| DIAGNOSTIC THORACIC IMAGINGDIAGNOSTIC THORACIC IMAGINGNOTICE Medicine is an ever-changing science. As new research and clinical experience: broaden our knowledge, changes in treatment and drug therapy are required, ‘The authors and the publisher of this work have checked with sources be- lieved to be reliable in their efforts to provide information that is complete: and generally in accord with the standards accepted at the time of publica tion, However, in view of the possibility of human error or changes in medical sciences, neither the editors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the: information contained herein isin every respect accurate or complete, and they ‘disclaim all responsibility for any errors of omissions or for the results obtained from use of the information contained in this work. Readers are encouraged. to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not bbeen made in the recommended dose or in the contraindications for adminis tration. This recommendation is of particular importance in connection with new or infrequently used drugs.DIAGNOSTIC THORACIC IMAGING Wallace T. Miller, Jr., MD Associate Professor of Radiology Associate Chair for Education, Department of Radiology University of Pennsylvania Schoo! of Medicine Philadelphia, Pennsylvania McGraw-Hill Medical Publishing Division New York Chicago San Francisco Lisbon London Madrid Mexico City Milan New Delhi San Juan Seoul Singapore Sydney TorontoCopyright © 2006 by The McGraw-Hill Companies Inc. Al rights reserved. 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Under no circumstances shall McGraw- Ul andor ts iensorsbe Fable for any indirect, incidental, special, punitive, consequential or simular damages that result fom the use of or ibility to use the ‘work even if any of them has been advised ofthe possibilty of suck damages. This limitation of ability shall apply to any claim or cause whatsoever whether such aim or cause arses in contac, tort or otherwise DOE: 10,103610071413006To my Dad, whose teaching was the genesis for this book.For more information about this ite, cick here CONTENTS m. 10. 1. 12. 13. 14, 15. PREFACE ACKNOWLEDGMENTS. DIFFUSE LUNG DISEASES DIFFUSE ALVEOLAR LUNG DISEASES ISOLATED DIFFUSE GROUND-GLASS OPACITY DIFFUSE INTERSTITIAL LUNG DISEASE PULMONARY PARENCHYMAL FINDINGS OF DIFFUSE AIRWAY DISEASE AND DIFFUSE PULMONARY VASCULAR DISEASE FOCAL LUNG DISEASES ACUTE FOCAL ALVEOLAR OPACITIES AND ATELECTASIS NONSPECIFIC CHRONIC FOCAL ALVEOLAR OPACITIES AND (UNUSUAL ACUTE FOCAL ALVEOLAR OPACITIES. IMAGING NONSPECIFIC NODULES AND MASSES UNILATERAL OR ASYMMETRIC APICAL LUNG DISEASE IMAGING SPECIFIC NODULES, MASSES OR INFILTRATES, MEDIASTINAL DISORDERS DISORDERS AFFECTING THE TRACHEA ANTERIOR MEDIASTINAL DISORDERS AND THE CARDIAC COMPARTMENT MIDDLE MEDIASTINAL DISORDERS POSTERIOR MEDIASTINAL MASSES. ABNORMALITIES OF THE PULMONARY HILUM DISEASES OF THE PLEURA INDEX 44 67 155 215 217 282 312 390 422 465 467 523 598 706 732 788 859PREFACE ‘The purpose of this book is to provide a comprehensive review ‘of pattern recognition in thoracic imaging. Since the undeslying pathology is constant, it seems reasonable that the imaging char- acteristics of diseases should be the same regardless of imaging ‘modality. Thus, my intention is to unify chest radiographic and chest computed tomographic (CT) patterns of thoracic disorders. CT should merely represent a mote detailed look at the thoracic ‘organs. When appropriate, magnetic resonance imaging and nu- clear medicine imaging features are also incorporated into the discussion of a disorder, Furthermore, | believe that accurate imaging diagnosis of thoracic disease can be achieved only with the use of appropriate clinical history. A given imaging appear- ance will be specific for a particular disorder in relatively few cases. Therefore, the characteristic clinical presentations of the various thoracic diseases are discussed in conjunction with the imaging findings. ‘The book is divided into three parts, all of which follow a similar format. Each part is divided into chapters based on imaging appearance. In each chapter, disorders that characteris- tically present with a given imaging appearance are discussed, ‘The discussion of each disorder includes the most salient patho- logic, histologic, and clinical features followed by the char- acteristic findings for chest radiography, CT, and other imag- ing modalities. Differentiating features, both clinical and ra- iographic, between etiologies that produce the same imag- ing pattern are emphasized when possible, Some diseases may have several imaging features. In such cases, the disease is dis- ‘cussed under each pattern but the most comprehensive review of the subject occurs under the most characteristic pattern for the disease. One problem in the dissemination of radiographic informa- tion is the inexact nature of many radiographic terms. One con- ‘sequence is that two individuals who interpet the same film may se different words to describe the same radiographic findings. ‘An even more serious consequence is that two observers may use the same words to describe two different findings. This is ‘one reason why this fext is heavily illustrated, in the hope that the reader will associate the terms used in the text with the imag ing findings. The text at the beginning of each part includes a discussion of the terms used to describe the various. imaging findings in that part, so that the reader can accurately link the terms with the imaging findings. Copyright © 2006 by The McGraw-Hill Companies, Inc. Click here for terms of useACKNOWLEDGMENTS | would like to thank Reuben Meatich, my former chairman, for encouraging me to start writing this book. Without his push, T ‘would not have started this project. Before I had editors, I had residents. Many residents have reviewed and critiqued clement ofthis text at various stages of the project; would lke to thank themall for theirhelpin refining the text, However, three residents stand out as my most enduring helpers: Dean Batten, Sandra Allison, and Scott Akers. Thave worked with many outstanding radiology colleagues. ‘Overtime, they have supported me in my acaclemic endeavors and have enriched my working environment. Some individuals ‘whom I would like to thank personally include my colleagues in the chest radiology section: Warren Gefter, Judy Aronchick, ‘Anna Kelansky, Rosita Shah, and Drew Torigian. This book would notexistf did not have clinical colleagues. The many cases illustrating this text often have detailed clinical histories as well as final answers, Since the completion of my residency, Tam sure that T have learned more from my many friends in clinical medicine than from any other source. Some in- dividuals who deserve special note are: John Hansen-Flaschen, Rob Kotloff, Greg Tino, and Milt Rossman of the Pulmonary ‘and Critical Care division of Internal Medicine, and Steve Gluckman, Neil Fishman, Mindy Schuster, and Rob MacGreg- ‘gor of the Infectious Disease division of Internal Medicine. ‘This book contains more than 2000 radiographic images, Most of the images were photographed by one of four mem- bers of the Media Services group: Andrea Kaldrovics, Steve ‘Strommer, Dave Brown, and Juanita James. I thank these indi- viduals for their hard work and dedication I would also like to thank my secretary Barbara Gallagher for her help in preparing the manuscript. Lastly, I would like to thank Christina for everything else. Copyright © 2008 by The McGraw-Hill Companies, In. Cick here for terms of use.Part | DIFFUSE LUNG DISEASES ‘When evaluating pulmonary parenchyma, one of the most im- portant distinctions to be made is the difference between focal lung disease and diffuse lung disease (nearly uniform involve- ‘ment of both lungs). Recognition of a diffuse lung disease dicales that the disorder is affecting the entire lung as a unit and generally implies systemic disorders (e.g., sepsis, connec- tive tissue disorders, autoimmune conditions, hypoproteinemia) ‘r global distribution of a toxic agent (eg., asbestosis, hyper- sensitivity pneumonitis, amniotic fuid embolism). In general, these diseases affect both lungs in a relatively symmetric fash- ion. Although they may produce imaging abnormalities that have zonal predominance, such as a predilection for the lung bases (or the midlung zones, in most cases large region of both lungs is involved with the disease. “Focal” lung diseases are those that involve only a portion of the two lungs. A unilateral process is by definition a “focal” pro- cess because it does not involve both lungs uniformly. Recog- nition of a unifocal process suggests that there is a damaging agent that begins to disrupt the function of the lung and spreads ‘outward from an original site. This characteristically implicates entities stich as infection, neoplasm, trauma, and infarction, ‘Abnormalities that involve multiple regions of the pulmonary parenchyma but with intervening normal parenchyma can be designated as “multifocal” In general, multifocal disorders rep- resent multiple areas of focal lung disease; therefore, they have differentials similar to focal lung disease. However, there is a borderline where diffuse and multifocal lung diseases meet. At this border, abnormalities may represent either a diffuse or mul- tifocal disease. One of the most important distinctions in thoracic radiology is the difference between alveolar and interstitial diseases. Onra- diographs and computed tomography (CT), interstitial diseases appear as an increase in the number and thickness of lines or dots in the pulmonary parenchyma. The opacity and attenua- tion of the lung change very litle or not at all. Alveolar dis- ceases appear as increased opacity or increased attenuation of the pulmonary parenchyma. The vascular markings and interti- tial lines that are normally seen are obscured by the absence of air in the alveoli. This is a manifestation of the silhouette sign, ‘one of the cardinal signs of alveolar disease. On the chest ra- diograph, the vast majority of identifiable structures, including the heart, aortic arch, pulmonary hila, and pulmonary vascu- lature, are identifiable because they are surrounded by ait. In other words, the air-tissue differences in x-ray attenuation pro- ‘duce a definable border. These structures become obscured in the absence of ait. This effect is known as the silhouette sign For similar reasons, bronchi that normally are invisible because there is no contrast between air in the alveoli and air in the bronchi, become visible in the presence of alveolar consolida- tion because there is now a fluid-air interface between the air in the bronchi and the fluid or tissue in the alveoli. This appearance thas been named air-bronchograms and is an important finding indicating the presence of alveolar disease, Diffuse alveolar dis- orders are discussed in Chapter 1; diffuse interstitial disorders are discussed in Chapter 3. Ground-glass opacity represents a borderline condition that ‘can represent subradiographic interstitial abnormality ora faint alveolar disorder, in which the abnormality incompletely fills the alveoli. A consequence of the incomplete filling of alve- oli is the absence of silhouette sign, air bronchograms, and some other features that usually are present in alveolar diseases. Disorders producing ground-glass opacity are discussed in Chapter 2 Other pulmonary disorders result in relative decrease in pul- monary opacity. This is most often a manifestation of obstructive Jung diseases but also may be a manifestation of pulmonary vas- cular diseases, In obstructive lung diseases, the alveoli become ‘overdistended with ar that results in a higher proportion of ar to lung tissue. This is manifested as decreased pulmonary opacity, also known as pulmonary oligemia, Because blood represents a large fraction of the lang mass, any vascular disorder that results in an overall diminution in blood volume of the lung will result in a higher proportion of air to lung mass. Once again, this ap- pears as decreased pulmonary opacity similar to that seen with obstructive lung diseases, The causes of pulmonary oligemia are reviewed in Chapter 4 Copyright © 2006 by The McGraw-Hil Companias, Inc. Clck here for tems of useCrater 1 DIFFUSE ALVEOLAR LUNG DISEASES Diffuse alveolar diseases are readily subdivided into four gen- eral categories of disease defined by the type of fluid that fills the alveolar spaces. Thus, the alveoli may be filled with frank hem- orrhage, inflammatory exudate, or a simple transudate. Rarely alveoli may be filled with other more complex material such as the abnormal surfactant seen in pulmonary alveolar proteinosis ‘or the cells of bronchoalveolar carcinoma, This leads to the com- mon adage: Diffuse alveolar disease can be caused by "blood, pus, water, or other.” PULMONARY EDEMA Pulmonary edema is the most common cause of diffuse alveolar ‘opacity, accounting for the vast majority of cases. Therefore, ‘when encountering a case of diffuse alveolar lung disease, pul- ‘monary edema (especially hydrostatic [cardiogenic] pulmonary edema) should be the first choice diagnosis unless there is ov ‘whelming clinical information implicating another cause fori fuse alveolar lung disease. Pulmonary edema is a result of imbalances in the Starling forces that govern the transport of fluids between the vascular and interstitial spaces of the lung. During homeostasis there is a balance among intravascular hydrostatic pressure, interstitial hydrostatic pressure, plasma oncotic pressure, and interstitial tissue oncotic pressure such that there is no net transport of wa- ter across the capillary endothelium. Disturbance of this equi- librium leads to the net transport of water and solutes into the interstitial space, If the disequilibrium continues, the intersti- tial lymphatics may become overwhelmed and fluid passes into the alveoli, leading to diffuse alveolar edema.' Interestingly, the alveolar flooding appears to be an all-or-nothing phenomenon ‘with individual alveoli either being completely air filled or com- pletely fluid filed This mixture of air and fluid makes the alve- lar opacity appear heterogeneous, one ofthe characteristics that distinguishes most alveolar filling processes from pleural fluid and chest wall masses that characteristically cause homogenous ‘opacity chest radiographs. ‘Typically, pulmonary edema is subdivided into two major etiologic subcategories, hydrostatic pulmonary edema and in- creased permeability pulmonary edema (Table 1-1). In hydro- static edema, increased intravascular hydrostatic pressure results in anet force driving water and solutes into the interstitial and subsequently the alveolar spaces of the lung. In increased perme- ability edema, disruption of the capillary endothelial membrane allows plasma proteins to leak into the interstitial space. The proteins exert an osmotic force drawing water into the intersti- tial space, which eventually overflows into the alveolar spaces with overwhelming volume of water and solute.! Although many cases fall into one or the other category of pulmonary ‘edema, itis also common for there to be combinations of hydro- static and increased permeability forces resulting in pulmonary edema, HYDROSTATIC EDEMA Left-sided heart failure is the most common cause of hydrostatic pulmonary edema and pulmonary edema in general. Rarely, ‘causes of venous obstruction or increased pulmonary circula- tion may result in hydrostatic edema, Heart Disease Left-sided heart failure is by far the most common cause of Inydrostatic edema and thus the common distinction of hydro- Static edema as “cardiogenic” pulmonary edema. There are two primary mechanisms whereby heart failure results in venous hy- pertension and pulmonary edema. In one case there is increased ‘back pressure inthe left ventricle asa result of reduced ventricu- lar compliance as seen in chronic systemic hypertension, aortic valvular disease, ischemic heart disease, and cardiomyopathies. In the other case there is obstruction of forward flow through the mitral valve, as seen in mitral stenosis, left atrial stenosis, or cor triatriatum, Aslleft ventricular end-diastolic pressure increases, this pres ‘sure is transmitted in a retrograde fashion into the left atrium, then pulmonary veins, then venules, and ultimately to the pul- monary capillary bed. This results in an increase in intravase lar hydrostatic pressure creating an imbalance in the Starling forces and net force driving water from the intravascular space Ko the interstitial space. This produces interstitial pulmonary ‘edema and appears as increased interstitial lines on a chest radio- ‘graph, This interstitial abnormality is charactersticaly linear in appearance and is described in subsequent chapters. It has been estimated that the interstitial compartment can double in volume before alveolar flooding occurs. In addition, lymphatie flow can increase 10 times the normal amount before there is significant accumulation of edema fluid.' Increased water in the intersti- I space increases tissue hydrostatic pressure and also reduces, Copyright © 2006 by The McGraw-Hil Companies, Inc. Cck here for terms of use4 PART |_ DIFFUSE LUNG DISEASES TABLE is quite rare and in most cases recognition of a unilateral alve- Causes of Pulmonary Edema colar filling process should instigate a search for causes other than pulmonary edema. In fact, hydrostatic pulmonary edema is Hydrostatic edema so often symmetric in distribution that asymmetries in alveolar Heart disease (congestive heart failure) consolidation should lead the reader to consider the possibility Volume overload Pulmonary venous obstruction Postobstructive pulmonary edema (negative pressure eden) Increased capillary permeability ‘ARDS Sepsis Aspiration Pneumonia Trauma Burns Pancreatitis Disseminated intravascular coagulation Drug overdose Neurogenic edema High altitude edema Near drowning Fat emboli syndrome “Amniotic fluid embolism syndrome ‘Toxic inhalation ‘Smoke Silosillers disease (nitrogen dioxide) Sulfur dioxide Chlorine gas Phosgene gas Other Drugs (Chemotherapy ‘Cytosine aribinoside Gemcytobine Interleukin TT All transretinoie acid Methotrexate Other Other medications Aspirin cit drugs Heroine and other opiates Cocaine ‘Transfusion-related acute lung injury Hypersensitivity pneumonitis Hypoproteinemia Citthosis Nephrotie syndrome tissue oncotic pressure, both of which tend to counteract intersti- tial edema. Once these and other factors are overwhelmed, fluid passes through the alveolar membrane and results in alveolar ‘edema, Some researchers have noted that interstitial edema usu- ally is apparent when the pulmonary capillary wedge pressure exceeds 15 mm Hg. When the wedge pressure exceeds 25 mm Hg, alveolar flooding usually occurs. With imaging, hydrostatic alveolar pulmonary edematends to appear as patchy or confluent regions of alveolar consolidation involving both lungs (Fig. 1-1), Unilateral pulmonary edema ‘of a process such as pneumonia, superimposed on a background ‘of pulmonary edema (Fig. 1-2) Hydrostatic alveolar pulmonary edema has a predilection for the periilar regions of the lung. Most often it begins centrally ‘and spreads peripherally as it becomes more severe.