Volume 38 • Number 18 August 31, 2015

Unilateral : Clinical Scenarios and Differential Diagnosis Kathleen E. Jacobs, MD, and Paul Stark, MD

After participating in this activity, the radiologist should be better able to describe the basic pathophysiology and characteristic imaging features of pulmonary edema, identify etiologies of unilateral pulmonary edema on the basis of an understanding of the underlying pathogenesis and clinical context, and identify entities that may mimic unilateral pulmonary edema.

Category: General Radiology is determined by net liquid movement across the capillary Subcategory: Chest membrane. Modality: Radiography Pulmonary edema may be classifi ed into four types on the basis of the mechanism: hydrostatic pressure edema, perme- ability edema with diffuse alveolar damage, permeability Key Words: Unilateral Pulmonary Edema, Ipsilateral edema without diffuse alveolar damage, and mixed edema. Pulmonary Edema, Contralateral Pulmonary Edema The mechanism of hydrostatic pressure edema is increased intravascular hydrostatic pressure relative to extrav ascular Pulmonary edema is one of the most commonly encountered hydrostatic pressure, which will drive liquid into the extra- pathologic processes in chest radiology. Although pulmonary vascular space. Examples of hydrostatic pressure edema edema has classically a bilateral and symmetric distribution, include left ventricular failure, volume overload, and renal unilateral pulmonary edema is less common and may be con- failure. Clinically, intravascular hydrostatic pressure of the fused easily with . Familiarity with the causes of pulmonary capillaries is deduced from measurement of pul- unilateral pulmonary edema is important for correct diagnosis monary capillary wedge pressure (PCWP). PCWP of 15 to and patient management. 20 mm Hg leads to pulmonary vascular cephalization. When PCWP exceeds 20 mm Hg, interstitial pulmonary edema Pathophysiology and Classifi cation of develops, which manifests as thickening of the interlobular Pulmonary Edema septa such as and peribronchial cuffi ng, perivas- Pulmonary edema is defi ned as abnormal accumulation of cular cuffi ng, and subtle ground-glass opacities on chest liquid in the extravascular compartments. Distribution radiographs. If PCWP exceeds 25 mm Hg, alveolar pulmo- of liquid in the intravascular and extravascular compartments nary edema develops, with liquid-fi lling alveoli manifesting as perihilar ground-glass opacities progressing to consolida- tion, usually without air bronchograms.1 Dr. Jacobs is Radiology Resident, and Dr. Paul Stark is Professor Emeritus, Permeability edema results from increased porosity of the Department of Radiology, University of California San Diego, and Chief of Cardiothoracic Radiology, VA San Diego Health Care System, 3350 La Jolla tight junctions in the alveolar-capillary membrane, which Village Dr, Mail Code 114, San Diego, CA 92161; E-mail: paul.stark2@ may occur with or without damage to the alveolar membrane. gmail.com. Permeability edema with diffuse alveolar damage leads The authors and all staff in a position to control the content of this CME activity clinically to acute respiratory distress syndrome (ARDS), and their spouses/life partners (if any) have disclosed that they have no relation- ships with, or fi nancial interests in, any commercial organizations pertaining to which may be precipitated by severe pneumonia, sepsis, this educational activity. trauma, pancreatitis, or blood transfusion. Early alveolar

Lippincott Continuing Medical Education Institute, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Lippincott Continuing Medical Education Institute, Inc., designates this enduring material for a maximum of 2 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. To earn CME credit, you must read the CME article and complete the quiz and evaluation on the enclosed answer form, answering at least seven of the 10 quiz questions correctly. This continuing medical education activity expires on August 30, 2016. 1

