Harrisons Principles of Internal Medicine Self-Assessment and Board Review 18th Ed.

SECTION VI. Disorders of the Respiratory System

ANSWERS

VI-1. The answer is E. (Chap. 251) An experienced clinician should be able to gain significant insight into the cause of dyspnea or cough in a patient by a thorough pulmonary examination. Wheezes are most commonly high-pitched sounds heard predominantly on expiration and are indicative of obstruction of small airways. The most frequent cause of wheezing is asthma, which results in polyphonic wheezing due to the dynamic variability in airway obstruction throughout the lung fields. However, many other diseases cause wheezing, including congestive heart failure. This so-called “cardiac asthma” is due to peribronchiolar edema that results in narrowing of the adjacent airways. In contrast, rhonchi are caused by obstruction of medium-sized airways and are associated with a lower pitch and more coarse sound. The most common cause of rhonchi is secretions in the airways. Stridor is another breath sound that is commonly labeled as wheezing, but is indicative of upper airway obstruction. When compared to wheezing associated with small airway disease, stridor is loudest during inspiration, although it can be heard during expiration as well.

Crackles (or rales) are predominantly heard during inspiration and are considered a sign of alveolar or interstitial lung disease. A variety of diseases cause crackles including pneumonia, pulmonary edema, and any cause of interstitial lung fibrosis. Some clinicians attempt to distinguish between the “wet” crackles of pulmonary edema or pneumonia compared to the “dry” crackles of interstitial lung disease. However, this is not a reliable finding. A better way to differentiate between the alveolar and interstitial causes of crackles is to test for the presence of egophony. When alveolar filling is present, the “EEE” sound will be heard as a “AH” sound; however, in interstitial lung disease the “EEE” sound will be preserved. Whispered pectoriloquy will also be intensified in alveolar filling processes, but not interstitial lung disease.

The lack of breath sounds is important to note, but can be caused by many factors including severe bullous lung disease, emphysema, pneumothorax, or pleural effusion.

VI-2. The answer is B. (Chap. 251) This patient presents with subacute-onset dyspnea and an examination consistent with pleural effusion. Dullness to percussion can be seen with consolidation, atelectasis, and pleural effusion. With consolidation, voice transmission is increased during expiration so that one may hear whispered pectoriloquy or egophony. However, in both pleural effusion and atelectasis, breath sounds are diminished and there is no augmentation of voice transmission. Although this patient could have either atelectasis or pleural effusion, the lack of tracheal deviation points to pleural effusion. Atelectasis would have to be of many segments to account for these findings, and such significant airway collapse would generally cause ipsilateral tracheal deviation. The clinician would expect to find pleural effusion on chest film, and the most appropriate next management step would be thoracentesis to aid in the diagnosis of the etiology and for symptomatic relief. With a lack of symptoms to suggest infection, antibiotics are not indicated. Similarly, in the absence of wheezing or significant sputum production, bronchodilators and deep suctioning are unlikely to be helpful. Bronchoscopy may be indicated ultimately in the management of this patient, particularly if malignancy is suspected; however, the most appropriate first attempt at diagnosis is by means of thoracentesis.

VI-3. The answer is B. (Chap. 252) The functional residual capacity of the lung refers to the volume of air that remains in the lung following a normal tidal respiration. This volume of air represents the point at which the outward recoil of the chest wall is in equilibrium with the inward elastic recoil of the lungs. The lungs would remain at this volume if not for the actions of the respiratory muscles. The functional residual capacity is comprised of two lung volumes: the expiratory reserve volume and the residual volume. The expiratory reserve volume represents the additional volume of air that can be exhaled from the lungs when acted upon by the respiratory muscles of exhalation. The residual volume is the volume of air that remains in the lung following a complete exhalation and is determined by the closing pressure of the small airways.

VI-4. The answer is D. (Chap. 252) This patient presents with subacute dyspnea, stridor, and airflow obstruction, which are consistent with a diagnosis of subglottic stenosis related to his prior prolonged mechanical ventilation. This is confirmed by the finding of fixed airflow obstruction on the flow-volume loop. Flow-volume loops are derived from spirometry. Following a maximum inspiratory effort from residual volume, an individual forces the maximum volume of air from the lungs, and the resultant flows are plotted against the volume. By convention, inspiration is shown on the lower portion of the curve and expiration is on the top. There are characteristic patterns of airflow obstruction that can be evaluated by examining this curve. A fixed central airflow obstruction results in flattening of the flow-volume loop in both inspiration and expiration, yielding the characteristic boxlike effect in this patient. Examples of fixed airflow obstruction include tracheal stenosis and an obstructing central airway tumor. Other patterns of large airway obstruction are a variable intrathoracic obstruction and variable extrathoracic obstruction. In these situations, flattening of the flow-volume curve occurs on only one limb of the flow-volume loop, and the pattern of flattening can be explained by the dynamic changes in pressure that affect the trachea. A variable intrathoracic obstruction causes flattening of the flow-volume curve only on expiration. During inspiration the pleural pressure is more negative than the tracheal pressure, and the trachea remains unimpeded to flow. However, when pleural pressure rises on expiration relative to tracheal pressure, there is collapse of the trachea and flattening of the flow-volume curve. An example of a variable intrathoracic obstruction is tracheomalacia. In contrast, the variable extrathoracic defect leads to flattening of the flow-volume loop on inspiration but not expiration. The relevant pressure acting on airflow in the trachea in an extrathoracic obstruction is atmospheric pressure. During inspiration, the tracheal pressure drops below atmospheric pressure, leading to compromised airflow and the characteristic flattening of the flow-volume loop. However, tracheal pressure rises above atmospheric pressure during expiration, leading to a normal expiratory curve.

VI-5. The answer is B. (Chap. 252) Pregnancy is a known risk factor for the development of venous thromboembolic disease and should be suspected in any pregnant patient presenting with acute dyspnea. Determining the need for further testing in a pregnant patient should take into account the potential risks of radiation exposure on the fetus. Unfortunately, the signs and symptoms of pulmonary embolism are often nonspecific. Most chest x-rays are normal, and sinus tachycardia may be the only finding on electrocardiogram. In addition, in the pregnant patient dyspnea is common due to a variety of factors including increased size of the uterus and the effects of progesterone as a central respiratory stimulant. The normal arterial blood gas in pregnancy shows a chronic respiratory alkalosis with a pH ranging as high as 7.47 and PaCO2 between 30 and 32 mmHg. Calculation of the alveolar-arterial gradient (A-a gradient) can be helpful in this situation. It is easy to be fooled by the presence of a normal oxygen saturation and partial pressure of oxygen on arterial blood gas, but the A-a gradient may still be elevated in the presence of respiratory alkalosis. To calculate the A-a gradient, one first must calculate the alveolar oxygen tension with the alveolar gas equation shown below:

image where,

PiO2 = inspired partial pressure of oxygen = image, and

R = respiratory quotient = carbon dioxide production/oxygen consumption = ∼0.8

In this patient, calculation of the image. At the same time the measured arterial partial pressure of oxygen was 85. Thus, the A-a gradient is elevated at 32 mmHg and should prompt the physician to perform further workup for pulmonary embolism. The choice of test for diagnosis of pulmonary embolism in pregnant patients is most commonly CT pulmonary angiography, although ventilation-perfusion scanning may also be used.

VI-6. The answers are 1. C; 2. B; 3. D; 4. A. (Chap. 252) Ventilatory function can be easily measured with lung volume measurement and the FEV1/FVC ratio. A decreased FEV1/FVC ratio diagnoses obstructive lung disease. Alternatively, low lung volumes, specifically decreased TLC, and occasionally decreased RV diagnose restrictive lung disease. With extensive air trapping in obstructive lung disease, TLC is often increased and RV may also be increased. VC is proportionally decreased. MIP measures respiratory muscle strength and is decreased in patients with neuromuscular disease. Thus, myasthenia gravis will produce low lung volumes and decreased MIP, whereas patients with idiopathic pulmonary fibrosis will have normal muscle strength and subsequently a normal MIP, but decreased TLC and RV. In some cases of pulmonary parenchymal restrictive lung disease, the increase in elastic recoil results in an increased FEV1/FVC ratio.

VI-7. The answer is C. (Chap. 252) In this patient presenting with multilobar pneumonia, hypoxemia is present that does not correct with increasing the concentration of inspired oxygen. The inability to overcome hypoxemia or the lace of a notable increase in PaO2 with increasing fraction of inspired oxygen to 1.0 physiologically defines a shunt. A shunt occurs when deoxygenated blood is transported to the left heart and systemic circulation without having the capability of becoming oxygenated. Causes of shunt include alveolar collapse (atelectasis), intra-alveolar filling processes, intrapulmonary vascular malformations, or structural cardiac disease leading to right-to-left shunt. In this case, the patient has multilobar pneumonia leading to alveoli that are being perfused but are unable to participate in gas exchange because they are filled with pus and inflammatory exudates. Acute respiratory distress syndrome is another common cause of shunt physiology. Ventilation-perfusion mismatch is the most common cause of hypoxemia and results when there are some alveolar units with low ratios (low ventilation to perfusion) that fail to fully oxygenate perfused blood. When blood is returned to the left heart, the poorly oxygenated blood admixes with blood from normal alveolar units. The resultant hypoxemia is less severe than with shunt and can be corrected with increasing the inspired oxygen concentration. Hypoventilation with or without other causes of hypoxemia is not present in this case as the PaCO2 is less than 40 mmHg, indicating hyperventilation. The acidosis present in this case is of a metabolic rather than a pulmonary source. Because the patient is paralyzed, she is unable to increase her respiratory rate above the set rate to compensate for the metabolic acidosis.

