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Pulmonary Candidiasis after Hematopoietic Stem Cell Transplantation: Thin-Section CT Findings¹

¹ From the Departments of Radiology (T.F., N.L.M., A.O.) and Pathology (J.D.F.), Vancouver Hospital and Health Sciences Centre and University of British Columbia, 855 W 12th Ave, Vancouver, BC, Canada V5Z 1M9; Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (K.S.L.); and Department of Radiology, Hospital de Sant Pau, Universitat Autónoma de Barcelona, Spain (T.F.). Received November 10, 2003; revision requested January 28, 2004; final revision received September 2; accepted September 29. Address correspondence to T.F. (e-mail: 19429tfc{at}comb.es).

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION References

 
PURPOSE: To retrospectively evaluate thin-section computed tomographic (CT) findings in hematopoietic stem cell transplant (ie, bone marrow transplant) patients with histopathologically proved pulmonary candidiasis.

MATERIALS AND METHODS: Ethical approval was obtained from the institutional review board of each of the three institutions; informed consent was not required. The study included 17 hematopoietic stem cell transplant recipients with proved pulmonary candidiasis. Histopathologic specimens were acquired at transbronchial biopsy (n = 8), open lung biopsy (n = 6), and autopsy (n = 3). The patients included seven men and 10 women (age range, 20–62 years; mean age, 37 years). The thin-section CT scans were retrospectively reviewed by two thoracic radiologists for the presence, appearance, and distribution of parenchymal abnormalities.

RESULTS: Multiple nodules were present in 15 (88%) patients, including centrilobular nodules and tree-in-bud pattern in seven (41%) patients. Nodules were bilateral in 12 patients and unilateral in three. An associated halo of ground-glass opacity was identified in five (33%) patients. Nodules were the only CT finding in five patients (29%). Areas of air-space consolidation were identified in 11 (65%) patients. Areas of ground-glass opacity were seen in six (35%) of 17 patients and were always associated with other abnormalities. Other less common CT findings included pleural effusion (n = 3), thickening of the bronchial walls (n = 2), and cavitation (n = 1).

CONCLUSION: The most common thin-section CT findings of pulmonary candidiasis in hematopoietic stem cell transplant patients are multiple bilateral nodular opacities often associated with areas of consolidation.

© RSNA, 2005

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION References

 
The importance of fungal infections in the clinical course of patients undergoing hematopoietic stem cell transplantation (ie, bone marrow transplantation) has increased substantially during the past decades (1). Candida species have been increasingly recognized as a source of fungal pneumonia in patients with hematologic malignancies (acute leukemia and lymphoma), chemotherapy induced neutropenia, intravenous drug abuse, hematopoietic stem cell transplantation, and acquired immune deficiency syndrome (1–5). A definitive diagnosis of Candida pneumonia is difficult to establish, and Candida colonization is common in immunocompromised patients.

The chest radiographic features of Candida pneumonia have been previously described (2,3). Buff et al (3) identified unilateral and bilateral lobar and segmental air-space disease in 20 patients, with pure Candida albicans pneumonia confirmed at autopsy. Cavitation, masslike opacity, or a miliary pattern was not identified. In another autopsy series of 15 infants with candidiasis, the most common radiographic pattern consisted of progressive air-space disease, which was seen in all cases; focal cavitation was present in two patients who had an embolic form of Candida infection (2).

Thin-section CT of the chest is considered the primary imaging modality in the early diagnosis of opportunistic infections in patients after hematopoietic stem cell transplantation (6). To our knowledge, however, the CT findings of Candida pneumonia have received little attention in the literature. Thus, the purpose of our study was to retrospectively evaluate thin-section CT findings in hematopoietic stem cell transplant patients with histopathologically proved pulmonary candidiasis.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION References

 
Patients
We retrospectively reviewed findings in 17 recipients of allogeneic hematopoietic stem cell transplants who had a histologically proved diagnosis of Candida species pulmonary infection and had undergone CT examination at one of the three institutions between January 1995 and July 2002. Ethical approval was obtained from the local institutional review board of each of the three institutions. Informed consent was not required. These patients represented all individuals from each institution who met the inclusion criteria. The mean age of the patients was 37 years (age range, 20–62 years), and there were 10 women and seven men. Clinical records were reviewed by two of the authors (T.F. and J.D.F.) for signs and symptoms, predisposing conditions, and clinical course. The diseases for which hematopoietic stem cell transplantation was performed were acute nonlymphocytic leukemia (n = 6), chronic myelogenous leukemia (n = 5), acute lymphocytic leukemia (n = 4), and Hodgkin disease (n = 2).