CCDRv38n18.inddDRv38n18.indd 1 66/30/15/30/15 7:087:08 PMPM fi lling with liquid in a peripheral and dependent distribution aspiration, bronchial obstruction, unilateral pulmonary venous with air bronchograms is a characteristic imaging feature of occlusion, and prolonged lateral decubitus positioning. diffuse alveolar damage in ARDS. Examples of permeability Reexpansion pulmonary edema is the best described etiol- edema without diffuse alveolar damage include heroin- ogy of unilateral pulmonary edema (Figures 1 and 2). Chronic induced and high-altitude pulmonary edema. lung collapse results in decreased lung compliance secondary Mixed pulmonary edema is multifactorial, combining fea- to decreased surfactant production and thickening of the tures of hydrostatic and permeability edema. Examples pulmonary microvascular endothelium. When the lung is rap- include neurogenic pulmonary edema, upper airway obstruc- idly reexpanded in the setting of thoracentesis for hydrothorax tion-induced pulmonary edema, and many of the entities or chest tube placement for pneumothorax, mechanical injury associated with unilateral pulmonary edema as described associated with stretching of the alveoli and capillary endothe- below. lium increases alveolar-capillary permeability. Reperfusion injury with release of cytokines and oxygen-free radicals fur- Ipsilateral Unilateral Pulmonary Edema ther contributes to alveolar damage. A component of hydro- Unilateral pulmonary edema may occur ipsilateral or con- static pressure edema results from decreased extravascular tralateral to the side of pulmonary abnormality. Causes of interstitial hydrostatic pressure because of applied negative ipsilateral pulmonary edema include rapid lung reexpansion, suction pressure. Onset of pulmonary edema is acute, devel- reimplantation response or acute rejection after lung trans- oping within hours of lung reexpansion. It may progress for plantation, acute mitral regurgitation, pulmonary contusion, 24 to 48 hours but should resolve gradually over 5 to 7 days. Reexpansion pulmonary edema typically involves the entire lung, but it may involve a single lobe or segment. Slow

A B

Figure 1. A: Spontaneous left-sided pneumothorax. B: Reexpansion pulmonary edema in the left lung after insertion of a thoracostomy tube and rapid evacuation of the pneumothorax.

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CCDRv38n18.inddDRv38n18.indd 2 66/30/15/30/15 7:087:08 PMPM Figure 2. Right-sided reexpansion pulmonary edema after rapid drainage of 4 L of pleural effusion in a patient with liver cirrhosis and hepatic hydrothorax. lung reexpansion with removal of approximately 1 L per day of air or liquid and avoidance of negative suction pressure can Figure 4. Acute rejection of the right lung 1 week after lung trans- 1,2 plantation. This demonstrates right unilateral prevent the development of pulmonary edema. pulmonary edema. Two processes may occur after lung transplantation, either of which can cause pulmonary edema of the transplanted pressure. Decreased surfactant production increases intra- lung: reimplantation response (Figure 3) and acute rejection alveolar surface tension with concurrent retention of alveolar (Figure 4). Reimplantation response occurs in nearly all trans- liquid. Lymphatic disruption further contributes to pulmonary planted , developing 24 hours postoperatively, peaking edema by preventing clearance of extravascular liquid.3 on postoperative day 4, and gradually clearing for up to several Acute rejection after lung transplantation results in perme- weeks. Both hypoxic injury of the transplanted lung before ability edema, with a cell-mediated immune response caus- surgery, and reperfusion injury of the transplanted lung after ing perivascular monocyte infi ltration. Acute rejection can surgery, damage the alveolar-capillary membrane. Redistri- have an identical imaging appearance as reimplantation bution of blood fl ow from the contralateral native lung to the response, but acute rejection occurs later after surgery, within transplanted lung also increases intravascular hydrostatic several days to weeks.3 Asymmetric pulmonary edema occurs in approximately 9% of patients admitted with acute mitral valve regurgitation (Figure 5).4 Acute mitral regurgitation most commonly

Figure 3. Twenty-four hours after right lung transplantation, reim- plantation response developed in the transplanted right lung. This Figure 5. Acute mitral valvular regurgitation secondary to rupture chest radiograph shows unilateral pulmonary edema with ground- of a papillary muscle, resulting in right lung pulmonary edema glass opacifi cation. with preferential involvement of the right upper lobe. 3