‘ It also resolves first in the periphery and then progressively resolves medially The perihilar predilection of hydrostatic edema is at its most extreme in the case of the “bat's wing” or “butterfly” pattem of edema (Fig. 1-3). In this patter the central portions ‘of the lung are extensively consolidated but the most peripheral 2 to 3 cm of lung are relatively uninvolved. This pattern, al- ‘though strongly associated with hydrostatic pulmonary edema, isa teatvely rare phenomenon, identified in only 5% of cases Hydrostatic edema also tends to he most severe in the de- Pendent portions of the lung as a result of gravitational forces ‘One notable exception to this rule can be seen when pulmonary ‘edema is the result of mitral regurgitation, With mitral regurgi- tation, there is preferential regurgitant flow into the upper lobe pulmonary veins. This can resultin correspondingly higher pres- sues in the upper lobe vasculature and the development of upper lobe pulmonary edema (see Fig. 1-2).8? The upper lobe pul- ‘monary edema is more frequently seen in the right apex than the left apex because of the direction of the regurgitant jet, Volume Overload Excessive intravenous fluid administration has been shown to produce pulmonary edema in patients without known heart dis- ‘ease, even among healthy young male volunteers administered large volume of normal saline solution.'"° Pulmonary edema resulting from volume overload is a form of hydrostatic edema ‘with increased intravascular pressures. Patients with renal in- sulficiency and liver disease appear to be at increased risk for pulmonary edema. This is in part « result of volume overload ‘but also includes other mechanisms such as decreased plasma ‘oncotic pressure from hypoalbuminemia,! Radiographic manifestations of volume overload pulmonary ‘edema are most often venous engorgement and mild interstitial ‘edema, Diffuse alveolar edema is rare, except when complicated bby renal insufficiency or liver disease. When it does occur, vol- ‘ume overload alveolar edema resembles cardiogenic pulmonary ‘edema (Fig. 1-4. Pulmonary Venous Obstruction Rarely, noncardiac diseases may result in pulmonary venous ob- struction and resultant pulmonary edema. Causes include pul- ‘monary veno-ocelusive disease, fibrosing mediastinitis, congen- ital venous stenosis, otal or partial anomalous venous return, andCHAPTER 1_ DIFFUSE ALVEOLAR LUNG DISEASES FIGURE 1-1. Cardiogenic edema, This 30-year intravenous drug abuser had undergone mitral and tricuspid valve repairs for bacterial endocarditis. He now presents with dyspnea. (A) Posteroanterior chest radiograph demonstrates extensive bilateral alveolar consolidation. Computed tomography im ‘ages atthe level ofthe (B) pulmonary artery and (C) inferior pulmonary veins demonstrate extensive bilateral consolidation and ground-glass opacity, Note that the disease i more sever i the dependent portions ofthe lung. There is also a smal right pleural effusion, These findings are characteristic of severe hydrostatic pulmonary edema, FIGURE 1-2. Asymmetic pulmonary edema. A- Anteroposterior chest radiograph was obtained following mitral valve eplacement inthis 67-year-old woman. The examination reveals focal area ‘of consolidation in the right upper lobe in association with diffuse interstitial opacities that radiate from the hilum. This combination of findings could represent cither interstitial pulmonary edema ‘with a superimposed right upper lobe pneumonia or widespread asymmetric pulmonary edema, [B. Anteroposterior chest radiograph taken | day later after diuretic therapy demonstrates near re ‘olution of the right uppet Tobe opacity that represented asymmetric pulmonary edema, Right upper Tobe edema is strongly associated with mitral regurgitation where the regurgitant jet produces locally {increased pressures inthe upper lobe pulmonary veins with focal increase in pulmonary edema,PARTI DIFFUSE LUNG DISEASES FIGURE 1-3. Batwing pattem of cardiogenic edema, This 48-year-old woman presented with acute chest pain, dyspnea, and hypotension. A. Anteroposterior chest radiograph demonstrates bilateral perihilar opacification with sparing ofthe lang periphery. Although uncommon, dhs pattern is char. fcteristc of severe cardiogenic pulmonary edems. B, Anteropostetior chest radiograph I day later demonstrates some interval improvement in difuse consoldation tha is more uniform i distribution, ‘This later appearance isthe more asual appearance of severe cardiogenic edem, A — c FIGURE1-4. Volume overload pulmonary edema. This 78-year old man required extensive volume resuscitation for chabdomyolysis and developed acute dyspnea. (A) Posteroanteror chest radiograph reveals widespread alveolar opacities with a central, perhilar distribution, Compated tomography (CT) images atthe level of the (B) carina and (C) apex of the diaphragm demonstrate perihilar consolidation with sparing ofthe peripheral ling. Note the multiple air bronchograms and bilateral pleural effusions. The diffuse, symmetric, perihilar alveolar opacities seen on the chest radiograph and CT are characteristic of hydrostatic edema. Pleural effusions are a common ancillary find Radiographic findings esolved with diuresis,CHAPTER 1_DIFFUSE ALVEOLAR LUNG DISEASES FIGURE 1.5. Postobstructive pulmonary edema, This 33-year-old patient was intubated for se- vere laryngospasmn. A. Anteroposterior chest radiograph of the left lung demonstrates mild perihiar pulmonary opacities with a few air bronchograms. B, Anteroposterior chest radiograph obtained 0 minutes later demonstrates complete resolution ofthe pulmonary opacities without therapy other ‘than intubation. Given the clinica history. these findings are indiative of negative pressure pulmonary ‘edema secondary to forced inspiration against a closed glottis invasion or compression of the pulmonary veins by an adjacent neoplasm.’ With the exception of pulmonary veno-occlusive disease, these disorders cause pulmonary edema by narrowing the central pulmonary veins. Central venous narrowing impedes Forward flow, causing pulmonary venous hypertension and re- sultant hydrostatic pulmonary edema, Pulmonary veno-occlusive disease is an idiopathic disorder that results in thrombotic obstruction of the small pulmonary veins and venules but leaves the larger central veins patent. The presence of patent larger veins results in the paradoxie find- ing of normal pulmonary capillary wedge pressure in these pa tients with pulmonary arterial hypertension. ‘This often lethal condition demonstrates no sex oF age predominance ‘These causes of edema may be indistinguishable from the pulmonary edema caused by heart disease. Occasionally, only fone or a few of the pulmonary veins are involved, which can resultin focal pulmonary edema involving only the lung supplied by the obstructed vein, One study of pulmonary veno-occlusive disease noted that the combination of centrilobular ground-glass nodules. septal thickening, and mild mediastinal adenopathy is characteristic of the pulmonary edema present in this unusual disorder."? Postobstructive Pulmonary Edema Postobstructive pulmonary edema, also known as negative pres- sure pulmonary edema, isa rare form of pulmonary edema that ‘results from acute occlusion of the upper airway. This can be sec- ‘ondary to an impacted foreign body, laryngospasm, epiglotttis, ‘or strangulation. The proposed mechanism of pulmonary edema is as follows. Forceful inspiration against and obstructed central airway results in a lower than normal intrathoracic pressure that inereases venous return, Increased venous blood flow results in a hydrostatic pressure gradient between the intravascularand extravascular compartments leading to pulmonary edema.'*'* ‘The radiographic manifestations are identical to the intersti- tial and alveolar pulmonary edema resulting from cardiac causes, with the notable exception that the heart usually is normal insize. ‘The association of diffuse alveolar lung disease and recent air- \way obstruction should lead to the diagnosis of negative pressure ‘or postobstructive pulmonary edema (Fig. 1-5). INCREASED PERMEABILITY EDEMA. ‘There are a large number of causes of increased permeability ‘edema, Most common of these is adult respiratory distress syn- drome (ARDS). Other causes include acute neurologic events: near drowning; fat and amniotic uid emboli; transfusions of ‘blood products: acute hypersensitivity pneumonitis; low protein states; and exposure to toxic inhalations, certain medications, or high altitude. Adult Respiratory Distress Syndrome Acute respiratory distress syndrome (ARDS) isthe second most ‘common cause of diffuse alveolar lung disease after cardiogenic pulmonary edema, ARDS and ardiogenicedema account for the vvast majority of cases of diffuse alveolar lung disease: therefore,8 PART|_ DIFFUSE LUNG DISEASES they should be the first considerations when evaluating such cases, Lack of consistent diagnostic criteria hampered the compar- {son of studies of prognosis, treatment, and outcome in ARDS. AAs a result of these difficulties, the American-European con- sensus conference established a series of clinical, physiologic, and radiographic criteria defining ARDS.'* According to this schema the criteria for the diagnosis of ARDS include (a) acute ‘onset, (b) Pa0,/Fiog < 200 mm Hg, (c) bilateral pulmonary “infiltrates” on frontal chest radiograph, and (@) pulmonary artery wedge pressure < 18 mm Hg (when measured) or no evidence of left atrial hypertension. Ths clinical entity usually corresponds tothe pathologic pattern in diffuse alveolar damage (DAD)! ARDS appears to be a manifestation ofa generalized inflam- ‘matory disorder that has been termed systemic inflammatory esponse syndrome. This involves damage to endothelial cells in a wide varity of organs. including the lung, kidneys, hear, gastrointestinal system, and brain.'*"” This widespread damage ‘may explain the common association of ARDS with multisystem ‘organ dysfunction. "ARDS appears to be a common physiologic response to a wide variety of insults. Most frequently these include sep- sis, aspiration of gastric contents, overwhelming pneumonia, severe trauma, multiple fractures, major burns, pancreatitis, prolonged hypotension, disseminated intravascular coagulation (DIC), drug overdose, and coronary artery bypass surgery." “The exact pathogenesis of ARDS is uncertain, but multiple fac- {ors appear to be involved, including hypotension, leukocyte- induced endothelial injury, qualitative and quantitative surfac- tant abnormalities, complement activation, clotting abnormali- ties, oxygen radicals, and various eytokines.! ‘The pathologic outcome of ARDS, known as diffuse alveolar damage (DAD) is commonly subdivided into three phases of disease: the exudative, proliferative, and fibrotic phases.' The exudative phase, which occurs within hours of the initial insult, is characterized by interstitial and alveolar edema associated with capillary congestion. Alveolar edema is composed of a proteinaceous exudate with a variable number of red blood cells Laterin the exudative phase there may be abundant intra-alveolar ‘macrophages and type II pneumocyte hyperplasia. ‘The proliferative phase usually is seen 7 to 28 days after the initial injury and is characterized by fibroblast proliferation in the alveolar and interstitial spaces in association with a mononuclear cell inflammation. The fibroblasts produce col- lagen and a provisional matrix. In some individuals this may progress to the fibrotic phase, in which there is sufficient colla- ‘gen deposition to cause interstitial fibrosis. Patients present with dyspnea, tachypnea, cough, and agita- tion after one of the many inciting events. Arterial blood gas analysis demonstrates hypoxemia and often an increased Peo. Clinical manifestations of disease almost universally precede radiographic findings and in most cases the patient requires me- chanical ventilation before radiographic evidence of disease. ‘Thus, a diagnosis of ARDS should not be made in patients who are not intubated except in rare circumstances. ‘The prognosis for ARDS is dismal, with amontality of greater than 50¢%.2° Approximately 90% of patients who die do so within the first 2 weeks after diagnosis.’ This exceedingly high mor- tality may be related tothe high incidence of multisystem organ failure associated with ARDS. One study correlates increased ‘mortality rates with the increased number of dysfunctioning or- ‘gans in patients with ARDS.” ‘The radiographic manifestations of ARDS often correlate with the pathokogic phases of disease. In the first days of ARDS. the radiograph resembles cardiogenic pulmonary edema ‘and as such appears as widespread, fluffy alveolar opacities, corresponding to the alveolar exuidates characteristic of the exudative phase of ARDS. The first radiograph initially may appear patchy with scattered zones of alveolar opacification al- temating with areas of relatively less opacified lung. Most often this pattem of involvement rapidly progresses to a more uni- form, bilateral consolidation of both lungs (Figs. 1-6 t0 1-8), This uniform bilateral consolidation is quite characteristic of ARDS and is less common in cardiogenic edema, therefore, it may be an important clue to the diagnosis, Another distin ‘guishing feature between cardiogenic edema and ARDS is the presence of air bronchograms that are almost never seen in car- diogenic edema but are more frequently seen in ARDS (sce Figs. 1-7 and 1-8). Lastly, cardiogenic edema usually fluctu- ates from examination to examination because of clinical alter- ations in fluid balance and volume status, whereas ARDS devel- ‘ops rapidly and maintains a relatively constant appearance from day to day, Changes in ARDS may only become apparent after ‘comparison is made between examinations obtained many days apart The one factor that can alter the radiographic appearance ‘of ARDS from day to day is a change in ventilator settings.” ‘Changes in airway pressures, tidal volumes, and especially pos- itive end expiratory pressure (PEEP) can dramatically alter the presence or absence of radiographic opacities. Therefore, it may bbe necessary to compare radiographic appearance with knowl- edge of ventilator settings to accurately evaluate changes in ARDS because apparent clearance or worsening may be arti- factual resulting fom ventilator adjustments rather than real changes in the severity of disease. In the second, subacute phase of ARDS, after approximately 7 days, the radiographic appearance is subtly altered. It appears less fluffy and has a more defined, harder-edged, reticular ap- pearance (see Fig, 1-6)!" This corresponds to the proliferative phase of ARDS and likely reflects fibroblastic proliferation and the deposit of collagen. ‘Most patients who survive ARDS have slow resolution, over ‘weeks or months, of their clinical abnormalities and chest ra- diographic findings."