis generally requires histologic demonstration of noncaseating granulomas in biopsies from a patient with other typical associated manifestations. Other granulomatous diseases (eg, berylliosis, tuberculosis, fungal infections) and lymphoma must be excluded. Biopsy of easily accessible sites (eg, palpable lymph nodes, skin lesions, or salivary glands) is likely to be positive. Transbronchial lung biopsy has a high yield (75–90%) as well, especially in patients with radiographic evidence of parenchymal involvement. Some clinicians believe that tissue biopsy is not necessary when stage I radiographic findings are detected in a clinical situation that strongly favors the diagnosis of sarcoidosis (eg, a young black woman with erythema nodosum). Biopsy is essential whenever clinical and radiographic findings suggest the possibility of an alternative diagnosis such as lymphoma. Bronchoalveolar lavage fluid in sarcoidosis is usually characterized by an increase in lymphocytes and a high CD4/CD8 cell ratio. Bronchoalveolar lavage does not establish a diagnosis but may be useful in following the activity of sarcoidosis in selected patients. All patients require a complete ophthalmologic evaluation.

Treatment

Indications for treatment with oral corticosteroids (prednisone, 0.5–1.0 mg/kg/d) include disabling constitutional symptoms, hypercalcemia, iritis, uveitis, arthritis, central nervous system involvement, cardiac involvement, granulomatous hepatitis, cutaneous lesions other than erythema nodosum, and progressive pulmonary lesions. Long-term therapy is usually required over months to years. Serum ACE levels usually fall with clinical improvement. Immunosuppressive drugs and cyclosporine have been tried, primarily when corticosteroid therapy has been exhausted, but experience with these drugs is limited.

Prognosis

The outlook is best for patients with hilar adenopathy alone; radiographic involvement of the lung parenchyma is associated with a worse prognosis. Erythema nodosum portends a good outcome. About 20% of patients with lung involvement suffer irreversible lung impairment, characterized by progressive fibrosis, bronchiectasis, and cavitation. Pneumothorax, hemoptysis, mycetoma formation in lung cavities, and respiratory failure often complicate this advanced stage. Myocardial sarcoidosis occurs in about 5% of patients, sometimes leading to restrictive cardiomyopathy, cardiac dysrhythmias, and conduction disturbances. Death from pulmonary insufficiency occurs in about 5% of patients.

Patients require long-term follow-up; at a minimum, yearly physical examination, pulmonary function tests, chemistry panel, ophthalmologic evaluation, chest radiograph, and ECG.

Baughman RP: Pulmonary sarcoidosis. Clin Chest Med 2004; 25:521.

Paramothayan NS et al: Corticosteroids for pulmonary sarcoidosis. Cochrane Database Syst Rev 2005;(2):CD001114.

Statement on sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999. Am J Respir Crit Care Med 1999;160: 736.

Thomas KW et al: Sarcoidosis. JAMA 2003;289:3300.

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Pulmonary Alveolar Proteinosis

Pulmonary alveolar proteinosis is a disease in which phospholipids accumulate within alveolar spaces. The condition may be primary (idiopathic) or secondary (occurring in immune deficiency; hematologic malignancies; inhalation of mineral dusts; or following lung infections, including tuberculosis and viral infections). Progressive dyspnea is the usual presenting symptom, and chest radiograph shows bilateral alveolar infiltrates suggestive of pulmonary edema. The diagnosis is based on demonstration of characteristic findings on bronchoalveolar lavage (milky appearance and PAS-positive lipoproteinaceous material) in association with typical clinical and radiographic features. In some cases, transbronchial or surgical lung biopsy (revealing amorphous intra-alveolar phospholipid) is necessary.

The course of the disease varies. Some patients experience spontaneous remission; others develop progressive respiratory insufficiency. Pulmonary infection with nocardia or fungi may occur. Therapy for alveolar proteinosis consists of periodic whole lung lavage.

Trapnell BC et al: Pulmonary alveolar proteinosis. N Engl J Med 2003;349:2527.

Eosinophilic Pulmonary Syndromes

Eosinophilic pulmonary syndromes are a diverse group of disorders typically characterized by eosinophilic pulmonary infiltrates, peripheral blood eosinophilia, and pulmonary symptoms such as dyspnea and cough. Many patients have constitutional symptoms, including fever. Chronic eosinophilic pneumonia is predominantly a disorder of women characterized by fever, night sweats, weight loss, and dyspnea. Pulmonary infiltrates on chest radiography are invariably peripheral. Therapy with oral prednisone (1 mg/kg daily for 1–2 weeks followed by a gradual taper over many months) usually results in dramatic improvement; however, most patients require at least 10–15 mg of prednisone every other day for a year or more (sometimes indefinitely) to prevent relapses.

Other eosinophilic pulmonary syndromes demonstrate a variety of patterns of pulmonary infiltrates associated with exposure to various drugs (common drugs include nitrofurantoin, phenytoin, ampicillin, acetaminophen, and ranitidine) or infection with helminths (eg, ascaris, hookworms, strongyloides) or filariae (eg, Wuchereria bancrofti, Brugia malayi, tropical pulmonary eosinophilia). Löffler's syndrome is acute eosinophilic pneumonia with transient pulmonary infiltrates. Pulmonary eosinophilia can also be a feature of many other processes, including ABPA, Churg-Strauss syndrome, systemic hypereosinophilic syndromes, eosinophilic granuloma of the lung (properly referred to as pulmonary Langerhans cell histiocytosis), neoplasms, and numerous interstitial lung diseases. No precipitating cause may be apparent in as many as one-third of cases. If an extrinsic cause is identified, therapy consists of removal of the offending drug or treatment of the underlying parasitic infection. Corticosteroid treatment (prednisone, 1 mg/kg body weight orally per day) should be instituted if no treatable extrinsic cause is discovered. The response to corticosteroids is usually dramatic. Recurrences are common.

Milbrandt EB et al: Progressive infiltrates and eosinophilia with multiple possible causes. Chest 2000;118:230.

Mochimaru H et al: Clinicopathological differences between acute and chronic eosinophilic pneumonia. Respirology 2005;10:76.

Disorders of the Pulmonary Circulation

Pulmonary Venous Thromboembolism

Essentials of Diagnosis

  • Predisposition to venous thrombosis, usually of the lower extremities.

  • One or more of the following: dyspnea, chest pain, hemoptysis, syncope.

  • Tachypnea and a widened alveolar-arterial Po2 difference.

  • Characteristic defects on ventilation-perfusion lung scan, helical CT scan of the chest, or pulmonary arteriogram.

General Considerations

Pulmonary venous thromboembolism, often referred to as pulmonary embolism, is a common, serious, and potentially fatal complication of thrombus formation within the deep venous circulation. Pulmonary venous thromboembolism is estimated to cause 200,000 deaths each year in the United States and is the third leading cause of death among hospitalized patients. Despite this prevalence, the majority of cases are not recognized antemortem, and fewer than 10% of patients with fatal emboli have received specific treatment for the condition. Management demands a vigilant systematic approach to diagnosis and an understanding of risk factors so that appropriate preventive therapy can be given.

Many substances can embolize to the pulmonary circulation, including air (during neurosurgery, from central venous catheters), amniotic fluid (during active labor), fat (long bone fractures), foreign bodies (talc in

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injection drug users), parasite eggs (schistosomiasis), septic emboli (acute infectious endocarditis), and tumor cells (renal cell carcinoma). The most common embolus is thrombus, which may arise anywhere in the venous circulation or heart but most often originates in the deep veins of the major calf muscles. Thrombi confined to the calf rarely embolize to the pulmonary circulation. However, about 20% of calf vein thrombi propagate proximally to the popliteal and ileofemoral veins, at which point they may break off and embolize to the pulmonary circulation. Pulmonary emboli will develop in 50–60% of patients with proximal deep venous thrombosis (DVT); half of these embolic events will be asymptomatic. Nearly 70% of patients who have symptomatic pulmonary emboli will have lower extremity DVT when evaluated.

Pulmonary embolism and DVT are two manifestations of the same disease. The risk factors for pulmonary emboli are the risk factors for thrombus formation within the venous circulation: venous stasis, injury to the vessel wall, and hypercoagulability (Virchow's triad). Venous stasis increases with immobility (bed rest—especially postoperative—obesity, stroke), hyperviscosity (polycythemia), and increased central venous pressures (low cardiac output states, pregnancy). Vessels may be damaged by prior episodes of thrombosis, orthopedic surgery, or trauma. Hypercoagulability can be caused by medications (oral contraceptives, hormonal replacement therapy) or disease (malignancy, surgery) or may be the result of inherited gene defects. The most common inherited cause in white populations is resistance to activated protein C, also known as factor V Leiden. The trait is present in approximately 3% of healthy American men and in 20–40% of patients with idiopathic venous thrombosis. Other major risks for hypercoagulability include the following: deficiencies or dysfunction of protein C, protein S, and antithrombin III; prothrombin gene mutation; and the presence of antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibody).

Pulmonary thromboembolism has multiple physiologic effects. Physical obstruction of the vascular bed and vasoconstriction from neurohumoral reflexes both increase pulmonary vascular resistance. Massive thrombus may cause right ventricular failure. Vascular obstruction increases physiologic dead space (wasted ventilation) and leads to hypoxemia through right-to-left shunting, decreased cardiac output, and surfactant depletion causing atelectasis. Reflex bronchoconstriction promotes wheezing and increased work of breathing.

Clinical Findings

A. Symptoms and Signs

The clinical diagnosis of pulmonary thromboembolism is notoriously difficult for two reasons. First, the clinical findings depend on both the size of the embolus and the patient's preexisting cardiopulmonary status. Second, common symptoms and signs of pulmonary emboli are not specific to this disorder (Table 9-20).

Indeed, no single symptom or sign or combination of clinical findings is specific to pulmonary thromboembolism. Some findings are fairly sensitive: dyspnea and pain on inspiration occur in 75–85% and 65–75% of patients, respectively. Tachypnea is the only sign reliably found in more than half of patients. A common clinical strategy is to use combinations of clinical findings to identify patients at low risk for pulmonary thromboembolism. For example, 97% of patients in the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study with angiographically proved pulmonary emboli had one or more of three findings: dyspnea, chest pain with breathing, or tachypnea. Such a sensitive screen allows exclusion of the diagnosis on clinical grounds in a small number of patients. To establish the diagnosis or to exclude it definitively, further testing is required in the majority of patients.

B. Laboratory Findings

The ECG is abnormal in 70% of patients with pulmonary thromboembolism. However, the most common abnormalities are sinus tachycardia and nonspecific ST and T wave changes, each seen in approximately 40% of patients. Five percent or less of patients in the PIOPED study had P pulmonale, right ventricular hypertrophy, right axis deviation, and right bundle branch block.

Arterial blood gases usually reveal acute respiratory alkalosis due to hyperventilation. The arterial PO2 and the alveolar-arterial oxygen difference (A-a- DO2) are most often abnormal in patients with pulmonary thromboembolism compared with healthy, age-matched controls. However, arterial blood gases are not diagnostic: among patients who presented for evaluation in the PIOPED study, neither the PO2 nor the A-a-DO2 differentiated between those with and those without pulmonary emboli. Profound hypoxia with a normal chest radiograph in the absence of preexisting lung disease is highly suspicious for pulmonary thromboembolism.

Plasma levels of D-dimer, a degradation product of cross-linked fibrin, are elevated in the presence of thrombus. Using a D-dimer threshold between 300 and 500 ng/mL, the quantitative enzyme-linked immunosorbent assay (ELISA) has shown a sensitivity for venous thromboembolism of 95–97% and a specificity of 45%. Therefore, a D-dimer < 500 ng/mL using ELISA provides strong evidence against venous thromboembolism, with a likelihood ratio of 0.11–0.13. Two considerations have delayed widespread inclusion of plasma D-dimer assays into diagnostic algorithms. First, the accurate quantitative ELISA used in clinical research takes several hours to perform and is not widely available. Commonly used latex agglutination assays are much less sensitive and are difficult to standardize. Second, the D-dimer is elevated in most hospitalized patients, particularly those with malignancies or following surgery. Appropriate diagnostic thresholds are not yet established for inpatients.

Table 9-20. Frequency of specific symptoms and signs in patients at risk for pulmonary thromboembolism.

  UPET1 PE+ (n = 327) PIOPED2 PE+ (n = 117) PIOPED2 PE- (n = 248)
Symptoms
   Dyspnea 84% 73% 72%
   Respirophasic chest pain 74% 66% 59%
   Cough 53% 37% 36%
   Leg pain nr 26% 24%
   Hemoptysis 30% 13% 8%
   Palpitations nr 10% 18%
   Wheezing nr 9% 11%
   Anginal pain 14% 4% 6%
Signs
   Respiratory rate ≥ 16 UPET, ≥ 20 PIOPED 92% 70% 68%
   Crackles (rales) 58% 51% 40%3
   Heart rate ≥ 100/min 44% 30% 24%
   Fourth heart sound (S4) nr 24% 13%3
   Accentuated pulmonary component of second heart sound (S2P) 53% 23% 13%3
   T ≥ 37.5°C UPET, ≥ 38.5°C PIOPED 43% 7% 12%
   Homans' sign nr 4% 2%
   Pleural friction rub nr 3% 2%
   Third heart sound (S3) nr 3% 4%
   Cyanosis 19% 1% 2%
1Data from the Urokinase-Streptokinase Pulmonary Embolism Trial, as reported in Bell WR, Simon TL, DeMets DL: The clinical features of submassive and massive pulmonary emboli. Am J Med 1977;62:355.
2Data from patients enrolled in the PIOPED study, as reported in Stein PD et al: Clinical, laboratory, roentgenographic, and electrocardiographic findings in patients with acute pulmonary embolism and no preexisting cardiac or pulmonary disease. Chest 1991;100:598.
3P < .05 comparing patients in the PIOPED study.
PE+ = confirmed diagnosis of pulmonary embolism; PE- = diagnosis of pulmonary embolism ruled out; nr = not reported.

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C. Imaging and Special Examinations

1. Chest radiography

The chest radiograph is necessary to exclude other common lung diseases and to permit interpretation of the ventilation-perfusion ([V with dot above]/[Q with dot above]) scan, but it does not establish the diagnosis by itself. The chest radiograph was normal in only 12% of patients with confirmed pulmonary thromboembolism in the PIOPED study. The most frequent findings were atelectasis, parenchymal infiltrates, and pleural effusions. However, the prevalence of these findings was the same in hospitalized patients without pulmonary thromboembolism. A prominent central pulmonary artery with local oligemia (Westermark's sign) or pleural-based areas of increased opacity that represent intraparenchymal hemorrhage (Hampton's hump) are uncommon. Paradoxically, the chest radiograph may be most helpful when normal in the setting of hypoxemia.

2. Lung scanning

A perfusion scan is performed by injecting radiolabeled microaggregated albumin into the venous system, allowing the particles to embolize to the pulmonary capillary bed. To perform a ventilation scan, the patient breathes a radioactive gas or aerosol while the distribution of radioactivity in the lungs is recorded.

A defect on perfusion scanning represents diminished blood flow to that region of the lung. This finding is not specific for pulmonary embolism. Defects in the perfusion scan are interpreted in conjunction with the ventilation scan to give a high, low, or intermediate (indeterminate) probability that pulmonary thromboembolism is the cause of the abnormalities. Criteria for the combined

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interpretation of ventilation and perfusion scans (commonly referred to as a single test, the [V with dot above]/[Q with dot above] scan) are complex, confusing, and not completely standardized. A normal perfusion scan excludes the diagnosis of clinically significant pulmonary thromboembolism (negative predictive value of 91% in the PIOPED study). A high-probability [V with dot above]/[Q with dot above] scan is most often defined as having two or more segmental perfusion defects in the presence of normal ventilation and is sufficient to make the diagnosis of pulmonary thromboembolism in most instances (positive predictive value of 88% among PIOPED patients). In the presence of abnormal pulmonary vasculature, as commonly happens in prior pulmonary thromboembolism, or if the clinical pretest probability for embolism is low, angiography may be indicated even in the presence of a high-probability [V with dot above]/[Q with dot above] scan.

[V with dot above]/[Q with dot above] scans are most helpful when they are either normal or indicate a high probability of pulmonary thromboembolism. Such readings are reliable—interobserver agreement is best for normal and high-probability scans, and they carry predictive power. The likelihood ratios associated with normal and high-probability scans are 0.10 and 18, respectively, indicating significant and frequently conclusive changes from pretest to posttest probability.

However, 75% of PIOPED [V with dot above]/[Q with dot above] scans were nondiagnostic, ie, of low or intermediate probability. At angiography, these patients had an overall incidence of pulmonary thromboembolism of 14% and 30%, respectively. The likelihood ratios associated with low-probability and intermediate scans are 0.36 and 1.2, respectively, confirming the clinical impression that these studies add little diagnostic information. One of the most important findings of PIOPED was that the clinical assessment of pretest probability could be used to aid the interpretation of the [V with dot above]/[Q with dot above] scan. For those patients with low-probability [V with dot above]/[Q with dot above] scans and a low (20% or less) clinical pretest probability of pulmonary thromboembolism, the diagnosis was confirmed in only 4%. Such patients may reasonably be observed without angiography. All other patients with nondiagnostic [V with dot above]/[Q with dot above] scans require further testing to determine the presence of venous thromboembolism.