CCDRv38n18.inddDRv38n18.indd 3 66/30/15/30/15 7:087:08 PMPM occurs in the setting of myocardial infarction, with dysfunction can be similar to postobstructive pneumonia, but if clinical or rupture of the papillary muscles or chordae tendineae. The features of infection are present, the differential diagnosis regurgitant jet is directed toward the right superior pulmonary should favor pneumonia. vein during ventricular systole, resulting in preferential right Unilateral pulmonary venous occlusion by tumors or upper lobe pulmonary edema. Acute exacerbation of chronic thrombosis leads to stasis with subsequent increase in pul- mitral regurgitation in a patient with rheumatic heart disease monary vascular resistance, potentially resulting in hydro- or cardiomyopathy also may cause pulmonary edema, but static pressure edema in the ipsilateral lung.1,7 the cardiac silhouette is more likely to be enlarged with left Prolonged lateral decubitus positioning should be consid- atrial dilatation. ered as a cause of unilateral pulmonary edema in patients Pulmonary contusion results in hemorrhagic permeability who are unconsciousness and intubated for a long period. edema secondary to shear mechanical injury of the alveolar- Gravity increases blood fl ow and capillary hydrostatic pres- capillary membrane. Chest radiographic changes become sure in the dependent lung. Pulmonary edema is further exac- evident within 4 to 6 hours after injury, peak at 24 to 48 hours erbated by decreased surfactant production with prolonged after injury, and resolve within 3 to 10 days.5 Concurrent .7 volume overload from IV resuscitation, transfusion, and aspi- ration can complicate interpretation of the chest radiograph Contralateral Pulmonary Edema and also must be considered in the differential diagnosis of Unilateral pulmonary edema occurring contralateral to the pulmonary edema after chest trauma. side of pulmonary abnormality is driven predominantly by Aspiration-induced pulmonary edema results from chem- hydrostatic pressure edema in the normal lung. ical injury to the alveolar-capillary membrane (Figure 6). In the setting of unilateral lung disease, hydrostatic pres- Pulmonary edema manifests during the acute phase, within sure pulmonary edema will preferentially involve the con- 2 hours of aspiration. In the later phase, approximately 4 to tralateral normal lung. Entities that cause unilateral lung 6 hours after aspiration, an infl ammatory response ensues disease include asymmetric emphysema, lobectomy, and with neutrophilic infi ltration and de-epithelialization of bron- Swyer-James-MacLeod syndrome. In the patient with asym- chial mucosa causing chemical pneumonia. It is important metric emphysema, hypoxic vasoconstriction and vascular to note that gastric pH must be less than 2.5 to elicit chemical defi ciency in the diseased lung lead to increased perfusion injury. Aspiration of higher-pH contents will not produce of the contralateral normal lung. When hydrostatic pressure pulmonary edema but is more likely to cause bacterial 6 increases, such as in left ventricular failure, pulmonary edema pneumonia. will occur in the nonemphysematous lung. Swyer-James- Bronchial obstruction may be caused by tumors, mucous MacLeod syndrome is a type of postinfectious plugging, foreign body aspiration, or ligation during surgery. obliterans that occurs early in childhood.7 Abnormal develop- Hypoxic injury and increased surface tension caused by lack ment of alveolar buds results in a reduced number of pulmo- of surfactant in the nonaerated lung result in alveolar-capillary nary capillaries and subsequent increased pulmonary membrane damage and permeability edema. Continued vascular resistance. Therefore, should left ventricular failure obstruction leads to retained proteinaceous secretions, result- 7 occur, cardiogenic pulmonary edema will involve preferen- ing in the “drowned lung” appearance. Imaging appearance tially the hyperperfused, normal lung. Unilateral congenital interruption of the pulmonary arteries and unilateral obstruction of the pulmonary arteries by tumors or thromboemboli also can result in pulmonary edema of the contralateral lung. Blood fl ow is shunted to patent pulmonary arteries in the normal lung, resulting in pulmonary arterial hyperperfusion and, potentially, pulmonary edema. Pulmonary edema is reported to occur in less than 10% of both acute (Figure 7) and chronic cases of pulmonary thromboembolism.1

Differential Diagnosis Various disease entities may cause unilateral lung opacifi - cation, thereby mimicking unilateral pulmonary edema. In unilateral lung disease such as emphysema or thrombo- embolism, shunting of blood fl ow causes relative enlarge- ment of hilar pulmonary vessels and increased opacifi cation of the normal lung. When compared with the hypoperfused, abnormal lung, one may confuse these imaging fi ndings with pulmonary edema (Figure 8). Absence of Kerley lines, which are only present with increased extravascular liquid, is an important distinguishing feature. For indeterminate cases, Figure 6. Status after acute aspiration of gastric content into the CT is a helpful examination to confi rm or exclude the presence right lung with unilateral chemical pneumonia and pulmonary of pulmonary edema. edema, preferentially involving the right upper lobe and the basal segments of the right lower lobe, but sparing the superior seg- Amiodarone pulmonary toxicity in a patient who has ment of the right lower lobe. undergone coronary artery bypass graft (CABG) is a unique 4

