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Imaging of Pulmonary Viral Pneumonia 1 STATE OF THE ART STATE

n

Tomás Franquet , MD, PhD Imaging and clinical manifestations of viral pneumonia are protean and not reliably predictive of its origin. All pa- tients with neutropenic fever and normal fi ndings at chest

REVIEWS AND COMMENTARY radiography should undergo thin-section computed tomogra- phy to determine whether parenchyma abnormalities are present. Although the radiologic manifestations of viral pneumonia are nonspecifi c and diffi cult to differentiate from those of other infections, it is important to consider viral infection when confronted with a rapidly progressive pneumonia in patients with risk factors for infection. Al- though defi nitive diagnosis cannot be made on the basis of imaging features alone, the use of a combination of clini- cal and radiographic fi ndings can substantially improve the accuracy of diagnosis in this disease . Online CME See www.rsna.org/ry_cme.html q RSNA, 2011

Learning Objectives: Supplemental material: http :// radiology . rsna . org/ lookup After reading the article and taking the test, the reader will / suppl / doi : 10 . 1148 /radiol . 11092149 /-/DC1 be able to n Describe the role of thin-section thoracic CT in the diagnosis viral pneumonia. n Identify the most common features of pulmonary viral infections at thin-section CT. n Describe the most common viral infections in immuno- competent and in immunocompromised patients.

Accreditation and Designation Statement The RSNA is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The RSNA designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 CreditTM . Physicians should only claim credit commensurate with the extent of their participation in the activity. Disclosure Statement The ACCME requires that the RSNA, as an accredited provider of CME, obtain signed disclosure statements from authors, editors, and reviewers for this case. For this journal-based CME activity, author disclosures are listed at the end of this article. The editor and the reviewers indicated that they have no relevant relationships to disclose.

1 From the Department of Radiology, Hospital de Sant Pau, Avda Sant Antoni M. Claret 167, Barcelona 08128, Spain. Received November 19, 2009; revision requested January 7, 2010; revision received February 4; accepted February 17; fi nal version accepted March 1; fi nal review by T.F. February 24, 2011. Address correspondence to the author (e-mail: [email protected] ) .

q RSNA, 2011

18 radiology.rsna.org n Radiology: Volume 260: Number 1—July 2011 STATE OF THE ART: Imaging of Pulmonary Viral Pneumonia Franquet

ore than 55 million people die each up to 50%–64% of patients admitted to tive reaction that may be seen in a variety year worldwide, and pneumonia the hospital with pneumonia. The recent of clinical contexts. In other words, orga- M is among the leading causes (1 ). development of multidetector helical com- nizing pneumonia may result from a vari- Viral infections are an increasingly fre- puted tomographic (CT) scanners capa- ety of causes or underlying pathologic quent cause of pulmonary disease world- ble of rapid scanning and acquisition processes, including viral infections. wide. Unfortunately, the diagnosis of of thin sections has revolutionized the Most respiratory viruses damage cells viral pneumonia still relies heavily on thin-section CT technique. Volumetric directly through cytopathic effects me- clinician suspicion in the proper set- thin-section CT with thin detectors (0.5– diated by means of either viral-directed ting, which is based on host risk fac- 0.625 mm) has become the routine in cell lysis or the inhibition of host cell tors, presentation, and exposures. The many institutions. New serologic tests RNA, protein, and DNA synthesis. Other diagnostic approach involves a consid- have also come to the aid of the clinician, viruses (eg, cytomegalovirus [CMV], ade- eration of the likely pathogens on the and sophisticated molecular methods are novirus, or herpesvirus) may produce basis of the patient’s presenting signs becoming more commonplace in routine specifi c nuclear changes or characteris- and symptoms and his or her immuno- diagnosis of acute respiratory disease tic cytoplasmic inclusions (11 ) ( Fig 1 ). logic condition (2 ,3 ). The clinical mani- in both immunocompetent and high-risk Cytopathic respiratory viruses (eg, festations of most viral infections are patients (1 , 6 – 8 ). Confi rmation of the di- infl uenza, adenovirus, and herpesvirus similar. Although most of these infec- agnosis and identifi cation of the specifi c group) cause a virus-specifi c lung injury tions in nonimmunocompromised per- agent can be accomplished with use of pattern. Infl uenza virus affects the epi- sons are self-limited, some patients can tissue cultures, serologic tests, detection thelium diffusely and, in severe cases, re- develop severe pneumonitis ( 4 ). Clini- of viral antigens within respiratory tract sults in necrotizing bronchitis and/or bron- cally, viral pneumonia in adults can be secretions or blood with use of mono- chiolitis and diffuse alveolar damage. divided into two groups: so-called atyp- clonal antibodies, detection of virus- The histologic features of infl uenza ical pneumonia in otherwise healthy hosts associated molecules with use of in situ pneumonia are epithelial necrosis of the and viral pneumonia in immunocom- hybridization or polymerase chain reac- airways with submucosal chronic infl am- promised hosts (5 ). Infl uenza virus types tion (PCR), and observation of virus- mation. Fatal infl uenza pneumonia rep- A and B account for most viral pneumo- induced changes cytologically or histolog- resents a necrotizing bronchiolitis with nias in immunocompetent adults (5 ). It ically (9 , 10 ). The purpose of this review diffuse alveolar damage, which can be has been considered that clinical his- is to provide a framework with which to hemorrhagic. tory, results of physical examination, better understand respiratory viral infec- Adenovirus has its greatest effect in and imaging features cannot enable the tions, the diverse clinical settings in which the terminal bronchioles and may pro- prediction of the etiologic agent. Further- they occur, and their potential importance duce bronchiolitis or even bronchiectasis more, a pathogen is identifi ed in only in these varying clinical contexts. While (12 – 14 ). The bronchiolitis may be necro- acknowledging the less-than-defi nitive tizing and result in a necrotizing broncho- Essentials diagnostic role of CT in their diagnosis, pneumonia similar to that seen in severe n Viral pulmonary infections are I will also include discussion of those herpes simplex infection (13 ) (Fig 2). clinically important in both immu- conditions in which an understanding of The herpes group of viruses (herpes nocompromised and immunocom- the pathologic characteristics can be use- simplex, varicella-zoster, CMV, Epstein- petent patients; despite its limita- ful to the interpretation of thin-section Barr virus [EBV]) may cause focal cyto- tions, CT is currently the imaging CT fi ndings. The epidemiology and path- pathic effects in either the airway or modality of choice for the evalua- ogenesis of viral infections are discussed alveoli. The histologic features of herpes tion of pulmonary viral infections. in Appendix E1 (online). simplex lower respiratory tract infection n Although the CT features of viral pulmonary infections are usually Histologic Features of Viral Infections Published online nonspecifi c, precise imaging char- 10.1148/radiol.11092149 Content codes: Various histopathologic patterns of acterization is essential; knowl- lung injury have been described in viral Radiology 2011; 260:18– 39 edge of CT fi ndings has a substan- pneumonia. Although some of these tial effect on the treatment of Abbreviations: patterns may be relatively unique to a patients suspected of having pul- AIDS = acquired immunodefi ciency syndrome specifi c clinical context, others are non- monary viral infections. CMV = cytomegalovirus specifi c with respect to either the cause EBV = Epstein-Barr virus n Knowledge of the underlying or pathogenesis. HMPV = human metapneumovirus pathologic characteristics of Viruses can result in several patho- HTLV-1 = human T-cell lymphotropic virus type 1 these diseases aids in the differ- logic forms of lower respiratory tract PCR = polymerase chain reaction entiation of viral infections from RSV = respiratory syncytial virus infection, including tracheobronchitis, SARS = severe acute respiratory syndrome other entities that may have bronchiolitis, and pneumonia. Organiz- overlapping imaging features. ing pneumonia is a nonspecifi c repara- Author stated no fi nancial relationship to disclose.