3. CT

Helical CT arteriography is rapidly supplanting [V with dot above]/[Q with dot above] scanning as the initial diagnostic study for suspected pulmonary thromboembolism. Helical CT arteriography requires administration of intravenous radiocontrast dye but is otherwise noninvasive. It is very sensitive for the detection of thrombus in the proximal pulmonary arteries but less so in the segmental and subsegmental arteries. Test results vary widely by study and facility. Factors influencing results include patient size and cooperation, the type and quality of the scanner, the imaging protocol, and the experience of the radiologist. One report comparing helical CT with standard arteriography reported sensitivity of 53–60% and specificity of 81–97%. Comparing helical CT to the [V with dot above]/[Q with dot above] scan as the initial test for pulmonary thromboembolism, detection of thrombi is comparable, but more nonthromboembolism pulmonary diagnoses are made with CT scanning. Independent of cost and availability, helical CT may offer advantages as a screening examination, especially in hospitalized patients and in patients with significant comorbidities. A contentious issue is whether a negative helical CT requires any further evaluation. False-negative results may occur in up to 20% of helical CTs. Advocates contend that these false-negatives represent small peripheral thromboemboli and that such patients can be monitored off anticoagulation without undue risk. One study reported a venous thromboembolism rate of 0.8% in 3-month follow-up of 376 patients with negative helical CT scans, but the mortality rate at 3 months was 10.1%. Further study is required to clarify the role of this diagnostic modality, especially in view of ongoing advances in CT technology and the increasing availability of multi-detector-row scanners.

4. Venous thrombosis studies

Seventy percent of patients with pulmonary thromboembolism will have DVT on evaluation, and approximately half of patients with DVT will have pulmonary thromboembolism on angiography. Since the history and physical examination are neither sensitive nor specific for pulmonary thromboembolism and since the results of [V with dot above]/[Q with dot above] scanning are frequently equivocal, documentation of DVT in a patient with suspected pulmonary thromboembolism establishes the need for treatment and may preclude pulmonary arteriography.

Commonly available diagnostic techniques include venous ultrasonography, impedance plethysmography, and contrast venography. In most centers, venous ultrasonography is the test of choice to detect proximal DVT. Inability to compress the common femoral or popliteal veins in symptomatic patients is diagnostic of first-episode DVT (positive predictive value of 97%); full compressibility of both sites excludes proximal DVT (negative predictive value of 98%). The test is less accurate in distal thrombi, recurrent thrombi, or in asymptomatic patients. Impedance plethysmography relies on changes in electrical impedance between patent and obstructed veins to determine the presence of thrombus. Accuracy is comparable though not quite as high as ultrasonography. Both ultrasonography and impedance plethysmography are useful in the serial examination of patients with high clinical suspicion of venous thromboembolism but negative leg studies. In patients with suspected first-episode DVT and a negative ultrasound or impedance plethysmography examination, multiple studies have confirmed the safety of withholding anticoagulation while conducting two sequential studies on days 1–3 and 7–10. Similarly, patients with nondiagnostic [V with dot above]/[Q with dot above] scans and an initial negative venous ultrasound or impedance plethysmography examination may be monitored off therapy with serial leg studies over 2 weeks. When serial examinations are negative for proximal DVT, the risk of subsequent venous thromboembolism over the following 6 months is less than 2%.

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Contrast venography remains the reference standard for the diagnosis of DVT. An intraluminal filling defect is diagnostic of venous thrombosis. However, venography has significant shortcomings and has been replaced by venous ultrasound as the diagnostic procedure of choice. Difficulties include patient discomfort, expense, allergic reactions to radiocontrast media, contrast-induced phlebitis, and technical difficulties in cannulation of dorsal foot veins and in the interpretation of studies. There is a significant (2–4%) risk of developing venous thrombosis from the procedure—a risk that may be higher than the false-negative rate of noninvasive studies. Venography is used principally in complex situations where there is discrepancy between clinical suspicion and noninvasive testing.

5. Pulmonary arteriography

Pulmonary arteriography remains the reference standard for the diagnosis of pulmonary thromboembolism. An intraluminal filling defect in more than one projection establishes a definitive diagnosis. Secondary findings highly suggestive of pulmonary thromboembolism include abrupt arterial cutoff, asymmetry of blood flow—especially segmental oligemia—or a prolonged arterial phase with slow filling. Pulmonary arteriography was performed in 755 patients in the PIOPED study. A definitive diagnosis was established in 97%; in 3% the studies were nondiagnostic. Four patients (0.8%) with negative arteriograms subsequently had pulmonary thromboemboli at autopsy. Serial arteriography has demonstrated minimal resolution of thrombus prior to day 7 following presentation. Thus, negative arteriography within 7 days of presentation excludes the diagnosis.

Pulmonary arteriography is a safe but invasive procedure with well-defined morbidity and mortality data. Minor complications occur in approximately 5% of patients. Most are allergic contrast reactions, transient renal dysfunction, or related to percutaneous catheter insertion; cardiac perforation and arrhythmias are reported but rare. Among the PIOPED patients who underwent arteriography, there were five deaths (0.7%) directly related to the procedure. Pulmonary hypertension is thought to increase the risk of serious complications, though a study of patients with average pulmonary arterial pressures of 74/34 mm Hg developed no major complications or deaths associated with pulmonary arteriography.

The appropriate role of pulmonary arteriography in the diagnosis of pulmonary thromboembolism remains a subject of active debate. There is wide agreement that arteriography is indicated in several specific situations: in patients with nondiagnostic [V with dot above]/[Q with dot above] scans, intermediate or high clinical pretest probability of pulmonary thromboembolism, and negative noninvasive leg studies; in any patient in whom the diagnosis is in doubt when there is a high clinical pretest probability of pulmonary thromboembolism; and when the diagnosis of pulmonary thromboembolism must be established with certainty, as when anticoagulation is contraindicated or placement of an inferior vena cava filter is contemplated.

6. MRI

MRI has sensitivity and specificity equivalent to contrast venography in the diagnosis of DVT. It has improved sensitivity when compared with venous ultrasound in the diagnosis of DVT, without loss of specificity. The test is noninvasive and avoids the use of potentially nephrotoxic radiocontrast dye. However, it remains expensive and not widely available. Artifacts introduced by respiratory and cardiac motion have limited the use of MRI in the diagnosis of pulmonary thromboembolism. New techniques have improved sensitivity and specificity to levels comparable with helical CT, but MRI remains primarily a research tool for pulmonary thromboembolism.

7. Integrated approach

The integrated approach uses the clinical likelihood of venous thromboembolism along with the overlapping results of noninvasive testing to come to one of three decision points: to establish venous thromboembolism (pulmonary thromboembolism or DVT) as the diagnosis, to exclude venous thromboembolism with sufficient confidence to follow the patient without therapy, or to refer the patient for pulmonary arteriography. An ideal diagnostic algorithm would proceed in a stepwise fashion to come to these decision points in a cost-effective way at minimal risk to the patient. We present two such algorithms in Figure 9-3.

Prevention

Venous thromboembolism is often clinically silent until it presents with significant morbidity or mortality. It is a prevalent disease, clearly associated with identifiable risk factors. For example, the incidence of proximal DVT, pulmonary thromboembolism, and fatal pulmonary thromboembolism in untreated patients undergoing hip fracture surgery is reported to be 10–20%, 4–10%, and 0.2–5%, respectively. There is unambiguous evidence of the efficacy of prophylactic therapy in this and other clinical situations, yet it remains underused. Only about 50% of surgical deaths from pulmonary thromboembolism had received any form of preventive therapy. Tables 9-21 and 9-22 provide overviews of strategies for the prevention of venous thromboembolism.

Options for therapy begin with mechanical devices such as graduated-compression stockings and intermittent pneumatic compression. The latter improves venous return and may increase endogenous fibrinolysis by stimulating the vascular endothelium. Standard pharmacologic therapy in medical patients is low-dose unfractionated heparin, 5000 units subcutaneously every 8–12 hours. Low-molecular-weight (LMW) heparins are more expensive but have several advantages compared with unfractionated heparin: better bioavailability, once- or twice-daily dosing, and a lower incidence of heparin-associated thrombocytopenia. In high-risk surgical patients, LMW heparins can be administered without the need for

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coagulation monitoring and dose adjustments, as would be the case with unfractionated heparin.

Figure 9-3. Two simple algorithms to guide evaluation of suspected venous thromboembolism. The standard algorithm is based on the results of ventilation-perfusion lung scanning using PIOPED data. Management of patients with ventilation-perfusion lung scans of low and indeterminate probability must always be guided by clinical judgment based upon cumulative clinical information and the degree of suspicion of pulmonary thromboembolism. The second algorithm uses D-dimer, helical CT, and venous ultrasonography to describe an evidence-based, efficient evaluation that reflects emerging practice. This second algorithm is not based on the experience of the standard ventilation-perfusion approach but anticipates a shift toward use of helical CT as the primary diagnostic test in pulmonary thromboembolism.

Table 9-21. Selected methods for the prevention of venous thromboembolism.

Risk Group Recommendations for Prophylaxis
Surgical patients
   General surgery
      Low-risk: Minor procedures, age under 40, and no clinical risk factors Early ambulation
      Moderate risk: Minor procedures with additional thrombosis risk factors; age 40-60, and no other clinical risk factors; or major operations with age under 40 without additional clinical risk factors ES, or LDUH, or LMWH, or IPC; plus early ambulation if possible
      Higher risk: Major operation, over age 40 or with additional risk factors LDUH, or LMWH, or IPC
      Higher risk plus increased risk of bleeding ES or IPC
      Very high risk: Multiple risk factors LDUH, or higher-dose LMWH, plus ES or IPC
      Selected very high risk Consider ADPW, INR 2.0-3.0, or postdischarge LMWH
   Orthopedic surgery
      Elective total hip replacement surgery Subcutaneous LMWH, or ADPW, or adjusted-dose heparin started preoperatively; plus IPC or ES
      Elective total knee replacement surgery LMWH, or ADPW, or IPC
      Hip fracture surgery LMWH or ADPW
   Neurosurgery
      Intracranial neurosurgery IPC with or without ES; LDUH and postoperative LMWH are acceptable alternatives; IPC or ES plus LDUH or LMWH may be more effective than either modality alone in high-risk patients.
      Acute spinal cord injury LMWH; IPC and ES may have additional benefit when used with LMWH. In the rehabilitation phase, conversion to full-dose warfarin may provide ongoing protection.
   Trauma
      With an identifiable risk factor for thromboembolism LMWH; IPC or ES if there is a contraindication to LMWH; consider duplex ultrasound screening in very high risk patients; IVC filter insertion if proximal DVT is identified and anticoagulation is contraindicated.
Medical patients
   Acute myocardial infarction Subcutaneous LDUH, or full-dose heparin; if heparin is contraindicated, IPC and ES may provide some protection.
   Ischemic stroke with impaired mobility LMWH or LDUH or danaparoid; IPC or ES if anticoagulants are contraindicated
   General medical patients with clinical risk factors; especially patients with cancer, congestive heart failure, or severe pulmonary disease Low-dose LMWH, or LDUH
   Cancer patients with indwelling central venous catheters Warfarin, 1 mg/d, or LMWH
ADPW = adjusted-dose perioperative warfarin: begin 5-10 mg the day of or the day following surgery; adjust dose to INR 2.0-3.0; DVT = deep venous thrombosis; ES = elastic stockings; IPC = intermittent pneumatic compression; IVC = inferior vena cava; LDUH = low-dose unfractionated heparin: 5000 units subcutaneously every 8-12 hours starting 1-2 hours before surgery; LMWH = low-molecular-weight heparin. See Table 9-24 for dosing regimens.
Recommendations assembled from Geerts WH et al: Prevention of venous thromboembolism. Chest 2001;119(Suppl):132.

Table 9-22. Selected low-molecular-weight heparin and heparinoid regimens to prevent venous thromboembolism.

Risk Group Drug Subcutaneous Dose1 Administration Regimen Cost2
General surgery, moderate risk Dalteparin (Fragmin) 2500 units 1-2 h preop and qd postop $18.08/dose
Enoxaparin (Lovenox) 20 mg 1-2 h preop and qd postop $22.26/dose
Nadroparin (Fraxiparin) 2850 units 2-4 h preop and qd postop No price available: Not available in USA
Tinzaparin (Innohep) 3500 units 2 h preop and qd postop $28.22/dose
General surgery, high risk Dalteparin (Fragmin) 5000 units 8-12 preop and qd postop $29.34/dose
Danaparoid (Orgaran) 750 units 1-4 h preop and q12 h postop No price available: Not available in USA
Enoxaparin (Lovenox) 40 mg 1-2 h preop and qd postop $29.68/dose
Enoxaparin (Lovenox) 30 mg q12 h starting 8-12 h postop $22.26/dose
Orthopedic surgery Dalteparin (Fragmin) 5000 units 8-12 h preop and qd starting 12-24 h postop $29.34/dose
Dalteparin (Fragmin) 2500 units 6-8 h postop then 5000 units qd $18.08/dose
Danaparoid (Orgaran) 750 units 1-4 preop and q12 h postop No price available: Not available in USA
Enoxaparin (Lovenox) 30 mg q12 h starting 12-24 h postop $22.26/dose
Enoxaparin (Lovenox) 40 mg qd starting 10-12 h preop $29.68/dose
Nadroparin (Fraxiparin) 38 units/kg 12 h preop, 12 h postop, and qd on postop days 1, 2, 3; then increase to 57 units/kg qd No price available: Not available in USA
Tinzaparin (Innohep) 75 units/kg qd starting 12-24 h postop $36.29/dose (60 kg pt)
Tinzaparin (Innohep) 4500 units 12 h preop and qd postop $36.29/dose
Major trauma Enoxaparin (Lovenox) 30 mg q12h starting 12-36 h postinjury if hemostatically stable $21.41/dose
Acute spinal cord injury Enoxaparin (Lovenox) 30 mg q12h $21.41/dose
Medical conditions Dalteparin (Fragmin) 2500 units qd $17.22/dose
Danaparoid (Orgaran) 750 units q12h No price available: Not available in USA
Enoxaparin (Lovenox) 40 mg qd $28.54/dose
Nadroparin (Fraxiparin) 2850 units qd No price available: Not available in USA
1Dose expressed in anti-Xa units; for enoxaparin, 1 mg = 100 anti-Xa units.
2Average wholesale price (AWP, for AB-rated generic when available) for quantity listed. Source: Red Book Update, Vol. 24, No. 4, April 2005. AWP may not accurately represent the actual pharmacy cost because wide contractual variations exist among institutions.
Preop = preoperatively; Postop = postoperatively; qd = once daily.
Modified and reproduced with permission, from Geerts WH et al: Prevention of venous thromboembolism. Chest 2001;119:132S.

Treatment

A. Anticoagulation

Anticoagulation is not definitive therapy but a form of secondary prevention. Heparin binds to and accelerates the ability of antithrombin III to inactivate thrombin, factor Xa, and factor IXa. It thus retards additional thrombus formation, allowing endogenous fibrinolytic mechanisms to lyse existing clot. The standard regimen of heparin followed by 6 months of oral warfarin results in an 80–90% reduction in the risk of both recurrent venous thrombosis and death from pulmonary thromboembolism.

Heparin has troublesome pharmacokinetics. Its clearance is dose-dependent; it is highly protein-bound; and a minimum or threshold level is necessary to achieve an antithrombotic effect. It is necessary to monitor the activated partial thromboplastin time (aPTT) and adjust dosing to maintain the aPTT 1.5–2.5 times control. In patients with a moderate to high clinical likelihood of pulmonary thromboembolism and no contraindications, full anticoagulation with heparin should begin with the diagnostic evaluation. Once the diagnosis of proximal DVT or pulmonary thromboembolism is established, it is critical to ensure adequate therapy. Failure to achieve therapeutic heparin levels within 24 hours is associated with a fivefold-increased risk of clot propagation. The weight-based regimen in Table 9-23 is superior to standard dosing. Heparin causes immune-mediated thrombocytopenia in 3% of patients; therefore, the platelet count should be determined frequently for the first 14 days of therapy.

Table 9-23. Intravenous heparin dosing based on body weight.

Initial dosing
  1. Load with 80 units/kg IV, then
  2. Initiate a maintenance infusion at 18 units/kg/h
  3. Check activated partial thromboplastin time (aPTT) in 6 hours
Dose adjustment schedule based on aPTT results
   < 35 s (< 1.2 × control) Rebolus with 80 units/kg; increase infusion by 4 units/kg/h
   35-45 s (1.2-1.5 × control) Rebolus with 40 units/kg; increase infusion by 2 units/kg/h
   46-70 s (1.5-2.3 × control) No change
   71-90 s (2.3-3 × control) Decrease infusion rate by 2 units/kg/h
   > 90 s (> 3 × control) Stop infusion for 1 hour, then decrease infusion by 3 units/kg/h
Repeat aPTT every 6 hours for the first 24 hours. If the aPTT is 46-70 s after 24 hours, then recheck once daily every morning. If the aPTT is outside this therapeutic range at 24 hours, continue checking every 6 hours until it is 46-70 s. Once it has been in the therapeutic range on two consecutive measurements after 24 hours, check once daily every morning.
Adapted from Raschke RA et al: The weight-based heparin dosing nomogram compared with a “standard care” nomogram. Ann Intern Med 1993;119:874.

Table 9-24. Selected low-molecular-weight heparin anticoagulation regimens.