* However, occasionally, individuals may be left with chronic fibrotic-appearing lungs. When this occurs itoften resembles idiopathic pulmonary fibrosis on radiographs and CT (Fig. 1-9), Because of their increased sensitivity, CT scans frequently demonstrate residual lung damage as a result of previous ARDS (Fig. 1-10). Ina study of 15 patients, radio- _graphs obtained 6 months after recovery from ARDS showed in- tersttial abnormality interpreted as fibrosis in 13 patients (87% ‘of cases). Interestingly, these abnormalities predominated in the ventral portion of the ung and correlated with the dura- tion of ventilation and the severity of the ARDS injury. The authors speculated that these abnormalities are more likely tobeCHAPTER 1_ DIFFUSE ALVEOLAR LUNG DISEASES FIGURE 1-6, Adult respiratory distress syndrome affer pneumonia. This 56-year-old man under- ‘ent emergent coronary artery bypass graft for carciogenic shock. A. Preoperaiive chest radbograph demonstrates a focal area of consolidation at the right lung base consistent with pneumonia. B. Antero. posterior chest radiograph at day 3 after surgery demonstrates diffuse alveolar opacification uniformly spread across both lungs. This is characteristic of pulmonary edema and could be secondary to con gestive heart failure oF ARDS, Note the multiple appliances indicating recent eardise surgery, C Anteroposterior chest radiograph on day 8 after surgery demonstrates persistence of diffuse alveolar ‘opacity, This constancy is characteristic of the persistent abnormality of ARDS. Note the extensive subculuneous emphysema. Ai leaks are quite common in ARDS because ofthe decreased compliance ‘of the lung and often manifest as subeutancous emphysema or pneumomediastinum, D, E. Computed tomography (CT) images obtained on the samme day as (B) demonstrate heterogeneous pulmnonsry consolidation with small areas of ground-glass opacification. This ix characteristic of the exudative phases of ARDS. Note that there ure some arcas of relatively normal lung interspersed with the con solidated Tung. This has been reported to be more common when ARDS results from a pulmonary ‘cause inthis ease the preoperative pneumonia. A small pneumothoran is noted inthe right emithorax ‘and there are multiple surgical appliances from cardiac surgery. FG. CT images obtained on the same ay as (C) demonstrate decreased alveolar consolidation and increased ground-glass opacity. Note also some areas of reticular abnormality in the left ower lobe on image (F) and in both lower lobes fon image (G). This harder, ticular appearance is characteristic of the proliferative phase of ARDS. Note the persistent right pneumothorax and new subeutancous emphysema and pacumomediastinum, evidence of the decreased compliance ofthe langs in ARDS,FIGURE 1-7. Adultrespratory distress syndrome after pneumonia. This 22-year-oldnursing student presented with fever and cough, A. Pesteroanterior chest rdiograph demonstrates a focal urea of ‘consolidation inthe right upper lobe consistent with pneumonia. B. Anteroposterior chest radiograph 3 days later demonstrates diffuse alveolar opacification uniformly spread across both lungs. Note theCHAPTER 1_ DIFFUSE ALVEOLAR LUNG DISEASES FIGURE 1-8. Adult respiratory distress syndrome caused by sepsis. This 80-year-old man devel- ‘oped unexplained fevers and hypotension 2 weeks after cardiac surgery. A. Anteroposterior chest radiograph demonstrates diffuse alveolar opacification, uniformly spread across both lungs, Note the ‘multiple air bronchograms, a finding more often associated with ARDS than other causes of pul: ‘monary edema. The left ling appears more opacified because a lft apical pneumothorax is causing atelectasis of the left lung. B,C. Computed tomography images obtained 3 days after (A) reveal & ‘combination of ground-glass pacification and consolidation of the lungs. Note the gradient of in- creasing density from anterior to posterior. This gradient is a common feature often seen in ARDS, "Note also that the pulmonary opacities are muck more uniform than in Figures 1-6 and 1-7. This more ‘uniform appearance of ARDS has been associated with nonpulmonary causes of ARDS, inthis case, sepsis ‘manifestations of therapy, barotrauma, and oxy gen toxicity than residua of DAD from ARDS. On CT images, ARDS most often demonstrates bilateral _ground-glass opacification, pulmonary consolidation, of a com- bination of both.'” This is often most severe in the gravity- dependent regions of the lung. Unlike chest radiographs, which characteristically demonstrate uniform consolidation across the lung parenchyma, CT scan opacification often (75% of the time) appears inhomogeneous or patchy (sce Figs. 1-6 and 1-7). Some authors have noted a distnet, gravity-dependent distribution of pulmonary opacitiesinthe early exudative phases of ARDS."*-® ‘They described a relatively well-aerated ventral lang, and a con- solidated dependent lung with a zone of ground-glass opacity between these two extremes. There also appears to be a cranio- ccaudad distribution of density with relatively less involvement at the apices and increased consolidation at the bases." In the later, proliferative phases of disease. the overall lung density decreases and there is increased interstitial reticulation and less alveolar consolidation (see Fig. 1-6). Subpleural air cysts, eys- tic air collections in the lung adjacent tothe pleura, may appear at this time and are a manifestation of barotrauma? Other authors have noted that ARDS secondary to extrapulmonary FIGURE 1-7. Continued multiple ar bronchograms. Air bronchograms are uncommon in eardio- ‘genic edema and usualy are indicative of ARDS when they are found in association with ditfase ‘consolidation. C, Anteroposterior chest radiograph 17 days later demonstrates persistence of diffuse alveolar opacity. This constancy is characteristic of the persistent abnormality of ARDS. D, Magnified i of i ng es el my cms crs es ol Mk ular appearance. Ths is characteristic Othe proliferative phase of ARDS when ftwoblastic production begins, E. Computed tomography ‘mages obtained on the same day as (B) demonstrate dense consolidation inthe right upper lobe ‘consistent with the Focus of pneumonia. The remaining lung demonstrates helerogencous pulmonary ‘consolidation with small areas of ground: glass opacification, characteristic of the exudative phases ‘of ARDS. Note that there are some areas of relatively normal lung interspersed with the consolidated lung. This has been reported to be more common when ARDS results from a pulmonary cause, in this ease prewmoniPARTI DIFFUSE LUNG DISEASES FIGURE 1.9. Residual fibrosis from adult respiratory distress sym drome. This 67-year-old man had a prolonged period of ARDS result- ing from automobile trauma, Four months later he remained dyspneic. PPosteroanterior chest radiographs demonstrates fine interstitial abnor- ‘ality rindomly scattered thronghou! the lungs. ti primarily present in the subpleural lang and has a fine reticular character. This is com: sistent with the fibrotic phase of ARDS, a relatively uncommon late manifestation of ARDS. insults is more likely to present with uniform opacification of the lung parenchyma and that ARDS owing to direct pulmonary insults is more likely to appear as heterogenous or patchy opaci- fication (see Figs. 1-6 t0 1-8). Although itis rare to detect pleural effusions on portable chest radiographs, small pleural effusions are commonly seen on CT examinations, which are more sensitive to small amounts of pleural fluid Neurogenic Edema Neurogenic edema is a rare form of pulmonary edema that can result froma variety of neurologic events, but is most commonly seen after head trauma and seizures.°*“° Although the cause of neurogenic edema is uncertain, the current experimental evi- dence has led to the following hypothesis: Brain injury results in increased intracranial pressure that leads to excessive adren- ergic stimulation that in turn causes increased pulmonary pres- sures and resultant right-sided heart failure. It is believed that these high pulmonary pressures damage the capillary endothe~ lium and cause a capillary teak.'*! Thus, neurogenic edema initially appears to be atype of hydrostatic edema, but it rapidly becomes a permeability edema as a result of pressure-related damage to the capillary endothelium, Although well described, neurogenic edema is a rare phe- omenon among. individuals with brain injury, When found, it 6d €> ee FIGURE 1-10. Residual fibrosis from adult re atory distress syndrome This 58-year-old man hhad developed ARDS secondary to bowel perforation 3 months before, He continued to experience dlyspnea. Computed tomography images atthe level ofthe (A) aortic arch, (B) main pulmonary arteries, and (C) pulmonary veins reveals a diffuse interstitial abnormality characterized by sub- pleural reticulation and grt ‘lass opacity. Note the larger ineat bands of fibrosis associated with areas of architectural distortion in the right lower lobe in images (B) and (C), These findings are the imaging manifestations ofthe fibrotic phase of ARDS,CHAPTER 1_ DIFFUSE ALVEOLAR LUNG DISEASES 13 FIGURE 1-11. Neurogenic edema, This 48-year-old woman devel: ‘oped severe headache and mental status changes that were soon fal: lowed by respiratory Failure. Posteroanteior chest radiograph reveals extensive alveolar consolidation throughout both lungs. There is slight sparing of the left lower lung zone, The abnormality is otherwise uni- formly distributed throughout hth lungs. This pattern is consistent with cextensive pulmonary edema and is ikely a form of neurogenic edema inthe setting of altered mental status, The patients headache was found to be secondary to subarachnoid hemorrhage from rupture of berry characteristically develops within hours of the initial insult and resolves spontaneously within afew days of onset, given gener- alized clinical support.“ ‘The radiographic appearance of neurogenic edema is similar to the Wide vatiety of other causes of pulmonary edema. It is characterized by diffuse, bilateral, alveolar pulmonary opacities. ‘Occasionally it may appear with unusual distributions such as unilateral or upper lobe-predominant alveolar opacities.' Others have noted that the pulmonary edema often is heterogenously rather than homogenously distributed throughout the lungs (Fig. 1-1)" High-Altitude Pulmonary Edema Pulmonary edema associated with acute exposure to high alti- tudes is known as high-altitude pulmonary edema (HAPE). Most often HAPE is secondary fo acute exposure of individuals to al- titudes greater than 3500 m above sea level. However, rarely it cean be seen in exposures to elevations as Jow as 2750 m above sea level.##45 This is discovered most often in young and other- ‘wise healthy residents of a high-altitude locale who return home following a few days to several weeks spent at sea level 647 A recent study suggests that many individuals develop subclinical pulmonary edema while ascending high alttudes.** This study prospectively evaluated 262 consecutive climbers of Monte Rosa (4559 m) in the Ttalian Alps and demonstrated rales. or chest radiographic evidence of interstitial edema in 15% of individ- uals. Only one individual was so severely affected by HAPE that evacuation was required. Clinically symptomatic patients present with neurologic, gastrointestinal, muscular, pulmonary, ‘or systemic symptoms such as headache, dizziness, restlessness, fatigue, nausea, vomiting, myalgias, cough, dyspnea on exertion weakness, anorexia, or fever within the first few days of arriving at high altitude.” ‘The current hypothesis ofthe pathogenesis of HAPE suggests that hypoxia caused by high altitudes results in heterogeneous vasoconstriction of the pulmonary arterial bed, The few vessels that remain vasodilated experience exceedingly high pulmonary pressures, because they carry the bulk of the pulmonary blood flow. These high pressures cause shearing forces on the vessel ‘wall and result in microvascular endothelial damage that causes capillary leak leading to permeability edema," ‘The radiographic appearance of HAPE is similar to all other forms of pulmonary edema. Greater than 90% of patients who present with clinical symptoms of HAPE have dependent sir- space consolidation.**** Some researchers have suggested that pulmonary edema is most often symmetric, whereas others claim that an asymmetric distribution is more common.** This lat- ter group found that HAPE often is unilateral, with 45% oecur- Fing primarily in the right lung, 10% occurring primarily in the left lung, and only 45% occurring in a bilateral and symmetric fashion, Peribronchial and perivascular cuffing are common in association with alveolar opacities, Kerley B lines may be seen inapproximately 15%. Pleural effusions are rare at presentation, bat commonly develop within 24 t0 48 hours. Patients rapiclly respond to oxygen therapy or return to sea level, Chest radiographs usually return to normal within 24 to 48 hours.! Near Drowning Near drowning is the term applied to the condition of individu- als who develop respiratory impairment as a result of inhalation of a large volume of fresh or sea water. Near drowning is a rare event seen most frequently in children. Pathologic studies hhave shown that all near-drowning events result in damage tothe pulmonary epithelium.** This is probably because the aspirated water isnot sterile and often contains particulate matter such as ‘mud, sand, and other debris. Secondary pneumonias and ARDS are potential complications. Although experimental evidence stiggests that aspiration of highly toxic fluid, such as sea water, is more poisonous to the lungs than fresh water, clinical ex- perience does not show significant differences in outcomes of Patients who have experienced salt water versus fresh water near drowning.°" The volume of water aspirated appears to be the ‘most important determinant of outcome. Experimental studies ‘of salt water and fresh water aspiration in animals suggest that there is a volume of aspiration beyond which there is a nearly universal fatality.” In adult humans, this threshold is estimated to be approximately 1.5 L of salt water and 3 L of fresh water ‘The patients clinical condition at the time of presentation totheFIGURE1-12. Drowning-related pulmonary edema. This patient was rescued | hour afler jumping into river from abridge. Anteroposter chest radiograph reveals extensive alveolar opacification of both lungs ‘characteristic of pulmonary edema secondary to drowning. The patient never recovered and was pronounced deed. hospital also is an important determinant of outcome. In two retrospective studies of near- Thus the diagnosis of fat embolism rests on recognition of the tem- poral association of diffuse alveolar opacities with recent bone trauma or orthopedic manipulation, Resolution of pulmonary ‘opacities usually occurs within 1 week but may persist up to 1 month.” FIGURE 1-13. Fat emboli syndrome. During surgical placement of total knee arthroplasty, this 84-year-old man developed ace res Piratory decompensation. Transesophageal echocardiography at the time of the procedure noted a shower of echogenic material passing through the right atrium, Anteroposterior chest radiograph demon strates widespread alveolar opacities. Several large bullae are also noted inthe right upper lobe. In the setting of recent bone trauma, a diagnosis ‘of fat emboli syndrome with noncardiogenic pulmonary edema should be madeCHAPTER 1_ DIFFUSE ALVEOLAR LUNG DISEASES 15 FIGURE 1-14, Fat emboli syndrome. This 83-year-old man was re covering from a total knee arthroplasty performed | hour previously when he developed acute dyspnea and hypoxia. Anteroposterior chest radiograph reveals widespread pulmonary opacities, These appear to have a mixed interstitial and alveolar character and resemble moderate congestive heart failure: however, the temporal association with w re- ‘cent orthopedic procedure should prompt the diagnosis of fat emboli syndrome. In one study, CT findings in six patients with fat embolism synklromie included dependent consolidation and ground-glass ‘pacity similar to ARDS.” The authors also noted nodular areas ‘of consolidation or ground-glass opacification, especially within the upper lung zones. Amniotic Fluid Embolus Inrare situations, most oftem after a tumultuous labor in mult parous woman, contents of the amniotic cavity can be driven into the maternal circulation via tears in the uterine veins, resulting in embolization of amniotic fluid and debris into the maternal culation. Thisis known as amniotic fluid embolism andisamong the most devastating complications of late-term pregnancy, re- sulting in cardiopulmonary collapse, permeability pulmonary edema, and DIC.’S* The exact incidence of the disorder is un- known, bat it has been estimated that 10% of peripartum deaths are related to amniotic fluid embolism.”” Evidence suggests that the combination of labor-induced tears in the uterine veins and rupture of the overlying fetal mem branes are necessary for the transmission of amniotic fluid into the maternal circulation, This usually occurs at either the lower ‘uterine segment or beneath the placental site.” ‘The cause of pulmonary edema in amniotic fluid embolism appears to be multifactorial, There is evidence that amniotic fluid embolism is associated with myocardial dysfunction: thus, pulmonary edema in part may be a function of heat failure.”*? It is also believed that elements in amniotic fuid cause pul- monary endothelial damage resulting in permeability edema identical to ARDS.*°*" In addition to causing pulmonary edema, amniotic fluid em- botism can lead to coagulation disturbances, the most severe of which is DIC. In some patients with premature rupture of mem- branes, infected amniotic luid embolization may cause septic shock. "2° Amniotic fluid embolism characteristically occurs during or soon after labor ofa full-term pregnancy." Patients present with the acute onset of dyspnea, cyanosis, or shock. Up to 40% of pa- tients also have serologic evidence of DIC. Predisposing factors include tumultuous labor, advanced maternal age. multiparity, premature placental separation, and intrauterine fetal distress oF demise. ‘The radiographic appearance of amniotic fluid embolism is similar to ARDS and is characterized by widespread air-space opacities." IF the patient survives, the opacities usually per- sistfor several weeks but occasionally resolve within a few days. AAs in most diffuse alveolar disorders, accurate diagnosis is de~ Pendent on association of the radiographic abnormalities with the appropriate clinical history, in this case the immediate post- partum period, INHALED PULMONARY TOXINS Inhalation of a variety of toxic gases and aerosols can result in chemical damage to the airway and alveolar epithelium, ‘Acutely, this can result in diffuse noncardiogenic pulmonary ‘edema, Chronically, this can produce large airway strictures or small airway fibrosis, known as bronchiolitis obliterans. The ‘most common example occurs after smoke inhalation during exposure to a fire. A variety of other industrial or occupational ‘exposures also may be seen and present a similar radiographic appearance. ‘Smoke Inhalation Individuals exposed to fire and smoke inhalation are prone to a variety of injuries that can result indirect and indirect pulmonary compromise. Burns to a large area of skin surface predispose the patient to shock and sepsis, both of which may result in ARDS. However, less commonly, smoke inhalation may cause direct in- jury to the respiratory system leading to respiratory impairment. ‘Thermal burns and chemical burns caused by toxic particulates in the fire can result in airway necrosis, pulmonary congestion ‘and intraalveolar hemorthage."