CCDRv38n18.inddDRv38n18.indd 4 66/30/15/30/15 7:087:08 PMPM Figure 9. CT scan in a patient with amiodarone toxicity and uni- lateral, right-sided, nonspecifi c interstitial pneumonia. The pref- erential involvement of the right lung is explained by hyper perfusion of the right lung secondary to left phrenic nerve paralysis with of the left lung, subsequent unilateral hypoxic vaso- constriction, and redirection of the pulmonary vascular fl ow to the Figure 7. Right-sided pulmonary edema secondary to massive right lung. pulmonary embolus to the left proximal pulmonary artery, which occurred intraoperatively during prostatectomy. Additional causes of unilateral lung opacifi cation include pneumonia and radiation injury. Both may present as asym- scenario of unilateral lung opacifi cation. Phrenic nerve injury metric consolidation. Clinical signs of infection such as fever during CABG results in left hemidiaphragm paralysis, with or leukocytosis clearly favor pneumonia. In the setting of decreased ventilation of the left lung. Hypoxic vasoconstric- radiation injury, comparison with remote images to assess tion directs blood fl ow to the right lung, resulting in increased prior presence of tumors, and a history of radiation therapy exposure to circulating amiodarone.8 Amiodarone pulmonary confi ned to one hemithorax, are helpful to determine the cor- toxicity most commonly manifests as nonspecifi c interstitial rect diagnosis. pneumonia with peripheral or peribronchovascular ground- glass opacities and consolidation (Figure 9). Conclusion Lymphangitic tumor spread is an uncommon entity that Pulmonary edema is multifactorial, primarily involving also may mimic unilateral pulmonary edema. CT fi ndings of increased intravascular hydrostatic pressure, increased alveolar- thickened interlobular septa with or without the presence of capillary membrane permeability, or both. Pulmonary edema ground-glass opacities are not diagnostic of lymphangitic can be asymmetric, involving the lung either ipsilateral or con- tumor spread—asymmetric pulmonary edema and pneumo- tralateral to the side of a pulmonary abnormality. This CME nia must remain in the differential diagnosis. However, activity emphasizes that although unilateral pulmonary edema known history of malignancy and the presence of enlarged is a potentially confusing fi nding, clinical context and ancillary / hilar mediastinal lymph nodes with perilymphatic nodules imaging fi ndings can help narrow the differential diagnosis. in the lung parenchyma are important clues that will favor a diagnosis of lymphangitic tumor spread. Acknowledgment The authors thank Dr. Helga E. Stark for her help with illustrations.

References 1. Glueker T, Capasso P, Schnyder P, et al. Clinical and radiologic features of pulmonary edema. Radiographics. 1999;19:1507-1531. 2. Tarver RD, Broderick LS, Conces DJ. Reexpansion pulmonary edema. J Thoracic Imaging. 1996;11:198-209. 3. Stark P. Lung transplantation: imaging of early and late complications. Contemp Diagnos Radiol. 2010;33:1-6. 4. Schnyder PA, Sarraj AM, Duvoisin BE, et al. Pulmonary edema associated with mitral regurgitation: prevalence of predominant involvement of the right upper lobe. Am J Roentgenol. 1993;161:33-36. 5. Cohn SM, DuBose JJ. Pulmonary contusion: an update on recent advances in clinical management. World J Surg. 2010;34:1959-1970. 6. Marik PE. Aspiration pneumonitis and aspiration pneumonia. N Engl J Med. Figure 8. Swyer-James-MacLeod syndrome (unilateral bronchi- 2001;344:665-671. olitis of the right lung). The right lung is hyperlucent because of 7. Calenoff L, Kruglik GD, Woodruff A. Unilateral pulmonary edema. Radiology. hypoxic vasoconstriction and gas trapping. This CT scan shows 1978;126:19-24. lateralization of blood fl ow with increased attenuation in the con- 8. Sheldon PJ, Crawford SW, Richman KM, Stark P. Coronary artery bypass graft tralateral normal left lung, mimicking pulmonary edema. surgery and phrenic nerve injury: another twist. Clin Intensive Care. 2000;11:1-4.