Drug Suggested Treatment Dose 1(Subcutaneous)
Dalteparin 200 units/kg once daily (not to exceed 18,000 units/dose)
Enoxaparin 1.5 mg/kg once daily (single dose not to exceed 180 mg)
Nadroparin 86 units/kg twice daily for 10 days, or 171 units/kg once daily (single dose not to exceed 17,000 units)
Tinzaparin 175 units/kg once daily
1Dose expressed in anti-Xa units; for enoxaparin, 1 mg = 100 anti-Xa units.
Modified and reproduced with permission, from Hyers TM et al: Antithrombotic therapy for venous thromboembolic disease. Chest 2001;119(Suppl):176S.

LMW heparins are depolymerized preparations of heparin with multiple advantages over unfractionated heparin. They exhibit less binding to cells and proteins and have superior bioavailability, a longer plasma half-life, and more predictable dose-response characteristics. They appear to carry an equivalent or lower risk of hemorrhage, and immune-mediated thrombocytopenia is less common. LMW heparins are as effective as unfractionated heparin in the treatment of venous thromboembolism. They are administered in dosages determined by body weight once or twice daily without the need for coagulation monitoring, and subcutaneous administration appears to be as effective as the intravenous route. This profile makes LMW heparins ideal for home-based therapy of venous thromboembolism. Home-based therapy appears safe and efficacious in a small number of selected patients. Table 9-24 sets forth selected LMW heparin anticoagulation regimens.

Anticoagulation therapy for venous thromboembolism is continued for a minimum of 3 months, so oral anticoagulant therapy with warfarin is usually initiated concurrently with heparin. Warfarin affects hepatic synthesis of vitamin K-dependent coagulant proteins. It usually requires 5–7 days to become therapeutic; therefore, heparin is generally continued for 5 days. Warfarin is safe if begun concurrently with heparin, initially at a dose of 2.5–10 mg/d. The lower dose is preferred in elderly patients. Maintenance therapy usually requires 2–15 mg/d. Adequacy of therapy must be monitored by following the

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prothrombin time, most often adjusted for differences in reagents and reported as the international normalized ratio (INR). The target INR is 2.5, with the acceptable range from 2.0 to 3.0; below 2.0, there is an increased risk of thrombosis; above 4.0, there is an increased risk of hemorrhage. Warfarin has interactions with many drugs. Meticulous attention to medications is part of the routine management of every patient receiving warfarin. Warfarin is a pregnancy category X medication, indicating known fetopathic and teratogenic effects. When oral anticoagulation with warfarin is contraindicated, LMW heparin is a convenient alternative.

The optimal duration of anticoagulation therapy for venous thromboembolism is unknown. There appears to be a protective benefit to continued anticoagulation in first-episode venous thromboembolism (twice the rate of recurrence in 6 weeks compared with 6 months of therapy) and recurrent disease (eightfold risk of recurrence in 6 months compared with 4 years of therapy). These studies do not distinguish patients with reversible risk factors, such as surgery or transient immobility, from patients who have a nonreversible hypercoagulable state such as factor V Leiden, inhibitor deficiency, antiphospholipid syndrome, or malignancy. A randomized controlled trial of low-dose warfarin (INR 1.5–2.0) versus no therapy following 6 months of standard therapy in patients with idiopathic DVT was stopped early. The protective benefits of continued anticoagulation include fewer DVTs in addition to a trend toward lower mortality despite more hemorrhage in the warfarin group. Risk reductions were consistent across groups with and without inherited thrombophilia.

For many patients, venous thrombosis is a recurrent disease, and continued therapy will result in a lower rate of recurrence at the cost of an increased risk of hemorrhage. Therefore, the appropriate duration of therapy will need to take into consideration potentially reversible risk factors, the individual's age, the likelihood and potential consequences of hemorrhage, and patient preferences for continued therapy. It is reasonable to continue therapy for 6 months after a first episode when there is a reversible risk factor, 12 months after a first-episode idiopathic thrombus, and 6–12 months to indefinitely in patients with nonreversible risk factors or recurrent disease. If confirmed, these data may lead to lifelong low-dose anticoagulation.

The major complication of anticoagulation is hemorrhage. Risk factors for hemorrhage include the intensity of the anticoagulant effect; the duration of therapy; concomitant administration of drugs such as aspirin that interfere with platelet function; and patient characteristics, particularly increased age, previous gastrointestinal hemorrhage, and coexistent renal insufficiency.

The reported incidence of major hemorrhage following intravenous administration of unfractionated heparin is nil to 7%; that of fatal hemorrhage is nil to 2%. The incidence with LMW heparins is not statistically different. There is no information comparing hemorrhage rates at different doses of heparin. The risk of subtherapeutic heparin administration in the first 24–48 hours after diagnosis is significant; it appears to outweigh the risk of short-term supratherapeutic heparin levels. The incidence of hemorrhage during therapy with warfarin is reported to be between 3% and 4% per patient year. The frequency varies with the target INR and is consistently higher when the INR exceeds 4.0. There is no apparent additional antithrombotic benefit in venous thromboembolism with a target INR above 2.0–3.0.

B. Thrombolytic Therapy

Streptokinase, urokinase, and recombinant tissue plasminogen activator (rt-PA; alteplase) increase plasmin levels and thereby directly lyse intravascular thrombi. In patients with established pulmonary thromboembolism, thrombolytic therapy accelerates resolution of emboli within the first 24 hours compared with standard heparin therapy. This is a consistent finding using angiography, [V with dot above]/[Q with dot above] scanning, echocardiography, and direct measurement of pulmonary artery pressures. However, at 1 week and 1 month after diagnosis, these agents show no difference in outcome compared with heparin and warfarin. There is no evidence that thrombolytic therapy improves mortality. Subtle improvements in pulmonary function, including improved single-breath diffusing capacity and a lower incidence of exercise-induced pulmonary hypertension, have been observed. The reliability and clinical importance of these findings is unclear. The major disadvantages of thrombolytic therapy compared with heparin are its greater cost and a significant increase in major hemorrhagic complications. The incidence of intracranial hemorrhage in patients with pulmonary thromboemboli treated with alteplase is 2.1% compared with 0.2% in patients treated with heparin.

Current evidence supports thrombolytic therapy for pulmonary thromboembolism in patients at high risk for death in whom the more rapid resolution of thrombus may be lifesaving. Such patients are usually hemodynamically unstable despite heparin therapy. Absolute contraindications to thrombolytic therapy include active internal bleeding and stroke within the past 2 months. Major contraindications include uncontrolled hypertension and surgery or trauma within the past 6 weeks.

C. Additional Measures

Interruption of the inferior vena cava may be indicated in patients with a major contraindication to anticoagulation who have or are at high risk for development of proximal DVT or pulmonary embolus. Placement of an inferior vena cava filter is also recommended for recurrent thromboembolism despite adequate anticoagulation, for chronic recurrent embolism with pulmonary hypertension, and with the concurrent performance of surgical pulmonary embolectomy or pulmonary thromboendarterectomy. Percutaneous transjugular placement of a mechanical filter is the preferred mode of inferior

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vena cava interruption. These devices reduce the short-term incidence of pulmonary thromboemboli in patients presenting with proximal lower extremity DVT. However, they are associated with a two-fold increased risk of recurrent DVT in the first 2 years following placement.

In rare critically ill patients for whom thrombolytic therapy is contraindicated or unsuccessful, mechanical or surgical extraction of thrombus may be indicated. Pulmonary embolectomy is an emergency procedure of last resort with a very high mortality rate. It is now performed only in a few specialized centers. Several catheter devices to fragment and extract thrombus through a transvenous approach have been reported in small numbers of patients. Comparative outcomes with surgery, thrombolytic therapy, or heparin have not been studied.

Prognosis

Pulmonary thromboembolism is estimated to cause more than 50,000 deaths annually. In the majority of deaths, pulmonary thromboembolism is not recognized antemortem or death occurs before specific treatment can be initiated. These statistics highlight the importance of preventive therapy in high-risk patients. The outlook for patients with diagnosed and appropriately treated pulmonary thromboembolism is generally good. Overall prognosis depends on the underlying disease rather than the pulmonary thromboembolism itself. Death from recurrent thromboemboli is uncommon, occurring in less than 3% of cases. Perfusion defects resolve in most survivors. Approximately 1% of patients develop chronic thromboembolic pulmonary hypertension. Selected patients may benefit from pulmonary endarterectomy.

Blom JW et al: Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 2005;293:715.

Buller HR et al: Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126(3 Suppl): 401S.

Geerts WH et al: Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126(3 Suppl):338S.

Hirsh J et al: New anticoagulants. Blood 2005;105:453.

Hull RD: Revisiting the past strengthens the present: an evidence-based medicine approach for the diagnosis of deep venous thrombosis. Ann Intern Med 2005;142:583.

Nijkeuter M et al: Resolution of thromboemboli in patients with acute pulmonary embolism: a systematic review. Chest 2006;129:192.

Perrier A et al: Multidetector-row computed tomography in suspected pulmonary embolism. N Engl J Med 2005;352:1760.

Quiroz R et al: Clinical validity of a negative computed tomography scan in patients with suspected pulmonary embolism: a systematic review. JAMA 2005;293:2012.

Roy PM et al: Systematic review and meta-analysis of strategies for the diagnosis of suspected pulmonary embolism. BMJ 2005;331:259.

van Belle A et al; Christopher Study Investigators: Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA 2006;295:172.

Wells PS et al: Does this patient have deep vein thrombosis? JAMA 2006;295:199.

Pulmonary Hypertension

Essentials of Diagnosis

  • Dyspnea, fatigue, chest pain, and syncope on exertion.

  • Narrow splitting of second heart sound with loud pulmonary component; findings of right ventricular hypertrophy and cardiac failure in advanced disease.

  • Hypoxemia and increased wasted ventilation on pulmonary function tests.

  • Electrocardiographic evidence of right ventricular strain or hypertrophy and right atrial enlargement.

  • Enlarged central pulmonary arteries on chest radiograph.

General Considerations

The pulmonary circulation is unique because of its high blood flow, low pressure (normally 25/8 mm Hg, mean 12), and low resistance (normally 200–250 dynes/sec/cm-5). It can accommodate large increases in blood flow during exercise with only modest increases in pressure because of its ability to recruit and distend lung blood vessels. Contraction of smooth muscle in the walls of pulmonary arteriolar resistance vessels becomes an important factor in numerous pathologic states. Pulmonary hypertension is present when pulmonary artery pressure rises to a level inappropriate for a given cardiac output. Once present, pulmonary hypertension is self-perpetuating. It introduces secondary structural abnormalities in pulmonary vessels, including smooth muscle hypertrophy and intimal proliferation, and these may eventually stimulate atheromatous changes and in situ thrombosis, leading to further narrowing of the arterial bed.

Primary (idiopathic) pulmonary hypertension (see Chapter 10) is a rare disorder of the pulmonary circulation occurring mostly in young and middle-aged women. Untreated, it is characterized by progressive dyspnea, a rapid downhill course, and an invariably fatal outcome. This condition is also called plexogenic pulmonary arteriopathy, in reference to the characteristic

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histopathologic plexiform lesion found in muscular pulmonary arteries. It has been observed in occasional patients with HIV infection.

Table 9-25. Mechanisms of pulmonary hypertension and examples of corresponding clinical conditions.

Reduction in cross-sectional area of pulmonary arterial bed
   Vasoconstriction
      Hypoxemia from any cause (chronic lung disease, sleep-disordered breathing, etc)
      Acidosis
   Loss of vessels
      Lung resection
      Emphysema
      Vasculitis
      Interstitial lung disease
      Collagen-vascular disease
   Obstruction of vessels
      Pulmonary embolism (thromboemboli, tumor emboli, etc)
      In situ thrombosis
      Schistosomiasis
      Sickle cell disease
   Narrowing of vessels
      Secondary structural changes due to pulmonary hypertension
Increased pulmonary venous pressure
   Constrictive pericarditis
   Left ventricular failure or reduced compliance
   Mitral stenosis
   Left atrial myxoma
   Pulmonary veno-occlusive disease
   Mediastinal diseases compressing pulmonary veins
Increased pulmonary blood flow
   Congenital left-to-right intracardiac shunts
Increased blood viscosity
   Polycythemia
Miscellaneous
   Pulmonary hypertension occurring in association with hepatic cirrhosis and portal hypertension
   HIV infection

Selected mechanisms responsible for secondary pulmonary hypertension and examples of corresponding clinical conditions are set forth in Table 9-25. Pulmonary arteriolar vasoconstriction due to chronic hypoxemia may complicate any chronic lung disease and compound the effects of loss of pulmonary blood vessels (as seen with disorders such as emphysema and pulmonary fibrosis) and obstruction of the pulmonary vascular bed (as seen with disorders such as chronic pulmonary thromboembolic disease). Sustained increases in pulmonary venous pressure from disorders such as left ventricular failure (systolic, diastolic, or both), mitral stenosis, and pulmonary veno-occlusive disease may cause “postcapillary” pulmonary hypertension. Increased pulmonary blood flow due to intracardiac shunts and increased blood viscosity due to polycythemia can also cause pulmonary hypertension. Pulmonary hypertension has also been associated with hepatic cirrhosis and portal hypertension.

Pulmonary veno-occlusive disease is a rare cause of postcapillary pulmonary hypertension occurring in children and young adults. The cause is unknown, but associations with various conditions such as viral infection, bone marrow transplantation, chemotherapy, and malignancy have been described. The disease is characterized by progressive fibrotic occlusion of pulmonary veins and venules, along with secondary hypertensive changes in the pulmonary arterioles and muscular pulmonary arteries. Nodular areas of pulmonary congestion, edema, hemorrhage, and hemosiderosis are found. Chest radiography reveals prominent, symmetric interstitial markings, Kerley B lines, pulmonary artery dilation, and normally sized left atrium and left ventricle. Antemortem diagnosis is often difficult but is occasionally established by open lung biopsy. There is no effective therapy, and most patients die within 2 years as a result of progressive pulmonary hypertension.

Clinical Findings

A. Symptoms and Signs

Secondary pulmonary hypertension is difficult to recognize clinically in the early stages, when symptoms and signs are primarily those of the underlying disease. Pulmonary hypertension may cause or contribute to dyspnea, present initially on exertion and later at rest. Dull, retrosternal chest pain resembling angina pectoris may be present. Fatigue and syncope on exertion also occur, presumably a result of reduced cardiac output related to elevated pulmonary artery pressures or bradycardia.

The signs of pulmonary hypertension include narrow splitting of the second heart sound, accentuation of the pulmonary component of the second heart sound, and a systolic ejection click. In advanced cases, tricuspid and pulmonary valve insufficiency and signs of right ventricular failure and cor pulmonale are found.

B. Laboratory Findings

Polycythemia is found in many cases of pulmonary hypertension that are associated with chronic hypoxemia. Electrocardiographic changes are those of right axis deviation, right ventricular hypertrophy, right ventricular strain, or right atrial enlargement.

C. Imaging and Special Examinations

Radiographs and high-resolution CT scans of the chest can assist in the diagnosis of pulmonary hypertension and determination of the cause. In chronic

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disease, dilation of the right and left main and lobar pulmonary arteries and enlargement of the pulmonary outflow tract are seen; in advanced disease, right ventricular and right atrial enlargement are seen. Peripheral “pruning” of large pulmonary arteries is characteristic of pulmonary hypertension in severe emphysema.

Echocardiography is helpful in evaluating patients thought to have mitral stenosis, left atrial myxoma, and pulmonary valvular disease and may also reveal right ventricular enlargement and paradoxical motion of the interventricular septum. Doppler ultrasonography is a reliable noninvasive means of estimating pulmonary artery systolic pressure. However, precise hemodynamic measurements can only be obtained with right heart catheterization, which is helpful when postcapillary pulmonary hypertension, intracardiac shunting, or thromboembolic disease is considered as part of the differential diagnosis.

The diagnosis of pulmonary hypertension cannot be made on routine pulmonary function tests. Some results may help identify the cause; eg, diminution of the pulmonary capillary bed may cause reduction in the single breath diffusing capacity.

The following studies may be useful to exclude causes of secondary pulmonary hypertension: liver function tests, HIV test, collagen-vascular serologic studies, polysomnography, [V with dot above]/[Q with dot above] lung scanning, pulmonary angiography, and surgical lung biopsy. [V with dot above]/[Q with dot above] lung scanning is very helpful in identifying patients with pulmonary hypertension caused by recurrent pulmonary thromboemboli, a condition that is often difficult to recognize clinically.

Treatment

Treatment of primary pulmonary hypertension is discussed in Chapter 10. Treatment of secondary pulmonary hypertension consists mainly of treating the underlying disorder. Early recognition of pulmonary hypertension is crucial to interrupt the self-perpetuating cycle responsible for rapid clinical progression. By the time most patients present with signs and symptoms of pulmonary hypertension, however, the condition is far advanced. If hypoxemia or acidosis is detected, corrective measures should be started immediately. Supplemental oxygen administered for at least 15 hours per day has been demonstrated to slow the progression of pulmonary hypertension in patients with hypoxemic COPD.

Permanent anticoagulation is indicated in primary pulmonary hypertension but should be given only to those patients with secondary pulmonary hypertension at high risk for thromboembolism. Vasodilator therapy using various pharmacologic agents (eg, calcium antagonists, hydralazine, isoproterenol, diazoxide, nitroglycerin) has shown disappointing results in secondary pulmonary hypertension. Patients most likely to benefit from long-term pulmonary vasodilator therapy are those who respond favorably to a vasodilator challenge at right heart catheterization. It is clear that long-term oral vasodilator therapy should be used only if hemodynamic benefit is documented. Complications of pulmonary vasodilator therapy include systemic hypotension, hypoxemia, and even death.