Results of blood and sputum cultures, as well as any diagnostic and surgical procedures, were also recorded. The diagnosis of Candida infection in all cases was made on the basis of histologic findings. Histopathologic specimens were acquired at transbronchial biopsy (n = 8), open lung biopsy (n = 6), and autopsy (n = 3). All patients had fever resistant to antibiotic treatment.

CT Examination
The CT scans were obtained either before or after the microbiologic diagnosis. The interval between CT examination and tissue diagnosis ranged from 1 to 16 days (median, 3 days). The CT scans were obtained at three different institutions by using different types of scanners and CT protocols. The following CT scanners were used: Somaton Plus 4 (Siemens, Erlangen, Germany), Toshiba 900 or Asteion (Toshiba Medical Systems, Tokyo, Japan), or HiLight (GE Medical Systems, Milwaukee, Wis). The scans were obtained at end inspiration with 1.0- or 2-mm collimation and at 10- or 20-mm intervals from the apex of the lung to the diaphragm and were reconstructed with an edge-enhancing algorithm. The scans were obtained by using 120 kV and 200–320 mA. The lungs were viewed at a window width of 1000–1500 HU and a level of –600 to –700 HU.

CT scans were retrospectively reviewed by two radiologists (T.F. and N.L.M.) with more than 10 years of experience in thoracic CT image interpretation. Findings and interpretations were based on consensus opinion. The CT examinations were performed an average of 3 days after the onset of symptoms (range, 1–8 days), and only one CT scan per patient was evaluated. In all cases, the histopathologic material was compared with the imaging findings.

CT images were assessed for the presence, extent, and anatomic distribution of air-space consolidation; areas of ground-glass opacity; centrilobular branching structures; nodules; interlobular septal thickening; thickening of the bronchovascular bundles; and pleural effusion. Ground-glass opacity was defined as an area of hazy increased attenuation without obscuration of underlying vascular markings. Air-space consolidation was considered present when the opacities obscured the underlying vessels. Parenchymal nodules were subcategorized according to their diameter (smaller and larger than 10 mm), distribution (centrilobular, peribronchovascular, subpleural, random), location (upper and lower lung zone), marginal characteristics (smooth and irregular), and number (single and multiple). Centrilobular nodules were defined as parenchymal opacities located in the central portion of the secondary pulmonary lobule. Nodules were also assessed as to whether or not they were surrounded by a halo of ground-glass opacity. Linear opacities were further subclassified as septal thickening or nonseptal linear opacities. Nonseptal linear opacity was considered present when any linear opacity with variable thickness and length distinct from interlobular septa or bronchovascular bundles was identified. Associated findings such as pleural effusion were also assessed.

The anatomic distribution was assessed as predominantly in the upper, middle, or lower lung zones or as predominately peripheral, central, or peribronchial. Peripheral distribution was considered present when the abnormalities were seen mostly in the outer third of the lung; central distribution, if most abnormalities were in the inner third of the lung; peribronchial distribution, if abnormalities occurred along the bronchovascular bundles; and random distribution, if abnormalities did not fall into any of the aforementioned categories. The distribution was further subclassified as lobar, segmental, and patchy or nonsegmental. Zonal predominance was divided into being upper or lower. Upper lung zone predominance was considered present when most of the abnormalities were above the level of carina, and lower zone predominance was considered when the abnormalities were below that level.