*° Radiographic findings in- clude evidence of interstitial and alveolar edema as well as focal ‘opacities interpreted as atelectasis (Fig, 1-15). Other Toxic Inhalations Nitrogen dioxide, sulfur dioxide, chlorine gas, and phosgene ‘gas are some of the highly toxic gases that can result in air- ‘way necrosis and capillary leak pulmonary edema. These16 PARTI DIFFUSE LUNG DISEASES FIGURE 1-15. Pulmonary edema caused by smoke inhalation. This ‘man was Found unconscious in a burning house. Anteroposterior chest radiograph demonstrates widespread, faint, alveolar opacities, formly distributed throughout both lungs. This is consistent with p ‘monary edema caused by smoke inhalation, gases, when hydrolyzed upon exposure to water on mucous ‘membranes, become nitrous acid, sulfuric acid and hydrochlo- ric acid and produce chemical bums. Acutely, this results in increased capillary permeability edema indistinguishable from permeability edema secondary to other causes. In the case of nitrogen dioxide and sulfur dioxide exposute, ifthe patient sur- vives the intial acute pulmonary edema, bronchial necrosis can result in widespread scarring and airway obliteration, patholog- ically identified as bronchiolitis obliterans.” Bronchiolits obliterans is more completely discussed in Chapter 4 ‘A variety of occupations can expose patients to these toxic ‘gases. Industries with exposure to sulfur dioxide include pulp and paper manufacturing, refrigeration, oil refining, and fruit preservation." Chlorine gas exposure can occur at plastics, textiles, and water purification plants and pulp mils.!°" One po- tential household exposure can occur by mixing bleach with a cleaning solution containing phosphoric acid. This combination chemically produces chlorine gas.'" Phosgene gas is an agent used in chemical warfare. Nitrogen dioxide may be encountered during buming of shoe polish and with exposure to explosives during mining operations." However, the most important and extensively studied nitrogen dioxide exposure is known as Silo-fllers discase.!°” Fresh silage, the green fodder stored in silos, creates nitrogen dioxide and nitrogen tetroxide in the first 2 weeks after placement into the silo.""""" These brown yellow gases are heavier than air; therefore, they are confined land concentrated by the silo walls. Individuals who enter the silo during this period can be exposed to high concentrations of nitrogen dioxide with subsequent pulmonary toxicity. DRUG-RELATED DIFFUSE ALVEOLAR LUNG DISEASE ‘A variety of drugs have been associated with diffuse alveolar Tung disease, usually increased capillary permeability edema, and leading to diffuse alveolar damage. Some of the most well- documented causes include a variety of oncologic medications, high-dose aspirin, and several illicit drugs. Oncotogie medica- tions known to cause pulmonary edema include the related an- timetabolites, cytosine arabinoside (Ara C) and gemeitabi the cytokines interleukin-2 and tumor necrosis factor; and the differentiation promotor, all trans-retinoic acid (ATRA). The il- licit drugs most commonly associated with pulmonary edema are heroine and cocaine. Methotrexate is a commonly used an- timetabolite that may cause a diffuse interstitial or alveolar lang disease thought to be secondary to a hypersensitivity reaction, This also is reviewed herein, Cytosine Arabinoside Cytosine arabinoside (ARA C) is most commonly used in the therapy for acute leukemia and non-Hodgkin's lymphoma It induces a capillary leak pulmonary edema in as many as 15% to 30% of patients."""™ Pulmonary edema characteris- tically develops in association with fevers up to 6 weeks after therapy." Radiographic findings consist of linear interstitial ‘opacities, airspace consolidation, or both, which are character- istic of pulmonary edema (Fig. 1-16). In patients who recover, FIGURE 1-16. Pulmonary edema caused by cytosine arabinoside therapy. This 45-year-old woman was receiving cytosine arabinoside (Ara) as part of therapy for acute myelogenous leukemia when shede- veloped dyspnea on exertion. Anteroposterior chest radiograph reveals Widespread, patchy alveolar opacities widely distributed throughout ‘the lungs. Differential diagnosis includes hydrostatic and capillary leak ‘pulmonary edema and diffuse alveolar hemorrhage. This proved to be ‘result ofa capillary leak syndrome caused by AraC.CHAPTER 1_ DIFFUSE ALVEOLAR LUNG DISEASES inical resolution occurs within 2 weeks and radiographic res~ olution occurs within 3 weeks, Gemcitabine Gemcitabine isa drug that is chemically related to cytosine ara- binoside, which is used in the therapy of solid tumors. It also hhas been associated with the development of noncardiogenic pulmonary edema."!5"6 Although a modest percentage of pa- tients (5% to 8%) report mild dyspnea, non-cardiogenic edema is rare and has been reported in only 0.1% of patients receiving the drug. Interleukin-2 Interleukin-2 (IL-2) is a biologic response modifier used in the therapy of melanoma and renal cell carcinoma. It has been as- sociated with a syndrome of respiratory failure, hypotension, and peripheral edema that has been shown to be secondary to a capillary permeability edema,!!*!!” This appears to be a dose- ‘elated phenomenon. Early reports indicated an incidence of high as 20% of patients; however, more recent literature suggests a decreasing incidence of this complication, probably because ‘of the recognition ofthe potential oxicity of this medication and subsequent optimization of the therapeutic regimen." In two retrospective reviews of IL-2 toxicity, the most common radio- ‘araphic finding of IL-2 toxicity was pleural effusion, which was seen in approximately one-half of patients."?° Radiographic evidence of pulmonary edema also was common. It had an in- terstitial character in approximately one-half of all patients and demonstrated an alveolar appearance in another one-fourth of all patients, All Trans-retinoic Acid Al trans-retinoic acid (ATRA) is a vitamin A derivative that can induce granulocytic differentiation and promote apoptosis of leukemic promyelocytes; therefore, it is used in the ther- apy of promyelocytic leukemia." Pulmonary toxicity is seen in approximately 15% to 25% of patients receiving ATRA for promyelocytic leukemia,!2!~! This is often a life-threatening complication of therapy. Clinical symptoms include fever and respiratory distress, weight gain, peripheral edema, pleural or pericardial effusions, and hypotension.'"'"" High-dose cor- ticosteroids administration may be a life-saving therapy. The radiographic appearance is one of widespread alveolar opacity similar to other causes of severe pulmonary edema. Aspirin (Acetylsalicylic Acid) igh doses of acetylsalicylic acid (aspirin) have been sporadi- cally associated with the development of acute capillary perme ability pulmonary edema. This is most commonly seen inelderly individuals who become acclimated to taking increasingly large 7 FIGURE 1-17. Pulmonary edema caused by aspirin overdose, As @ result of severe chronic joint pains, this 26-year-old man with sickle cell disease had been ingesting large doses of asprin when he presented with ‘dyspnea. His serum salicylate levels on admission were three times the ‘maximum therapentic level. Anteroposterior chest radiograph demon- states widespread pooely defined alveolar opacities widely listibuted throughout the lungs. These opacities spontaneously resolved over the next few days after withdrawal ofall salicylates, These were presumed to represent aspirin related pulmonary edema, (Thanks 1o Wallace T: Miller, MD, fr the loan of this case.) doses of aspirin to alleviate pain.!™!°5 With the advent of mul- tiple other medications to control pain, this complication has become rare. Pulmonary edema usually resolves with falling serum levels of the medication.!"8 Chest radiographs reveal dif- fuse alveolar lung disease typical of noncardiogenic pulmonary edema (Fig. 1-17). Opiates ‘Overddoses of opiate derivatives, most commonly have been as- ted with a high protein pulmonary edema, suggesting a ca illary permeability pulmonary edema." This phenomenon is rarely encountered except in heroin overdose, where it may bbe seen in up to 15% of cases." The exact mechanism caus- ing capillary leak remains elusive. The radiographic appearance is typical of many causes of capillary leak pulmonary edema with widespread alveolar consolidation, often with a perihilar distribution,'™ The edema characteristically resolves. within a few days.!"5 Coc Cocaine and crack are known causes of pulmonary edema. Cocaine-associated pulmonary edema may result from a cap- illary leak phenomenon secondary to endothelial injury or18 PARTI DIFFUSE LUNG DISEASES FIGURE 1-18, Crack lung. This 38-year-old woman presented in respiratory distress after over- dose of erack cocaine and a botle of her husband's medications, A. Anteroposterior chest radiograph demonstrates diffuse alveolar consolidation thair bronchograms characteristic of severe pulmonary edema. Toxicology screen was positive for cocaine, tricyclic antidepressants, and alcohol. B. Antero- posterior chest radiograph 3 days Inter demonstrates resolution of pulmonary edema. hydrostatic edema caused by cardiac toxicity. or both," Cocaine use also has been associated with diffuse pulmonary hemorthage."*!" Patients typically present within hours of use, complaining of dyspnea, chest pain, and cough that is occa- sionally productive of black sputum. "44 Radiographic man- ifestations are characteristcally bilateral, symmetric, perihilar interstitial or airspace opacities, similar to pulmonary edema from other causes (Fig. 1-18)."6 The edema characteris- tically resolves spontaneously within a few days. Pulmonary hhemorthage may have a similar appearance with widespread bi- lateral air-space consolidation or occasionally focal air-space consolidation, "7-8 Methotrexate ‘Methotrexate is an antimetabotite commonly used in the ther- apy for a variety of malignancies. It also has been used to treat a variety of autoimmune disorders such as psoriasis, primary biliary cirthosis, cheumatoid arthritis (RA), and inflammatory bowel disease." The incidence of drug-related toxicity is ‘uncertain bat appears to be between 0.5% to 14% of patients receiving. low-dose methotrexate,'*!!5 The pathogenesis of the disorder is unknown but there is some evidence, in- cluding blood eosinophilia and tissue evidence of granuloma- tous inflammation, that methotrexate lung toxicity represents a hypersensitivity reaction.!7 Most patients present with dysp- tea, dry cough, fever, and bibasilar crackles of several weeks’ duration. '* Serum eosinophilia has been cited in one-third of cases, Pulmonary function studies reveal a restrictive ventilatory defect or impaired gas exchange, In most cases, the disorder is rapidly reversible after cessation of the medication and leaves zo clinical or radiographic deficit.!*!5* ‘Studies report that the initial radiographic manifestation is of basilar predominant, diffuse reticular, or ground-glass pattern to the lungs." "This may progress to widespread patchy alveo- lar opacities that regress to interstitial opacitiesand complete res- ‘olution after discontinuation ofthe medication (Fig, 1-19)."-'¢" ‘Computed tomography scans demonstrate ground-glass opacity, septal lines, ot widespread consolidation." TRANSFUSION-RELATED ACUTE LUNG INJURY ‘As a result of improvements in cross-matching, transfusion- ‘elated pulmonary edema is now a rare complication of blood product transfusions.' Although transfusions may be associ~ ated with fluid overload and lead to hydrostatic edema, true transfusion-related pulmonary edema is a capillary permeabil- ity edema caused by antigen-antibody reactions between the donor blood and host tissues. Several studies have shown that leukoagglutinins or human leucocyte antigen incompatibility is the mechanism of lung injury inthe majority of cases.'©°"! The antibodies may originate from the donor or recipient serum, Patients typically present with the acute onset of chills, fever, tachycardia, dyspnea, and nonproductive cough within a few hours of the administration of blood products." Chest radio- ‘graphs usually demonstrate perihilar and lower lobe pulmonary ‘opacities resembling other causes of pulmonary edema. In pa- tients without pre-existing cardiac disease, the heart is normal inCHAPTER 1_ DIFFUSE ALVEOLAR LUNG DISEASES FIGURE 1-19. Methotrexate lung toxicity. This 71-year-old woman, ‘who was receiving methotrexate for severe psoriatic arbritis, developed progressive acute dyspnea. Anteroposterior chest radiograph reveals diffuse alveolar opacities that obscure the pulmonary vascular mark- ings. This abnormality resolved with discontinuation ofthe methotrex- ate and represents permeability edema secondary to methotrexate hy- persensitvity, size (Fig. 1-20), Radiographic opacities typically resolve within a few days. INHALED ALLERGENS (EXTRINSIC ALLERGIC ALVEOLITIS) Hypersensitivity pneumonitis (HP), or extrinsic allergic alveoli- tis, isa lung disorder seen in response to inhalation of a wide variety of organic dusts. Exposure to antigens in the dust, usually bird proteins or microorganisms, results in an immune response ‘with a variety of clinical, pathologic, and radiographic manifes- tations. This is discussed most completely in Chapter 3. In large acute exposures, the patient may develop capillary congestion with a polymorphonuclear cellular infiltrate within the alveoli, Damage from inflammatory reaction can lead to capillary leak; thus, HP represents a form of permeability cedema.!®” Later acute-stage disease results in a combination of bronchiolitis and alveolitis with loose granuloma formation. '®* ‘Acutely patients develop bilateral, widespread alveolar opac- ities that resemble capillary leak permeability of any cause (Fig. 1-21). The consolidation may be diffuse or involve pri- ‘marily the lower lung zones." Because of the nonspecificty of the radiographic appearance, diagnosis is dependent on recogni- tion ofthe characteristic radiographic abnormality in association ‘ith recent large-volume exposure to an organic dust. These are largely occupationally related; therefore, a careful occupational history usually is necessary to make the diagnosis. Chronic exposure to an antigen can result in granulomatous interstitial fibrosis, Chronic hypersensitivity pneumonitis may have a variety of radiographic manifestations. This is liscussed in Chapters 2 and 3. HYPOPROTEINEMIA (CIRRHOSIS, NEPHROTIC SYNDROME) ‘As mentioned, patients with liver and renal dysfunction are predisposed to developing pulmonary edema." A variety of mechanisms appear to contribute to the development of pul- ‘monary edema. These include decreased oncotic pressure from hhypoproteinemia and increased capillary permeability as well as increased hydrostatic pressure as a result of hypervolemia. Ascites, pleural effusions, and pericardial effusions are ‘among the most common thoracic manifestations of chronic liver and renal dysfunction. Many patients with cirrhosis and nephritic syndrome have concomitant cardiac dysfunction and ‘pulmonary edema is moderately common in these patients, How- ever, in the absence of cardiac dysfunction, pulmonary edema is uncommon and when encountered is most often very mild in degree. This usually appears as vascular engorgement and mild interstitial edema, Alveolar edema is rare (Fig. 1-22). PNEUMONIA Pneumonia commonly results from bacterial infection and usu- ally produces a unifocal or few scattered focal alveolar opaci- ties on chest radiographs and CT scans. Recognition of adiffuse pulmonary abnormality in the setting of a suspected pneumo- nia should prompt investigation for less common etiologies of ‘pulmonary infection. The differential for diffuse pneumonias is similar regardless ofthe specific diffuse pattem. Diffuse patterns that are associated with pneumonia include the linear interstitial patter, diffuse ground-glass pattern, and diffuse alveolar pat- tem, In general, those cases manifesting as linear interstitial or diffuse ground-glass patterns tend to be milder and those ap- pearing as diffuse alveolar patterns are mote severe infections, ‘The pneumonias that most commonly appear as diffuse alveolar ‘opacities are Pneumocystis jiroveci pneumonia (PCP) and viral peumonias (Table 1-2). These viruses include influenza, aden ‘virus, herpes simplex, and varicella-zoster. The only bacterial ‘pneumonias that commonly appear asa diffuse alveolar process fae those secondary to excessive aspiration. Fungal Pneumonia Most fungal pneumonias (e-g,, histoplasmosis, cryptococcosis, coccidioidomycosis) appear as one of several focal nodular or irregular alveolar opacities. One notable exception to this rule is Pneumocystis jiroveci pneumonia (PCP). Pneumocystis Pneumonia Pneumocystis jiroveci pneumonia is an important opportunis- tic pneumonia that is frequently seen in immunocompromisedPART DIFFUSE LUNG DISEASES FIGURE 1-20. Transfusion-related acute lng injury, This 65-year-old woman received a blood transfusion shortly after undergoing a Whipple procedare for pancreatic carcinoma. Within a few hours of transfusion she developed fever, tachycardia, and dyspnea. (A) Anteroposterior chest ra- sliograph reveals widespread inhomogeneous alveolar opacities Uniformly distributed throughout the lungs. These findings are characteristic of moderate to severe pulmonary edema. Their temporal as- sociation with a blood transfusion indicates a transfusion reaction with capillary leak as a result of antigen-antibody reactions tothe blood products. Computed tomography images a the level of the (B) anteroposterior window and (C) pulmonary veins demonstrate a combination of diffuse ground-glass ‘opacities with areas of patchy consolidation, There is also mild interlobular septal thickening. These findings are consistent with wiclespread interstitial and alveolar pulmonary edema, in his case owing to the transfusion reaction, patients, in particular those with HIV infection, following or- ‘gan transplantation, and those on chronic levels of high-dose corticosteroids. Although PCP most often appears as diffuse ‘ground-glass opacity on radiographs and CT, itis also among the ‘most common pneumonias to produce diffuse alveolar opacities (Fig. 1-23).