Continuous long-term intravenous infusion (using a portable pump) of prostacyclin (PGI2; epoprostenol), a potent pulmonary vasodilator, has been shown to confer hemodynamic and symptomatic benefits in selected patients with primary or secondary pulmonary hypertension. This is the first therapy to demonstrate improved survival of patients with primary pulmonary hypertension. Limitations of continuous infusion prostacyclin are difficulties in titration, technical problems with portable delivery systems, and the high cost of the drug. Newer agents in research trials include subcutaneous (treprostinil), inhaled (iloprost), and oral (beraprost) prostacyclin analogues, endothelin receptor antagonists (bosentan), and phosphodiesterase inhibitors (sildenafil).

Patients with marked polycythemia (hematocrit > 60%) should undergo repeated phlebotomy in an attempt to reduce blood viscosity. Cor pulmonale complicating pulmonary hypertension is treated by managing the underlying pulmonary disease and by using diuretics, salt restriction and, in appropriate patients, supplemental oxygen. The use of digitalis in cor pulmonale remains controversial. Pulmonary thromboendarterectomy may benefit selected patients with pulmonary hypertension secondary to chronic thrombotic obstruction of major pulmonary arteries.

Single or double lung transplantation may be performed on patients with end-stage primary pulmonary hypertension. The 2-year survival rate is 50%.

Prognosis

The prognosis in secondary pulmonary hypertension depends on the course of the underlying disease. Patients with pulmonary hypertension due to fixed obliteration of the pulmonary vascular bed generally respond poorly to therapy; development of cor pulmonale in these cases implies a poor prognosis. The prognosis is favorable when pulmonary hypertension is detected early and the conditions leading to it are readily reversed.

Doyle RL et al: American College of Chest Physicians. Surgical treatments/interventions for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004;126(1 Suppl):63S.

Farber HW et al: Pulmonary arterial hypertension. N Engl J Med 2004;351:1655.

Pengo V et al: Thromboembolic Pulmonary Hypertension Study Group. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004;350:2257.

Rubin LJ et al: Evaluation and management of the patient with pulmonary arterial hypertension. Ann Intern Med 2005; 143:282.

Wright JL et al: Pulmonary hypertension in chronic obstructive pulmonary disease: current theories of pathogenesis and their implications for treatment. Thorax 2005;60: 605.

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Pulmonary Vasculitis

Wegener's granulomatosis is an idiopathic disease manifested by a combination of glomerulonephritis, necrotizing granulomatous vasculitis of the upper and lower respiratory tracts, and varying degrees of small vessel vasculitis. Chronic sinusitis, arthralgias, fever, skin rash, and weight loss are frequent presenting symptoms. Specific pulmonary complaints occur less often. The most common sign of lung disease is nodular pulmonary infiltrates, often with cavitation, seen on chest radiography. Tracheal stenosis and endobronchial disease are sometimes seen. The diagnosis is most often based on serologic testing and biopsy of lung, sinus tissue, or kidney with demonstration of necrotizing granulomatous vasculitis. See Chapter 20.

Allergic angiitis and granulomatosis (Churg-Strauss syndrome) is an idiopathic multisystem vasculitis of small and medium-sized arteries that occurs in patients with asthma. Histologic features include fibrinoid necrotizing epithelioid and eosinophilic granulomas. The skin and lungs are most often involved, but other organs, including the heart, gastrointestinal tract, liver, and peripheral nerves, may also be affected. Marked peripheral eosinophilia is the rule. Abnormalities on chest radiographs range from transient infiltrates to multiple nodules. This illness may be part of a spectrum that includes polyarteritis nodosa.

Treatment of pulmonary vasculitis consists of combination therapy with corticosteroids and cyclophosphamide. Oral prednisone (1 mg/kg ideal body weight per day initially, tapering slowly to alternate-day therapy over 3–6 months) is the corticosteroid of choice; in Wegener's granulomatosis, some clinicians may omit the use of corticosteroids. For fulminant vasculitis, therapy may be initiated with intravenous methylprednisolone (up to 1 g intravenously per day) for several days. Cyclophosphamide (1–2 mg/kg ideal body weight per day initially, with dosage adjustments to avoid neutropenia) is given daily by mouth for at least 1 year after complete remission is obtained and then is slowly tapered.

Five-year survival rates in patients with these vasculitis syndromes have been improved by the combination therapy. Complete remissions can be achieved in over 90% of patients with Wegener's granulomatosis. The addition of trimethoprim-sulfamethoxazole (one double-strength tablet by mouth twice daily) to standard therapy may help prevent relapses, but its role as sole therapy or as part of combination therapy in patients with active disease remains uncertain.

Langford CA: Update on Wegener granulomatosis. Cleve Clin J Med 2005;72:689.

Noth I et al: Churg-Strauss syndrome. Lancet 2003;361:587.

Seo P et al: The antineutrophil cytoplasmic antibody-associated vasculitides. Am J Med 2004;117:39.

Alveolar Hemorrhage Syndromes

Diffuse alveolar hemorrhage may occur in a variety of immune and nonimmune disorders. Hemoptysis, alveolar infiltrates on chest radiograph, anemia, dyspnea, and occasionally fever are characteristic. Rapid clearing of diffuse lung infiltrates within 2 days is a clue to the diagnosis of diffuse alveolar hemorrhage. Pulmonary hemorrhage can be associated with an increased DLCO.

Causes of immune alveolar hemorrhage have been classified as anti-basement membrane antibody disease (Goodpasture's syndrome), vasculitis and collagen vascular disease (systemic lupus erythematosus, Wegener's granulomatosis, systemic necrotizing vasculitis, and others), and pulmonary capillaritis associated with idiopathic rapidly progressive glomerulonephritis. Nonimmune causes of diffuse hemorrhage include coagulopathy, mitral stenosis, necrotizing pulmonary infection, drugs (penicillamine), toxins (trimellitic anhydride), and idiopathic pulmonary hemosiderosis.

Goodpasture's syndrome is idiopathic recurrent alveolar hemorrhage and rapidly progressive glomerulonephritis. The disease is mediated by anti-glomerular basement membrane antibodies. Goodpasture's syndrome occurs mainly in men who are in their 30s and 40s. Hemoptysis is the usual presenting symptom, but pulmonary hemorrhage may be occult. Dyspnea, cough, hypoxemia, and diffuse bilateral alveolar infiltrates are typical features. Iron deficiency anemia and microscopic hematuria are usually present. The diagnosis is based on characteristic linear IgG deposits in glomeruli or alveoli by immunofluorescence and on the presence of anti-glomerular basement membrane antibody in serum. Combinations of immunosuppressive drugs (initially methylprednisolone, 30 mg/kg intravenously over 20 minutes every other day for three doses, followed by daily oral prednisone, 1 mg/kg/d; with cyclophosphamide, 2 mg/kg by mouth per day) and plasmapheresis have yielded excellent results.

Idiopathic pulmonary hemosiderosis is a disease of children or young adults characterized by recurrent pulmonary hemorrhage; in contrast to Goodpasture's syndrome, renal involvement and anti-glomerular basement membrane antibodies are absent, but iron deficiency is typical. Treatment of acute episodes of hemorrhage with corticosteroids may be useful. Recurrent episodes of pulmonary hemorrhage may result in interstitial fibrosis and pulmonary failure.

Collard HR et al: Diffuse alveolar hemorrhage. Clin Chest Med 2004;25:583.

Environmental & Occupational Lung Disorders

Smoke Inhalation

The inhalation of products of combustion may cause serious respiratory complications. As many as one-third

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of patients admitted to burn treatment units have pulmonary injury from smoke inhalation. Morbidity and mortality due to smoke inhalation exceed those attributed to the burns themselves. The death rate of patients with both severe burns and smoke inhalation exceeds 50%.

All patients suspected of having significant smoke inhalation must be assessed for three consequences of smoke inhalation: impaired tissue oxygenation, thermal injury to the upper airway, and chemical injury to the lung. Impaired tissue oxygenation results from inhalation of carbon monoxide or cyanide and is an immediate threat to life. The management of patients with carbon monoxide and cyanide poisoning is discussed in Chapter 39. The clinician must recognize that patients with carbon monoxide poisoning display a normal partial pressure of oxygen in arterial blood (PaO2) but have a low measured (ie, not oximetric) hemoglobin saturation (SaO2). Immediate treatment with 100% oxygen is essential and should be continued until the measured carboxyhemoglobin level falls to less than 10% and concomitant metabolic acidosis has resolved.

Thermal injury to the mucosal surfaces of the upper airway occurs from inhalation of hot gases. Complications become evident by 18–24 hours. These include edema, impaired ability to clear oral secretions, and upper airway obstruction, producing inspiratory stridor. Respiratory failure occurs in severe cases. Early management (see also Chapter 38) includes the use of a high-humidity face mask with supplemental oxygen, gentle suctioning to evacuate oral secretions, elevation of the head 30 degrees to promote clearing of secretions, and topical epinephrine to reduce edema of the oropharyngeal mucous membrane. Helium-oxygen gas mixtures (Heliox) may reduce labored breathing due to upper airway narrowing. Close monitoring with arterial blood gases and later with oximetry is important. Examination of the upper airway with a fiberoptic laryngoscope or bronchoscope is superior to routine physical examination. Endotracheal intubation is often necessary to establish airway patency and is likely to be necessary in patients with deep facial burns or oropharyngeal or laryngeal edema. Tracheotomy should be avoided if possible because of an increased risk of pneumonia and death from sepsis.

Chemical injury to the lung results from inhalation of toxic gases and products of combustion, including aldehydes and organic acids. The site of lung injury depends on the solubility of the gases inhaled, the duration of exposure, and the size of inhaled particles that transport noxious gases to distal lung units. Bronchorrhea and bronchospasm are seen early after exposure along with dyspnea, tachypnea, and tachycardia. Labored breathing and cyanosis may follow. Physical examination at this stage reveals diffuse wheezing and rhonchi. Bronchiolar and alveolar edema (eg, ARDS) may develop within 1–2 days after exposure. Sloughing of the bronchiolar mucosa may occur within 2–3 days, leading to airway obstruction, atelectasis, and worsening hypoxemia. Bacterial colonization and pneumonia are common by 5–7 days after the exposure.

Treatment of smoke inhalation consists of supplemental oxygen, bronchodilators, suctioning of mucosal debris and mucopurulent secretions via an indwelling endotracheal tube, chest physical therapy to aid clearance of secretions, and adequate humidification of inspired gases. Positive end-expiratory pressure (PEEP) has been advocated to treat bronchiolar edema. Judicious fluid management and close monitoring for secondary bacterial infection with daily sputum Gram stains round out the management protocol.

The routine use of corticosteroids for chemical lung injury from smoke inhalation has been shown to be ineffective and may even be harmful. Routine or prophylactic use of antibiotics is not recommended.

Patients who survive should be watched for the late development of bronchiolitis obliterans.

Miller K et al: Acute inhalation injury. Emerg Med Clin North Am 2003;21:533.

Sheridan R: Specific therapies for inhalation injury. Crit Care Med 2002;30:718.

Pulmonary Aspiration Syndromes

Aspiration of foreign material into the tracheobronchial tree results from various disorders that impair normal deglutition, especially disturbances of consciousness and esophageal dysfunction.

Aspiration of Inert Material

Aspiration of inert material may cause asphyxia if the amount aspirated is massive and if cough is impaired, in which case immediate tracheobronchial suctioning is necessary. Most patients suffer no serious sequelae from aspiration of inert material.

Aspiration of Toxic Material

Aspiration of toxic material into the lung usually results in clinically evident pneumonia. Hydrocarbon pneumonitis is caused by aspiration of ingested petroleum distillates, eg, gasoline, kerosene, furniture polish, and other household petroleum products. Lung injury results mainly from vomiting and secondary aspiration. Therapy is supportive. The lung should be protected from repeated aspiration with a cuffed endotracheal tube if necessary. Lipoid pneumonia is a chronic syndrome related to the repeated aspiration of oily materials, eg, mineral oil, cod liver oil, and oily nose drops; it often occurs in elderly patients with impaired swallowing. Patchy infiltrates in dependent lung zones and lipid-laden macrophages in expectorated sputum are characteristic findings.

“Café Coronary”

Acute obstruction of the upper airway by food is associated with difficulty in swallowing, old age, dental

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problems that impair chewing, and use of alcohol and sedative drugs. The Heimlich procedure is lifesaving in many cases.

Retention of an Aspirated Foreign Body

Retention of an aspirated foreign body in the tracheobronchial tree may produce both acute and chronic conditions, including recurrent pneumonia, bronchiectasis, lung abscess, atelectasis, and postobstructive hyperinflation. Occasionally, a misdiagnosis of asthma, COPD, or lung cancer is made in adult patients who have aspirated a foreign body. The plain chest radiograph usually suggests the site of the foreign body. In some cases, an expiratory film, demonstrating regional hyperinflation due to a check-valve effect, is helpful. Bronchoscopy is usually necessary to establish the diagnosis and attempt removal of the foreign body.

Baharloo F et al: Tracheobronchial foreign bodies: presentation and management in children and adults. Chest 1999;115: 1357.

Chronic Aspiration of Gastric Contents

Chronic aspiration of gastric contents may result from primary disorders of the larynx or the esophagus, such as achalasia, esophageal stricture, systemic sclerosis (scleroderma), esophageal carcinoma, esophagitis, and gastroesophageal reflux. In the last condition, relaxation of the tone of the lower esophageal sphincter allows reflux of gastric contents into the esophagus and predisposes to chronic pulmonary aspiration, especially at night. Cigarette smoking, consumption of alcohol, and use of theophylline are known to relax the lower esophageal sphincter. Pulmonary disorders linked to gastroesophageal reflux and chronic aspiration include bronchial asthma, pulmonary fibrosis, and bronchiectasis. Even in the absence of aspiration, acid in the esophagus may trigger bronchospasm through reflex mechanisms.

The diagnosis of chronic aspiration is difficult. Ambulatory monitoring of esophageal pH for 24 hours detects esophageal reflux. Esophagogastroscopy and barium swallow are sometimes necessary to rule out esophageal disease. Management consists of elevation of the head of the bed, cessation of smoking, weight reduction, and antacids, H2-receptor antagonists (eg, cimetidine, 300–400 mg), or proton pump inhibitors (eg, omeprazole, 20 mg) at night. Metoclopramide (10–15 mg orally four times daily or 20 mg at bedtime) or bethanechol (10–25 mg at bedtime) may also be helpful in some patients with gastroesophageal reflux.

Acute Aspiration of Gastric Contents (Mendelson's Syndrome)

Acute aspiration of gastric contents is often catastrophic. The pulmonary response depends on the characteristics and amount of the gastric contents aspirated. The more acidic the material, the greater the degree of chemical pneumonitis. Aspiration of pure gastric acid (pH < 2.5) causes extensive desquamation of the bronchial epithelium, bronchiolitis, hemorrhage, and pulmonary edema. Acute gastric aspiration is one of the most common causes of ARDS. The clinical picture is one of abrupt onset of respiratory distress, with cough, wheezing, fever, and tachypnea. Crackles are audible at the bases of the lungs. Hypoxemia may be noted immediately after aspiration occurs. Radiographic abnormalities, consisting of patchy alveolar infiltrates in dependent lung zones, appear within a few hours. If particulate food matter has been aspirated along with gastric acid, radiographic features of bronchial obstruction may be observed. Fever and leukocytosis are common even in the absence of superinfection.

Treatment of acute aspiration of gastric contents consists of supplemental oxygen, measures to maintain the airway, and the usual measures for treatment of acute respiratory failure. There is no evidence to support the routine use of corticosteroids or prophylactic antibiotics after gastric aspiration has occurred. Secondary pulmonary infection, which occurs in about one-fourth of patients, typically appears 2–3 days after aspiration. Management of this complication depends on the observed flora of the tracheobronchial tree. Hypotension secondary to alveolocapillary membrane injury and intravascular volume depletion is common and is managed with the judicious administration of intravenous fluids.

Marik PE: Aspiration pneumonitis and aspiration pneumonia. N Engl J Med 2001;344:665.

Occupational Pulmonary Diseases

Many acute and chronic pulmonary diseases are directly related to inhalation of noxious substances encountered in the workplace. Disorders that are due to chemical agents may be classified as follows: (1) pneumoconioses, (2) hypersensitivity pneumonitis, (3) obstructive airway disorders, (4) toxic lung injury, (5) lung cancer, (6) pleural diseases, and (7) miscellaneous disorders.

Pneumoconioses

Pneumoconioses are chronic fibrotic lung diseases caused by the inhalation of coal dust and various other inert, inorganic, or silicate dusts (Table 9-26). Pneumoconioses due to inhalation of inert dusts may be asymptomatic disorders with diffuse nodular infiltrates on chest radiograph. Clinically important pneumoconioses include coal workers' pneumoconiosis, silicosis, and asbestosis. Treatment for each is supportive.

A. Coal Worker's Pneumoconiosis

In coal worker's pneumoconiosis, ingestion of inhaled coal dust by alveolar macrophages leads to the formation

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of coal macules, usually 2–5 mm in diameter, which appear on chest radiograph as diffuse small opacities that are especially prominent in the upper lung. Simple coal worker's pneumoconiosis is usually asymptomatic; pulmonary function abnormalities are unimpressive. Cigarette smoking does not increase the prevalence of coal worker's pneumoconiosis but may have an additive detrimental effect on ventilatory function. In complicated coal worker's pneumoconiosis (“progressive massive fibrosis”), conglomeration and contraction in the upper lung zones occur, with radiographic features resembling complicated silicosis. Caplan's syndrome is a rare condition characterized by the presence of necrobiotic rheumatoid nodules (1–5 cm in diameter) in the periphery of the lung in coal workers with rheumatoid arthritis.

