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Original Research |
1 Department of Diagnostic Radiology, the University of Parana, Curitiba,
Brazil.
2 Department of Diagnostic Radiology, the University of Rio de Janeiro, Rio de
Janeiro, Brazil.
3 Bone Marrow Transplantation Unit, the University of Parana, Curitiba,
Brazil.
4 Department of Radiology, Vancouver General Hospital, 899 W 12th Ave.,
Vancouver, BC V5Z 1M9, Canada.
Received September 13, 2004;
accepted after revision November 2, 2004.
Address correspondence to N. L. Müller
(nestor.muller{at}vch.ca).
Abstract
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MATERIALS AND METHODS. This study included 111 consecutive bone marrow transplant recipients who had documented pulmonary infection, high-resolution CT of the chest performed within 24 hr of the beginning of symptoms, and proven diagnosis within 1 week of the onset of symptoms. Two radiologists analyzed the CT scans and reached final decisions regarding the findings by consensus. Statistical analysis was performed using the Fisher's exact test and multivariate analysis; a p value of less than 0.05 was considered statistically significant.
RESULTS. The pulmonary infections were due to viruses (n = 57), bacteria (n = 26), fungi (n = 21), and protozoa (n = 1). Six patients had more than one organism responsible for the infection. Nodules that were 1 cm or more in diameter were seen in 13 (62%) of 21 patients with fungal pneumonia, five (19%) of 26 patients with bacterial pneumonia (p = 0.0059), three (10%) of 30 with respiratory syncytial virus (RSV) pneumonia (p = 0.0001), and three (14%) of 22 with cytomegalovirus pneumonia (p = 0.0016). The halo sign was present in 10 of 21 patients with fungal pneumonia, two of 26 with bacterial pneumonia (p = 0.0026), three of 30 with RSV pneumonia (p = 0.0036), and one of 22 with cytomegalovirus pneumonia (p = 0.0015). There was no statistically significant difference in the prevalence of the other CT patterns including small nodules, ground-glass attenuation, and air-space consolidation among viral, bacterial, and fungal infections (all p > 0.05).
CONCLUSION. The presence of large nodules and visualization of the halo sign are most suggestive of fungal infection. Other high-resolution CT patterns are not helpful in distinguishing among the various types of infection seen in bone marrow transplant recipients.
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Several authors have emphasized the importance of high-resolution CT in the diagnosis of pulmonary infections after bone marrow transplantation [4-11]. High-resolution CT may show pulmonary abnormalities in patients with normal findings on radiographs and is superior to radiography in depicting the pattern and extent of abnormalities [4-7]. Several studies have described the high-resolution CT manifestations of pulmonary infections in bone marrow transplant patients [8-11]. These studies have been limited to a relatively small number of patients and have focused mainly on the description of specific infections. Limited information is available about high-resolution CT features that may allow distinction among the various types of infection. The aim of this study was to review the high-resolution CT findings in 111 patients who had infectious pulmonary complications after bone marrow transplantation and to determine distinguishing imaging features among the various types of infection.
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The study group was composed of 45 females and 66 males who ranged in age from 1 to 56 years (mean age, 23.7 years; median age, 22 years). All but one patient received allogeneic bone marrow transplantation. The transplantation was performed for the treatment of the following diseases: chronic myelogenous leukemia (n = 42), severe aplastic anemia (n = 33), acute nonlymphocytic leukemia (n = 11), myelodysplastic syndrome (n = 8), Fanconi's anemia (n = 8), acute lymphocytic leukemia (n = 7), and Hodgkin's disease (n = 2).