-'""- Diffuse alveolar opacities represent the ‘most severe manifestation of PCP. This appearance usually is preceded by diffuse ground-glass opacity (Fig. 1-24). When present, alveolar PCP often causes respiratory failure and re- quires mechanical ventilation. Details of PCP are discussed in greater detail in Chapter 2. Viral Pneumonia ‘Most viral respiratory illnesses cause diseases of the upper aerodigestive tract resulting in rhinitis, pharyngitis, and laryngi tis. lis the unusual viral infection that affects the lower respira- tory tract, which includes the bronchi, pulmonary interstitium, ‘and pulmonary alveolus, These infections may cause abnormal- ities identifiable on chest radiographs and CT. Tn general, inter stitial infections, bronchitis, and bronchiolitis appear as ground- ‘ass opacities or interstitial abnormalities. These findings are discussed in greater detail in subsequent chapters. Vira infec- tions that cause exudation of fluid into the alveoli can result in either diffuse alveolar opacities or diffuse ground-glass opacity ‘on imaging studies. The appearance as diffuse alveolar opaci- ties is particularly characteristic of the influenza Viruses but can be seen with adenovirus, herpes simplex viruses, and varicella- zoster virus. Hantavirus pulmonary syndrome is an unusual vi- ral infection that appears to cause a capillary leak permeability ‘edema that may manifest as a linear interstitial pattern in the carly phases of disease and progress to severe bilateral alveolar ‘opacity subsequently, INFLUENZA Vinuses. The viruses cansing influenza are a group of highly infectious RNA viruses with the ability to change the structure of their glycoprotein coats, This ability allows the fluenza virus to mutate into new forms that are antigenically dissimilarand avoid host immunity."”” The combination of rapid transmission of disease and antigenic mutability are the primaryCHAPTER 1_ DIFFUSE ALVEOLAR LUNG DISEASES A FIGURE 1-21. Acute hypersensitivity pneumonitis. This 26-year-old man presented with progres sive dyspnea, fever, and eosinophilia, He worked in a dairy processing plant mixing raw milk. (A) ‘Anteroposterior chest radiograph demonstrates widespread mixed interstitial and alveolar opacities, ‘These findings are characteristic of pulmonary ederna that in this case is a result of acute hypersen sitivity pneumonitis related to workplace exposure. Computed tomography images obtained 2 days. later after improvement in clinical symptom at the Level ofthe (B) carina and (C) pulmonary veins demonstrate Widespread groundl-gass opacities and focal areas of dependent consolidation in associ- ation with small bilateral pleural effusions. These are consistent with mild pulmonary edema caused bby improving hypersensitivity preumonitis, factors allowing the influenza virus to cause epidemic and pan- " In the general population, some indi- Viduals develop painful, vesicular lesions about the mouth (usti- ally herpes simplex I) or genitals (usually herpes simplex I). Herpes simplex virus pneumonia is a rare event and is most commonly a complication of reactivation of the virus in im- ‘munocompromised patients such as organ transplant recipients, patients with ALDS, patients with severe burns, or patients with ‘malignancies."°5~"™* Becanse it represents a reactivation infection, herpes sim- plex pneumonia characteristcally occurs in the months im- ‘mediately after organ transplantation (most commonly 12 to 47 days). Immunosuppression is instituted at the time of ‘transplantation; thus, reactivation of the viral particles is most likely to occur once adequate immunosuppression is achieved Augmentation of immunosuppression may increase the risk of HSV pneumonia in those patients who were seropositive for the virus before transplantation"! Patients usually have oral or gen- ital ulcers before the onset of pulmonary symptoms. Dyspnea, cough, and fever herald the onset of pneumonia. Definitive diagnosis requires demonstration of characteris- tic histopathologic changes in lung biopsy tissue, monoctonal immunofluorescent staining of tissue, or tissue culture iden- tification of HSV in lung tissues. As with cytomegalovirus infection, asymptomatic viral shedding in respiratory secre- tions is not uncommon and does not necessarily indicate active infection*® Intravenous acyclovir is the therapy of choice for pulmonary and other visceral HSV infection." Prophylactic administration of acyclovir has recuced the incidence of reac- tivation and may prevent deaths from this serious opportunistic infection." ‘The chest radiograph most often demonstrates multifocal or diffuse consolidation and is a manifestation of diffuse hematoge- nous dissemination of the virus (Fig. 1-26)222* Ground- ass opacification also may be found in isolation without consolidation." Unifocal infiltrates may be seen but are Jess common." Computed tomography scans also demon- strate diffuse or multifocal areas of consolidation with areas of ‘ground-glass opacification. Rarely, only ground-glass opacifi- cation is present." Associated pleural effusions commonly are found both by CT and chest radiographs." \Vanicetia Zoster Vins, Varicella-zoster virus (VZV) is a type of herpesvirus. Like other herpesviruses, it can Tie dor- ‘mant in host cutaneous sensory ganglia to be reactivated at times of diminished host immunity. Varicella or chickenpox is a result of the primary infection and is characterized by a disseminated vesicular rash, Zoster or “shingles” represents re- activation of the virus and characteristically causes a painfulCHAPTER 1_ DIFFUSE ALVEOLAR LUNG DISEASES. 23 Progressive severe Pnewmocystis carinii pneumonia. This 30-year-old HIV- positive man presented with dyspnea and fever. A. Posteroanterior chest radiograph demon- strates diffuse ground. glass opacities, Note the fait sir bronchograms present. This ts atypical presentation of Pneumocystis carinii pneumonia (PCP) and is the most likely diagnosis inthis HIV-positive individual, Bronchoscopic washings revealed Pneumocystis carinii. B. Antcro> postetior chest radiograph obtained II days later shows dramatic progression of lung disease, despite appropriate antibiotic coverage. The lungs are diffusely consolidated with multiple air bronchograms. Computed tomography images a the time of the second chest radiograph at the level of the (C) carina, and (D) apex of the diaphragm demonstrated a gradient from round:glas opacity anteriorly to diffuse consolidation posteriorly. FIGURE 1-24. vesicular rash in the dermatome supplied by the infected gan- slion. Reactivation may occur in any individual but is more com- ‘monly encountered in patients with depressed immune systems stich as transplant recipients and patients with Lymphoprolifera- tive malignancies. *” Although pneumonia may be a sequela of either form of the infection, it is more commonly a com- plication of the primary infection and may occur in as many as 15% of cases.2™2” Pneumonia usually is associated with pleuritic chest pain, hemoptysis, dyspnea, cough, malaise, and fatigue. Varicella-zoster virus pneumonia characteristically presents with diffuse ill-defined, “fuzzy” nodular densities (Fig, 1-27).2"° The nodules usually are 5 to 15 mm in diameter and are spread uniformly throughout the lung. This pattem may be called the acinar nodular pattern, Computed tomography scans also demonstrate small nodular opacities widely disseminated throughout the lungs.*"" On CT scans, there often are surround ing ground-glass opacification that may account for the indis- tinct character of the nodules on chest radiographs. In more advanced cases, the nodules may become confluent and appear as faintly nodular, diffuse alveolar opacities. Some patients may show diffuse tiny nodular calcifications years later that repre Hantavieus. ‘monary disorder secondary to infection with Sin Nombre virus (SNV). a type of Hantavirus. This syndrome was first reported Hantavirus pulmonary syndrome is a rare pul-PART1 DIFFUSE LUNG DISEASES FIGURE 1-25, Adenovirus pneumonia, Complaining of fever, cough and dyspnea, this 42-year-old woman had a history of diabetes mellitus, systernic hypertension, and prior re ‘nal transplantation. A. Initial chest radiograph reveals heterogencous, faintly nodular areas of ‘consolidation throughout both ings. This likely copresents a diffuse pneumonia such as Preu- ‘mocystis carinii pneumonia or a viral pneumonia. Given the history of renal transplantation ‘an opportunistic infection i likely B. Anteroposterior chest radiograph obtained 2 days later ‘shoves progression of lung disease with mare uniform consolidation. Airbronchograms are n0% ‘present. Computed tomography images at day 4 after presentation al the level of the (C) carina and (D) apex of the diaphragm demonstrate widespread but heterogencous consolidation of ‘oth lings with faint nodular character resembling the initial chest radiograph. Viral cultures during an outbreak of unexplained deaths in the rural popu- lation of the southwestern United States.""* The syndrome is characterized by a prodrome of fever. myalgia, cough, dyspnea, gastrointestinal upset, and headache. This progresses rapidly to acute pulmonary edema and hypotension that is often fatal Death occurred a mean of 8 day’ after the onset of symptoms, in three-fourths of the 17 patients inthe initial outbreak?" The mode of infection appears to be inhalation of airborne particles from the urine and feces of infected rodents, usually deer mice. Although the disorder is primarily found in the southwestern United States, cases have been reported in 31 states2!* Patho- logic evaluation of the lungs reveals a capillary leak pulmonary ‘edema with scant to moderate hyaline membranes and intersti- tial lymphocytic infiltrate, There is also evidence that the virus causes direct myocardial depression that contributes to and, in ‘ultimately revealed adenovirus asthe causative organism, fact, may be primarily responsible for the high mortality associ- ated with this syndrome. Itis unclear whether pulmonary edema results from direct viral infection or is caused by virally induced immune mediated damage to the pulmonary endothelium. ‘The imaging findings of Hantavirus pulmonary syndrome are those of a capillary leak pulmonary edema. Interstitial pul- ‘monary edema, seen as the linear interstitial pattern, is the most ‘common radiographic finding and is scen in the majority of cases (Fig. 1-28) "4215 Approximately two-thirds of cases progress to diffuse alveolar consolidation as a result of capillary leak This is often perihilar in distribution and resembles cardiogenic pulmonary edema with the notable exception of a normal-sized heart, Alveolar disease is associated with high mortality, Pleural cffusions also are common and are detected in approximately ‘one-half of cases.CHAPTER 1_ DIFFUSE ALVEOLAR LUNG DISEASES SeRioUS ACUTE RESPIRATORY SYNDROME. Serious acute res- piratory syndrome (SARS) is a highly infectious, often fatal respiratory infection with a recently discovered coronavirus.""° ‘The coronavirus, known as SARS-Cov. is transmitted primarily through respiratory tract secretions ordirect contact. SARS-CoV is genetically similar to previously known coronaviruses but it is the first known coronavirus to cause severe respiratory illness in immunocompetent adults !° Prodromal symptoms such as headache, malaise, and myal- gias are common. The majority of patients develop a high fever a mean of 7 days after exposure." Dry cough, dyspnea, and arthralgia frequently are present.* Mild hypoxemia is seen in approximately one-half of patients and 10% to 20% require in- tubation and mechanical ventilation "7-2"? 25 FIGURE 1-26. Herpes simplex pneumonia. This 32-year-old HIV- Positive woman presented with dyspnea, fevers, anda vesicular ash ‘on her perineum and face. (A) Initial chest radiograph reveals hetero- ‘geneous, faintly nodular areas of consolidation at both Tung bases but ‘with greater involvement ofthe right lung. The presence of a vesicu- lar rash and fever should suggest a herpes group viral pneumonia. (C) Anteroposterior chest radiograph, obtained 3 days later, (B) anteropos- terior chest radiograph, obtained 5 days after presentation (C) shows progressive widespread, heterogeneous consolidation of both lungs, Histologic evaluation of a surgical lung biopsy demonstrated herpes simplex infection. Approximately one-half of patients present with a focal re- ‘gion of consolidation, resembling a bacterial pneumonia." However, approximately one-third of patients present with mul- tifocal or diffuse consolidation. Disease may rapidly progress from more limited areas of disease to multifocal or diffuse con- solidation of the lungs bilaterally.=2""=° The pattern of disease ‘and the age of the patient at presentation have prognostic sig- nificance. Young patients usually present with a normal chest radiograph or one demonstrating a focal opacity and have a fa- vorable clinical outcome.?!2 Elderly patients with comorbid diseases are more likely to present with diffuse consolidation and have a high fatality rate 2!222 Computed tomography scans may demonstrate focal or dif- fuse consolidation, focal or diffuse ground-glass opacity, or a26 FIGURE 1-27. Varicella pneumonia. This 32-year-old man pre- sented with a vesicular rash. He denied pulmonary symptoms. (A) Posteroanterior chest radiograph and (B) magnified view of the right lung demonstrat difuse alveolar consolidation. Note that the consol- ‘dation is composed of confluent fuzzy nodular opacities. This appear- lance sometimes is refered to as the acinar nodular pattern and is characteristic feature of varicella pneumonia combination of findings°22.2 Computed tomography of- ten shows the disease 10 be more extensive than recognized ‘on chest radiographs.” In the early phases of disease SARS ‘most often appears as areas of ground-glass opacification 2°24 Later, in the acute phase, there are often multifocal areas of frank consolidation.