VI-8. The answer is D. (Chap. 253) This patient presents with a slowly progressive illness manifested by dyspnea on exertion, dry cough, clubbing, and the presence of crackles on examination. In addition, the pulmonary function tests demonstrate restrictive lung disease. This scenario is characteristic of an individual with interstitial lung disease, most commonly idiopathic pulmonary fibrosis in individuals at this age. A more thorough history should be obtained to determine if there are any other exposures or symptoms that could identify other causes of interstitial lung disease. The next step in the evaluation of this patient is to perform a high-resolution computed tomography scan (HRCT) of the chest. The high-resolution technique for CT imaging employs thinner cross-sectional images at approximately 1–2 mm rather than the usual 7–10 mm. This creates more visible details and is particularly useful for recognizing subtle changes of the interstitium and small airways including interstitial lung disease, bronchiolitis, and bronchiectasis. Bronchoscopy with transbronchial biopsy typically does not provide the detail required to adequately diagnose interstitial lung disease. It may be considered if there are specific features on HRCT that would suggest an alternative diagnosis. However, in most instances, the pathologic diagnosis of interstitial lung disease requires a surgical lung biopsy to provide a definitive diagnosis. This patient’s symptoms do not suggest coronary artery disease or congestive heart failure. Thus, echocardiography and nuclear stress testing are not indicated.

CT scanning has evolved over the years to offer several different techniques that are useful in a variety of circumstances. Standard CT imaging is most useful for the evaluation and staging of lung masses. Helical CT scanning requires only a single breath hold and provides continuous collection of data with improved contrast enhancement and thinner collimation. Once the data are obtained, the images can be reconstructed into other views including sagittal and coronal planes as well as 3D volumetric representations. A recent use of this technology is employed in the setting of “virtual bronchoscopy” to aid in the planning and performance of bronchoscopy. Multidetector CT scans can obtain multiple slices in a single rotation that are thinner than the usual cuts. Multidetector CT scanners are used in the performance of the CT pulmonary angiogram.

VI-9. The answer is E. (Chap. 254) The patient in this clinical scenario presents with symptoms typical of asthma, including shortness of breath and wheezing. She also manifests evidence of atopy, the most common risk factor for developing asthma, with sensitivity to outdoor allergens and cats. In addition, the patient has a history of allergic rhinitis and eczema, both of which are commonly seen in individuals with asthma. Indeed, over 80% of asthma patients have a concomitant diagnosis of allergic rhinitis. Atopy is present in 40–50% of the population of affluent countries, but only a small proportion of these individuals develop asthma. Many studies have shown a genetic predisposition via family history and recent genome-wide screens, but no single genetic profile has show high positive predictive value. Overall, the prevalence of asthma in developed countries has increased over the past 30 years, but recently has leveled off with a prevalence of about 15% in children and 10–12% in adults. Asthma deaths remain rare and have decreased in recent decades. In the 1960s, asthma deaths did increase with an overuse of short-acting beta-agonist medications. However, since the introduction of inhaled corticosteroids as maintenance therapy, deaths have declined. Risk factors for fatal asthma include frequent use of rescue inhalers, lack of therapy with inhaled corticosteroids, and prior hospitalizations for asthma. Interestingly, the overall disease severity does not vary significantly within a given patient over the course of the disease. Individuals who have mild asthma typically continue to have mild asthma, whereas as those with severe disease present with severe disease. Diagnosis of asthma can be made by demonstrating airflow obstruction with significant reversibility on bronchodilator administration. In this case, the FEV1/FVC ratio is decreased to 70%, which is low. In addition, the FEV1 increases by 12.4% and 230 mL. This meets the criteria for bronchodilator reversibility of an increase of at least 200 mL and 12%. Bronchopro-vocation testing with methacholine may be considered in individuals who have suspected asthma but have normal pulmonary function tests.

VI-10. The answer is B. (Chap. 254) The pathology of asthma has largely been determined by examining bronchial biopsies of patients with asthma as well as the lungs of individuals who die from asthma. These pathologic changes are centered around the airways with sparing of the alveolar spaces. The airways are infiltrated by eosinophils, activated T lymphocytes, and activated mucosal mast cells. However, the degree of inflammation does not correlate with the severity of asthma. Another common finding in all asthmatics and individuals with eosinophilic bronchitis is thickening of the basement membrane due to collagen deposition in the subepithelium. The airway smooth muscle is hypertrophied as well. Overall, this leads to thickening of the airway wall, which may also exhibit edematous fluid, particularly in those with fatal asthma. In cases of fatal asthma, it is also common to find multiple airways that are occluded by mucous plugs. However, the disease is limited to the airways, and infiltration of the alveolar spaces by inflammatory cells is not seen.

VI-11. The answer is E. (Chap. 254) A step up in asthma therapy should be considered when a patient continues to have symptoms after 3 months on appropriate therapy. Symptoms to consider when determining whether asthma therapy should be increased include presence of daily symptoms, nocturnal awakening more than once weekly, and limitations in daily activity. Physicians should also review the use of rescue inhalers and lung function when making decisions to step up therapy. In addition, the use of standard asthma severity questionnaires such as the Asthma Control Score may be helpful. When stepping up therapy in mild persistent asthma, the preferred next step in therapy is increasing to medium-dose inhaled corticosteroids or adding a long-acting beta-agonist. However, an alternate therapy that can be considered is adding a leukotriene antagonist, low-dose theophylline, or the leukotriene synthesis inhibitor zileuton to low-dose inhaled corticosteroids.

VI-12. The answer is C. (Chap. 254) The preferred method for diagnosing asthma is demonstration of airflow obstruction on spirometry that is at least partially reversible. This is demonstrated in option C with a decreased FEV1/FVC ratio, decreased FEV1, and a significant increase in FEV1 following administration of albuterol. For an individual to be considered responsive to a bronchodilator, the individual should experience an increase in either FEV1 or FVC of at least 200 mL and 12%. Option A describes someone with postviral cough syndrome, which can persist for several weeks following a viral upper respiratory infection. Option B describes someone with exercise-induced bronchoconstriction (EIB), which, in the absence of other symptoms to suggest asthma, should not be diagnosed as asthma. Isolated EIB lacks the characteristic airway inflammation of asthma and does not progress to asthma. While it is estimated that 80–90% of individuals with asthma experience EIB, many individuals who have EIB do not also have asthma. EIB is caused by hyperventilation with inhalation of cool, dry air that leads to bronchospasm. Option D describes someone with occupational asthma that has occurred after working with animals in the medical laboratory for many years. Symptoms that are characteristic of occupational asthma are symptoms only while at work that improve on the weekends and during holidays. Option E describes a patient with chronic obstructive pulmonary disease (COPD). In COPD, 25–48% of individuals can demonstrate bronchial hyperresponsiveness in response to methacholine.

VI-13. The answer is D. (Chap. 254) A step-down in asthma therapy can be considered when an individual has been clinically stable for 3–6 months. Factors demonstrating appropriate asthma control include daytime symptoms 2 or fewer times weekly, nighttime symptoms 2 or fewer times monthly, use of rescue inhaler 2 or fewer times weekly, FEV1 or peak expiratory flow rate at least 80% of personal best, or appropriate control by validated asthma control questionnaires such as the Asthma Control Test or Asthma Therapy Assessment Questionnaire. When stepping down therapy, it is important to review the medications and their dosages. This patient is currently being managed with low-dose inhaled corticosteroids plus a long-acting beta-agonist. At this point, the best course of therapy is to stop the long-acting beta-agonist salmeterol. Since the dose of fluticasone the patient is receiving is already at a low dose, it would not be recommended to decrease it further, and it is never appropriate to treat with a long-acting beta-agonist alone without inhaled corticosteroids. In a large clinical trial, asthma mortality increased in individuals treated with long-acting beta-agonists in the absence of therapy with inhaled corticosteroids. Adding another medication is not indicated as the patient is demonstrating good asthma control.

VI-14. The answer is D. (Chap. 254) Omalizumab is a blocking antibody that binds to and neutralizes circulating immunoglobulin E (IgE) to inhibit IgE-mediated reactions. Omalizumab therapy can be considered for the outpatient treatment of severe, persistent asthma requiring high-dose inhaled corticosteroids in the presence of sensitivity to an aeroallergen. In clinical trials, treatment with omalizumab has been demonstrated to decrease the number of exacerbations in individual experiences and most individuals are also able to decrease the amount of oral or inhaled corticosteroids they are using. Elevations in serum IgE are frequently seen in asthmatic patients, and omalizumab can be considered in individuals whose IgE ranges from 30 to 700 IU/L. However, the manufacturer recommends not giving omalizumab therapy with marked elevations in IgE (>700 IU/L). Omalizumab is given as an injection every 2–4 weeks and must be given in an office setting because rare anaphylactic reactions can occur. If an individual is experiencing an acute exacerbation of asthma, omalizumab is typically held. However, it is not necessary to normalize lung function or discontinue oral steroids prior to initiating therapy with omalizumab.