The infectious complications after bone marrow transplantation were due to respiratory syncytial virus (RSV) (n = 30), bacteria (n = 26), fungi (n = 21), cytomegalovirus (CMV) (n =22), herpes simplex virus type 2 (n = 3), influenza virus (n = 1), parainfluenza virus (n = 1), and toxoplasmosis (n = 1). Six patients had more than one organism responsible for the infection, including five cases of fungus and bacteria and one case of fungus and CMV. The bacterial pneumonias were due to Staphylococcus aureus in 12 patients, Pseudomonas aeruginosa in eight patients, Streptococcus viridans in four patients, Klebsiella pneumoniae in one patient, and Enterococcus faecalis in one patient. Fungal infections were caused by Aspergillus species in 17 patients, Candida albicans in three patients, and both Aspergillus and Candida species in one patient (Table 1).
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The pathogens responsible for the infectious episodes were documented by the following methods: bronchoalveolar lavage (n = 26), sputum culture (n = 22), sputum culture and bronchoalveolar lavage (n = 14), biopsy (n = 8), and autopsy (n = 10). Fungal infection was diagnosed from culture and histologic evidence of tissue invasion (n =15). A positive blood culture in the presence of compatible clinical and radiologic findings was considered diagnostic in six cases of fungal pneumonia [11-13]. Diagnosis of RSV pneumonia was based on positive direct fluorescence antibody testing in specimens obtained at nasal washings, nasopharyngeal swab, and bronchoalveolar lavage [14]. The 20 patients with positive direct fluorescence antibody testing in specimens from nasal washings had respiratory symptoms and showed clinical and radiologic improvement after specific treatment [15, 16]. The diagnosis of CMV pneumonia was based on detection of the characteristic inclusion bodies in material obtained at bronchoalveolar lavage, autopsy, or lung biopsy. Positive polymerase chain reaction test results of blood, CMV antigenemia, clinical and imaging evidence of pulmonary disease, or improvement after specific treatment was considered diagnostic of CMV pneumonia in five cases [17]. Diagnosis of bacterial infection was based on a positive culture of sputum or bronchoscopic aspirate in most cases combined with positive blood or pleural fluid cultures.
All CT examinations were performed on a Somatom ART scanner (Siemens Medical Solutions). The images were obtained at end-inspiration using a 2-mm collimation at 10-mm intervals and were reconstructed with a high-spatial-frequency algorithm and photographed using window settings appropriate to lung parenchyma (width, 1,500 H; level, -700 H) and mediastinum (width, 400 H; level, 20 H).
Two radiologists analyzed the high-resolution CT scans and reached final decisions regarding the findings by consensus. The following high-resolution CT findings were evaluated: pattern of the pulmonary abnormalities (nodules, tree-in-bud pattern, air-space opacities, and ground-glass attenuation), distribution of the lesions (central or peripheral; unilateral or bilateral; symmetric or asymmetric; and upper, middle, or lower zones), bronchial wall thickening, mediastinal lymph node enlargement, and pleural effusions. The nodules were classified as large (1 cm in diameter) or small (< 1 cm in diameter).
Ground-glass attenuation was defined as hazy increased attenuation of the lung without obscuration of the bronchial and vascular margins; air-space consolidation, as homogeneous increase in pulmonary parenchymal attenuation that obscured the margins of vessels and airway walls; small nodule, as a round opacity less than 10 mm in diameter; large nodule, as round opacity equal to or greater than 10 mm; tree-in-bud pattern, as centrilobular branching structures that resemble a budding tree; bronchial wall thickening, as thickness of the bronchial wall greater than one sixth of the bronchial diameter; and lymph node enlargement, as lymph nodes with short-axis diameter of greater than 10 mm. The pattern of ground-glass opacities was classified as diffuse, patchy, or focal. The distribution of air-space consolidation was classified as segmental or nonsegmental and as patchy or focal. Criteria for these findings were those defined in the Fleischner Society's glossary of terms [18].
The clinical and high-resolution CT data were entered into a spreadsheet (Excel 2003, Microsoft). Statistical analysis was performed using the Fisher's exact test and multivariate analysis, and a p value of less than 0.05 was considered statically significant.