Table 9-26. Selected pneumoconioses.

Disease Agent Occupations
Metal dusts
   Siderosis Metallic iron or iron oxide Mining, welding, foundry work
   Stannosis Tin, tin oxide Mining, tin-working, smelting
   Baritosis Barium salts Glass and insecticide manufacturing
Coal dust
   Coal worker's pneumoconiosis Coal dust Coal mining
Inorganic dusts
   Silicosis Free silica (silicon dioxide) Rock mining, quarrying, stone cutting, tunneling, sandblasting, pottery, diatomaceous earth
Silicate dusts
   Asbestosis Asbestos Mining, insulation, construction, shipbuilding
   Talcosis Magnesium silicate Mining, insulation, construction, shipbuilding
   Kaolin pneumoconiosis Sand, mica, aluminum silicate Mining of china clay; pottery and cement work
   Shaver's disease Aluminum powder Manufacture of corundum

B. Silicosis

In silicosis, extensive or prolonged inhalation of free silica (silicon dioxide) particles in the respirable range (0.3–5 mcm) causes the formation of small rounded opacities (silicotic nodules) throughout the lung. Calcification of the periphery of hilar lymph nodes (“eggshell” calcification) is an unusual radiographic finding that strongly suggests silicosis. Simple silicosis is usually asymptomatic and has no effect on routine pulmonary function tests; in complicated silicosis, large conglomerate densities appear in the upper lung and are accompanied by dyspnea and obstructive and restrictive pulmonary dysfunction. The incidence of pulmonary tuberculosis is increased in patients with silicosis. All patients with silicosis should have a tuberculin skin test and a current chest radiograph. If old, healed pulmonary tuberculosis is suspected, multidrug treatment for tuberculosis (not single-agent preventive therapy) should be instituted.

C. Asbestosis

Asbestosis is a nodular interstitial fibrosis occurring in workers exposed to asbestos fibers (shipyard and construction workers, pipefitters, insulators) over many years (typically 10–20 years). Patients with asbestosis usually seek medical attention at least 15 years after exposure with the following symptoms and signs: progressive dyspnea, inspiratory crackles, and in some cases, clubbing and cyanosis. The radiographic features of asbestosis include linear streaking at the lung bases, opacities of various shapes and sizes, and honeycomb changes in advanced cases. The presence of pleural calcifications may be a clue to diagnosis. High-resolution CT scanning is the best imaging method for asbestosis because of its ability to detect parenchymal fibrosis and define the presence of coexisting pleural plaques. Cigarette smoking in asbestos workers increases the prevalence of radiographic pleural and parenchymal changes and markedly increases the incidence of lung carcinoma. It may also interfere with the clearance of short asbestos fibers from the lung. Pulmonary function studies show restrictive dysfunction and reduced diffusing capacity. The presence of a ferruginous body in tissue suggests significant asbestos exposure; however, other histologic features must be present for diagnosis. There is no specific treatment.

Cugell DW et al: Asbestos and the pleura: a review. Chest 2004; 125:1103.

Kuschner WG et al: Occupational lung disease. Part 2. Discovering the cause of diffuse parenchymal lung disease. Postgrad Med 2003;113:81.

Scarisbrick D: Silicosis and coal workers' pneumoconiosis. Practitioner 2002;246:114.

Hypersensitivity Pneumonitis

Hypersensitivity pneumonitis (extrinsic allergic alveolitis) is a nonatopic, nonasthmatic allergic pulmonary disease. It is manifested mainly as an occupational disease (Table 9-27), in which exposure to inhaled organic agents leads to acute and eventually chronic pulmonary disease. Acute illness is characterized by sudden onset of malaise, chills, fever, cough, dyspnea, and nausea 4–8 hours after exposure to the offending agent. This may occur after the patient has left work or even at night and

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thus may mimic paroxysmal nocturnal dyspnea. Bibasilar crackles, tachypnea, tachycardia, and (occasionally) cyanosis are noted. Small nodular densities sparing the apices and bases of the lungs are noted on chest radiograph. Pulmonary function studies reveal restrictive dysfunction and reduced diffusing capacity. Laboratory studies reveal an increase in the white blood cell count with a shift to the left, hypoxemia, and the presence of precipitating antibodies to the offending agent in serum. Hypersensitivity pneumonitis antibody panels against common offending antigens are available.

Table 9-27. Selected causes of hypersensitivity pneumonitis.

Disease Antigen Source
Farmer's lung Micropolyspora faeni, Thermoactinomyces vulgaris Moldy hay
“Humidifier” lung Thermophilic actinomycetes Contaminated humidifiers, heating systems, or air conditioners
Bird fancier's lung (“pigeon-breeder's disease”) Avian proteins Bird serum and excreta
Bagassosis Thermoactinomyces sacchari and T vulgaris Moldy sugar cane fiber (bagasse)
Sequoiosis Graphium, aureobasidium, and other fungi Moldy redwood sawdust
Maple bark stripper's disease Cryptostroma (Coniosporium) corticale Rotting maple tree logs or bark
Mushroom picker's disease Same as farmer's lung Moldy compost
Suberosis Penicillium frequentans Moldy cork dust
Detergent worker's lung Bacillus subtilis enzyme Enzyme additives

Acute hypersensitivity pneumonitis is characterized by interstitial infiltrates of lymphocytes and plasma cells, with noncaseating granulomas in the interstitium and air spaces. A subacute hypersensitivity pneumonitis syndrome (15% of cases) has been described that is characterized by the insidious onset of chronic cough and slowly progressive dyspnea, anorexia, and weight loss. Chronic respiratory insufficiency and the appearance of pulmonary fibrosis on radiographs may occur after repeated exposure to the offending agent. Surgical lung biopsy is occasionally necessary for diagnosis. Diffuse fibrosis is the hallmark of the subacute and chronic phases.

Treatment of hypersensitivity pneumonitis consists of identification of the offending agent, avoidance of further exposure, and, in severe acute or protracted cases, oral corticosteroids (prednisone, 0.5 mg/kg daily as a single morning dose, tapered to nil over 4–6 weeks). Change in occupation is often unavoidable.

Jacobs RL et al: Hypersensitivity pneumonitis: beyond classic occupational disease-changing concepts of diagnosis and management. Ann Allergy Asthma Immunol 2005;95:115.

Lacasse Y et al: Clinical diagnosis of hypersensitivity pneumonitis. Am J Respir Crit Care Med 2003;168:952.

Obstructive Airway Disorders

Occupational pulmonary diseases manifested as obstructive airway disorders include occupational asthma, industrial bronchitis, and byssinosis.

A. Occupational Asthma

It has been estimated that from 2% to 5% of all cases of asthma are related to occupation. Offending agents in the workplace are numerous; they include grain dust, wood dust, tobacco, pollens, enzymes, gum arabic, synthetic dyes, isocyanates (particularly toluene diisocyanate), rosin (soldering flux), inorganic chemicals (salts of nickel, platinum, and chromium), trimellitic anhydride, phthalic anhydride, formaldehyde, and various pharmaceutical agents. Diagnosis of occupational asthma depends on a high index of suspicion, an appropriate history, spirometric studies before and after exposure to the offending substance, and peak flow rate measurements in the workplace. Bronchial provocation testing may be helpful in some cases. Treatment consists of avoidance of further exposure to the offending agent and bronchodilators, but symptoms may persist for years after workplace exposure has been terminated.

B. Industrial Bronchitis

Industrial bronchitis is chronic bronchitis found in coal miners and others exposed to cotton, flax, or hemp dust. Chronic disability from industrial bronchitis is infrequent.

C. Byssinosis

Byssinosis is an asthma-like disorder in textile workers caused by inhalation of cotton dust. The pathogenesis is obscure. Chest tightness, cough, and dyspnea are characteristically worse on Mondays or the first day back at work, with symptoms subsiding later in the week. Repeated exposure leads to chronic bronchitis.

Toxic Lung Injury

Toxic lung injury from inhalation of irritant gases is discussed in the section on smoke inhalation. Silo-filler's disease is acute toxic high-permeability pulmonary

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edema caused by inhalation of nitrogen dioxide encountered in recently filled silos. Bronchiolitis obliterans is a common late complication, which may be prevented by early treatment of the acute reaction with corticosteroids. Extensive exposure to silage gas may be fatal.

Lung Cancer

Many industrial pulmonary carcinogens have been identified, including asbestos, radon gas, arsenic, iron, chromium, nickel, coal tar fumes, petroleum oil mists, isopropyl oil, mustard gas, and printing ink. Cigarette smoking acts as a cocarcinogen with asbestos and radon gas to cause bronchogenic carcinoma. Asbestos alone causes malignant mesothelioma. Almost all histologic types of lung cancer have been associated with these carcinogens. Chloromethyl methyl ether specifically causes small cell carcinoma of the lung.

Pleural Diseases

Occupational diseases of the pleura may result from exposure to asbestos (see above) or talc. Inhalation of talc causes pleural plaques that are similar to those caused by asbestos. Benign asbestos pleural effusion occurs in some asbestos workers and may cause chronic blunting of the costophrenic angle on chest radiograph.

Other Occupational Pulmonary Diseases

Occupational agents are also responsible for other pulmonary disorders. These include berylliosis, an acute or chronic pulmonary disorder related to exposure to beryllium, which is absorbed through the lungs or skin and widely disseminated throughout the body. Acute berylliosis is a toxic, ulcerative tracheobronchitis and chemical pneumonitis following intense and severe exposure to beryllium. Chronic berylliosis, a systemic disease closely resembling sarcoidosis, is more common. Chronic pulmonary beryllium disease is thought to be an alveolitis mediated by the proliferation of beryllium-specific helper-inducer T cells in the lung. Exposure to beryllium now occurs in machining and handling of beryllium products and alloys. Beryllium miners are not at risk for berylliosis. Beryllium is no longer used in fluorescent lamp production, which was a source of exposure before 1950.

American Thoracic Society Statement: Occupational contribution to the burden of airway disease. Am J Respir Crit Care Med 2003;167:787.

Glazer CS et al: Occupational interstitial lung disease. Clin Chest Med 2004;25:467.

Kim JS et al: Imaging of nonmalignant occupational lung disease. J Thorac Imaging 2002;17:238.

Mapp CE et al: Occupational asthma. Am J Respir Crit Care Med 2005;172:280.

Singh N et al: Review: occupational and environmental lung disease. Curr Opin Pulm Med 2002;8:117.

Drug-Induced Lung Disease

Typical patterns of pulmonary response to drugs implicated in drug-induced respiratory disease are summarized in Table 9-28. Pulmonary injury due to drugs occurs as a result of allergic reactions, idiosyncratic reactions, overdose, or undesirable side effects. In most patients, the mechanism of pulmonary injury is unknown.

Precise diagnosis of drug-induced pulmonary disease is often difficult, because results of routine laboratory studies are not helpful and radiographic findings

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are not specific. A high index of suspicion and a thorough medical history of drug usage are critical to establishing the diagnosis of drug-induced lung disease. The clinical response to cessation of the suspected offending agent is also helpful. Acute episodes of drug-induced pulmonary disease usually disappear 24–48 hours after the drug has been discontinued, but chronic syndromes may take longer to resolve. Challenge tests to confirm the diagnosis are risky and rarely performed.

Table 9-28. Pulmonary manifestations of selected drug toxicities.

Asthma
   β-Blockers
   Aspirin
   Nonsteroidal anti-inflammatory drugs
   Histamine
   Methacholine
   Acetylcysteine
   Aerosolized pentamidine
   Any nebulized medication
Chronic cough
   Angiotensin-converting enzyme inhibitors
Pulmonary infiltration
   Without eosinophilia
      Amitriptyline
      Azathioprine
      Amiodarone
   With eosinophilia
      Sulfonamides
      L-Tryptophan
      Nitrofurantoin
      Penicillin
      Methotrexate
      Crack cocaine
Drug-induced systemic lupus erythematosus
   Hydralazine
   Procainamide
   Isoniazid
   Chlorpromazine
   Phenytoin
Interstitial pneumonitis/fibrosis
   Nitrofurantoin
   Bleomycin
   Busulfan
   Cyclophosphamide
   Methysergide
   Phenytoin
Pulmonary edema
   Noncardiogenic
      Aspirin
      Chlordiazepoxide
      Cocaine
      Ethchlorvynol
      Heroin
   Cardiogenic
      β-Blockers
Pleural effusion
   Bromocriptine
   Nitrofurantoin
   Any drug inducing systemic lupus erythematosus
   Methysergide
   Chemotherapeutic agents
Mediastinal widening
   Phenytoin
   Corticosteroids
   Methotrexate
Respiratory failure
   Neuromuscular blockade
      Aminoglycosides
      Succinylcholine
      Gallamine
      Dimethyltubocurarine (metocurine)
   Central nervous system depression
      Sedatives
      Hypnotics
      Opioids
      Alcohol
      Tricyclic antidepressants
      Oxygen

Treatment of drug-induced lung disease consists of discontinuing the offending agent immediately and managing the pulmonary symptoms appropriately.

Inhalation of crack cocaine may cause a spectrum of acute pulmonary syndromes, including pulmonary infiltration with eosinophilia, pneumothorax and pneumomediastinum, bronchiolitis obliterans, and acute respiratory failure associated with diffuse alveolar damage and alveolar hemorrhage. Corticosteroids have been used with variable success to treat alveolar hemorrhage.

Babu KS et al: Drug-induced airway diseases. Clin Chest Med 2004;25:113.

Huggins JT et al: Drug-induced pleural disease. Clin Chest Med 2004;25:141.

Radiation Lung Injury

The lung is an exquisitely radiosensitive organ that can be damaged by external beam radiation therapy. The degree of pulmonary injury is determined by the volume of lung irradiated, the dose and rate of exposure, and potentiating factors (eg, concurrent chemotherapy, previous radiation therapy in the same area, and simultaneous withdrawal of corticosteroid therapy). Symptomatic radiation lung injury occurs in about 10% of patients treated for carcinoma of the breast, 5–15% of patients treated for carcinoma of the lung, and 5–35% of patients treated for lymphoma. Two phases of the pulmonary response to radiation are apparent: an acute phase (radiation pneumonitis) and a chronic phase (radiation fibrosis).

Radiation Pneumonitis

Radiation pneumonitis usually occurs 2–3 months (range 1–6 months) after completion of radiotherapy and is characterized by insidious onset of dyspnea, intractable dry cough, chest fullness or pain, weakness, and fever. The pathogenesis of acute radiation pneumonitis is unknown, but there is speculation that hypersensitivity mechanisms are involved. The dominant histopathologic findings are a lymphocytic interstitial pneumonitis progressing to an exudative alveolitis. Inspiratory crackles may be heard in the involved area. In severe disease, respiratory distress and cyanosis occur that are characteristic of ARDS. An increased white blood cell count and elevated sedimentation rate are common. Pulmonary function studies reveal reduced lung volumes, reduced lung compliance, hypoxemia, reduced diffusing capacity, and reduced maximum voluntary ventilation. Chest radiography, which correlates poorly with the presence of symptoms, usually demonstrates an alveolar or nodular infiltrate limited to the irradiated area. Air bronchograms are often observed. Sharp borders of the infiltrate may help distinguish radiation pneumonitis from other conditions such as infectious pneumonia, lymphangitic spread of carcinoma, and recurrent tumor. No specific therapy is proved to be effective in radiation pneumonitis, but prednisone (1 mg/kg/d orally) is commonly given immediately for about 1 week. The dose is then reduced and maintained at 20–40 mg/d for several weeks, then slowly tapered. Radiation pneumonitis may improve in 2–3 weeks following onset of symptoms as the exudative phase resolves. Acute respiratory failure, if present, is treated supportively. Death from ARDS is unusual.

Pulmonary Radiation Fibrosis

Pulmonary radiation fibrosis occurs in nearly all patients who receive a full course of radiation therapy for cancer of the lung or breast. Patients who experience radiation pneumonitis develop pulmonary fibrosis after an intervening period (6–12 months) of well-being. Most patients are asymptomatic, though slowly progressive dyspnea may occur. Radiation fibrosis may occur with or without antecedent radiation pneumonitis. Cor pulmonale and chronic respiratory failure are rare. Radiographic findings include obliteration of normal lung markings, dense interstitial and pleural fibrosis, reduced lung volumes, tenting of the diaphragm, and sharp delineation of the irradiated area. No specific therapy is proved effective, and corticosteroids have no value.

Other Complications of Radiation Therapy

Other complications of radiation therapy directed to the thorax include pericardial effusion, constrictive pericarditis, tracheoesophageal fistula, esophageal candidiasis, radiation dermatitis, and rib fractures. Small pleural effusions, radiation pneumonitis outside the irradiated area, spontaneous pneumothorax, and complete obstruction of central airways are unusual occurrences.

Abratt RP et al: Pulmonary complications of radiation therapy. Clin Chest Med 2004;25:167.

Camus P et al: Interstitial lung disease induced by drugs and radiation. Respiration 2004;71:301.