Radiology: Volume 260: Number 1—July 2011 n radiology.rsna.org 19 STATE OF THE ART: Imaging of Pulmonary Viral Pneumonia Franquet

Figure 1 Figure 2 Figure 3

Figure 2: Histopathologic features of respiratory

Figure 1: Histopathologic features of pulmo- syncytial virus (RSV) bronchiolitis in a child. Photo- Figure 3: Histopathologic features of necrotizing nary CMV infection. Photomicrograph (hematoxylin- micrograph (hematoxylin-eosin stain; original mag- herpes pneumonia. Image from scanning low-power eosin stain; original magnification, 3 400 ) nifi cation, 3 400) shows two adjacent bronchioles microscopy (hematoxylin-eosin stain; original mag- shows numerous CMV-infected cells; they are with a marked transmural cellular infi ltrate (bronchi- nifi cation, 3 20) shows nodular zones of necrosis, enlarged and contain nuclei with prominent olitis) (arrowheads) and some associated meta- some of which are bronchiolocentric (arrows). amphophilic inclusions (arrowheads). (Image plastic changes in the mucosa. Ulcerative mucosal (Image courtesy of T. Colby, MD, Mayo Clinic, courtesy of T. Colby, MD, Mayo Clinic, Scotts- changes are also seen (arrow). (Image courtesy of T. Scottsdale, Ariz.) dale, Ariz.) Colby, MD, Mayo Clinic, Scottsdale, Ariz.)

include necrosis of the airway epithelium, Coxsackievirus B, reoviruses, and damage (intraalveolar edema, fi brin, necrotizing pneumonia as the reaction rhinoviruses may also infect the lungs, and variable cellular infi ltrates with a spreads from the airways to the adjacent usually producing interstitial pneumonias hyaline membrane), intraalveolar hem- parenchyma, diffuse alveolar damage, with diffuse alveolar damage. Human orrhage, and interstitial (intrapulmonary miliary nodules, and scattered larger nod- papilloma viruses are known to cause re- or airway) infl ammatory cell infi ltra- ules (15 ) (Fig 3). Multicentric areas of current papillomas and have been linked tion ( 20 ). hemorrhage may appear centered on air- to lung cancer. ways. An acute lung injury pattern may In immunocompetent individuals, Clinical Manifestations be present, with interstitial edema, con- RSV and parainfl uenza viruses may pro- gestion, and infl ammation. Histologic duce necrotizing bronchiolitis charac- The clinical signs and symptoms of viral features of varicella-zoster virus pneu- terized by exudates within bronchiolar pneumonia are often nonspecifi c, and monia include endothelial damage in small lumen, infl ammatory cells in the wall the clinical course of infection will be vessels, with focal hemorrhagic necro- of bronchioles, a peribronchiolar reac- highly dependent on the overall immune sis, mononuclear infi ltration of alveolar tion with chronic infl ammatory cells, and status of the host (3 ). Acute bronchioli- walls, and fi brinous exudates in the alve- exudate in alveoli. In immunocompro- tis is a term most often used to describe oli (16 ). Late sequelae of varicella-zoster mised patients, parainfl uenza viruses an illness in infants and children char- infection consist of multiple 1–2-mm- produce giant cell pneumonia with dif- acterized by acute wheezing with con- diameter calcifi ed nodules (17 ). fuse alveolar damage indistinguishable comitant signs of respiratory viral infec- The histologic fi ndings in CMV pneu- from that caused by measles pneumonia. tion (21 ). RSV is the etiologic agent in most monia include either an acute intersti- Measles virus may involve both air- patients, but other viruses (adenovirus, tial pneumonia or a miliary pattern. Acute ways and lung parenchyma, producing infl uenza, parainfl uenza) and nonviral interstitial pneumonia is characterized bronchitis and/or bronchiolitis and in- pathogens (mycoplasma, Chlamydia spe- by a diffuse mild alveolar widening by terstitial pneumonia. cies) can cause a similar syndrome (22 ). edema and mononuclear cells, airspace The predominant pathologic process Symptomatic acute bronchiolitis in fi brinous exudate and/or hyaline mem- of hantavirus pulmonary syndrome and adults is relatively rare but can be caused branes with relatively scant neutrophils, severe acute respiratory syndrome (SARS) by infectious agents such as RSV. Be- and prominent type 2 alveolar lining cells is diffuse alveolar damage and diffuse cause small airways in adults contribute ( Fig 4); foci of organizing pneumonia lung disease characterized histologically less to total pulmonary resistance, acute are often found. The miliary pattern is by interstitial edema and central alveo- infectious bronchiolitis may spare adults similar to that of other miliary viral in- lar fi lling (18 ,19 ) ( Fig 5). the severe symptoms characteristic of fections; nodules contain the infected The radiologic fi ndings refl ect the bronchiolitis in infants. Acute bronchi- cells with the characteristic cytoplasmic variable extent of the histopathologic olitis in adults may also be seen with inclusions of CMV. features, which include diffuse alveolar aspiration, toxic inhalation, connective

20 radiology.rsna.org n Radiology: Volume 260: Number 1—July 2011 STATE OF THE ART: Imaging of Pulmonary Viral Pneumonia Franquet

Figure 4 Figure 5 and not invariably associated with pneu- monia; lower respiratory tract symp- toms are found in 10% of cases (3 ).

Laboratory Identifi cation Methods Differentiation of common respiratory infections due to Streptococcus pneu- moniae and those due to Mycoplasma pneumoniae , Chlamydophila pneumo- niae , or Legionella pneumophila as well as those due to viruses is essential to allow correct decisions concerning the antibiotics to be administered (3 ). Figure 4: Histopathologic features of a CMV inter- Figure 5: Histopathologic features of diffuse Diagnosis of respiratory viruses is stitial pneumonia. Photomicrograph (hematoxylin- alveolar damage in a patient with SARS. Photomi- still diffi cult, with only a small percent- eosin stain; original magnifi cation, 3 100) shows crograph (hematoxylin-eosin stain; original magnifi - age of cases being routinely diagnosed. interstitial widening with formation of micronodules cation, 3 200) demonstrates that alveolar septa Although viral culture has been the ref- (arrows). This is associated with acute lung injury show complete loss of epithelium and are lined by erence standard, it has considerable lim- and some hyaline membranes (arrowheads). (Image hyaline membranes (arrowheads); intraalveolar itations (ie, depending on the virus, it courtesy of T. Colby, MD, Mayo Clinic, Scottsdale, edematous material is also present (arrows). (Image may take 3–14 days for cultures to yield Ariz.) courtesy of T. Colby, MD, Mayo Clinic, Scottsdale, results). Ariz.) The development of better diagnos- tissue diseases, lung and bone marrow tic tests has markedly improved our transplantation, and Stevens-Johnson cause can be established with certainty ability to detect multiple viral patho- syndrome (23 ). only in approximately 50% of patients gens (3 ). These techniques include cul- Pathologic studies of acute infec- with pneumonia. The probable predom- ture to prove replication of complete tious bronchiolitis have shown intense inant organism varies with the host’s epi- viral particles, hybridization techniques acute and chronic infl ammation of small demiologic factors, the severity of illness, performed with or without PCR to de- bronchioles with associated epithelial and the laboratory approach used to es- tect viral nucleic acids, immunohisto- necrosis and sloughing. There may be tablish the diagnosis. chemistry to detect viral proteins, elec- associated edema as well as infl amma- Although most attention traditionally tron microscopy to demonstrate a fully tory exudate and mucus in the bron- focuses on bacterial causes of severe assembled virus, and measurements of chiolar lumen (24 ). community-acquired pneumonia, viruses a specifi c host immune response to the The possibility of pneumonia should can also cause serious lower respiratory virus in either serum or cells or tissue. be considered in any patient who has new tract infections. The predominant re- The most appropriate specimens are respiratory symptoms (including cough, spiratory viruses that can cause severe nasopharyngeal aspirates, nasopharyn- sputum, or dyspnea), particularly when pneumonia include infl uenza and RSV. geal and throat swabs, and those from these symptoms are accompanied by fever The clinical manifestations of viral bronchoalveolar lavage (26 ). or abnormalities at physical examination infections often vary from patient to pa- of the chest (eg, rhonchi and rales). tient and cannot be reliably used to es- Nucleic Acid Amplifi cation Tests Pneumonia is also increasingly prev- tablish a specifi c (microbiologic) diagno- The introduction of highly sensitive nu- alent in patients with specifi c comorbidi- sis. The initial symptoms and signs may cleic acid amplifi cation tests has dra- ties or risk factors, including smoking, be categorized into several clinical syn- matically improved the ability to detect chronic obstructive pulmonary disease, dromes (25 ). A “cold” is characterized multiple respiratory viruses such as in- asthma, diabetes mellitus, malignancy, by upper respiratory tract symptoms fl uenza, RSV, rhinovirus, parainfl uenza, heart failure, neurologic diseases, nar- and includes tonsillopharyngitis, phar- and adenovirus (27 –29 ). cotic and alcohol use, and chronic liver yngitis, epiglottitis, sinusitis, otitis me- The most familiar formats use DNA disease. dia, and conjunctivitis. The “infl uenza” or RNA target amplifi cation methods for A thorough physical examination, pos- syndrome, which may be caused by viruses enhanced sensitivity above that of culture teroanterior and lateral chest radiog- other than infl uenza, consists primar- and antigen-based procedures (28 ). raphy, and a blood leukocyte count with ily of abrupt fever, headache, myalgias, a differential cell count should be per- and malaise. The disease manifestations PCR formed when pneumonia is suspected. of several viruses (eg, human parainfl u- The value of PCR in identifying respi- Even with intensive laboratory in- enza virus, RSV, and infl uenza) are often ratory viruses in clinical samples has vestigation, the specifi c microbiologic confi ned to the upper respiratory tract been clearly shown, and as much as a