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The parenchymal abnormalities seen on high-resolution CT in the various pulmonary infections and their time of occurrence are summarized in Table 1. Pleural effusion was seen in two patients with fungal pneumonia, four with bacterial pneumonia, and two with viral pneumonia. None of the patients had mediastinal lymphadenopathy.
Fungal Pneumonia
Seventeen of the 21 cases of fungal pneumonias were caused by
Aspergillus organisms, three by Candida albicans, and one by
both organisms. Nodules were the most common finding in these patients
(Table 1). Large nodules were
seen in 13 patients (62%); in 10 of these 13 patients, one or more nodules
were surrounded by a halo of ground-glass attenuation (halo sign)
(Fig. 1). Small nodules in a
predominantly centrilobular distribution were noted in eight cases (38%), and
a tree-in-bud pattern was seen in three patients
(Fig. 2). Nodules were the only
abnormality in 11 patients. In five cases, the nodules were associated with
areas of air-space consolidation; in one case, with ground-glass opacities;
and in one case, with both.
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Bacterial Pneumonia
Twenty-six patients had bacterial pneumonia
(Table 1). Twenty-one of these
patients (81%) had nodular opacities, including 16 patients (61%) with small
centrilobular nodules and five (19%) with large nodules
(Fig. 3). In three patients,
the small centrilobular nodules were associated with a tree-in-bud pattern.
Two patients had a halo of ground-glass attenuation surrounding the nodules,
and one had large nodule cavitation.
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Overall, of the patients with bacterial pneumonia four (15%) had only nodules and three (12%) had only consolidation; the remaining patients (73%) had various combinations of nodules, consolidation, and ground-glass attenuation.
Viral Pneumonia
RSV pneumonia—Six of the 30 patients with RSV pneumonia had
normal findings on CT scans. Nodular lesions were seen in 19 patients (63%)
(Fig. 5 and
Table 1). Sixteen cases (53%)
had small centrilobular nodules, three had branching opacities (tree-in-bud
pattern), and three had large nodules. Three of the 16 patients with
centrilobular nodules had a tree-in-bud pattern. In three patients, the
nodules were surrounded by a halo of ground-glass attenuation.
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Seven patients (23%) had areas of ground-glass attenuation, which was diffuse in four cases, focal in two, and patchy in one (Fig. 6). The ground-glass opacities were bilateral and symmetric in four patients and asymmetric in three.
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CMV pneumonia—All 22 patients with CMV pneumonia had abnormal findings on CT scans. Multiple small nodules were seen in 13 patients (59%), and large nodules were detected in three (14%) (Fig. 7). The distribution of the lesions most commonly was bilateral and symmetric (n = 11) and peripheral (n = 14) and had no zonal predominance.
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Air-space consolidation was present in seven patients (31%), and in all cases, it involved mainly the peripheral lung regions of the middle and lower zones. Ground-glass opacities were observed in 15 patients (68%), being diffuse in seven patients, patchy in seven patients, and focal in one patient (Fig. 8).
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Overall, of the patients with CMV pneumonia, four (18%) had only nodules, two (9%) had only consolidation, and two (9%) had only ground-glass attenuation. The remaining patients (64%) had various combinations of nodules, ground-glass attenuation, and consolidation.
Other viral pneumonias—Three patients had herpes simplex virus type 2 pneumonia. Small centrilobular nodules were seen in two patients, and large nodules with a halo sign were found in one patient. Diffuse or patchy areas of ground-glass attenuation were noted in all patients.
Influenza pneumonia was diagnosed in one patient. High-resolution CT showed small centrilobular nodules and patchy nonsegmental consolidation. The patient with parainfluenza B pneumonia presented with focal nonsegmental consolidation and areas of mosaic perfusion.
Other Organisms and Mixed Pneumonias
One patient had Toxoplasma gondii pneumonia. On high-resolution
CT, this patient had diffuse ground-glass attenuation with superimposed smooth
interlobular septal thickening and intralobular linear opacities resulting in
a crazy paving pattern.