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CCDRv38n18.inddDRv38n18.indd 5 66/30/15/30/15 7:087:08 PMPM CME QUIZ: VOLUME 38, NUMBER 18 To earn CME credit, you must read the CME article and complete the quiz and evaluation on the enclosed answer form, answering at least seven of the 10 quiz questions correctly. Select the best answer and use a blue or black pen to completely fi ll in the corresponding box on the enclosed answer form. Please indicate any name and address changes directly on the answer form. If your name and address do not appear on the answer form, please print that information in the blank space at the top left of the page. Make a photocopy of the completed answer form for your own fi les and mail the original answer form in the enclosed postage-paid business reply envelope. Only two entries will be considered for credit. Your answer form must be received by Lippincott CME Institute, Inc., by August 30, 2016. At the end of each quarter, all CME participants will receive individual issue certifi cates for their CME participation in that quarter. These individual certifi cates will include your name, the publication title, the volume number, the issue number, the article title, your participation date, the AMA credit awarded, and any subcategory credit earned (if applicable). For more information, call (800) 638-3030. All CME credit earned via Contemporary Diagnostic Radiology will apply toward continuous certifi cation requirements. ABR continuous certifi cation requires 75 CME credits every 3 years, at least 25 of which must be self-assessment CME (SA-CME) credits. All SAM credits earned via Contemporary Diagnostic Radiology are now equivalent to SA-CME credits (www.theabr.org). Online quiz instructions: To take the quiz online, log on to your account at www.cdrnewsletter.com, and click on the “CME” tab at the top of the page. Then click on “Access the CME activity for this newsletter,” which will take you to the log-in page for http://cme.lww.com. Enter your username and password. Follow the instructions on the site. You may print your offi cial certifi cate immediately. Please note: Lippincott CME Institute will not mail certifi cates to online participants. Online quizzes expire on the due date.

1. A patient with cirrhosis presents to the emergency depart- 6. Which one of the following pulmonary entities is associated ment with . Chest radiography reveals with ipsilateral pulmonary edema? complete right hemithorax opacifi cation with contralateral A. Unilateral pulmonary venous occlusion , suggesting a large right pleural effusion. B. Pulmonary arterial occlusion The most appropriate therapy is chest tube placement with C. Unilateral emphysema A. full lung reexpansion within 24 hours D. Single lobectomy B. full lung reexpansion within 48 hours E. Lymphangitic tumor spread to the lung C. setting to low pressure negative suction 7. In a patient with Swyer-James-MacLeod syndrome who devel- D. 1 L of pleural effusion removed per day ops left ventricular failure, which one of the following will be E. 2 L of pleural effusion removed per day affected by pulmonary edema? 2. A patient presents to the emergency department with sub- A. Ipsilateral lung sternal and acute hypotension. Chest radiography B. Contralateral normal lung demonstrates diffuse opacifi cation of the right upper lobe C. Bilateral lungs without volume loss. The most likely diagnosis is D. Ipsilateral lower lobe A. pneumonia E. Contralateral lower lobe B. acute mitral valve regurgitation 8. One day after lung transplantation, chest radiography dem- C. onstrates diffuse increased opacifi cation of the transplanted D. aspiration lung. The most likely diagnosis is E. adenocarcinoma A. acute transplant rejection 3. Which one of the following unilateral conditions may cause B. aspiration contralateral pulmonary edema? C. pneumonia A. Bronchial obstruction D. reimplantation response B. Pulmonary venous occlusion E. bronchial stenosis at anastomosis C. Pulmonary arterial occlusion 9. Which one of the following is a key distinguishing radiographic D. Prolonged lateral decubitus positioning feature of pulmonary interstitial edema? E. Pneumothorax treatment A. Redistribution of pulmonary vascular fl ow 4. The pathogenesis of reexpansion pulmonary edema follow- B. Indistinctness of perihilar vessels ing treatment of a pneumothorax or hydrothorax includes all C. Kerley lines of the following, except D. Pleural effusion A. mechanical injury at the alveolar membrane E. Peripheral consolidation B. increased extravascular interstitial hydrostatic pressure 10. Alveolar pulmonary edema occurs when PCWP is C. decreased surfactant production A. 5 mm Hg D. increased alveolar-capillary membrane permeability B. 10 mm Hg E. oxygen-free radical injury to the alveolar membrane C. 15 mm Hg 5. All of the following are causes of permeability pulmonary D. 20 mm Hg edema, except E. >25 mm Hg A. volume overload B. high-altitude sickness C. heroin overdose D. pancreatitis E. pulmonary contusion

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