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three- to fourfold increase in positive spec- associated with increased frequency and attenuation pattern) are a recognized imens has been found when PCR test- severity of viral infections include very fi nding in some viral infections caused ing is added to conventional cell culture young and old age, malnutrition, and by hypoventilation of alveoli distal to and/or “standard” serologic methods. The immunologic disorders. bronchiolar obstruction (infl ammation or downside of PCR is that it may be too sen- Chest radiographs demonstrate nor- cicatricial scarring of many bronchioles), sitive, in that it can detect small amounts mal fi ndings or unilateral or patchy bi- which leads to secondary vasoconstric- of residual viral nucleic acid when there lateral areas of consolidation, nodular tion (and, consequently, underperfused is no other laboratory or clinical evidence opacities, bronchial wall thickening, and lung) and is seen on CT scans as areas that a viral infection is present. Factors small pleural effusions; lobar consolida- of decreased attenuation ( 44– 46 ). Paired that lead to negative laboratory results tion is uncommon in patients with viral CT scans obtained in inspiration and include poor specimen handling and col- pneumonia. Patients may develop acute expiration are useful for differentiating lection, low viral copy numbers, and in- pneumonia with rapid progression to bronchiolar disease from pulmonary vas- hibitors in the clinical sample (10 ). acute respiratory distress syndrome. cular disease and some diffuse infi ltrative Although radiographic fi ndings alone diseases that may also cause a mosaic Reverse Transcriptase PCR are not suffi cient for the defi nitive diagno- pattern. In bronchiolar disease, the re- Reverse transcriptase PCR is a modi- sis of viral pneumonia, in combination gions of decreased attenuation seen in fi cation of PCR used when the initial with clinical fi ndings they can substan- the lung at inspiration are also seen at template is RNA rather than DNA. Reverse tially improve the accuracy of diagnosis expiration owing to air trapping and show transcriptase PCR can be used to am- in this disease. little increase in attenuation or decrease plify a much higher number of DNA cop- in volume as seen with primary vascular ies present in bacteria, fungi, virus, or Thin-Section CT Findings lung disease (47 , 48 ) ( Fig 6 ). other proteins (10 ). An increasing number of patients un- Uninvolved segments of lung show Despite the obvious advantages of dergo thin-section CT when there is high normal or increased perfusion with re- these newer procedures, there may be clinical suspicion of pneumonia with nor- sulting normal or increased attenuation, potential limitations to DNA amplifi ca- mal or questionable radiographic fi nd- respectively. In the specifi c context, co- tion technology in the diagnostic micro- ings (32 – 38 ). In a study of 87 consec- existing infl ammatory small airways and biology laboratory, as follows: (a) False- utive patients with febrile neutropenia, parenchyma disease may both contribute negative test results may occur because Heussel et al (39 ) noted that the CT scan to a mosaic attenuation pattern (49 ). of the presence of substances in the revealed a pulmonary lesion not seen Nevertheless, differentiation between specimen that inhibit nucleic acid extrac- on the radiograph in 50% of subjects. the various causes of a mosaic attenuation tion or amplifi cation, (b) careful inter- The CT signs of pulmonary viral in- pattern on CT scans (diffuse infi ltrative, pretation of results is necessary, (c) the fection will depend on the underlying small airways, and occlusive vascular dis- procedure is technically complex, (d) pathologic process. They are quite sim- eases) is not always straightforward and equipment is expensive, and (e) there is ilar simply because the underlying path- may, on occasion, cause diagnostic dif- a lack of standardization (30 , 31 ). ogenic mechanism, depending on the fi culties (45 ,48 ). virulence of the virus, is related to var- Ground-glass opacity and consoli- iable extents of histopathologic features dation.— A ground-glass opacity is a hazy Imaging of Viral Pneumonia such as diffuse alveolar damage (intraal- increase in attenuation seen in a variety In patients suspected of having viral pneu- veolar edema, fi brin, and variable cellu- of interstitial and alveolar processes. In monia, imaging is performed to help de- lar infi ltrates with a hyaline membrane), the context of pulmonary infectious tect disease, assess disease extent, per- intraalveolar hemorrhage, and intersti- diseases, coexisting thickening of the form follow-up assessment of response tial (intrapulmonary or airway) infl am- interstitium and partial fi lling of the air- to treatment, and guide interventional matory cell infi ltration (40 , 41 ). spaces may both contribute to ground- diagnostic procedures (eg, bronchos- The spectrum of CT fi ndings encoun- glass opacity and consolidation (Fig 7). copy with bronchoalveolar lavage). tered in various pulmonary viral diseases Nevertheless, other noninfectious con- It can be diffi cult to differentiate viral is not particularly wide and encompasses ditions characterized by ground-glass pneumonia from other infectious pro- fi ve main categories: (a) parenchymal opacity include interstitial pulmonary cesses, and the cause of infection (eg, attenuation disturbances; (b) ground- edema, pulmonary hemorrhage (in which viral vs pyogenic or fungal) cannot be glass opacity and consolidation; (c) nod- there is thickening of the interstitium reliably ascertained from its imaging ules, micronodules, and tree-in-bud opac- and partial fi lling of the airspaces with appearance. ities; (d) interlobular septal thickening; blood), hypersensitivity pneumonitis, re- and (e) bronchial and/or bronchiolar spiratory bronchiolitis, organizing pneu- Conventional Radiographic Findings wall thickening (42 ,43 ). monia, and alveolar proteinosis (50 – 54 ). Radiologic features are dependent on Parenchymal attenuation distur- Areas of pulmonary consolidation are several host factors, including age and bances.— Patchy inhomogeneities in the most often patchy and poorly defi ned underlying immune status; risk factors attenuation of lung parenchyma (mosaic (consistent with bronchopneumonia) or

22 radiology.rsna.org n Radiology: Volume 260: Number 1—July 2011 STATE OF THE ART: Imaging of Pulmonary Viral Pneumonia Franquet

Figure 6 Figure 7

Figure 6: Transverse expiratory thin-section CT scan through the lower lobes in a 44-year-old woman with constrictive obliterative bron- chiolitis secondary to a severe viral lower respiratory tract infection.