Five patients had mixed pneumonia caused by bacteria plus fungi (n = 5). One of these patients had small centrilobular nodules, one had large nodules, two had bilateral ground-glass opacities, and two had bilateral areas of consolidation. One patient had mixed pneumonia caused by CMV plus fungi. The only finding in this patient was diffuse bronchial wall thickening.
Comparison of the CT Findings of the Various Infections
Large nodules were most common in patients with fungal pneumonia, being
seen in 13 (62%) of the 21 patients with fungal pneumonia, five (19%) of 26
with bacterial pneumonia (p = 0.0059), three (10%) of 30 with RSV
pneumonia (p = 0.0001), and three (14%) of 22 with CMV pneumonia
(p = 0.0016) (Table
2). The halo sign also was more frequent in patients with fungal
pneumonia, being seen in 10 (48%) of the 21 patients with fungal pneumonia,
two (8%) of 26 with bacterial pneumonia (p = 0.0026), three (10%) of
30 with RSV pneumonia (p = 0.0036), and one (5%) of 22 with CMV
pneumonia (p = 0.0015). There was no other statistically significant
difference among viral, fungal, and bacterial pneumonias
(Table 2). There was a
statistical difference in the presence of patchy ground-glass attenuation
between CMV and RSV (p = 0.0072). However, there was no statistical
difference overall in patchy ground-glass attenuation between viral pneumonias
and fungal or bacterial pneumonias (Table
2).
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Fungal pneumonia is one of the main causes of morbidity and mortality after bone marrow transplantation [13, 23, 24]. The most common organism of fungal pneumonia is Aspergillus species, being responsible for 90% of such infections [7]. Candida species, usually Candida albicans, is the second most frequent fungal organism and is seen most commonly in patients with leukemia and lymphoma [25].
The lung lesions in invasive pulmonary aspergillosis are characterized by vascular invasion and occlusion of small- to medium-sized pulmonary arteries by fungal hyphae [26]. The resulting areas of hemorrhagic infarction are seen on CT as nodules surrounded by areas of ground-glass attenuation (halo sign) [11, 27, 28]. Several studies have shown the value of high-resolution CT in the diagnosis of invasive pulmonary aspergillosis. Common findings include large nodules, frequently with a halo of ground-glass attenuation, and focal areas of consolidation [11, 27, 28]. Although the halo sign in immunocompromised patients is most suggestive of invasive aspergillosis, this sign has also been described in patients with Candida infection, cryptococcosis, CMV pneumonia, herpes simplex virus infection, and Kaposi's sarcoma [12, 27, 29].
Pulmonary candidiasis may spread to the lung via a hematogenic or endobronchial route. When from endobronchial seeding, candidiasis is limited usually to the lungs, may present with consolidation or nodules, and tends to involve mainly the lower lobes. Hematogenic dissemination results in symmetric nodular lesions throughout the lungs and often is associated with extrapulmonary disease. The characteristic pathologic findings consist of hemorrhagic nodules that usually measure 2-4 mm in diameter and frequently have a necrotic center containing the organisms [30]. The high-resolution CT findings that are suggestive of pulmonary candidiasis include solitary or multiple nodules, ground-glass opacities, and areas of air-space consolidation [7, 25, 30].
The most common finding of fungal infection in the current study was large nodules and masses, which were seen in 13 (62%) of 21 patients. Small nodules were identified in eight patients. Cavitation was seen in only one patient. Large nodules were more common in patients with fungal pneumonia than in those with bacterial or viral pneumonia. The halo sign was also more frequent in patients with fungal pneumonia than in other pneumonias.
The most common organisms resulting in bacterial pneumonia in bone marrow transplant patients before marrow engraftment are gram-negative bacteria from the intestinal flora or oral mucosa and gram-positive organisms, particularly Staphylococcus and Streptococcus species. During the early phase after bone marrow transplantation, the most frequent causes of bacterial pneumonia are gram-negative organisms including Pseudomonas aeruginosa and Escherichia coli [7, 10, 19]. Six months after bone marrow transplantation bacterial sinopulmonary infections are caused most frequently by gram-positive organisms, such as Streptococcus pneumoniae and Staphylococcus aureus. Gram-negative bacteria, most commonly Haemophilus influenzae and Pseudomonas species, are found in patients with obstructive airway disease [7].
