Case 281: Thoracic Air Leak Syndrome in a Patient with Hematopoietic Stem Cell Transplantation and Graft-versus-Host Disease

Image Findings

Nonenhanced CT showed extensive areas of air density in the mediastinum (Fig 1), spinal canal (Fig 2), and subcutaneous and soft tissues of the neck (Fig 3) and chest. There were linear air-filled spaces in the pulmonary interstitial tissue and along the bronchovascular bundles (Fig 1) that indicated pulmonary interstitial emphysema. Large airways were intact on the CT images (Fig 4). Nonenhanced CT of the chest showed a diffuse mosaic attenuation pattern in both lungs (Fig 1). Regions with lower attenuation contained smaller-caliber vessels, suggesting that the heterogeneous attenuation was due to varying geographic perfusion. Expiratory CT images could not be obtained because the patient was unable to comply. Mild bronchiectasis with diffuse spatial distribution and subtle bronchial wall thickening were present (Fig 5). There was no evidence of interstitial lung disease. Transverse diameters of the main pulmonary artery and ascending aorta at the level of the right pulmonary artery bifurcation were 27.1 mm and 28 mm, respectively.

Figure 1:

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Figure 2:

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Figure 3:

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Figure 4:

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Figure 5:

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Discussion

Subcutaneous and soft-tissue emphysema in the neck and chest, pneumomediastinum, pneumorrhachis, and pulmonary interstitial emphysema indicate the diagnosis of thoracic air leak syndrome (TALS). Diffuse air trapping seen on CT images of the chest and simultaneous skin and liver chronic GVHD strongly indicate bronchiolitis obliterans (BO) as the underlying disease leading to TALS in this patient.

TALS is a late-onset pulmonary complication of allogeneic hematopoietic stem cell transplantation (HSCT). TALS is an uncommon sequela, with a cumulative incidence of 0.83%–2.1% in different reports (1–3). The median time from transplantation to the diagnosis of TALS is approximately 1 year, but it may develop as early as 2 months after transplantation (2,3). To appropriately define TALS in the setting of HSC-kT, TALS refers to the spontaneous leakage of air from normal air-containing structures in a lung that is affected by other complications of HSCT (4). The first spaces in which the leaked air usually accumulates are the places that are immediately close to the alveoli, including the pulmonary interstitial tissue, mediastinum, and pleural space. From there, the air may propagate further to more distant structures, such as the pericardium, spinal canal, muscles, and subcutaneous tissue. In practice, any spontaneous pulmonary interstitial emphysema, pneumomediastinum, pneumothorax, pneumopericardium, pneumorrhachis, soft tissue, and subcutaneous emphysema in a allogeneic HSCT recipient after excluding other potential causes is considered to be TALS (4). In this case, the diagnosis of TALS was established based on the presence of pulmonary interstitial emphysema, pneumomediastinum, pneumorrhachis, and soft-tissue and subcutaneous emphysema without any apparent cause other than BO.

TALS is commonly associated with BO according to the reported cases (1). It is proposed that narrowing of the small airways in the process of BO impedes the backflow of air from alveoli to upper airways during expiration. Thus, air is trapped in the alveoli, intra-alveolar pressure rises, the alveolar wall is disrupted, and gas extrudes from alveoli to the adjacent tissues (4). TALS may occur in a lung affected by a long-standing BO or early in the course of it.

BO usually manifests with dyspnea and nonproductive cough. National Institutes of Health diagnostic criteria for BO require the presence of new-onset obstructive lung disease, the absence of infection, and either evidence of chronic GVHD in other organs or air trapping seen in pulmonary function tests or on expiratory CT images (5). Radiologically, BO is characterized by expiratory air trapping (100%), bronchiectasis (42.4%), bronchial wall thickening (73%), and centrilobular nodule (39.4%) (6). The mosaic pattern of lung attenuation is the salient radiologic feature of BO. Hyperinflated areas, which are distal to obstructed small airways, appear less attenuated than the normal areas of the lungs. In addition to airway disorders, mosaic attenuation pattern can be observed in pulmonary vascular and interstitial lung diseases. Expiratory CT scanning is a valuable method to detect air trapping. In the presence of normal small airways, it is expected that the attenuation of different portions of lung parenchyma will increase comparably during expiration. If the small airways are partially obstructed due to disease, a smaller portion of gas present in the airspaces distal to the involved airways can be expelled during expiration. Therefore, during expiration, the attenuation of these areas will not increase in accordance with regions with normal small airways. If air trapping is found at expiratory CT scanning, it is highly specific for small-airway disease. There are some clues on lung CT images that can be used to differentiate the causes of mosaic attenuation pattern in the lungs. Signs of elevated pulmonary arterial pressure, including an enlarged main pulmonary artery, increased bronchoarterial ratio, dilated right ventricle, and flattening and left-sided bowing of the interventricular septum, are indicative of pulmonary vascular disease. Airspace opacities, interlobular septal thickening, and reticular and reticulonodular opacities are associated with either interstitial lung disease with secondary distortion of distal airways or diseases that primarily involve both the bronchial tree and the pulmonary interstitial tissue. The presence of bronchiectasis, bronchial wall thickening, centrilobular nodules, and tree-in-bud opacities signal airway disorders (7). CT images in this case showed diffuse mosaic attenuation pattern without any apparent sign of abnormality in pulmonary vasculature and disorders of airspaces and pulmonary interstitium. Radiologic findings and concurrent chronic GVHD in other organs make BO the most likely diagnosis as the underlying cause of TALS in this patient.