“ SARS is discussed most completely in Chapter 5. ‘Orwiee Virat PNEUMONIAS. The five viruses previously de- scribed are those most commonly associated with diffuse alve- olar lung disease. However, rarely other viral infections may produce a diffuse alveolar pneumonia (Fig. 1-29). Bacterial Pneumonia Bacterial pneumonias appear as unifocal or multifocal alveolar ‘opacities in the vast majority of cases. Diffuse consolidation of PARTI DIFFUSE LUNG DISEASES the lungs is quite rare but occurs occasionally. Thus, diagnosis ‘ofa bacterial pneumonia should be discouraged in patients with diffuse alveolar opacities except in rare instances. A notable exception to this rule is polymicrobial aspiration pneumonia that may present as diffuse alveolar opacities, Aspiration Pneumonia Aspiration pneumonia is the most common diffuse pneumo- nia in hospitalized patients, The res piratory compromise caused bby aspiration of oropharyngeal or gastric secretions can o¢- ‘cur by three distinct mechanisms. The aspirated fluid itself can fill alveoli and impair gas exchange Alternatively or syn- cchronously, a noninfectious pneumonitis may result from in- flammatory agents within the aspirated secretions such as gastric acids and inflammation-inducing particulates. There is experi- ‘mental evidence that when the acidity of pulmonary secretions is below a pH of 2.5 a chemical pneumonitis may occur as a resultCHAPTER 1_ DIFFUSE ALVEOLAR LUNG DISEASES 27 A FIGURE 1-28. Hantavirus pulmonary syndrome. This middle-aged man complained of progressive dyspnea, nonproductive cough, fever, nausea, and myalgias. He had recently remodeled his basement in rural Pennsylvania, The basement was noted tobe infested with rus. A. Posteroanterior chest radio- ‘graph demonstrates interstitial prominence characterized by Kerley A and B lines, This is typical of the Linear Interstitial patter and is most commonly caused by pulmonary edema. B, Posteoanterior chest radiograph obtained 2 days later shows progression of disease that now appears as bilateral alveolar consolidation with slight perikilar predominance. Note the normal size heat. Cultures ul- ‘imately revealed Hantavirus as the cause for noncandiogenic pulmonary edema. (Thanks to Lacey Washingion, MD, forthe loan of this case.) of the acidity of the fuid2* In addition, a direct inflammatory pneumonitis may result in response to particulates, such as bits ‘of food, within the aspirated fluid ”"”* Lastly. oral microorgan- isms can be transported with the aspirated fluid into the airways, and result in infectious pneumonia. Aspiration of sufficient quantities of oropharyngeal or gas- Irie secretions to cause respiratory compromise is almost never seen in the absence of an underlying predisposing condition. Predisposing factors include impaired mental status as seen in patients with coma, recent trauma, general anesthesia, seizures, and strokes (Fig. 1-30)" Patients with impaired swallow- ing or esophageal dysfunction such as achalasia, scleroderma, esophageal strictures, or diverticula also are predisposed to as- piration and aspiration pneumonia” Lastly, the presence of ‘oropharyngeal tubes such as nasogastric suction tubes and feed- ing tubes may predispose patients to aspiration." Initially, histologic evaluation reveals pulmonary edema or hemorthage. This is followed by the development of necrotic debris and hyaline membrane formation. Occasionally, particu- late foreign material may be present. Inthe end stages, diffuse alveolar damage develops. Patients often present with signs and symptoms of respiratory impairment such as dyspnea, cough, increased respiratory rate ‘or hypoxia. Fevers may occur at a later time, once bacterial in- fection becomes the dominant feature of disease. Occasionally, patients have a history of vomiting or gagging, which provides a clue to the diagnosis. In patients who ate comatose with en- dotracheal or tracheostomy tubes, airway suctioning revealing food particles may be the first sign of aspiration. In most cases, the radiographic appearance of aspiration is that of multifocal alveolar opacities, characteristically in dependent areas of the lung. In erect patients this is in the basilar segments of the lower lobes. In supine patients this is in the superior segments of the lower lobes and the pos- terior segments of the upper lobes because the airways to these segments are directed posteriorly "°° When the aspi- ration is at its most severe, the pulmonary opacities may be widespread, involving nearly the entire pulmonary parenchyma and resembling alveolar cardiogenic edema (see Fi Fig. 1-3), Pulmonary opacities usually are present soon after the on- set of symptoms because the aspirated fluid itself fills alveoli ‘and presents as an alveolar opacity. The inflammatory pneu- monitis induced by gastric acid and particulate debris develops within hours following aspiration and is evident on radiographs. In cases where the pulmonary opacities are a result of sterile as- Pirated fluid or chemical pneumonitis, the opacities may resolve within a few days. Ifinfectious oral flora are aspirated, the radio graphic opacities usually persist for a week or more if a pneu- ‘monia develops. In some cases of severe aspiration pneumonia,28 PARTI _DIFFUSE LUNG DISEASES FIGURE 1-29. Cytomegalovirus pneumonia. This 33-year-old man was HIV positive with ‘widespread cutancous Kapori's sarcoma. He developed rapidly progressive dyspnea and by. ‘poxia. A. Initial ches radiograph demonstrated a diffuse interstitial abnormality characterized ‘by lines radiating from the hilum and Kerley B lines present inthe right costophrenic angle. This ‘does not readily fit any ofthe interstitial paitems deseribed inthis text but best corresponds with ‘the Linear Interstitial pattern. Differential possibilities include interstitial pulmonary edema, interstitial pneumonia, and palmonary Kaposi's sarcoma. B. Portable chest radiograph demon: ‘strates marked progression of diffuse lung disease that is now densely alveolar with areus of _airbronchograms. Computed tomography images at the level of the (C) carina and (D) apex of ‘the diaphragm confirm the presence of diffuse alveolar consolidation, This rapidly progressive Process should be either a diffuse pneumonia or noncardiogenic edema. Surgical lung biopsy the disease progresses to ARDS and may take weeks toclinically and radiographically resolve. DIFFUSE ALVEOLAR HEMORRHAGE Radiographically, the appearance of diffuse alveolar hemor thage (DAH) may range from faint ground-glass opacity to diffuse alveolar consolidation.” Alveolar hemorrhage may result from a large number of disorders; however, when dif- fuse the differential diagnosis is more limited (Table 1-3). The most common causes of diffuse alveolar hemorrhage in outpatients are the group of entities often referred to as the “pulmonary-renal syndromes.”=* Most important of ‘demonstrated cytomegalovirus pneumonia, without other concomit 3 pathogens identiied, these are Goodpasture's disease, systemic lupus erythemato- sus (SLE), and Wegener's granulomatosis. Although these disorders may have other pulmonary manifestations, dif- fuse alveolar hemorrhage is among,the most common radio- graphically identifiable abnormality.** Vasculitides other than Wegener's granulomatosis, such as Churg-Strauss. vasculitis ‘and microscopic polyangitis (formerly called microscopic pot- yarteritis nodosa or pauci-immune vasculitis) also may result in diffuse alveolar hemorrhage. Patients with tymphoma and leukemia also are prone to diffuse alveolar hemorrhage, prob- ably as a result of platelet deficiency or malfunction. Bone marrow transplant recipients may experience diffuse alveolar hemorrhage that is associated with a high mortality. Pa- tients with bleeding disorders (e., those with antiphospholipidCHAPTER 1_ DIFFUSE ALVEOLAR LUNG DISEASES 29 FIGURE 1-30. Pseudomonas pneumonia, After surgical resection of bowel stricturcs, this 52-year-old woman with Crofn's disease de ‘veloped fevers and cough. Anteroposterior chest radiograph reveals ‘widespread alveolar opacities with air branchograms that only spare the left lung apex. Most offen this appearance represents asymmet- ric pulmonary edema. However, with the history of fever and cough this was subsequently shown to represent pscudomonas pocuronia. It likely developed as a result of aspiration daring general anesthesia. FIGURE 1-31. Aspiration pneumonia. This 45-yearold man ‘was found unconscious. Anteroposterior chest radiograph shows ‘widespread alveolar opacities with air bronchograms. Note how this ‘pneumonia resembles the batwing pattern of cardiogenic pulmonary edema. However, the unconscious state ofthe patient indicates a pred: position to aspiration pneumonia, Subsequent clinical course confined 4 diagnosis of aspiration pneumonia. The pneumonia is most severe in the posterior segments ofthe upper lobes and the superior segments of the lower lobes, the characteristic distribution for aspiration, TABLE Causes of Diffuse Alveolar Hemorrhage ‘Pulmonary renal syndromes Vasculitis Wegener's granulomatosis ‘Churg-Sirauss syndrome Microscopie polyangiitis (microscopic polyaterits nodose, ‘pauci-immune vasculitis) Other vasculitides ‘Systemic lypus erytematosis Goodpasture's disease IgA nephropathy Other Bone marrow infiltration Lymphoma Leukemia Other Bone marrow transplantation Idiopathic pulmonary hemosiderosis Bleeding diathesis [Endogenous causes ‘Antiphospholipid antibody syndrome Protein C deficiency Other Exogenous causes Heparin Warfarin Other antibody syndrome or DIC), and patients on anticoagulant med- ations also may develop diffuse alveolar hemorrhage.?™ 1d- iopathic hemosiderosis isa rare disorder of unknown etiology associated with diffuse alveolar hemorrhage that typically oc- ‘curs in children less than 10 years old. Hemoptysis may provide a clue to the diagnosis of diffuse alveolar hemorrhage, Unfortunately not all individual with dif- fuse alveolar hemorthage present with hemoptysis. Thus, the correct diagnosis often is dependent on the correlation of diffuse infiltrates with clinical features that suggest one of the known causes of diffuse alveolar hemorrhage. For example, the pres- ence of concurrent renal insufficiency may be a clue to the diag- nosis of one of the pulmonary renal syndromes. The presence of systemic systems such as arthralgias, rash, and so on may pro- Vide a clue to some of the systemic diseases leading to diffuse alveolar hemorrhage such as SLE and the vasculitides. When severe, DAH fils the alveoli and obscures the in- tersttial markings on both chest radiographs and CT images: however. when mild, it often appears as a diffuse ground-glass ‘opacity THE PULMONARY-RENAL SYNDROMES, Goodpasture’s Syndrome ‘Goodpasture’s syndrome is an uncommon autoimmune disor- der resulting in autoantibodies to the glomerular and alveolarPARTI DIFFUSE LUNG DISEASES Goodpasture"s disease: diffuse alveolar hemorrhage. FIGURE 1-32. ‘This 41-year-old woman presented with dyspnea and hemoptysis. An teroposterior chest radiograph demonstrates diffuse alveolar opacities. With the history of hemoptysis, these opacities most likely represent lffuse alveolar hemorrhage. An outpatient presentation of DAH most often is secondary to one of the pulmonary-renal syndromes, Open lung biopsy demonstrated the characteristic linear immunofluerescence characteristic of Goodpasture's disease basement membranes. Immunofluorescent stains of the kid- ney and lung show characteristic linear staining of the basement ‘membranes of the glomeruli and alveoli. Inthe kidney, it causes acute glomerulonephritis and in the lung results in diffuse alve- lar hemorrhage and mild interstitial fibro Hemoptysis is the presenting symptom in the majority of pa- tients, and is often associated with dyspnea, fatigue, and pallor. Pulmonary disease usually precedes the onset of renal insuffi- ciency. Urinalysis intially may be normal but patients usually ‘develop proteinuria with cellularand granular casts at some stage of disease. ‘Chest radiographs characterstically demonstrate a diffuse alveolar Hung disease but may have a unilateral predominance (Fig. 1-32)2" As the hemorrhage resolves, the opacities often become progressively less visible and may ultimately appear as ‘ground-glass opacities. Computed tomography scans may show frank consolidation or diffuse ground-glass opacities that often take a centrilobular distribution.” Systemic Lupus Erythematosus ‘Systemic lupus erythematosus (SLE) is among the most com- ‘mon of the connective tissue diseases. It appears to be of multi- factorial etiology with an interaction of genetic, immune, envi- ronmental, and endocrine factors resulting in clinically evident disease. This disease has a striking female to male predomi- nance (10:1) and characteristically affects young and middle- aged individuals. There are a wide variety of thoracic man- ifestations, most commonly including pleural and pericardial FIGURE 1-33, Diffuse alveolar hemorshage resulting from systemic lupus erythematosus. This 19-year-old womanhhad history of systemic lupus erythematosus (SLE) wi chronic renal failure and serologic ev idence of lupus anticoagulant. She had experienced muliple episodes ‘of venous thrombosis and was on chronic anticoagulation with warfarin ‘sodium. Atthe time ofthis film she presented with hemoptysis, Antero- posterior chest radiograph demonstrates diffuse alveolar consolidation ‘with multiple ar bronchograms consistent with DAH. Diffuse alveolar ‘hemorrhage likcly resulted from a combination of medications and her underlying clotting disorder. effusions; however, pleural fibrosis, pulmonary interstitial fibro- sis, vasculitis, pulmonary arterial hypertension, and diffuse alve- ‘lar hemorthage also are seen. When patients with SLE present with diffuse air-space consolidation or ground-glass opacity, diffuse alveolar hemorrhage is the most common etiology (Fig. 1-33), Wegener's Granulomatosis and Other Pulmonary Vasculitides Wegener's granulomatosis is an idiopathic systemic granulo- matous disorder primarily affecting the paranasal sinuses, lung, and renal cortex. Its etiology remains unknown, although it is ‘commonly assumed to be in part an autoimmune phenomenon, ‘Most patients present in middle age with the insidious onset of sinonasal or pulmonary symptoms. Most patients have renal disease at some time during their illness, However, it is uncommon for renal dysfunction to be present at the time of presentation; therefore, the diagnosis of Wegener's gran- uulomatosis should not be excluded because of the absence of renal disease." Approximately 85% to 90% of patients ‘with disseminated Wegener's granulomatosis and 75% of pa- tients with limited Wegener's granulomatosis have serum pos- itive for C-ANCA (cytoplasmic staining antineutrophil cyto- plasmic antibodies). This form of ANCA staining is seen ‘only rarely in other vasculitides and some infections; therefore, C-ANCA represents a moderately sensitive and specific marker for Wegener's granulomatosis Radiographic manifestations are most commonly one or multiple pulmonary nodules or masses that are frequentlyCHAPTER 1_ DIFFUSE ALVEOLAR LUNG DISEASES cavitary?" However, diffuse alveolar hemorthage also is a frequent manifestation, Ths may appear aspatehy or dftuse ae CChurg-Strauss syndrome is a rare vasculitis associated with asthma, fever, and blood eosinophilia.” The cause remains un- mown but is thought to have an autoimmune basis, It charac- teristically presents in patients in theit thirties to fifties who have a history of asthma. Multiorgan involvement is com- ‘mon, and skin, gastrointestinal, neurologic, and pulmonary sys- tems are affected. Purpuric rashes, small bowel or colonic ul- ceration, peripheral and cranial neuropathies, and pulmonary vasculitis: and alveolar hemorthage are some of the possible ‘manifestations.”*' Many patients have elevated ANCA titers but unlike Wegener's granulomatosis usually have the less specific, pericytoplasmic cytoplasmic staining (P-ANCA). Radiographic ‘manifestations are most commonly transient nonsegmental areas of consolidation Diffuse alveolar hemorrhage is uncommon but may occur. “Microscopic polyangitis (microscopic polyarteritis nodosa) is a necrotizing vasculitis that predominantly affects arteri- 31 ‘oles, venules, and capillaries with an average age of onset of 50 years." As with other small vessel pulmonary vasculitides, the cause remains unknown but is thought to have an auto- immune basis. The disorder most commonly involves the kid- ney but also frequently has joint, skin, and pulmonary involve- ‘ment, Pulmonary vascularinvolvement resultsin diffuse alveolar hemorthage.* Henoch-Schonlein purpura (HSP) or IgA nephropathy is a rare vasculitic syndrome characterized by nonthrombocytopenic purpura, arthralgias, absominal pain, and glomerulonephritis. This syndrome most commonly involves the kidney and bowel, where it can produce hematuria, proteinuria, glomerulonephii- tis, and intestinal hemorrhage. It most often affects children and adolescents but may be encountered at any age? The dise cease appears to be secondary to deposition of IgA containing circulating immune complexes.™* Pulmonary involvement is rare but most often represents a capillaritis with resultant in- traalveolar hemorrhage ***** Chest radiographs and chest CT demonstrate diffuse pulmonary consolidation or ground-glass ‘opacity similar to other causes of diffuse alveolar hemorthage (Fig. 1-34) 8837 FIGURE 1-34. | Henoch Schonlein purpura-associated diffuse alveolar hemorthage. This 28-year~ ‘old man had undergone renal transplantation 10 years before. The renal transplant had failed 3 months prior to presentation with severe acute dyspnea. (A) Posteroanterior chest radiograph demonstrates ‘widespread consolidation that has an underlying nodular character. This is a nonspecific finding with a wide differential including noncardiogenic edema and diffuse pneumonia. The presence of known ‘renal disease raises the possibility that this abnormality represents a pulmonary-renal syndrome with associated DAH, Computed tomography images at the level of the (B) aortic arch and (C) pulmonary ‘eins demonstrate widespread but not uniform consolidation of all lobes. This ix unlikely to be & result of pulmonary edema because ofthe spared areas of ung but could be a manifestation of either a ‘pneumonia or heterogeneous DAH. Bronchoscopy demonstrated the presence of hemorrhage within the airway and open lung biopsy revealed a vasculitis consistent with HISP. Ii likely that steroids "used to prevent transplant rejection had the additional benefit of treating his HSP and preventing DAH ‘until his medications were discontinued with demise of his renal transplant.32 PART1 DIFFUSE LUNG DISEASES FIGURE 1-35. Diffuse alveolar hemorrhage in acute leukemia. This 54-year-old woman with acute promyelocytic leukernia presented with ‘decreasing mental status, dyspnea, and fevers. Anteroposterior chest r sliograph demonstrates widespread heterogencous pulmonary alveolar ‘opacities. This could represeat a widespread peumonia ar DAH. The patient also was noted to be thrombocytopenic and bronchoalveolar Tavage demonstrated the presence of hemorrhage in the lung. Diffuse alveolar hemorthage is nearly always a manifestation of thrombocy: topenia in patients with leukemia and lymphoma. A diagnosis of DAH should be discouraged in the absence of thrombocytopenia. Note that {his example of DAH produced asymmetric pulmonary opacities. This isespecially common onthe initial x-rays following hemorthage. Later ‘exams often become more symmetric. LYMPHOMA AND LEUKEMIA. Diffuse alveolar hemorthage is the second most common pul- monary complication of the hematologic malignancies." (Pneumoniais the most common pulmonary complication.) This is more common in leukemia than Iymphoma and is virtually