There are bilateral well-demarcated patchy areas of increased and Figure 7: Transverse thin-section CT scan at the level of the bron- decreased lung attenuation. Whereas hypoattenuated areas contain few chus intermedius in a patient with RSV infection shows a hazy increase and small pulmonary vessels (arrows), hyperattenuated areas contain in lung opacity without obscuration of underlying vessels. enlarged pulmonary vessels (arrowheads), refl ecting the pulmonary blood fl ow distribution toward normal ventilated areas. Figure 9 Figure 8

Figure 9: Transverse thin-section CT scan through the lower lobes in a Figure 8: Transverse thin-section CT scan at the level of the bron- patient with infl uenza A virus infection shows bilateral multiple small chus intermedius in a patient with infl uenza A virus shows ill-defi ned branching opacities (arrows) representing dilated peripheral bronchioles. centrilobular nodules (arrows). Peripheral subpleural consolidation in the apical segment of left lower lobe (arrowhead) represents Centrilobular nodules are most com- coalescence of nodules. monly seen in patients with disease that primarily affects centrilobular bronchioles focal and well-defi ned (consistent with ameter may be seen in a number of lung and results in infl ammation, infi ltration, lobar pneumonia). As with consolida- infections. Nodule size is helpful in the or fi brosis of the surrounding interstitium tion, a variety of acute and chronic lung differential diagnosis of infectious causes and alveoli (55 ) ( Fig 8 ). These nodules diseases may result in lobular areas of of nodules. Franquet et al (37 ) compared may be dense and of homogeneous atten- ground-glass opacity, which give the lung the CT fi ndings in 78 consecutive immu- uation or show ground-glass opacity. a mosaic appearance. Lobular ground- nocompromised patients with solitary or The tree-in-bud fi nding, which is usu- glass opacity may be seen in patients multiple nodular opacities of proved in- ally indicative of small airways disease, with infection (eg, bronchopneumonia, fectious origin. There was a good cor- refl ects the presence of dilated centri- viral infections, Pneumocystis jirovecii relation between the size of the nodules lobular bronchioles with lumina that pneumonia, or M pneumoniae ). and their origin. Patients whose nodules are impacted with mucus, fl uid, or pus; Nodules, micronodules, and tree-in- were smaller than 10 mm in diameter this fi nding is often associated with bud opacities.— Nodules 1–10 mm in di- were most likely to have a viral infection. peribronchiolar infl ammation (56 ) (Fig 9).

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Figure 10 Figure 11

Figure 10: Transverse thin-section CT scan through the lower lobes in a patient with adenovirus infection shows patchy bilateral ground- Figure 11: Transverse thin-section CT scan at the level of the aortic glass opacities with superimposed linear opacities (crazy-paving arch in a patient with parainfl uenza virus infection shows bilateral pattern) (arrows). ground-glass opacities and bronchial wall thickening (arrows).

Furthermore, in most cases, a tree-in- chioles by infl ammatory exudates and try of the virus capsid (helical vs icosa- bud appearance is associated with air- bronchiolar wall thickening from edema hedral), and (c) the presence or absence ways infection. Infectious diseases asso- and smooth muscle hyperplasia pro- of a lipid envelope. ciated with cellular bronchiolitis and duce the thin-section CT features of The respiratory viruses can be di- centrilobular nodules include endobron- atelectasis, air trapping, centrilobular vided into two large groups according chial spread of tuberculosis, nontuber- nodules, and bronchiolar wall thickening. to the type of nuclei acid they contain culous mycobacteria bronchopneumo- Air trapping may be present because of ( Table 2 ). nia (57 – 62 ), and infectious bronchiolitis associated bronchiolitis (Fig 11). A sum- (56 ). Branching or centrilobular nodules mary of CT fi ndings in viral pneumonia Selected RNA Virus–related Diseases and mosaic perfusion are seen in pa- is shown in Table 1 . Infl uenza.— Infl uenza viruses are single- tients with viral bronchiolitis ( 63, 64 ). In clinical practice, radiologists will stranded RNA viruses that belong to Similar fi ndings may also be observed have to consider that there are many the family Orthomyxoviridae. Infl uenza with bacterial and fungal pneumonia noninfectious or different infectious dis- viruses are important human respira- and in patients with allergic bronchopul- orders that should be differentiated from tory pathogens that cause seasonal upper monary aspergillosis ( 65 ). viral pneumonia. A combined strategy respiratory tract infections in the com- Interlobular septal thickening.— Sep- consisting of thin-section CT and guided munity, endemic infections, and periodic, tal thickening may be seen in the pres- bronchoscopy with bronchoalveolar la- unpredictable pandemics (70 ). The great- ence of interstitial fl uid, cellular infi ltra- vage performed within the fi rst 24 hours est infl uenza pandemic, the so-called tion, or fi brosis and can have a smooth, after CT could improve the diagnos- Spanish infl uenza, spread worldwide in nodular, or irregular contour in different tic yield and subsequent therapeutic 1918 and resulted in the deaths of ap- pathologic processes. In the context of changes in these patients. proximately 50 million people (71 , 63 ). viral diseases, the most dramatic cause Infl uenza type A is the most impor- of widespread smooth thickening of the tant of the respiratory viruses with re- Viral Pathogens of the Respiratory interlobular septa is acute respiratory spect to the morbidity and mortality in Tract distress syndrome (66 ). the general population. They are more Smooth septal thickening may also Viral infections of the respiratory tract common during infancy and often may be seen in association with ground-glass include both those considered to be prin- lead to severe lower respiratory tract opacity, a pattern termed “crazy pav- cipal respiratory viruses, whose replica- disease. In adults, infections are usually ing” ( Fig 10 ); this pattern, initially de- tion is generally restricted to the respi- mild and restricted to the upper respi- scribed as typical of alveolar proteinosis, ratory tract, and others whose respira- ratory tract. Infl uenza A virus is trans- has an extensive differential diagnosis tory involvement is part of a generalized mitted from person to person by aero- (27 , 67– 69 ). infection. Viruses are classifi ed on the solized or respiratory droplets. In the Bronchial and bronchiolar wall thick- basis of (a) the type and structure of United States, more than 35 000 deaths ening.— Bronchiolar wall thickening may the nucleic acid in the viral genome and and 200 000 hospitalizations due to in- occur due to infl ammation or fi brosis. the strategy used in its replication (eg, fl uenza occur annually, and the number In viral bronchitis, obstruction of bron- DNA or RNA), (b) the type of symme- is increasing (64 ).

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Table 1 Summary of CT Findings in Viral Pneumonia

Parenchymal Ground-Glass Nodules, Micronodules, Interlobular Bronchial and/or Attenuation Opacity and and Tree-in-Bud Septal Bronchiolar Wall Cause of Pneumonia Disturbances Consolidation Opacities Thickening Thickening Other

RNA viruses Infl uenza A … +++ +++ … … … Avian fl u (H5N1) … +++ + … … Pneumatocele, pleural effusion Swine-origin infl uenza A (H1N1) … +++ … … … … Parainfl uenza 1–4 … +++ +++ … … … RSV … +++ +++ … +++ … HMPV * … +++ +++ … … … Measles … +++ +++ ++ ++ Pleural effusion, lymphadenopathy Enteroviruses … … … … … … Hantavirus … +++ ++ +++ … Acute respiratory distress syndrome Coronavirus (SARS) … +++ … +++ … Crazy-paving pattern DNA viruses Adenovirus … ++ … … +++ Bronchiectasis Herpes simplex virus … +++ ++ … … Nodules with halo sign Varicella … ++ +++ … … Nodules with halo sign or calcifi ed CMV … +++ ++ … … Nodules with halo sign EPV … +++ + + … Nodules with halo sign

Note.—Plus signs indicate the relative frequency of the fi ndings from lowest (+) to highest (+++). * HMPV = human metapneumovirus.