VI-15. The answer is C. (Chap. 255) This patient has an acute presentation with pulmonary infiltrates and a pleural effusion, both of which have an increased percentage of eosinophils. In the United States, drug reactions are the most common cause of pulmonary infiltrates with eosinophilia (PIE syndrome), and among the drugs that can cause eosinophilia, nitrofurantoin is the most common. Nitrofurantoin is known to cause two types of pulmonary drug reaction. The acute drug reaction occurs within hours to days of starting nitrofurantoin. Patients present with dry cough, dyspnea, and fever. Chest radiograph demonstrates bilateral infiltrates. In a minority of cases, a pleural effusion is seen. Differential cell count demonstrates eosinophilia in both the pleural and bronchoalveolar lavage fluids. Treatment of nitrofurantoin-associated pulmonary eosinophilia consists primarily of stopping the medication. In severe cases, oral corticosteroids can be used as well, but this does not supersede the need to discontinue the nitrofurantoin. High doses of steroids are typically not required for drug-related pulmonary eosinophilia. While pulmonary infections can cause pulmonary eosinophilia, this patient has a typical time course and presentation for nitrofurantoin-associated lung disease. Therefore, one would not wait for cultures before recommending stopping the nitrofurantoin. Multiple drugs have been associated with eosinophilic pulmonary reactions. In addition to nitrofurantoin, they include sulfonamides, NSAIDs, penicillins, thiazides, tricyclic antidepressants, hydralazine, and chlorpropamide, among others. Levothyroxine, however, is not known to cause any lung disease. Both hypo- and hyperthyroidism can be associated with pleural effusions from the primary disease or associated heart failure. However, they are not associated with eosinophilic lung disease, and adjusting the levothyroxine dose is not indicated.

VI-16 and VI-17. The answers are B and E, respectively. (Chap. 249) The patient has a subacute presentation of hypersensitivity pneumonitis related to exposure to bird droppings and feathers at work. Hypersensitivity pneumonitis is a delayed-type hypersensitivity reaction that has a variety of presentations. Some people develop acute onset of shortness of breath, fevers, chills, and dyspnea within 6–8 hours of antigen exposure. Others may present subacutely with worsening dyspnea on exertion and dry cough over weeks to months. Chronic hypersensitivity pneumonitis presents with more severe and persistent symptoms with clubbing. Progressive worsening is common with the development of chronic hypoxemia, pulmonary hypertension, interstitial pulmonary fibrosis, and respiratory failure. The diagnosis relies on a variety of tests. Peripheral eosinophilia is not a feature of this disease as the disease is mediated through T-cell inflammation. Other nonspecific markers of inflammation may be elevated, including the erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, and serum immunoglobulins. Neutrophilia and lymphopenia may be seen. If a specific antigen is suspected, serum precipitins directed toward that antigen may be demonstrated. However, these tests are neither sensitive nor specific for the presence of disease. Chest radiography may be normal or show a diffuse reticulonodular infiltrate. High-resolution chest CT is the imaging modality of choice and shows ground-glass infiltrates in the lower lobes. Centrilobular infiltrates are often seen as well. In the chronic stages, patchy emphysema is the most common finding. Histopathologically, interstitial alveolar infiltrates predominate, with a variety of lymphocytes, plasma cells, and occasional eosinophils and neutrophils being seen. Loose, noncaseating granulomas are typical.

Treatment requires removing the individual from exposure to the antigen. If this is not possible, the patient should wear a mask that prevents small-particle inhalation during exposure. In patients with mild disease, removal from antigen exposure alone may be sufficient to treat the disease. More severe symptoms require therapy with glucocorticoids at an equivalent prednisone dose of 1 mg/kg daily for 7–14 days. The steroids are then gradually tapered over 2–6 weeks.

VI-18. The answer is C. (Chap. 256) Mesothelioma is a rare malignancy of the pleura and peritoneum with almost all cases associated with asbestos exposure. It is notable that the exposure to asbestos could seem almost minimal, but still confer significant risk. Exposures of less than 1–2 years or those that have occurred more than 40 years in the past have been demonstrated to confer an increased risk of mesothelioma. While tobacco smoking in association with asbestos exposure increases the risk of lung cancer several fold, there is no additive or exponential risk of mesothelioma in those who smoke. Mesothelioma most often presents with a persistent unilateral pleural effusion that may mask the underlying pleural tumor. However, the pleura may be diffusely thickened. Even with large effusions, no mediastinal shift is seen on chest radiograph because the pleural thickening associated with the disease leads to a fixed chest cavity size and thoracic restriction. The most difficult diagnostic dilemma in these patients is to differentiate mesothelioma from metastatic lung carcinoma (usually adenocarcinoma), as many patients are at risk for both tumors, and lung cancer is far and away the most common malignancy seen in those individuals with asbestos exposure and cigarette smoking. Pleural fluid cytology is not adequate for the diagnosis of most individuals with mesothelioma, with samples being positive for the disease in less than 50% of individuals. Most often video-assisted thoracoscopy is required to directly visualize the pleural surfaces and direct biopsy sampling. Unfortunately, there is no proven effective therapy for mesothelioma, and most patients die from local extension of the disease.

VI-19. The answer is E. (Chap. 256) Silicosis results from the inhalation of free silica (or crystalline quartz) and is associated with mining, stonecutting, foundry work, and quarrying. The chronic form of silicosis has been associated with an increased risk of a variety of diseases. Silica is known to be cytotoxic to alveolar macrophages and thus places patients at increased risk of pulmonary infections that rely on cellular immunity, including Mycobacterium tuberculosis, atypical mycobacteria, and fungus. In addition, silicosis is associated with the development of connective tissue disorders including rheumatoid arthritis with rheumatoid nodules (Caplan syndrome) and scleroderma. Finally, silica is listed as a probable lung carcinogen.

VI-20. The answer is D. (Chap. 256) Occupational lung diseases have been associated with a wide variety of organic and inorganic exposures in the workplace and clinically can range from primarily an airways disease to progressive pulmonary fibrosis. When evaluating a patient for a new pulmonary diagnosis, it is important to perform a detailed occupational history to determine if there is a possibility that the patient’s profession may be causing or perpetuating the disease process. Specific clinical syndromes are associated with well-defined clinical exposures. The inorganic dusts include asbestos, silica, coal dust, beryllium, and a variety of other metals. Asbestos and silica are among the most common exposures. Asbestos exposure is associated with mining, construction, and ship repair. In areas near where asbestos mining has occurred, the general population also has shown an increased risk of asbestos-related lung disease. Clinically, asbestos exposure is associated with a range of clinical syndromes including asbestosis, benign pleural plaques and pleural effusions, lung cancer, and mesothelioma. Silica exposure is common among miners, stone masons, and individuals involved in sand blasting or quarrying. A variety of clinical syndromes can occur with silica exposure, the most severe being progressive massive fibrosis with masslike upper-lobe consolidating nodules (>1 cm). Coal mining is also associated with a clinical picture similar to silicosis and progressive massive fibrosis. Beryllium is a lightweight metal that is highly conductive and is used in high-tech industries. The classic disease associated with beryllium exposure is a chronic granulomatous disease similar in clinical appearance to sarcoidosis. Other metals can produce any number of clinical syndromes. Welders of galvanized metal who utilize zinc oxide are susceptible to metal fume fever and present with an acute self-limited influenza-like illness.

Organic dusts that can lead to occupational lung disease include cotton dust, grain dust, toxic chemicals, and other agricultural dusts, among many others. Cotton milling and processing can present with a clinical syndrome known as byssinosis, which has asthma-like features. Many of the organic dust exposures also lead to hypersensitivity pneumonitis. Examples of hypersensitivity pneumonitis syndromes related to occupational exposures include farmer’s lung, pigeon breeder’s lung, and malt worker’s lung. Typically, a specific antigen can be identified as the culprit for the development of hypersensitivity pneumonitis. In farmer’s lung, the most common cause is thermophilic Actinomycesspecies found in moldy hay.

VI-21. The answer is B. (Chaps. 254 and 256) The patient presents with typical asthma symptoms; however, the symptoms are escalating and now require nearly constant use of oral steroids. It is of note that the symptoms are worse during weekdays and better on weekends. This finding suggests that there is an exposure during the week that may be triggering the patient’s asthma. Often textile workers have asthma resulting from the inhalation of particles. The first step in diagnosing a work-related asthma trigger is to check FEV1 before and after the first shift of the workweek. A decrease in FEV1 would suggest an occupational exposure. Skin testing for allergies would not be likely to pinpoint the work-related exposure. Although A. fumigatus can be associated with worsening asthma from allergic bronchopulmonary aspergillosis, this would not result in a fluctuation in symptoms throughout the week. The patient does not require further testing to diagnose that he has asthma; therefore, a methacholine challenge is not indicated. Finally, the exercise physiology test is generally used to differentiate between cardiac and pulmonary causes or deconditioning as etiologies for shortness of breath.

VI-22. The answer is D. (Chap. 256) The patient presents with acute-onset pulmonary symptoms, including wheezing, with no other medical problems. He is a farmer and was recently handling hay. The clinical presentation and radiogram are consistent with farmer’s lung, a hypersensitivity pneumonitis caused by Actinomyces. In this disorder, spores of actinomycetes in moldy hay are inhaled and produce a hypersensitivity pneumonitis. The disorder is seen most commonly in rainy periods, when the spores multiply. Patients present generally 4–8 hours after exposure with fever, cough, and shortness of breath without wheezing. Chest radiograms often show patchy, bilateral, often upper-lobe infiltrates. The exposure history will differentiate this disorder from other types of pneumonia.