Pleural Diseases

Pleuritis

Pain due to acute pleural inflammation is caused by irritation of the parietal pleura. Such pain is localized,

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sharp, and fleeting; it is made worse by coughing, sneezing, deep breathing, or movement. When the central portion of the diaphragmatic parietal pleura is irritated, pain may be referred to the ipsilateral shoulder. There are numerous causes of pleuritis. The setting in which pleuritic pain develops helps narrow the differential diagnosis. In young, otherwise healthy individuals, pleuritis is usually caused by viral respiratory infections or pneumonia. The presence of pleural effusion, pleural thickening, or air in the pleural space requires further diagnostic and therapeutic measures. Simple rib fracture may cause severe pleurisy.

Treatment of pleuritis consists of treating the underlying disease. Analgesics and anti-inflammatory drugs (eg, indomethacin, 25 mg orally two or three times daily) are often helpful for pain relief. Codeine (30–60 mg orally every 8 hours) may be used to control cough associated with pleuritic chest pain if retention of airway secretions is not a likely complication. Intercostal nerve blocks are sometimes helpful but the benefit is usually transient.

Pleural Effusion

Essentials of Diagnosis

  • May be asymptomatic; chest pain frequently seen in the setting of pleuritis, trauma, or infection; dyspnea is common with large effusions.

  • Dullness to percussion and decreased breath sounds over the effusion.

  • Radiographic evidence of pleural effusion.

  • Diagnostic findings on thoracentesis.

General Considerations

There is constant movement of fluid from parietal pleural capillaries into the pleural space at a rate of 0.01 mL/kg body weight/h. Absorption of pleural fluid occurs through parietal pleural lymphatics. The resultant homeostasis leaves 5–15 mL of fluid in the normal pleural space. A pleural effusion is an abnormal accumulation of fluid in the pleural space. Pleural effusions may be classified by differential diagnosis (Table 9-29) or by underlying pathophysiology. Five pathophysiologic processes account for most pleural effusions: increased production of fluid in the setting of normal capillaries due to increased hydrostatic or decreased oncotic pressures (transudates); increased production of fluid due to abnormal capillary permeability (exudates); decreased lymphatic clearance of fluid from the pleural space (exudates); infection in the pleural space (empyema); and bleeding into the pleural space (hemothorax).

Diagnostic thoracentesis should be performed whenever there is a new pleural effusion and no clinically apparent cause. Observation is appropriate in some situations (eg, symmetric bilateral pleural effusions in the setting of congestive heart failure), but an atypical presentation or failure of an effusion to resolve as expected warrants thoracentesis. Sampling allows visualization of the fluid in addition to chemical and microbiologic analyses to identify the pathophysiologic processes listed above. A definitive diagnosis is made through positive cytology or identification of a specific causative organism in approximately 25% of cases. In another 50–60% of patients, identification of relevant pathophysiology in the appropriate clinical setting greatly narrows the differential diagnosis and leads to a presumptive diagnosis.

Table 9-29. Causes of pleural fluid transudates and exudates.

Transudates Exudates
Congestive heart failure (≈90% of cases)
Cirrhosis with ascites
Nephrotic syndrome
Peritoneal dialysis
Myxedema
Acute atelectasis
Constrictive pericarditis
Superior vena cava obstruction
Pulmonary embolism
Pneumonia (parapneumonic effusion)
Cancer
Pulmonary embolism
Bacterial infection
Tuberculosis
Connective tissue disease
Viral infection
Fungal infection
Rickettsial infection
Parasitic infection
Asbestos
Meigs' syndrome
Pancreatic disease
Uremia
Chronic atelectasis
Trapped lung
Chylothorax
Sarcoidosis
Drug reaction
Post-myocardial infarction syndrome

Clinical Findings

A. Symptoms and Signs

Patients with pleural effusions most often report dyspnea, cough, or respirophasic chest pain. Symptoms are more common in patients with existing cardiopulmonary disease. Small pleural effusions are less likely to be symptomatic than larger effusions. Physical findings are usually absent in small effusions. Larger effusions may present with dullness to percussion and diminished or absent breath sounds over the effusion. Compressive atelectasis may cause bronchial breath sounds and egophony just above the effusion. A massive effusion with increased intrapleural pressure may

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cause contralateral shift of the trachea and bulging of the intercostal spaces. A pleural friction rub indicates infarction or pleuritis.

B. Laboratory Findings

The gross appearance of pleural fluid helps identify several types of pleural effusion. Grossly purulent fluid signifies empyema, an infection of the pleural space. Milky white pleural fluid should be centrifuged. A clear supernatant above a pellet of white cells indicates empyema, whereas a persistently turbid supernatant suggests a chylous effusion. Analysis of this supernatant reveals chylomicrons and a high triglyceride level (> 100 mg/dL), often from traumatic disruption of the thoracic duct. Hemorrhagic pleural effusion is a mixture of blood and pleural fluid. Ten thousand red cells per milliliter create blood-tinged pleural fluid; 100,000/mL create grossly bloody pleural fluid. Hemothorax is the presence of gross blood in the pleural space, usually following chest trauma or instrumentation. It is defined as a ratio of pleural fluid hematocrit to peripheral blood hematocrit > 0.5.

Pleural fluid samples should be sent for measurement of protein, glucose, and LDH in addition to total and differential white blood cell counts. Chemistry determinations are used to classify effusions as transudates or exudates. This classification is important because the differential diagnosis for each entity is vastly different (Table 9-29). A pleural exudate is an effusion that has one or more of the following laboratory features: (1) ratio of pleural fluid protein to serum protein > 0.5; (2) ratio of pleural fluid LDH to serum LDH > 0.6; (3) pleural fluid LDH greater than two-thirds the upper limit of normal serum LDH.

Transudates have none of these features. Transudates occur in the setting of normal capillary integrity and suggest the absence of local pleural disease. Distinguishing laboratory findings include a glucose equal to serum glucose, pH between 7.40 and 7.55, and fewer than 1000 white blood cells/mcL with a predominance of mononuclear cells. Causes include increased hydrostatic pressure (congestive heart failure accounts for 90% of transudates), decreased oncotic pressure (hypoalbuminemia, cirrhosis), and greater negative pleural pressure (acute atelectasis). Exudates form as a result of pleural disease associated with increased capillary permeability or reduced lymphatic drainage. Bacterial pneumonia and cancer are the most common causes of exudative effusion, but there are many other causes with characteristic laboratory findings. These findings are summarized in Table 9-30.

Pleural fluid pH is useful in the assessment of parapneumonic effusions. A pH below 7.30 suggests the need for drainage of the pleural space. An elevated amylase level in pleural fluid suggests pancreatitis, pancreatic pseudocyst, adenocarcinoma of the lung or pancreas, or esophageal rupture.

Thoracentesis with culture and pleural biopsy is indicated in suspected tuberculous pleural effusion. Pleural fluid culture is 44% sensitive, and the combination of closed pleural biopsy with culture and histologic examination for granulomas is 70–90% sensitive for the diagnosis of pleural tuberculosis.

Pleural fluid specimens should be sent for cytologic examination in all cases of exudative effusions in patients suspected of harboring an underlying malignancy. The diagnostic yield depends on the nature and extent of the underlying malignancy. Sensitivity is between 50% and 65%. A negative cytologic examination in a patient with a high prior probability of malignancy should be followed by one repeat thoracentesis. If that examination is negative, thoracoscopy (by a pulmonologist or by VATS) is preferred to closed pleural biopsy. The sensitivity of thoracoscopy is 92–96%.

C. Imaging

The lung is less dense than water and floats on pleural fluid that accumulates in dependent regions. Subpulmonary fluid may appear as lateral displacement of the apex of the diaphragm with an abrupt slope to the costophrenic sulcus or a greater than 2-cm separation between the gastric air bubble and the lung. On a standard upright chest radiograph, approximately 75–100 mL of pleural fluid must accumulate in the posterior costophrenic sulcus to be visible on the lateral view, and 175–200 mL must be present in the lateral costophrenic sulcus to be visible on the frontal view. Chest CT scans may identify as little as 10 mL of fluid. At least 1 cm of fluid on the decubitus view is necessary to permit blind thoracentesis. Ultrasonography is useful to guide thoracentesis in the setting of smaller effusions.

Pleural fluid may become trapped (loculated) by pleural adhesions, thereby forming unusual collections along the lateral chest wall or within lung fissures. Round or oval fluid collections in fissures that resemble intraparenchymal masses are called pseudotumors. Massive pleural effusion causing opacification of an entire hemithorax is most commonly caused by cancer but may be seen in tuberculosis and other diseases.

Treatment

A. Transudative Pleural Effusion

Transudative pleural effusions characteristically occur in the absence of pleural disease. Treatment is directed at the underlying condition. Therapeutic thoracentesis for severe dyspnea typically offers only transient benefit. Pleurodesis and tube thoracostomy are rarely indicated.

B. Malignant Pleural Effusion

Approximately 15% of patients dying of cancer are reported to have malignant pleural effusions. Almost any form of cancer may cause effusions, but the most common causes are lung cancer (one-third of cases) and breast cancer. In 5–10% of malignant pleural effusions, no primary tumor is identified.

Between 40% and 80% of exudative pleural effusions are malignant, while over 90% of malignant pleural effusions are exudative. The most common mechanisms

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contributing to the formation of malignant effusions include direct tumor involvement of the pleura, local inflammation in response to tumor spread, and impairment or disruption of lymphatics. The term “paramalignant pleural effusion” refers to an effusion in a patient with cancer when repeated attempts to identify tumor cells in the pleura or pleural fluid are nondiagnostic but when there is a presumptive relation to the underlying malignancy. For example, superior vena cava syndrome with elevated systemic venous pressures causing a transudative effusion would be “paramalignant.”

Table 9-30. Characteristics of important exudative pleural effusions.

Etiology or Type of Effusion Gross Appearance White Blood Cell Count (cells/mcL) Red Blood Cell Count (cells/mcL) Glucose Comments
Malignant effusion Turbid to bloody; occasionally serous 1000 to < 100,000 M 100 to several hundred thousand Equal to serum levels; < 60 mg/dL in 15% of cases Eosinophilia uncommon; positive results on cytologic examination
Uncomplicated parapneumonic effusion Clear to turbid 5000-25,000 P < 5000 Equal to serum levels Tube thoracostomy unnecessary
Empyema Turbid to purulent 25,000-100,000 P < 5000 Less than serum levels; often very low Drainage necessary; putrid odor suggests anaerobic infection
Tuberculosis Serous to serosanguineous 5000-10,000 M < 10,000 Equal to serum levels; occasionally < 60 mg/dL Protein > 4.0 g/dL and may exceed 5 g/dL; eosinophils (> 10%) or mesothelial cells (> 5%) make diagnosis unlikely
Rheumatoid effusion Turbid; greenish yellow 1000-20,000 M or P < 1000 < 40 mg/dL Secondary empyema common; high LDH, low complement, high rheumatoid factor, cholesterol crystals are characteristic
Pulmonary infarction Serous to grossly bloody 1000-50,000 M or P 100 to > 100,000 Equal to serum levels Variable findings; no pathognomonic features
Esophageal rupture Turbid to purulent; red-brown < 5000 to > 50,000 P 1000-10,000 Usually low High amylase level (salivary origin); pneumothorax in 25% of cases; effusion usually on left side; pH < 6.0 strongly suggests diagnosis
Pancreatitis Turbid to sero-sanguineous 1000-50,000 P 1000-10,000 Equal to serum levels Usually left-sided; high amylase level
Key: M = mononuclear cell predominance; P = polymorphonuclear leukocyte predominance; LDH = lactate dehydrogenase.

Most patients with malignant effusions have advanced disease and multiple symptoms. Dyspnea occurs in over half of patients with malignant pleural effusions. The cause of dyspnea is probably related to mechanical distortion of the lung and chest wall. Hypoxemia from intrapulmonary shunting and [V with dot above]/[Q with dot above] mismatching is common and may be severe. Treatment may be systemic, with therapy for the underlying malignancy; or local, to address specific symptoms related to the effusion itself. Local treatment usually involves drainage through repeated thoracentesis or placement of a chest tube. Pleurodesis is a procedure by which an irritant is placed into the pleural space following chest tube drainage and lung reexpansion. The goal is to form fibrous adhesions between the visceral and parietal pleura, resulting in obliteration of the pleural space to prevent or significantly reduce reaccumulation of pleural fluid. Multiple agents have been used for pleurodesis, but the two in most common use are doxycycline (500 mg in 50–100 mL saline) and sterile, asbestos-free talc (by poudrage at thoracoscopy using 5 g or instillation of talc slurry through a chest tube using 4–5 g in 50 mL saline). Doxycycline and talc are associated with a 70–75% and a 90% success rate, respectively. Major side effects are pain and fever, which appear to be less common with talc. Pain associated with pleurodesis can be extreme. Patients should be

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premedicated with an anxiolytic-amnestic agent in addition to opioid analgesics.

C. Parapneumonic Pleural Effusion

Parapneumonic pleural effusions are exudates that accompany approximately 40% of bacterial pneumonias. They are divided into three categories: simple or uncomplicated, complicated, and empyema. Uncomplicated parapneumonic effusions are free-flowing sterile exudates of modest size that resolve quickly with antibiotic treatment of pneumonia. They do not need drainage. Empyema is gross infection of the pleural space indicated by positive Gram stain or culture. Empyema should always be drained by tube thoracostomy to facilitate clearance of infection and to reduce the probability of fibrous encasement of the lung, causing permanent pulmonary impairment.

Complicated parapneumonic effusions present the most difficult management decisions. They tend to be larger than simple parapneumonic effusions and to show more evidence of inflammatory stimuli such as low glucose level, low pH, or evidence of loculation. Inflammation probably reflects ongoing bacterial invasion of the pleural space despite rare positive bacterial cultures. The morbidity associated with complicated effusions is due to their tendency to form a fibropurulent pleural “peel,” trapping otherwise functional lung and leading to permanent impairment. Tube thoracostomy is indicated when pleural fluid glucose is < 60 mg/dL or the pH is < 7.2. These thresholds have not been prospectively validated and should not be interpreted strictly. The clinician should consider drainage of a complicated effusion if the pleural fluid pH is between 7.2 and 7.3 or the LDH is > 1000 units/mL. Pleural fluid cell count and protein have little diagnostic value in this setting.

Tube thoracostomy drainage of empyema or parapneumonic effusions is frequently complicated by loculation that prevents adequate drainage. Intrapleural injection of fibrinolytic agents (streptokinase, 250,000 units, or urokinase, 100,000 units, in 50–100 mL of normal saline once or twice daily) has been reported to improve drainage, shorten hospitalization, and reduce the need for surgery. Reported success rates in small studies are between 70% and 90%.

D. Hemothorax

A small-volume hemothorax that is stable or improving on chest radiographs may be managed by close observation. In all other cases, hemothorax is treated by immediate insertion of a large-bore thoracostomy tube to (1) drain existing blood and clot, (2) quantify the amount of bleeding, (3) reduce the risk of fibrothorax, and (4) permit apposition of the pleural surfaces in an attempt to reduce hemorrhage. Thoracotomy may be indicated to control hemorrhage, remove clot, and treat complications such as bronchopleural fistula formation.

Colice GL et al: Medical and surgical treatment of parapneumonic effusions: an evidence-based guideline. Chest 2000; 118:1158.

Shaw P et al: Pleurodesis for malignant pleural effusions. Cochrane Database Syst Rev 2004;(1):CD002916.

Yataco JC et al: Pleural effusions: evaluation and management. Cleve Clin J Med 2005;72:854.

Spontaneous Pneumothorax

Essentials of Diagnosis

  • Acute onset of unilateral chest pain and dyspnea.

  • Minimal physical findings in mild cases; unilateral chest expansion, decreased tactile fremitus, hyperresonance, diminished breath sounds, mediastinal shift, cyanosis and hypotension in tension pneumothorax.

  • Presence of pleural air on chest radiograph.

General Considerations

Pneumothorax, or accumulation of air in the pleural space, is classified as spontaneous (primary or secondary) or traumatic. Primary spontaneous pneumothorax occurs in the absence of an underlying lung disease, whereas secondary spontaneous pneumothorax is a complication of preexisting pulmonary disease. Traumatic pneumothorax results from penetrating or blunt trauma. Iatrogenic pneumothorax may follow procedures such as thoracentesis, pleural biopsy, subclavian or internal jugular vein catheter placement, percutaneous lung biopsy, bronchoscopy with transbronchial biopsy, and positive-pressure mechanical ventilation. Tension pneumothorax usually occurs in the setting of penetrating trauma, lung infection, cardiopulmonary resuscitation, or positive-pressure mechanical ventilation. In tension pneumothorax, the pressure of air in the pleural space exceeds ambient pressure throughout the respiratory cycle. A check-valve mechanism allows air to enter the pleural space on inspiration and prevents egress of air on expiration.

Primary pneumothorax affects mainly tall, thin boys and men between the ages of 10 and 30 years. It is thought to occur from rupture of subpleural apical blebs in response to high negative intrapleural pressures. Family history and cigarette smoking may also be important factors.

Secondary pneumothorax occurs as a complication of COPD, asthma, cystic fibrosis, tuberculosis, Pneumocystis pneumonia, menstruation (catamenial pneumothorax), and a wide variety of interstitial lung diseases including sarcoidosis, lymphangioleiomyomatosis, Langerhans cell histiocytosis, and tuberous sclerosis. Aerosolized pentamidine and a prior history of Pneumocystis pneumonia are considered risk factors for the development of pneumothorax. One-half of patients with pneumothorax in the setting of recurrent Pneumocystis pneumonia will develop

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pneumothorax on the contralateral side. The mortality rate of pneumothorax in Pneumocystis pneumonia is high.