Table 2 Avian fl u (H5N1).— Avian infl uenza is caused by the H5N1 subtype of the Selected Viruses Causing Respiratory Syndromes infl uenza A virus ( 73 ,74 ). Most human Family Species and Subtype infections appear to be the result of close contact with infected birds—usually RNA viruses poultry or their products ( 73 , 75 , 76 ). Orthomyxoviridae Infl uenza A (subtype: avian fl u [H5N1], swine-origin In May 1997, an infl uenza H5N1 virus infl uenza A [H1N1]), infl uenza B was isolated from a previously healthy Paramyxoviridae Parainfl uenza 1–4, measles 3-year-old boy in Hong Kong who died Metapneumoviridae RSV, HMPV Picornaviridae Enteroviruses of severe pneumonia complicated by acute Retroviruses HTLV-1 * respiratory distress syndrome (77 ). In Bunyaviridae Hantavirus November and December of the same Coronaviridae Coronaviruses (subtype: SARS coronavirus) year, 18 additional cases of human H5N1 DNA virus (Adenoviridae) Adenovirus, herpes simplex virus (HSV ), varicella-zoster infections were identifi ed—six of which virus, CMV, EBV, human papilloma virus were fatal (78 ). According to World Health Organization statistics, as of June 19, * HTLV-1 = Human T-cell lymphotropic virus type 1. 2008, 385 human infections had been confi rmed from 15 countries; of these infections, 243 were fatal. Approximately The symptoms of infl uenza begin including solid organ transplant recip- 90% of confi rmed infections have been rapidly with fever, usually 101°–102°F ients ( 72 ). Oikonomou et al ( 65 ) re- in persons 40 years of age and younger. (38°–39°C), and is associated with myal- viewed the thin-section CT fi ndings in Most of those infected were previously gias, headache, lethargy, and respira- four patients with hematologic malig- healthy individuals. Signs and symp- tory tract symptoms of dry cough, rhin- nancies and infl uenza A pneumonitis toms of infection included fever, cough, orrhea, and sore throat. and found that the predominant thin- diarrhea, shortness of breath, lympho- In recent years, both infl uenza and section CT fi ndings were ground-glass cytopenia, and thrombocytopenia. The parainfl uenza viruses have been rec- opacities, consolidation, centrilobular overall case fatality rate for influ- ognized as a major cause of respiratory nodules, and branching linear opacities enza A (H5N1) infections exceeds 60% illness in immunocompromised patients, ( Fig 12 ). ( 79 –81 ).

Radiology: Volume 260: Number 1—July 2011 n radiology.rsna.org 25 STATE OF THE ART: Imaging of Pulmonary Viral Pneumonia Franquet

Figure 12 Figure 13

Figure 12: Transverse thin-section CT scan through the upper lobes in a patient with infl uenza pneumonia shows extensive bilateral ground- glass opacities. Areas of ground-glass opacity are associated with both intra- and interlobular septal thickening (crazy-paving pattern). Figure 13: Transverse thin-section CT scan at the level of the bron- chus intermedius in a patient with avian fl u H5N1 pneumonia shows Most chest radiographs are abnormal a rounded area of consolidation (arrow) surrounded by ground- at presentation, with multifocal consol- glass opacity in the lingula. idation the most common radiographic fi nding. The most common CT fi ndings monia in 18 patients with proved swine- of seasonal upper respiratory tract infec- consist of focal, multifocal, or diffuse origin infl uenza A virus; 12 of the 18 tion in adults and children (92 ). Human ground-glass opacities or areas of con- patients required mechanical ventilation parainfl uenza virus is genetically and anti- solidation ( 76 ) ( Fig 13 ). Pseudocavita- and seven died. genically divided into types 1–4. Although tion, pneumatocoele formation, lymph- On June 11, 2009, the World Health parainfl uenza types 1–4 are all respiratory adenopathy, and centrilobular nodules Organization declared the fi rst pandemic pathogens in humans, types 1–3 are the are often seen. During the course of of the 21st century caused by swine- most common cause of disease (93 ). disease, pleural effusions and cavitation origin infl uenza virus A (H1N1) (87 ). Ac- Recently, parainfl uenza virus type 3 can also develop (76 ). tually, the virus continues to spread glob- has been recognized as a substantial Reverse transcriptase PCR is the ally and its transmission among humans cause of respiratory illness in immuno- most commonly used test for diagnos- appears to be high; however, its viru- compromised patients, including solid ing H5N1 infection (6 ). The test can be lence is not greater than that observed organ transplant recipients (94 ). done on nasal and pharyngeal swabs, with seasonal infl uenza (85 , 87 ). The dis- The CT fi ndings of parainfl uenza virus respiratory specimens, blood, cerebro- ease has spread rapidly since then, with infection are variable, consisting of multi- spinal fl uid, and feces (82 ). 254 206 cases having been documented ple small peribronchial nodules, ground- Swine infl uenza (H1N1).— In the worldwide as of September 7, 2009, and glass opacities, and airspace consolida- spring of 2009, an outbreak of severe an estimated 2837 deaths (88 ). tion ( 94 – 96 ) ( Fig 15 ). pneumonia was reported in conjunction Reverse transcriptase PCR is the most RSV.— RSV is a ubiquitous cause of with the concurrent isolation of a novel commonly used test for making a clini- respiratory infection, with a worldwide swine-origin infl uenza A (H1N1) virus, cal diagnosis of H1N1 infection and dif- distribution and seasonal occurrence. widely known as swine fl u, in Mexico ferentiating it from seasonal infl uenza RSV is the most frequent viral cause of (approximately 1600 cases) (83 ). viruses (89 ,90 ). lower respiratory tract infection in in- Although it seems that the virulence The predominant CT fi ndings are fants (97 ). The major risk factors for of this microorganism is not currently unilateral or bilateral ground-glass opac- severe RSV disease in children are pre- very high, and in most of the infected ities with or without associated focal or maturity ( , 36 weeks gestation), congen- patients it only causes a mild respira- multifocal areas of consolidation. At mul- ital heart disease, chronic lung disease, tory disease, some deaths, particularly tidetector CT, the ground-glass opacities immunocompromised status, and mul- in Mexico, have been reported ( 84 , 85 ). and areas of consolidation have a pre- tiple congenital abnormalities (21 , 68). The cause of these deaths is not yet dominant peribronchovascular and sub- In immunocompetent adults, RSV in- known but logically they could be due pleural distribution, resembling organiz- fection usually manifests with rhinor- to severe pulmonary complications such ing pneumonia (91 ) ( Fig 14 ). rhea, pharyngitis, cough, bronchitis, head- as acute respiratory distress syndrome Parainfl uenza virus.— Parainfl uenza ache, fatigue, and fever. In older persons, or secondary pneumonia. Perez-Padilla viruses belong to the family Paramyxoviri- particularly those with chronic cardio- et al (86 ) reported bilateral patchy pneu- dae and are known to be a common cause pulmonary illnesses, severe pneumonia

26 radiology.rsna.org n Radiology: Volume 260: Number 1—July 2011 STATE OF THE ART: Imaging of Pulmonary Viral Pneumonia Franquet