VI-23. The answer is A. (Chap. 257) Health care–associated pneumonia (HCAP) has emerged as a new category of pneumonia distinct from community-acquired pneumonia (CAP), as individuals at risk of HCAP frequently have multidrug-resistant organisms more typical of hospital-acquired pneumonia (HAP). Several risk factors have been identified for HCAP, and specific organisms are more commonly seen in specific situations. For example, methicillin-resistant Staphylococcus aureus (MRSA) has not only been associated with hospitalization for more than 48 hours, but also any hospitalization for 2 or more days in the preceding 3 months, as well as with individuals residing in nursing homes or extended care facilities, chronic dialysis, home infusion therapy, home wound care, or a family member with a multidrug-resistant infection. Antibiotic therapy in the preceding 3 months is not associated with the development of MRSA as a cause of HCAP, but is associated with Pseudomonas aeruginosa and multidrug-resistant (MDR) Enterobacteriaceae as causes of HCAP.

VI-24. The answer is B. (Chap. 257) The diagnosis and treatment of community-acquired pneumonia (CAP) often incorporate a combination of clinical, radiographic, and laboratory features to determine the most likely etiology and treatment. In most instances of CAP, outpatient treatment is sufficient, and definitive etiologic diagnosis of the causative organism is not required, nor is it cost-effective. However, the outpatient diagnosis of CAP most often does require confirmation by chest radiograph, as the sensitivity and specificity of the findings on physical examination are about 58% and 67%, respectively. In addition, chest radiograph may identify risk factors for more severe clinical courses such as multifocal infiltrates. Moreover, outside of the 2% of individuals admitted to intensive care for treatment of CAP, there are no data that treatment directed against the specific causative organism is superior to empiric therapy. In some instances, one may decide to attempt to determine a causative organism for CAP, particularly in individuals who have risk factors for resistant organisms or if the patient fails to respond appropriately to initial antibiotic therapy. The most common way CAP is diagnosed is via sputum culture with Gram stain. The primary purpose of the Gram stain is to ensure that the sputum is an adequate lower respiratory sample for culture with fewer than 10 squamous epithelial cells and more than 25 neutrophils per high-powered field. However, at times it can suggest a specific diagnosis based on the appearance. Generally, the yield from sputum culture is 50% or less, even in cases of bacteremic pneumococcal pneumonia. The yield from blood cultures is also low, even when collected prior to initiation of antibiotics, at 5–14%. More recently, antigen tests or polymerase chain reaction (PCR) testing directed against specific organisms has gained favor. The most common antigen test that is performed is for Legionella pneumophila, as this organism does not grow in culture unless performed on specific media. Antigen and PCR tests are also available for Streptococcus pneumoniae and Mycoplasma pneumoniae, but given the costs they are not frequently performed

VI-25. The answer is D. (Chap. 257) Determining the appropriate empiric coverage for community-acquired pneumonia (CAP) initially requires determining if the severity of illness warrants admission to the hospital. Clinical rules for determining the potential severity of pneumonia have been developed including the Pneumonia Severity Index (PSI) and the CURB-65 criteria. While the PSI has the largest body of research to support its use, the model includes 20 variables, which may be impractical in a busy clinical practice. The CURB-65 criteria include only five variables: (1) Confusion; (2) Urea greater than 7 mmol/L; (3) Respiratory rate greater than or equal to 30/min; (4) Blood pressure less than or equal to 90/60; and (5) age of 65 or older. This patient meets none of the criteria for hospitalization and is not hypoxemic or in a high-risk group for complications from CAP. Therefore, he can safely be treated as an outpatient without further diagnostic workup, as his history, physical examination, and chest radiograph are all consistent with the diagnosis of CAP. The empiric antibiotic regimen recommended by the Infectious Diseases Society of America and the American Thoracic Society for individuals who are previously healthy and have not received antibiotics in the prior 3 months is either doxycycline or a macrolide such as azithromycin or clarithromycin. In outpatients with significant medical comorbidities or antibiotics within the prior 3 months, the suggested antibiotic therapy is either a respiratory fluoroquinolone or a beta-lactam plus a macrolide.

VI-26. The answer is E. (Chap. 257) Ventilator-associated pneumonia (VAP) is a common complication of endotracheal intubation and mechanical ventilation. Prevalence estimates indicate that 70% of patients requiring mechanical ventilation for 30 days or longer will have at least one instance of VAP. However, the epidemiology of VAP has been difficult to accurately study as no single set of criteria is reliably diagnostic of VAP. Generally, it is thought that VAP has a tendency to be overdiagnosed for a variety of reasons, including the high rates of tracheal colonization with pathogenic organisms and the multiple alternative causes of fevers and/or pulmonary infiltrates in critically ill patients. Quantitative cultures have gained favor, as the quantitative nature is thought to discriminate better between colonization and active infection. A variety of approaches have been advocated including endotracheal aspirates yielding more than 106 organisms or protected brush specimens from distal airways yielding more than 103 organisms. However, the quantitative yield of these tests can be highly influenced by even a single dose of antibiotics, and antibiotic changes are common in critically ill patients, particularly when a new fever has emerged. Thus, the lack of growth on quantitative culture may be difficult to interpret in this setting. More recently, there has been growing use of the Clinical Pulmonary Infection Score (CPIS), which incorporates a variety of clinical, radiographic, and laboratory factors to determine the likelihood of VAP, although its true utility in clinical practice remains to be fully determined.

VI-27. The answer is D. (Chap. 257) Aspiration can lead to anaerobic infection and chemical pneumonitis. The etiologic differential diagnosis of community-acquired pneumonia (CAP) in a patient with a history of recent travel to the southwestern United States should include CoccidioidesAspergillus has a worldwide distribution and is not a cause of CAP syndrome. Alcohol use predisposes patients to anaerobic infection, likely due to aspiration, as well as S. pneumoniaeKlebsiella is classically associated with CAP in alcoholic patients, but in reality this is rarely seen. Patients with structural lung disease, such as cystic fibrosis or bronchiectasis, are at risk for a unique group of organisms including P. aeruginosa and S. aureus. Poor dental hygiene is associated with anaerobic infections.

VI-28. The answer is D. (Chap. 258) Bronchiectasis occurs when there is irreversible dilation of the distal airways and can occur in a focal or diffuse fashion. The most common cause of diffuse bronchiectasis worldwide is prior granulomatous infection due to Mycobacterium tuberculosis. In the developed world, tuberculosis is a less common cause of bronchiectasis, with nontuberculous mycobacteria such as Mycobacterium avium-intracellulare complex being a more common cause, particularly in the midlung fields. Other potential etiologies of diffuse bronchiectasis include cystic fibrosis, postradiation pneumonitis, immunoglobulin deficiency, end-stage fibrotic lung disease, and recurrent aspiration. However, despite extensive workup, as many as 25–50% of cases remain idiopathic.

VI-29. The answer is C. (Chap. 258) Bronchiectasis is a disorder with a variable presentation depending on cause. In inherited disorders such as cystic fibrosis, the symptoms of bronchiectasis most often begin in early childhood. However, in general, the incidence of bronchiectasis increases with age, typically affecting women more than men. The primary clinical symptom of bronchiectasis is a daily productive cough. Classically, the sputum is described as large volume with a thick tenacious character. Hemoptysis may also occur in association with bronchiectasis. The physical examination may demonstrate crackles or wheezing with mild to moderate airflow obstruction on pulmonary function testing. In more advanced cases, digital clubbing may be seen. The diagnosis of bronchiectasis is often suspected based on clinical symptoms, but confirmation of diagnosis on high-resolution CT imaging of the chest is recommended. The chest radiograph may show tram tracking, but is frequently normal and is of insufficient sensitivity to definitively make the diagnosis. On high-resolution chest CT imaging, bronchiectatic airways appear dilated more than 1.5 times the size of the adjacent pulmonary artery. In addition, the airways fail to taper in the periphery, and airways may be identifiable within 1 cm of the pleural surface, which is clearly abnormal. Bronchial wall thickening and inspissated secretions may also be seen. Contrast administration is not necessary to visualize bronchiectasis. Once bronchiectasis is confirmed as the etiology of the patient’s chronic cough, workup for the underlying etiology of the bronchiectasis should be performed and would likely include sputum cultures for mycobacteria and bacteria, serum immunoglobulin, and α1 antitrypsin levels, among others.

VI-30. The answer is A. (Chap. 258) This patient presents with a clinical history that is consistent with a polymicrobial lung abscess with infection by anaerobic bacteria. Often individuals present with an indolent course and nonspecific symptoms including fever, fatigue, and weight loss. Cough with a foul-smelling sputum production may also be seen. Individuals presenting with lung abscess often have risk factors for aspiration and evidence of periodontal infection. In more advanced cases, the lung abscess can erode into the pleura, creating an empyema with associated pleuritic chest pain. Although chest radiograph often demonstrates a cavitary lesion, a CT may be performed to determine the extent of the disease and whether there are associated lesions. Bacterial, mycobacterial, and fungal cultures should be performed, but this should not delay treatment of the most likely cause of the lung abscess. A sputum culture on an expectorated sample will only detect aerobic organisms, and the detection of anaerobes would be confounded by the presence of multiple oral anaerobes that could contaminate an expectorated specimen. Initial treatment should be directed primarily at anaerobic organisms. Recommended antibiotics are clindamycin IV 600 mg four times daily or a β-lactam/β-lactamase inhibitor combination (ampicillin-sulbactam, amoxicillin-clavulanic acid). Metronidazole is not recommended because it has poor activity against the microaerophilic streptococci that commonly infect lung abscesses. The duration of treatment is not well defined. Some experts recommend continuing therapy until the abscess has entirely healed. Persistence of fever beyond 5–7 days should prompt the clinician to investigate further. Potential complications include development of empyema or a bronchopleural fistula. In addition, one should consider performing bronchoscopy to rule out an obstructing lesion. Percutaneous or surgical intervention is generally not required unless the patient fails to respond to antibiotic therapy or has a lung abscess greater than 6 cm.