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION References

 
Thin-section CT scans demonstrated bilateral abnormalities in 14 (82%) patients (Table), and multiple nodules were identified in 15 (88%) of 17 patients. The nodules ranged from 3 to 30 mm in diameter; in nine patients, they were greater than 10 mm in diameter (Fig 1). The nodules were bilateral in 12 patients and unilateral in three. They had a centrilobular (n = 7) and random distribution (n = 8) and involved mainly the lower lung zones. Nodules were the only CT finding in four (24%) patients. In 12 cases, they were associated with other findings such as ground-glass opacity (n = 5), air-space consolidation (n = 9), branching linear opacities resulting in a tree-in-bud pattern (n = 7), and cavitation (n = 1) (Fig 2). The nodules had a halo of ground-glass opacity (Fig 3) in five (33%) cases, irregular margins in six (40%) cases, and well-defined margins in four (27%) cases (Figs 4, 5). Consolidation was identified as an associated finding, with nodules in nine patients. Consolidation was identified in 11 (65%) cases and was the predominant feature in six (54%) cases (Fig 6). In eight (73%) cases, these areas had a lobular or subsegmental distribution, whereas in three (27%) cases they had a segmental distribution. Areas of consolidation were randomly distributed throughout the lungs in all cases. In the overall group, consolidation was the only abnormality in one (9%) patient (Fig 7).

View larger version (149K): [in this window] [in a new window] [Download PPT slide]   Figure 1a. Candida albicans infection in a 28-year-old man with acute myeloid leukemia and hematopoietic stem cell transplant. (a) Transverse thin-section (1-mm collimation, lung window) CT scan of upper lobes shows bilateral multifocal patchy areas of ground-glass opacity and a nodule greater than 1 cm (arrow) with a surrounding halo of ground-glass opacity in the superior segment of the right lower lobe.(b) Low-power photomicrograph shows that ill-defined nodules seen at CT represent intravascular candidiasis and diffuse chronic inflammatory granulation tissue response centered on pulmonary artery. (Hematoxylin-eosin stain; original magnification, x40.)

View larger version (180K): [in this window] [in a new window] [Download PPT slide]   Figure 1b. Candida albicans infection in a 28-year-old man with acute myeloid leukemia and hematopoietic stem cell transplant. (a) Transverse thin-section (1-mm collimation, lung window) CT scan of upper lobes shows bilateral multifocal patchy areas of ground-glass opacity and a nodule greater than 1 cm (arrow) with a surrounding halo of ground-glass opacity in the superior segment of the right lower lobe.(b) Low-power photomicrograph shows that ill-defined nodules seen at CT represent intravascular candidiasis and diffuse chronic inflammatory granulation tissue response centered on pulmonary artery. (Hematoxylin-eosin stain; original magnification, x40.)

View larger version (115K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Fungal infection in a 23-year-old man with severe neutropenia secondary to chemotherapy and hematopoietic stem cell transplant for acute myelogenous leukemia. Transverse thin-section (1-mm collimation) CT scan through the hila demonstrates multiple ill-defined nodules in the right upper lobe; one of the nodules is cavitated (*). C albicans was diagnosed at thoracoscopic biopsy.

View larger version (140K): [in this window] [in a new window] [Download PPT slide]   Figure 3a. Pneumonia due to C albicans in a 25-year-old man with acute myeloid leuke-mia and hematopoietic stem cell transplant.(a) Transverse thin-section (1-mm collimation) CT scan of the right lung shows multiple, scattered, and poorly defined centrilobular nodules of different sizes. Diffuse ground-glass opacity is also visible. (b) Photomicrograph shows a hemorrhagic infarct containing fungal colonies within blood vessels and the infarcted tissue. (Hematoxylin-eosin stain; original magnification, x400.)

View larger version (171K): [in this window] [in a new window] [Download PPT slide]   Figure 3b. Pneumonia due to C albicans in a 25-year-old man with acute myeloid leuke-mia and hematopoietic stem cell transplant.(a) Transverse thin-section (1-mm collimation) CT scan of the right lung shows multiple, scattered, and poorly defined centrilobular nodules of different sizes. Diffuse ground-glass opacity is also visible. (b) Photomicrograph shows a hemorrhagic infarct containing fungal colonies within blood vessels and the infarcted tissue. (Hematoxylin-eosin stain; original magnification, x400.)

View larger version (122K): [in this window] [in a new window] [Download PPT slide]   Figure 4a. Pneumonia due to C albicans in a 45-year-old man who underwent hematopoietic stem cell transplantation. (a) Transverse thin-section (1-mm collimation) CT scan through the hila demonstrates bilateral well-defined tiny nodules in a random distribution. (b) Photomicrograph shows granulomatous inflammation and fibrosis surrounding a central area of necrosis (*). Histiocytes and giant cells are visible in the periphery of granuloma. (Hematoxylin-eosin stain; original magnification, x400.)