Clinical Findings

A. Symptoms and Signs

Chest pain ranging from minimal to severe on the affected side and dyspnea occur in nearly all patients. Symptoms usually begin during rest and usually resolve within 24 hours even if the pneumothorax persists. Alternatively, pneumothorax may present with life-threatening respiratory failure if underlying COPD or asthma is present.

If pneumothorax is small (less than 15% of a hemithorax), physical findings, other than mild tachycardia, are unimpressive. If pneumothorax is large, diminished breath sounds, decreased tactile fremitus, and decreased movement of the chest are often noted. Tension pneumothorax should be suspected in the presence of marked tachycardia, hypotension, and mediastinal or tracheal shift.

B. Laboratory Findings

Arterial blood gas analysis is often unnecessary but reveals hypoxemia and acute respiratory alkalosis in most patients. Left-sided primary pneumothorax may produce QRS axis and precordial T wave changes on the ECG that may be misinterpreted as acute myocardial infarction.

C. Imaging

Demonstration of a visceral pleural line on chest radiograph is diagnostic and may only be seen on an expiratory film. A few patients have secondary pleural effusion that demonstrates a characteristic air-fluid level on chest radiography. In supine patients, pneumothorax on a conventional chest radiograph may appear as an abnormally radiolucent costophrenic sulcus (the “deep sulcus” sign). In patients with tension pneumothorax, chest radiographs show a large amount of air in the affected hemithorax and contralateral shift of the mediastinum.

Differential Diagnosis

If the patient is a young, tall, thin, cigarette-smoking man, the diagnosis of primary spontaneous pneumothorax is usually obvious and can be confirmed by chest radiograph. In secondary pneumothorax, it is sometimes difficult to distinguish loculated pneumothorax from an emphysematous bleb. Occasionally, pneumothorax may mimic myocardial infarction, pulmonary embolization, or pneumonia.

Complications

Tension pneumothorax may be life-threatening. Pneumomediastinum and subcutaneous emphysema may occur as complications of spontaneous pneumothorax. If pneumomediastinum is detected, rupture of the esophagus or a bronchus should be considered.

Treatment

Treatment depends on the severity of pneumothorax and the nature of the underlying disease. In a reliable patient with a small (< 15% of a hemithorax), stable spontaneous primary pneumothorax, observation alone may be appropriate. Many small pneumothoraces resolve spontaneously as air is absorbed from the pleural space; supplemental oxygen therapy may increase the rate of reabsorption. Simple aspiration drainage of pleural air with a small-bore catheter (eg, 16 gauge angiocatheter or larger drainage catheter) can be performed for spontaneous primary pneumothoraces that are large or progressive. Placement of a small-bore chest tube (7F to 14F) attached to a one-way Heimlich valve provides protection against development of tension pneumothorax and may permit observation from home. The patient should be treated symptomatically for cough and chest pain, and followed with serial chest radiographs every 24 hours.

Patients with secondary pneumothorax, large pneumothorax, tension pneumothorax, or severe symptoms or those who have a pneumothorax on mechanical ventilation should undergo chest tube placement (tube thoracostomy). The chest tube is placed under water-seal drainage, and suction is applied until the lung expands. The chest tube can be removed after the air leak subsides.

All patients who smoke should be advised to discontinue smoking and warned that the risk of recurrence is 50%. Future exposure to high altitudes, flying in unpressurized aircraft, and scuba diving should be avoided.

Indications for thoracoscopy or open thoracotomy include recurrences of spontaneous pneumothorax, any occurrence of bilateral pneumothorax, and failure of tube thoracostomy for the first episode (failure of lung to reexpand or persistent air leak). Surgery permits resection of blebs responsible for the pneumothorax and pleurodesis by mechanical abrasion and insufflation of talc.

Management of pneumothorax in patients with Pneumocystis pneumonia is challenging because of a tendency toward recurrence, and there is no consensus on the best approach. Use of a small chest tube attached to a Heimlich valve has been proposed to allow the patient to leave the hospital. Some clinicians favor its insertion early in the course.

Prognosis

An average of 30% of patients with spontaneous pneumothorax experience recurrence of the disorder after either observation or tube thoracostomy for the first episode. Recurrence after surgical therapy is less frequent. Following successful therapy, there are no long-term complications.

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Baumann MH et al: Management of spontaneous pneumothorax: an American College of Chest Physicians Delphi consensus statement. Chest 2001;119:590.

Sahn SA et al: Spontaneous pneumothorax. N Engl J Med 2000;342:868.

Disorders of Control of Ventilation

The principal influences on ventilatory control are arterial PCO2, pH, PO2, and brainstem tissue pH. These variables are monitored by peripheral and central chemoreceptors. Under normal conditions, the ventilatory control system maintains arterial pH and PCO2 within narrow limits; arterial PO2 is more loosely controlled.

Abnormal control of ventilation can be seen with a variety of conditions ranging from rare disorders such as Ondine's curse, neuromuscular disorders, myxedema, starvation, and carotid body resection to more common disorders such as asthma, COPD, obesity, congestive heart failure, and sleep-related breathing disorders. A few of these disorders will be discussed in this section.

Caruana-Montaldo B et al: The control of breathing in clinical practice. Chest 2000;117:205.

Perrin C et al: Pulmonary complications of chronic neuromuscular diseases and their management. Muscle Nerve 2004; 29:5.

Prabhakar NR et al: Peripheral chemoreceptors in health and disease. J Appl Physiol 2004;96:359.

Primary Alveolar Hypoventilation

Primary alveolar hypoventilation (“Ondine's curse”) is a rare syndrome of unknown cause characterized by inadequate alveolar ventilation despite normal neurologic function and normal airways, lungs, chest wall, and ventilatory muscles. Hypoventilation is even more marked during sleep. Individuals with this disorder are usually nonobese males in their third or fourth decades who have lethargy, headache, and somnolence. Dyspnea is absent. Physical examination may reveal cyanosis and evidence of pulmonary hypertension and cor pulmonale. Hypoxemia and hypercapnia are present and improve with voluntary hyperventilation. Erythrocytosis is common. Treatment with ventilatory stimulants is usually unrewarding. Augmentation of ventilation by mechanical methods (phrenic nerve stimulation, rocking bed, mechanical ventilators) has been helpful to some patients. Adequate oxygenation should be maintained with supplemental oxygen, but nocturnal oxygen therapy should be prescribed only if diagnostic nocturnal polysomnography has demonstrated its efficacy and safety. Primary alveolar hypoventilation resembles—but should be distinguished from—central alveolar hypoventilation, in which impaired ventilatory drive with chronic respiratory acidemia and hypoxemia follows an insult to the brainstem (eg, bulbar poliomyelitis, infarction, meningitis, encephalitis, trauma).

Obesity-Hypoventilation Syndrome (Pickwickian Syndrome)

In obesity-hypoventilation syndrome, alveolar hypoventilation appears to result from a combination of blunted ventilatory drive and increased mechanical load imposed upon the chest by obesity. Voluntary hyperventilation returns the PCO2 and the PO2 toward normal values, a correction not seen in lung diseases causing chronic respiratory failure such as COPD. Most patients with obesity-hypoventilation syndrome also suffer from obstructive sleep apnea (see below), which must be treated aggressively if identified as a comorbid disorder. Therapy of obesity-hypoventilation syndrome consists mainly of weight loss, which improves hypercapnia and hypoxemia as well as the ventilatory responses to hypoxia and hypercapnia. NPPV is helpful in some patients. Respiratory stimulants may be helpful and include theophylline, acetazolamide, and medroxyprogesterone acetate, 10–20 mg every 8 hours orally. Improvement in hypoxemia, hypercapnia, erythrocytosis, and cor pulmonale are goals of therapy.

Buchwald H et al: Bariatric surgery: a systematic review and meta-analysis. JAMA 2004;292:1724.

Olson AL et al: The obesity hypoventilation syndrome. Am J Med 2005;118:948.

Hyperventilation Syndromes

Hyperventilation is an increase in alveolar ventilation that leads to hypocapnia. It may be caused by a variety of conditions, such as pregnancy, hypoxemia, obstructive and infiltrative lung diseases, sepsis, hepatic dysfunction, fever, and pain. The term “central neurogenic hyperventilation” denotes a monotonous, sustained pattern of rapid and deep breathing seen in comatose patients with brainstem injury of multiple causes. Functional hyperventilation may be acute or chronic. Acute hyperventilation presents with hyperpnea, paresthesias, carpopedal spasm, tetany, and anxiety. Chronic hyperventilation may present with various nonspecific symptoms, including fatigue, dyspnea, anxiety, palpitations, and dizziness. The diagnosis of chronic hyperventilation syndrome is established if symptoms are reproduced during voluntary hyperventilation. Once organic causes of hyperventilation have been excluded, treatment of acute hyperventilation consists of rebreathing expired gas from a paper bag held over the face in order to decrease respiratory alkalemia and its associated symptoms. Anxiolytic drugs may also be useful.

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Foster GT et al: Respiratory alkalosis. Respir Care 2001;46:384.

Laffey JG et al: Hypocapnia. N Engl J Med 2002;347:43.

Sleep-Related Breathing Disorders

Abnormal ventilation during sleep is manifested by apnea (breath cessation for at least 10 seconds) or hypopnea (decrement in airflow with drop in hemoglobin saturation of at least 4%). Episodes of apnea are central if ventilatory effort is absent for the duration of the apneic episode, obstructive if ventilatory effort persists throughout the apneic episode but no airflow occurs because of transient obstruction of the upper airway, and mixed if absent ventilatory effort precedes upper airway obstruction during the apneic episode. Pure central sleep apnea is uncommon; it may be an isolated finding or may occur in patients with primary alveolar hypoventilation or with lesions of the brainstem. Obstructive and mixed sleep apneas are more common and may be associated with life-threatening cardiac arrhythmias, severe hypoxemia during sleep, daytime somnolence, pulmonary hypertension, cor pulmonale, systemic hypertension, and secondary erythrocytosis.

Definitive diagnostic evaluation for suspected sleep apnea should include otolaryngologic examination and overnight polysomnography (the monitoring of multiple physiologic factors during sleep). Electroencephalography, electro-oculography, electromyography, electrocardiography, pulse oximetry, and measurement of respiratory effort and airflow are performed in a complete evaluation. Screening may be performed using home nocturnal pulse oximetry, which when normal has a high negative predictive value in ruling out significant sleep apnea.

Obstructive Sleep Apnea

Essentials of Diagnosis

  • Daytime somnolence or fatigue.

  • A history of loud snoring with witnessed apneic events.

  • Overnight polysomnography demonstrating apneic episodes with hypoxemia.

General Considerations

Upper airway obstruction during sleep occurs when loss of normal pharyngeal muscle tone allows the pharynx to collapse passively during inspiration. Patients with anatomically narrowed upper airways (eg, micrognathia, macroglossia, obesity, tonsillar hypertrophy) are predisposed to the development of obstructive sleep apnea. Ingestion of alcohol or sedatives before sleeping or nasal obstruction of any type, including the common cold, may precipitate or worsen the condition. Hypothyroidism and cigarette smoking are additional risk factors for obstructive sleep apnea. Before making the diagnosis of obstructive sleep apnea, a drug history should be obtained and a seizure disorder, narcolepsy, and depression should be excluded.

Clinical Findings

A. Symptoms and Signs

Most patients with obstructive or mixed sleep apnea are obese, middle-aged men. Systemic hypertension is common. Patients may complain of excessive daytime somnolence, morning sluggishness and headaches, daytime fatigue, cognitive impairment, recent weight gain, and impotence. Bed partners usually report loud cyclical snoring, breath cessation, witnessed apneas, restlessness, and thrashing movements of the extremities during sleep. Personality changes, poor judgment, work-related problems, depression, and intellectual deterioration (memory impairment, inability to concentrate) may also be observed.

Physical examination may be normal or may reveal systemic and pulmonary hypertension with cor pulmonale. The patient may appear sleepy or even fall asleep during the evaluation. The oropharynx is frequently found to be narrowed by excessive soft tissue folds, large tonsils, pendulous uvula, or prominent tongue. Nasal obstruction by a deviated nasal septum, poor nasal airflow, and a nasal twang to the speech may be observed. A “bull neck” appearance is common.

B. Laboratory Findings

Erythrocytosis is common. A hemoglobin level and thyroid function tests should be obtained. Observation of the sleeping patient reveals loud snoring interrupted by episodes of increasingly strong ventilatory effort that fail to produce airflow. A loud snort often accompanies the first breath following an apneic episode. Polysomnography reveals apneic episodes lasting as long as 60 seconds. Oxygen saturation falls, often to very low levels. Bradydysrhythmias such as sinus bradycardia, sinus arrest, or atrioventricular block may occur. Tachydysrhythmias, including paroxysmal supraventricular tachycardia, atrial fibrillation, and ventricular tachycardia, may be seen once airflow is reestablished.

Treatment

Weight loss and strict avoidance of alcohol and hypnotic medications are the first steps in management. Weight loss may be curative, but most patients are unable to lose the 10–20% of body weight required. Nasal continuous positive airway pressure (nasal CPAP) at night is curative in many patients. Polysomnography is frequently necessary to determine the level of CPAP (usually 5–15 cm H2O) necessary to abolish obstructive apneas. Unfortunately, only about 75% of patients continue

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to use nasal CPAP after 1 year. Pharmacologic therapy for obstructive sleep apnea is disappointing. Supplemental oxygen may lessen the severity of nocturnal desaturation but may also lengthen apneas. Polysomnography is necessary to assess the effects of oxygen therapy; it should not be routinely prescribed. Mechanical devices inserted into the mouth at bedtime to hold the jaw forward and prevent pharyngeal occlusion have modest effectiveness in relieving apnea; however, patient compliance is not optimal.

Uvulopalatopharyngoplasty (UPPP), a procedure consisting of resection of pharyngeal soft tissue and amputation of approximately 15 mm of the free edge of the soft palate and uvula, is helpful in approximately 50% of selected patients. It is more effective in eliminating snoring than apneic episodes. UPPP may now be performed on an outpatient basis with a laser. Nasal septoplasty is performed if gross anatomic nasal septal deformity is present. Tracheotomy relieves upper airway obstruction and its physiologic consequences and represents the definitive treatment for obstructive sleep apnea. However, it has numerous adverse effects, including granuloma formation, difficulty with speech, and stoma and airway infection. Furthermore, the long-term care of the tracheotomy, especially in obese patients, can be difficult. Tracheotomy and other maxillofacial surgery approaches are reserved for patients with life-threatening arrhythmias or severe disability who have not responded to conservative therapy.

Some patients with sleep apnea have nocturnal bradycardia. A pilot study in 15 patients with either central or obstructive sleep apnea showed some improvement in oxygen saturation with atrial pacing. This single study must be considered preliminary.

Bao G et al: Upper airway resistance syndrome—one decade later. Curr Opin Pulm Med 2004;10:461.

Caples SM et al: Obstructive sleep apnea. Ann Intern Med 2005;142:187.

Shamsuzzaman AS et al: Obstructive sleep apnea: implications for cardiac and vascular disease. JAMA 2003;290:1906.

White DP: Pathogenesis of obstructive and central sleep apnea. Am J Respir Crit Care Med 2005;172:1363.

Acute Respiratory Failure

Respiratory failure is defined as respiratory dysfunction resulting in abnormalities of oxygenation or ventilation (CO2 elimination) severe enough to threaten the function of vital organs. Arterial blood gas criteria for respiratory failure are not absolute but may be arbitrarily established as a PO2 under 60 mm Hg or a PCO2 over 50 mm Hg. Acute respiratory failure may occur in a variety of pulmonary and nonpulmonary disorders (Table 9-31). A complete discussion of treatment of acute respiratory failure is beyond the scope of this chapter. Only a few selected general principles of management will be reviewed here.

Clinical Findings

Symptoms and signs of acute respiratory failure are those of the underlying disease combined with those of hypoxemia or hypercapnia. The chief symptom of hypoxemia is dyspnea, though profound hypoxemia may exist in the absence of complaints. Signs of hypoxemia include cyanosis, restlessness, confusion, anxiety, delirium, tachypnea, bradycardia or tachycardia, hypertension, cardiac dysrhythmias, and tremor. Dyspnea and headache are the cardinal symptoms of hypercapnia. Signs of hypercapnia include peripheral and conjunctival hyperemia, hypertension, tachycardia, tachypnea, impaired consciousness, papilledema, and asterixis. The symptoms and signs of acute respiratory failure are both insensitive and nonspecific; therefore, the physician must maintain a high index of suspicion and obtain arterial blood gas analysis if respiratory failure is suspected.

Treatment

Treatment of the patient with acute respiratory failure consists of (1) specific therapy directed toward the underlying disease; (2) respiratory supportive care directed toward the maintenance of adequate gas exchange; and (3) general supportive care. Only the last two aspects are discussed below.

A. Respiratory Support

Respiratory support has both nonventilatory and ventilatory aspects.

1. Nonventilatory aspects

The main therapeutic goal in acute hypoxemic respiratory failure is to ensure adequate oxygenation of vital organs. Inspired oxygen concentration should be the lowest value that results in an arterial hemoglobin saturation of ≥ 90% (PO2 ≥ 60 mm Hg). Higher arterial oxygen tensions are of no proven benefit. Restoration of normoxia may rarely cause hypoventilation in patients with chronic hypercapnia; however, oxygen therapy should not be withheld for fear of causing progressive respiratory acidemia. Hypoxemia in patients with obstructive airway disease is usually easily corrected by administering low-flow oxygen by nasal cannula (1–3 L/min) or Venturi mask (24–40%). Higher concentrations of oxygen are necessary to correct hypoxemia in patients with ARDS, pneumonia, and other parenchymal lung diseases.