Other possible causes of the air leak in an HSCT recipient include organizing pneumonia, pleuroparenchymal fibroelastosis, and Pneumocystis jiroveci pneumonia (PJP). Organizing pneumonia is a predominantly interstitial lung disease that may complicate HSCT. Air leak syndrome has been reported in association with organizing pneumonia (2). Although fever may not exist in an immunosuppressed patient, it is present in about 60% of patients with HSCT with organizing pneumonia (8). Chest CT images of organizing pneumonia usually contain ground-glass opacities, airspace consolidation, or interlobular septal thickening (9). Lack of fever and all the mentioned radiologic features make the diagnosis of organizing pneumonia unlikely.

Pleuroparenchymal fibroelastosis (PPFE) is a rare pulmonary sequela in survivors of HSCT that may manifest as air leak syndrome. Histopathologic examination shows pleural fibrosis with fibroelastic alterations in subpleural regions. The typical CT pattern seen in patients with PPFE is pleural and subpleural thickening that may accompany interstitial reticulation and traction bronchiectasis (4). The characteristic pleural and subpleural changes of PPFE were not found in this patient; therefore, the probability of this diagnosis was small.

PJP occurs in 0.63% of patients who undergo allogeneic HSCT. About one-fourth of patients develop PJP beyond day 270 after HSCT (10). The subacute course, shortness of breath, cough, and immunosuppressive therapy for chronic GVHD, while not being on chemoprevention for PJP, are important clues that necessitate consideration of PJP as a differential diagnosis in this patient. Mosaic attenuation pattern, pneumomediastinum, pneumorrhachis, and subcutaneous emphysema, which are present in this case, have been reported in association with PJP. However, imaging hallmarks of PJP comprising ground-glass appearance, consolidation, and interlobular septal thickening were absent. We concluded that the probability of PJP was low in this case.

In conclusion, we discussed the clinical manifestations, radiologic findings, and differential diagnosis of TALS after HSCT. The appearance of any spontaneous extra-alveolar air on thoracic images in an HSCT recipient must bring the diagnosis of TALS into consideration. This case underscores the importance of incorporating clinical and radiologic investigations for proper diagnosis and management of pulmonary complications after HSCT.

Congratulations to the 168 individuals and eight resident groups that submitted the most likely diagnosis (thoracic air leak syndrome) for Diagnosis Please, Case 281. The names and locations of the individuals and resident groups, as submitted, are as follows:

Individual responses

Pablo J. Abbona, MD, Newport Beach, CA

Gholamali Afshang, MD, Tinley Park, IL

Gensuke Akaike, MD, Seattle, WA

Oguz Akin, MD, New York, NY

Asaad M. Alazami, MD, MBBS, Riyadh, Saudi Arabia

Albert J. Alter, MD, PhD, Blanchardville, WI

Ricardo Mamede Lopes Antunes, MD, Lisbon, Portugal

Ryo Aoki, Yokohama, Japan

Roshan K. Arjal, MD, Chicago, IL

Kenneth F. Baliga, MD, Rockford, IL

Tameem A. Bhat, MD, Jammu, India

Manon N. Braat, MD, Utrecht, Netherlands

Douglas C. Brown, MD, Virginia Beach, VA

Maria Lucia Brun, MD, Bogota, Colombia

Ian A. Burgess, MD, Manly, Australia

David P. Burrowes, MD, Calgary, Canada

Charles H. Bush, MD, Gainesville, FL

Arzu Canan, MD, Dallas, TX

Phillip Ming-da Cheng, MD, MS, Culver City, CA

Daniel M. Chernoff, MD, PhD, Saratoga Springs, NY

Luis Cid Barria, MD, Quilpue, Chile

Mauricio Ramos Corral, MD, El Paso, TX

Marco A. Cura, MD, Dallas, TX

Felice D'Antuono, MD, Rocchetta Sant'Antonio, Italy

Srinivas Dandamudi, MD, Vijayawada, India

Anil K. Dasyam, MD, Pittsburgh, PA

Anthony Davila, MD, Houston, TX

Marc G. De Baets, MD, Collina D'Oro, Switzerland

Peter De Baets, MD, Damme, Belgium

Mustafa Kemal Demir, MD, Istanbul, Turkey

Thaworn Dendumrongsup, MD, Songkhla, Thailand

Seyed A. Emamian, MD, PhD, Bethesda, MD

Eric W. Emig, MD, Littleton, NH

Brett D. Ferdinand, MD, Livingston, NJ

Francis T. Flaherty, MD, Ridgefield, CT

Maria K. Florez Leguia, MD, Medellin, Colombia

Akira Fujikawa, MD, Tokyo, Japan

Toshihiro Furuta, MD, PhD, Bunkyo-ku, Japan

Pauline Germaine, DO, Cherry Hill, NJ

Bradley S. Gluck, MD, Southampton, NY

Alvaro Gomez Naar, MD, Salta Capital, Argentina

Taku Gomi, Tokyo, Japan

Vasco Goncalves-Matoso, MD, Morges, Switzerland

Wataru Gonoi, MD, PhD, Tokyo, Japan

Maria A. Gosein, MBBS, FRCR, Santa Cruz, Trinidad And Tobago

Osamu Hasegawa, MD, Koriyama, Japan

Yuki Hayashi, Hamamatsu, Japan

Christoph Hefel, Feldkirch, Austria

Yuusuke Hirokawa, MD, Kyoto, Japan

Masatoshi Hotta, Shinjuku, Japan

Alvaro Huete Garin, MD, Santiago, Chile

Alberto C. Iaia, MD, Wilmington, DE

Noriatsu Ichiba, MD, Otsu, Japan

Shintaro Ichikawa, MD, PhD, Chuo, Japan

Mitsuru Ikeda, MD, Handa, Japan

Takashi Ikeuchi, MD, Moriyama, Japan

Hiroki Ikuma, MD, Tsu, Japan

Akitoshi Inoue, MD, PhD, Rochester, MN

Muhammad U. Islam, FRCR, FRCPC, Sydney, Canada

Catarina Janicas, MD, Agualva-cacem, Portugal

Klaudia Jumaa, MD, Georgetown, Canada

Katsuhiko Kato, MD, PhD, Nagoya, Japan

Koki Kato, MD, Utsunomiya, Japan

Douglas S. Katz, MD, Mineola, NY

Yasushi Kawata, MD, Akita, Japan

Thomas W. Keimig, MD, Pleasant Ridge, MI

Mihran A. Khdhir, MBChB, Beirut, Lebanon

Takao Kiguchi, MD, PhD, Ichinomiya, Japan

Jacobo Kirsch, MD, Weston, FL

Takuji Kiryu, MD, PhD, Gifu, Japan

Jakob Kist, MD, PhD, Naarden, Netherlands

Osamu Kizu, MD, Otsu, Japan

Mitchell A. Klein, MD, Mequon, WI

Artur Komorowski, MD, Owczary, Poland

Masamichi Koyama, MD, PhD, Tokyo, Japan

Mario A. Laguna, MD, Franklin, WI

David A. Lisle, MBBS, Brisbane, Australia

Edgar Lorente, MD, Valencia, Spain

David A. Lynch, MBBCh, Denver, CO

Stephen V. Manghisi, MD, Closter, NJ

Daniel A. Marichal, MD, Topeka, KS

Sota Masuoka, MD, Setagaya-ku, Japan

Satoshi Matsushima, MD, Tokyo, Japan

Sebastian R. McWilliams, MBBCh, Dublin, Ireland

Alfonso Mendez Avellaneda, MD, San Miguel de Tucuman, Argentina

Manabu Minami, MD, PhD, Yokohama, Japan

Zeyad Moqbel, MD, Alexandria, Egypt

Tiago N. Morato, MD, Brasilia, Brazil

Toshio Moritani, MD, PhD, Ann Arbor, MI