Figure 14 Figure 15

Figure 14: Coronal reformation multidetector CT scan in a 46-year- Figure 15: Transverse thin-section CT scan through the lower lobes old man with swine-origin infl uenza A (H1N1) viral infection shows bilat- in a patient with parainfl uenza pneumonia shows a central area of eral lobular and subsegmental areas of consolidation involving mainly consolidation in the right lower lobe and ground-glass opacities the subpleural lung regions (arrowheads). in the left lower lobe. may occur, leading to respiratory fail- illness occurs in premature infants with to the family Paramyxoviridae that causes ure. It is a known cause of life-threaten- or without chronic lung disease and in- a febrile illness with rash in children. ing pneumonia in hematopoietic stem cell fants and young children with congen- Measles virus is highly contagious and transplant recipients and those with he- ital heart disease (100 , 101 ). transmitted from person to person by matologic malignancies. In adults, epidemiologic studies have either aerosolized droplet nuclei or di- Gasparetto et al (98 ) reviewed the demonstrated that HMPV infection ac- rect contact with contaminated respira- thin-section CT fi ndings in 20 patients counted for 4% of cases among patients tory secretions. After an incubation time with RSV pneumonitis after hematopoi- with community-acquired pneumonia or of almost 2 weeks, disease starts with a etic stem cell transplantation and found chronic obstructive pulmonary disease prodromal phase of fever, cough, and that the predominant patterns of abnor- exacerbations (102 , 103 ) and caused a coryza (106 ). A few days later, a general- mality were small centrilobular nodules nonspecifi c respiratory illness in more ized maculopapular skin rash appears— (50%), airspace consolidation (35%), than 2% of patients with cancer (104 ). often in combination with conjunctivitis. ground-glass opacities (30%), and bron- Moreover, HMPV accounted for 9% of Whereas mild pulmonary infection chial wall thickening (30%) ( Fig 16 ). all acute respiratory infections in pa- often occurs in healthy adults, severe The abnormalities were located in the tients with hematologic malignancies, pneumonia, with an often protracted and central and peripheral areas of the lungs with a mortality rate of 11% in the sub- fatal course, may occur in immunocom- and manifested with a predominantly set of patients who developed lower re- promised and debilitated patients. The bilateral and asymmetric distribution. spiratory infection (99 ). mortality in adult measles pneumonitis HMPV.— HMPV is a recently identi- Recently, Franquet et al (105 ) re- appears to be lower than that in chil- fi ed RNA virus, genus Metapneumovirus. viewed CT fi ndings in fi ve patients with dren; the reported mortality rates vary Like RSV, HMPV is usually associated HMPV pneumonia and found that the considerably, from 1% up to 36% (107 ). with acute respiratory tract infections predominant fi ndings were patchy areas CT fi ndings of measles pneumonia including upper airway disease, lower of ground-glass attenuation, small nod- are nonspecifi c and include bronchial wall airway bronchitis and bronchiolitis, in- ules, and multifocal areas of consolidation thickening , centrilobular nodules, ground- fl uenza-like syndrome, and pneumonia. in a bilateral asymmetric distribution glass opacity, interlobular septal thicken- Although HMPV has been implicated ( Fig 17 ). Pulmonary parenchymal in- ing, pleural effusion, and lymphadenop- in 4%–21% of infants with acute bron- volvement during the course of HMPV athy ( 20 , 107 – 109 ) ( Fig 18 ). Nakanishi chiolitis, their symptoms are clinically pneumonia infection may result in in- et al (110 ) reported that centrilobular indistinguishable from those elicited by terstitial lung disease and fi brosis. nodules, ground-glass opacity, and in- RSV (99 ). Children typically present with Measles.— Measles is one of the three terlobular septal thickening may indi- rhinorrhea, fever exceeding 100.4°F major infectious diseases worldwide and cate a measles-specifi c, virus-induced ( . 38°C), nonproductive cough, pro- causes approximately 1.5 million child- pneumonia. gressive dyspnea, hypoxemia, and bron- hood deaths per year. Measles is a single- In most measles cases, diagnosis is chiolitis. An increased risk for severe stranded RNA enveloped virus belonging based on clinical symptoms only. The

Radiology: Volume 260: Number 1—July 2011 n radiology.rsna.org 27 STATE OF THE ART: Imaging of Pulmonary Viral Pneumonia Franquet

Figure 16 Figure 18

Figure 16: Transverse thin-section CT scan through the upper lobes in a patient with respiratory syncytial pneumonia shows bilateral Figure 18: Transverse thin-section CT scan at the level of the carina ill-defi ned centrilobular nodules (arrows) and bronchial wall in a patient with measles infection shows multiple centrilobular nodules thickening (arrowhead). (arrowhead) and bilateral areas of lobular consolidation (arrows).

Figure 17 count for most viruses recovered from and thickening of the bronchovascular children with summertime upper respi- bundles in the peripheral lung (121 ). ratory tract infections (112 ). Most infec- Hantavirus.— The genus Hantavirus tions are not associated with pneumonia. comprises a genetically homogeneous Lower respiratory tract infection may group of enveloped, single-stranded RNA occur sporadically, and some entero- viruses belonging to the family Bunya- virus serotypes are capable of producing viridae. During the spring of 1993, an fulminant, frequently fatal disease in emerging rodent-borne zoonotic disease, the newborn infant. In the fi rst few characterized by severe acute respira- days of life, fatal cases of enterovirus tory failure, rapid clinical progression, pneumonia caused by echovirus types and high case-fatality rates, occurred 6, 9, and 11 and group A coxsackievirus among healthy adults in the southwest- type 3 have been reported ( 113 –115 ). ern United States (122 ). Enterovirus 69 has been isolated from Hantavirus infection may cause dif- the throat secretions of infants with bron- fuse airspace disease, termed hantavirus Figure 17: Close-up view of transverse thin- chiolitis and pneumonia (116 ). pulmonary syndrome (123 ). The incu- section CT scan at the level of the right lower lobe HTLV-1.— HTLV-1 is an RNA retro- bation period for hantavirus pulmonary in a patient with HMPV infection after hematopoi- virus. It is the fi rst retrovirus to be as- syndrome is typically 1–2 weeks but etic stem cell transplantation shows multiple centri- sociated with human disease (117 ). It is ranges from 1 to 4 weeks. The prodromal lobular nodules (arrows) and focal areas of transmitted by sexual contact, by blood stage is usually 3–5 days (range, 1–10 consolidation (arrowhead). transfusion, from mother to child trans- days) ( 124 ). Patients have an abrupt placentally, and via breast feeding. onset of symptoms, which include fever, The lung is a preferential site for myalgia, malaise, chills, anorexia, and most common method is the demon- HTLV-1 infection ( 118 ). HTLV-1 is an headache. stration of measles virus–specifi c IgM in a etiologic retrovirus of adult T-cell leuke- Although hantavirus pulmonary syn- single serum sample, but a more than mia or lymphoma (117 , 119 ). Myelopa- drome and acute interstitial pneumonia fourfold titer increase in paired serum thy, Sjögren syndrome, and lymphocytic can share similar clinical presentations, samples is also formal proof of a recent pneumonitis have been reported in as- acute interstitial pneumonia and fatal measles virus infection. Virus detection sociation with HTLV-1 infection (120 ). cases of hantavirus pulmonary syndrome may be performed by means of virus iso- Clinical-pathologic and radiologic can generally be differentiated on clini- lation or reverse transcriptase PCR (111 ). similarities have been demonstrated in cal and histologic grounds, and this dis- Coxsackievirus, echovirus, and entero- patients with HTLV-1–associated bron- tinction can be further confi rmed immu- virus.— Coxsackievirus is a RNA virus, chiolitis and in those with diffuse pan- nohistochemically (18 ). genus Enterovirus. The human neonate bronchiolitis (121 ). CT fi ndings in pa- Histologically, changes are charac- is uniquely susceptible to coxsackievirus tients with HTLV-1 consist mainly of cen- teristic for exudative (eg, focal hya- and echovirus disease. Enteroviruses ac- trilobular nodules, ground-glass opacity, line membranes, extensive intraalveolar

28 radiology.rsna.org n Radiology: Volume 260: Number 1—July 2011 STATE OF THE ART: Imaging of Pulmonary Viral Pneumonia Franquet