Limited information is available concerning the high-resolution CT findings of bacterial pneumonia in bone marrow transplantation patients. The chest radiography findings in this group of patients have been described as being similar to those seen in immunocompetent patients, with predominance of focal areas of air-space consolidation [10, 19]. Lossos et al. [31], in a study of 52 episodes of bacterial pneumonia after bone marrow transplantation, observed 12 cases (23%) with involvement of only one lobe or segment. Reittner et al. [32] studied the high-resolution CT findings of 114 patients with pneumonia. That study included 35 cases of bacterial pneumonia (five of them in immunocompromised patients), and the most common findings were air-space consolidation (85%), ground-glass opacities (31%), reticular opacities (22%), and small centrilobular nodules (17%). The frequency of air-space consolidation and ground-glass opacities in the current study was similar, being present in 69% and 35% of patients, respectively. However, small centrilobular nodules were seen more frequently in our study, being observed in 13 (50%) of 26 cases. Five patients (19%) presented with large nodules. In most of the patients with bacterial pneumonia (21/26, 81%), the abnormalities involved more than one lung segment; in five cases (19%), they were observed in only one segment or lobe.
Viral infections usually occur in seasonal outbreaks in the community. The most common organisms in bone marrow transplantation patients are RSV, adenovirus, influenza virus, and parainfluenza virus [9, 16]. The dissemination of these infections to the lower respiratory tract is associated with a significant increase in mortality [15]. Ko et al. [14] reviewed the high-resolution CT of patients with RSV pneumonia after lung transplantation. The most common findings were air-space consolidation and areas of ground-glass attenuation [14]. Gasparetto et al. [33] reviewed the high-resolution CT features of 20 patients with RSV pneumonia after bone marrow transplantation. The predominant findings were small centrilobular nodules and patchy areas of consolidation and ground-glass opacities in a bilateral asymmetric distribution [33]. In the current study, small centrilobular nodules were seen in 16 (53%) of 30 patients, air-space consolidation in 10 patients (33%), and ground-glass opacities in seven patients (23%).
CMV is one of the most common causes of viral infection after bone marrow transplantation [8, 21]. The infection is caused by reactivation of the latent virus at a time of profound immunosuppression or infusion of CMV-seropositive marrow or blood products into a CMV-seronegative recipient [1, 3]. The most common high-resolution CT manifestations of CMV pneumonia are small centrilobular nodules, air-space consolidation, and ground-glass opacities [9, 17, 34]. Similar findings were seen in the current study, ground-glass opacities being seen in 68% of patients, small centrilobular nodules in 50%, and areas of air-space consolidation in 32%. These abnormalities usually are bilateral, diffuse, and asymmetric in distribution. Less common findings included large nodules and a tree-in-bud pattern.
Our study has several limitations. It is retrospective and includes a relatively small number of patients with each type of infection. The study included consecutive patients who underwent CT within 24 hr of the onset of symptoms and who had proven diagnosis. Although the study included nearly equal subsets of fungal, bacterial, and CMV and RSV pneumonias, it cannot be inferred that these infections are equally common. We believe that bacterial and fungal infections are more common than viral pneumonias in patients with bone marrow transplant. However, many of these patients are treated empirically on the basis of clinical and radiologic findings and do not have a definitive diagnosis.
In conclusion, there is a considerable overlap among the high-resolution CT manifestations of viral, bacterial, and fungal pneumonias in bone marrow transplant patients. Large nodules and the halo sign are findings that are statistically more common in patients with fungal pneumonia. Ground-glass opacities, air-space consolidation, and small nodules are not helpful in the differential diagnosis of various pulmonary infections after bone marrow transplantation.
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