VI-31. The answer is D. (Chap. 258) The combination of infertility and recurrent sinopulmonary infections should prompt consideration of an underlying disorder of ciliary dysfunction that is termed primary ciliary dyskinesia. These disorders account for approximately 5–10% of cases of bronchiectasis. A number of deficiencies have been described, including malfunction of dynein arms, radial spokes, and microtubules. All organ systems that require ciliary function are affected. The lungs rely on cilia to beat respiratory secretions proximally and subsequently to remove inspired particles, especially bacteria. In the absence of this normal host defense, recurrent bacterial respiratory infections occur and can lead to bronchiectasis. Otitis media and sinusitis are common for the same reason. In the genitourinary tract, sperm require cilia to provide motility. Kartagener’s syndrome is a combination of sinusitis, bronchiectasis, and situs inversus. It accounts for approximately 50% of patients with primary ciliary dyskinesia. Cystic fibrosis is associated with infertility and bilateral upper-lobe infiltrates. It causes a decreased number of sperm or absent sperm on analysis because of the congenital absence of the vas deferens. Sarcoidosis, which is often associated with bihilar adenopathy, is not generally a cause of infertility. A water balloon–shaped heart is found in those with pericardial effusions, which one would not expect in this patient.

VI-32. The answer is E. (Chap. 259) Cystic fibrosis (CF) is a common autosomal-recessive disorder that affects 1 out of every 3000 live births in the Caucasian population of North America and Europe. There have been more than 1500 mutations identified in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR)—the abnormal protein identified in CF. This protein is a large transmembrane protein involved in the transport of chloride and other ions, and abnormalities of the CFTR lead to abnormalities of salt and water transport. The primary clinical manifestations of CF are due to the effects of the mutated CFTR in the lungs, gastrointestinal tract, and pancreas. In the lungs, abnormal CFTR leads to thick, sticky mucus with abnormal mucociliary clearance. A patient will have recurrent respiratory infections with development of cystic bronchiectasis over time. The presenting manifestation in infancy is often meconium ileus and can lead to constipation and distal intestinal obstruction in adults. Failure of the CFTR in the pancreas prevents appropriate release of pancreatic enzymes to allow for proper digestion of food, especially fatty foods, with resultant malnutrition and steatorrhea. While most patients with CF present in infancy or childhood, about 5% of all individuals with CF will not be diagnosed until adulthood. Presenting symptoms in adulthood can be myriad and often result from minor mutations of the CFTR gene. These symptoms can include recurrent lung and sinus infections, malnutrition, sinus disease, and infertility, especially absence of the vas deferens in men. The standard test for the diagnosis of CF is the sweat chloride test. Elevated values are pathognomonic for CF, with a cutoff of greater than 70 meq/L in adults being diagnostic. Values greater than approximately 35 meq/L fall within the indeterminate range. DNA analysis for common CF mutations is often performed, and one would want to demonstrate two alleles known to cause CF before making the diagnosis, as the disease is autosomal recessive. Identification of only one allele only identifies the carrier state. In some individuals, the diagnosis can remain elusive. In such cases, referral to a tertiary center for nasal potential difference (PD) testing can be helpful, as CF patients demonstrate an elevated baseline nasal PD with failure to respond to stimulation with beta-agonists. Presence of Pseudomonas aeruginosa is common in adults with CF, but is not specific for the diagnosis of the disease as bronchiectasis from any cause can lead to P. aeruginosa colonization.

VI-33. The answer is C. (Chap. 259) Individuals with cystic fibrosis (CF) experience recurrent pulmonary and sinus infections. In childhood, the most commonly isolated organisms are Haemophilus influenzae and Staphylococcus aureus. However, over time, most adults demonstrate Pseudomonas aeruginosa. It is now recognized that chronic colonization with Pseudomonas, especially multidrug-resistant organisms, is associated with a more rapid decline in lung function. The Cystic Fibrosis Foundation recommends quarterly office visits with a physician, with assessment of respiratory cultures at each visit. When Pseudomonas is initially detected, attempts to eradicate the organism should be undertaken. Clinical trials have not definitively determined the best regimen for eradicating Pseudomonas, but the most common utilized treatment is the aminoglycoside antibiotic tobramycin given as a nebulized solution twice daily every other month with follow-up cultures at the next office visit to determine if the therapy should be continued. For all patients chronically colonized with Pseudomonas, inhaled tobramycin every other month should be continued on an indefinite basis. In addition, azithromycin 500 mg three times weekly or 250 mg daily is also utilized. Whether azithromycin primarily exerts its beneficial effect through anti-inflammatory or antimicrobial actions is not definitively known at the present time. As the patient is clinically well without any symptoms of acute exacerbation, the use of intravenous antibiotics is not required. Chest wall oscillation and hypertonic saline are both mechanisms to improve airway clearance. By history and lung function, the patient is achieving adequate airway clearance at the present time, so escalation of care in this area is not required.

VI-34. The answer is B. (Chap. 259) Patients with cystic fibrosis are at risk for colonization and/or infection with a number of pathogens, and in general these infections have a temporal relationship. In childhood, the most frequently isolated organisms are Haemophilus influenzae and Staphylococcus aureus. As patients age, Pseudomonas aeruginosa becomes the predominant pathogen. Interestingly, Aspergillus fumigatus is found in the airways of up to 50% of cystic fibrosis patients. All these organisms merely colonize the airways but occasionally can also cause disease. Burkholderia (previously called Pseudomonascepacia can occasionally be found in the sputum of cystic fibrosis patients, where it is always pathogenic and is associated with a rapid decline in both clinical parameters and pulmonary function testing. Atypical mycobacteria can occasionally be found in the sputum but are often merely colonizers. Acinetobacter baumannii is not associated with cystic fibrosis; rather, it is generally found in nosocomial infections.

VI-35. The answer is D. (Chap. 260) Chronic obstructive pulmonary disease (COPD) affects more than 10 million Americans and is currently the fourth leading cause of death in the United States. Worldwide, COPD is also increasing as cigarette smoking, the primary risk factor for the development of COPD, is increasing in prevalence throughout the world. While cigarette smoking is clearly identified as a risk factor for COPD, other factors have also been identified to contribute to the risk of COPD. In many developing countries, the prevalence of smoking among women remains low. However, the incidence of COPD is increasing in women as well as men. In many developing countries, this increased incidence of COPD in women is attributable to the use of biomass fuels in poorly ventilated areas for heat and cooking. In addition, passive cigarette smoke exposure may also contribute. Occupational exposures also lead to an increased risk of COPD. While some exposures such as cotton textile dust and gold mining have not been definitively associated with COPD, coal dust exposure is a risk factor for emphysema in both smokers and nonsmokers. Inherent properties of the airways also affect the risk of COPD. Airway hyperresponsiveness increases the risk of lung function decline and is a risk factor for COPD. While there is much interest in the role of chronic or recurrent infections as a risk factor for COPD, there has been no proven link.

VI-36. The answer is B. (Chap. 260) Chronic obstructive pulmonary disease (COPD) is a disease process encompassing the clinical entities of emphysema and chronic bronchitis. COPD is defined pathophysiologically by the presence of irreversible airflow obstruction with hyperinflation and impaired gas exchange. The airflow obstruction occurs for several reasons including decreased elastic recoil of the lungs, increased airway inflammation, and increased closure of small airways due to loss of tethering in emphysematous lungs. This leads to early closure of airways in expiration with air trapping and hyperinflation. Finally, the loss of alveoli in emphysematous lungs leads to a progressive decline in gas exchange with alterations of ventilation-perfusion relationships. On pulmonary function testing, these pathophysiologic changes result in a typical pattern, with the primary characteristic of COPD being a decrease in the FEV1/FVC ratio and FEV1. The severity of airflow obstruction is graded by the degree of decline in the percentage predicted FEV1. The FVC may or may not be decreased. With hyperinflation, the total lung capacity increases with a concomitant increase in residual volume. Finally, the diffusion capacity for carbon monoxide is also characteristically decreased in most cases of COPD. Some patients with pure chronic bronchitis without any emphysematous component may have a preserved carbon monoxide diffusing capacity (DLCO). This same pattern of pulmonary function testing can be seen in asthma with the exception of the DLCO, which is normal or increased in asthma.

VI-37. The answer is D. (Chap. 260) This patient has a known diagnosis of chronic obstructive pulmonary disease (COPD) with worsening symptoms and pulmonary function testing consistent with a moderate degree of disease. By the Global Initiative for Lung Disease (GOLD) criteria, the patient would have stage II disease. He is currently undermanaged with a short-acting beta-agonist only in the setting of limiting symptoms. Unfortunately, there is no medical therapy that alters mortality or definitively decreases the rate of decline in lung function in COPD, with the exception of smoking cessation, oxygen for chronic hypoxemia, and lung volume reduction surgery in a small subset of highly selected patients. Therefore, the goal of therapy in COPD is to improve symptoms and quality of life. The best initial medication for this patient would be to add a long-acting bronchodilator in the form of the antimuscarinic agent tiotropium. In large randomized controlled trials, tiotropium has been demonstrated to improve symptoms and decrease exacerbations in COPD. Ipratropium, a short-acting anticholinergic medication, also improves symptoms, but has not been similarly shown to decrease exacerbation rate. Combinations of long-acting beta-agonists and inhaled glucocorticoids have also been shown to decrease exacerbations and improve quality of life in those with COPD. The largest trial of these medications to date has demonstrated a trend toward improved mortality. Currently the recommendation for initiation of long-acting beta-agonist and inhaled glucocorticoid combinations is to consider starting the medication if the patient has two or more exacerbations yearly or demonstrates significant acute bronchodilator reactivity on pulmonary function testing. At one time, physicians considered prescribing long-term oral glucocorticoids if a patient demonstrated significant improvement in lung function in response to a trial of oral steroids. However, long-term treatment with steroids has an unfavorable risk-benefit ratio including weight gain, osteoporosis, and increased risk of infection, especially pneumonia. Oxygen therapy improves outcomes in individuals who are hypoxemic at rest or have borderline hypoxemia with evidence of end-organ damage (pulmonary hypertension, polycythemia, etc.). While oxygen may be prescribed for individuals with isolated exercise or nocturnal hypoxemia, research to date has not demonstrated any change in outcomes with oxygen in these settings.