Figure 19

Figure 19: (a) Bedside chest radiograph in a patient with severe hantavirus pulmonary syndrome shows extensive bilateral interstitial opac- ities. (b) Frontal chest radiograph obtained 6 hours later demonstrates rapid progression to diffuse perihilar and lower lung consolidation , refl ecting associated diffuse alveolar damage. (Images courtesy of Loren Ketai, MD, Albuquerque, NM.) edema, fi brin, and variable numbers SARS.— SARS caused by SARS- cells, and bronchiolar injury with loss of infl ammatory cells) and proliferative associated coronavirus is a systemic infec- of cilia are other observed features (eg, proliferation of reparative type II tion that clinically manifests as progres- (136 , 137 ). Patients who die after the 10th pneumocytes, fi broblastic thickening of sive pneumonia (129 – 131 ). SARS was fi rst day of illness present with a mixture of the alveolar septa with severe airspace detected in the Guangdong Province of acute changes and those of the organizing disorganization, and distortion of lung China in late 2002, with major outbreaks phase of diffuse alveolar damage ( 19 ) architecture) stages of diffuse alveolar in Hong Kong, Guangdong, Singapore, ( Fig 5). damage ( 18). and Toronto and Vancouver, Canada The imaging features of SARS-asso- Chest radiographs may be initially (132 ). More than 8000 people were af- ciated coronavirus infection consist of normal but progressively worsen, dis- fected, with a mortality rate of 10%. unilateral or bilateral ground-glass opac- playing signs of pulmonary edema and The typical clinical manifestation of ities, focal unilateral or bilateral areas acute respiratory distress syndrome SARS-associated coronavirus includes of consolidation, or a mixture of both. ( 125 , 126 ). The fi ndings at chest radi- an incubation period of 2–10 days, early In the areas of ground-glass opacifi ca- ography may represent differences in systemic symptoms followed within 2–7 tion, thickening of the intralobular in- the extent of alveolar epithelial dam- days by dry cough or shortness of breath, terstitium or interlobular septa may be age seen in hantavirus pulmonary syn- the development of radiographically con- present (Fig 20). If marked septal thick- drome and acute respiratory distress fi rmed pneumonia by day 7–10, and, in ening occurs, a crazy-paving appear- syndrome (127 ). The lack of peripheral many cases, lymphocytopenia (133 , 134 ). ance results (134 ,138 – 141 ). Cavitation, distribution of initial airspace disease, Criteria for the confi rmation of SARS calcifi cation, a reticular or nodular pat- the prominence of interstitial edema, at laboratory analysis include detection tern of opacifi cation, lymphadenopathy, and the presence of pleural effusions of antibodies in a convalescent-phase or pleural effusion are not features of early in the disease process are in con- blood serum sample, detection of SARS- SARS ( 14 ). trast to the typical radiographic fi ndings associated coronavirus in a clinical speci- in acute respiratory distress syndrome men with reverse transcriptase PCR, or Selected DNA Viruses ( 126 ) ( Fig 19 ). isolation of SARS-associated coronavirus Adenovirus.— Human adenoviruses are The CT appearances of hantavirus in a cultured clinical specimen (135 ). nonenveloped, double-stranded DNA pulmonary syndrome consist of exten- Histologically, acute diffuse alveolar viruses belonging to the family Adeno- sive bilateral ground-glass opacities, damage with airspace edema is the most viridae. More than 50 serotypes have thickened interlobular septa, few poorly prominent feature in patients who die been described, and approximately half defi ned small nodules, bronchial wall before the 10th day after onset of illness. of these serotypes are known human thick ening, and small bilateral pleural Hyaline membranes, interstitial edema, pathogens. Depending on the serotype, effusions (128 ). interstitial infi ltrates of infl ammatory adenovirus may cause respiratory disease

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Figure 20 Figure 21

Figure 20: Transverse thin-section CT scan at the level of the lower pulmonary veins in a patient with SARS infection shows a focal area of consolidation in the medial segment of the left lower lobe (arrows) and bilateral ground-glass opacities in the lower lobes (arrowheads). (Image courtesy of Nestor L. Müller, MD, Vancouver, Canada.) Figure 21: Transverse thin-section CT scan at end expiration in a patient with Swyer-James-MacLeod syndrome after adenovirus bron- chiolitis in childhood shows a decrease in attenuation and vascularity of (serotypes 1–3 and 7) or other illnesses the right lung; a hyperattenuating zone is also visible in the posterior such as gastroenteritis, keratoconjunc- left upper lobe. The peripheral pulmonary markings are diminutive tivitis, cystitis, meningoencephalitis, and as a result of vascular narrowing, and a clear shift of the hepatitis. Adenoviral infections are more mediastinum to the left is also seen (arrow). common from fall to spring. Humans are the reservoir for the chial wall thickening, and bronchiectasis Herpes simplex virus type 1.— adenoviruses that cause human disease. ( 14, 147, 148 ). Air trapping is commonly Herpes simplex virus type 1 pneumonia Adenovirus accounts for 5%–10% of visible on expiratory CT scans as areas may be a life-threatening infection seen acute respiratory infections in infants of low attenuation that represent regions almost exclusively in immunocompro- and children but for less than 1% of re- of lung that are poorly ventilated and mised and/or mechanically ventilated spiratory illnesses in adults (142 ). perfused (146 ,147 , 149 –151 ) ( Fig 21 ). patients, usually as a component of poly- Swyer-James-MacLeod syndrome is Adenovirus infections in immuno- microbial infection (156 ). Herpes sim- considered to be an acquired disease sec- compromised individuals (eg, stem cell plex virus pneumonia is rare in patients ondary to adenovirus infection in child- and solid organ transplant recipients) who have undergone solid organ or he- hood (143 – 146 ). A typical infection pro- are increasingly recognized as substan- matopoietic stem cell transplantation duces cough, nasal congestion, and coryza tial causes of morbidity and mortality. or those who have received cytotoxic or and is often accompanied by systemic In the stem cell transplantation popula- immunosuppressive agents. Histologi- symptoms such as headache, fever, chills, tion, the frequency of disease ranges cally, diagnosis depends on recognition malaise, and myalgia. from 3% to 47% (152 ). Adenovirus pneu- of herpes virus cytopathic changes in In a study by Chang et al ( 146 ) of 19 monia has been documented in kidney infected cells (eg, mild nucleomegaly children with postinfectious bronchioli- and liver transplant recipients (144 ) and formation of intranuclear viral par- tis obliterans, chest radiographs showed but has only been sporadically reported ticles that coalesce, forming eosino- five patterns: (a) unilateral hyperlu- in lung transplant recipients (153 ). A philic viral inclusions) (Fig 1 ). cency of increased volume, (b) complete rapidly fatal adenovirus necrotizing pneu- Umans et al (157 ) reviewed the ra- collapse of the affected lobe, (c) unilat- monia, early in the posttransplantation diographic fi ndings in 14 patients with eral hyperlucency of a small or normal- course, may occur in the pediatric pop- herpes simplex virus pneumonia. The sized lung, (d) bilateral hyperlucent ulation (153 ). abnormalities in 12 patients manifested lungs, and (e) mixed pattern of persis- The radiographic manifestations con- as lung opacifi cation, which was pre- tent collapse and hyperlucent and peri- sist of patchy bilateral areas of consolida- dominantly lobar or more extensive and bronchial thickening. Thin-section CT tion in a lobular or segmental distribution always bilateral. Although most patients fi ndings in postinfectious bronchiolitis and/or bilateral ground-glass opacities had a mixed airspace and interstitial obliterans consist of sharply marginated with a random distribution (144 , 154 ) pattern of opacity, 11 showed at least an focal areas of increased and decreased ( Fig 22 ). In children, adenovirus may airspace consolidation. Lobar, segmen- lung opacity with reduced vessel size result in lobar collapse, especially of the tal, or subsegmental atelectasis was pre- in low-attenuation lung regions, bron- right upper lobe (155 ). sent in seven patients. Pleural effusions

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Figure 22 Figure 23

Figure 22: Transverse thin-section CT scan at the level of the carina in a patient with adenovirus infection shows combination of bilateral widespread areas of ground-glass opacity with bilateral subsegmental areas of consolidation (arrows). (Image courtesy of Kyung Soo Lee, MD, Figure 23: Transverse thin-section CT scan at the level of the bron- Seoul, Korea.) chus intermedius in a patient with herpesvirus infection shows multiple, bilateral, and randomly distributed pulmonary nodules surrounded by a halo of ground-glass opacity (arrows).