View larger version (130K): [in this window] [in a new window] [Download PPT slide]   Figure 4b. Pneumonia due to C albicans in a 45-year-old man who underwent hematopoietic stem cell transplantation. (a) Transverse thin-section (1-mm collimation) CT scan through the hila demonstrates bilateral well-defined tiny nodules in a random distribution. (b) Photomicrograph shows granulomatous inflammation and fibrosis surrounding a central area of necrosis (*). Histiocytes and giant cells are visible in the periphery of granuloma. (Hematoxylin-eosin stain; original magnification, x400.)

View larger version (109K): [in this window] [in a new window] [Download PPT slide]   Figure 5a. Candida pneumonia in a 52-year-old man who underwent hematopoietic stem cell transplantation. (a) Transverse thin-section (1-mm collimation) CT scan at the level of the lower pulmonary veins shows multiple ill-defined bilateral nodules with a surrounding halo of ground-glass opacity. (b) Photomicrograph of one of the multiple nodular inflammatory foci evenly distributed throughout the lung. This nodule consists of colonies of Candida species centered on a blood vessel. Surrounding the nodule is little inflammatory interstitial thickening and engorgement of alveolar capillaries. (Hematoxylin-eosin stain; original magnification, x200.)

View larger version (128K): [in this window] [in a new window] [Download PPT slide]   Figure 5b. Candida pneumonia in a 52-year-old man who underwent hematopoietic stem cell transplantation. (a) Transverse thin-section (1-mm collimation) CT scan at the level of the lower pulmonary veins shows multiple ill-defined bilateral nodules with a surrounding halo of ground-glass opacity. (b) Photomicrograph of one of the multiple nodular inflammatory foci evenly distributed throughout the lung. This nodule consists of colonies of Candida species centered on a blood vessel. Surrounding the nodule is little inflammatory interstitial thickening and engorgement of alveolar capillaries. (Hematoxylin-eosin stain; original magnification, x200.)

View larger version (110K): [in this window] [in a new window] [Download PPT slide]   Figure 6. C albicans bronchopneumonia in a 23-year-old man with neutropenia following hematopoietic stem cell transplantation. Transverse thin-section (1-mm collimation) CT scan of the right lung shows consolidation in the posterior segment of right upper lobe, thickening of bronchiolar walls, and branching distal structures (tree-in-bud pattern) (arrows). Photomicrograph (not shown) obtained from video-assisted thoracoscopic biopsy revealed acute and chronic inflammation with alveolar fibrin.

View larger version (83K): [in this window] [in a new window] [Download PPT slide]   Figure 7. C albicans infection and subsequent diffuse alveolar damage in a 23-year-old man with neutropenia following hematopoietic stem cell transplantation. Transverse thin-section CT scan trough the hila shows extensive areas of ground-glass opacity and left upper lobe consolidation. Photomicrograph (not shown) obtained from video-assisted thoracoscopic biopsy revealed that consolidation seen at CT corresponded to areas of alveolar edema, diffuse alveolar septal thickening, and hyaline membranes.

Biopsy and Autopsy Findings
Pathologic examination of transbronchial biopsy (n = 8), open lung biopsy (n = 6), and autopsy (n = 3) confirmed the diagnosis of Candida infection in all cases. At autopsy, evidence of extrathoracic hematogenous dissemination (hepatosplenic) was found in two patients. Samples obtained from bronchoalveolar lavage were cultured and showed growth in all cases. Associated bacterial pathogens were documented in seven cases (41%) (Pseudomonas aeruginosa in five cases and Haemophilus influenzae in two). In all seven cases in which additional bacteria were cultured, Candida species was the predominant pathogen at pathologic examination.