VI-38. The answer is E. (Chap. 260) Acute exacerbations of chronic obstructive pulmonary disease (COPD) are marked by an increase in dyspnea, an increase in sputum, and a change in sputum color. Acute exacerbations of COPD account for more than $10 billion in health care expenditures annually in the United States, with a significant morbidity and mortality associated with these exacerbations. Prompt treatment can improve symptoms and decrease hospitalizations and mortality in this setting. In patients presenting with hypercarbic respiratory failure in the setting of an acute exacerbation, the treatment that has demonstrated the strongest reduction in mortality is noninvasive positive pressure ventilation (NIPPV) when compared to traditional mechanical ventilation. NIPPV also decreases the need for endotracheal intubation, complications, and length of stay in the hospital. Antibiotics, bronchodilators, and glucocorticoids are all cornerstones of therapy in the treatment of acute exacerbations in COPD, but have not been demonstrated in clinical trials to have similar mortality benefits in the situation of acute hypercarbic respiratory failure. Specifically, no benefit is demonstrated for intravenous versus oral corticosteroids. Likewise, the choice of antibiotic should be made based on local susceptibility patterns, and the need for broad-spectrum antibiotics that cover Pseudomonas is not typically indicated.

VI-39. The answer is C. (Chap. 260) The only therapies that have been proven to improve survival in patients with COPD are smoking cessation, oxygen in patients with resting hypoxemia, and lung volume reduction surgery in a very small subset of highly selected patients. This patient probably has resting hypoxemia resulting from the presence of an elevated jugular venous pulse, pedal edema, and an elevated hematocrit. Theophylline has been shown to increase exercise tolerance in patients with COPD through a mechanism other than bronchodilation. Oral glucocorticoids are not indicated in the absence of an acute exacerbation and may lead to complications if they are used indiscriminately. Atenolol and enalapril have no specific role in therapy for COPD but are often used when there is concomitant hypertension or cardiovascular disease.

VI-40. The answer is E. (Chap. 261) Usual interstitial pneumonia is the pathologic hallmark of idiopathic pulmonary fibrosis (IPF), but can occur in rheumatologic disorders or secondary to exposures. If no other cause is identified on history or serologic workup, then the patient is given the diagnosis of IPF. IPF is a disease that typically presents with progressive dyspnea on exertion and dry cough in an older individual. It is rare in individuals younger than 50. On physical examination, inspiratory crackles and clubbing are common. Pulmonary function tests demonstrate restrictive ventilatory defect with a low DLCO. High-resolution chest CT shows interstitial fibrosis that is worse in the bases and begins in the subpleural areas. Bronchoscopy is insufficient for histologic confirmation, and a surgical lung biopsy is required for definitive diagnosis. The natural history of IPF is one of continued progression of disease and a high mortality rate. Acute exacerbations also occur with a rapid progression of symptoms associated with a pattern of diffuse ground-glass opacities on CT. These are associated with a high mortality. Unfortunately, no therapy has been found to be effective for the treatment of IPF. Referral for lung transplantation or participation in clinical trials should be considered in all patients with a diagnosis of IPF.

VI-41. The answer is C. (Chap. 261) In many cases of interstitial lung disease, bronchoscopy can offer some clues to the cause of the disease. Diffuse alveolar hemorrhage (DAH) is a pathologic process that can occur in many diseases including vasculitis, Goodpasture’s syndrome, systemic lupus erythematosus, crack cocaine use, mitral stenosis, and idiopathic pulmonary hemosiderosis, among many others. On bronchoscopy, one would expect to see a progressively increasing bloody return on sequential aliquots of lavage fluid. Microscopic examination would show hemosiderin-laden macrophages and red blood cells. Atypical hyperplastic type II pneumocytes are seen in diffuse alveolar damage or cases of drug toxicity. Ferruginous bodies and dust particles are found in asbestos-related pulmonary disease. Lymphocytosis is common to hypersensitivity pneumonitis and sarcoidosis. Hypersensitivity pneumonitis has a low CD4:CD8 ratio, whereas sarcoidosis has an elevated CD4:CD8 ratio. The bronchoalveolar lavage fluid in pulmonary alveolar proteinosis has a milky appearance with foamy macrophages.

VI-42 and VI-43. The answers are E and E, respectively. (Chap. 261) Pulmonary alveolar proteinosis (PAP) is a rare disorder with an incidence of approximately one per million. The disease usually presents in those between the ages of 30 and 50 and is slightly more common in men. Three distinct subtypes have been described: congenital, acquired, and secondary (most frequently caused by acute silicosis or hematologic malignancies). Interestingly, the pathogenesis of the disease has been associated with antibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) in most cases of acquired disease in adults. The pathobiology of the disease is failure of clearance of pulmonary surfactant. These patients typically present with subacute dyspnea on exertion with fatigue and low-grade fevers. Associated laboratory abnormalities include polycythemia, hypergammaglobulinemia, and increased LDH levels. Classically, the CT appearance is described as “crazy pavement” with ground-glass alveolar infiltrates in a perihilar distribution and intervening areas of normal lung. Bronchoalveolar lavage is diagnostic, with large amounts of amorphous proteinaceous material seen. Macrophages filled with periodic acid–Schiff (PAS)-positive material are also frequently seen. The treatment of choice is whole-lung lavage through a double-lumen endotracheal tube. Survival at 5 years is higher than 95%, although some patients will need a repeat whole-lung lavage. Secondary infection, especially with Nocardia, is common, and these patients should be followed closely.

VI-44. The answer is E. (Chap. 261) This patient’s clinical presentation and CT imaging are consistent with the diagnosis of idiopathic pulmonary fibrosis (IPF), which is manifested histologically as usual interstitial pneumonitis (UIP). On microscopic examination, UIP is characterized by a heterogeneous appearance on low magnification with normal-appearing alveoli adjacent to severely fibrotic alveoli. There is lymphocytic infiltrate and scattered foci of fibroblasts within the alveolar septae. End-stage fibrosis results in honeycombing with loss of all alveolar structure. The typical clinical presentation of IPF/UIP is slowly progressive exertional dyspnea with a nonproductive cough. Clinical examination reveals dry crackles and digital clubbing. Patients with IPF are usually older than 50 years, and more than two-thirds have a history of current or former tobacco use. In the typical clinical situation of an older individual, a high-resolution CT scan of the chest can be diagnostic and shows subpleural pulmonary fibrosis that is greatest at the lung bases. As disease progresses, traction bronchiectasis and honeycombing are characteristic on CT scan. The cause of UIP is unknown, and no therapies have been shown to improve survival in this disease, with the exception of lung transplantation.

The presence of a dense, amorphous material in alveolar spaces that is periodic acid–Schiff positive is characteristic of pulmonary alveolar proteinosis. Pulmonary alveolar proteinosis is an interstitial lung disease that presents with progressive dyspnea, and CT imaging shows characteristic “crazy paving” with ground-glass infiltrates and thickened alveolar septae. Fibrosis is not present. Alveolar destruction with emphysematous changes would be seen in chronic obstructive pulmonary disease (COPD). The presence of crackles without wheezing or hyperinflation on examination does not suggest COPD. Furthermore, clubbing is not typically seen in COPD. Diffuse alveolar damage is seen in acute interstitial pneumonitis and acute respiratory distress syndrome (ARDS). These disorders present with a rapid, acute course that is not present in this case. The formation of non-caseating granulomas is typical of sarcoidosis, a systemic disease that usually presents in younger individuals. It is more common in those of African-American race. A typical CT in sarcoidosis would show interstitial infiltrates and hilar lymphadenopathy. End-stage disease may result in pulmonary fibrosis, but it is greatest in the upper lobes. Poorly formed granulomas may be seen in hypersensitivity pneumonitis.

VI-45. The answer is A. (Chap. 261) Pulmonary complications are common in patients with systemic lupus erythematosus (SLE). The most common manifestation is pleuritis with or without effusion. Other possible manifestations include pulmonary hemorrhage, diaphragmatic dysfunction with loss of lung volumes (the so-called shrinking lung syndrome), pulmonary vascular disease, acute interstitial pneumonitis, and bronchiolitis obliterans organizing pneumonia. Other systemic complications of SLE also cause pulmonary complications, including uremic pulmonary edema and infectious complications. Chronic progressive pulmonary fibrosis is not a complication of SLE. Cavitary lung nodules are typical of Wegener’s granulomatosis but may also be seen in a variety of necrotizing lung infections.