2. Ventilatory aspects

Ventilatory support consists of maintaining patency of the airway and ensuring adequate alveolar ventilation. Mechanical ventilation may be provided via face mask (noninvasive) or through tracheal intubation.

a. Noninvasive positive-pressure ventilation

NPPV delivered via a full face mask or nasal mask has become first-line therapy in COPD patients with hypercapnic respiratory failure who can protect and maintain

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the patency of their airway, handle their own secretions, and tolerate the mask apparatus. Several studies have demonstrated the effectiveness of this therapy in reducing intubation rates and ICU stays in patients with ventilatory failure. Patients with acute lung injury or ARDS or those who suffer from severely impaired oxygenation do not benefit and should be intubated if they require mechanical ventilation. A bilevel positive pressure ventilation mode is preferred for most patients.

Table 9-31. Selected causes of acute respiratory failure in adults.

Airway disorders
   Asthma
   Acute exacerbation of chronic bronchitis or emphysema
   Obstruction of pharynx, larynx, trachea, main stem bronchus, or lobar bronchus by edema, mucus, mass, or foreign body
Pulmonary edema
   Increased hydrostatic pressure
   Left ventricular dysfunction (eg, myocardial ischemia, heart failure)
      Mitral regurgitation
      Left atrial outflow obstruction (eg, mitral stenosis)
      Volume overload states
   Increased pulmonary capillary permeability
      Acute respiratory distress syndrome
      Acute lung injury
   Unclear etiology
      Neurogenic
      Negative pressure (inspiratory airway obstruction)
      Reexpansion
      Tocolytic-associated
Parenchymal lung disorders
   Pneumonia
   Interstitial lung diseases
   Diffuse alveolar hemorrhage syndromes
   Aspiration
   Lung contusion
Pulmonary vascular disorders
   Thromboembolism
   Air embolism
   Amniotic fluid embolism
Chest wall, diaphragm, and pleural disorders
   Rib fracture
   Flail chest
   Pneumothorax
   Pleural effusion
   Massive ascites
   Abdominal distention and abdominal compartment syndrome
Neuromuscular and related disorders
   Primary neuromuscular diseases
      Guillain-Barré syndrome
      Myasthenia gravis
      Poliomyelitis
      Polymyositis
   Drug- or toxin-induced
      Botulism
      Organophosphates
      Neuromuscular blocking agents
      Aminoglycosides
   Spinal cord injury
   Phrenic nerve injury or dysfunction
   Electrolyte disturbances: hypokalemia, hypophosphatemia
   Myxedema
Central nervous system disorders
   Drugs: sedative, hypnotic, opioid, anesthetics
   Brain stem respiratory center disorders: trauma, tumor, vascular disorders, hypothyroidism
   Intracranial hypertension
   Central nervous system infections
Increased CO2 production
   Fever
   Infection
   Hyperalimentation with excess caloric and carbohydrate intake
   Hyperthyroidism
   Seizures
   Rigors
   Drugs

b. Tracheal intubation

Indications for tracheal intubation include (1) hypoxemia despite supplemental oxygen, (2) upper airway obstruction, (3) impaired airway protection, (4) inability to clear secretions, (5) respiratory acidosis, (6) progressive general fatigue, tachypnea, use of accessory respiratory muscles, or mental status deterioration, and (7) apnea. In general, orotracheal intubation is preferred to nasotracheal intubation in urgent or emergency situations because it is easier, faster, and less traumatic. The position of the tip of the endotracheal tube at the level of the aortic arch should be verified by chest radiograph immediately following intubation, and auscultation should be performed to verify that both lungs are being inflated. Only tracheal tubes with high-volume, low-pressure air-filled cuffs should be used. Cuff inflation pressure should be kept below 20 mm Hg if possible to minimize tracheal mucosal injury.

c. Mechanical ventilation

Indications for mechanical ventilation include (1) apnea, (2) acute hypercapnia

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that is not quickly reversed by appropriate specific therapy, (3) severe hypoxemia, and (4) progressive patient fatigue despite appropriate treatment.

Several modes of positive-pressure ventilation are available. Controlled mechanical ventilation (CMV; also known as assist-control or A-C) and synchronized intermittent mandatory ventilation (SIMV) are ventilatory modes in which the ventilator delivers a minimum number of breaths of a specified tidal volume each minute. In both CMV and SIMV, the patient may trigger the ventilator to deliver additional breaths. In CMV, the ventilator responds to breaths initiated by the patient above the set rate by delivering additional full tidal volume breaths. In SIMV, additional breaths are not supported by the ventilator unless the pressure support mode is added. Numerous alternative modes of mechanical ventilation now exist, the most popular being pressure support ventilation (PSV), pressure control ventilation (PCV), and CPAP.

PEEP is useful in improving oxygenation in patients with diffuse parenchymal lung disease such as ARDS. It should be used cautiously in patients with localized parenchymal disease, hyperinflation, or very high airway pressure requirements during mechanical ventilation.

d. Complications of mechanical ventilation

Potential complications of mechanical ventilation are numerous. Migration of the tip of the endotracheal tube into a main bronchus can cause atelectasis of the contralateral lung and overdistention of the intubated lung. Barotrauma (alternatively referred to as “volutrauma”), manifested by subcutaneous emphysema, pneumomediastinum, subpleural air cysts, pneumothorax, or systemic gas embolism, may occur in patients whose lungs are overdistended by excessive tidal volumes, especially those with hyperinflation caused by airflow obstruction. Subtle parenchymal lung injury due to overdistention of alveoli is another potential hazard. Strategies to avoid barotrauma include deliberate hypoventilation through the use of low mechanical tidal volumes and respiratory rates, resulting in “permissive hypercapnia.”

Acute respiratory alkalosis caused by overventilation is common. Hypotension induced by elevated intrathoracic pressure that results in decreased return of systemic venous blood to the heart may occur in patients treated with PEEP, those with severe airflow obstruction, and those with intravascular volume depletion. Ventilator-associated pneumonia is another serious complication of mechanical ventilation.

B. General Supportive Care

Maintenance of adequate nutrition is vital; parenteral nutrition should be used only when conventional enteral feeding methods are not possible. Overfeeding, especially with carbohydrate-rich formulas, should be avoided, because it can increase CO2 production and may potentially worsen or induce hypercapnia in patients with limited ventilatory reserve. However, failure to provide adequate nutrition is more common. Hypokalemia and hypophosphatemia may worsen hypoventilation due to respiratory muscle weakness. Sedative-hypnotics and opioid analgesics are frequently used. They should be titrated carefully to avoid oversedation, leading to prolongation of intubation. Temporary paralysis with a nondepolarizing neuromuscular blocking agent is occasionally used to facilitate mechanical ventilation and to lower oxygen consumption. Prolonged muscle weakness due to an acute myopathy is a potential complication of these agents. Myopathy is more common in patients with renal dysfunction and in those given concomitant corticosteroids.

Psychological and emotional support of the patient and family, skin care to avoid decubitus ulcers, and meticulous avoidance of nosocomial infection and complications of tracheal tubes are vital aspects of comprehensive care for patients with acute respiratory failure.

Attention must also be paid to preventing complications associated with serious illness. Stress gastritis and ulcers may be avoided by administering sucralfate, histamine H2-receptor antagonists, or proton pump inhibitors. There is some concern that the latter two agents, which raise the gastric pH, may permit increased growth of gram-negative bacteria in the stomach, predisposing to pharyngeal colonization and ultimately nosocomial pneumonia; many clinicians therefore prefer sucralfate. The risk of DVT and pulmonary embolism may be reduced by subcutaneous administration of heparin (5000 units every 12 hours), the use of LMW heparin, or placement of a sequential compression device on an extremity.

Course & Prognosis

The course and prognosis of acute respiratory failure vary and depend on the underlying disease. The prognosis of acute respiratory failure caused by uncomplicated sedative or narcotic drug overdose is excellent. Acute respiratory failure in patients with COPD who do not require intubation and mechanical ventilation has a good immediate prognosis. On the other hand, ARDS associated with sepsis has an extremely poor prognosis, with mortality rates of about 90%. Overall, adults requiring mechanical ventilation for all causes of acute respiratory failure have survival rates of 62% to weaning, 43% to hospital discharge, and 30% to 1 year after hospital discharge.

Calfee CS et al: Recent advances in mechanical ventilation. Am J Med 2005;118:584.

Esteban A et al: Noninvasive positive-pressure ventilation for respiratory failure after extubation. N Engl J Med 2004;350:2452.

Garland A et al: Outcomes up to 5 years after severe, acute respiratory failure. Chest 2004;126:1897.

Honrubia T et al: Noninvasive vs conventional mechanical ventilation in acute respiratory failure: a multicenter, randomized controlled trial. Chest 2005;128:3916.

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MacIntyre NR et al; National Association for Medical Direction of Respiratory Care: Management of patients requiring prolonged mechanical ventilation: report of a NAMDRC consensus conference. Chest 2005;128:3937.

Perrin C et al: Pulmonary complications of chronic neuromuscular diseases and their management. Muscle Nerve 2004; 29:5.

Raju P et al: The pathogenesis of respiratory failure: an overview. Respir Clin N Am 2000;6:195.

Acute Respiratory Distress Syndrome

Essentials of Diagnosis

  • Acute onset of respiratory failure.

  • Bilateral radiographic pulmonary infiltrates.

  • Absence of elevated left atrial pressure (if measured, pulmonary capillary wedge pressure ≤ 18 mm Hg).

  • Ratio of partial pressure of oxygen in arterial blood (PaO2) to fractional concentration of inspired oxygen (FIO2) < 200, regardless of the level of PEEP.

General Considerations

ARDS denotes acute hypoxemic respiratory failure following a systemic or pulmonary insult without evidence of heart failure. ARDS is the most severe form of acute lung injury and is characterized by bilateral, widespread radiographic pulmonary infiltrates, normal pulmonary capillary wedge pressure (≤ 18 mm Hg) and a PaO2/FIO2 ratio < 200. ARDS may follow a wide variety of clinical events (Table 9-32). Common risk factors for ARDS include sepsis, aspiration of gastric contents, shock, infection, lung contusion, nonthoracic trauma, toxic inhalation, near-drowning, and multiple blood transfusions. About one-third of ARDS patients initially have sepsis syndrome. Pro-inflammatory cytokines released from stimulated inflammatory cells appear to be pivotal in lung injury. Although the mechanism of lung injury varies with the cause, damage to capillary endothelial cells and alveolar epithelial cells is common to ARDS regardless of cause. Damage to these cells causes increased vascular permeability and decreased production and activity of surfactant; these abnormalities lead to interstitial and alveolar pulmonary edema, alveolar collapse, and hypoxemia.

Table 9-32. Selected disorders associated with ARDS.

Systemic Insults Pulmonary Insults
Trauma
Sepsis
Pancreatitis
Shock
Multiple transfusions
Disseminated intravascular coagulation
Burns
Drugs and drug overdose
   Opioids
   Aspirin
   Phenothiazines
   Tricyclic antidepressants
   Amiodarone
   Chemotherapeutic agents
   Nitrofurantoin
   Protamine
Thrombotic thrombocytopenic purpura
Cardiopulmonary bypass
Head injury
Paraquat
Aspiration of gastric contents
Embolism of thrombus, fat, air, or amniotic fluid
Miliary tuberculosis
Diffuse pneumonia (eg, SARS)
Acute eosinophilic pneumonia
Cryptogenic organizing pneumonitis
Upper airway obstruction
Free-base cocaine smoking
Near-drowning
Toxic gas inhalation
   Nitrogen dioxide
   Chlorine
   Sulfur dioxide
   Ammonia
   Smoke
Oxygen toxicity
Lung contusion
Radiation exposure
High-altitude exposure
Lung reexpansion or reperfusion
ARDS = acute respiratory distress syndrome; SARS = severe acute respiratory syndrome.

Clinical Findings

ARDS is marked by the rapid onset of profound dyspnea that usually occurs 12–48 hours after the initiating event. Labored breathing, tachypnea, intercostal retractions, and crackles are noted on physical examination. Chest radiography shows diffuse or patchy bilateral infiltrates that rapidly become confluent; these characteristically spare the costophrenic angles. Air bronchograms occur in about 80% of cases. Upper lung zone venous engorgement is distinctly uncommon. Heart size is normal, and pleural effusions are small or nonexistent. Marked hypoxemia occurs that is refractory to treatment with supplemental oxygen. Many patients with ARDS demonstrate multiple organ failure, particularly involving the kidneys, liver, gut, central nervous system, and cardiovascular system.

Differential Diagnosis

Since ARDS is a physiologic and radiographic syndrome rather than a specific disease, the concept of differential diagnosis does not strictly apply. Normal-permeability (“cardiogenic” or hydrostatic) pulmonary edema must be excluded, however, because specific therapy is available for that disorder. Measurement of

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pulmonary capillary wedge pressure by means of a flow-directed pulmonary artery catheter may be required in selected patients with suspected cardiac dysfunction. Routine use of the Swan-Ganz catheter in ARDS is discouraged.

Prevention

No measures that effectively prevent ARDS have been identified; specifically, prophylactic use of PEEP in patients at risk for ARDS has not been shown to be effective. Intravenous methylprednisolone does not prevent ARDS when given early to patients with sepsis syndrome or septic shock.

Treatment

Treatment of ARDS must include identification and specific treatment of the underlying precipitating and secondary conditions (eg, sepsis). Meticulous supportive care must then be provided to compensate for the severe dysfunction of the respiratory system associated with ARDS and to prevent complications (see above).

Treatment of the hypoxemia seen in ARDS usually requires tracheal intubation and positive-pressure mechanical ventilation. The lowest levels of PEEP (used to recruit atelectatic alveoli) and supplemental oxygen required to maintain the PaO2 above 60 mm Hg or the SaO2 above 90% should be used. Efforts should be made to decrease FIO2 to less than 60% as soon as possible in order to avoid oxygen toxicity. PEEP can be increased as needed as long as cardiac output and oxygen delivery do not decrease and airway pressures do not increase excessively. Prone positioning may transiently improve oxygenation in selected patients by helping recruit atelectatic alveoli; however, great care must be taken during the maneuver to avoid dislodging catheters and tubes.

A variety of mechanical ventilation strategies are available. A multicenter study of 800 patients demonstrated that a protocol using volume-cycled ventilation with small tidal volumes (6 mL/kg of ideal body weight) resulted in a 10% absolute mortality reduction over standard therapy; this trial reported the lowest mortality (31%) of any intervention to date for ARDS.

Cardiac output that falls when PEEP is used may be improved by reducing the level of PEEP or by the judicious use of inotropic drugs (eg, norepinephrine); administering fluids to increase intravascular volume should be done only with great caution because increases in pulmonary capillary pressure worsen pulmonary edema in the presence of increased capillary permeability. Therefore, the goal of fluid management is to maintain pulmonary capillary wedge pressure at the lowest level compatible with adequate cardiac output. Crystalloid solutions should be used when intravascular volume expansion is necessary. Diuretics should be used to reduce intravascular volume if pulmonary capillary wedge pressure is elevated.

Oxygen delivery can be increased in anemic patients by ensuring that hemoglobin concentrations are at least 7 g/dL; patients are not likely to benefit from higher levels. Increasing oxygen delivery to supranormal levels through the use of inotropes and high hemoglobin concentrations is not clinically useful and may be harmful. Strategies to decrease oxygen consumption include the appropriate use of sedatives, analgesics, and antipyretics.

A large number of innovative therapeutic interventions to improve outcomes in ARDS patients have been or are being investigated. Unfortunately, to date, none have consistently shown benefit in clinical trials. Systemic corticosteroids have been studied extensively with variable and inconsistent results. While recent studies suggest a benefit in late-phase ARDS, confirmatory studies are required before they can be recommended for use on a routine basis.

Course & Prognosis

The mortality rate associated with ARDS is 30–40%. If ARDS is accompanied by sepsis, the mortality rate may reach 90%. The major causes of death are the primary illness and secondary complications such as multiple organ system failure or sepsis. Median survival is about 2 weeks. Many patients who succumb to ARDS and its complications die after withdrawal of support (see Withdrawal of Support in Chapter 5). Most survivors of ARDS are left with some pulmonary symptoms (cough, dyspnea, sputum production), which tend to improve over time. Mild abnormalities of oxygenation, diffusing capacity, and lung mechanics persist in some individuals.

Adhikari N et al: Pharmacologic therapies for adults with acute lung injury and acute respiratory distress syndrome. Cochrane Database Syst Rev 2004;(4):CD004477.

Bernard GR: Acute respiratory distress syndrome: a historical perspective. Am J Respir Crit Care Med 2005;172:798.

Hager DN et al: Tidal volume reduction in patients with acute lung injury when plateau pressures are not high. Am J Respir Crit Care Med 2005;172:1241.

Matthay MA et al: Acute lung injury and the acute respiratory distress syndrome: four decades of inquiry into pathogenesis and rational management. Am J Respir Cell Mol Biol 2005;33:319.

Richard C et al: Early use of the pulmonary artery catheter and outcomes in patients with shock and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2003;290:2713.

Rubenfeld GD et al: Incidence and outcomes of acute lung injury. N Engl J Med 2005;353:1685.

Schwarz MI et al: “Imitators” of the ARDS: implications for diagnosis and treatment. Chest 2004;125:1530.

Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000;342:1301.