Kyoko Nagai, MD, Yokohama, Japan

Tammam N. Nehme, MD, Hinsdale, IL

Nariman Nezami, MD, Baltimore, MD

Stephanie A. Nguyen, MD, Calgary, Canada

Tomokazu Nishiguchi, PhD, FRANZCR, North Sydney, Australia

Sarah Nobles, MD, Seattle, WA

Hayato Nozawa, Hamamatsu, Japan

Ken Oba, MD, Chuoku, Japan

Roque Oca, MD, Bilbao, Spain

Ryusuke Ookura, MD, Kobe, Japan

Michael D. Orsi, MD, San Antonio, TX

Klaus Orth, Aachen, Germany

Vishal Panchal, MD, Oakland, CA

Ananya Panda, MD, MBBS, Rochester, MN

Ioannis E. Papachristos, MD, Agrinio, Greece

Suresh K. Patel, MD, Chicago, IL

Narendrakumar P. Patel, MD, Newburgh, NY

Krishna R. Pillai, MD, La Porte, IN

Diogo L. Pinheiro, MD, Curitiba, Brazil

Rubem Pochaczevsky, MD, Palm Harbor, FL

Ameen H. Rageh I, MBBS, Lahore, Pakistan

John Raseman, MD, Wauwatosa, WI

Ryan P. Rebello, MD, Dundas, Canada

Jhonathan Reina Alzate, MD, Medellin, Colombia

James Roberts, MD, MSc, Vancouver, Canada

Manoel S. Rocha, MD, PhD, Sao Paulo, Brazil

Daniel Romeu Vilar, MD, Bertamirans, Spain

Rocky C. Saenz, DO, Farmington Hills, MI

Atsushi Saiga, MD, Chiba, Japan

Akihiko Sakata, MD, Wakayama, Japan

Yusuke Sakurai, Nagoya, Japan

Meir H. Scheinfeld, MD, PhD, Suffern, NY

Pierre Schmit, MD, Halifax, Canada

Steven M. Schultz, MD, Fort Worth, TX

Stephen D. Scotti, MD, Minneapolis, MN

Anthony J. Scuderi, MD, Greensburg, PA

Palmi N. Shah, MD, Chicago, IL

Akshit Sharma, MBBS, MD, Jammu, India

Taro Shimono, MD, PhD, Osaka, Japan

Ichiro Shirouzu, MD, Tokyo, Japan

Evan S. Siegelman, MD, Media, PA

Michael S. Siegfried, MD, Glencoe, IL

Carlos Francisco Silva, MD, Setubal, Portugal

Ken Simmons, MD, Sydney, Australia

Shakti P. Singh, MD, Delhi, India

Stephen E. Slawson, MD, Joplin, MO

Paul Stark, MD, La Jolla, CA

Hongliang Sun, MD, Beijing, China

Brooks W. Taber, MD, Cary, NC

Taku Tajima, MD, PhD, Minato-ku, Japan

Naoshi Tajima, MD, Bunkyo, Japan

Hiroaki Takahashi, MD, Rochester, MN

Taro Takeda, MD, Hashima-gun, Japan

Eliko Tanaka, MD, Yokohama, Japan

Takashi Tanaka, MD, PhD, Okayama, Japan

Alexander M. Tassopoulos, MD, Detroit, MI

Kotani Tomoya, MD, Moriguchi, Japan

Eugene Tong, MD, Austin, TX

John L. Torres Castiblanco, Sr, MD, Bogota, Colombia

Stamos J. Trakadas, MD, Athens, Greece

Mitsuteru Tsuchiya, MD, Hamamatsu, Japan

Meric Tuzun, MD, Ankara, Turkey

Umit Tuzun, MD, Istanbul, Turkey

Furkan Ufuk, MD, Denizli, Turkey

Harsha Vardhan, MD, Chennai, India

Ricardo L. Videla, Sr, MD, Cordoba, Argentina

Jose S. Vilar, MD, Valencia, Spain

Ainhoa Viteri, MD, Bilbao, Spain

Christopher P. Vittore, MD, Belvidere, IL

Patrick M. Vos, MD, Vancouver, Canada

Jeffrey H. West, MD, Jacksonville, FL

Joseph L. Whetstone, MD, Portland, OR

Jun Woo, MD, Tokyo, Japan

George S. Wu, MD, Danville, PA

Takayuki Yamamoto, MD, Bordeaux, France

Rabab I. Yasin, MD, Shebin Elkom, Egypt

Stanko Yovichevich, MD, Sydney, Australia

Daisuke Yunaiyama, Tokyo, Japan

Dahua Zhou, MD, Old Westbury, NY

Resident group responses

Fundacion Santa Fe De Bogota University Hospital Radiology Residents, Bogota, Colombia

Hospital De Santa Maria Radiology Residents, Lisbon, Portugal

Massachusetts General Hospital Radiology Residents, Boston, MA

Mater Dei Hospital Radiology Residents, Msida, Malta

Montefiore Medical Center Radiology Residents, Bronx, NY

Prince of Songkla University Radiology Residents, Songkhla, Thailand

University of Pennsylvania Radiology Residents, Philadelphia, Pa

Virginia Commonwealth University Health System Radiology Residents, Richmond, VA