Histologic Findings
Histopathologic material was correlated with findings at thin-section CT. In eight of the 15 patients who had nodules in the present series, at least one of the nodules was surrounded by a halo of ground-glass opacity. Histologically, five of these cases showed well-defined granulomas; the remaining three cases demonstrated pulmonary nodules consisting exclusively of localized Candida organisms and focal inflammatory reaction. Areas of ground-glass opacity or consolidation seen on CT scans (n = 13) corresponded to alveolar necrosis, proteinaceous exudate, a variable polymorphonuclear inflammatory response, and areas of exudative or proliferative phase of diffuse alveolar damage. The predominant histologic findings in these patients consisted of interstitial fibroblastic proliferation and lymphocytic infiltration associated with type 2 pneumocyte hyperplasia, hyaline membrane formation, and intraalveolar exudates with or without organization. The six patients who had poorly defined centrilobular nodules at CT were shown to have bronchiolar and peribronchiolar accumulations of macrophages, red blood cells, and fibrin. In two cases, the nodules were surrounded by a halo of ground-glass opacity. The halo in these cases consisted of a zone of less dense inflammatory reaction and hemorrhage. In the only case in which cavitation was demonstrated, histologic findings of superimposed bacterial infection were also present.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION References

 
Candida species have been increasingly recognized as an important source of fungal pneumonia in immunocompromised patients, particularly in those with underlying malignancy (acute leukemia and lymphoma), intravenous drug abuse, acquired immune deficiency syndrome, and hematopoietic stem cell transplant (1–3,5–9). Candida species are a frequent cause of fungemia in the recipient of hematopoietic stem cell transplant, with the portal of entry believed to be the gastrointestinal tract or indwelling catheters (10,11). Factors that predispose recipients of hematopoietic stem cell transplant to candidal infections include the type of transplant (allogeneic vs autologous), increased age, acute graft-versus-host disease, and prolonged granulocytopenia (6).

Although Candida species are frequently isolated from bronchoscopic samples, it is difficult to ascertain whether a positive culture was consistent with a pathogen responsible for pneumonia or whether it occurred as a contaminant (7,8). There is no reliable test for the diagnosis of a Candida infection, and a definitive diagnosis of invasive pulmonary candidiasis is based on the histologic demonstration of yeasts in lung tissue, the presence of fungus in normally sterile tissues, or the invasion of noncontinuous organs secondary to hematogenous spread (8). In our series, we accepted Candida as a pathogen only when it was confirmed at open lung biopsy, transbronchial biopsy, or autopsy.

The incidence of Candida pneumonia varies among different series. Data from reports of 1295 autopsies from two large teaching hospitals showed an incidence of 2.1% (9). Patients infected with Candida species have a relatively rapid onset of clinical symptoms, such as productive cough, fever that is unresponsive to broad-spectrum antibiotics, chest pain, and tachypnea (9). Candida species enter the lungs by aspiration or hematogenous dissemination. As with other opportunistic infections, the tissue response depends on the route of infection, the immune status of the host, the presence of additional intrapulmonary pathogens, and the aspiration of gastric contents. Whereas airway spread of fungi results in an acute bronchopneumonia or in multiple pulmonary nodules with irregular margins and sometimes evidence of necrosis, hematogenous dissemination results in miliary and/or multiple well- or ill-defined pulmonary nodules consisting of colonies of organisms around the blood vessels (10,11).

Several recent studies have demonstrated that thin-section CT is the most sensitive imaging method to detect early lung changes in immunocompromised patients with acute pulmonary diseases (12–15). CT scans may depict disease not depicted on radiographs, may depict features characteristic or suggestive of a specific disease, and assist in guiding biopsy (13). However, limited information is available about the thin-section CT findings of Candida pneumonia. To our knowledge, the findings have been largely limited to isolated cases seen in reviews of various infections and to other acute lung diseases seen in immunocompromised patients (14).

In the 17 patients in the present study with pathologically proved pulmonary candidiasis, the thin-section CT findings were relatively nonspecific. Nodules were the major CT finding in 12 (70%) of the 17 patients. They ranged from 3 to 30 mm in diameter, were multiple, and were well defined or associated with other parenchymal findings such as air-space consolidation, tree-in-bud pattern, and ground-glass opacity. In five cases, the nodules were surrounded by discrete areas of ground-glass opacity (CT halo sign) (16). Histologic correlation showed that the dense core of the nodules corresponded to a zone of coagulative necrosis due to Candida pseudohyphae growing from a thrombosed blood vessel lumen, and the halo corresponded to a mixture of edema and hemorrhage surrounding the infarct. Although previously described as being characteristic of invasive aspergillosis (16–18), the CT halo sign has been shown to occur in association with hemorrhagic nodules of varying causes (19), as well as some nonhemorrhagic infections such as actinomycosis (20). Histologically, five of these cases showed well-defined granulomas; the remaining three cases demonstrated pulmonary nodules consisting exclusively of localized Candida colonies. Autopsy findings in three cases revealed diverse pathologic features at different areas. Microscopically, the lung parenchyma contained pulmonary edema with hyaline membrane formation and cellular fibromyxoid-organizing air-space exudates, similar to those of acute respiratory distress syndrome.