always associated with a thrombocytopenia, Some researchers believe that both thrombocytopenia as well as a second insult, such as diffuse alveolar damage, are necessary to result in dif- fuse alveolar hemorrhage.” Radiographs and chest CT show ‘widespread pulmonary opacity appearing as cither frank consol- idation oF diffuse ground-glass opacity similar to other causes of diffuse alveolar hemorrhage (Fig. 1-35)" Bone Marrow Transplantation Autologous (receiving a reinfusion of ones own bone marrow) and allogenic (receiving an infusion of a donor's bone marrow) ‘bone marrow transplantation (BMT) now are common therapies forthe treatment of aplastic anemia, acute and chronic leukemia, lymphoma, multiple myeloma, and some solid malignancies." Despite its success, BMT is a highly risky procedure, associated with multiple life-threatening complications. Diffuse alveolar hhemorthage is among the most feared pulmonary complications, FIGURE1-36. Diffuse alveolarhemorshage resulting from bone mar- row transplantation, One day following bone marrow transplantation for lymphoma, this 30-year-old woman presented with dyspnea. An: {cropostcrior chest radiograph demonstrates uniform, widespread alve- ‘lar opacities. In ths clinica setting, this is highly likely to represent DAH, a frequently lethal complication of bone marrow transplantation, Bronchorcopic evalustion confirmed the diagnosis of DAH, with an associated mortality that approaches 79%.2* Approx- imately one in five patients receiving autologous BMT devel- ‘ps this complication. It also may be seen in patients receiv- ing allogenic BMT. Symptoms of progressive dyspnea, cough, and hypoxemia characteristically develop 7 to 40 days after the transplantation.” Chest radiograph and CT findings usually consist of diffuse, bilateral, air-space consolidation or ground- glass opacity (Fig. 1-36). Occasionally these findings are asymmetric or even unilateral in distribution. Coagulation Disorders Rarely, patents with a coagulation disorder may develop dif- fuse alveolar hemorthage. Although this is reported in patients receiving anticoagulant therapy, itis seen more often in individ uals with endogenous coagulation disorders such as antiphos- pholipid antibody syndrome, cryogtobulinemia, DIC, and factor V deficiency (see Fig. ig. 1-37)” On chest radi graphs and CT, these patients demonstrate diffuse air-space con- solidation and ground-glass opacity simitar the other causes of diffuse alveolar hemorthage PRIMARY PULMONARY HEMOSIDEROSIS. Idiopathic pulmonary hemorrhage, also known as primary pul- monary hemosiderosis and idiopathic pulmonary hemosidero- sis, is a rare idiopathic disorder that manifests as diffuse alveolar hemorrhage, Histopathologic evaluation demonstrates histologic characteristics, including linear immunofluorescence, identical to that seen in Goodpasture's syndrome.”*” IdiopathicCHAPTER 1 DIFFUSE ALVEOLAR LUNG DISEASES 33 A FIGURE 1-37. Diffuse alveolar hemorrhage 4 patient with eryoglobulinemia. This 43-year- ‘old woman with a history of intravenous drug abuse—related hepatitis C presented with progressive extremity pain and peripheral neuropathy. She developed acute respiratory failure several days after admission. (A) A chest radiograph demonstrates widespread alveolar opacities with air bronchograms. ‘Thispattern most commonly is secondary to cardiogenic edema or adult respiratory distress syndrome, ‘Computed tomography images atthe level ofthe (B) carina und (C) pulmonary veins reveal widespread ‘ut heterogeneous pulmonary consolidation with slight upper lobe predominance. This pattern is too heterogeneous to be consistent with eardiogensc edema but could be a manifestation of DAH, ‘widespread pneumonia, or less likely a capillary leak edema. Surgical ling biopsy revealed DAH secondary to cryoglobulinemia pulmonary hemosiderosis may reptesent a form of Goodpas- ture’s syndrome without renal disease. It is characteristically seen in children less than 10 years old but occasionally devel- ‘ops in teenagers and young adults” It may present insidiously with anemia, lethargy, and weakness or acutely with fever and hemoptysis. The chest radiographic and CT appearance is iden- tical to Goodpasture’s syndrome. OTHER UNUSUAL CAUSES OF DIFFUSE ALVEOLAR LUNG DISEASE ‘Three unusual causes of diffuse alveolar opacities are pulmonary alveolar proteinosis (PAP), bronchoalveolar carcinoma (BAC), ‘and acute interstitial pneumonia (AIP), These ate disparate enti- ‘ies only finked by their common ability to cause diffuse alveolar ‘opacities on chest radiographs and CT. Pulmonary Alveolar Proteinosis Pulmonary alveolar proteinosis (PAP) is arare disorder in which there is accumulation of abnormal protein and lipid-rich material derived from surfactant that abnormally persists within the alve~ oli of the lung.” Most often PAP is an idtopathic disorder that is currently believed to represent an autoimmune disorder targeting granulocyte-macrophage colony-—stimulating factor’® However, occasionally it may be associated with genetic mu- tations involving surfactant production and reclamation oF may be associated with some antecedent conditions such as silico- sis, leukemia, lymphoma, and HIV infection 27” This rare disorder is discussed more fully in Chapter 2. Tn many cases chest radiographs demonstrate diffuse alveolar consolidation (Fig. 1-38). However, in cases of less severe dis- cease diffuse ground-glass opacities are present, often with non- specific increases in interstitial markings”? Thin section CT characteristically shows ground-glass opacity and thicken- ing ofthe intralobular septa ofthe secondary pulmonary lobules, creating a pattern known as “erazy paving."?””-*! Ground-alass ‘opacity without interstitial thickening or alveolar consolidation also may be seen (Fig. 1-39). Bronchoalveolar Carcinoma Bronchoalveolar carcinoma (BAC) is a form of well- differentiated pulmonary adenocarcinoma. It ofien has an in- dolent clinical course and a wide variety of radiographic ap- pearances, including solitary pulmonary nodules, focal alveolar ‘opacities resembling pneumonia, ground-glass nodules, and iso- lated diffuse ground-glass opacities, as well as diffuse pul- ‘monary consolidation (Fig. 1-40). This is discussed most fully in Chapter 7FIGURE1-38. Pulmonary alveolarprotcinosis. This 35-year-old His- ‘panic man presented with chronic, progressive dyspnea. Anteroposte- ror chest radiograph reveal diffuse alveolar opacities that form inn= ‘merable small nodular opacities. Note thatthe nodules have indistinct ‘margins. This is indicative of an air-space disorder rather than inter stitial nodular disorder and sometimes is called the acinar nodular pat- tem. This usually i indicative ofa chronic alveolar disorder. Open lung biopsy was diagnostic of pulmonary alveolar proteinosis, PARTI DIFFUSE LUNG DISEASES FIGURE 1-40, Bronchoalveolar carcinoma, This 67-year-old woman ‘complained of slowly progressive dyspnea. Anteroposterior chest ra- sdiograph reveals widespread alveolar consolidation with an underlying ‘nodular character. Like Figure 1-37, this sometimes is ealled the acinar ‘nodular pattem and often i associated with chronic alveolar disorders. ‘There is also elevation of the right hemidiaphragm. Transbronchial biopsy yielded a diagnosis of well- differentiated adenocarcinoma con- sistent with a bronchoalveolar carcinoma. (Thanks to Wallace T. Miller, MD, for the loan of this case.) eo os FIGURE 1-39. Pulmonary alveolar proteinosis. This 17-year-old woman developed rapidly progres- sive dyspmea. (A) Anteroposterior chest radiograph reveais severe alveolar consolidation. Computed tomography images at the level of the (B) main pulmonary artery and (C) apex of the diaphragm demonstrate innumerable fuzzy nodular opacities consistent with alveolar nodules as well as more confluent consolidation at the lung bases. Ths is a nonspecific nding: however, the airspace nodular pattem is known to be associated with pulmonary alveolar proteinosis, which was confimed at open Tung biopsy.CHAPTER 1_DIFFUSE ALVEOLAR LUNG DISEASES 35 FIGURE 1-41, Acute interstitial pneumonia. This 61-year-old woman presented with dysprea that progressively incteased in severity over the course of a month, despite antibiotic therapy. (A) Pos- {eroanterior chest radiograph demonstrates pootly defined multifocal alveolar opacities in the lungs bilaterally. Computed tomography images atthe level of the (B) aortic arch, (C) carina, and (D) apex of the diaphragm demonstrate multifocal ground-glass and alveolar opacities. (E) Posteroanterior chest radiograph 3 months later demonstrated progression of the abnormality, which now appeared as diffuse alveolar opacities, which could represent progressive diffuse pneumonia or hypersensitiv- ity pneumonitis, However, open biopsy demonstrated diffuse alveolar damage without organisms oF ‘granulomas consistent with a diagnosis of acute interstitial pneumonia, Acute Interstitial Preumoni ‘Acute interstitial pneumonia (AIP) is a rapidly progressive terstitial fibrosis that resembles the proliferative stage of dif- fuse alveolar damage, the histologic manifestation of ARDS. This differs from the other interstitial pneumonias in the exten- sive active fibrosis causing interstitial thickening. This active fibrosis is characterized by proliferating fibroblasts with mini- mal collagen deposition? At later stages of disease there may be areas of honeycomb formation similar to usual interstitial pneumonia (UIP). This disorder was originally called Hamman- Rich syndrome, and was thought to be an acute variant of UIP,36 However, current evidence does not support link between UIP and ATP. Current thinking stiggests that ATP represents an idio- pathic, subacute form of ARDS. ‘Acute interstitial pneumonia characteristically presents with progressive dyspnea leading to respiratory failure over a few ‘weeks to months. A viral-like prodrome may precede the onset of AIP. Chest radiographs of patients with AIP often show diffuse alveolar opacities that resemble ARDS. Chest CT may show alveolar consolidation or ground-glass opacity or both often with associated traction bronchiectasis (Fig. 1-41)2%228 Acute Eosinophilic Pneumonia Acute eosinophilic pneumonia isan unusual acute Tung injury re- sembling ARDS. Histologically there is diffuse alveolar damage ‘with numerous intra-alveolar and interstitial eosinophils.25 ‘This disorder can occur at any age. Patients usually present with acute onset of dyspnea, fever, and hypoxia.*54 Many patients also have cough, chest pain, or myalgias "25 Ap- proximately one-half of patients have eosinophilia identified ‘on peripheral blood counts." Respiratory failure is of- ten sufficiently severe to require mechanical ventilation. Some patients resolve spontaneously; most others rapidly improve, ‘ith resolution of symptoms within a week after corticosteroid therapy.?**285 ‘The chest radiograph typically resembles pulmonary edema, ranging from diffuse interstitial opacities with Kerley B lines to widespread alveolar consolidation.” It is believed that the interstitial opacities represent the early phases of disease that usually rapidly spread to diffuse alveolar consolidation 2° ‘The most common radiographic finding is of diffuse alveotar opacities. 2°"! The remainder of patients demonstrate dif- fuse mixed alveolar and interstitial opacities or diffuse interstitial ‘opacities resembling interstitial pulmonary edema. Small bilat- eral pleural effusions are ly encountered at some time during the course of disease.2¥7272293 CT scans often demonstrate diffuse ground-glass opaci- fication in association with interlobalar septal thicken- ing.529°212 In other cases there is diffuse air-space opaci cation. Pleural effusions are found on CT scans in the majority of patients.752> SUMMARY As should be apparent, there are few radiographic clues to distin- ‘guish among the various causes of diffuse alveolar lung disease: therefore, clinical history and demographics become essential to narrowing the differential diagnosis. Cardiogenic pulmonary edema and ARDS represent the two most common causes of the diffuse alveolar pattern and should be the first diagnoses considered in any patient with diffuse pulmonary opacification, If these diagnoses are considered unlikely, then clinical history should provide important additional clues. PARTI _ DIFFUSE LUNG DISEASES A history of hemoptysis should prompt consideration of caiises of diffuse alveolar hemorrhage. Ina patient without an- tecedent clinical history of a disorder known to produce DAH, the occurrence of DAH most often is secondary to one of the ‘pulmonary-renal syndromes or vasculitides. Fevers or leukocytosis should lead to consideration of the ‘causes of diffuse alveolar pneumonia. Often the patient has a his- tory of immunosuppression, in which ease Pnewmoeystis carinii ‘and opportunistic Viral infections should be considered. In an ‘otherwise heathy outpatient, a diffuse pneumonia most often is a manifestation of influenza virus or adenovirus. In a debil- itated hospitalized patient, aspiration pneumonia often is the cause. In the absence of fevers or hemoptysis, most causes of the diffuse alveolar pattern represent pulmonary edema. 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Berrigan TH Jr, Carsky EW, Heitzman ER, Fat embolism, Roentgenographic pathologic correlation in 3 caset. AJR Am J Roentgenol 1966;96:967. 72. Curtis AM, Knowles GD, Putnam CE, etal. The three syndromes of far embolism: Pulmonary manifestations. Yale J Biol Med 1979;52:149. 73. Williams JR, Bonte FJ, Pulmonary damage in nonpenetrating chest injuries. Radiol Clin North Am 1963;1:439. 74, Arakawa H, Kurihara H, Nakajima Yamaki, K. Pulmonary fat ‘embolism syndrome: CT Findings in sx patients. J Comput Assist Tomogr 2000;24:2 75. King MB, Harmon KR. Unusual forms of pulmonary embolism. Clin Chest Med 1994:15:561 16. Dudney TM, Elliott CG. Pulmonary embolism from amniotic ‘uid, fat, and ait. Prog Cardiovasc Dis 1994;36:447. 77. Philip RS. Amniotic Buid embolism. NY State J Med 1967:67: 2085. 78. Dib NY, Bajwa T, Amniotic fuid embolism causing severe lef ventricular dysfunction and death: Case report and review ofthe erature. Cathet Cardiovase Diagn 1996;39:17. 79. Clark SL. New Concepts of amniotic uid embolism, A review. Obstet Gynecol 1990:45:360, 80, Masson RG, Ruggieri J, Siddiqui M. Amniotic uid embolism: Definitive diagnosis in a survivor. Am Respir Dis 1979:120:187. 6 PARTI DIFFUSE LUNG DISEASES 81. Koegler A, Sauder P, Marolf A, etal. Amniotic fuid embolism: A ‘ease with noa-cardiogenic pulmonary edema, Intensive Care Med 1998:20:85, 82. Woodlield DG, Galloway RK, Smart GE. Coagulation defect asso- Sarcoiwosis. GGO is among the least common presentations of sarcoidosis. This appearance is rarely seen on chest radio- ‘graphs (Fig. 2-16) (CTimages of sarcoidosis will most often reveal a bronchovas- cular interstitial patter of lung disease but rarely can appear as ID-GGO. When GGOs do occur in patients with sarcoidosis, careful inspection of the CT image will often reveal a fine stip- pled appearance to the ground glass, as if it were composed of innumerable, tiny, 1- to 2-mm ill-defined nodules (Fig. 2-17), Sarcoidosis, HP, and RBILD are the causes of GGO most likely to give this fine stippled appearance. Rarely sarcoidosis may appear as multiple large alveolar masses. This patter is known as “alveolar sarcoid.” On chest radiographs, these appear as large round alveolar opacities, but on CT they may be composed of multiple large round regions of ground-glass consolidation (Fig. 2-18). This ap- Pearance is virtually pathognomonic of sarcoidosis. Details ‘of the imaging manifestations of sarcoidosis are presented in Chapter 3. Other Rare Diseases, Which May Appear as Isolated Diffuse Ground-Glass Opa Some other disorders which are known to present as ID-GGO in- ‘clude pulmonary alveolar proteinosis (PAP), bronchiolitis oblit- cerans organizing pneumonia (BOOP), and bronchoalveolar car- cinoma (BAC). There are a plethora of other exceedingly rare ‘causes of ID-GGO. PULMONARY ALVEOLAR PROTEINOSIS. Pulmonary alveolar pro- teinosis (PAP) is a rare disorder of middle-aged adults, which ‘This 46-year-old woman presented with dyspnea and a restrictive deficit on pul- ‘monary fanction testing. A chest radiograph (not shown) was interpreted as normal. Axial CT images atthe level of (A) the great vessels and (B) pulmonary veins reveal GGO widely distributed throughout the lngs. These opacities also form the mosaic pattern. Finally, when viewed closely the ground glass has a fine stippled appearance as if it were produced by innumerable, confluent micronodles, This ‘combination of GGOs and stippled or micronodular pattem is most commonly seen in HP, RBILD, land sarcoidosis. Transbronchial biopsy confirmed a diagnosis of sarcoidosis.CHAPTER 2_ ISOLATED DIFFUSE GROUND-GLASS OPACI 57 ae \ A B year-old woman was clinically asymptomatic but received a CT scan for unrelated rea- ms sons. Axial CT images atthe level of (A) the great ves sels, (B) carina, and (C) pulmonary veins demonstrate smultple, nearly perfectly round areas of GGO. This ap- pearance of very round ground-glass masses is trongly associated with alveolar sarcoidosis. Differential diag- ‘nosis would include bronchoalveolar carcinoma. Trans ‘bronchial biopsies confirmed a diagnosis of sarcoidonis, ‘causes the subacute onset of slowly progressive, incapacitating dyspnea. The disorder isthe result of the accumulation of pro- tein and lipid rich material within the alveoli ofthe lung, which is derived from lung surfactant."""