Figure 24 virus or acquired immunodefi ciency syn- drome (AIDS) with chickenpox are at high risk for developing varicella pneu- monia ( 161). The thin-section CT appearances in varicella pneumonia largely refl ect the multicentric hemorrhage and necrosis centered on airways (162 ). Common fi nd- ings include numerous nodular opac- ities measuring 5–10 mm in diameter, some with a surrounding halo of ground- glass opacity (halo sign), patchy ground- glass opacities, and coalescence of nod- ules (162 ) A miliary distribution may also occur ( 162 ,163 ). After antiviral chemo- therapy, imaging fi ndings disappear con- Figure 24: Transverse thin-section CT scan at the level of the lower lobes in a patient with healed varicella-zoster infection shows multiple, bilateral, and currently with healing of skin lesions randomly distributed well-defi ned small pulmonary nodules—some of which ( 162 ). Occasionally, lesions may calcify are calcifi ed (arrows). and persist as well-defi ned, randomly scattered, 2–3-mm densely calcifi ed nod- ules (17 ) ( Fig 24 ). can also develop during the course of enpox) is a common contagious infection CMV.— CMV is a DNA virus and a the disease (34 ,157 , 158). in childhood, with increasing frequency in member of the Herpesviridae family, Common fi ndings at CT include adults (160 ). Pneumonia, although rare, which includes varicella-zoster virus , patchy lobular, subsegmental, or seg- is the most serious complication af- herpes simplex virus types 1 and 2, and mental consolidation and ground-glass fecting adults with chickenpox. Varicella EBV. It is a widely distributed human opacities; associated small centrilob- pneumonia is estimated to occur in one pathogen and has the capacity to remain ular nodules and tree-in-bud pattern of every 400 cases of adulthood chick- latent in a variety of nucleated cells. CMV have been described in patients in- enpox infections, being more common does not produce clinical disease in most fected with herpes simplex virus type 2 in pregnant and immunosuppressed pa- people with an intact immune system. ( 159 ) (Fig 23 ). tients (16 ). CMV pneumonia is a major cause of Varicella virus.— Varicella virus Predisposing conditions include un- morbidity and mortality following he- (varicella-zoster virus) is a double- derlying leukemia and lymphoma and matopoietic stem cell and solid organ stranded DNA virus and a member of other causes of immunodefi ciency. Pa- transplantation and in patients with AIDS the Herpesviridae family. Varicella (chick- tients with human immunodefi ciency in whom CD4 cells are decreased to

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Figure 25 Figure 26

Figure 26: Close-up view of transverse thin- section CT scan obtained with a multidetector unit in a young patient with tracheobronchial papillomatosis Figure 25: Coronal thin-section CT scan obtained with a multidetector shows a small nodule (papilloma) arising from the unit in a 41-year-old man with CMV infection after hematopoietic stem tracheal wall (arrowhead). A thin-walled cyst is also cell transplantation shows multiple, bilateral, and randomly distributed visible in the right upper lobe (arrow). (Image cour- small ill-defi ned pulmonary nodules, some of which are surrounded by a tesy of Kyung Soo Lee, MD, Seoul, Korea.) halo of ground-glass opacity (arrow). Note the presence of multiple small branch opacities representing cellular bronchiolitis (arrowheads). (Image courtesy of Dante L. Escuissato, MD, Curitiba, Brazil.) pharyngitis, and lymphadenopathy–which are often accompanied by splenomegaly fewer than 100 cells per cubic millime- lobar consolidation, diffuse and focal ( 174 ). EBV pneumonia is rare either ter. CMV infection occurs in up to 70% ground-glass opacities, irregular reticu- in immunocompetent or immunocom- of bone marrow transplant recipients, lar opacities, and multiple miliary nodules promised subjects. Mild, asymptomatic and approximately one-third develop or small nodules with associated areas pneu monitis occurs in about 5%–10% CMV pneumonia (164 ). This complica- of ground-glass opacity (halo sign) (164 , of cases of infectious mononucleosis tion characteristically occurs during the 169 – 172) ( Fig 25 ). ( 174 , 175 ). postengraftment period (30–100 days Nevertheless, the fi ndings of CMV EBV has also been associated with after transplantation), with a median on- infection in patients with AIDS seem the development of Burkitt lymphoma, set time of 50–60 days after transplan- to differ from those in patients without Hodgkin lymphoma, nasopharyngeal car- tation (165 , 166). AIDS (171 ). McGuinness et al (173 ) de- cinoma, and other EBV-associated dis- Although CMV antigenemia assay has scribed the thin-section CT fi ndings in eases such as EBV-associated hemophago- been a major advance in the diagnosis 21 patients with AIDS and CMV pneu- cytic lymphoproliferative syndrome and of CMV infection in organ transplanta- monia. The most common abnormal- chronic active EBV infection (176 ). tion (167 ), recent evaluations of reverse ities consisted of ground-glass opacity , The CT manifestations of EBV pneu- transcriptase PCR have revealed that consolidation, and discrete pulmonary monia are similar to those of other viral PCR and antigenemia assay could pro- nodules or masses that measure be- pneumonias. The fi ndings usually consist vide false-negative results when virus tween 1 and 3 cm. These investigators of lobar consolidation, diffuse and focal levels are quite low (168 ). pointed out that the possibility of CMV parenchymal haziness, irregular reticular Histologically, CMV has four major pneumonia should be considered in pa- opacities, and multiple miliary nodules patterns of lung involvement: (a) mili- tients with AIDS, particularly if they have or small nodules with associated areas ary pattern, (b) diffuse interstitial pneu- Kaposi sarcoma and areas of dense con- of ground-glass opacity (halo sign). monitis, (c) hemorrhagic pneumonia, solidation or masslike opacities. Although Human papilloma virus.— Human pap- and (d) CMV inclusions associated with consolidation is also relatively com- illoma virus is a double-stranded DNA minimal infl ammation of lung injury. monly seen in patients without AIDS, it virus that only infects humans. Recur- Because of the obvious overlap in is not dense and does not result in mass- rent respiratory papillomatosis is often terms of pathologic characteristics, it is like opacities (173 ). associated with human papilloma virus not surprising that the thin-section CT EBV.— EBV is a ubiquitous human types 6 and 11. The papillomas may be fi ndings for each pattern will vary and herpesvirus with worldwide distribution. multiple (tracheobronchial papillomatosis) be modulated by the exact nature of Primary infection with EBV occurs early and involve the lung parenchyma. The the underlying pathologic condition. CT in life and manifests as infectious mono- characteristic radiographic manifestations features of CMV pneumonia consist of nucleosis with the typical triad of fever, consist of bilateral, multiple thin-walled

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cysts and nodules. On CT scans, cysts immunocompromised adults. Chest 2004 ; severe acute respiratory syndrome (SARS). are round or irregular in shape and usu- 125 ( 4 ): 1343– 1351 . Histopathology 2004; 45 ( 2 ): 119 – 124 . ally less than 5 cm in diameter; cysts usu- 5 . Sullivan CJ , Jordan MC . Diagnosis of viral 20 . Kim EA , Lee KS , Primack SL , et al . Viral ally show smooth but asymmetric thick pneumonia. Semin Respir Infect 1988 ; pneumonias in adults: radiologic and walls (2–3 mm) (177 , 178) (Fig 26). The 3 ( 2 ): 148 – 161. pathologic fi ndings. RadioGraphics 2002 ; 22 (Spec Issue): S137 – S149 . papillomas, either nodules or masses, of- 6 . Daum LT , Canas LC , Arulanandam BP , ten have lobulated margins and measure Niemeyer D , Valdes JJ , Chambers JP . Real- 21 . Hall CB . Respiratory syncytial virus and less than 3 cm in diameter (179 ). time RT-PCR assays for type and subtype parainfl uenza virus. N Engl J Med 2001 ; detection of infl uenza A and B viruses. 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