Multifocal air-space consolidation without lobar predilection was the major radiographic CT finding in six (35%) of 17 patients. Pathologically, areas of consolidation were shown to represent areas of bronchopneumonia, intraalveolar hemorrhage, and exudates. In three cases, consolidation corresponded to areas of alveolar edema, diffuse alveolar septal thickening, and hyaline membranes. In the only case in which cavitation was demonstrated, histologic findings of superimposed bacterial infection were also present. Although bacterial organisms could be seen together with Candida infection in diseased lung sections, Candida species was shown to be the predominant pathogen in all of our cases. Cavitation may result from associated bacterial infection or after hemorrhagic lung infarcts (2).

Small-airway infection leads to inflammatory changes to the walls of bronchioles, resulting in airway wall thickening and dilatation. Patchy areas of infectious bronchiolitis were seen in seven patients. Typically, the thin-section CT findings consist of centrilobular opacities arranged in a tree-in-bud pattern manifested by small Y- and V-shaped opacities in the lung periphery, which represent bronchioles that are impacted with inflammatory secretions. Although bacteria are the most common cause of infectious bronchiolitis in immunocompromised patients, the differential diagnosis for this pattern includes mycobacterial, viral, and fungal infections (6,14). In our study, less common CT manifestations of Candida pneumonia included thickening of the bronchial walls and pleural effusion.

The CT manifestations of pulmonary candidiasis are similar to those described in other pulmonary infections. The nodular opacities and the focal or multifocal areas of air-space consolidation seen on images obtained in most of our patients are indistinguishable from those obtained in patients with other opportunistic infections, particularly invasive aspergillosis and mucormycosis (18–21). Similar CT findings may also be seen with viral infections (22,23). In Mycoplasma pneumoniae and bacterial pneumonias caused by Nocardia species, Staphylococcus aureus, and P aeruginosa, nodular opacities are usually ill defined, variable in size, and may occupy not only the centrilobular region but most of the lobule (24–26).

In the past, Candida pneumonia was usually diagnosed at autopsy. With the increase of invasive biopsy procedures and aggressive surgical management, premortem diagnosis is increasingly common. In our series, histologic diagnosis at transbronchial biopsy yielded a definitive diagnosis in eight cases. The variability of the CT findings in Candida pneumonia reflects the diverse patterns of pathologic reaction and the stage of disease. To our knowledge, this is the first study in which pulmonary CT appearances in hematopoietic stem cell transplant recipients with pulmonary Candida infection were documented.

Our study had several limitations: It was retrospective and was limited to allogeneic hematopoietic stem cell transplant recipients in whom both CT and biopsy or autopsy were performed. In addition, the comparison of CT with pathologic findings was performed retrospectively and was limited by the nature of the pathologic material. Despite these limitations, our findings serve to allow a better understanding of the pathologic features responsible for the various CT patterns in Candida pneumonia.

We conclude that the most common thin-section CT findings of Candida pneumonia in hematopoietic stem cell transplant recipients are multiple bilateral nodules often associated with areas of air-space consolidation. This pattern is relatively nonspecific and is seen in other opportunistic infections.

	FOOTNOTES

 
Authors stated no financial relationship to disclose.

Author contributions: Guarantors of integrity of entire study, T.F., N.L.M.; study concepts and design, T.F., N.L.M.; literature research, T.F.; clinical studies, T.F., N.L.M., K.S.L.; data acquisition, J.D.F., T.F., N.L.M.; data analysis/interpretation, A.O.; statistical analysis, A.O.; manuscript preparation and definition of intellectual content, T.F.; manuscript editing, T.F., N.L.M.; manuscript revision/review, N.L.M.; manuscript final version approval, T.F., N.L.M., K.S.L., J.D.F.

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This Article Abstract Figures Only Full Text (PDF) All Versions of this Article: 2361031772v1 236/1/332    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Franquet, T. Articles by Flint, J. D. Search for Related Content PubMed PubMed Citation Articles by Franquet, T. Articles by Flint, J. D.