~'°* PAP occurs in three clinical forms: congenital, secondary, and idiopathic." Congenital PAP is a result of mutationsin the genes encoding surfactant protein B or C or the fc chain of the receptor for granulocyte-macrophage colony-stimulating factor (GM-CSF),1°5-107 Some hematologic cancers, immunosuppressive medica- tions, inhalation of inorganic dust (e2., silica) or toxic fumes, and certain infections may cause the development of PAP.!*-!!4 This is the secondary form of disease and is a result of func- tional impairment or reduced numbers of alveolar macrophages. Ninety percent of individuals with PAP will have idiopathic PAP.™ It is now believed that this form of disease is an au- toimmune disorder targeting GM-CSF! ‘The median age at the time of diagnosis is 39 years."'S Seventy-two percent of individuals will have a history of smoking.'"® PAP has been found most often in men. The male predominance may be a result of the more frequent use, histor- ically, of tobacco by men. Patients will typically presentwith cough and progressive ex- ertional dyspnea of insidious onset.!"*“!"? Occasionally, fever, chest pain, or hemoptysis will occur, especially if secondary infection is present.! Patients with PAP are predisposed to respiratory infections, sometimes from opportunistic organisms." Patients will typically follow one of three clinical courses. A minority, approximately 8% (24 of 303 cases inone series), will spontaneously improve." Other patients will have stable but persistent symptoms and others will demonstrate progressive deterioration. One retrospective study of 343 cases, revealed a 75% five-year survival rate.""* Approximately three fourths of the deaths were a result of progressive respiratory failure and one-fifth were a result of associated uncontrolled infection ‘The treatment of PAP depends on the underlying cause. Pa- tients with the congenital form of the disorder will receive sup- Portive care.!"* Treatment of the underlying condition wil usu- ally correct secondary PAP" Idiopathic PAP has been treated with whole-lung lavage for which there is some retrospec- tive data to support improved pulmonary function and survival with this therapy.!'5 Currently, there are prospective trials of GM-CSF therapy." In many cases chest radiographs will demonstrate diffuse alveolar consolidation. However, in cases of less severe dis- cease, diffuse GGO is present, often with nonspecific increased frstitial markings.!"”-!! The extent of radiographic abnor- malities is often disproportionately greater than the severity of the symptoms and physical fndings."™ Thin-section CT wi characteristially show GGO in association with thickening of the intralobular septa of the secondary pulmonary lobules. This pattem, which has been termed the “crazy paving appearance.” and when present is quite suggestive of PAP! (Fig, 2-19), (The pattern of intralobular thickening is discussed under the heading “The Septal Interstitial Pattern” in Chapter 3.) BRONCHIOUITIS OBLITERANS ORGANIZING PNEUMONIA. Bron- chiolitis obliterans organizing pneumonia (BOOP) is a pat- tem of lung injury, which may be idiopathic or secondary58 PART! DIFFUSE LUNG DISEASES ~~ | Sei mA A € FIGURE2-19, This 53-year-old man had slowly progressive dyspneato the point of severe disability ‘when he presented to medical attention. He had no previous serious ilnesses. (A) PA chest radiograph reveals diffuse, pulmonary opacification with a peribilar predominance and associated nonspecific prominence of interstitial markings. Differential diagnosis would include an opportunistic infection suchas PCP or CMY pncumoniat perhaps the patient has undiagnosed HIV infection. Hypersensitivity ‘pneumonitis is also likely cause fr this abnormality. Inthe absence of an enlarged bear, pulmonary ‘edema would be unlikely. Diffuse alveolar hemorrhage from Wegener's granulomatosis or Gaodpas ture's syndrome or from another cause would also be a consideration. Rarely, pulmonary alveolar proteinosis and bronchoalveolar cell carcinoma may present in this fashion. Axial thin-section CT images at the level ofthe (B) aortic arch and (C) pulmonary veins confirm the presence of GGOs but also reveal intralobular interstitial thickening, This combination of ground GGOs and the interstitial thickening has been termed “crazy paving.” Thisis a nonspecific finding but in the setting of chronic illness is strongly suggestive of pulmonary alveolar proteinosis. consolidation, and ID-GGO. Most often, diffuse BAC will have to a variety of pulmonary insults, especially infectious pneu- monia, The American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classifiea- n Conference has identified cryptogenic organizing pneumo- tia (COP) as the preferred term for idiopathic BOOP.” COP is rare inflammatory condition presenting with progressive dys- ‘pnea and often with fever and constitutional symptoms. COP will usually appear as haphazard alveolar opacities scattered throughout the lungs.‘ It may also appear as the ground-glass pattern in.a minority of patients" (Fig, 2-20) BRONCHOALVEOLAR CARGNOMA. A form of well-dfferen- tiated pulmonary adenocarcinoma, bronchoalveolar carcinoma (BAO), may have a wide variety of radiographic appearances including solitary pulmonary nodule, focal alveolar opacity re- sembling pneumonia, ground-glass nodules, diffuse alveolar dominant mass.or infiltrate with associated diffuse GGO. How- ever, rarely, there will be no such sentinel patch and only ID- ‘GGO will be present!” (Fig, 2-21), BAC is discussed most fully in Chapter 7. SCENARIO 4: PATIENTS WITH THE ACUTE DEVELOPMENT OF DYSPNEA ‘The interstitial causes of ID-GGO will usually have a prolonged clinical presentation and will have a chest radiograph which is ‘most often normal in appearance or demonstrates nonspecific “interstitial” abnormalities. The alveolar causes of ID-GGO will, usually present acutely and will often have chest radiographs, which demonstrate diffuse alveolar consolidation. ID-GGO inCHAPTER 2_ ISOLATED DIFFUSE GROUND-GLASS OPACI 59 c FIGURE 2-20. This 61-year-old man presented with a 10-pound weight loss, decreased appetite, and dyspnea. (A) PA cl radiograph demonstrates diffuse, faint pulmonary opacification, which might be characerized as diffuse GGO. Axial CT images atthe level of the (B) aortic arch and (C) pulmonary veins reveals patches of GGO with a fine centrilobular character. These are associated ‘with a nonspecific patter of intralobalar interstitial thickening. Histologic evaluation ofthe surgical biopsy ofthe lung demonstrated bronchiolitis obl FIGURE2-21. This 83-year-old man presented with hrombophebitis and herpes zoster rash. Review of systems also noted dyspnea and a ‘Spound weightloss. PA chest midiograph demonstrates a faint diffuse lung abnormality, which is best characterized as GGO. This is lightly worse in the right upper lobe but is present diffusely. Open biopsy demonstrated bronchoalveolar carcinoma ans organizing pneumonia (BOOP). ARDS, other causes of permeability edema, or diffuse alveolar hemorrhage. Acute Alveolar Diseases Appearing as Diffuse Ground-Glass Opacity ‘When ID-GGO presents acutely one should consider pulmonary ‘edema or diffuse alveolar hemorrhage as a cause. In a study of the causes of ID-GGO, acute alveolar diseases such as cardio genic and capillary leak pulmonary edema and diffuse alveolar hemorrhage accounted for 19% (6 of 32) of path-proven causes of ID-GGO!’ This series required pathologic proof of diagno for a case to be included in the study. As a result, pulmonary ‘edema as a cause of ID-GGO was probably underrepresented. It is my belief that cardiogenic pulmonary edema is probably the single most common cause of ID-GGO on CT scans. Pulmonary Edema Its likely that all causes of pulmonary edema can occasionally result in ID-GGO, For practical purposes, the most common ‘causes are cardiogenic edema and ARDS. CARDIOGENIC INTERSTITIAL PULMONARY EDEMA, Interstitial pulmonary edema will most often take a linear interstitial pat- temon chest radiographs, However, on thin-section CT, the most60 a PART1 DIFFUSE LUNG DISEASES FIGURE 2-22. This 48-year-old man had recently undergone esophagoctomy and gastric interposi- ton presented wit persistent postoperative fevers. (A) AP chest radiograph demonstrates mild diffuse lung disease, which is most commonly due to congestive heart failure, A chest CT scan was obtained to search for occult mediastinal collections. Ten-illimeter axial images at the level of (B) the aortic arch and (C) the pulmonary veins demonstrate widespread GGOs with a perihilar distribution. No ‘meastnal collection was found. Although there is a moderately wide differential diagnosis for these findings, in thisclinical seting, the GGOs are most likely a manifestation of pulmonary edema, Serial ‘examinations showed clearing ofthe abnormality following diuretic therapy. ‘common manifestation of interstitial edema is ID-GGO. Atother times, interstitial edema may appear as septal thickening or the septal interstitial patter, The GGO associated with interstitial ‘edema will often have a central, perihilar distribution and be as- sociated with enlarged pulmonary vessels and an enlarged heart (Fig. 2-22). A detailed description of the manifestations of alve- lar edema is provided in Chapter | and of interstitial pulmonary edema in Chapter 3 Aputt Reseimarory Disteess SYNDROME. The chest radio- ‘graph of ARDS will characteristically appear as diffuse alveolar consolidation and often the CT scan will mirror this appearance. However, moderately frequently, ARDS will appear as ID-GGO on CT scans.'27 This will most often be a manifestation of the earlier exudative phase of disease. ARDS is discussed more fully in Chapter 1 OtHeR NONCARDIOGENIC PULMONARY EDEMA. As stated pre- viously, it is likely that all types of pulmonary edema can ‘occasionally present as ID-GGO (see Figs, 1-20, 2-8, 2-23). This has been reported with near drowning and fat emboli syndrome," 7) . 4“ B + - 2 c Diffuse Alveolar Hemorthage Diffuse alveolar hemorrhage (DAH) has a variety of causes. ‘These include the pulmonary renal syndromes suchas Wegener's ‘granulomatosis and other small vessel pulmonary vasculitides, Goodpasture’s disease, and systemic lupus erythematosis. Pa- tients with leukemia and lymphoma may be predisposed to DAH probably because of thrombocytopenia. Patients with coagu- lation disorders such as antiphospholipid antibody syndrome, ccryoglobulinemia, and disseminated intravascular coagulation (DIC) may also experience DAH. Diffuse alveolar hemorthage is also an often fatal complication of bone marrow transplanta tion, These various causes of DAH are discussed more fully in the section entitled “Diffuse Alveolar Lung Disease.” Chest radiographs of DAH will most often appear as widespread pulmonary alveolar consolidation. However, occasionally, the pulmonary opacities will be quite faint and appear as GGO on the chest radiograph. CT scans of DAH may reveal frank consolidation with obliteration of the pulmonary vascular markings, but mote often they will appear as ID-GGO -24 and 2-25). On thin-section CT images, these opac-CHAPTER 2 ISOLATED DIFFUSE GROUND-GLASS OPACITY 61 FIGURE 2-23. This 25-year-old woman presented tothe emergency room with mild dyspnea, and ‘chest and abdominal pain. (A) PA chest radiograph was interpreted as normal. CT images atthe level of the (B) aonic arch and (C) pulmonary veins demonstrate a central distribution of ID-GGO. In the absence of adalitional history, Would most likely be a result of one ofthe chronic interstitial diseases, which presents with ID-GGO, However, on further questioning, the patient revealed that she hhad smoked crack cocaine in the hours prior to presentation. A diagnosis of noncardiogenic edema duc to crack use was made. CT findings had resolved on a study 2 weeks later. involve the centers of the secondary pulmonary lobule, in which case they are called centrilobular opacities. Alternately, they may affect or spare adjacent pulmonary lobules in which they are identified as a lobular pattern, Lastly, they may have a random heterogeneous distribution. SCENARIO 5: DEBILITATED. HOSPITALIZED PATIENTS Itis quite common for generally debilitated hospitalized patients, toreceive CT'scans in the evaluation fora wide variety of clinical indications unrelated to dyspnea or hypoxia. For example, chest CT scans will often be performed in a search for explanations of a persistent fever in a patient residing in the intensive care unit, ID-GGO in these patients will most often signify mild interstitial pulmonary edema due to congestive heart failure or volume overload, unless they have some features of the other clinical syndromes described here, such as immunosuppression, neutropenia, thrombocytopenia, or cancer chemotherapy. SCENARIO 6: THE PREMATURE INFANT 1K is common for the chest radiographs of premature infants to have a diffuse ground-glass appearance. This is typical of ‘neonatal respiratory distress syndrome. Neonatal Respiratory Distress Syndrome Neonatal respiratory distress syndrome (RDS) is known to be a manifestation of surfactant deficiency in premature i fants resulting in increased surface tension within alveoli and diffuse microatelectasis.'"! This process causes severe respi- ratory distress in these infants, often requiring mechanical ventilation. ‘The characteristic radiographic appearance of diffuse gran- Ular oF GGO histologically represents diffuse microatelectas (Fig. 2-26). Normally, this is a routine diagnosis when GG is seen on radiographs of premature infants. CT scans are not ‘commonly performed in these infants SUMMARY Unlike GGOs in the company of other imaging findings, ID- GGO is caused by a relatively limited group of diseases. These ccan be grouped into four large categories of disease: (a) op- Portunistic infections, (b) acute alveolar diseases, (c) chronic interstitial diseases, and (4) other more unusual lung disorders. ‘The most common causes of ID-GGO are listed by disease cat- egory in Table 2-1, Furthermore, the presentation of ID-GGO ‘often falls in one of several clinical scenarios, which engen- der more limited differential diagnosis. These scenarios are (a)62 PARTI DIFFUSE LUNG DISEASES immunocompromised hosts, (b) patients with bone marrow sup- pression, usually receiving cancer chemotherapy, (c) outpatients ‘with progressive dyspnea, (d) inpatients and outpatients with acutely developing dyspnea, (e) acutely ill inpatients, and (f) ‘premature infants. In immunocompromised patients, ID-GGO will usually signify a diffuse infection such as PCP or vi- ral pneumonia, Those patients with bone marrow suppression will usually have ID-GGO as a result of one of four causes: diffuse infections, diffuse alveolar hemorrhage, volume over- load, or dig toxicity. Outpatients with chronic progressive dyspnea will most often have one of the chronic interstitial FIGURE 2-24. This 56-year-old man presented with hemoptysis and acute onset of dys ‘pnea. Initial (A) PA chest radiograph demonstrates faint GGOs. These can be distinguished from an underexposed film by the absence ofthe normal lower lung zane vascular markings, ‘which have been silhouetted by the GGOx, The acute presentation of symptoms suggests that the ID-GGO is most likely to be a manifestation of an acute alveolar disorder and the history of hemoptysis suggests DAH as the cause. (B) A chest radiograph 3 days later demonstrates diffuse alveolar consolidation confirming an acute alveolar cause, probably DAH, forthe radiographic abnormality, CT images atthe Yevel of the (C) aor arch and (D) pulmonary veins demonstrate diffuse GO. Serum serologies resulted in a diagnosis of systemic lupus erythematosis asthe cause for diffuse alveolar hemorrhage diseases, which presents as ID-GGO. These are most com- monly HP and NSIP but also include AIP, DIP, RBILD, and sarcoidosis. Rarely this presentation will signify some other rare ceauses of ID-GGO such as PAP, BAC, and COP. Inpatients and ‘outpatients with acutely developing dyspnea and without other predisposing conditions will usually have one of the acute alve- ‘lar causes of ID-GGO such as cardiogenic pulmonary edema, ARDS, or DAH. Inpatients who are il, with incidentally discov- ered ID-GGO, will usually have cardiogenic edema. 1D-GGO in premature infants will indicate primary respiratory distress syndromeCHAPTER 2_ ISOLATED DIFFUSE GROUND-GLASS OPACITY 63 A 3 FIGURE 2-25, This 21-year-old woman hal a severa-month history of joint pain when she pre sented with acute development of cough, fever, hemoptysis, and a rash. Anal ‘of her urine also demonstrated proteinuria (A) A chest radiograph reveals faint GGOs primarily at the lung bases. This opacity could potentally represent her overlying soft tissues, however, the absence ofthe normal ‘pulmonary vascular shadows confirms the presence of a faint alveolar process. Given the presence of ‘hemoptysis and proteinuria, the GGO is likely to represent diffuse alveolar hemorrhage (DAH) as 4 result of a pulmonary-renal syndrome, CT images atthe level ofthe (B) carina and (C) pulmonary veins demonstrate a combination of diffuse GGOs and more dependent alveolar consolidation, likely representing DAH. Evaluation of lung tissue from a thoracoscopic lang biopsy demonstrated a small vessel vasculitis consistent with pauci-immune vasculitis. REFERENCES FIGURE2-26. This premature infant required mechanical ventilation for respiratory failure atthe time of birth, AP chest radiograph demon- strated diffuse hazy opacity throughout both lungs characteristic of the ‘ground: glass patter. In this clinical scenario these findings ae indica- tive of primary respiratory distress syndrome secondary to surfactant deficiency. 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