VI-46. The answer is E. (Chap. 261) This patient with rheumatoid arthritis (RA) is presenting with pulmonary symptoms, and the biopsy shows a pattern of cryptogenic organizing pneumonia (COP), a known pulmonary manifestation of rheumatoid arthritis. COP (formerly bronchiolitis obliterans organizing pneumonia, BOOP) usually presents in the fifth or sixth decade with a flulike illness. Symptoms include fever, malaise, weight loss, cough, and dyspnea. Inspiratory crackles are common, and late inspiratory squeaks may also be heard. Pulmonary function testing reveals restrictive lung disease. The typical pattern on high-resolution chest CT is patchy areas of airspace consolidation, nodular opacities, and ground-glass opacities that occur more frequently in the lower lung zones. Pathology shows the presence of granulation tissue plugging airways, alveolar ducts, and alveoli. There is frequently chronic inflammation in the alveolar interstitium. Treatment with high-dose steroids is effective in two-thirds of individuals, with most individuals being able to be tapered to lower doses over the first year. Azathioprine is an immunosuppressive therapy that is commonly used in interstitial lung disease due to usual interstitial pneumonitis. While it may be considered in COP that is unresponsive to glucocorticoids, it would not be a first-line agent used without concomitant steroid therapy. RA has multiple pulmonary complications. However, therapy with infliximab or methotrexate, which is useful for severe RA, is not used in the treatment of COP. Methotrexate also has pulmonary side effects and may cause pulmonary fibrosis. Hydroxychloroquine is frequently useful for joint symptoms in autoimmune disorders. Its major side effect is retinal toxicity, and it is not known to cause COP.

VI-47. The answer is B. (Chap. 262) The D-dimer measured by enzyme-linked immunosorbent assay (ELISA) is elevated in the setting of breakdown of fibrin by plasmin, and the presence of a positive D-dimer can prompt the need for additional imaging for deep venous thrombosis and/or pulmonary embolus in specific clinical situations where the patient would be considered to have an elevation in D-dimer. However, one must be cautious about placing value on an elevated D-dimer in other situations where there can be an alternative explanation for the elevated level. Of the scenarios listed in the question, the only patient who would be expected to have a negative D-dimer would be the patient with calf pain and recent air travel. The presence of a normal alveolar-arterial oxygen gradient cannot reliably differentiate between those with and without pulmonary embolism. In all the other scenarios, elevations in D-dimer could be related to other medical conditions and provide no diagnostic information to inform the clinician regarding the need for further evaluation. Some common clinical situations in which the D-dimer is elevated include sepsis, myocardial infarction, cancer, pneumonia, the postoperative state, and the second and third trimesters of pregnancy.

VI-48. The answer is B. (Chap. 262) Clinically, individuals with massive pulmonary embolus present with hypotension, syncope, or cyanosis. The hypotension and syncope occur due to acute right ventricular overload, and elevated troponin or NT-pro-brain natriuretic peptide can result from this right ventricular strain. Both elevated troponin and NT-pro-brain natriuretic peptide predict worse outcomes in pulmonary embolism. Further prognostic signs of massive pulmonary embolism include the presence of right ventricular enlargement on CT of the chest or right ventricular hypokinesis on echo-cardiogram. The presence of hemoptysis, pleuritic chest pain, or cough in association with pulmonary embolism most commonly indicates a small peripheral lesion.

VI-49. The answer is B. (Chap. 262) For many years, ventilation-perfusion imaging (V-Q) was the standard for the diagnosis of pulmonary embolism (PE). Determination of abnormal V-Q imaging can be difficult. To call a V-Q scan a high-probability scan, one needs to see two or more segmental perfusion defects in the setting of normal ventilation. In patients with underlying lung disease, however, ventilation is frequently abnormal, and most patients with PE do not actually have high-probability V-Q scans. When there is a high-probability V-Q scan, the likelihood of PE is 90% or greater. Alternatively, patients with normal perfusion imaging have a very low likelihood of PE. Most patients fall into either the low or intermediate probability of having a PE by V-Q imaging. In this setting, 40% of patients with a high clinical suspicion of PE are determined by pulmonary angiography to indeed have a PE despite having a low-probability V-Q scan. At the present time, V-Q scanning is largely supplanted by multidetector-row spiral CT angiography of the chest. When compared to conventional CT scanning with intravenous contrast, the multidetector spiral CT can provide evaluation of the pulmonary arteries to the sixth-order branches, a level of resolution that is as good as or exceeds that of conventional invasive pulmonary angiography. In addition, the CT allows evaluation of the right and left ventricles as well as the lung parenchyma to provide additional information regarding prognosis in acute PE or alternative diagnosis in the patient with dyspnea. Magnetic resonance angiography is a rarely used alternative to the above modalities in patients with contrast dye allergy. This technique provides the ability to detect large proximal PEs, but lacks reliability for segmental and subsegmental PE.

VI-50. The answer is E. (Chap. 262) This patient is presenting with massive pulmonary embolus with ongoing hypotension, right ventricular dysfunction, and profound hypoxemia requiring 100% oxygen. In this setting, continuing with anticoagulation alone is inadequate, and the patient should receive circulatory support with fibrinolysis if there are no contraindications to therapy. The major contraindications to fibrinolysis include hypertension greater than 180/110 mmHg, known intracranial disease or prior hemorrhagic stroke, recent surgery, or trauma. The recommended fibrinolytic regimen is recombinant tissue plasminogen activator (rTPA), 100 mg IV over 2 hours. Heparin should be continued with the fibrinolytic to prevent a rebound hypercoagulable state with dissolution of the clot. There is a 10% risk of major bleeding with fibrinolytic therapy, with a 1–3% risk of intracranial hemorrhage. The only indication approved by the U.S. Food and Drug Administration for fibrinolysis in pulmonary embolus (PE) is for massive PE presenting with life-threatening hypotension, right ventricular dysfunction, and refractory hypoxemia. In submassive PE presenting with preserved blood pressure and evidence of right ventricular dysfunction on echocardiogram, the decision to pursue fibrinolysis is made on a case-by-case basis. In addition to fibrinolysis, the patient should also receive circulatory support with vasopressors. Dopamine and dobutamine are the vasopressors of choice for the treatment of shock in PE. Caution should be taken with ongoing high-volume fluid administration, as a poorly functioning right ventricle may be poorly tolerant of additional fluids. Ongoing fluids may worsen right ventricular ischemia and further dilate the right ventricle, displacing the interventricular septum to the left to worsen cardiac output and hypotension. If the patient had contraindications to fibrinolysis and was unable to be stabilized with vasopressor support, referral for surgical embolectomy should be considered. Referral for inferior vena cava filter placement is not indicated at this time. The patient should be stabilized hemodynamically as a first priority. The indications for inferior vena cava filter placement are active bleeding, precluding anticoagulation, and recurrent deep venous thrombosis on adequate anticoagulation.

VI-51. The answer is E. (Chap. 262) Warfarin should not be used alone as initial therapy for the treatment of venous thromboembolic disease (VTE) for two reasons. First, warfarin does not achieve full anticoagulation for at least 5 days, as its mechanism of action is to decrease the production of vitamin K–dependent coagulation factors in the liver. Second, a paradoxical reaction that promotes coagulation may also occur upon initiation of warfarin as it also decreases the production of the vitamin K–dependent anticoagulants protein C and protein S, which have shorter half-lives than the procoagulant factors. For many years, unfractionated heparin delivered IV was the treatment of choice for VTE. However, it requires frequent monitoring of activated partial thromboplastin time (aPTT) levels and hospitalization until therapeutic international normalized ratio (INR) is achieved with warfarin. There are now several safe and effective alternatives to unfractionated heparin that can be delivered SC. Low-molecular-weight heparins (enoxaparin, tinzaparin) are fragments of unfractionated heparin with a lower molecular weight. These compounds have a greater bioavailability, longer half-life, and more predictable onset of action. Their use in renal insufficiency should be considered with caution because low-molecular-weight heparins are renally cleared. Fondaparinux is a direct factor Xa inhibitor that, like low-molecular-weight heparins, requires no monitoring of anticoagulant effects and has been demonstrated to be safe and effective in treating both deep venous thrombosis and pulmonary embolism.

VI-52. The answer is E. (Chap. 263) Parapneumonic effusions are one of the most common causes of the exudative pleural effusion. When an effusion is identified in association with pneumonia, it is prudent to perform a thoracentesis if the fluid can be safely accessed. One way to know if there is enough fluid for thoracentesis is to perform a lateral decubitus film and observe if there is 10 mm of free flowing fluid along the chest wall-pleural interface. However, if the fluid does not layer, this may indicate that it is a complex loculated fluid. A loculated effusion often indicates an infected effusion and may require chest tube drainage or surgical intervention. Other factors that are associated with the need for more invasive procedures include pleural fluid pH less than 7.20, pleural fluid glucose less than 60 mg/dL (<3.3 mmol/L), positive Gram stain or culture of the pleural fluid, and presence of gross pus in the pleural space (empyema). Fluid recurrence following initial thoracentesis does indicate a complicated pleural effusion, but a repeat thoracentesis should be performed to ensure that no concerning features have developed.

VI-53. The answer is A. (Chap. 263) The characteristics of the pleural fluid in this patient are consistent with an exudate by Light’s criteria. These criteria are as follows: pleural fluid protein/serum protein greater than 0.5, pleural fluid LDH/serum LDH greater than 0.6, and pleural fluid LDH more than two-thirds of the upper limit of normal serum values. If one of the criteria is met, then the effusion would be classified as an exudate. This patient clearly meets the criteria for an exudate. Exudative pleural effusions occur when there are alterations in the local environment that change the formation and absorption of pleural fluid. The most common causes of exudative pleural effusion are infection and malignancy. Other less common causes include pulmonary embolism, chylothorax, autoimmune diseases, asbestos exposure, drug reactions, hemothorax, and postoperative cardiac surgery or other cardiac injury, among others. Unfortunately, 25% of transudative effusions can be incorrectly identified as exudates by these criteria. Most often this occurs when the effusion has an increased number of cells to cause an elevation in the LDH or has been treated with diuretics to cause an increase in pleural fluid protein. Transudative effusions are most often caused by heart failure, but can also be seen in cirrhosis, nephrotic syndrome, and myxedema.

VI-54. The answer is A. (Chap. 263) The pleural fluid characteristics are typical of a chylothorax, which occurs when there has been an injury to the thoracic duct leading to accumulation of chyle in the pleural space. The most common cause of chylothorax is traumatic disruption of the thoracic duct, especially following surgeries. The surgeries that have been associated most often with chylothorax are esophagectomy and correction of congenital heart disease. The patient often presents with rapidly progressive shortness of breath within a few weeks of the surgery and has large pleural effusions. The appearance of a milky fluid on thoracentesis should alert one to the possibility of chylothorax and prompt measurement of triglyceride levels of the pleural fluid. A triglyceride level of more than 110 mg/dL (1.2 mmol/L) is characteristic of chylothorax. The treatment of chylothorax is placement of a chest tube with administration of octreotide, a somatostatin analogue. While it is not entirely clear why this is effective, the hypothesis is that octreotide decreases splanchnic blood flow and thereby decreases triglyceride production and thoracic duct flow. Patients are often also asked to stop all oral intake to further decrease chyle production. If conservative measures fail, the thoracic duct ligation can be performed. Prolonged chest tube drainage is contraindicated, however, as the high protein content in the drained fluid can lead to malnutrition and increased infection risk.

VI-55. The answer is B. (Chap. 263) A primary spontaneous pneumothorax occurs in the absence of trauma to the thorax. Most individuals who present with a primary spontaneous pneumothorax are young, and primary spontaneous pneumothorax occurs almost exclusively in cigarette smokers, with cigarette smoking being the primary risk factor. Primary spontaneous pneumothorax is also more common in men and has been associated with a tall, thin body habitus. The primary cause is the rupture of small apical pleural blebs or cysts, and the CT scan of the chest is often normal. About half of individuals will experience more than one primary spontaneous pneumothorax. The initial treatment is simple needle aspiration, which is most commonly done with ultrasound or CT guidance. Oxygen is given simultaneously to speed resorption of the residual air in the pleural space. If conservative treatment fails, tube thoracostomy can be performed. Pneumothoraces that fail to resolve or are recurrent often require thoracoscopy with stapling of blebs and pleural abrasion, a treatment that is effective in almost 100% of cases.

VI-56. The answer is B. (Chap. 263) The most common cause of pleural effusion is left ventricular failure. Pleural effusions occur in heart failure when there are increased hydrostatic forces increasing the pulmonary interstitial fluid and the lymphatic drainage is inadequate to remove the fluid. Right-sided effusions are more common than left-sided effusions in heart failure. Thoracentesis would show a transudative fluid. Pneumonia can be associated with a parapneumonic effusion or empyema. Parapneumonic effusions are the most common cause of exudative pleural effusions and are second only to heart failure as a cause of pleural effusions. Empyema refers to a grossly purulent pleural effusion. Malignancy is the second most common cause of exudative pleural effusion. Breast and lung cancers and lymphoma cause 75% of all malignant pleural effusions. On thoracentesis, the effusion is exudative. Cirrhosis and pulmonary embolus are far less common causes of pleural effusions.

VI-57. The answer is E (Chap. 264) Patients with amyotrophic lateral sclerosis (ALS) often develop hypoventilation due to involvement of their respiratory pump muscles, e.g., diaphragm, intercostal muscles, and sternocleidomastoids. Noninvasive positive pressure ventilation (NIPPV) has been used successfully in the therapy of patients with hypoventilation such as ALS. Nocturnal NIPPV can improve daytime hypercapnea, prolong survival, and improve health-related quality of life. Current ALS guidelines are to institute NIPPV if symptoms of hypoventilation exist and PaCO2 is 45 mmHg or greater, nocturnal desaturation to less than 89% is documented for 5 consecutive minutes, maximal inspiratory pressure is less than 60 cmH2O, or FVC is less than 50% predicted. Symptoms of hypoventilation are not particular to ALS and may include the following: dyspnea during activities of daily living, orthopnea in diseases that affect diaphragm function, poor quality sleep, daytime hypersomnolence, early morning headaches, anxiety, and impaired cough in neuromuscular disease.

VI-58. The answer is C. (Chap. 264) The patient has muscular dystrophy and is at risk for the development of hypoventilation. Many patients with hypoventilation are relatively asymptomatic or only endorse symptoms after pointed questions about sleep quality, morning headache, or orthopnea due to diaphragmatic weakness if present. The patient described here has asymptomatic hypoxemia and a normal chest radiograph aside from low lung volumes. Ventilation-perfusion mismatch and shunt are unlikely to be present without infiltrates, thus atelectasis, mucous plug, and pneumonia are not the correct answers. The patient has no risk factors described for methemoglobinemia. The most likely explanation is the presence of hypoventilation with alveolar hypoxia due to elevated PaCO2 through the alveolar gas equation. An arterial blood gas measurement would confirm this with elevation in PaCO2, depressed PaO2, and a normal A-a gradient.

VI-59. The answer is B. (Chap. 264) The physiologic effects of hypoventilation are typically magnified during sleep because of a further reduction in central respiratory drive. Hyper-capnia causes cerebral vasodilation, which manifests as headache upon wakening. The headache typically resolves soon after awakening as cerebral vascular tone returns to normal with increased ventilation. Patients with frequent nocturnal arousals from sleep and patients with nocturnal hypoventilation commonly complain of daytime somnolence and may also exhibit confusion and fatigue. Hypoventilation causes an increase in PCO2and an obligatory fall in PO2. The hypoxemia can stimulate erythropoiesis and result in polycythemia. With central hypoventilation disorders, patients may also have impaired cranial nerve reflexes or muscular function, causing aspiration.

VI-60. The answer is D. (Chap. 266) Common indications for lung transplantation include chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, suppurative lung disease such as cystic fibrosis, and pulmonary arterial hypertension. Five-year survival is similar for all indications for lung transplantation at approximately 50%. For most indications, double-lung transplantation is the preferred procedure, and it is mandatory for patients with suppurative lung disease like cystic fibrosis. In general, in patients with idiopathic pulmonary arterial hypertension, double-lung transplantation is preferred because of concern of overcirculation in the low-resistance vascular bed of the transplanted lung when a native lung is present with markedly elevated pulmonary vascular resistance. It is very rare for the primary disease to recur after transplantation, and this has not been described in idiopathic pulmonary arterial hypertension. The right ventricle is highly plastic and will generally recover function after elevated pulmonary vascular resistance is removed by lung transplantation. Subsequently, it is rare to perform heart-lung transplantation in pulmonary arterial hypertension patients unless there is concomitant complex congenital heart disease that cannot be repaired at the time of lung transplantation.

VI-61. The answer is A. (Chap. 266) The long-term complications of lung transplantation are multisystem and range from the diseases that affect the lung and are complications of a foreign body in the chest to distant organ disease, either due to infections or complications of immunosuppressive therapy. Although osteoporosis, post-transplant lymphoproliferative disorders, and chronic kidney disease are important complications of steroids, calcineurin inhibitors, and other agents used for immunosuppression, the major complications post-transplant are in the lung. Primary graft dysfunction is a form of acute lung injury immediately after lung transplantation and is relatively rare, with severe disease occurring in only 10–20% of cases. Airway complications such as anastomotic dehiscence or stenosis have similar occurrence rates, but can usually be managed bronchoscopically with good survival. Rejection of transplanted organ is very common and is the main limitation to better medium- and long-term outcomes. Rejection occurs as acute cellular rejection often presenting with cough, low-grade fever, dyspnea, infiltrates on radiographs, and declining lung function. In contrast, chronic rejection typically presents with advancing obstruction on pulmonary function testing, no infiltrates, and worsening dyspnea on exertion. This constellation in post-transplant patients is termed bronchiolitis obliterans syndrome. Fifty percent of lung transplant patients have some degree of bronchiolitis obliterans syndrome, and it is the main impediment to better long-term survival. Therapy is often with augmented immunosuppression, although there is no consensus of how to do this or the duration of this augmentation.

VI-62. The answer is B (Chap. 266) Chronic kidney disease is a common finding in patients after lung transplantation and is associated with poorer outcomes. While rarely patients may have hemolytic-uremic syndrome underlying the kidney disease, it is usually acute, and the most common etiology of gradually progressive decline in renal function is calcineurin inhibitor neuropathy. Cyclosporine and tacrolimus are calcineurin inhibitors commonly used in immunosuppressive regimens after lung transplantation. The exact mechanism of this toxicity is unclear but may include a direct toxicity of inhibition of the calcineurin-NFAT system within the kidney, alteration in glomerular blood flow, and host/environment interactions within the kidney with calcineurin inhibitors. Prednisone, albuterol, and mycophenolate mofetil are not known to be nephrotoxic.

VI-63. The answer is B. (Chap. 266) The optimal timing for lung transplantation is critical to improve survival and add quality-adjusted life years. Individuals with cystic fibrosis should be considered for lung transplantation when the FEV1 is less than 30% predicted or is rapidly falling. Other indications for lung transplantation in cystic fibrosis include oxygen-dependent respiratory failure, hypercapnia, and pulmonary hypertension.